A morbidly obese 54-year-old woman presented to the emergency department after experiencing generalized abdominal pain for 3 days. She rated the pain as 5 on a scale of 10 and described it as dull, cramping, waxing and waning, not radiating, and not relieved with changes of position—in fact, not alleviated by anything she had tried. Her pain was associated with nausea and 1 episode of vomiting. She also experienced constipation before the onset of pain.

She denied recent trauma, recent travel, diarrhea, fevers, weakness, shortness of breath, chest pain, other muscle pains, or recent changes in diet. She also denied having this pain in the past. She said she had unintentionally lost some weight but was not certain how much. She denied tobacco, alcohol, or illicit drug use. She had no history of surgery.

Her medical history included hypertension, anemia, and uterine fibroids. Her current medications included losartan, hydrochlorothiazide, and albuterol. She had no family history of significant disease.

INITIAL EVALUATION AND MANAGEMENT

On admission, her temperature was 97.8°F (36.6°C), heart rate 100 beats per minute, blood pressure 136/64 mm Hg, respiratory rate 18 breaths per minute, oxygen saturation 97% on room air, weight 130.6 kg, and body mass index 35 kg/m².

She was alert and oriented to person, place, and time. She was in mild discomfort but no distress. Her lungs were clear to auscultation, with no wheezing or crackles. Heart rate and rhythm were regular, with no extra heart sounds or murmurs. Bowel sounds were normal in all 4 quadrants, with tenderness to palpation of the epigastric area, but with no guarding or rebound tenderness.

Laboratory test results

Notable results of blood testing at presentation were as follows:

• Hemoglobin 8.2 g/dL (reference range 12.3–15.3)
• Hematocrit 26% (41–50)
• Mean corpuscular volume 107 fL (80–100)
• Blood urea nitrogen 33 mg/dL (8–21); 6 months earlier it was 16
• Serum creatinine 3.6 mg/dL (0.58–0.96); 6 months earlier, it was 0.75
• Albumin 3.3 g/dL (3.5–5)
• Calcium 18.4 mg/dL (8.4–10.2); 6 months earlier, it was 9.6
• Corrected calcium 19 mg/dL.

Findings on imaging, electrocardiography

Chest radiography showed no acute cardiopulmonary abnormalities. Abdominal computed tomography without contrast showed no abnormalities within the pancreas and no evidence of inflammation or obstruction. Electrocardiography showed sinus tachycardia.

DIFFERENTIAL DIAGNOSIS

1. Which is the most likely cause of this patient’s symptoms?

• Primary hyperparathyroidism
• Malignancy
• Her drug therapy
• Familial hypercalcemic hypocalciuria

In total, her laboratory results were consistent with macrocytic anemia, severe hypercalcemia, and acute kidney injury, and she had generalized symptoms.

Primary hyperparathyroidism

A main cause of hypercalcemia is primary hyperparathyroidism, and this needs to be ruled out. Benign adenomas are the most common cause of primary hyperparathyroidism, and a risk factor for benign adenoma is exposure to therapeutic levels of radiation.³

In hyperparathyroidism, there is an increased secretion of parathyroid hormone (PTH), which has multiple effects including increased reabsorption of calcium from the urine, increased excretion of phosphate, and increased expression of 1,25-hydroxyvitamin D hydroxylase to activate vitamin D. PTH also stimulates osteoclasts to increase their expression of receptor activator of nuclear factor kappa B ligand (RANKL), which has a downstream effect on osteoclast precursors to cause bone reabsorption.³

Inherited primary hyperparathyroidism tends to present at a younger age, with multiple overactive parathyroid glands.³ Given our patient’s age, inherited primary hyparathyroidism is thus less likely.

The probability that malignancy is causing the hypercalcemia increases with calcium levels greater than 13 mg/dL. Epidemiologically, in hospitalized patients with hypercalcemia, the source tends to be malignancy.⁴ Typically, patients who develop hypercalcemia from malignancy have a worse prognosis.⁵

Solid tumors and leukemias can cause hypercalcemia. The mechanisms include humoral factors secreted by the malignancy, local osteolysis due to tumor invasion of bone, and excessive absorption of calcium due to excess vitamin D produced by malignancies.⁵ The cancers that most frequently cause an increase in calcium resorption are lung cancer, renal cancer, breast cancer, and multiple myeloma.¹

Solid tumors with no bone metastasis and non-Hodgkin lymphoma that release PTH-related protein (PTHrP) cause humoral hypercalcemia in malignancy. The patient is typically in an advanced stage of disease. PTHrP increases serum calcium levels by decreasing the kidney’s ability to excrete calcium and by increasing bone turnover. It has no effect on intestinal absorption because of its inability to stimulate activated vitamin D₃. Thus, the increase in systemic calcium comes directly from breakdown of bone and inability to excrete the excess.

PTHrP has a unique role in breast cancer: it is released locally in areas where cancer cells have metastasized to bone, but it does not cause a systemic effect. Bone resorption occurs in areas of metastasis and results from an increase in expression of RANKL and RANK in osteoclasts in response to the effects of PTHrP, leading to an increase in the production of osteoclastic cells.¹

Tamoxifen, an endocrine therapy often used in breast cancer, also causes a release of bone-reabsorbing factors from tumor cells, which can partially contribute to hypercal­cemia.⁵

Myeloma cells secrete RANKL, which stimulates osteoclastic activity, and they also  release interleukin 6 (IL-6) and activating macrophage inflammatory protein alpha. Serum testing usually shows low or normal intact PTH, PTHrP, and 1,25-dihydroxyvitamin D.¹

Patients with multiple myeloma have a worse prognosis if they have a high red blood cell distribution width, a condition shown to correlate with malnutrition, leading to deficiencies in vitamin B₁₂ and to poor response to treatment.⁶ Up to 14% of patients with multiple myeloma have vitamin B₁₂ deficiency.⁷

Our patient’s recent weight loss and severe hypercalcemia raise suspicion of malignancy. Further, her obesity makes proper routine breast examination difficult and thus increases the chance of undiagnosed breast cancer.⁸ Her decrease in renal function and her anemia complicated by hypercalcemia also raise suspicion of multiple myeloma.

Hypercalcemia due to drug therapy

Thiazide diuretics, lithium, teriparatide, and vitamin A in excessive amounts can raise the serum calcium concentration.⁵ Our patient was taking a thiazide for hypertension, but her extremely high calcium level places drug-induced hypercalcemia as the sole cause lower on the differential list.

Familial hypercalcemic hypocalciuria

Familial hypercalcemic hypocalciuria is a rare autosomal-dominant cause of hypercalcemia in which the ability of the body (and especially the kidneys) to sense levels of calcium is impaired, leading to a decrease in excretion of calcium in the urine.³ Very high calcium levels are rare in hypercalcemic hypocalciuria.³ In our patient with a corrected calcium concentration of nearly 19 mg/dL, familial hypercalcemic hypocalciuria is very unlikely to be the cause of the hypercalcemia.

WHAT ARE THE NEXT STEPS IN THE WORKUP?

As hypercalcemia has been confirmed, the intact PTH level should be checked to determine whether the patient’s condition is PTH-mediated. If the PTH level is in the upper range of normal or is minimally elevated, primary hyperparathyroidism is likely. Elevated PTH confirms primary hyperparathyroidism. A low-normal or low intact PTH confirms a non-PTH-mediated process, and once this is confirmed, PTHrP levels should be checked. An elevated PTHrP suggests humoral hypercalcemia of malignancy. Serum protein electrophoresis, urine protein electrophoresis, and a serum light chain assay should be performed to rule out multiple myeloma.

Vitamin D toxicity is associated with high concentrations of 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D metabolites. These levels should be checked in this patient.

Other disorders that cause hypercalcemia are vitamin A toxicity and hyperthyroidism, so vitamin A and thyroid-stimulating hormone levels should also be checked.⁵

CASE CONTINUED

After further questioning, the patient said that she had had lower back pain about 1 to 2 weeks before coming to the emergency room; her primary care doctor had said the pain was likely from muscle strain. The pain had almost resolved but was still present.

The results of further laboratory testing were as follows:

• Serum PTH 11 pg/mL (15–65)
• PTHrP 3.4 pmol/L (< 2.0)
• Protein electrophoresis showed a monoclonal (M) spike of 0.2 g/dL (0)
• Activated vitamin D < 5 ng/mL (19.9–79.3)
• Vitamin A 7.2 mg/dL (33.1–100)
• Vitamin B₁₂ 194 pg/mL (239–931)
• Thyroid-stimulating hormone 1.21 mIU/ L (0.47–4.68
• Free thyroxine 1.27 ng/dL (0.78–2.19)
• Iron 103 µg/dL (37–170)
• Total iron-binding capacity 335 µg/dL (265–497)
• Transferrin 248 mg/dL (206–381)
• Ferritin 66 ng/mL (11.1–264)
• Urine protein (random) 100 mg/dL (0–20)
• Urine microalbumin (random) 5.9 mg/dL (0–1.6)
• Urine creatinine clearance 88.5 mL/min (88–128)
• Urine albumin-creatinine ratio 66.66 mg/g (< 30).

A nuclear bone scan showed increased bone uptake in the hip and both shoulders, consistent with arthritis, and increased activity in 2 of the lower left ribs, associated with rib fractures secondary to lytic lesions. A skeletal survey at a later date showed multiple well-circumscribed “punched-out” lytic lesions in both forearms and both femurs.

2. What should be the next step in this patient’s management?

• Intravenous (IV) fluids
• Calcitonin
• Bisphosphonate treatment
• Denosumab
• Hemodialysis

Initial treatment of severe hypercalcemia includes the following:

Start IV isotonic fluids at a rate of 150 mL/h (if the patient is making urine) to maintain urine output at more than 100 mL/h. Closely monitor urine output.

Give calcitonin 4 IU/kg in combination with IV fluids to reduce calcium levels within the first 12 to 48 hours of treatment.

Give a bisphosphonate, eg, zoledronic acid 4 mg over 15 minutes, or pamidronate 60 to 90 mg over 2 hours. Zoledronic acid is preferred in malignancy-induced hypercal­cemia because it is more potent. Doses should be adjusted in patients with renal failure.

Give denosumab if hypercalcemia is refractory to bisphosphonates, or when bisphosphonates cannot be used in renal failure.⁹

Hemodialysis is performed in patients who have significant neurologic symptoms irrespective of acute renal insufficiency.

Our patient was started on 0.9% sodium chloride at a rate of 150 mL/h for severe hypercalcemia. Zoledronic acid 4 mg IV was given once. These measures lowered her calcium level and lessened her acute kidney injury.

ADDITIONAL FINDINGS

Urine testing was positive for Bence Jones protein. Immune electrophoresis, performed because of suspicion of multiple myeloma, showed an elevated level of kappa light chains at 806.7 mg/dL (0.33–1.94) and normal lambda light chains at 0.62 mg/dL (0.57–2.63). The immunoglobulin G level was low at 496 mg/dL (610–1,660). In patients with severe hypercalcemia, these results point to a diagnosis of malignancy. Bone marrow aspiration study showed greater than 10% plasma cells, confirming multiple myeloma.

MULTIPLE MYELOMA

The diagnosis of multiple myeloma is based in part on the presence of 10% or more of clonal bone marrow plasma cells¹⁰ and of specific end-organ damage (anemia, hypercalcemia, renal insufficiency, or bone lesions).⁹

Bone marrow clonality can be shown by the ratio of kappa to lambda light chains as  detected with immunohistochemistry, immunofluorescence, or flow cytometry.11 The normal ratio is 0.26 to 1.65 for a patient with normal kidney function. In this patient, however, the ratio was 1,301.08 (806.67 kappa to 0.62 lambda), which was extremely out of range. The patient’s bone marrow biopsy results revealed the presence of 15% clonal bone marrow plasma cells.

Multiple myeloma causes osteolytic lesions through increased activation of osteoclast activating factor that stimulates the growth of osteoclast precursors. At the same time, it inhibits osteoblast formation via multiple pathways, including the action of sclerostin.¹¹ Our patient had lytic lesions in 2 left lower ribs and in both forearms and femurs.

Hypercalcemia in multiple myeloma is attributed to 2 main factors: bone breakdown and macrophage overactivation. Multiple myeloma cells increase the release of macrophage inflammatory protein 1-alpha and tumor necrosis factor, which are inflammatory proteins that cause an increase in macrophages, which cause an increase in calcitriol.¹¹ As noted, our patient’s calcium level at presentation was 18.4 mg/dL uncorrected and 18.96 mg/dL corrected.

Cast nephropathy can occur in the distal tubules from the increased free light chains circulating and combining with Tamm-Horsfall protein, which in turn causes obstruction and local inflammation,¹² leading to a rise in creatinine levels and resulting in acute kidney injury,¹² as in our patient.

TREATMENT CONSIDERATIONS IN MULTIPLE MYELOMA

Our patient was referred to an oncologist for management.

In the management of multiple myeloma, the patient’s quality of life needs to be considered. With the development of new agents to combat the damages of the osteolytic effects, there is hope for improving quality of life.^13,14 New agents under study include anabolic agents such as antisclerostin and anti-Dickkopf-1, which promote osteoblastogenesis, leading to bone formation, with the possibility of repairing existing damage.¹⁵

TAKE-HOME POINTS

• If hypercalcemia is mild to moderate, consider primary hyperparathyroidism.
• Identify patients with severe symptoms of hypercalcemia such as volume depletion, acute kidney injury, arrhythmia, or seizures.
• Confirm severe cases of hypercalcemia and treat severe cases effectively.
• Severe hypercalcemia may need further investigation into a potential underlying malignancy.

A morbidly obese 54-year-old woman presented to the emergency department after experiencing generalized abdominal pain for 3 days. She rated the pain as 5 on a scale of 10 and described it as dull, cramping, waxing and waning, not radiating, and not relieved with changes of position—in fact, not alleviated by anything she had tried. Her pain was associated with nausea and 1 episode of vomiting. She also experienced constipation before the onset of pain.

She denied recent trauma, recent travel, diarrhea, fevers, weakness, shortness of breath, chest pain, other muscle pains, or recent changes in diet. She also denied having this pain in the past. She said she had unintentionally lost some weight but was not certain how much. She denied tobacco, alcohol, or illicit drug use. She had no history of surgery.

Her medical history included hypertension, anemia, and uterine fibroids. Her current medications included losartan, hydrochlorothiazide, and albuterol. She had no family history of significant disease.

INITIAL EVALUATION AND MANAGEMENT

On admission, her temperature was 97.8°F (36.6°C), heart rate 100 beats per minute, blood pressure 136/64 mm Hg, respiratory rate 18 breaths per minute, oxygen saturation 97% on room air, weight 130.6 kg, and body mass index 35 kg/m².

She was alert and oriented to person, place, and time. She was in mild discomfort but no distress. Her lungs were clear to auscultation, with no wheezing or crackles. Heart rate and rhythm were regular, with no extra heart sounds or murmurs. Bowel sounds were normal in all 4 quadrants, with tenderness to palpation of the epigastric area, but with no guarding or rebound tenderness.

Laboratory test results

Notable results of blood testing at presentation were as follows:

• Hemoglobin 8.2 g/dL (reference range 12.3–15.3)
• Hematocrit 26% (41–50)
• Mean corpuscular volume 107 fL (80–100)
• Blood urea nitrogen 33 mg/dL (8–21); 6 months earlier it was 16
• Serum creatinine 3.6 mg/dL (0.58–0.96); 6 months earlier, it was 0.75
• Albumin 3.3 g/dL (3.5–5)
• Calcium 18.4 mg/dL (8.4–10.2); 6 months earlier, it was 9.6
• Corrected calcium 19 mg/dL.

Findings on imaging, electrocardiography

Chest radiography showed no acute cardiopulmonary abnormalities. Abdominal computed tomography without contrast showed no abnormalities within the pancreas and no evidence of inflammation or obstruction. Electrocardiography showed sinus tachycardia.

DIFFERENTIAL DIAGNOSIS

1. Which is the most likely cause of this patient’s symptoms?

• Primary hyperparathyroidism
• Malignancy
• Her drug therapy
• Familial hypercalcemic hypocalciuria

In total, her laboratory results were consistent with macrocytic anemia, severe hypercalcemia, and acute kidney injury, and she had generalized symptoms.

Primary hyperparathyroidism

A main cause of hypercalcemia is primary hyperparathyroidism, and this needs to be ruled out. Benign adenomas are the most common cause of primary hyperparathyroidism, and a risk factor for benign adenoma is exposure to therapeutic levels of radiation.³

In hyperparathyroidism, there is an increased secretion of parathyroid hormone (PTH), which has multiple effects including increased reabsorption of calcium from the urine, increased excretion of phosphate, and increased expression of 1,25-hydroxyvitamin D hydroxylase to activate vitamin D. PTH also stimulates osteoclasts to increase their expression of receptor activator of nuclear factor kappa B ligand (RANKL), which has a downstream effect on osteoclast precursors to cause bone reabsorption.³

Inherited primary hyperparathyroidism tends to present at a younger age, with multiple overactive parathyroid glands.³ Given our patient’s age, inherited primary hyparathyroidism is thus less likely.

The probability that malignancy is causing the hypercalcemia increases with calcium levels greater than 13 mg/dL. Epidemiologically, in hospitalized patients with hypercalcemia, the source tends to be malignancy.⁴ Typically, patients who develop hypercalcemia from malignancy have a worse prognosis.⁵

Solid tumors and leukemias can cause hypercalcemia. The mechanisms include humoral factors secreted by the malignancy, local osteolysis due to tumor invasion of bone, and excessive absorption of calcium due to excess vitamin D produced by malignancies.⁵ The cancers that most frequently cause an increase in calcium resorption are lung cancer, renal cancer, breast cancer, and multiple myeloma.¹

Solid tumors with no bone metastasis and non-Hodgkin lymphoma that release PTH-related protein (PTHrP) cause humoral hypercalcemia in malignancy. The patient is typically in an advanced stage of disease. PTHrP increases serum calcium levels by decreasing the kidney’s ability to excrete calcium and by increasing bone turnover. It has no effect on intestinal absorption because of its inability to stimulate activated vitamin D₃. Thus, the increase in systemic calcium comes directly from breakdown of bone and inability to excrete the excess.

PTHrP has a unique role in breast cancer: it is released locally in areas where cancer cells have metastasized to bone, but it does not cause a systemic effect. Bone resorption occurs in areas of metastasis and results from an increase in expression of RANKL and RANK in osteoclasts in response to the effects of PTHrP, leading to an increase in the production of osteoclastic cells.¹

Tamoxifen, an endocrine therapy often used in breast cancer, also causes a release of bone-reabsorbing factors from tumor cells, which can partially contribute to hypercal­cemia.⁵

Myeloma cells secrete RANKL, which stimulates osteoclastic activity, and they also  release interleukin 6 (IL-6) and activating macrophage inflammatory protein alpha. Serum testing usually shows low or normal intact PTH, PTHrP, and 1,25-dihydroxyvitamin D.¹

Patients with multiple myeloma have a worse prognosis if they have a high red blood cell distribution width, a condition shown to correlate with malnutrition, leading to deficiencies in vitamin B₁₂ and to poor response to treatment.⁶ Up to 14% of patients with multiple myeloma have vitamin B₁₂ deficiency.⁷

Our patient’s recent weight loss and severe hypercalcemia raise suspicion of malignancy. Further, her obesity makes proper routine breast examination difficult and thus increases the chance of undiagnosed breast cancer.⁸ Her decrease in renal function and her anemia complicated by hypercalcemia also raise suspicion of multiple myeloma.

Hypercalcemia due to drug therapy

Thiazide diuretics, lithium, teriparatide, and vitamin A in excessive amounts can raise the serum calcium concentration.⁵ Our patient was taking a thiazide for hypertension, but her extremely high calcium level places drug-induced hypercalcemia as the sole cause lower on the differential list.

Familial hypercalcemic hypocalciuria

Familial hypercalcemic hypocalciuria is a rare autosomal-dominant cause of hypercalcemia in which the ability of the body (and especially the kidneys) to sense levels of calcium is impaired, leading to a decrease in excretion of calcium in the urine.³ Very high calcium levels are rare in hypercalcemic hypocalciuria.³ In our patient with a corrected calcium concentration of nearly 19 mg/dL, familial hypercalcemic hypocalciuria is very unlikely to be the cause of the hypercalcemia.

WHAT ARE THE NEXT STEPS IN THE WORKUP?

As hypercalcemia has been confirmed, the intact PTH level should be checked to determine whether the patient’s condition is PTH-mediated. If the PTH level is in the upper range of normal or is minimally elevated, primary hyperparathyroidism is likely. Elevated PTH confirms primary hyperparathyroidism. A low-normal or low intact PTH confirms a non-PTH-mediated process, and once this is confirmed, PTHrP levels should be checked. An elevated PTHrP suggests humoral hypercalcemia of malignancy. Serum protein electrophoresis, urine protein electrophoresis, and a serum light chain assay should be performed to rule out multiple myeloma.

Vitamin D toxicity is associated with high concentrations of 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D metabolites. These levels should be checked in this patient.

Other disorders that cause hypercalcemia are vitamin A toxicity and hyperthyroidism, so vitamin A and thyroid-stimulating hormone levels should also be checked.⁵

CASE CONTINUED

After further questioning, the patient said that she had had lower back pain about 1 to 2 weeks before coming to the emergency room; her primary care doctor had said the pain was likely from muscle strain. The pain had almost resolved but was still present.

The results of further laboratory testing were as follows:

• Serum PTH 11 pg/mL (15–65)
• PTHrP 3.4 pmol/L (< 2.0)
• Protein electrophoresis showed a monoclonal (M) spike of 0.2 g/dL (0)
• Activated vitamin D < 5 ng/mL (19.9–79.3)
• Vitamin A 7.2 mg/dL (33.1–100)
• Vitamin B₁₂ 194 pg/mL (239–931)
• Thyroid-stimulating hormone 1.21 mIU/ L (0.47–4.68
• Free thyroxine 1.27 ng/dL (0.78–2.19)
• Iron 103 µg/dL (37–170)
• Total iron-binding capacity 335 µg/dL (265–497)
• Transferrin 248 mg/dL (206–381)
• Ferritin 66 ng/mL (11.1–264)
• Urine protein (random) 100 mg/dL (0–20)
• Urine microalbumin (random) 5.9 mg/dL (0–1.6)
• Urine creatinine clearance 88.5 mL/min (88–128)
• Urine albumin-creatinine ratio 66.66 mg/g (< 30).

A nuclear bone scan showed increased bone uptake in the hip and both shoulders, consistent with arthritis, and increased activity in 2 of the lower left ribs, associated with rib fractures secondary to lytic lesions. A skeletal survey at a later date showed multiple well-circumscribed “punched-out” lytic lesions in both forearms and both femurs.

2. What should be the next step in this patient’s management?

• Intravenous (IV) fluids
• Calcitonin
• Bisphosphonate treatment
• Denosumab
• Hemodialysis

Initial treatment of severe hypercalcemia includes the following:

Start IV isotonic fluids at a rate of 150 mL/h (if the patient is making urine) to maintain urine output at more than 100 mL/h. Closely monitor urine output.

Give calcitonin 4 IU/kg in combination with IV fluids to reduce calcium levels within the first 12 to 48 hours of treatment.

Give a bisphosphonate, eg, zoledronic acid 4 mg over 15 minutes, or pamidronate 60 to 90 mg over 2 hours. Zoledronic acid is preferred in malignancy-induced hypercal­cemia because it is more potent. Doses should be adjusted in patients with renal failure.

Give denosumab if hypercalcemia is refractory to bisphosphonates, or when bisphosphonates cannot be used in renal failure.⁹

Hemodialysis is performed in patients who have significant neurologic symptoms irrespective of acute renal insufficiency.

Our patient was started on 0.9% sodium chloride at a rate of 150 mL/h for severe hypercalcemia. Zoledronic acid 4 mg IV was given once. These measures lowered her calcium level and lessened her acute kidney injury.

ADDITIONAL FINDINGS

Urine testing was positive for Bence Jones protein. Immune electrophoresis, performed because of suspicion of multiple myeloma, showed an elevated level of kappa light chains at 806.7 mg/dL (0.33–1.94) and normal lambda light chains at 0.62 mg/dL (0.57–2.63). The immunoglobulin G level was low at 496 mg/dL (610–1,660). In patients with severe hypercalcemia, these results point to a diagnosis of malignancy. Bone marrow aspiration study showed greater than 10% plasma cells, confirming multiple myeloma.

MULTIPLE MYELOMA

The diagnosis of multiple myeloma is based in part on the presence of 10% or more of clonal bone marrow plasma cells¹⁰ and of specific end-organ damage (anemia, hypercalcemia, renal insufficiency, or bone lesions).⁹

Bone marrow clonality can be shown by the ratio of kappa to lambda light chains as  detected with immunohistochemistry, immunofluorescence, or flow cytometry.11 The normal ratio is 0.26 to 1.65 for a patient with normal kidney function. In this patient, however, the ratio was 1,301.08 (806.67 kappa to 0.62 lambda), which was extremely out of range. The patient’s bone marrow biopsy results revealed the presence of 15% clonal bone marrow plasma cells.

Multiple myeloma causes osteolytic lesions through increased activation of osteoclast activating factor that stimulates the growth of osteoclast precursors. At the same time, it inhibits osteoblast formation via multiple pathways, including the action of sclerostin.¹¹ Our patient had lytic lesions in 2 left lower ribs and in both forearms and femurs.

Hypercalcemia in multiple myeloma is attributed to 2 main factors: bone breakdown and macrophage overactivation. Multiple myeloma cells increase the release of macrophage inflammatory protein 1-alpha and tumor necrosis factor, which are inflammatory proteins that cause an increase in macrophages, which cause an increase in calcitriol.¹¹ As noted, our patient’s calcium level at presentation was 18.4 mg/dL uncorrected and 18.96 mg/dL corrected.

Cast nephropathy can occur in the distal tubules from the increased free light chains circulating and combining with Tamm-Horsfall protein, which in turn causes obstruction and local inflammation,¹² leading to a rise in creatinine levels and resulting in acute kidney injury,¹² as in our patient.

TREATMENT CONSIDERATIONS IN MULTIPLE MYELOMA

Our patient was referred to an oncologist for management.

In the management of multiple myeloma, the patient’s quality of life needs to be considered. With the development of new agents to combat the damages of the osteolytic effects, there is hope for improving quality of life.^13,14 New agents under study include anabolic agents such as antisclerostin and anti-Dickkopf-1, which promote osteoblastogenesis, leading to bone formation, with the possibility of repairing existing damage.¹⁵

TAKE-HOME POINTS

• If hypercalcemia is mild to moderate, consider primary hyperparathyroidism.
• Identify patients with severe symptoms of hypercalcemia such as volume depletion, acute kidney injury, arrhythmia, or seizures.
• Confirm severe cases of hypercalcemia and treat severe cases effectively.
• Severe hypercalcemia may need further investigation into a potential underlying malignancy.

A morbidly obese 54-year-old woman presented to the emergency department after experiencing generalized abdominal pain for 3 days. She rated the pain as 5 on a scale of 10 and described it as dull, cramping, waxing and waning, not radiating, and not relieved with changes of position—in fact, not alleviated by anything she had tried. Her pain was associated with nausea and 1 episode of vomiting. She also experienced constipation before the onset of pain.

She denied recent trauma, recent travel, diarrhea, fevers, weakness, shortness of breath, chest pain, other muscle pains, or recent changes in diet. She also denied having this pain in the past. She said she had unintentionally lost some weight but was not certain how much. She denied tobacco, alcohol, or illicit drug use. She had no history of surgery.

Her medical history included hypertension, anemia, and uterine fibroids. Her current medications included losartan, hydrochlorothiazide, and albuterol. She had no family history of significant disease.

INITIAL EVALUATION AND MANAGEMENT

On admission, her temperature was 97.8°F (36.6°C), heart rate 100 beats per minute, blood pressure 136/64 mm Hg, respiratory rate 18 breaths per minute, oxygen saturation 97% on room air, weight 130.6 kg, and body mass index 35 kg/m².

She was alert and oriented to person, place, and time. She was in mild discomfort but no distress. Her lungs were clear to auscultation, with no wheezing or crackles. Heart rate and rhythm were regular, with no extra heart sounds or murmurs. Bowel sounds were normal in all 4 quadrants, with tenderness to palpation of the epigastric area, but with no guarding or rebound tenderness.

Laboratory test results

Notable results of blood testing at presentation were as follows:

• Hemoglobin 8.2 g/dL (reference range 12.3–15.3)
• Hematocrit 26% (41–50)
• Mean corpuscular volume 107 fL (80–100)
• Blood urea nitrogen 33 mg/dL (8–21); 6 months earlier it was 16
• Serum creatinine 3.6 mg/dL (0.58–0.96); 6 months earlier, it was 0.75
• Albumin 3.3 g/dL (3.5–5)
• Calcium 18.4 mg/dL (8.4–10.2); 6 months earlier, it was 9.6
• Corrected calcium 19 mg/dL.

Findings on imaging, electrocardiography

Chest radiography showed no acute cardiopulmonary abnormalities. Abdominal computed tomography without contrast showed no abnormalities within the pancreas and no evidence of inflammation or obstruction. Electrocardiography showed sinus tachycardia.

DIFFERENTIAL DIAGNOSIS

1. Which is the most likely cause of this patient’s symptoms?

• Primary hyperparathyroidism
• Malignancy
• Her drug therapy
• Familial hypercalcemic hypocalciuria

In total, her laboratory results were consistent with macrocytic anemia, severe hypercalcemia, and acute kidney injury, and she had generalized symptoms.

Primary hyperparathyroidism

A main cause of hypercalcemia is primary hyperparathyroidism, and this needs to be ruled out. Benign adenomas are the most common cause of primary hyperparathyroidism, and a risk factor for benign adenoma is exposure to therapeutic levels of radiation.³

In hyperparathyroidism, there is an increased secretion of parathyroid hormone (PTH), which has multiple effects including increased reabsorption of calcium from the urine, increased excretion of phosphate, and increased expression of 1,25-hydroxyvitamin D hydroxylase to activate vitamin D. PTH also stimulates osteoclasts to increase their expression of receptor activator of nuclear factor kappa B ligand (RANKL), which has a downstream effect on osteoclast precursors to cause bone reabsorption.³

Inherited primary hyperparathyroidism tends to present at a younger age, with multiple overactive parathyroid glands.³ Given our patient’s age, inherited primary hyparathyroidism is thus less likely.

The probability that malignancy is causing the hypercalcemia increases with calcium levels greater than 13 mg/dL. Epidemiologically, in hospitalized patients with hypercalcemia, the source tends to be malignancy.⁴ Typically, patients who develop hypercalcemia from malignancy have a worse prognosis.⁵

Solid tumors and leukemias can cause hypercalcemia. The mechanisms include humoral factors secreted by the malignancy, local osteolysis due to tumor invasion of bone, and excessive absorption of calcium due to excess vitamin D produced by malignancies.⁵ The cancers that most frequently cause an increase in calcium resorption are lung cancer, renal cancer, breast cancer, and multiple myeloma.¹

Solid tumors with no bone metastasis and non-Hodgkin lymphoma that release PTH-related protein (PTHrP) cause humoral hypercalcemia in malignancy. The patient is typically in an advanced stage of disease. PTHrP increases serum calcium levels by decreasing the kidney’s ability to excrete calcium and by increasing bone turnover. It has no effect on intestinal absorption because of its inability to stimulate activated vitamin D₃. Thus, the increase in systemic calcium comes directly from breakdown of bone and inability to excrete the excess.

PTHrP has a unique role in breast cancer: it is released locally in areas where cancer cells have metastasized to bone, but it does not cause a systemic effect. Bone resorption occurs in areas of metastasis and results from an increase in expression of RANKL and RANK in osteoclasts in response to the effects of PTHrP, leading to an increase in the production of osteoclastic cells.¹

Tamoxifen, an endocrine therapy often used in breast cancer, also causes a release of bone-reabsorbing factors from tumor cells, which can partially contribute to hypercal­cemia.⁵

Myeloma cells secrete RANKL, which stimulates osteoclastic activity, and they also  release interleukin 6 (IL-6) and activating macrophage inflammatory protein alpha. Serum testing usually shows low or normal intact PTH, PTHrP, and 1,25-dihydroxyvitamin D.¹

Patients with multiple myeloma have a worse prognosis if they have a high red blood cell distribution width, a condition shown to correlate with malnutrition, leading to deficiencies in vitamin B₁₂ and to poor response to treatment.⁶ Up to 14% of patients with multiple myeloma have vitamin B₁₂ deficiency.⁷

Our patient’s recent weight loss and severe hypercalcemia raise suspicion of malignancy. Further, her obesity makes proper routine breast examination difficult and thus increases the chance of undiagnosed breast cancer.⁸ Her decrease in renal function and her anemia complicated by hypercalcemia also raise suspicion of multiple myeloma.

Hypercalcemia due to drug therapy

Thiazide diuretics, lithium, teriparatide, and vitamin A in excessive amounts can raise the serum calcium concentration.⁵ Our patient was taking a thiazide for hypertension, but her extremely high calcium level places drug-induced hypercalcemia as the sole cause lower on the differential list.

Familial hypercalcemic hypocalciuria

Familial hypercalcemic hypocalciuria is a rare autosomal-dominant cause of hypercalcemia in which the ability of the body (and especially the kidneys) to sense levels of calcium is impaired, leading to a decrease in excretion of calcium in the urine.³ Very high calcium levels are rare in hypercalcemic hypocalciuria.³ In our patient with a corrected calcium concentration of nearly 19 mg/dL, familial hypercalcemic hypocalciuria is very unlikely to be the cause of the hypercalcemia.

WHAT ARE THE NEXT STEPS IN THE WORKUP?

As hypercalcemia has been confirmed, the intact PTH level should be checked to determine whether the patient’s condition is PTH-mediated. If the PTH level is in the upper range of normal or is minimally elevated, primary hyperparathyroidism is likely. Elevated PTH confirms primary hyperparathyroidism. A low-normal or low intact PTH confirms a non-PTH-mediated process, and once this is confirmed, PTHrP levels should be checked. An elevated PTHrP suggests humoral hypercalcemia of malignancy. Serum protein electrophoresis, urine protein electrophoresis, and a serum light chain assay should be performed to rule out multiple myeloma.

Vitamin D toxicity is associated with high concentrations of 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D metabolites. These levels should be checked in this patient.

Other disorders that cause hypercalcemia are vitamin A toxicity and hyperthyroidism, so vitamin A and thyroid-stimulating hormone levels should also be checked.⁵

CASE CONTINUED

After further questioning, the patient said that she had had lower back pain about 1 to 2 weeks before coming to the emergency room; her primary care doctor had said the pain was likely from muscle strain. The pain had almost resolved but was still present.

The results of further laboratory testing were as follows:

• Serum PTH 11 pg/mL (15–65)
• PTHrP 3.4 pmol/L (< 2.0)
• Protein electrophoresis showed a monoclonal (M) spike of 0.2 g/dL (0)
• Activated vitamin D < 5 ng/mL (19.9–79.3)
• Vitamin A 7.2 mg/dL (33.1–100)
• Vitamin B₁₂ 194 pg/mL (239–931)
• Thyroid-stimulating hormone 1.21 mIU/ L (0.47–4.68
• Free thyroxine 1.27 ng/dL (0.78–2.19)
• Iron 103 µg/dL (37–170)
• Total iron-binding capacity 335 µg/dL (265–497)
• Transferrin 248 mg/dL (206–381)
• Ferritin 66 ng/mL (11.1–264)
• Urine protein (random) 100 mg/dL (0–20)
• Urine microalbumin (random) 5.9 mg/dL (0–1.6)
• Urine creatinine clearance 88.5 mL/min (88–128)
• Urine albumin-creatinine ratio 66.66 mg/g (< 30).

A nuclear bone scan showed increased bone uptake in the hip and both shoulders, consistent with arthritis, and increased activity in 2 of the lower left ribs, associated with rib fractures secondary to lytic lesions. A skeletal survey at a later date showed multiple well-circumscribed “punched-out” lytic lesions in both forearms and both femurs.

2. What should be the next step in this patient’s management?

• Intravenous (IV) fluids
• Calcitonin
• Bisphosphonate treatment
• Denosumab
• Hemodialysis

Initial treatment of severe hypercalcemia includes the following:

Start IV isotonic fluids at a rate of 150 mL/h (if the patient is making urine) to maintain urine output at more than 100 mL/h. Closely monitor urine output.

Give calcitonin 4 IU/kg in combination with IV fluids to reduce calcium levels within the first 12 to 48 hours of treatment.

Give a bisphosphonate, eg, zoledronic acid 4 mg over 15 minutes, or pamidronate 60 to 90 mg over 2 hours. Zoledronic acid is preferred in malignancy-induced hypercal­cemia because it is more potent. Doses should be adjusted in patients with renal failure.

Give denosumab if hypercalcemia is refractory to bisphosphonates, or when bisphosphonates cannot be used in renal failure.⁹

Hemodialysis is performed in patients who have significant neurologic symptoms irrespective of acute renal insufficiency.

Our patient was started on 0.9% sodium chloride at a rate of 150 mL/h for severe hypercalcemia. Zoledronic acid 4 mg IV was given once. These measures lowered her calcium level and lessened her acute kidney injury.

ADDITIONAL FINDINGS

Urine testing was positive for Bence Jones protein. Immune electrophoresis, performed because of suspicion of multiple myeloma, showed an elevated level of kappa light chains at 806.7 mg/dL (0.33–1.94) and normal lambda light chains at 0.62 mg/dL (0.57–2.63). The immunoglobulin G level was low at 496 mg/dL (610–1,660). In patients with severe hypercalcemia, these results point to a diagnosis of malignancy. Bone marrow aspiration study showed greater than 10% plasma cells, confirming multiple myeloma.

MULTIPLE MYELOMA

The diagnosis of multiple myeloma is based in part on the presence of 10% or more of clonal bone marrow plasma cells¹⁰ and of specific end-organ damage (anemia, hypercalcemia, renal insufficiency, or bone lesions).⁹

Bone marrow clonality can be shown by the ratio of kappa to lambda light chains as  detected with immunohistochemistry, immunofluorescence, or flow cytometry.11 The normal ratio is 0.26 to 1.65 for a patient with normal kidney function. In this patient, however, the ratio was 1,301.08 (806.67 kappa to 0.62 lambda), which was extremely out of range. The patient’s bone marrow biopsy results revealed the presence of 15% clonal bone marrow plasma cells.

Multiple myeloma causes osteolytic lesions through increased activation of osteoclast activating factor that stimulates the growth of osteoclast precursors. At the same time, it inhibits osteoblast formation via multiple pathways, including the action of sclerostin.¹¹ Our patient had lytic lesions in 2 left lower ribs and in both forearms and femurs.

Hypercalcemia in multiple myeloma is attributed to 2 main factors: bone breakdown and macrophage overactivation. Multiple myeloma cells increase the release of macrophage inflammatory protein 1-alpha and tumor necrosis factor, which are inflammatory proteins that cause an increase in macrophages, which cause an increase in calcitriol.¹¹ As noted, our patient’s calcium level at presentation was 18.4 mg/dL uncorrected and 18.96 mg/dL corrected.

Cast nephropathy can occur in the distal tubules from the increased free light chains circulating and combining with Tamm-Horsfall protein, which in turn causes obstruction and local inflammation,¹² leading to a rise in creatinine levels and resulting in acute kidney injury,¹² as in our patient.

TREATMENT CONSIDERATIONS IN MULTIPLE MYELOMA

Our patient was referred to an oncologist for management.

In the management of multiple myeloma, the patient’s quality of life needs to be considered. With the development of new agents to combat the damages of the osteolytic effects, there is hope for improving quality of life.^13,14 New agents under study include anabolic agents such as antisclerostin and anti-Dickkopf-1, which promote osteoblastogenesis, leading to bone formation, with the possibility of repairing existing damage.¹⁵

TAKE-HOME POINTS

• If hypercalcemia is mild to moderate, consider primary hyperparathyroidism.
• Identify patients with severe symptoms of hypercalcemia such as volume depletion, acute kidney injury, arrhythmia, or seizures.
• Confirm severe cases of hypercalcemia and treat severe cases effectively.
• Severe hypercalcemia may need further investigation into a potential underlying malignancy.

Despite guidelines recommending low-dose oral glucocorticoids over high-dose intravenous (IV) glucocorticoids for inpatient management of acute exacerbations of chronic obstructive pulmonary disease (COPD), we have observed that most patients still receive high-dose IV therapy before being transitioned to low-dose oral therapy at discharge. Clinical inertia undoubtedly plays a significant role in the slow adoption of new recommendations, but in this era of evidence-based practice, the unfortunate lack of data supporting low over high steroid doses for acute exacerbations of COPD also contributes to hesitancy of physicians.

A SIGNIFICANT AND GROWING BURDEN

COPD is one of the most common pulmonary conditions managed by hospitalists today, and by the year 2030, it is predicted to become the third leading cause of death worldwide.¹

COPD is also a significant economic burden, costing $50 billion to manage in the United States, most of that from the cost of lengthy hospital stays.² COPD patients have 1 to 2 exacerbations per year.³ Bacterial and viral infections are responsible for most exacerbations, and 15% to 20% are from air pollution and other environmental causes of airway inflammation.³

CHALLENGES TO CHANGING PRACTICE

Glucocorticoids are the gold standard for treatment of acute exacerbations of COPD. It is well-documented that compared with placebo, glucocorticoids reduce mortality risk, length of hospital stay, and exacerbation recurrence after 1 month.⁴ And while high-dose IV steroid therapy has been the standard approach, oral administration has been found to be noninferior to IV administration with regard to treatment and length of hospital stay.⁵

While adverse effects are more common at higher doses, the optimal dose and duration of systemic glucocorticoid therapy for acute exacerbations of COPD are still largely at the discretion of the physician. The 2019 report of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends low doses (40 mg) for no more than 5 to 7 days for exacerbations, based on reports that showed no worse outcomes with low-dose oral than with high-dose IV therapy.^6,7 (In the 2010 study by Lindenauer et al,⁷ 92% of nearly 80,000 patients received high-dose IV steroids, reflecting standard practice at that time.) However, the GOLD guidelines do not address mortality rates, length of stay, or readmission rates for either approach, as they are devised to direct treatment in patients with stable mild to advanced COPD, not exacerbations.

Mortality rates

Aksoy et al⁸ established that, compared with placebo, low-dose steroids improved mortality rates in a subset of patients with acute exacerbations, specifically those with eosinophilic exacerbations. This study followed the 2013 Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial, which showed mortality rates were not lower with 14 days of low-dose prednisone treatment than with 5 days.9

Length of hospital stay

With regard to length of hospital stay, in 2011 Wang et al¹⁰ found no statistically significant difference between high- and low-dose steroid treatment.However, the REDUCE trial found that low-dose steroids shortened the median length of stay by 1 day compared with placebo.⁹

Hospital readmission rates

The REDUCE trial found no statistically significant difference in readmission rates when comparing 5 days of low-dose treatment vs 14 days.⁹ However, Aksoy et al⁸ found that readmission rates were significantly lower with low-dose treatment than with placebo.No study has yet examined readmission rates with high-dose vs low-dose steroid treatment.

What does the evidence tell us?

Low-dose oral glucocorticoid treatment shows definitive benefits in terms of lower mortality rates, shorter hospital length of stay, and lower readmission rates vs placebo in the treatment of acute exacerbations of COPD. Furthermore, a 14-day course is no better than 5 days in terms of mortality rates. And low-dose glucocorticoid treatment shows reduced mortality rates in addition to similar hospital length of stay when compared to high-dose glucocorticoid treatment.

Together, these findings lend credibility to the current GOLD recommendations. However, we have observed that in sharp contrast to the leading clinical guidelines, most patients hospitalized for acute exacerbations of COPD are still treated initially with high-dose IV corticosteroids. Why?

Obstacles that perpetuate the use of high-dose over low-dose treatment include lack of knowledge of glucocorticoid pharmacokinetics among clinicians, use of outdated order sets, and the reflex notion that more of a drug is more efficacious in its desired effect. In addition, administrative obstacles include using high-dose IV steroids to justify an inpatient stay or continued hospitalization.

COUNTERING THE OBSTACLES: THE HOSPITALIST’S ROLE

To counter these obstacles, we propose standardization of inpatient treatment of acute exacerbations of COPD to include initial low-dose steroid treatment in accordance with the most recent GOLD guidelines.⁶ This would benefit the patient by reducing undesirable effects of high-dose steroids, and at the same time reduce the economic burden of managing COPD exacerbations. Considering the large number of hospitalizations for COPD exacerbation each year, hospitalists can play a large role in this effort by routinely incorporating the low-dose steroid recommendation into their clinical practice.

Despite guidelines recommending low-dose oral glucocorticoids over high-dose intravenous (IV) glucocorticoids for inpatient management of acute exacerbations of chronic obstructive pulmonary disease (COPD), we have observed that most patients still receive high-dose IV therapy before being transitioned to low-dose oral therapy at discharge. Clinical inertia undoubtedly plays a significant role in the slow adoption of new recommendations, but in this era of evidence-based practice, the unfortunate lack of data supporting low over high steroid doses for acute exacerbations of COPD also contributes to hesitancy of physicians.

A SIGNIFICANT AND GROWING BURDEN

COPD is one of the most common pulmonary conditions managed by hospitalists today, and by the year 2030, it is predicted to become the third leading cause of death worldwide.¹

COPD is also a significant economic burden, costing $50 billion to manage in the United States, most of that from the cost of lengthy hospital stays.² COPD patients have 1 to 2 exacerbations per year.³ Bacterial and viral infections are responsible for most exacerbations, and 15% to 20% are from air pollution and other environmental causes of airway inflammation.³

CHALLENGES TO CHANGING PRACTICE

Glucocorticoids are the gold standard for treatment of acute exacerbations of COPD. It is well-documented that compared with placebo, glucocorticoids reduce mortality risk, length of hospital stay, and exacerbation recurrence after 1 month.⁴ And while high-dose IV steroid therapy has been the standard approach, oral administration has been found to be noninferior to IV administration with regard to treatment and length of hospital stay.⁵

While adverse effects are more common at higher doses, the optimal dose and duration of systemic glucocorticoid therapy for acute exacerbations of COPD are still largely at the discretion of the physician. The 2019 report of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends low doses (40 mg) for no more than 5 to 7 days for exacerbations, based on reports that showed no worse outcomes with low-dose oral than with high-dose IV therapy.^6,7 (In the 2010 study by Lindenauer et al,⁷ 92% of nearly 80,000 patients received high-dose IV steroids, reflecting standard practice at that time.) However, the GOLD guidelines do not address mortality rates, length of stay, or readmission rates for either approach, as they are devised to direct treatment in patients with stable mild to advanced COPD, not exacerbations.

Mortality rates

Aksoy et al⁸ established that, compared with placebo, low-dose steroids improved mortality rates in a subset of patients with acute exacerbations, specifically those with eosinophilic exacerbations. This study followed the 2013 Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial, which showed mortality rates were not lower with 14 days of low-dose prednisone treatment than with 5 days.9

Length of hospital stay

With regard to length of hospital stay, in 2011 Wang et al¹⁰ found no statistically significant difference between high- and low-dose steroid treatment.However, the REDUCE trial found that low-dose steroids shortened the median length of stay by 1 day compared with placebo.⁹

Hospital readmission rates

The REDUCE trial found no statistically significant difference in readmission rates when comparing 5 days of low-dose treatment vs 14 days.⁹ However, Aksoy et al⁸ found that readmission rates were significantly lower with low-dose treatment than with placebo.No study has yet examined readmission rates with high-dose vs low-dose steroid treatment.

What does the evidence tell us?

Low-dose oral glucocorticoid treatment shows definitive benefits in terms of lower mortality rates, shorter hospital length of stay, and lower readmission rates vs placebo in the treatment of acute exacerbations of COPD. Furthermore, a 14-day course is no better than 5 days in terms of mortality rates. And low-dose glucocorticoid treatment shows reduced mortality rates in addition to similar hospital length of stay when compared to high-dose glucocorticoid treatment.

Together, these findings lend credibility to the current GOLD recommendations. However, we have observed that in sharp contrast to the leading clinical guidelines, most patients hospitalized for acute exacerbations of COPD are still treated initially with high-dose IV corticosteroids. Why?

Obstacles that perpetuate the use of high-dose over low-dose treatment include lack of knowledge of glucocorticoid pharmacokinetics among clinicians, use of outdated order sets, and the reflex notion that more of a drug is more efficacious in its desired effect. In addition, administrative obstacles include using high-dose IV steroids to justify an inpatient stay or continued hospitalization.

COUNTERING THE OBSTACLES: THE HOSPITALIST’S ROLE

To counter these obstacles, we propose standardization of inpatient treatment of acute exacerbations of COPD to include initial low-dose steroid treatment in accordance with the most recent GOLD guidelines.⁶ This would benefit the patient by reducing undesirable effects of high-dose steroids, and at the same time reduce the economic burden of managing COPD exacerbations. Considering the large number of hospitalizations for COPD exacerbation each year, hospitalists can play a large role in this effort by routinely incorporating the low-dose steroid recommendation into their clinical practice.

Despite guidelines recommending low-dose oral glucocorticoids over high-dose intravenous (IV) glucocorticoids for inpatient management of acute exacerbations of chronic obstructive pulmonary disease (COPD), we have observed that most patients still receive high-dose IV therapy before being transitioned to low-dose oral therapy at discharge. Clinical inertia undoubtedly plays a significant role in the slow adoption of new recommendations, but in this era of evidence-based practice, the unfortunate lack of data supporting low over high steroid doses for acute exacerbations of COPD also contributes to hesitancy of physicians.

A SIGNIFICANT AND GROWING BURDEN

COPD is one of the most common pulmonary conditions managed by hospitalists today, and by the year 2030, it is predicted to become the third leading cause of death worldwide.¹

COPD is also a significant economic burden, costing $50 billion to manage in the United States, most of that from the cost of lengthy hospital stays.² COPD patients have 1 to 2 exacerbations per year.³ Bacterial and viral infections are responsible for most exacerbations, and 15% to 20% are from air pollution and other environmental causes of airway inflammation.³

CHALLENGES TO CHANGING PRACTICE

Glucocorticoids are the gold standard for treatment of acute exacerbations of COPD. It is well-documented that compared with placebo, glucocorticoids reduce mortality risk, length of hospital stay, and exacerbation recurrence after 1 month.⁴ And while high-dose IV steroid therapy has been the standard approach, oral administration has been found to be noninferior to IV administration with regard to treatment and length of hospital stay.⁵

While adverse effects are more common at higher doses, the optimal dose and duration of systemic glucocorticoid therapy for acute exacerbations of COPD are still largely at the discretion of the physician. The 2019 report of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends low doses (40 mg) for no more than 5 to 7 days for exacerbations, based on reports that showed no worse outcomes with low-dose oral than with high-dose IV therapy.^6,7 (In the 2010 study by Lindenauer et al,⁷ 92% of nearly 80,000 patients received high-dose IV steroids, reflecting standard practice at that time.) However, the GOLD guidelines do not address mortality rates, length of stay, or readmission rates for either approach, as they are devised to direct treatment in patients with stable mild to advanced COPD, not exacerbations.

Mortality rates

Aksoy et al⁸ established that, compared with placebo, low-dose steroids improved mortality rates in a subset of patients with acute exacerbations, specifically those with eosinophilic exacerbations. This study followed the 2013 Reduction in the Use of Corticosteroids in Exacerbated COPD (REDUCE) trial, which showed mortality rates were not lower with 14 days of low-dose prednisone treatment than with 5 days.9

Length of hospital stay

With regard to length of hospital stay, in 2011 Wang et al¹⁰ found no statistically significant difference between high- and low-dose steroid treatment.However, the REDUCE trial found that low-dose steroids shortened the median length of stay by 1 day compared with placebo.⁹

Hospital readmission rates

The REDUCE trial found no statistically significant difference in readmission rates when comparing 5 days of low-dose treatment vs 14 days.⁹ However, Aksoy et al⁸ found that readmission rates were significantly lower with low-dose treatment than with placebo.No study has yet examined readmission rates with high-dose vs low-dose steroid treatment.

What does the evidence tell us?

Low-dose oral glucocorticoid treatment shows definitive benefits in terms of lower mortality rates, shorter hospital length of stay, and lower readmission rates vs placebo in the treatment of acute exacerbations of COPD. Furthermore, a 14-day course is no better than 5 days in terms of mortality rates. And low-dose glucocorticoid treatment shows reduced mortality rates in addition to similar hospital length of stay when compared to high-dose glucocorticoid treatment.

Together, these findings lend credibility to the current GOLD recommendations. However, we have observed that in sharp contrast to the leading clinical guidelines, most patients hospitalized for acute exacerbations of COPD are still treated initially with high-dose IV corticosteroids. Why?

Obstacles that perpetuate the use of high-dose over low-dose treatment include lack of knowledge of glucocorticoid pharmacokinetics among clinicians, use of outdated order sets, and the reflex notion that more of a drug is more efficacious in its desired effect. In addition, administrative obstacles include using high-dose IV steroids to justify an inpatient stay or continued hospitalization.

COUNTERING THE OBSTACLES: THE HOSPITALIST’S ROLE

To counter these obstacles, we propose standardization of inpatient treatment of acute exacerbations of COPD to include initial low-dose steroid treatment in accordance with the most recent GOLD guidelines.⁶ This would benefit the patient by reducing undesirable effects of high-dose steroids, and at the same time reduce the economic burden of managing COPD exacerbations. Considering the large number of hospitalizations for COPD exacerbation each year, hospitalists can play a large role in this effort by routinely incorporating the low-dose steroid recommendation into their clinical practice.

Information was omitted from Table 1 on page 596 of the article, Makin V, Lansang MC. Diabetes management: beyond hemoglobin A_1c (Cleve Clin J Med 2019; 86[9]:595–600, doi:10.3949/ccjm.86a.18031).

The sodium-glucose cotransporter 2 (SGLT2) inhibitors pose a low risk of hypoglyemia, and that should have been noted in the table. The corrected table appears below and online.

Information was omitted from Table 1 on page 596 of the article, Makin V, Lansang MC. Diabetes management: beyond hemoglobin A_1c (Cleve Clin J Med 2019; 86[9]:595–600, doi:10.3949/ccjm.86a.18031).

The sodium-glucose cotransporter 2 (SGLT2) inhibitors pose a low risk of hypoglyemia, and that should have been noted in the table. The corrected table appears below and online.

Information was omitted from Table 1 on page 596 of the article, Makin V, Lansang MC. Diabetes management: beyond hemoglobin A_1c (Cleve Clin J Med 2019; 86[9]:595–600, doi:10.3949/ccjm.86a.18031).

The sodium-glucose cotransporter 2 (SGLT2) inhibitors pose a low risk of hypoglyemia, and that should have been noted in the table. The corrected table appears below and online.

“The most valuable of all talents is that of never using two words when one will do.“
—Thomas Jefferson

Attendings, residents, and medical students identify education as a top purpose of team rounds.¹ Learners report being dissatisfied with teaching on rounds most of the time.² Time with learners is a finite resource that has become even more precious with increasing clinical demands and work hour restrictions.³ Attendings report insufficient time to teach on rounds, and often neglect teaching because of time constraints.⁴ What can we do to in the face of this conflict between time and teaching?

One approach to this problem is what we call “ultra-brief, deliberate teaching sessions.” These sessions, or UBDTs, led by clinicians, create dedicated time for teaching on service. UBDTs ideally occur before team rounds because, in our experience, this is when the team is most unified and focused. Our sessions are time-limited (5 minutes or less) and designed so they are applicable to clinical scenarios the team is actively facing. Other learners can also lead these sessions with faculty coaching. Sessions of germane size and scope include: (1) Focus on a single clinical question from the previous day; (2) Discuss Choosing Wisely^® recommendations from a single specialty; (3) Provide a concise cognitive framework for a diagnostic or treatment dilemma (eg, draw a simple algorithm to evaluate causes of hyponatremia); (4) Review one image or electrocardiogram; (5) Present one case-based multiple-choice question; (6) Prime the team with a structured approach to a difficult conversation (eg, opioid discussions, goals of care).

As an example, if our team orders intravenous antihypertensives overnight, a UBDT session on asymptomatic hypertension would occur. The first minute may involve a discussion on the definition of hypertensive emergency versus asymptomatic hypertension. Next, we spend one minute asking learners the common causes of inpatient hypertension (eg, missed medications, pain, anxiety, withdrawal), highlighting that this warrants a bedside assessment. For two minutes, we next discuss the management options for asymptomatic hypertension with an emphasis on the avoidance of intravenous antihypertensives, tying this back to our current patient. Questions are welcomed, and a one-page summary of the major points and references is distributed during or after the talk. A repository of common topics and summaries may be a useful faculty development resource to be shared.

We have found UBDTs to be easy to implement for a variety of clinician educators. Because they are so brief and focused, they are also fun to create and share among teaching faculty. Importantly, these sessions should not delay clinical work. To ensure the avoidance of this trap, don’t select a topic that is too large or involves complex clinical reasoning, exceeds 5 minutes, or lead a UBDT session in a distracting environment or without preparation.

While we have not found a way to slow down time, UBDT sessions prior to the start of rounds can prioritize teaching, ensure the delivery of important content, and engage learners without significantly delaying clinical work. We invite you to try one!

Acknowledgments

The authors thank John Ragsdale, MD, MS for his leadership and support for UBDTs.

Disclosures

We have no relevant conflicts of interest to report. No payment or services from a third party were received for any aspect of this submitted work. We have no financial relationships with entities in the bio-medical arena that could be perceived to influence, or that give the appearance of potentially influencing, what was written in this submitted work.

“The most valuable of all talents is that of never using two words when one will do.“
—Thomas Jefferson

Attendings, residents, and medical students identify education as a top purpose of team rounds.¹ Learners report being dissatisfied with teaching on rounds most of the time.² Time with learners is a finite resource that has become even more precious with increasing clinical demands and work hour restrictions.³ Attendings report insufficient time to teach on rounds, and often neglect teaching because of time constraints.⁴ What can we do to in the face of this conflict between time and teaching?

One approach to this problem is what we call “ultra-brief, deliberate teaching sessions.” These sessions, or UBDTs, led by clinicians, create dedicated time for teaching on service. UBDTs ideally occur before team rounds because, in our experience, this is when the team is most unified and focused. Our sessions are time-limited (5 minutes or less) and designed so they are applicable to clinical scenarios the team is actively facing. Other learners can also lead these sessions with faculty coaching. Sessions of germane size and scope include: (1) Focus on a single clinical question from the previous day; (2) Discuss Choosing Wisely^® recommendations from a single specialty; (3) Provide a concise cognitive framework for a diagnostic or treatment dilemma (eg, draw a simple algorithm to evaluate causes of hyponatremia); (4) Review one image or electrocardiogram; (5) Present one case-based multiple-choice question; (6) Prime the team with a structured approach to a difficult conversation (eg, opioid discussions, goals of care).

As an example, if our team orders intravenous antihypertensives overnight, a UBDT session on asymptomatic hypertension would occur. The first minute may involve a discussion on the definition of hypertensive emergency versus asymptomatic hypertension. Next, we spend one minute asking learners the common causes of inpatient hypertension (eg, missed medications, pain, anxiety, withdrawal), highlighting that this warrants a bedside assessment. For two minutes, we next discuss the management options for asymptomatic hypertension with an emphasis on the avoidance of intravenous antihypertensives, tying this back to our current patient. Questions are welcomed, and a one-page summary of the major points and references is distributed during or after the talk. A repository of common topics and summaries may be a useful faculty development resource to be shared.

We have found UBDTs to be easy to implement for a variety of clinician educators. Because they are so brief and focused, they are also fun to create and share among teaching faculty. Importantly, these sessions should not delay clinical work. To ensure the avoidance of this trap, don’t select a topic that is too large or involves complex clinical reasoning, exceeds 5 minutes, or lead a UBDT session in a distracting environment or without preparation.

While we have not found a way to slow down time, UBDT sessions prior to the start of rounds can prioritize teaching, ensure the delivery of important content, and engage learners without significantly delaying clinical work. We invite you to try one!

Acknowledgments

The authors thank John Ragsdale, MD, MS for his leadership and support for UBDTs.

Disclosures

We have no relevant conflicts of interest to report. No payment or services from a third party were received for any aspect of this submitted work. We have no financial relationships with entities in the bio-medical arena that could be perceived to influence, or that give the appearance of potentially influencing, what was written in this submitted work.

“The most valuable of all talents is that of never using two words when one will do.“
—Thomas Jefferson

Attendings, residents, and medical students identify education as a top purpose of team rounds.¹ Learners report being dissatisfied with teaching on rounds most of the time.² Time with learners is a finite resource that has become even more precious with increasing clinical demands and work hour restrictions.³ Attendings report insufficient time to teach on rounds, and often neglect teaching because of time constraints.⁴ What can we do to in the face of this conflict between time and teaching?

One approach to this problem is what we call “ultra-brief, deliberate teaching sessions.” These sessions, or UBDTs, led by clinicians, create dedicated time for teaching on service. UBDTs ideally occur before team rounds because, in our experience, this is when the team is most unified and focused. Our sessions are time-limited (5 minutes or less) and designed so they are applicable to clinical scenarios the team is actively facing. Other learners can also lead these sessions with faculty coaching. Sessions of germane size and scope include: (1) Focus on a single clinical question from the previous day; (2) Discuss Choosing Wisely^® recommendations from a single specialty; (3) Provide a concise cognitive framework for a diagnostic or treatment dilemma (eg, draw a simple algorithm to evaluate causes of hyponatremia); (4) Review one image or electrocardiogram; (5) Present one case-based multiple-choice question; (6) Prime the team with a structured approach to a difficult conversation (eg, opioid discussions, goals of care).

As an example, if our team orders intravenous antihypertensives overnight, a UBDT session on asymptomatic hypertension would occur. The first minute may involve a discussion on the definition of hypertensive emergency versus asymptomatic hypertension. Next, we spend one minute asking learners the common causes of inpatient hypertension (eg, missed medications, pain, anxiety, withdrawal), highlighting that this warrants a bedside assessment. For two minutes, we next discuss the management options for asymptomatic hypertension with an emphasis on the avoidance of intravenous antihypertensives, tying this back to our current patient. Questions are welcomed, and a one-page summary of the major points and references is distributed during or after the talk. A repository of common topics and summaries may be a useful faculty development resource to be shared.

We have found UBDTs to be easy to implement for a variety of clinician educators. Because they are so brief and focused, they are also fun to create and share among teaching faculty. Importantly, these sessions should not delay clinical work. To ensure the avoidance of this trap, don’t select a topic that is too large or involves complex clinical reasoning, exceeds 5 minutes, or lead a UBDT session in a distracting environment or without preparation.

While we have not found a way to slow down time, UBDT sessions prior to the start of rounds can prioritize teaching, ensure the delivery of important content, and engage learners without significantly delaying clinical work. We invite you to try one!

Acknowledgments

The authors thank John Ragsdale, MD, MS for his leadership and support for UBDTs.

Disclosures

We have no relevant conflicts of interest to report. No payment or services from a third party were received for any aspect of this submitted work. We have no financial relationships with entities in the bio-medical arena that could be perceived to influence, or that give the appearance of potentially influencing, what was written in this submitted work.

Providing access to clinical trials for native American, veteran, and active-duty military patients can be a challenge, but a significant number of trials are now recruiting from those populations. Many trials explicitly recruit patients from the US Department of Veterans
Affairs (VA), the military, and Indian Health Service. The VA Office of Research and Development alone sponsors more than 480 research initiatives, and many more are sponsored by Walter Reed National Medical Center and other major defense and VA facilities. The clinical trials listed below are all open as of October 24, 2018; have at least 1 VA, DoD, or IHS location recruiting patients; and are focused on preventing diabetes mellitus or improving patient care. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials. gov.

Diabetes Prevention Program Outcomes Study (DPPOS)

The Diabetes Prevention Program (DPP) was a multicenter trial examining the ability of an intensive lifestyle or metformin to prevent or delay the development of diabetes in a high risk population due to the presence of impaired glucose tolerance (IGT). The DPP has ended early demonstrating that lifestyle reduced diabetes onset by 58% and metformin reduced diabetes onset by 31%.

ID: NCT00038727
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases
Location: George Washington University, Rockville, Maryland

Efforts to Improve Diabetes Control

The primary objectives of this study are: (1) test the longterm effectiveness of a peer mentor model on improving glucose control, blood pressure, LDL levels, diabetes mellitus quality of life, and depression scores in a mixed race population of poorly controlled diabetic veterans; (2) test the effectiveness of using former peer mentees as peer mentors as a means of creating a self-sustaining program; and (3) test the effects of becoming a mentor on those who were originally mentees given a growing literature that being a mentor is good for your health. Secondary objectives include: (1) in those randomized to being a mentee, explore mentor characteristics associated with improved HbA1c.

ID: NCT01651117
Sponsor: VA Office of Research and Development
Location: Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania

A Patient-Centered Strategy for Improving Diabetes Prevention in Urban American Indians

The goal of the proposed research is to identify effective patient-centered strategies to prevent diabetes in high-risk populations in real world settings. The investigators will accomplish this by conducting a randomized controlled trial comparing an enhanced Diabetes Prevention Program addressing psychosocial stressors to a standard version in a high-risk population of urban American Indian
and Alaskan Native peoples within a primary care setting.

ID: NCT02266576
Sponsor: Stanford University
Locations: Timpany Center of San Jose State University, California; Stanford University School of Medicine, California

Physical activity is the cornerstone of good diabetes management, and yet effective physical activity intervention is not available. The investigators developed a lifestyle intervention based on individual’s home activity patterns. The goal of the study is to test the efficacy of this intervention among veterans with diabetes in a randomized-controlled trial. In addition to physical activity, the investigators will also assess if the intervention will improve social participation among veterans.

ID: NCT02268916
Sponsor: VA Office of Research and Development
Location: VA Ann Arbor Healthcare System, Michigan

Caring Others Increasing EngageMent in PACT (CO-IMPACT)

This trial will compare two methods of increasing engagement in care and success in diabetes management, among patients with diabetes with high-risk features, who also have family members involved in their care.

ID: NCT02328326
Sponsor: VA Office of Research and Development
Locations: VA Ann Arbor Healthcare System, Michigan;VA Pittsburgh Healthcare System, Pennsylvania

STEP UP to Avert Amputation in Diabetes (STEP UP)

This study will evaluate a comprehensive tailored behavioral intervention aimed to improve foot self-care and self-monitoring (combined with dermal thermometry) to prevent recurrent ulcers in Veterans at highest risk of amputation. This intervention may be a novel strategy for improving self-care and early detection of foot abnormalities in this at-risk population using psychological theories to target multiple health behaviors simultaneously. This could be an efficient and cost-effective approach to improve diabetes-related foot health behavior, and other risk factors in patients who are vulnerable to devastating consequences related to amputation.

ID: NCT02356848
Sponsor: VA Office of Research and Development
Location: Manhattan Campus of the VA NY Harbor Healthcare System

Physical Activity Behavior Change for Older Adults After Dysvascular Amputation (PABC)

This pilot study will use mobile-health technology to deliver an intervention designed for lasting physical activity behavior change. The study will assess the feasibility of using the Physical Activity Behavior Change (PABC) intervention for Veterans with lower limb amputation. This intervention will be delivered using wrist-worn wearable activity sensors and a home-based tablet computer to allow real-time physical activity feedback and video interface between the participants and the therapist.

ID: NCT02738086
Sponsor: VA Office of Research and Development
Location: Rocky Mountain Regional VA Medical Center, Aurora, Colorado

ForgIng New Paths to Prevent DIabeTes (FINDIT)

This study will evaluate the effects of screening for type 2 diabetes mellitus (T2DM) and brief counseling about screening test results on weight and key health behaviors among veterans with risk factors for T2DM. Study participants will be randomly assigned to 1 of 2 study groups: (1) Blood Test Group; or (2) Brochure Group. Participants in the Blood Test Group will complete a blood test called hemoglobin A1c (HbA1c) which measures average blood sugar levels. Participants will receive brief counseling about the results from their primary care provider or someone authorized to speak on their behalf. Participants randomly selected for the Brochure Group will review a handout from the VA National Center for Health Promotion and Disease Prevention (NCP) on recommended screening tests and immunizations. All participants will be asked to complete a survey prior to study group assignment, immediately after a Primary Care appointment, 3 months after enrollment, and 12 months after enrollment.

ID: NCT02747108
Sponsor: VA Office of Research and Development
Location: VA Ann Arbor Healthcare System, Michigan

Using Technology to Share Fitness Goals and Results to Improve Diabetes Outcomes

The investigators will recruit DoD beneficiaries, aged 18 years or older and diagnosed with type 2 diabetes. Patients will be randomized into one of two groups. Group 1 will use a fitness tracker but will not be able to see other participants data and group 2 will use a fitness tracker and will be able to see other members daily and weekly results. Outcome measures will be assessed at baseline, 3 months and 6 months to include hemoglobin A1c, weight, body mass index, blood pressure, and number of hours and days fitness tracker is used. The goal is to see if the group randomized into an online community will have improved activity and outcome measurements compared with those who use the pedometer alone.

ID: NCT02761018
Sponsor: Mike O’Callaghan Military Hospital
Location: Mike O’Callaghan Federal Medical Center, Nellis Air Force Base, Nevada

Healthy Living Partnerships to Prevent Diabetes in Veterans Pilot Study (HELP Vets)

Diabetes and obesity are both major public health concerns and the prevalence of diabetes is even higher in the patient population of the VA. This planning project is designed to adapt a successful weight-loss program for delivery through an existing outpatient clinic to reach local veterans at risk for developing diabetes. The information gathered as a part of this project will be used to plan a larger trial designed to improve the health of veterans by offering them a diabetes prevention program through their usual source of healthcare.

ID: NCT02835495
Sponsor: Wake Forest University Health Sciences
Location: Wake Forest School of Medicine

Mindful Stress Reduction in Diabetes Self-Management Education for Veterans (MindSTRIDE)

The purpose of this study is to see if adding Mindfulness training to diabetes education reduces feelings of stress and makes it easier to adhere to healthy behaviors that improve diabetes outcomes (such as hemoglobin A1c).

ID: NCT02928952
Sponsor: VA Office of Research and Development
Location: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, Pennsylvania

Improving Diabetes Care Through Effective Personalized Patient Portal Interactions

Patient-facing eHealth technologies are those that connect patients and the healthcare system, and include online patient portals. Although many organizations are adopting patient portals, there is limited understanding of how the different portal features help improve health outcomes. This study is designed to develop and test an intervention to improve adoption and use of patient portal features for diabetes management.

ID: NCT02953262
Sponsor: VA Office of Research and Development
Locations: Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts; VA Boston Healthcare System Jamaica Plain Campus, Massachusetts.

Home-Based Kidney Care in Native American’s of New Mexico (HBKC)

People reach end stage renal disease (ESRD) due to progressive chronic kidney disease (CKD), which is associated with increased risk for heart disease and death. The burden of chronic kidney disease is increased among minority populations compared to Caucasians. New Mexico American Indians are experiencing an epidemic of chronic kidney disease due primarily to the high rates of obesity and diabetes. The present study entitled Home-Based Kidney Care is designed to delay / reduce rates of ESRD by early interventions in CKD. Investigators propose to assess the safety and efficacy of conducting a full-scale study to determine if home based care delivered
by a collaborative team composed of community health workers, the Albuquerque Area Indian Health Board and University of New Mexico faculty will decrease the risk for the development and the progression of CKD.

ID: NCT03179085
Sponsor: University of New Mexico
Location: University of New Mexico, Albuquerque

INcreasing Veteran EngagemeNT to Prevent Diabetes (INVENT)

This study will evaluate a VA MyHealtheVet Secure Messaging intervention that uses different intervention messaging strategies designed to increase engagement in behaviors to prevent type 2 diabetes (T2DM). After completing a baseline survey, participants will be randomly assigned to receive different novel presentations of information about ways to prevent T2DM through both secure messaging and US mail. The investigators will test the 5 presentations that each: (1) represent an innovative approach from behavioral economics or health psychology with great promise to increase engagement in behaviors to prevent T2DM among patients with prediabetes; and (2) have not been tested in this setting.

ID: NCT03403231
Sponsor: VA Office of Research and Development
Location: VA Ann Arbor Healthcare System, Michigan

Self-efficacy, Beliefs and Adherence—Pilot and Feasibility Trial of a Pharmacist-led Intervention

This study uses an intervention mixed methods design. The overall purpose is to improve medication adherence and assess the clinical impact on diabetes outcomes among patients with uncontrolled diabetes. We will examine if usual care combined with a clinic-based health literacy/psychosocial support intervention improves medication adherence compared to usual care alone. A randomized controlled trial will be conducted at William S. Middleton Memorial Veterans Hospital in Madison, targeting individuals with
uncontrolled diabetes. The patient-centered health literacy intervention will focus on enhancing patients’ self-efficacy and addressing patients’ negative beliefs in medicine and illness.

ID: NCT03406923
Sponsor: University of Wisconsin, Madison
Location: William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin

Practical Telemedicine to Improve Control and Engagement for Veterans With Clinic-Refractory Diabetes Mellitus (PRACTICE-DM)

Diabetes generates significant morbidity, mortality, and costs within the Veterans Health Administration (VHA). Veterans with persistently poor diabetes control despite clinic-based care are among the highest-risk diabetes patients in VHA, and contribute disproportionately to VHA’s massive burden of diabetes complications and costs. VHA critically needs effective, practical management alternatives for veterans whose diabetes does not respond to clinic-based management. The proposed study will address this need by leveraging VHA’s unique Home Telehealth capacity to deliver comprehensive telemedicine-based management for veterans with persistently poor diabetes control despite clinic-based care. Because this intensive intervention is delivered using only existing Home Telehealth workforce, infrastructure, and technical resources—which are ubiquitous at VHA centers nationwide—it could represent an effective, practical approach to improving outcomes in veterans with PPDM, potentially translating to a substantial reduction in VHA’s diabetes burden.

ID: NCT03520413
Sponsor: VA Office of Research and Development
Locations: Durham VA Medical Center, North Carolina; Hunter Holmes McGuire VA Medical Center, Richmond, Virginia

Cooking for Health

Type 2 diabetes is a leading cause of morbidity and mortality among American Indians in the US. Although healthy diet is a key component of diabetes management programs, many American Indians face contextual barriers to adopting a healthy diet including: difficulty budgeting for food on low-incomes, low literacy and numeracy when purchasing food, and limited cooking skills. The proposed project will develop, implement, and evaluate a culturally-targeted healthy foods budgeting, purchasing, and cooking skills intervention aimed at improving the cardio-metabolic health of American Indians with type 2 diabetes who live in rural areas.

ID: NCT03699709
Sponsor: University of Washington
Location: Missouri Breaks Industries Research, Eagle Butte, South Dakota

Providing access to clinical trials for native American, veteran, and active-duty military patients can be a challenge, but a significant number of trials are now recruiting from those populations. Many trials explicitly recruit patients from the US Department of Veterans
Affairs (VA), the military, and Indian Health Service. The VA Office of Research and Development alone sponsors more than 480 research initiatives, and many more are sponsored by Walter Reed National Medical Center and other major defense and VA facilities. The clinical trials listed below are all open as of October 24, 2018; have at least 1 VA, DoD, or IHS location recruiting patients; and are focused on preventing diabetes mellitus or improving patient care. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials. gov.

Diabetes Prevention Program Outcomes Study (DPPOS)

The Diabetes Prevention Program (DPP) was a multicenter trial examining the ability of an intensive lifestyle or metformin to prevent or delay the development of diabetes in a high risk population due to the presence of impaired glucose tolerance (IGT). The DPP has ended early demonstrating that lifestyle reduced diabetes onset by 58% and metformin reduced diabetes onset by 31%.

ID: NCT00038727
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases
Location: George Washington University, Rockville, Maryland

Efforts to Improve Diabetes Control

The primary objectives of this study are: (1) test the longterm effectiveness of a peer mentor model on improving glucose control, blood pressure, LDL levels, diabetes mellitus quality of life, and depression scores in a mixed race population of poorly controlled diabetic veterans; (2) test the effectiveness of using former peer mentees as peer mentors as a means of creating a self-sustaining program; and (3) test the effects of becoming a mentor on those who were originally mentees given a growing literature that being a mentor is good for your health. Secondary objectives include: (1) in those randomized to being a mentee, explore mentor characteristics associated with improved HbA1c.

ID: NCT01651117
Sponsor: VA Office of Research and Development
Location: Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania

A Patient-Centered Strategy for Improving Diabetes Prevention in Urban American Indians

The goal of the proposed research is to identify effective patient-centered strategies to prevent diabetes in high-risk populations in real world settings. The investigators will accomplish this by conducting a randomized controlled trial comparing an enhanced Diabetes Prevention Program addressing psychosocial stressors to a standard version in a high-risk population of urban American Indian
and Alaskan Native peoples within a primary care setting.

ID: NCT02266576
Sponsor: Stanford University
Locations: Timpany Center of San Jose State University, California; Stanford University School of Medicine, California

Physical activity is the cornerstone of good diabetes management, and yet effective physical activity intervention is not available. The investigators developed a lifestyle intervention based on individual’s home activity patterns. The goal of the study is to test the efficacy of this intervention among veterans with diabetes in a randomized-controlled trial. In addition to physical activity, the investigators will also assess if the intervention will improve social participation among veterans.

ID: NCT02268916
Sponsor: VA Office of Research and Development
Location: VA Ann Arbor Healthcare System, Michigan

Caring Others Increasing EngageMent in PACT (CO-IMPACT)

This trial will compare two methods of increasing engagement in care and success in diabetes management, among patients with diabetes with high-risk features, who also have family members involved in their care.

ID: NCT02328326
Sponsor: VA Office of Research and Development
Locations: VA Ann Arbor Healthcare System, Michigan;VA Pittsburgh Healthcare System, Pennsylvania

STEP UP to Avert Amputation in Diabetes (STEP UP)

This study will evaluate a comprehensive tailored behavioral intervention aimed to improve foot self-care and self-monitoring (combined with dermal thermometry) to prevent recurrent ulcers in Veterans at highest risk of amputation. This intervention may be a novel strategy for improving self-care and early detection of foot abnormalities in this at-risk population using psychological theories to target multiple health behaviors simultaneously. This could be an efficient and cost-effective approach to improve diabetes-related foot health behavior, and other risk factors in patients who are vulnerable to devastating consequences related to amputation.

ID: NCT02356848
Sponsor: VA Office of Research and Development
Location: Manhattan Campus of the VA NY Harbor Healthcare System

Physical Activity Behavior Change for Older Adults After Dysvascular Amputation (PABC)

This pilot study will use mobile-health technology to deliver an intervention designed for lasting physical activity behavior change. The study will assess the feasibility of using the Physical Activity Behavior Change (PABC) intervention for Veterans with lower limb amputation. This intervention will be delivered using wrist-worn wearable activity sensors and a home-based tablet computer to allow real-time physical activity feedback and video interface between the participants and the therapist.

ID: NCT02738086
Sponsor: VA Office of Research and Development
Location: Rocky Mountain Regional VA Medical Center, Aurora, Colorado

ForgIng New Paths to Prevent DIabeTes (FINDIT)

This study will evaluate the effects of screening for type 2 diabetes mellitus (T2DM) and brief counseling about screening test results on weight and key health behaviors among veterans with risk factors for T2DM. Study participants will be randomly assigned to 1 of 2 study groups: (1) Blood Test Group; or (2) Brochure Group. Participants in the Blood Test Group will complete a blood test called hemoglobin A1c (HbA1c) which measures average blood sugar levels. Participants will receive brief counseling about the results from their primary care provider or someone authorized to speak on their behalf. Participants randomly selected for the Brochure Group will review a handout from the VA National Center for Health Promotion and Disease Prevention (NCP) on recommended screening tests and immunizations. All participants will be asked to complete a survey prior to study group assignment, immediately after a Primary Care appointment, 3 months after enrollment, and 12 months after enrollment.

ID: NCT02747108
Sponsor: VA Office of Research and Development
Location: VA Ann Arbor Healthcare System, Michigan

Using Technology to Share Fitness Goals and Results to Improve Diabetes Outcomes

The investigators will recruit DoD beneficiaries, aged 18 years or older and diagnosed with type 2 diabetes. Patients will be randomized into one of two groups. Group 1 will use a fitness tracker but will not be able to see other participants data and group 2 will use a fitness tracker and will be able to see other members daily and weekly results. Outcome measures will be assessed at baseline, 3 months and 6 months to include hemoglobin A1c, weight, body mass index, blood pressure, and number of hours and days fitness tracker is used. The goal is to see if the group randomized into an online community will have improved activity and outcome measurements compared with those who use the pedometer alone.

ID: NCT02761018
Sponsor: Mike O’Callaghan Military Hospital
Location: Mike O’Callaghan Federal Medical Center, Nellis Air Force Base, Nevada

Healthy Living Partnerships to Prevent Diabetes in Veterans Pilot Study (HELP Vets)

Diabetes and obesity are both major public health concerns and the prevalence of diabetes is even higher in the patient population of the VA. This planning project is designed to adapt a successful weight-loss program for delivery through an existing outpatient clinic to reach local veterans at risk for developing diabetes. The information gathered as a part of this project will be used to plan a larger trial designed to improve the health of veterans by offering them a diabetes prevention program through their usual source of healthcare.

ID: NCT02835495
Sponsor: Wake Forest University Health Sciences
Location: Wake Forest School of Medicine

Mindful Stress Reduction in Diabetes Self-Management Education for Veterans (MindSTRIDE)

The purpose of this study is to see if adding Mindfulness training to diabetes education reduces feelings of stress and makes it easier to adhere to healthy behaviors that improve diabetes outcomes (such as hemoglobin A1c).

ID: NCT02928952
Sponsor: VA Office of Research and Development
Location: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, Pennsylvania

Improving Diabetes Care Through Effective Personalized Patient Portal Interactions

Patient-facing eHealth technologies are those that connect patients and the healthcare system, and include online patient portals. Although many organizations are adopting patient portals, there is limited understanding of how the different portal features help improve health outcomes. This study is designed to develop and test an intervention to improve adoption and use of patient portal features for diabetes management.

ID: NCT02953262
Sponsor: VA Office of Research and Development
Locations: Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts; VA Boston Healthcare System Jamaica Plain Campus, Massachusetts.

Home-Based Kidney Care in Native American’s of New Mexico (HBKC)

People reach end stage renal disease (ESRD) due to progressive chronic kidney disease (CKD), which is associated with increased risk for heart disease and death. The burden of chronic kidney disease is increased among minority populations compared to Caucasians. New Mexico American Indians are experiencing an epidemic of chronic kidney disease due primarily to the high rates of obesity and diabetes. The present study entitled Home-Based Kidney Care is designed to delay / reduce rates of ESRD by early interventions in CKD. Investigators propose to assess the safety and efficacy of conducting a full-scale study to determine if home based care delivered
by a collaborative team composed of community health workers, the Albuquerque Area Indian Health Board and University of New Mexico faculty will decrease the risk for the development and the progression of CKD.

ID: NCT03179085
Sponsor: University of New Mexico
Location: University of New Mexico, Albuquerque

INcreasing Veteran EngagemeNT to Prevent Diabetes (INVENT)

This study will evaluate a VA MyHealtheVet Secure Messaging intervention that uses different intervention messaging strategies designed to increase engagement in behaviors to prevent type 2 diabetes (T2DM). After completing a baseline survey, participants will be randomly assigned to receive different novel presentations of information about ways to prevent T2DM through both secure messaging and US mail. The investigators will test the 5 presentations that each: (1) represent an innovative approach from behavioral economics or health psychology with great promise to increase engagement in behaviors to prevent T2DM among patients with prediabetes; and (2) have not been tested in this setting.

ID: NCT03403231
Sponsor: VA Office of Research and Development
Location: VA Ann Arbor Healthcare System, Michigan

Self-efficacy, Beliefs and Adherence—Pilot and Feasibility Trial of a Pharmacist-led Intervention

This study uses an intervention mixed methods design. The overall purpose is to improve medication adherence and assess the clinical impact on diabetes outcomes among patients with uncontrolled diabetes. We will examine if usual care combined with a clinic-based health literacy/psychosocial support intervention improves medication adherence compared to usual care alone. A randomized controlled trial will be conducted at William S. Middleton Memorial Veterans Hospital in Madison, targeting individuals with
uncontrolled diabetes. The patient-centered health literacy intervention will focus on enhancing patients’ self-efficacy and addressing patients’ negative beliefs in medicine and illness.

ID: NCT03406923
Sponsor: University of Wisconsin, Madison
Location: William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin

Practical Telemedicine to Improve Control and Engagement for Veterans With Clinic-Refractory Diabetes Mellitus (PRACTICE-DM)

Diabetes generates significant morbidity, mortality, and costs within the Veterans Health Administration (VHA). Veterans with persistently poor diabetes control despite clinic-based care are among the highest-risk diabetes patients in VHA, and contribute disproportionately to VHA’s massive burden of diabetes complications and costs. VHA critically needs effective, practical management alternatives for veterans whose diabetes does not respond to clinic-based management. The proposed study will address this need by leveraging VHA’s unique Home Telehealth capacity to deliver comprehensive telemedicine-based management for veterans with persistently poor diabetes control despite clinic-based care. Because this intensive intervention is delivered using only existing Home Telehealth workforce, infrastructure, and technical resources—which are ubiquitous at VHA centers nationwide—it could represent an effective, practical approach to improving outcomes in veterans with PPDM, potentially translating to a substantial reduction in VHA’s diabetes burden.

ID: NCT03520413
Sponsor: VA Office of Research and Development
Locations: Durham VA Medical Center, North Carolina; Hunter Holmes McGuire VA Medical Center, Richmond, Virginia

Cooking for Health

Type 2 diabetes is a leading cause of morbidity and mortality among American Indians in the US. Although healthy diet is a key component of diabetes management programs, many American Indians face contextual barriers to adopting a healthy diet including: difficulty budgeting for food on low-incomes, low literacy and numeracy when purchasing food, and limited cooking skills. The proposed project will develop, implement, and evaluate a culturally-targeted healthy foods budgeting, purchasing, and cooking skills intervention aimed at improving the cardio-metabolic health of American Indians with type 2 diabetes who live in rural areas.

ID: NCT03699709
Sponsor: University of Washington
Location: Missouri Breaks Industries Research, Eagle Butte, South Dakota

Providing access to clinical trials for native American, veteran, and active-duty military patients can be a challenge, but a significant number of trials are now recruiting from those populations. Many trials explicitly recruit patients from the US Department of Veterans
Affairs (VA), the military, and Indian Health Service. The VA Office of Research and Development alone sponsors more than 480 research initiatives, and many more are sponsored by Walter Reed National Medical Center and other major defense and VA facilities. The clinical trials listed below are all open as of October 24, 2018; have at least 1 VA, DoD, or IHS location recruiting patients; and are focused on preventing diabetes mellitus or improving patient care. For additional information and full inclusion/exclusion criteria, please consult clinicaltrials. gov.

Diabetes Prevention Program Outcomes Study (DPPOS)

The Diabetes Prevention Program (DPP) was a multicenter trial examining the ability of an intensive lifestyle or metformin to prevent or delay the development of diabetes in a high risk population due to the presence of impaired glucose tolerance (IGT). The DPP has ended early demonstrating that lifestyle reduced diabetes onset by 58% and metformin reduced diabetes onset by 31%.

ID: NCT00038727
Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases
Location: George Washington University, Rockville, Maryland

Efforts to Improve Diabetes Control

The primary objectives of this study are: (1) test the longterm effectiveness of a peer mentor model on improving glucose control, blood pressure, LDL levels, diabetes mellitus quality of life, and depression scores in a mixed race population of poorly controlled diabetic veterans; (2) test the effectiveness of using former peer mentees as peer mentors as a means of creating a self-sustaining program; and (3) test the effects of becoming a mentor on those who were originally mentees given a growing literature that being a mentor is good for your health. Secondary objectives include: (1) in those randomized to being a mentee, explore mentor characteristics associated with improved HbA1c.

ID: NCT01651117
Sponsor: VA Office of Research and Development
Location: Corporal Michael J. Crescenz VA Medical Center, Philadelphia, Pennsylvania

A Patient-Centered Strategy for Improving Diabetes Prevention in Urban American Indians

The goal of the proposed research is to identify effective patient-centered strategies to prevent diabetes in high-risk populations in real world settings. The investigators will accomplish this by conducting a randomized controlled trial comparing an enhanced Diabetes Prevention Program addressing psychosocial stressors to a standard version in a high-risk population of urban American Indian
and Alaskan Native peoples within a primary care setting.

ID: NCT02266576
Sponsor: Stanford University
Locations: Timpany Center of San Jose State University, California; Stanford University School of Medicine, California

Physical activity is the cornerstone of good diabetes management, and yet effective physical activity intervention is not available. The investigators developed a lifestyle intervention based on individual’s home activity patterns. The goal of the study is to test the efficacy of this intervention among veterans with diabetes in a randomized-controlled trial. In addition to physical activity, the investigators will also assess if the intervention will improve social participation among veterans.

ID: NCT02268916
Sponsor: VA Office of Research and Development
Location: VA Ann Arbor Healthcare System, Michigan

Caring Others Increasing EngageMent in PACT (CO-IMPACT)

This trial will compare two methods of increasing engagement in care and success in diabetes management, among patients with diabetes with high-risk features, who also have family members involved in their care.

ID: NCT02328326
Sponsor: VA Office of Research and Development
Locations: VA Ann Arbor Healthcare System, Michigan;VA Pittsburgh Healthcare System, Pennsylvania

STEP UP to Avert Amputation in Diabetes (STEP UP)

This study will evaluate a comprehensive tailored behavioral intervention aimed to improve foot self-care and self-monitoring (combined with dermal thermometry) to prevent recurrent ulcers in Veterans at highest risk of amputation. This intervention may be a novel strategy for improving self-care and early detection of foot abnormalities in this at-risk population using psychological theories to target multiple health behaviors simultaneously. This could be an efficient and cost-effective approach to improve diabetes-related foot health behavior, and other risk factors in patients who are vulnerable to devastating consequences related to amputation.

ID: NCT02356848
Sponsor: VA Office of Research and Development
Location: Manhattan Campus of the VA NY Harbor Healthcare System

Physical Activity Behavior Change for Older Adults After Dysvascular Amputation (PABC)

This pilot study will use mobile-health technology to deliver an intervention designed for lasting physical activity behavior change. The study will assess the feasibility of using the Physical Activity Behavior Change (PABC) intervention for Veterans with lower limb amputation. This intervention will be delivered using wrist-worn wearable activity sensors and a home-based tablet computer to allow real-time physical activity feedback and video interface between the participants and the therapist.

ID: NCT02738086
Sponsor: VA Office of Research and Development
Location: Rocky Mountain Regional VA Medical Center, Aurora, Colorado

ForgIng New Paths to Prevent DIabeTes (FINDIT)

This study will evaluate the effects of screening for type 2 diabetes mellitus (T2DM) and brief counseling about screening test results on weight and key health behaviors among veterans with risk factors for T2DM. Study participants will be randomly assigned to 1 of 2 study groups: (1) Blood Test Group; or (2) Brochure Group. Participants in the Blood Test Group will complete a blood test called hemoglobin A1c (HbA1c) which measures average blood sugar levels. Participants will receive brief counseling about the results from their primary care provider or someone authorized to speak on their behalf. Participants randomly selected for the Brochure Group will review a handout from the VA National Center for Health Promotion and Disease Prevention (NCP) on recommended screening tests and immunizations. All participants will be asked to complete a survey prior to study group assignment, immediately after a Primary Care appointment, 3 months after enrollment, and 12 months after enrollment.

ID: NCT02747108
Sponsor: VA Office of Research and Development
Location: VA Ann Arbor Healthcare System, Michigan

Using Technology to Share Fitness Goals and Results to Improve Diabetes Outcomes

The investigators will recruit DoD beneficiaries, aged 18 years or older and diagnosed with type 2 diabetes. Patients will be randomized into one of two groups. Group 1 will use a fitness tracker but will not be able to see other participants data and group 2 will use a fitness tracker and will be able to see other members daily and weekly results. Outcome measures will be assessed at baseline, 3 months and 6 months to include hemoglobin A1c, weight, body mass index, blood pressure, and number of hours and days fitness tracker is used. The goal is to see if the group randomized into an online community will have improved activity and outcome measurements compared with those who use the pedometer alone.

ID: NCT02761018
Sponsor: Mike O’Callaghan Military Hospital
Location: Mike O’Callaghan Federal Medical Center, Nellis Air Force Base, Nevada

Healthy Living Partnerships to Prevent Diabetes in Veterans Pilot Study (HELP Vets)

Diabetes and obesity are both major public health concerns and the prevalence of diabetes is even higher in the patient population of the VA. This planning project is designed to adapt a successful weight-loss program for delivery through an existing outpatient clinic to reach local veterans at risk for developing diabetes. The information gathered as a part of this project will be used to plan a larger trial designed to improve the health of veterans by offering them a diabetes prevention program through their usual source of healthcare.

ID: NCT02835495
Sponsor: Wake Forest University Health Sciences
Location: Wake Forest School of Medicine

Mindful Stress Reduction in Diabetes Self-Management Education for Veterans (MindSTRIDE)

The purpose of this study is to see if adding Mindfulness training to diabetes education reduces feelings of stress and makes it easier to adhere to healthy behaviors that improve diabetes outcomes (such as hemoglobin A1c).

ID: NCT02928952
Sponsor: VA Office of Research and Development
Location: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, Pennsylvania

Improving Diabetes Care Through Effective Personalized Patient Portal Interactions

Patient-facing eHealth technologies are those that connect patients and the healthcare system, and include online patient portals. Although many organizations are adopting patient portals, there is limited understanding of how the different portal features help improve health outcomes. This study is designed to develop and test an intervention to improve adoption and use of patient portal features for diabetes management.

ID: NCT02953262
Sponsor: VA Office of Research and Development
Locations: Edith Nourse Rogers Memorial Veterans Hospital, Bedford, Massachusetts; VA Boston Healthcare System Jamaica Plain Campus, Massachusetts.

Home-Based Kidney Care in Native American’s of New Mexico (HBKC)

People reach end stage renal disease (ESRD) due to progressive chronic kidney disease (CKD), which is associated with increased risk for heart disease and death. The burden of chronic kidney disease is increased among minority populations compared to Caucasians. New Mexico American Indians are experiencing an epidemic of chronic kidney disease due primarily to the high rates of obesity and diabetes. The present study entitled Home-Based Kidney Care is designed to delay / reduce rates of ESRD by early interventions in CKD. Investigators propose to assess the safety and efficacy of conducting a full-scale study to determine if home based care delivered
by a collaborative team composed of community health workers, the Albuquerque Area Indian Health Board and University of New Mexico faculty will decrease the risk for the development and the progression of CKD.

ID: NCT03179085
Sponsor: University of New Mexico
Location: University of New Mexico, Albuquerque

INcreasing Veteran EngagemeNT to Prevent Diabetes (INVENT)

This study will evaluate a VA MyHealtheVet Secure Messaging intervention that uses different intervention messaging strategies designed to increase engagement in behaviors to prevent type 2 diabetes (T2DM). After completing a baseline survey, participants will be randomly assigned to receive different novel presentations of information about ways to prevent T2DM through both secure messaging and US mail. The investigators will test the 5 presentations that each: (1) represent an innovative approach from behavioral economics or health psychology with great promise to increase engagement in behaviors to prevent T2DM among patients with prediabetes; and (2) have not been tested in this setting.

ID: NCT03403231
Sponsor: VA Office of Research and Development
Location: VA Ann Arbor Healthcare System, Michigan

Self-efficacy, Beliefs and Adherence—Pilot and Feasibility Trial of a Pharmacist-led Intervention

This study uses an intervention mixed methods design. The overall purpose is to improve medication adherence and assess the clinical impact on diabetes outcomes among patients with uncontrolled diabetes. We will examine if usual care combined with a clinic-based health literacy/psychosocial support intervention improves medication adherence compared to usual care alone. A randomized controlled trial will be conducted at William S. Middleton Memorial Veterans Hospital in Madison, targeting individuals with
uncontrolled diabetes. The patient-centered health literacy intervention will focus on enhancing patients’ self-efficacy and addressing patients’ negative beliefs in medicine and illness.

ID: NCT03406923
Sponsor: University of Wisconsin, Madison
Location: William S. Middleton Memorial Veterans Hospital, Madison, Wisconsin

Practical Telemedicine to Improve Control and Engagement for Veterans With Clinic-Refractory Diabetes Mellitus (PRACTICE-DM)

Diabetes generates significant morbidity, mortality, and costs within the Veterans Health Administration (VHA). Veterans with persistently poor diabetes control despite clinic-based care are among the highest-risk diabetes patients in VHA, and contribute disproportionately to VHA’s massive burden of diabetes complications and costs. VHA critically needs effective, practical management alternatives for veterans whose diabetes does not respond to clinic-based management. The proposed study will address this need by leveraging VHA’s unique Home Telehealth capacity to deliver comprehensive telemedicine-based management for veterans with persistently poor diabetes control despite clinic-based care. Because this intensive intervention is delivered using only existing Home Telehealth workforce, infrastructure, and technical resources—which are ubiquitous at VHA centers nationwide—it could represent an effective, practical approach to improving outcomes in veterans with PPDM, potentially translating to a substantial reduction in VHA’s diabetes burden.

ID: NCT03520413
Sponsor: VA Office of Research and Development
Locations: Durham VA Medical Center, North Carolina; Hunter Holmes McGuire VA Medical Center, Richmond, Virginia

Cooking for Health

Type 2 diabetes is a leading cause of morbidity and mortality among American Indians in the US. Although healthy diet is a key component of diabetes management programs, many American Indians face contextual barriers to adopting a healthy diet including: difficulty budgeting for food on low-incomes, low literacy and numeracy when purchasing food, and limited cooking skills. The proposed project will develop, implement, and evaluate a culturally-targeted healthy foods budgeting, purchasing, and cooking skills intervention aimed at improving the cardio-metabolic health of American Indians with type 2 diabetes who live in rural areas.

ID: NCT03699709
Sponsor: University of Washington
Location: Missouri Breaks Industries Research, Eagle Butte, South Dakota

Portopulmonary hypertension (POPH) is a form of group 1 pulmonary arterial hypertension. When treating patients with POPH, baseline assessment is necessary so that response to therapy can be measured as the change from baseline. Patients should undergo echocardiography and right heart catheterization, and their exercise capacity and NYHA functional class should be determined. Patients with POPH should be considered for treatment if they are NYHA functional class II or above and/or their mean pulmonary artery pressure (MPAP) is greater than 35 mm Hg in transplant candidates. The goal in the treatment and management of POPH is to improve pulmonary hemodynamics by reducing the obstruction to pulmonary arterial flow and to preserve right ventricular function (Table). This article, the second in a 2-part review of POPH in patients with liver disease, reviews the role of medical therapy and liver transplantation in treatment. Evaluation and diagnosis of POPH are discussed in a separate article.

Medical Therapy

Prostanoids

Although prostacyclin and prostaglandin analogs entered routine clinical practice for POPH in the 1990s, reports of investigational use date back to the 1980s. Prostanoids are potent vasodilators with antiplatelet aggregation and antiproliferative properties. Prostacyclin synthase is reduced in patients with PAH, resulting in decreased concentration of prostacyclin with vasoconstriction and proliferative changes in the pulmonary vasculature.¹

Epoprostenol

Epoprostenol is also known as synthetic prostaglandin I₂ or prostacyclin. It was the first therapy approved for the treatment of PAH in 1995 by the US Food and Drug Administration (FDA) as a continuous intravenous infusion.^2,3 It also inhibits platelet aggregation and may help modulate pulmonary vascular remodeling.^4,5 Epoprostenol is derived from the metabolism of arachidonic acid and is a potent pulmonary and systemic vasodilator. One study reported an immediate 11.8% decrease in MPAP, 24% decrease in pulmonary vascular resistance (PVR) and 28% drop in systemic vascular resistance (SVR) during an epoprostenol infusion.⁶ The authors reported that epoprostenol was a more potent vasodilator than nitric oxide and may have a role in predicting the reversibility of POPH. In a case series of 33 patients with secondary pulmonary hypertension (including 7 patients with POPH) treated with continuous intravenous prostacyclin for approximately 1 year, exercise tolerance, NYHA functional class, and pulmonary hemodynamics improved in each patient compared to baseline.⁷ Krowka et al studied 14 patients with moderate to severe POPH treated with intravenous epoprostenol.⁸ No significant side effects were noted and treatment resulted in significant improvements in PVR, MPAP, and cardiac output. In 2007, Fix et al published a large retrospective cohort of patients with moderate to severe POPH.⁹ Nineteen patients treated with epoprostenol were compared to 17 patients with no treatment. After a median treatment period of 15.4 months, the epoprostenol group showed significant improvement in MPAP, PVR and cardiac output, but survival did not differ between the 2 groups.

Epoprostenol has often been considered a bridge to transplant in patients with POPH. Sussman et al described 8 consecutive patients with POPH who were treated with intravenous epoprostenol (2 to 8 ng/kg/min dose).¹⁰ Liver transplant was considered in 7 of the 8 patients when MPAP decreased to less than 35 mm Hg. Six patients were eventually listed for liver transplant, but 2 died waiting on the list. Long-term outcomes in the group of transplanted recipients were excellent. They remained alive and well at least 9 to 18 months post-transplant, and half did not require long-term vasodilator therapy post-orthotopic liver transplant. Similarly, Ashfaq et al published their data on 16 patients with moderate-to-severe POPH who were treated with vasodilator therapy.¹¹ MPAP decreased to acceptable levels in 75% of the treated patients, and 11 went on to liver transplantation. Rates of 1- and 5-year survival in the transplanted patients were 91% and 67% respectively. None of the patients who failed vasodilator therapy survived.

Epoprostenol has a short half-life (3 to 5 minutes) and requires continuous infusion through central access via an infusion pump. Aseptic technique must be maintained to avoid blood stream infections. Pump failure or loss of vascular access can result in rebound pulmonary vasoconstriction that can be life-threatening and requires immediate attention. Side effects associated with epoprostenol include flushing, headache, nausea/vomiting, bradycardia, chest pain, jaw pain, diarrhea, and musculoskeletal pain.

Patients on epoprostenol should be monitored for prostanoid overdose. In the case of patients with chronic liver disease, epoprostenol increases systemic vasodilation in patients with already low systemic vascular tone. As a result, cardiac output may increase to the point of high cardiac output failure. MPAP will remain elevated secondary to high cardiac output rather than high PVR. In these patients, right heart catheterization will show an elevated MPAP in the setting of normal to low PVR/transpulmonary gradient (TPG) values. Lowering the epoprostenol dose will successfully reduce both cardiac output and MPAP.

Treprostinil

Treprostinil is a prostacyclin analog that is available in intravenous, inhalational, and subcutaneous form, although subcutaneous dosing may be limited by pain. Sakai et al published a small case series of 3 patients with PAH and end-stage liver disease treated with intravenous treprostinil.¹² Pulmonary hemodynamics improved in all patients, and 2 patients went on to an uneventful liver transplantation. More than 10 years later, data were published on 255 patients with PAH on therapy with bosentan or sildenafil randomized to additional inhaled treprostinil.¹³ Treprostinil proved to be safe and well tolerated, with improvement in quality of life measures but no improvement in other secondary endpoints.

Iloprost

Inhaled iloprost is another prostacyclin that has a short therapeutic half-life of 20 to 30 minutes and requires frequent administration (6 to 9 times daily). In study in which patients with severe POPH were treated for up to 3 years with inhaled iloprost,¹⁴ survival rates at 1, 2, and 3 years were 77%, 62%, and 46%, respectively. A second study published in 2010 was designed to assess the acute effects of inhaled iloprost on pulmonary hemodynamics and evaluate the clinical outcome after 12 months of treatment.¹⁵ Iloprost was found to rapidly reduce pulmonary arterial pressure and PVR. In the long-term evaluation, inhaled iloprost increased the 6-minute walk distance (6MWD) and functional class, but no change was noted in the systolic pulmonary artery pressure. The authors concluded that iloprost might provide symptomatic improvement and improvement in exercise capacity.

Selexipag

Selexipag is an oral selective IP prostacyclin receptor agonist that is structurally distinct from other prostacyclins.¹⁶ In a phase 3 randomized double blind clinical trial, PAH patients treated with selexipag had lower composite of death or complication of PAH to the end of the study period.¹⁷ This effect was consistent across all dose ranges, but POPH patients were excluded from this study. Safety and efficacy of selexipag has not been evaluated in POPH patients.

Endothelin Receptor Antagonists

Endothelin receptor antagonists block the production of endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen that may contribute to the development of PAH. Three different receptors have been described: endothelin A, endothelin B, and endothelin B2. Elevated ET-1 levels have been reported in patients with chronic liver disease and may originate from hepatosplanchnic circulation.¹⁸

Bosentan

Bosentan is an oral, nonspecific, ET-1A and ET-1B receptor antagonist. Initial use of bosentan in patients with POPH was limited because of concern for hepatotoxicity. Approximately 10% of patients on bosentan were reported to have mild hepatic side effects in the form of elevated aminotransferases, but severe injury has been reported.¹⁹ One of the first clinical experiences of bosentan in patients with POPH was published in 2005. Hoeper et al followed 11 patients with Child A cirrhosis and severe POPH.²⁰ All patients included were in NYHA functional class III or IV and were treated with bosentan for over 1 year. Exercise capacity and symptoms improved in all treated patients. The medication was tolerated well and there was no evidence of drug-induced liver injury. A single case report showed the effectiveness of bosentan in a 43-year-old man with alcohol-related liver disease (Child-Pugh A) and right ventricular enlargement and dysfunction secondary to POPH.²¹ Pulmonary arterial pressure decreased, exercise capacity increased, and improvement was maintained over 2 years.

In a group of 31 patients with Child A or B cirrhosis and severe POPH, bosentan had significantly better effects than inhaled iloprost on exercise capacity, hemodynamics, and survival.¹⁴ One, 2, and 3-year survival rates in the bosentan group were 94%, 89%, and 89% (compared to 77%, 62%, and 46% in the iloprost group). Both drugs were considered safe with no reported hepatotoxicity. In 2013, Savale et al published data on 34 patients with POPH, Child-Pugh A and/or B who were treated with bosentan for a median of 43 months.²² The authors reported significant improvements in hemodynamics, NYHA functional class, and 6WMD. Event-free survival rates at 1, 2, and 3 years were 82%, 63%, and 47%, respectively.

Ambrisentan

Ambrisentan is a highly selective ET-1A receptor antagonist with once daily dosing and a lower risk of hepatotoxicity compared to bosentan. Fourteen patients with moderate to severe POPH treated with ambrisentan in 4 German hospitals were retrospectively analyzed.²³ Median follow-up was 16 months, and the study demonstrated significant improvement in exercise capacity and clinical symptoms without significant change in liver function tests. Cartin-Ceba et al published their experience of 13 patients with moderate to severe POPH treated with ambrisentan monotherapy.²⁴ Patients were followed for a median of 613 days and on treatment for a median time of 390 days. Significant improvements were shown in pulmonary arterial pressure and PVR without adverse effect on hepatic function. Over 270 patients with PAH (6% with POPH) received ambrisentan from March 2009 through June 2013 at a large United Kingdom portal hypertension referral center.²⁵ Discontinuation due to side effects was higher than previously reported. Discontinuation due to abnormal transaminases was uncommon.

Macitentan

Macitentan is a dual endothelin-receptor antagonist developed by modifying the structure of bosentan to increase efficacy and safety. The SERAPHIN trial compared oral macitentan to placebo in 250 patients with moderate to severe PAH, some of whom were also on a stable dose of oral or inhaled therapy for PAH.²⁶ Over a 2-year period, patients treated with macitentan were less likely to have progression of their disease or die on therapy (38% and 31% versus 46%), regardless of if they were receiving additional oral therapy and more likely to have improvement of their exercise capacity and WHO functional class. Nasopharyngitis and significant anemia were more common in the macitentan group, but there was no difference in the rate of liver function test abnormalities compared to placebo. Trials with macitentan are currently ongoing in patients with POPH.

Phosphodiesterase-5 Inhibitors

Cyclic guanosine monophosphate (cGMP) is the mediator of nitric oxide–induced vasodilation. Phosphodiesterase-5 (PDE-5) inhibitors prolong the vasodilatory effects of cyclic guanosine monophosphate by preventing its hydrolysis, thereby reducing the pulmonary arterial pressure.

Sildenafil

Sildenafil is the most widely accepted PDE-5 inhibitor for POPH. Fourteen patients with moderate to severe POPH were treated with sildenafil (50 mg 3 times per day) in an observational study published by Reichenberger et al in 2006.²⁷ Eight patients were newly started on sildenafil, whereas sildenafil was added to inhaled prostanoids in the remaining 6x patients. Sildenafil significantly decreased 66MWD, MPAP, PVR, and cardiac index alone or in combination with inhaled prostanoids.

Sildenafil has also been used as a bridge to transplant in liver transplant candidates with POPH. Ten patients with POPH treated with sildenafil monotherapy were followed for a 21±16 months.²⁸ Patients improved symptomatically and increased their 6MWD at 1 year by 30 meters or more. Three patients became transplant eligible and another 3 patients were stable, without progression of their liver disease or POPH. Four patients were not considered transplant candidates, 2 because of refractory POPH and 2 for other comorbidities. The authors concluded that sildenafil monotherapy could stabilize or improve pulmonary hemodynamics in patients with POPH and eventually lead to liver transplantation. Gough et al took a similar look at 9 patients with POPH treated with sildenafil.²⁹ All patients had initial and follow-up right heart catheterizations within a period of 3 years. Mean PVR improved in all patients, decreasing from 575 to 375 dynes/s/cm^–5. MPAP decreased to ≤ 35 mmHg in 4 patients, 1 of whom went on to receive a liver transplant. Overall sildenafil improved pulmonary hemodynamics in this small cohort of POPH patients.

Tadalafil

Tadalafil is another oral PDE-5 inhibitor but with a longer half-life than sildenafil. Unlike sildenafil, which requires 3 times daily dosing, tadalafil requires once daily administration. A few case reports have demonstrated tadalafil’s effectiveness for POPH in combination with other medical therapy (eg, sildenafil, ambrisentan).^30,31

Guanylate Cyclase Stimulator

Riociguat

Riociguat is a first-in-class activator of soluble form of guanylate cyclase that increases levels of cyclic GMP. Two randomized clinical trials, PATENT, a study in PAH patients, and CHEST, a study in patients with chronic thromboembolic pulmonary hypertension showed improvement in 6MWD at 12 weeks (PATENT) or 16 weeks (CHEST), with improvement in secondary endpoints such as PVR, N-terminal pro b-type natriuretic peptide and WHO functional class.^32,33 Riociguat may have potential advantages in patients with POPH given that it has a favorable liver safety profile. A subgroup analysis of patients enrolled in the PATENT study showed that 13 had POPH and 11 were randomized to receive riociguat 2.5 mg 3 times daily dose and 2 received placebo.³⁴ Riociguat was well tolerated and improved 6MWD that was maintained over 2 years in the open label extension.

Medications to Avoid

Nonselective beta-blockers are commonly recommended in patients with portal hypertension to help prevent variceal hemorrhage. However, in patients with POPH, beta-blockers have been shown to decrease exercise capacity and worsen pulmonary hemodynamics. A study of 10 patients with moderate to severe POPH who were receiving beta-blockers for variceal bleeding prophylaxis showed that 6MWD improved in almost all of the patients, cardiac output increased by 28%, and PVR decreased by 19% when beta-blockers were discontinued.³⁵ The authors concluded that the use of beta-blockers should be avoided in this patient population.

Calcium channel blockers should not be used in patients with POPH because they can cause significant hypotension due to systemic vasodilatation and decreased right ventricular filling. Patients with portal hypertension and chronic liver disease commonly have low systemic vascular resistance and are particularly susceptible to the deleterious effects of calcium channel blockers.

Transplantation

Liver transplantation is a potential cure for POPH and its role in POPH has evolved over the past 2 decades. In 1997, Ramsay et al published their review of 1205 consecutive liver transplants at Baylor University Medical Center (BUMC) in Texas.³⁶ The incidence of POPH in this group was 8.5%, with the majority of patients having mild POPH. Liver transplant outcomes were not affected by mild and moderate pulmonary hypertension. However, patients with severe POPH (n = 7, systolic pulmonary artery pressure > 60 mm Hg) had a mortality rate of 42% at 9 months post-transplantation and 71% at 36 months post-transplant. The surviving patients continued to deteriorate with progressive right heart failure and no improvement in POPH.

To understand the effect of liver transplantation on POPH, one must understand the hemodynamic changes that occur with POPH and during liver transplant. The right ventricle is able to manage the same volume as the left ventricle under normal circumstances, but is unable to pump against a significant pressure gradient.³⁷ In the setting of POPH, right ventricular hypertrophy occurs and RV output remains stable for some time. With time, pulmonary artery pressure increases secondary to pulmonary arteriolar vasoconstriction, intimal thickening, and progressive occlusion of the pulmonary vascular bed. Right ventricular failure may occur as a result. Cardiac output increases significantly at the time of reperfusion during liver transplant (up to 3-fold in 15 minutes),³⁸ and in the setting of a noncompliant vascular bed, the patient is at risk for right heart failure. This is the likely explanation to such high perioperative mortality rates in patients with uncontrolled POPH. Failure to decrease MPAP to less than 50 mm Hg is considered a complete contraindication to liver transplant at most institutions. Many transplant centers will list patients for liver transplant if MPAP can be decreased to less than 35 mm Hg and PVR < 400 dynes/s/cm^–5. These parameters are thought to represent an adequate right ventricular reserve and a compliant pulmonary vascular bed.³⁷ However, even with good pressure control, the anesthesiology and critical care teams must be prepared to deal with acute right heart failure peri-operatively. Intraoperative transesophageal echocardiography has been recommended to closely follow right ventricular function.³⁸ Inhaled or intravenous dilators are the most effective agents in the event of a pulmonary hypertensive crisis.

Review of Outcomes

A retrospective review evaluated 43 patients with untreated POPH who underwent attempted liver transplantation.³⁹ Data were collected from 18 peer-reviewed studies and 7 patients at the authors’ institution. Overall mortality was 35% (15 patients), with almost all of the deaths secondary to cardiac dysfunction. Two deaths occurred intraoperatively and 8 deaths occurred during the transplant hospitalization. The transplant could not be successfully completed in 4 of the patients. MPAP > 50 mm Hg was associated with 100% mortality, whereas patients with MPAP between 35 mm Hg and 50 mm Hg had a 50% mortality. No mortality was noted in patients with MPAP < 35 mm Hg.

Liver transplantation has been shown to be successful in patients with controlled POPH. Sussman et al published their data on 8 patients with severe POPH in 2006. In this prospective study, all patients were treated with sequential epoprostenol infusions and 7 of the 8 patients experienced a significant reduction in MPAP and PVR. Six patients were listed for liver transplant, 4 of who were transplanted successfully and alive up to 5 years later.

The Baylor University Medical Center published their data on POPH patients who received liver transplants in 2007.¹¹ POPH was confirmed by right heart catheterization in 30 patients evaluated for liver transplant. Sixteen patients were considered to be suitable candidates for transplant and MPAP was decreased to less than 35 mmHg in 12 patients with vasodilator therapy. Eleven patients eventually underwent liver transplant and 1- and 5-year survival rates were 91% and 67%.

Compared to medical therapy or liver transplant alone, patients who receive medical therapy followed by liver transplantation have the best survival. The Mayo Clinic retrospectively reviewed 74 POPH patients identified between 1994 and 2007.⁴⁰ Patients were categorized in 1 of 3 categories: no medical therapy, medical therapy alone for POPH, or medical therapy for POPH followed by liver transplantation. Patients who received no medical therapy for POPH and no liver transplant had the worst outcomes, with a dismal 5-year survival of only 14% with over 50% deceased at 1 year of diagnosis. Five-year survival was 45% in patients who received medical therapy only. Patients who received medical therapy with prostacyclin followed by liver transplantation had the best outcomes, with a 5-year survival of 67% versus 25% in those who were transplanted without prior prostacyclin therapy.

We reported the longest follow-up study for patients undergoing liver transplantation with POPH in 2014.⁴¹ Seven patients with moderate to severe POPH received a liver transplant at our institution between June 2004 and January 2011. Mean pulmonary artery pressure was reduced to < 35 mm Hg, with appropriate POPH therapy in all of the patients. Both the graft and patient survival rates were 85.7% after a median follow-up of 7.8 years. The 1 patient who did not survive died from complications related to recurrent hepatitis C and cirrhosis, not from POPH-related issues. Four of the remaining 6 patients continue to require oral vasodilator therapy post-transplant, suggesting irreversible remodeling of the pulmonary vasculature. Two patients (4.4 and 8.5 years post-transplant) have no evidence of pulmonary hypertension post-transplant and therefore do not require medical treatment for pulmonary hypertension. We concluded that POPH responsive to vasodilator therapy is an appropriate indication for liver transplant, with excellent long-term survival.

Hollatz et al published their data on 11 patients with moderate to severe POPH who were successfully treated (mostly with oral sildenafil and subcutaneous treprostinil) as a bridge to liver transplant.⁴² The mortality rate was 0, with a follow-up duration of 7 to 60 months. Interestingly, 7 of the 11 patients (64%) were off all pulmonary vasodilators post-transplant. Ashfaq et al reported similar results.¹¹ Nine of 11 patients with treated moderate to severe POPH who received liver transplants stopped vasodilator therapy at a median period of 9.2 months post-transplant. Raevens et al described a group of 3 patients with POPH who went on to liver transplant after their pulmonary pressures were decreased with combined oral vasodilator therapy: 1 required continued long-term vasodilator therapy, another was weaned off medications after transplant, and the third patient died during the liver transplant from perioperative complications that induced uncontrolled pulmonary hypertension.⁴³

Patient Selection

In 2006, the United Network for Organ Sharing (UNOS) initiated a policy whereby a higher priority for liver transplantation was granted for highly selected patients in the United States.⁴⁴ UNOS policy 3.6.4.5.6 upgraded POPH patients to a MELD score of 22, with an increase in MELD every 3 months as long as MPAP remained < 35 mm Hg and PVR remained < 400 dynes/s/cm^–5. One hundred fifty-five patients were granted MELD exception points for POPH between 2002 and 2010 and went on to receive liver transplants.⁴⁵ Goldberg et al collected data from the Organ Procurement and Transplantation Network (OPTN) and compared outcomes of patients with approved POPH MELD exception points versus waitlist candidates with no exception points.⁴⁶ One hundred fifty-five waitlisted patients received POPH MELD exception points, with only 43.1% meeting OPTN exception requirements. One-third did not fulfill hemodynamic criteria consistent with POPH or had missing data, and 80% went on to receive a liver transplant. Waitlist candidates receiving POPH MELD exception points also had increased waitlist mortality and several early post-transplant deaths. The authors felt these data highlighted the need for OPTN/UNOS to revise their policy for POPH MELD exceptions points, revise how points are rewarded, and continue research to help risk stratify these patients to minimize perioperative complications.

Conclusion

Several effective medical treatment regimens are available, including prostanoids, endothelin receptor antagonists, and PDE-5 inhibitors. Liver transplantation is a potential cure but is only recommended if MPAP can be decreased to ≤ 35 mmHg. Long-term follow-up studies have shown these patients do well several years post-transplant but may continue to require oral therapy for their POPH.

Portopulmonary hypertension (POPH) is a form of group 1 pulmonary arterial hypertension. When treating patients with POPH, baseline assessment is necessary so that response to therapy can be measured as the change from baseline. Patients should undergo echocardiography and right heart catheterization, and their exercise capacity and NYHA functional class should be determined. Patients with POPH should be considered for treatment if they are NYHA functional class II or above and/or their mean pulmonary artery pressure (MPAP) is greater than 35 mm Hg in transplant candidates. The goal in the treatment and management of POPH is to improve pulmonary hemodynamics by reducing the obstruction to pulmonary arterial flow and to preserve right ventricular function (Table). This article, the second in a 2-part review of POPH in patients with liver disease, reviews the role of medical therapy and liver transplantation in treatment. Evaluation and diagnosis of POPH are discussed in a separate article.

Medical Therapy

Prostanoids

Although prostacyclin and prostaglandin analogs entered routine clinical practice for POPH in the 1990s, reports of investigational use date back to the 1980s. Prostanoids are potent vasodilators with antiplatelet aggregation and antiproliferative properties. Prostacyclin synthase is reduced in patients with PAH, resulting in decreased concentration of prostacyclin with vasoconstriction and proliferative changes in the pulmonary vasculature.¹

Epoprostenol

Epoprostenol is also known as synthetic prostaglandin I₂ or prostacyclin. It was the first therapy approved for the treatment of PAH in 1995 by the US Food and Drug Administration (FDA) as a continuous intravenous infusion.^2,3 It also inhibits platelet aggregation and may help modulate pulmonary vascular remodeling.^4,5 Epoprostenol is derived from the metabolism of arachidonic acid and is a potent pulmonary and systemic vasodilator. One study reported an immediate 11.8% decrease in MPAP, 24% decrease in pulmonary vascular resistance (PVR) and 28% drop in systemic vascular resistance (SVR) during an epoprostenol infusion.⁶ The authors reported that epoprostenol was a more potent vasodilator than nitric oxide and may have a role in predicting the reversibility of POPH. In a case series of 33 patients with secondary pulmonary hypertension (including 7 patients with POPH) treated with continuous intravenous prostacyclin for approximately 1 year, exercise tolerance, NYHA functional class, and pulmonary hemodynamics improved in each patient compared to baseline.⁷ Krowka et al studied 14 patients with moderate to severe POPH treated with intravenous epoprostenol.⁸ No significant side effects were noted and treatment resulted in significant improvements in PVR, MPAP, and cardiac output. In 2007, Fix et al published a large retrospective cohort of patients with moderate to severe POPH.⁹ Nineteen patients treated with epoprostenol were compared to 17 patients with no treatment. After a median treatment period of 15.4 months, the epoprostenol group showed significant improvement in MPAP, PVR and cardiac output, but survival did not differ between the 2 groups.

Epoprostenol has often been considered a bridge to transplant in patients with POPH. Sussman et al described 8 consecutive patients with POPH who were treated with intravenous epoprostenol (2 to 8 ng/kg/min dose).¹⁰ Liver transplant was considered in 7 of the 8 patients when MPAP decreased to less than 35 mm Hg. Six patients were eventually listed for liver transplant, but 2 died waiting on the list. Long-term outcomes in the group of transplanted recipients were excellent. They remained alive and well at least 9 to 18 months post-transplant, and half did not require long-term vasodilator therapy post-orthotopic liver transplant. Similarly, Ashfaq et al published their data on 16 patients with moderate-to-severe POPH who were treated with vasodilator therapy.¹¹ MPAP decreased to acceptable levels in 75% of the treated patients, and 11 went on to liver transplantation. Rates of 1- and 5-year survival in the transplanted patients were 91% and 67% respectively. None of the patients who failed vasodilator therapy survived.

Epoprostenol has a short half-life (3 to 5 minutes) and requires continuous infusion through central access via an infusion pump. Aseptic technique must be maintained to avoid blood stream infections. Pump failure or loss of vascular access can result in rebound pulmonary vasoconstriction that can be life-threatening and requires immediate attention. Side effects associated with epoprostenol include flushing, headache, nausea/vomiting, bradycardia, chest pain, jaw pain, diarrhea, and musculoskeletal pain.

Patients on epoprostenol should be monitored for prostanoid overdose. In the case of patients with chronic liver disease, epoprostenol increases systemic vasodilation in patients with already low systemic vascular tone. As a result, cardiac output may increase to the point of high cardiac output failure. MPAP will remain elevated secondary to high cardiac output rather than high PVR. In these patients, right heart catheterization will show an elevated MPAP in the setting of normal to low PVR/transpulmonary gradient (TPG) values. Lowering the epoprostenol dose will successfully reduce both cardiac output and MPAP.

Treprostinil

Treprostinil is a prostacyclin analog that is available in intravenous, inhalational, and subcutaneous form, although subcutaneous dosing may be limited by pain. Sakai et al published a small case series of 3 patients with PAH and end-stage liver disease treated with intravenous treprostinil.¹² Pulmonary hemodynamics improved in all patients, and 2 patients went on to an uneventful liver transplantation. More than 10 years later, data were published on 255 patients with PAH on therapy with bosentan or sildenafil randomized to additional inhaled treprostinil.¹³ Treprostinil proved to be safe and well tolerated, with improvement in quality of life measures but no improvement in other secondary endpoints.

Iloprost

Inhaled iloprost is another prostacyclin that has a short therapeutic half-life of 20 to 30 minutes and requires frequent administration (6 to 9 times daily). In study in which patients with severe POPH were treated for up to 3 years with inhaled iloprost,¹⁴ survival rates at 1, 2, and 3 years were 77%, 62%, and 46%, respectively. A second study published in 2010 was designed to assess the acute effects of inhaled iloprost on pulmonary hemodynamics and evaluate the clinical outcome after 12 months of treatment.¹⁵ Iloprost was found to rapidly reduce pulmonary arterial pressure and PVR. In the long-term evaluation, inhaled iloprost increased the 6-minute walk distance (6MWD) and functional class, but no change was noted in the systolic pulmonary artery pressure. The authors concluded that iloprost might provide symptomatic improvement and improvement in exercise capacity.

Selexipag

Selexipag is an oral selective IP prostacyclin receptor agonist that is structurally distinct from other prostacyclins.¹⁶ In a phase 3 randomized double blind clinical trial, PAH patients treated with selexipag had lower composite of death or complication of PAH to the end of the study period.¹⁷ This effect was consistent across all dose ranges, but POPH patients were excluded from this study. Safety and efficacy of selexipag has not been evaluated in POPH patients.

Endothelin Receptor Antagonists

Endothelin receptor antagonists block the production of endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen that may contribute to the development of PAH. Three different receptors have been described: endothelin A, endothelin B, and endothelin B2. Elevated ET-1 levels have been reported in patients with chronic liver disease and may originate from hepatosplanchnic circulation.¹⁸

Bosentan

Bosentan is an oral, nonspecific, ET-1A and ET-1B receptor antagonist. Initial use of bosentan in patients with POPH was limited because of concern for hepatotoxicity. Approximately 10% of patients on bosentan were reported to have mild hepatic side effects in the form of elevated aminotransferases, but severe injury has been reported.¹⁹ One of the first clinical experiences of bosentan in patients with POPH was published in 2005. Hoeper et al followed 11 patients with Child A cirrhosis and severe POPH.²⁰ All patients included were in NYHA functional class III or IV and were treated with bosentan for over 1 year. Exercise capacity and symptoms improved in all treated patients. The medication was tolerated well and there was no evidence of drug-induced liver injury. A single case report showed the effectiveness of bosentan in a 43-year-old man with alcohol-related liver disease (Child-Pugh A) and right ventricular enlargement and dysfunction secondary to POPH.²¹ Pulmonary arterial pressure decreased, exercise capacity increased, and improvement was maintained over 2 years.

In a group of 31 patients with Child A or B cirrhosis and severe POPH, bosentan had significantly better effects than inhaled iloprost on exercise capacity, hemodynamics, and survival.¹⁴ One, 2, and 3-year survival rates in the bosentan group were 94%, 89%, and 89% (compared to 77%, 62%, and 46% in the iloprost group). Both drugs were considered safe with no reported hepatotoxicity. In 2013, Savale et al published data on 34 patients with POPH, Child-Pugh A and/or B who were treated with bosentan for a median of 43 months.²² The authors reported significant improvements in hemodynamics, NYHA functional class, and 6WMD. Event-free survival rates at 1, 2, and 3 years were 82%, 63%, and 47%, respectively.

Ambrisentan

Ambrisentan is a highly selective ET-1A receptor antagonist with once daily dosing and a lower risk of hepatotoxicity compared to bosentan. Fourteen patients with moderate to severe POPH treated with ambrisentan in 4 German hospitals were retrospectively analyzed.²³ Median follow-up was 16 months, and the study demonstrated significant improvement in exercise capacity and clinical symptoms without significant change in liver function tests. Cartin-Ceba et al published their experience of 13 patients with moderate to severe POPH treated with ambrisentan monotherapy.²⁴ Patients were followed for a median of 613 days and on treatment for a median time of 390 days. Significant improvements were shown in pulmonary arterial pressure and PVR without adverse effect on hepatic function. Over 270 patients with PAH (6% with POPH) received ambrisentan from March 2009 through June 2013 at a large United Kingdom portal hypertension referral center.²⁵ Discontinuation due to side effects was higher than previously reported. Discontinuation due to abnormal transaminases was uncommon.

Macitentan

Macitentan is a dual endothelin-receptor antagonist developed by modifying the structure of bosentan to increase efficacy and safety. The SERAPHIN trial compared oral macitentan to placebo in 250 patients with moderate to severe PAH, some of whom were also on a stable dose of oral or inhaled therapy for PAH.²⁶ Over a 2-year period, patients treated with macitentan were less likely to have progression of their disease or die on therapy (38% and 31% versus 46%), regardless of if they were receiving additional oral therapy and more likely to have improvement of their exercise capacity and WHO functional class. Nasopharyngitis and significant anemia were more common in the macitentan group, but there was no difference in the rate of liver function test abnormalities compared to placebo. Trials with macitentan are currently ongoing in patients with POPH.

Phosphodiesterase-5 Inhibitors

Cyclic guanosine monophosphate (cGMP) is the mediator of nitric oxide–induced vasodilation. Phosphodiesterase-5 (PDE-5) inhibitors prolong the vasodilatory effects of cyclic guanosine monophosphate by preventing its hydrolysis, thereby reducing the pulmonary arterial pressure.

Sildenafil

Sildenafil is the most widely accepted PDE-5 inhibitor for POPH. Fourteen patients with moderate to severe POPH were treated with sildenafil (50 mg 3 times per day) in an observational study published by Reichenberger et al in 2006.²⁷ Eight patients were newly started on sildenafil, whereas sildenafil was added to inhaled prostanoids in the remaining 6x patients. Sildenafil significantly decreased 66MWD, MPAP, PVR, and cardiac index alone or in combination with inhaled prostanoids.

Sildenafil has also been used as a bridge to transplant in liver transplant candidates with POPH. Ten patients with POPH treated with sildenafil monotherapy were followed for a 21±16 months.²⁸ Patients improved symptomatically and increased their 6MWD at 1 year by 30 meters or more. Three patients became transplant eligible and another 3 patients were stable, without progression of their liver disease or POPH. Four patients were not considered transplant candidates, 2 because of refractory POPH and 2 for other comorbidities. The authors concluded that sildenafil monotherapy could stabilize or improve pulmonary hemodynamics in patients with POPH and eventually lead to liver transplantation. Gough et al took a similar look at 9 patients with POPH treated with sildenafil.²⁹ All patients had initial and follow-up right heart catheterizations within a period of 3 years. Mean PVR improved in all patients, decreasing from 575 to 375 dynes/s/cm^–5. MPAP decreased to ≤ 35 mmHg in 4 patients, 1 of whom went on to receive a liver transplant. Overall sildenafil improved pulmonary hemodynamics in this small cohort of POPH patients.

Tadalafil

Tadalafil is another oral PDE-5 inhibitor but with a longer half-life than sildenafil. Unlike sildenafil, which requires 3 times daily dosing, tadalafil requires once daily administration. A few case reports have demonstrated tadalafil’s effectiveness for POPH in combination with other medical therapy (eg, sildenafil, ambrisentan).^30,31

Guanylate Cyclase Stimulator

Riociguat

Riociguat is a first-in-class activator of soluble form of guanylate cyclase that increases levels of cyclic GMP. Two randomized clinical trials, PATENT, a study in PAH patients, and CHEST, a study in patients with chronic thromboembolic pulmonary hypertension showed improvement in 6MWD at 12 weeks (PATENT) or 16 weeks (CHEST), with improvement in secondary endpoints such as PVR, N-terminal pro b-type natriuretic peptide and WHO functional class.^32,33 Riociguat may have potential advantages in patients with POPH given that it has a favorable liver safety profile. A subgroup analysis of patients enrolled in the PATENT study showed that 13 had POPH and 11 were randomized to receive riociguat 2.5 mg 3 times daily dose and 2 received placebo.³⁴ Riociguat was well tolerated and improved 6MWD that was maintained over 2 years in the open label extension.

Medications to Avoid

Nonselective beta-blockers are commonly recommended in patients with portal hypertension to help prevent variceal hemorrhage. However, in patients with POPH, beta-blockers have been shown to decrease exercise capacity and worsen pulmonary hemodynamics. A study of 10 patients with moderate to severe POPH who were receiving beta-blockers for variceal bleeding prophylaxis showed that 6MWD improved in almost all of the patients, cardiac output increased by 28%, and PVR decreased by 19% when beta-blockers were discontinued.³⁵ The authors concluded that the use of beta-blockers should be avoided in this patient population.

Calcium channel blockers should not be used in patients with POPH because they can cause significant hypotension due to systemic vasodilatation and decreased right ventricular filling. Patients with portal hypertension and chronic liver disease commonly have low systemic vascular resistance and are particularly susceptible to the deleterious effects of calcium channel blockers.

Transplantation

Liver transplantation is a potential cure for POPH and its role in POPH has evolved over the past 2 decades. In 1997, Ramsay et al published their review of 1205 consecutive liver transplants at Baylor University Medical Center (BUMC) in Texas.³⁶ The incidence of POPH in this group was 8.5%, with the majority of patients having mild POPH. Liver transplant outcomes were not affected by mild and moderate pulmonary hypertension. However, patients with severe POPH (n = 7, systolic pulmonary artery pressure > 60 mm Hg) had a mortality rate of 42% at 9 months post-transplantation and 71% at 36 months post-transplant. The surviving patients continued to deteriorate with progressive right heart failure and no improvement in POPH.

To understand the effect of liver transplantation on POPH, one must understand the hemodynamic changes that occur with POPH and during liver transplant. The right ventricle is able to manage the same volume as the left ventricle under normal circumstances, but is unable to pump against a significant pressure gradient.³⁷ In the setting of POPH, right ventricular hypertrophy occurs and RV output remains stable for some time. With time, pulmonary artery pressure increases secondary to pulmonary arteriolar vasoconstriction, intimal thickening, and progressive occlusion of the pulmonary vascular bed. Right ventricular failure may occur as a result. Cardiac output increases significantly at the time of reperfusion during liver transplant (up to 3-fold in 15 minutes),³⁸ and in the setting of a noncompliant vascular bed, the patient is at risk for right heart failure. This is the likely explanation to such high perioperative mortality rates in patients with uncontrolled POPH. Failure to decrease MPAP to less than 50 mm Hg is considered a complete contraindication to liver transplant at most institutions. Many transplant centers will list patients for liver transplant if MPAP can be decreased to less than 35 mm Hg and PVR < 400 dynes/s/cm^–5. These parameters are thought to represent an adequate right ventricular reserve and a compliant pulmonary vascular bed.³⁷ However, even with good pressure control, the anesthesiology and critical care teams must be prepared to deal with acute right heart failure peri-operatively. Intraoperative transesophageal echocardiography has been recommended to closely follow right ventricular function.³⁸ Inhaled or intravenous dilators are the most effective agents in the event of a pulmonary hypertensive crisis.

Review of Outcomes

A retrospective review evaluated 43 patients with untreated POPH who underwent attempted liver transplantation.³⁹ Data were collected from 18 peer-reviewed studies and 7 patients at the authors’ institution. Overall mortality was 35% (15 patients), with almost all of the deaths secondary to cardiac dysfunction. Two deaths occurred intraoperatively and 8 deaths occurred during the transplant hospitalization. The transplant could not be successfully completed in 4 of the patients. MPAP > 50 mm Hg was associated with 100% mortality, whereas patients with MPAP between 35 mm Hg and 50 mm Hg had a 50% mortality. No mortality was noted in patients with MPAP < 35 mm Hg.

Liver transplantation has been shown to be successful in patients with controlled POPH. Sussman et al published their data on 8 patients with severe POPH in 2006. In this prospective study, all patients were treated with sequential epoprostenol infusions and 7 of the 8 patients experienced a significant reduction in MPAP and PVR. Six patients were listed for liver transplant, 4 of who were transplanted successfully and alive up to 5 years later.

The Baylor University Medical Center published their data on POPH patients who received liver transplants in 2007.¹¹ POPH was confirmed by right heart catheterization in 30 patients evaluated for liver transplant. Sixteen patients were considered to be suitable candidates for transplant and MPAP was decreased to less than 35 mmHg in 12 patients with vasodilator therapy. Eleven patients eventually underwent liver transplant and 1- and 5-year survival rates were 91% and 67%.

Compared to medical therapy or liver transplant alone, patients who receive medical therapy followed by liver transplantation have the best survival. The Mayo Clinic retrospectively reviewed 74 POPH patients identified between 1994 and 2007.⁴⁰ Patients were categorized in 1 of 3 categories: no medical therapy, medical therapy alone for POPH, or medical therapy for POPH followed by liver transplantation. Patients who received no medical therapy for POPH and no liver transplant had the worst outcomes, with a dismal 5-year survival of only 14% with over 50% deceased at 1 year of diagnosis. Five-year survival was 45% in patients who received medical therapy only. Patients who received medical therapy with prostacyclin followed by liver transplantation had the best outcomes, with a 5-year survival of 67% versus 25% in those who were transplanted without prior prostacyclin therapy.

We reported the longest follow-up study for patients undergoing liver transplantation with POPH in 2014.⁴¹ Seven patients with moderate to severe POPH received a liver transplant at our institution between June 2004 and January 2011. Mean pulmonary artery pressure was reduced to < 35 mm Hg, with appropriate POPH therapy in all of the patients. Both the graft and patient survival rates were 85.7% after a median follow-up of 7.8 years. The 1 patient who did not survive died from complications related to recurrent hepatitis C and cirrhosis, not from POPH-related issues. Four of the remaining 6 patients continue to require oral vasodilator therapy post-transplant, suggesting irreversible remodeling of the pulmonary vasculature. Two patients (4.4 and 8.5 years post-transplant) have no evidence of pulmonary hypertension post-transplant and therefore do not require medical treatment for pulmonary hypertension. We concluded that POPH responsive to vasodilator therapy is an appropriate indication for liver transplant, with excellent long-term survival.

Hollatz et al published their data on 11 patients with moderate to severe POPH who were successfully treated (mostly with oral sildenafil and subcutaneous treprostinil) as a bridge to liver transplant.⁴² The mortality rate was 0, with a follow-up duration of 7 to 60 months. Interestingly, 7 of the 11 patients (64%) were off all pulmonary vasodilators post-transplant. Ashfaq et al reported similar results.¹¹ Nine of 11 patients with treated moderate to severe POPH who received liver transplants stopped vasodilator therapy at a median period of 9.2 months post-transplant. Raevens et al described a group of 3 patients with POPH who went on to liver transplant after their pulmonary pressures were decreased with combined oral vasodilator therapy: 1 required continued long-term vasodilator therapy, another was weaned off medications after transplant, and the third patient died during the liver transplant from perioperative complications that induced uncontrolled pulmonary hypertension.⁴³

Patient Selection

In 2006, the United Network for Organ Sharing (UNOS) initiated a policy whereby a higher priority for liver transplantation was granted for highly selected patients in the United States.⁴⁴ UNOS policy 3.6.4.5.6 upgraded POPH patients to a MELD score of 22, with an increase in MELD every 3 months as long as MPAP remained < 35 mm Hg and PVR remained < 400 dynes/s/cm^–5. One hundred fifty-five patients were granted MELD exception points for POPH between 2002 and 2010 and went on to receive liver transplants.⁴⁵ Goldberg et al collected data from the Organ Procurement and Transplantation Network (OPTN) and compared outcomes of patients with approved POPH MELD exception points versus waitlist candidates with no exception points.⁴⁶ One hundred fifty-five waitlisted patients received POPH MELD exception points, with only 43.1% meeting OPTN exception requirements. One-third did not fulfill hemodynamic criteria consistent with POPH or had missing data, and 80% went on to receive a liver transplant. Waitlist candidates receiving POPH MELD exception points also had increased waitlist mortality and several early post-transplant deaths. The authors felt these data highlighted the need for OPTN/UNOS to revise their policy for POPH MELD exceptions points, revise how points are rewarded, and continue research to help risk stratify these patients to minimize perioperative complications.

Conclusion

Several effective medical treatment regimens are available, including prostanoids, endothelin receptor antagonists, and PDE-5 inhibitors. Liver transplantation is a potential cure but is only recommended if MPAP can be decreased to ≤ 35 mmHg. Long-term follow-up studies have shown these patients do well several years post-transplant but may continue to require oral therapy for their POPH.

Portopulmonary hypertension (POPH) is a form of group 1 pulmonary arterial hypertension. When treating patients with POPH, baseline assessment is necessary so that response to therapy can be measured as the change from baseline. Patients should undergo echocardiography and right heart catheterization, and their exercise capacity and NYHA functional class should be determined. Patients with POPH should be considered for treatment if they are NYHA functional class II or above and/or their mean pulmonary artery pressure (MPAP) is greater than 35 mm Hg in transplant candidates. The goal in the treatment and management of POPH is to improve pulmonary hemodynamics by reducing the obstruction to pulmonary arterial flow and to preserve right ventricular function (Table). This article, the second in a 2-part review of POPH in patients with liver disease, reviews the role of medical therapy and liver transplantation in treatment. Evaluation and diagnosis of POPH are discussed in a separate article.

Medical Therapy

Prostanoids

Although prostacyclin and prostaglandin analogs entered routine clinical practice for POPH in the 1990s, reports of investigational use date back to the 1980s. Prostanoids are potent vasodilators with antiplatelet aggregation and antiproliferative properties. Prostacyclin synthase is reduced in patients with PAH, resulting in decreased concentration of prostacyclin with vasoconstriction and proliferative changes in the pulmonary vasculature.¹

Epoprostenol

Epoprostenol is also known as synthetic prostaglandin I₂ or prostacyclin. It was the first therapy approved for the treatment of PAH in 1995 by the US Food and Drug Administration (FDA) as a continuous intravenous infusion.^2,3 It also inhibits platelet aggregation and may help modulate pulmonary vascular remodeling.^4,5 Epoprostenol is derived from the metabolism of arachidonic acid and is a potent pulmonary and systemic vasodilator. One study reported an immediate 11.8% decrease in MPAP, 24% decrease in pulmonary vascular resistance (PVR) and 28% drop in systemic vascular resistance (SVR) during an epoprostenol infusion.⁶ The authors reported that epoprostenol was a more potent vasodilator than nitric oxide and may have a role in predicting the reversibility of POPH. In a case series of 33 patients with secondary pulmonary hypertension (including 7 patients with POPH) treated with continuous intravenous prostacyclin for approximately 1 year, exercise tolerance, NYHA functional class, and pulmonary hemodynamics improved in each patient compared to baseline.⁷ Krowka et al studied 14 patients with moderate to severe POPH treated with intravenous epoprostenol.⁸ No significant side effects were noted and treatment resulted in significant improvements in PVR, MPAP, and cardiac output. In 2007, Fix et al published a large retrospective cohort of patients with moderate to severe POPH.⁹ Nineteen patients treated with epoprostenol were compared to 17 patients with no treatment. After a median treatment period of 15.4 months, the epoprostenol group showed significant improvement in MPAP, PVR and cardiac output, but survival did not differ between the 2 groups.

Epoprostenol has often been considered a bridge to transplant in patients with POPH. Sussman et al described 8 consecutive patients with POPH who were treated with intravenous epoprostenol (2 to 8 ng/kg/min dose).¹⁰ Liver transplant was considered in 7 of the 8 patients when MPAP decreased to less than 35 mm Hg. Six patients were eventually listed for liver transplant, but 2 died waiting on the list. Long-term outcomes in the group of transplanted recipients were excellent. They remained alive and well at least 9 to 18 months post-transplant, and half did not require long-term vasodilator therapy post-orthotopic liver transplant. Similarly, Ashfaq et al published their data on 16 patients with moderate-to-severe POPH who were treated with vasodilator therapy.¹¹ MPAP decreased to acceptable levels in 75% of the treated patients, and 11 went on to liver transplantation. Rates of 1- and 5-year survival in the transplanted patients were 91% and 67% respectively. None of the patients who failed vasodilator therapy survived.

Epoprostenol has a short half-life (3 to 5 minutes) and requires continuous infusion through central access via an infusion pump. Aseptic technique must be maintained to avoid blood stream infections. Pump failure or loss of vascular access can result in rebound pulmonary vasoconstriction that can be life-threatening and requires immediate attention. Side effects associated with epoprostenol include flushing, headache, nausea/vomiting, bradycardia, chest pain, jaw pain, diarrhea, and musculoskeletal pain.

Patients on epoprostenol should be monitored for prostanoid overdose. In the case of patients with chronic liver disease, epoprostenol increases systemic vasodilation in patients with already low systemic vascular tone. As a result, cardiac output may increase to the point of high cardiac output failure. MPAP will remain elevated secondary to high cardiac output rather than high PVR. In these patients, right heart catheterization will show an elevated MPAP in the setting of normal to low PVR/transpulmonary gradient (TPG) values. Lowering the epoprostenol dose will successfully reduce both cardiac output and MPAP.

Treprostinil

Treprostinil is a prostacyclin analog that is available in intravenous, inhalational, and subcutaneous form, although subcutaneous dosing may be limited by pain. Sakai et al published a small case series of 3 patients with PAH and end-stage liver disease treated with intravenous treprostinil.¹² Pulmonary hemodynamics improved in all patients, and 2 patients went on to an uneventful liver transplantation. More than 10 years later, data were published on 255 patients with PAH on therapy with bosentan or sildenafil randomized to additional inhaled treprostinil.¹³ Treprostinil proved to be safe and well tolerated, with improvement in quality of life measures but no improvement in other secondary endpoints.

Iloprost

Inhaled iloprost is another prostacyclin that has a short therapeutic half-life of 20 to 30 minutes and requires frequent administration (6 to 9 times daily). In study in which patients with severe POPH were treated for up to 3 years with inhaled iloprost,¹⁴ survival rates at 1, 2, and 3 years were 77%, 62%, and 46%, respectively. A second study published in 2010 was designed to assess the acute effects of inhaled iloprost on pulmonary hemodynamics and evaluate the clinical outcome after 12 months of treatment.¹⁵ Iloprost was found to rapidly reduce pulmonary arterial pressure and PVR. In the long-term evaluation, inhaled iloprost increased the 6-minute walk distance (6MWD) and functional class, but no change was noted in the systolic pulmonary artery pressure. The authors concluded that iloprost might provide symptomatic improvement and improvement in exercise capacity.

Selexipag

Selexipag is an oral selective IP prostacyclin receptor agonist that is structurally distinct from other prostacyclins.¹⁶ In a phase 3 randomized double blind clinical trial, PAH patients treated with selexipag had lower composite of death or complication of PAH to the end of the study period.¹⁷ This effect was consistent across all dose ranges, but POPH patients were excluded from this study. Safety and efficacy of selexipag has not been evaluated in POPH patients.

Endothelin Receptor Antagonists

Endothelin receptor antagonists block the production of endothelin-1 (ET-1), a potent vasoconstrictor and smooth muscle mitogen that may contribute to the development of PAH. Three different receptors have been described: endothelin A, endothelin B, and endothelin B2. Elevated ET-1 levels have been reported in patients with chronic liver disease and may originate from hepatosplanchnic circulation.¹⁸

Bosentan

Bosentan is an oral, nonspecific, ET-1A and ET-1B receptor antagonist. Initial use of bosentan in patients with POPH was limited because of concern for hepatotoxicity. Approximately 10% of patients on bosentan were reported to have mild hepatic side effects in the form of elevated aminotransferases, but severe injury has been reported.¹⁹ One of the first clinical experiences of bosentan in patients with POPH was published in 2005. Hoeper et al followed 11 patients with Child A cirrhosis and severe POPH.²⁰ All patients included were in NYHA functional class III or IV and were treated with bosentan for over 1 year. Exercise capacity and symptoms improved in all treated patients. The medication was tolerated well and there was no evidence of drug-induced liver injury. A single case report showed the effectiveness of bosentan in a 43-year-old man with alcohol-related liver disease (Child-Pugh A) and right ventricular enlargement and dysfunction secondary to POPH.²¹ Pulmonary arterial pressure decreased, exercise capacity increased, and improvement was maintained over 2 years.

In a group of 31 patients with Child A or B cirrhosis and severe POPH, bosentan had significantly better effects than inhaled iloprost on exercise capacity, hemodynamics, and survival.¹⁴ One, 2, and 3-year survival rates in the bosentan group were 94%, 89%, and 89% (compared to 77%, 62%, and 46% in the iloprost group). Both drugs were considered safe with no reported hepatotoxicity. In 2013, Savale et al published data on 34 patients with POPH, Child-Pugh A and/or B who were treated with bosentan for a median of 43 months.²² The authors reported significant improvements in hemodynamics, NYHA functional class, and 6WMD. Event-free survival rates at 1, 2, and 3 years were 82%, 63%, and 47%, respectively.

Ambrisentan

Ambrisentan is a highly selective ET-1A receptor antagonist with once daily dosing and a lower risk of hepatotoxicity compared to bosentan. Fourteen patients with moderate to severe POPH treated with ambrisentan in 4 German hospitals were retrospectively analyzed.²³ Median follow-up was 16 months, and the study demonstrated significant improvement in exercise capacity and clinical symptoms without significant change in liver function tests. Cartin-Ceba et al published their experience of 13 patients with moderate to severe POPH treated with ambrisentan monotherapy.²⁴ Patients were followed for a median of 613 days and on treatment for a median time of 390 days. Significant improvements were shown in pulmonary arterial pressure and PVR without adverse effect on hepatic function. Over 270 patients with PAH (6% with POPH) received ambrisentan from March 2009 through June 2013 at a large United Kingdom portal hypertension referral center.²⁵ Discontinuation due to side effects was higher than previously reported. Discontinuation due to abnormal transaminases was uncommon.

Macitentan

Macitentan is a dual endothelin-receptor antagonist developed by modifying the structure of bosentan to increase efficacy and safety. The SERAPHIN trial compared oral macitentan to placebo in 250 patients with moderate to severe PAH, some of whom were also on a stable dose of oral or inhaled therapy for PAH.²⁶ Over a 2-year period, patients treated with macitentan were less likely to have progression of their disease or die on therapy (38% and 31% versus 46%), regardless of if they were receiving additional oral therapy and more likely to have improvement of their exercise capacity and WHO functional class. Nasopharyngitis and significant anemia were more common in the macitentan group, but there was no difference in the rate of liver function test abnormalities compared to placebo. Trials with macitentan are currently ongoing in patients with POPH.

Phosphodiesterase-5 Inhibitors

Cyclic guanosine monophosphate (cGMP) is the mediator of nitric oxide–induced vasodilation. Phosphodiesterase-5 (PDE-5) inhibitors prolong the vasodilatory effects of cyclic guanosine monophosphate by preventing its hydrolysis, thereby reducing the pulmonary arterial pressure.

Sildenafil

Sildenafil is the most widely accepted PDE-5 inhibitor for POPH. Fourteen patients with moderate to severe POPH were treated with sildenafil (50 mg 3 times per day) in an observational study published by Reichenberger et al in 2006.²⁷ Eight patients were newly started on sildenafil, whereas sildenafil was added to inhaled prostanoids in the remaining 6x patients. Sildenafil significantly decreased 66MWD, MPAP, PVR, and cardiac index alone or in combination with inhaled prostanoids.

Sildenafil has also been used as a bridge to transplant in liver transplant candidates with POPH. Ten patients with POPH treated with sildenafil monotherapy were followed for a 21±16 months.²⁸ Patients improved symptomatically and increased their 6MWD at 1 year by 30 meters or more. Three patients became transplant eligible and another 3 patients were stable, without progression of their liver disease or POPH. Four patients were not considered transplant candidates, 2 because of refractory POPH and 2 for other comorbidities. The authors concluded that sildenafil monotherapy could stabilize or improve pulmonary hemodynamics in patients with POPH and eventually lead to liver transplantation. Gough et al took a similar look at 9 patients with POPH treated with sildenafil.²⁹ All patients had initial and follow-up right heart catheterizations within a period of 3 years. Mean PVR improved in all patients, decreasing from 575 to 375 dynes/s/cm^–5. MPAP decreased to ≤ 35 mmHg in 4 patients, 1 of whom went on to receive a liver transplant. Overall sildenafil improved pulmonary hemodynamics in this small cohort of POPH patients.

Tadalafil

Tadalafil is another oral PDE-5 inhibitor but with a longer half-life than sildenafil. Unlike sildenafil, which requires 3 times daily dosing, tadalafil requires once daily administration. A few case reports have demonstrated tadalafil’s effectiveness for POPH in combination with other medical therapy (eg, sildenafil, ambrisentan).^30,31

Guanylate Cyclase Stimulator

Riociguat

Riociguat is a first-in-class activator of soluble form of guanylate cyclase that increases levels of cyclic GMP. Two randomized clinical trials, PATENT, a study in PAH patients, and CHEST, a study in patients with chronic thromboembolic pulmonary hypertension showed improvement in 6MWD at 12 weeks (PATENT) or 16 weeks (CHEST), with improvement in secondary endpoints such as PVR, N-terminal pro b-type natriuretic peptide and WHO functional class.^32,33 Riociguat may have potential advantages in patients with POPH given that it has a favorable liver safety profile. A subgroup analysis of patients enrolled in the PATENT study showed that 13 had POPH and 11 were randomized to receive riociguat 2.5 mg 3 times daily dose and 2 received placebo.³⁴ Riociguat was well tolerated and improved 6MWD that was maintained over 2 years in the open label extension.

Medications to Avoid

Nonselective beta-blockers are commonly recommended in patients with portal hypertension to help prevent variceal hemorrhage. However, in patients with POPH, beta-blockers have been shown to decrease exercise capacity and worsen pulmonary hemodynamics. A study of 10 patients with moderate to severe POPH who were receiving beta-blockers for variceal bleeding prophylaxis showed that 6MWD improved in almost all of the patients, cardiac output increased by 28%, and PVR decreased by 19% when beta-blockers were discontinued.³⁵ The authors concluded that the use of beta-blockers should be avoided in this patient population.

Calcium channel blockers should not be used in patients with POPH because they can cause significant hypotension due to systemic vasodilatation and decreased right ventricular filling. Patients with portal hypertension and chronic liver disease commonly have low systemic vascular resistance and are particularly susceptible to the deleterious effects of calcium channel blockers.

Transplantation

Liver transplantation is a potential cure for POPH and its role in POPH has evolved over the past 2 decades. In 1997, Ramsay et al published their review of 1205 consecutive liver transplants at Baylor University Medical Center (BUMC) in Texas.³⁶ The incidence of POPH in this group was 8.5%, with the majority of patients having mild POPH. Liver transplant outcomes were not affected by mild and moderate pulmonary hypertension. However, patients with severe POPH (n = 7, systolic pulmonary artery pressure > 60 mm Hg) had a mortality rate of 42% at 9 months post-transplantation and 71% at 36 months post-transplant. The surviving patients continued to deteriorate with progressive right heart failure and no improvement in POPH.

To understand the effect of liver transplantation on POPH, one must understand the hemodynamic changes that occur with POPH and during liver transplant. The right ventricle is able to manage the same volume as the left ventricle under normal circumstances, but is unable to pump against a significant pressure gradient.³⁷ In the setting of POPH, right ventricular hypertrophy occurs and RV output remains stable for some time. With time, pulmonary artery pressure increases secondary to pulmonary arteriolar vasoconstriction, intimal thickening, and progressive occlusion of the pulmonary vascular bed. Right ventricular failure may occur as a result. Cardiac output increases significantly at the time of reperfusion during liver transplant (up to 3-fold in 15 minutes),³⁸ and in the setting of a noncompliant vascular bed, the patient is at risk for right heart failure. This is the likely explanation to such high perioperative mortality rates in patients with uncontrolled POPH. Failure to decrease MPAP to less than 50 mm Hg is considered a complete contraindication to liver transplant at most institutions. Many transplant centers will list patients for liver transplant if MPAP can be decreased to less than 35 mm Hg and PVR < 400 dynes/s/cm^–5. These parameters are thought to represent an adequate right ventricular reserve and a compliant pulmonary vascular bed.³⁷ However, even with good pressure control, the anesthesiology and critical care teams must be prepared to deal with acute right heart failure peri-operatively. Intraoperative transesophageal echocardiography has been recommended to closely follow right ventricular function.³⁸ Inhaled or intravenous dilators are the most effective agents in the event of a pulmonary hypertensive crisis.

Review of Outcomes

A retrospective review evaluated 43 patients with untreated POPH who underwent attempted liver transplantation.³⁹ Data were collected from 18 peer-reviewed studies and 7 patients at the authors’ institution. Overall mortality was 35% (15 patients), with almost all of the deaths secondary to cardiac dysfunction. Two deaths occurred intraoperatively and 8 deaths occurred during the transplant hospitalization. The transplant could not be successfully completed in 4 of the patients. MPAP > 50 mm Hg was associated with 100% mortality, whereas patients with MPAP between 35 mm Hg and 50 mm Hg had a 50% mortality. No mortality was noted in patients with MPAP < 35 mm Hg.

Liver transplantation has been shown to be successful in patients with controlled POPH. Sussman et al published their data on 8 patients with severe POPH in 2006. In this prospective study, all patients were treated with sequential epoprostenol infusions and 7 of the 8 patients experienced a significant reduction in MPAP and PVR. Six patients were listed for liver transplant, 4 of who were transplanted successfully and alive up to 5 years later.

The Baylor University Medical Center published their data on POPH patients who received liver transplants in 2007.¹¹ POPH was confirmed by right heart catheterization in 30 patients evaluated for liver transplant. Sixteen patients were considered to be suitable candidates for transplant and MPAP was decreased to less than 35 mmHg in 12 patients with vasodilator therapy. Eleven patients eventually underwent liver transplant and 1- and 5-year survival rates were 91% and 67%.

Compared to medical therapy or liver transplant alone, patients who receive medical therapy followed by liver transplantation have the best survival. The Mayo Clinic retrospectively reviewed 74 POPH patients identified between 1994 and 2007.⁴⁰ Patients were categorized in 1 of 3 categories: no medical therapy, medical therapy alone for POPH, or medical therapy for POPH followed by liver transplantation. Patients who received no medical therapy for POPH and no liver transplant had the worst outcomes, with a dismal 5-year survival of only 14% with over 50% deceased at 1 year of diagnosis. Five-year survival was 45% in patients who received medical therapy only. Patients who received medical therapy with prostacyclin followed by liver transplantation had the best outcomes, with a 5-year survival of 67% versus 25% in those who were transplanted without prior prostacyclin therapy.

We reported the longest follow-up study for patients undergoing liver transplantation with POPH in 2014.⁴¹ Seven patients with moderate to severe POPH received a liver transplant at our institution between June 2004 and January 2011. Mean pulmonary artery pressure was reduced to < 35 mm Hg, with appropriate POPH therapy in all of the patients. Both the graft and patient survival rates were 85.7% after a median follow-up of 7.8 years. The 1 patient who did not survive died from complications related to recurrent hepatitis C and cirrhosis, not from POPH-related issues. Four of the remaining 6 patients continue to require oral vasodilator therapy post-transplant, suggesting irreversible remodeling of the pulmonary vasculature. Two patients (4.4 and 8.5 years post-transplant) have no evidence of pulmonary hypertension post-transplant and therefore do not require medical treatment for pulmonary hypertension. We concluded that POPH responsive to vasodilator therapy is an appropriate indication for liver transplant, with excellent long-term survival.

Hollatz et al published their data on 11 patients with moderate to severe POPH who were successfully treated (mostly with oral sildenafil and subcutaneous treprostinil) as a bridge to liver transplant.⁴² The mortality rate was 0, with a follow-up duration of 7 to 60 months. Interestingly, 7 of the 11 patients (64%) were off all pulmonary vasodilators post-transplant. Ashfaq et al reported similar results.¹¹ Nine of 11 patients with treated moderate to severe POPH who received liver transplants stopped vasodilator therapy at a median period of 9.2 months post-transplant. Raevens et al described a group of 3 patients with POPH who went on to liver transplant after their pulmonary pressures were decreased with combined oral vasodilator therapy: 1 required continued long-term vasodilator therapy, another was weaned off medications after transplant, and the third patient died during the liver transplant from perioperative complications that induced uncontrolled pulmonary hypertension.⁴³

Patient Selection

In 2006, the United Network for Organ Sharing (UNOS) initiated a policy whereby a higher priority for liver transplantation was granted for highly selected patients in the United States.⁴⁴ UNOS policy 3.6.4.5.6 upgraded POPH patients to a MELD score of 22, with an increase in MELD every 3 months as long as MPAP remained < 35 mm Hg and PVR remained < 400 dynes/s/cm^–5. One hundred fifty-five patients were granted MELD exception points for POPH between 2002 and 2010 and went on to receive liver transplants.⁴⁵ Goldberg et al collected data from the Organ Procurement and Transplantation Network (OPTN) and compared outcomes of patients with approved POPH MELD exception points versus waitlist candidates with no exception points.⁴⁶ One hundred fifty-five waitlisted patients received POPH MELD exception points, with only 43.1% meeting OPTN exception requirements. One-third did not fulfill hemodynamic criteria consistent with POPH or had missing data, and 80% went on to receive a liver transplant. Waitlist candidates receiving POPH MELD exception points also had increased waitlist mortality and several early post-transplant deaths. The authors felt these data highlighted the need for OPTN/UNOS to revise their policy for POPH MELD exceptions points, revise how points are rewarded, and continue research to help risk stratify these patients to minimize perioperative complications.

Conclusion

Several effective medical treatment regimens are available, including prostanoids, endothelin receptor antagonists, and PDE-5 inhibitors. Liver transplantation is a potential cure but is only recommended if MPAP can be decreased to ≤ 35 mmHg. Long-term follow-up studies have shown these patients do well several years post-transplant but may continue to require oral therapy for their POPH.

Pulmonary arterial hypertension (PAH) is a rare disease that is associated with high mortality and is characterized by pulmonary vascular remodeling. Portopulmonary hypertension (POPH) is a form of PAH that occurs in patients with portal hypertension where no alternative cause of PAH can be identified. POPH is documented in approximately 4.5% to 8.5% of liver transplant candidates,^1,2 but there is no relationship between the existence or severity of POPH and the severity of liver dysfunction.³ Mantz and Craig described the first case of POPH in a 53-year-old woman with enlarged pulmonary arteries that exhibited forceful pulsations more characteristic of the aorta than a low-pressure pulmonary trunk.⁴ Autopsy revealed findings of chronic liver disease including a stenotic portal vein, portocaval shunt, and esophageal varices. In both PAH and POPH, pre-capillary pulmonary arteries have characteristic lesions, such as intimal thickening, endothelial proliferation, and thrombotic changes. This 2-part article reviews the diagnosis and treatment of patients with POPH. Here, we review the epidemiology, prognosis, pathogenesis, and diagnosis of POPH; current treatment options for POPH are reviewed in a separate article.

Definition

The term POPH was first used by Yoshida et al in 1993 to describe the first successful liver transplant in a patient with POPH, a 39-year-old man with chronic hepatitis.⁵ The World Health Organization (WHO) classifies POPH as a form of Group 1 PAH.⁶ The criteria that must be met to make a diagnosis of POPH are shown in the Table 1.⁷

Moderate POPH is defined as a mean pulmonary artery pressure (MPAP) between 35 mm Hg and < 45 mm Hg, whereas severe POPH is MPAP ≥ 45 mm Hg. Moderate and severe POPH are considered contraindications to liver transplant because of high perioperative and postoperative mortality rates.⁸ In 2000, the Mayo Clinic retrospectively reviewed 43 patients with POPH who underwent attempted liver transplantation.⁹ The cardiopulmonary-related mortality rate in patients with a MPAP of 35 to < 50 mm Hg was 50% and 100% for those with MPAP > 50 mm Hg. No mortality was noted in patients with a pre-liver transplant MPAP of < 35 mm Hg and transpulmonary gradient (TPG) < 15 mm Hg.

Epidemiology

In 1983, a series of 17,901 autopsied patients showed a primary pulmonary hypertension prevalence of 0.13% and a prevalence of 0.73% in patients with cirrhosis.¹⁰ In 1987, Rich et al published data from the National Institutes of Health’s national registry of primary pulmonary hypertension.¹¹ The registry included data from 187 patients from 32 centers. Further analyses by Groves et al concluded that 8.3% of the patients likely had POPH.¹² Humbert et al published data on the French pulmonary hypertension registry experience in 2006.¹³ The French registry included 674 patients from 17 university hospitals; 10.4% of these patients had POPH. The largest prospective study was published by Hadengue et al in 1991.¹⁴ In this study, 507 patients hospitalized with portal hypertension but without known pulmonary hypertension underwent cardiac catheterization; 10 patients (2%) had pulmonary hypertension and more than half were clinically asymptomatic. Finally, the Registry to Evaluate Early And Long-term pulmonary arterial hypertension disease management (REVEAL registry) documented a 5.3% frequency of POPH (174 of 3525) in the United States.¹⁵

Prognosis

Individuals with POPH have worse outcomes compared to other forms of PAH. Median survival prior to the introduction of vasodilator therapy was a dismal 6 months and mean survival was 15 months.¹⁶ The cause of death in patients with POPH is equally distributed between right heart failure from POPH and direct complications of chronic liver disease.¹ Le Pavec et al retrospectively analyzed all patients referred to the French Referral Center with POPH between 1984 and 2004 (154 patients).¹ Approximately 50% of the patients were Child-Turcotte-Pugh class B or C, and 60% were classified as New York Health Association (NYHA) class III or IV. In these patients, 1-, 3-, and 5-year survival rates were 88%, 75%, and 68%, respectively. Major independent prognostic risk factors were presence and severity of cirrhosis and preservation of right ventricular function. Interestingly, NYHA functional class was not related to survival in this study, although it has clearly been identified as a strong prognostic factor in idiopathic PAH.

Krowka et al evaluated 174 patients with POPH enrolled in the REVEAL Registry,¹⁵ a multicenter, observational, US-based study comprised of more than 3500 patients with PAH. Despite having better hemodynamic parameters at diagnosis, patients with POPH had significantly poorer survival and all-cause hospitalization compared with patients with idiopathic PAH (IPAH) or hereditary PAH (HPAH). Two-year survival from enrollment was 67% in POPH versus 85% in those with IPAH/HPAH (P < 0.001). Five-year survival from time of diagnosis was 40% versus 64% (P < 0.001). Additionally, patients with POPH were less likely to be on PAH-specific therapy at enrollment, with only 25% on treatment at the time of entry. These findings were replicated in 2005 when Kawut et al retrospectively compared 13 patients with POPH with 33 patients with IPAH.¹⁷ Despite having a higher cardiac index and lower pulmonary vascular resistance than patients with IPAH, patients with POPH had a higher risk of death (hazard ratio, 2.8, P = 0.04), likely reflecting the combination of 2 serious diseases.

In 2008 the Mayo Clinic published their retrospective analysis of patients with POPH to determine the natural history of POPH.¹⁸ Patients were categorized into 3 groups: (1) no medical therapy for POPH and no liver transplant; (2) medical therapy for POPH alone; (3) medical therapy for POPH followed by liver transplant. The study included 74 patients between 1994 through 2007; 19 patients who did not receive treatment for POPH or liver transplant truly represented the natural history of POPH. Their 5-year survival was only 14%, and over half were deceased 1 year after diagnosis. The largest group consisted of patients who received therapy for POPH but no liver transplant. This group did remarkably better than those who received no therapy at all, with a 5-year survival of 45%. However, the patients with the overall best survival were those who received a combination of treatment for POPH followed by liver transplant. Their 5-year survival was 67%. Survival at 5 years was only 25% for the small group of patients who received transplant without PAH therapy. Once again, mortality did not correlate with the severity of hepatic dysfunction or baseline hemodynamic data.

Pathogenesis

The pathogenesis of POPH is unclear. Multiple studies have shown that there is minimal, if any, association with pulmonary hypertension and the severity of liver disease or portal hypertension.^19,20 Portal hypertension is the result of an increase in intrahepatic resistance and an increase in blood flow into the portal circulation. Collateral vessels develop and blood from the splanchnic circulation is allowed directly into the systemic venous circulation, bypassing the liver. One of the most widely accepted theories is that a humoral substance, that would otherwise be metabolized by the liver, is able to reach the pulmonary circulation through collaterals, resulting in POPH.²¹ Pelicelli et al evaluated the possible role of endothelin-1, interleukin-6, interleukin 1β, and tumor necrosis factor in the pathogenesis of POPH.²² Plasma concentrations of these cytokines were compared between patients with POPH and patients with cirrhosis but no POPH. Patients with POPH had higher concentrations of endothelin-1 and interleukin-6, suggesting antagonists for these cytokines may have a role in the treatment of POPH. The role of endothelin-1 was further supported by Kamath et al in 2000²³ when they determined the pulmonary vascular bed is exposed to increased levels of circulating endothelin-1a in the setting of cirrhosis. Endothelin-1 is a potent vasoconstrictor and facilitator of smooth muscle proliferation.

In addition to collateral circulation allowing mediators to reach the pulmonary arterial bed in portal hypertension, high flow may trigger a vasoproliferative process in the pulmonary vascular bed. Patients with advanced liver disease have a low systemic vascular resistance, with a compensatory increase in cardiac output. An increase in cardiac output can lead to shear stress of the pulmonary vascular endothelial layer. Although the resistance of the pulmonary vasculature may decrease rapidly to help normalize pulmonary pressures, persistent circulatory overload could result in irreversible vascular changes. Autopsy and lung explant studies show that POPH is characterized by obstructive and remodeling changes in the pulmonary arterial bed.²⁴ Initially, medial hypertrophy with smooth muscle proliferation is present. As the disease advances, platelet aggregates, in situ thrombosis, and intimal fibrosis develop. Finally, web-like lesions involving the entire pulmonary wall develop with recanalization for the passage of pulmonary arterial flow. These changes are identical to the changes observed in patients with other forms of PAH.

Not all patients with portal hypertension develop POPH, suggesting that genetic predisposition may play a role in POPH development. The Pulmonary Vascular Complications of Liver Study Group published a multicenter case-control study that attempted to identify genetic risk factors for POPH in patients with advanced liver disease.²⁵ More than 1000 common single nucleotide polymorphisms (SNPs) in 93 candidate genes were genotyped in each patient. When compared to controls, multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with an increased risk of POPH. One year earlier, the same study group concluded that female sex (adjusted odds ratio [OR], 2.90) and autoimmune hepatitis (adjusted OR, 4.02) were associated with a higher risk for POPH, whereas hepatitis C was associated with a decreased risk.²⁰

Clinical Presentation

Clinical presentation is variable in POPH. Patients referred to a pulmonologist will usually present with symptoms similar to patients with other forms of PAH. In a retrospective analysis of patients referred to the French Referral Center for Pulmonary Hypertension, 60% of the patients belonged to NYHA functional class III or IV.¹ In a series of 78 patients with POPH, the most common presenting pulmonary symptom was dyspnea on exertion (81%), followed by syncope, chest pain, and fatigue (< 33%).¹⁶ Symptoms such as syncope and chest pain are usually markers of severe POPH.³ Stigmata of portal hypertension, such as ascites, spider angiomata, and palmar erythema, may be present on exam. An accentuated pulmonary component of the second heart sound can be seen in 82% of patients and a systolic murmur caused by tricuspid regurgitation in 69% of patients.¹⁶ Patients with severe POPH may have jugular vein distention, peripheral edema, and a third heart sound.

Diagnostic Evaluation

Chest x-rays may show prominent pulmonary arteries and cardiomegaly in patients with POPH, whereas electrocardiogram can suggest right ventricular hypertrophy and right axis deviation. The best screening test for POPH in patients with portal hypertension is echocardiography. Routine screening for POPH is recommended during liver transplant evaluation in the practice guidelines from the American Association for the Study of Liver Disease.²⁶ Right-sided cardiac chamber enlargement and right ventricular pressure or volume overload can be assessed on echocardiography. Colle et al followed 165 patients evaluated for liver transplantation who underwent transthoracic Doppler echocardiography and right heart catheterization.²⁷ Seventeen patients met the criteria for POPH on echocardiography (presence of tricuspid regurgitation and calculated systolic pulmonary artery pressure over 30 mm Hg) and right heart catheterization confirmed the diagnosis in 10 patients. Right ventricular systolic pressure (RVSP) estimate of ≤ 30 mm Hg on 2-dimensional echo had a 100% sensitivity and negative predictive value. Positive predictive value was poor at 59%, reiterating the need for right heart catheterization in the diagnosis of POPH. When Kim et al used a RVSP threshold of 50 mm Hg, 72% had at least moderate pulmonary hypertension, including 30% with severe pulmonary hypertension.²⁸ Raevens et al analyzed data from 152 patients who underwent pretransplant echocardiography and catheterization.² Their data show a RVSP threshold of greater than 38 mm Hg by echocardiography had a specificity of 82% and sensitivity and negative predictive value of 100%. The European Respiratory Society recommendations state that PAH should be considered unlikely if echocardiography estimates a RVSP ≤36 mm Hg and likely if the RVSP is estimated at > 50 mm Hg.²⁹ We recommend repeating echocardiography every 6 to 12 months in patients listed for liver transplantation, as pulmonary hemodynamics may change over time.

Computed tomography (CT) may have a complementary role in the future for the noninvasive detection of POPH. In a study published in 2014, 49 patients referred for liver transplantation were retrospectively reviewed.³⁰ Measured CT signs included the main pulmonary artery/ascending aorta diameter ratio, the mean left and right main pulmonary artery diameter, and the enlargement of the pulmonary artery compared to the ascending aorta. Compared to the transthoracic echocardiography alone, an algorithm incorporating CT and echocardiography improved the detection of POPH (area under curve = 0.8, P < 0.0001).

A diagnosis of POPH can only be confirmed when PAH exists in a patient with portal hypertension, as determined by right heart catheterization, and no other cause of PAH can be identified. MPAP should be 25 mm Hg or greater, PVR of 240 dynes/s/cm^–5, wedge pressure of 15 mm Hg or less, and TPG greater than 12 mm Hg. Krowka et al showed the value of right heart catheterization in their 10-year prospective, echocardiography-catheterization algorithm study.¹⁹ Of 1235 liver transplant candidates who underwent echocardiography, 104 patients had a RVSP exceeding 50 mm Hg. Almost all of these patients had a right heart catheterization. All cause pulmonary hypertension (MPAP > 25 mm Hg) was confirmed in 90% of the patients, and 35% had a PVR < 240 dynes/s/cm^–5 and pulmonary capillary wedge pressure (PCWP) > 15 mm Hg, suggesting fluid overload. Forty-one patients had significant POPH, with a PVR > 400 dynes/s/cm^–5, and 24% also had an elevated PCWP. TPG was > 12 mm Hg in all of these patients, confirming POPH. As demonstrated by this study, right heart catheterization is required to confirm the diagnosis of POPH because high flow and fluid overload can lead to elevated pulmonary artery pressures.

Patients with POPH have a unique clinical profile with characteristics common to patients with primary pulmonary hypertension and chronic liver disease. In a retrospective review that compared 30 patients with PAH, 30 patients with chronic liver disease only, and 30 patients with catheterization-proved POPH,³¹ patients with POPH had elevated MPAP similar to those with primary PAH, but they also had reduced SVR and elevated cardiac index similar to those with chronic liver disease alone.

Besides POPH, 2 other common causes can lead to increased pulmonary arterial blood flow in patients with portal hypertension. First is a high-flow condition caused by increased cardiac output but with a normal PVR and PCWP. Fluid overload can also lead to pulmonary venous hypertension with increased PCWP, normal cardiac output, and normal PVR. Up to 25% of patients with POPH may present with marked excess volume caused by fluid retention.³ There can be an increase in both PCWP and PVR depending on the presence and the degree of fluid retention. TPG (MPAP – PCWP) > 12 mm Hg was introduced to make such patients less confusing and to help correct for increased PCWP secondary to fluid overload. Obstruction to pulmonary arterial flow is manifest by an increased TPG (Table 2).

POPH should be distinguished from hepatopulmonary syndrome (HPS), which is another pulmonary vascular consequence of liver disease. Unlike POPH, HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilation.³² Similar to other patients with liver disease, patients with HPS have a normal PVR and increased cardiac output secondary to a high-flow state. HPS is diagnosed by confirmation of an intrapulmonary shunt by echocardiogram. Injection of agitated saline results in saline bubbles being visualized in the left atrium 3 or more cardiac cycles after they appear in the right atrium. Currently, there is no effective medical treatment for HPS and liver transplantation is the only successful treatment.

Conclusion

POPH is an uncommon complication of chronic liver disease. It is defined as PAH in a patient with portal hypertension excluding other causes of PAH. The following criteria must be met to make a diagnosis of POPH: (1) evidence of portal hypertension; (2) MPAP ≥ 35 mm Hg; (3) PVR ≥ 240 dynes/s/cm⁵; (4) pulmonary capillary wedge pressure ≤ 15 mm Hg; and (5) TPG > 12 mm Hg. Individuals with POPH have worse outcomes compared to other forms of PAH, with a median survival of 6 months without medical therapy. The pathogenesis of POPH is unclear but may be related to a genetic predisposition since not all patients with portal hypertension develop POPH. Echocardiography is an excellent screening test for POPH, but a right heart catheterization must be performed to confirm the diagnosis.

Pulmonary arterial hypertension (PAH) is a rare disease that is associated with high mortality and is characterized by pulmonary vascular remodeling. Portopulmonary hypertension (POPH) is a form of PAH that occurs in patients with portal hypertension where no alternative cause of PAH can be identified. POPH is documented in approximately 4.5% to 8.5% of liver transplant candidates,^1,2 but there is no relationship between the existence or severity of POPH and the severity of liver dysfunction.³ Mantz and Craig described the first case of POPH in a 53-year-old woman with enlarged pulmonary arteries that exhibited forceful pulsations more characteristic of the aorta than a low-pressure pulmonary trunk.⁴ Autopsy revealed findings of chronic liver disease including a stenotic portal vein, portocaval shunt, and esophageal varices. In both PAH and POPH, pre-capillary pulmonary arteries have characteristic lesions, such as intimal thickening, endothelial proliferation, and thrombotic changes. This 2-part article reviews the diagnosis and treatment of patients with POPH. Here, we review the epidemiology, prognosis, pathogenesis, and diagnosis of POPH; current treatment options for POPH are reviewed in a separate article.

Definition

The term POPH was first used by Yoshida et al in 1993 to describe the first successful liver transplant in a patient with POPH, a 39-year-old man with chronic hepatitis.⁵ The World Health Organization (WHO) classifies POPH as a form of Group 1 PAH.⁶ The criteria that must be met to make a diagnosis of POPH are shown in the Table 1.⁷

Moderate POPH is defined as a mean pulmonary artery pressure (MPAP) between 35 mm Hg and < 45 mm Hg, whereas severe POPH is MPAP ≥ 45 mm Hg. Moderate and severe POPH are considered contraindications to liver transplant because of high perioperative and postoperative mortality rates.⁸ In 2000, the Mayo Clinic retrospectively reviewed 43 patients with POPH who underwent attempted liver transplantation.⁹ The cardiopulmonary-related mortality rate in patients with a MPAP of 35 to < 50 mm Hg was 50% and 100% for those with MPAP > 50 mm Hg. No mortality was noted in patients with a pre-liver transplant MPAP of < 35 mm Hg and transpulmonary gradient (TPG) < 15 mm Hg.

Epidemiology

In 1983, a series of 17,901 autopsied patients showed a primary pulmonary hypertension prevalence of 0.13% and a prevalence of 0.73% in patients with cirrhosis.¹⁰ In 1987, Rich et al published data from the National Institutes of Health’s national registry of primary pulmonary hypertension.¹¹ The registry included data from 187 patients from 32 centers. Further analyses by Groves et al concluded that 8.3% of the patients likely had POPH.¹² Humbert et al published data on the French pulmonary hypertension registry experience in 2006.¹³ The French registry included 674 patients from 17 university hospitals; 10.4% of these patients had POPH. The largest prospective study was published by Hadengue et al in 1991.¹⁴ In this study, 507 patients hospitalized with portal hypertension but without known pulmonary hypertension underwent cardiac catheterization; 10 patients (2%) had pulmonary hypertension and more than half were clinically asymptomatic. Finally, the Registry to Evaluate Early And Long-term pulmonary arterial hypertension disease management (REVEAL registry) documented a 5.3% frequency of POPH (174 of 3525) in the United States.¹⁵

Prognosis

Individuals with POPH have worse outcomes compared to other forms of PAH. Median survival prior to the introduction of vasodilator therapy was a dismal 6 months and mean survival was 15 months.¹⁶ The cause of death in patients with POPH is equally distributed between right heart failure from POPH and direct complications of chronic liver disease.¹ Le Pavec et al retrospectively analyzed all patients referred to the French Referral Center with POPH between 1984 and 2004 (154 patients).¹ Approximately 50% of the patients were Child-Turcotte-Pugh class B or C, and 60% were classified as New York Health Association (NYHA) class III or IV. In these patients, 1-, 3-, and 5-year survival rates were 88%, 75%, and 68%, respectively. Major independent prognostic risk factors were presence and severity of cirrhosis and preservation of right ventricular function. Interestingly, NYHA functional class was not related to survival in this study, although it has clearly been identified as a strong prognostic factor in idiopathic PAH.

Krowka et al evaluated 174 patients with POPH enrolled in the REVEAL Registry,¹⁵ a multicenter, observational, US-based study comprised of more than 3500 patients with PAH. Despite having better hemodynamic parameters at diagnosis, patients with POPH had significantly poorer survival and all-cause hospitalization compared with patients with idiopathic PAH (IPAH) or hereditary PAH (HPAH). Two-year survival from enrollment was 67% in POPH versus 85% in those with IPAH/HPAH (P < 0.001). Five-year survival from time of diagnosis was 40% versus 64% (P < 0.001). Additionally, patients with POPH were less likely to be on PAH-specific therapy at enrollment, with only 25% on treatment at the time of entry. These findings were replicated in 2005 when Kawut et al retrospectively compared 13 patients with POPH with 33 patients with IPAH.¹⁷ Despite having a higher cardiac index and lower pulmonary vascular resistance than patients with IPAH, patients with POPH had a higher risk of death (hazard ratio, 2.8, P = 0.04), likely reflecting the combination of 2 serious diseases.

In 2008 the Mayo Clinic published their retrospective analysis of patients with POPH to determine the natural history of POPH.¹⁸ Patients were categorized into 3 groups: (1) no medical therapy for POPH and no liver transplant; (2) medical therapy for POPH alone; (3) medical therapy for POPH followed by liver transplant. The study included 74 patients between 1994 through 2007; 19 patients who did not receive treatment for POPH or liver transplant truly represented the natural history of POPH. Their 5-year survival was only 14%, and over half were deceased 1 year after diagnosis. The largest group consisted of patients who received therapy for POPH but no liver transplant. This group did remarkably better than those who received no therapy at all, with a 5-year survival of 45%. However, the patients with the overall best survival were those who received a combination of treatment for POPH followed by liver transplant. Their 5-year survival was 67%. Survival at 5 years was only 25% for the small group of patients who received transplant without PAH therapy. Once again, mortality did not correlate with the severity of hepatic dysfunction or baseline hemodynamic data.

Pathogenesis

The pathogenesis of POPH is unclear. Multiple studies have shown that there is minimal, if any, association with pulmonary hypertension and the severity of liver disease or portal hypertension.^19,20 Portal hypertension is the result of an increase in intrahepatic resistance and an increase in blood flow into the portal circulation. Collateral vessels develop and blood from the splanchnic circulation is allowed directly into the systemic venous circulation, bypassing the liver. One of the most widely accepted theories is that a humoral substance, that would otherwise be metabolized by the liver, is able to reach the pulmonary circulation through collaterals, resulting in POPH.²¹ Pelicelli et al evaluated the possible role of endothelin-1, interleukin-6, interleukin 1β, and tumor necrosis factor in the pathogenesis of POPH.²² Plasma concentrations of these cytokines were compared between patients with POPH and patients with cirrhosis but no POPH. Patients with POPH had higher concentrations of endothelin-1 and interleukin-6, suggesting antagonists for these cytokines may have a role in the treatment of POPH. The role of endothelin-1 was further supported by Kamath et al in 2000²³ when they determined the pulmonary vascular bed is exposed to increased levels of circulating endothelin-1a in the setting of cirrhosis. Endothelin-1 is a potent vasoconstrictor and facilitator of smooth muscle proliferation.

In addition to collateral circulation allowing mediators to reach the pulmonary arterial bed in portal hypertension, high flow may trigger a vasoproliferative process in the pulmonary vascular bed. Patients with advanced liver disease have a low systemic vascular resistance, with a compensatory increase in cardiac output. An increase in cardiac output can lead to shear stress of the pulmonary vascular endothelial layer. Although the resistance of the pulmonary vasculature may decrease rapidly to help normalize pulmonary pressures, persistent circulatory overload could result in irreversible vascular changes. Autopsy and lung explant studies show that POPH is characterized by obstructive and remodeling changes in the pulmonary arterial bed.²⁴ Initially, medial hypertrophy with smooth muscle proliferation is present. As the disease advances, platelet aggregates, in situ thrombosis, and intimal fibrosis develop. Finally, web-like lesions involving the entire pulmonary wall develop with recanalization for the passage of pulmonary arterial flow. These changes are identical to the changes observed in patients with other forms of PAH.

Not all patients with portal hypertension develop POPH, suggesting that genetic predisposition may play a role in POPH development. The Pulmonary Vascular Complications of Liver Study Group published a multicenter case-control study that attempted to identify genetic risk factors for POPH in patients with advanced liver disease.²⁵ More than 1000 common single nucleotide polymorphisms (SNPs) in 93 candidate genes were genotyped in each patient. When compared to controls, multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with an increased risk of POPH. One year earlier, the same study group concluded that female sex (adjusted odds ratio [OR], 2.90) and autoimmune hepatitis (adjusted OR, 4.02) were associated with a higher risk for POPH, whereas hepatitis C was associated with a decreased risk.²⁰

Clinical Presentation

Clinical presentation is variable in POPH. Patients referred to a pulmonologist will usually present with symptoms similar to patients with other forms of PAH. In a retrospective analysis of patients referred to the French Referral Center for Pulmonary Hypertension, 60% of the patients belonged to NYHA functional class III or IV.¹ In a series of 78 patients with POPH, the most common presenting pulmonary symptom was dyspnea on exertion (81%), followed by syncope, chest pain, and fatigue (< 33%).¹⁶ Symptoms such as syncope and chest pain are usually markers of severe POPH.³ Stigmata of portal hypertension, such as ascites, spider angiomata, and palmar erythema, may be present on exam. An accentuated pulmonary component of the second heart sound can be seen in 82% of patients and a systolic murmur caused by tricuspid regurgitation in 69% of patients.¹⁶ Patients with severe POPH may have jugular vein distention, peripheral edema, and a third heart sound.

Diagnostic Evaluation

Chest x-rays may show prominent pulmonary arteries and cardiomegaly in patients with POPH, whereas electrocardiogram can suggest right ventricular hypertrophy and right axis deviation. The best screening test for POPH in patients with portal hypertension is echocardiography. Routine screening for POPH is recommended during liver transplant evaluation in the practice guidelines from the American Association for the Study of Liver Disease.²⁶ Right-sided cardiac chamber enlargement and right ventricular pressure or volume overload can be assessed on echocardiography. Colle et al followed 165 patients evaluated for liver transplantation who underwent transthoracic Doppler echocardiography and right heart catheterization.²⁷ Seventeen patients met the criteria for POPH on echocardiography (presence of tricuspid regurgitation and calculated systolic pulmonary artery pressure over 30 mm Hg) and right heart catheterization confirmed the diagnosis in 10 patients. Right ventricular systolic pressure (RVSP) estimate of ≤ 30 mm Hg on 2-dimensional echo had a 100% sensitivity and negative predictive value. Positive predictive value was poor at 59%, reiterating the need for right heart catheterization in the diagnosis of POPH. When Kim et al used a RVSP threshold of 50 mm Hg, 72% had at least moderate pulmonary hypertension, including 30% with severe pulmonary hypertension.²⁸ Raevens et al analyzed data from 152 patients who underwent pretransplant echocardiography and catheterization.² Their data show a RVSP threshold of greater than 38 mm Hg by echocardiography had a specificity of 82% and sensitivity and negative predictive value of 100%. The European Respiratory Society recommendations state that PAH should be considered unlikely if echocardiography estimates a RVSP ≤36 mm Hg and likely if the RVSP is estimated at > 50 mm Hg.²⁹ We recommend repeating echocardiography every 6 to 12 months in patients listed for liver transplantation, as pulmonary hemodynamics may change over time.

Computed tomography (CT) may have a complementary role in the future for the noninvasive detection of POPH. In a study published in 2014, 49 patients referred for liver transplantation were retrospectively reviewed.³⁰ Measured CT signs included the main pulmonary artery/ascending aorta diameter ratio, the mean left and right main pulmonary artery diameter, and the enlargement of the pulmonary artery compared to the ascending aorta. Compared to the transthoracic echocardiography alone, an algorithm incorporating CT and echocardiography improved the detection of POPH (area under curve = 0.8, P < 0.0001).

A diagnosis of POPH can only be confirmed when PAH exists in a patient with portal hypertension, as determined by right heart catheterization, and no other cause of PAH can be identified. MPAP should be 25 mm Hg or greater, PVR of 240 dynes/s/cm^–5, wedge pressure of 15 mm Hg or less, and TPG greater than 12 mm Hg. Krowka et al showed the value of right heart catheterization in their 10-year prospective, echocardiography-catheterization algorithm study.¹⁹ Of 1235 liver transplant candidates who underwent echocardiography, 104 patients had a RVSP exceeding 50 mm Hg. Almost all of these patients had a right heart catheterization. All cause pulmonary hypertension (MPAP > 25 mm Hg) was confirmed in 90% of the patients, and 35% had a PVR < 240 dynes/s/cm^–5 and pulmonary capillary wedge pressure (PCWP) > 15 mm Hg, suggesting fluid overload. Forty-one patients had significant POPH, with a PVR > 400 dynes/s/cm^–5, and 24% also had an elevated PCWP. TPG was > 12 mm Hg in all of these patients, confirming POPH. As demonstrated by this study, right heart catheterization is required to confirm the diagnosis of POPH because high flow and fluid overload can lead to elevated pulmonary artery pressures.

Patients with POPH have a unique clinical profile with characteristics common to patients with primary pulmonary hypertension and chronic liver disease. In a retrospective review that compared 30 patients with PAH, 30 patients with chronic liver disease only, and 30 patients with catheterization-proved POPH,³¹ patients with POPH had elevated MPAP similar to those with primary PAH, but they also had reduced SVR and elevated cardiac index similar to those with chronic liver disease alone.

Besides POPH, 2 other common causes can lead to increased pulmonary arterial blood flow in patients with portal hypertension. First is a high-flow condition caused by increased cardiac output but with a normal PVR and PCWP. Fluid overload can also lead to pulmonary venous hypertension with increased PCWP, normal cardiac output, and normal PVR. Up to 25% of patients with POPH may present with marked excess volume caused by fluid retention.³ There can be an increase in both PCWP and PVR depending on the presence and the degree of fluid retention. TPG (MPAP – PCWP) > 12 mm Hg was introduced to make such patients less confusing and to help correct for increased PCWP secondary to fluid overload. Obstruction to pulmonary arterial flow is manifest by an increased TPG (Table 2).

POPH should be distinguished from hepatopulmonary syndrome (HPS), which is another pulmonary vascular consequence of liver disease. Unlike POPH, HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilation.³² Similar to other patients with liver disease, patients with HPS have a normal PVR and increased cardiac output secondary to a high-flow state. HPS is diagnosed by confirmation of an intrapulmonary shunt by echocardiogram. Injection of agitated saline results in saline bubbles being visualized in the left atrium 3 or more cardiac cycles after they appear in the right atrium. Currently, there is no effective medical treatment for HPS and liver transplantation is the only successful treatment.

Conclusion

POPH is an uncommon complication of chronic liver disease. It is defined as PAH in a patient with portal hypertension excluding other causes of PAH. The following criteria must be met to make a diagnosis of POPH: (1) evidence of portal hypertension; (2) MPAP ≥ 35 mm Hg; (3) PVR ≥ 240 dynes/s/cm⁵; (4) pulmonary capillary wedge pressure ≤ 15 mm Hg; and (5) TPG > 12 mm Hg. Individuals with POPH have worse outcomes compared to other forms of PAH, with a median survival of 6 months without medical therapy. The pathogenesis of POPH is unclear but may be related to a genetic predisposition since not all patients with portal hypertension develop POPH. Echocardiography is an excellent screening test for POPH, but a right heart catheterization must be performed to confirm the diagnosis.

Pulmonary arterial hypertension (PAH) is a rare disease that is associated with high mortality and is characterized by pulmonary vascular remodeling. Portopulmonary hypertension (POPH) is a form of PAH that occurs in patients with portal hypertension where no alternative cause of PAH can be identified. POPH is documented in approximately 4.5% to 8.5% of liver transplant candidates,^1,2 but there is no relationship between the existence or severity of POPH and the severity of liver dysfunction.³ Mantz and Craig described the first case of POPH in a 53-year-old woman with enlarged pulmonary arteries that exhibited forceful pulsations more characteristic of the aorta than a low-pressure pulmonary trunk.⁴ Autopsy revealed findings of chronic liver disease including a stenotic portal vein, portocaval shunt, and esophageal varices. In both PAH and POPH, pre-capillary pulmonary arteries have characteristic lesions, such as intimal thickening, endothelial proliferation, and thrombotic changes. This 2-part article reviews the diagnosis and treatment of patients with POPH. Here, we review the epidemiology, prognosis, pathogenesis, and diagnosis of POPH; current treatment options for POPH are reviewed in a separate article.

Definition

The term POPH was first used by Yoshida et al in 1993 to describe the first successful liver transplant in a patient with POPH, a 39-year-old man with chronic hepatitis.⁵ The World Health Organization (WHO) classifies POPH as a form of Group 1 PAH.⁶ The criteria that must be met to make a diagnosis of POPH are shown in the Table 1.⁷

Moderate POPH is defined as a mean pulmonary artery pressure (MPAP) between 35 mm Hg and < 45 mm Hg, whereas severe POPH is MPAP ≥ 45 mm Hg. Moderate and severe POPH are considered contraindications to liver transplant because of high perioperative and postoperative mortality rates.⁸ In 2000, the Mayo Clinic retrospectively reviewed 43 patients with POPH who underwent attempted liver transplantation.⁹ The cardiopulmonary-related mortality rate in patients with a MPAP of 35 to < 50 mm Hg was 50% and 100% for those with MPAP > 50 mm Hg. No mortality was noted in patients with a pre-liver transplant MPAP of < 35 mm Hg and transpulmonary gradient (TPG) < 15 mm Hg.

Epidemiology

In 1983, a series of 17,901 autopsied patients showed a primary pulmonary hypertension prevalence of 0.13% and a prevalence of 0.73% in patients with cirrhosis.¹⁰ In 1987, Rich et al published data from the National Institutes of Health’s national registry of primary pulmonary hypertension.¹¹ The registry included data from 187 patients from 32 centers. Further analyses by Groves et al concluded that 8.3% of the patients likely had POPH.¹² Humbert et al published data on the French pulmonary hypertension registry experience in 2006.¹³ The French registry included 674 patients from 17 university hospitals; 10.4% of these patients had POPH. The largest prospective study was published by Hadengue et al in 1991.¹⁴ In this study, 507 patients hospitalized with portal hypertension but without known pulmonary hypertension underwent cardiac catheterization; 10 patients (2%) had pulmonary hypertension and more than half were clinically asymptomatic. Finally, the Registry to Evaluate Early And Long-term pulmonary arterial hypertension disease management (REVEAL registry) documented a 5.3% frequency of POPH (174 of 3525) in the United States.¹⁵

Prognosis

Individuals with POPH have worse outcomes compared to other forms of PAH. Median survival prior to the introduction of vasodilator therapy was a dismal 6 months and mean survival was 15 months.¹⁶ The cause of death in patients with POPH is equally distributed between right heart failure from POPH and direct complications of chronic liver disease.¹ Le Pavec et al retrospectively analyzed all patients referred to the French Referral Center with POPH between 1984 and 2004 (154 patients).¹ Approximately 50% of the patients were Child-Turcotte-Pugh class B or C, and 60% were classified as New York Health Association (NYHA) class III or IV. In these patients, 1-, 3-, and 5-year survival rates were 88%, 75%, and 68%, respectively. Major independent prognostic risk factors were presence and severity of cirrhosis and preservation of right ventricular function. Interestingly, NYHA functional class was not related to survival in this study, although it has clearly been identified as a strong prognostic factor in idiopathic PAH.

Krowka et al evaluated 174 patients with POPH enrolled in the REVEAL Registry,¹⁵ a multicenter, observational, US-based study comprised of more than 3500 patients with PAH. Despite having better hemodynamic parameters at diagnosis, patients with POPH had significantly poorer survival and all-cause hospitalization compared with patients with idiopathic PAH (IPAH) or hereditary PAH (HPAH). Two-year survival from enrollment was 67% in POPH versus 85% in those with IPAH/HPAH (P < 0.001). Five-year survival from time of diagnosis was 40% versus 64% (P < 0.001). Additionally, patients with POPH were less likely to be on PAH-specific therapy at enrollment, with only 25% on treatment at the time of entry. These findings were replicated in 2005 when Kawut et al retrospectively compared 13 patients with POPH with 33 patients with IPAH.¹⁷ Despite having a higher cardiac index and lower pulmonary vascular resistance than patients with IPAH, patients with POPH had a higher risk of death (hazard ratio, 2.8, P = 0.04), likely reflecting the combination of 2 serious diseases.

In 2008 the Mayo Clinic published their retrospective analysis of patients with POPH to determine the natural history of POPH.¹⁸ Patients were categorized into 3 groups: (1) no medical therapy for POPH and no liver transplant; (2) medical therapy for POPH alone; (3) medical therapy for POPH followed by liver transplant. The study included 74 patients between 1994 through 2007; 19 patients who did not receive treatment for POPH or liver transplant truly represented the natural history of POPH. Their 5-year survival was only 14%, and over half were deceased 1 year after diagnosis. The largest group consisted of patients who received therapy for POPH but no liver transplant. This group did remarkably better than those who received no therapy at all, with a 5-year survival of 45%. However, the patients with the overall best survival were those who received a combination of treatment for POPH followed by liver transplant. Their 5-year survival was 67%. Survival at 5 years was only 25% for the small group of patients who received transplant without PAH therapy. Once again, mortality did not correlate with the severity of hepatic dysfunction or baseline hemodynamic data.

Pathogenesis

The pathogenesis of POPH is unclear. Multiple studies have shown that there is minimal, if any, association with pulmonary hypertension and the severity of liver disease or portal hypertension.^19,20 Portal hypertension is the result of an increase in intrahepatic resistance and an increase in blood flow into the portal circulation. Collateral vessels develop and blood from the splanchnic circulation is allowed directly into the systemic venous circulation, bypassing the liver. One of the most widely accepted theories is that a humoral substance, that would otherwise be metabolized by the liver, is able to reach the pulmonary circulation through collaterals, resulting in POPH.²¹ Pelicelli et al evaluated the possible role of endothelin-1, interleukin-6, interleukin 1β, and tumor necrosis factor in the pathogenesis of POPH.²² Plasma concentrations of these cytokines were compared between patients with POPH and patients with cirrhosis but no POPH. Patients with POPH had higher concentrations of endothelin-1 and interleukin-6, suggesting antagonists for these cytokines may have a role in the treatment of POPH. The role of endothelin-1 was further supported by Kamath et al in 2000²³ when they determined the pulmonary vascular bed is exposed to increased levels of circulating endothelin-1a in the setting of cirrhosis. Endothelin-1 is a potent vasoconstrictor and facilitator of smooth muscle proliferation.

In addition to collateral circulation allowing mediators to reach the pulmonary arterial bed in portal hypertension, high flow may trigger a vasoproliferative process in the pulmonary vascular bed. Patients with advanced liver disease have a low systemic vascular resistance, with a compensatory increase in cardiac output. An increase in cardiac output can lead to shear stress of the pulmonary vascular endothelial layer. Although the resistance of the pulmonary vasculature may decrease rapidly to help normalize pulmonary pressures, persistent circulatory overload could result in irreversible vascular changes. Autopsy and lung explant studies show that POPH is characterized by obstructive and remodeling changes in the pulmonary arterial bed.²⁴ Initially, medial hypertrophy with smooth muscle proliferation is present. As the disease advances, platelet aggregates, in situ thrombosis, and intimal fibrosis develop. Finally, web-like lesions involving the entire pulmonary wall develop with recanalization for the passage of pulmonary arterial flow. These changes are identical to the changes observed in patients with other forms of PAH.

Not all patients with portal hypertension develop POPH, suggesting that genetic predisposition may play a role in POPH development. The Pulmonary Vascular Complications of Liver Study Group published a multicenter case-control study that attempted to identify genetic risk factors for POPH in patients with advanced liver disease.²⁵ More than 1000 common single nucleotide polymorphisms (SNPs) in 93 candidate genes were genotyped in each patient. When compared to controls, multiple SNPs in the genes coding for estrogen receptor 1, aromatase, phosphodiesterase 5, angiopoietin 1, and calcium binding protein A4 were associated with an increased risk of POPH. One year earlier, the same study group concluded that female sex (adjusted odds ratio [OR], 2.90) and autoimmune hepatitis (adjusted OR, 4.02) were associated with a higher risk for POPH, whereas hepatitis C was associated with a decreased risk.²⁰

Clinical Presentation

Clinical presentation is variable in POPH. Patients referred to a pulmonologist will usually present with symptoms similar to patients with other forms of PAH. In a retrospective analysis of patients referred to the French Referral Center for Pulmonary Hypertension, 60% of the patients belonged to NYHA functional class III or IV.¹ In a series of 78 patients with POPH, the most common presenting pulmonary symptom was dyspnea on exertion (81%), followed by syncope, chest pain, and fatigue (< 33%).¹⁶ Symptoms such as syncope and chest pain are usually markers of severe POPH.³ Stigmata of portal hypertension, such as ascites, spider angiomata, and palmar erythema, may be present on exam. An accentuated pulmonary component of the second heart sound can be seen in 82% of patients and a systolic murmur caused by tricuspid regurgitation in 69% of patients.¹⁶ Patients with severe POPH may have jugular vein distention, peripheral edema, and a third heart sound.

Diagnostic Evaluation

Chest x-rays may show prominent pulmonary arteries and cardiomegaly in patients with POPH, whereas electrocardiogram can suggest right ventricular hypertrophy and right axis deviation. The best screening test for POPH in patients with portal hypertension is echocardiography. Routine screening for POPH is recommended during liver transplant evaluation in the practice guidelines from the American Association for the Study of Liver Disease.²⁶ Right-sided cardiac chamber enlargement and right ventricular pressure or volume overload can be assessed on echocardiography. Colle et al followed 165 patients evaluated for liver transplantation who underwent transthoracic Doppler echocardiography and right heart catheterization.²⁷ Seventeen patients met the criteria for POPH on echocardiography (presence of tricuspid regurgitation and calculated systolic pulmonary artery pressure over 30 mm Hg) and right heart catheterization confirmed the diagnosis in 10 patients. Right ventricular systolic pressure (RVSP) estimate of ≤ 30 mm Hg on 2-dimensional echo had a 100% sensitivity and negative predictive value. Positive predictive value was poor at 59%, reiterating the need for right heart catheterization in the diagnosis of POPH. When Kim et al used a RVSP threshold of 50 mm Hg, 72% had at least moderate pulmonary hypertension, including 30% with severe pulmonary hypertension.²⁸ Raevens et al analyzed data from 152 patients who underwent pretransplant echocardiography and catheterization.² Their data show a RVSP threshold of greater than 38 mm Hg by echocardiography had a specificity of 82% and sensitivity and negative predictive value of 100%. The European Respiratory Society recommendations state that PAH should be considered unlikely if echocardiography estimates a RVSP ≤36 mm Hg and likely if the RVSP is estimated at > 50 mm Hg.²⁹ We recommend repeating echocardiography every 6 to 12 months in patients listed for liver transplantation, as pulmonary hemodynamics may change over time.

Computed tomography (CT) may have a complementary role in the future for the noninvasive detection of POPH. In a study published in 2014, 49 patients referred for liver transplantation were retrospectively reviewed.³⁰ Measured CT signs included the main pulmonary artery/ascending aorta diameter ratio, the mean left and right main pulmonary artery diameter, and the enlargement of the pulmonary artery compared to the ascending aorta. Compared to the transthoracic echocardiography alone, an algorithm incorporating CT and echocardiography improved the detection of POPH (area under curve = 0.8, P < 0.0001).

A diagnosis of POPH can only be confirmed when PAH exists in a patient with portal hypertension, as determined by right heart catheterization, and no other cause of PAH can be identified. MPAP should be 25 mm Hg or greater, PVR of 240 dynes/s/cm^–5, wedge pressure of 15 mm Hg or less, and TPG greater than 12 mm Hg. Krowka et al showed the value of right heart catheterization in their 10-year prospective, echocardiography-catheterization algorithm study.¹⁹ Of 1235 liver transplant candidates who underwent echocardiography, 104 patients had a RVSP exceeding 50 mm Hg. Almost all of these patients had a right heart catheterization. All cause pulmonary hypertension (MPAP > 25 mm Hg) was confirmed in 90% of the patients, and 35% had a PVR < 240 dynes/s/cm^–5 and pulmonary capillary wedge pressure (PCWP) > 15 mm Hg, suggesting fluid overload. Forty-one patients had significant POPH, with a PVR > 400 dynes/s/cm^–5, and 24% also had an elevated PCWP. TPG was > 12 mm Hg in all of these patients, confirming POPH. As demonstrated by this study, right heart catheterization is required to confirm the diagnosis of POPH because high flow and fluid overload can lead to elevated pulmonary artery pressures.

Patients with POPH have a unique clinical profile with characteristics common to patients with primary pulmonary hypertension and chronic liver disease. In a retrospective review that compared 30 patients with PAH, 30 patients with chronic liver disease only, and 30 patients with catheterization-proved POPH,³¹ patients with POPH had elevated MPAP similar to those with primary PAH, but they also had reduced SVR and elevated cardiac index similar to those with chronic liver disease alone.

Besides POPH, 2 other common causes can lead to increased pulmonary arterial blood flow in patients with portal hypertension. First is a high-flow condition caused by increased cardiac output but with a normal PVR and PCWP. Fluid overload can also lead to pulmonary venous hypertension with increased PCWP, normal cardiac output, and normal PVR. Up to 25% of patients with POPH may present with marked excess volume caused by fluid retention.³ There can be an increase in both PCWP and PVR depending on the presence and the degree of fluid retention. TPG (MPAP – PCWP) > 12 mm Hg was introduced to make such patients less confusing and to help correct for increased PCWP secondary to fluid overload. Obstruction to pulmonary arterial flow is manifest by an increased TPG (Table 2).

POPH should be distinguished from hepatopulmonary syndrome (HPS), which is another pulmonary vascular consequence of liver disease. Unlike POPH, HPS is characterized by a defect in arterial oxygenation induced by pulmonary vascular dilation.³² Similar to other patients with liver disease, patients with HPS have a normal PVR and increased cardiac output secondary to a high-flow state. HPS is diagnosed by confirmation of an intrapulmonary shunt by echocardiogram. Injection of agitated saline results in saline bubbles being visualized in the left atrium 3 or more cardiac cycles after they appear in the right atrium. Currently, there is no effective medical treatment for HPS and liver transplantation is the only successful treatment.

Conclusion

POPH is an uncommon complication of chronic liver disease. It is defined as PAH in a patient with portal hypertension excluding other causes of PAH. The following criteria must be met to make a diagnosis of POPH: (1) evidence of portal hypertension; (2) MPAP ≥ 35 mm Hg; (3) PVR ≥ 240 dynes/s/cm⁵; (4) pulmonary capillary wedge pressure ≤ 15 mm Hg; and (5) TPG > 12 mm Hg. Individuals with POPH have worse outcomes compared to other forms of PAH, with a median survival of 6 months without medical therapy. The pathogenesis of POPH is unclear but may be related to a genetic predisposition since not all patients with portal hypertension develop POPH. Echocardiography is an excellent screening test for POPH, but a right heart catheterization must be performed to confirm the diagnosis.

Dear colleagues,

I am excited to introduce the November issue of The New Gastroenterologist – which is also my first issue as the new Editor in Chief! First, I am incredibly grateful for this opportunity to be a part of the only existing publication tailored toward trainees and early-career gastroenterologists. Bryson Katona has done a remarkable job for the last 5 years as the publication’s inaugural EIC, as he has laid a great deal of groundwork and really set the standard going forward. Each issue has been a multifaceted compilation of salient clinical topics paired with brief but high-yield articles to help guide personal and professional growth; I hope to continue to do the same and maintain a high level of interest in our newsletter.

In this issue, the In Focus article, brought to you by Adeeti Chiplunker and Christina Ha (Cedars Sinai), discusses inpatient management of acute severe ulcerative colitis. It is an excellent review of the diagnostic workup and therapeutic options, and an important one, as therapies are quickly evolving in inflammatory bowel disease. We also have Manol Jovani (Johns Hopkins) help us navigate the daunting world of statistics, specifically focusing on the interpretation of the P value.

For those interested in or already pursuing careers in private practice but would not like to relinquish their research interests, Chris Fourment (Texas Digestive Disease Consultants) provides a series of helpful tips on how to be effective in conducting clinical research endeavors. In the realm of basic science, Melinda Engevik (Baylor College of Medicine) gives an informative breakdown on how to choose a lab that is the right fit for you.

Also in this issue, Sadeea Abbasi (Cedars Sinai) provides an array of tangible ways for gastroenterologists to become involved in health policy advocacy. Byron Cryer (UT Southwestern), Jesus Rivera-Nieves (UCSD), and Celena NuQuay (AGA) describe how the AGA has been promoting workforce diversity in academic gastroenterology via the FORWARD (Fostering Opportunities Resulting in Workforce and Research Diversity) program.

Finally, as the submission deadline for DDW^® 2020 approaches, abstract reviewers for the fellow-directed quality improvement (QI) projects from this past year share helpful tips on crafting memorable QI abstracts (Mohammad Bilal, UT-Galveston; Chung Sang Tse, Brown University; Manol Jovani, Johns Hopkins; and Mer Mietzelfeld, AGA).

If you are interested in contributing or have ideas for future TNG topics, please contact me ([email protected]), or Ryan Farrell ([email protected]), managing editor of TNG.
 

Sincerely,

Vijaya L. Rao, MD
Editor in Chief

Dr. Rao is assistant professor of medicine, University of Chicago, section of gastroenterology, hepatology & nutrition.

Dear colleagues,

I am excited to introduce the November issue of The New Gastroenterologist – which is also my first issue as the new Editor in Chief! First, I am incredibly grateful for this opportunity to be a part of the only existing publication tailored toward trainees and early-career gastroenterologists. Bryson Katona has done a remarkable job for the last 5 years as the publication’s inaugural EIC, as he has laid a great deal of groundwork and really set the standard going forward. Each issue has been a multifaceted compilation of salient clinical topics paired with brief but high-yield articles to help guide personal and professional growth; I hope to continue to do the same and maintain a high level of interest in our newsletter.

In this issue, the In Focus article, brought to you by Adeeti Chiplunker and Christina Ha (Cedars Sinai), discusses inpatient management of acute severe ulcerative colitis. It is an excellent review of the diagnostic workup and therapeutic options, and an important one, as therapies are quickly evolving in inflammatory bowel disease. We also have Manol Jovani (Johns Hopkins) help us navigate the daunting world of statistics, specifically focusing on the interpretation of the P value.

For those interested in or already pursuing careers in private practice but would not like to relinquish their research interests, Chris Fourment (Texas Digestive Disease Consultants) provides a series of helpful tips on how to be effective in conducting clinical research endeavors. In the realm of basic science, Melinda Engevik (Baylor College of Medicine) gives an informative breakdown on how to choose a lab that is the right fit for you.

Also in this issue, Sadeea Abbasi (Cedars Sinai) provides an array of tangible ways for gastroenterologists to become involved in health policy advocacy. Byron Cryer (UT Southwestern), Jesus Rivera-Nieves (UCSD), and Celena NuQuay (AGA) describe how the AGA has been promoting workforce diversity in academic gastroenterology via the FORWARD (Fostering Opportunities Resulting in Workforce and Research Diversity) program.

Finally, as the submission deadline for DDW^® 2020 approaches, abstract reviewers for the fellow-directed quality improvement (QI) projects from this past year share helpful tips on crafting memorable QI abstracts (Mohammad Bilal, UT-Galveston; Chung Sang Tse, Brown University; Manol Jovani, Johns Hopkins; and Mer Mietzelfeld, AGA).

If you are interested in contributing or have ideas for future TNG topics, please contact me ([email protected]), or Ryan Farrell ([email protected]), managing editor of TNG.
 

Sincerely,

Vijaya L. Rao, MD
Editor in Chief

Dr. Rao is assistant professor of medicine, University of Chicago, section of gastroenterology, hepatology & nutrition.

Dear colleagues,

I am excited to introduce the November issue of The New Gastroenterologist – which is also my first issue as the new Editor in Chief! First, I am incredibly grateful for this opportunity to be a part of the only existing publication tailored toward trainees and early-career gastroenterologists. Bryson Katona has done a remarkable job for the last 5 years as the publication’s inaugural EIC, as he has laid a great deal of groundwork and really set the standard going forward. Each issue has been a multifaceted compilation of salient clinical topics paired with brief but high-yield articles to help guide personal and professional growth; I hope to continue to do the same and maintain a high level of interest in our newsletter.

In this issue, the In Focus article, brought to you by Adeeti Chiplunker and Christina Ha (Cedars Sinai), discusses inpatient management of acute severe ulcerative colitis. It is an excellent review of the diagnostic workup and therapeutic options, and an important one, as therapies are quickly evolving in inflammatory bowel disease. We also have Manol Jovani (Johns Hopkins) help us navigate the daunting world of statistics, specifically focusing on the interpretation of the P value.

For those interested in or already pursuing careers in private practice but would not like to relinquish their research interests, Chris Fourment (Texas Digestive Disease Consultants) provides a series of helpful tips on how to be effective in conducting clinical research endeavors. In the realm of basic science, Melinda Engevik (Baylor College of Medicine) gives an informative breakdown on how to choose a lab that is the right fit for you.

Also in this issue, Sadeea Abbasi (Cedars Sinai) provides an array of tangible ways for gastroenterologists to become involved in health policy advocacy. Byron Cryer (UT Southwestern), Jesus Rivera-Nieves (UCSD), and Celena NuQuay (AGA) describe how the AGA has been promoting workforce diversity in academic gastroenterology via the FORWARD (Fostering Opportunities Resulting in Workforce and Research Diversity) program.

Finally, as the submission deadline for DDW^® 2020 approaches, abstract reviewers for the fellow-directed quality improvement (QI) projects from this past year share helpful tips on crafting memorable QI abstracts (Mohammad Bilal, UT-Galveston; Chung Sang Tse, Brown University; Manol Jovani, Johns Hopkins; and Mer Mietzelfeld, AGA).

If you are interested in contributing or have ideas for future TNG topics, please contact me ([email protected]), or Ryan Farrell ([email protected]), managing editor of TNG.
 

Sincerely,

Vijaya L. Rao, MD
Editor in Chief

Dr. Rao is assistant professor of medicine, University of Chicago, section of gastroenterology, hepatology & nutrition.

Introduction

Inpatient management of acute ulcerative colitis (UC) flares can be challenging because of the multiple patient and disease-related factors influencing therapeutic decision making. The clinical course during the first 24-72 hours of the hospitalization will likely guide the decision between rescue medical and surgical therapy. Using available evidence from clinical practice guidelines, we present a day-by-day guide to managing most hospitalized UC patients.

Day 0 – The emergency department (ED)

When an UC patient presents to the ED for evaluation, the initial assessments should focus on the acuity and severity of the flare. Key clinical features of disease severity include the presence of fever, tachycardia, hypotension, or weight loss in addition to worsened gastrointestinal symptoms of stool frequency relative to baseline, rectal bleeding, and abdominal pain. Acute severe ulcerative colitis (ASUC) is often defined using the modified Truelove and Witts criteria.¹ A patient meets criteria for ASUC if they have at least six bloody stools per day and at least one sign of systemic toxicity, such as heart rate greater than 90 bpm, temperature at or above 37.8° C, hemoglobin level below 10.5 g/dL, or elevated inflammatory markers.

Initial laboratory assessments should include complete blood counts to identify anemia, potential superimposed infection, or toxicity and a comprehensive metabolic profile to evaluate for dehydration, electrolyte abnormalities, hepatic injury or hypoalbuminemia (an important predictor of surgery), as well as assessment of response to treatment and readmission.^2,3 An evaluation at admission of C-reactive protein (CRP) is crucial because changes from the initial value will determine steroid response and predict need for surgical intervention or rescue therapy. A baseline fecal calprotectin can serve as a noninvasive marker that can be followed after discharge to monitor response to therapy.

Clostridioides difficile infection (CDI) must be ruled out in all patients presenting with ASUC regardless of history of antibiotic use or prior negative testing. Concomitant UC and CDI are associated with a four- to sixfold increased risk of in-hospital mortality and a two- to sixfold increased risk of bowel surgery.^4-6 Immunoassay testing is inexpensive and fast with a high specificity but has low sensitivity; nucleic acid amplification testing with polymerase chain reaction has a high sensitivity and specificity.⁷ Knowing which testing algorithm the hospital lab uses helps guide interpretation of results.

For patients meeting criteria for ASUC, obtaining at least an abdominal x-ray is important to assess for colonic dilation to further stratify the patient by risk. Colonic dilation, defined as a transverse colon diameter greater than 5.5 cm, places the patient in the category of fulminant colitis and colorectal surgical consultation should be obtained.⁸ A CT scan is often ordered first because it can provide a rapid assessment of intra-abdominal processes but is not routinely needed unless hemodynamic instability, an acute abdomen, or markedly abnormal laboratory testing (specifically white blood cell count with bandemia) is present as these can be indicators of toxic megacolon or perforation.^8-10

Day 1 – Assess disease severity and assemble the team

Obtaining a thorough clinical history is essential to classify disease severity and identify potential triggers for the acute exacerbation. Potential triggers may include infections, new medications, recent antibiotic use, recent travel, sick contacts, or cessation of treatments. Standard questions include asking about the timing of onset of symptoms, bowel movements during a 24-hour period, and particularly the presence of nocturnal bowel movements. If patients report bloody stools, inquire how often they see blood relative to the total number of bowel movements. The presence and nature of abdominal pain should be elicited, particularly changes in abdominal pain and comparison with previous disease flares. These clinical parameters are used to assess response to treatment; therefore, ask patients to keep a log of their stool frequency, consistency, rectal urgency, and bleeding each day to report to the team during daily rounds.

Once disease severity has been determined, intravenous corticosteroid therapy may be initiated, ideally once CDI and CMV have been excluded. The recommended dosing of intravenous corticosteroids is methylprednisolone 20 mg IV every 8 hours or equivalent. There is no evidence to support additional benefit for doses exceeding these amounts.⁸ Prior to starting parenteral corticosteroids, it is important to keep in mind the possible need for rescue therapy during the admission. Recommended testing includes hepatitis B surface antigen and antibody, hepatitis B core antibody and tuberculosis testing if there is no documented negative testing within the past 6-12 months. These labs should be drawn prior to steroid treatment to avoid delays in care and indeterminate results. Finally, a lipid profile is recommended for patients who may be cyclosporine candidates pending response to intravenous corticosteroids. Unless the patient has been admitted with a bowel obstruction, which should raise the suspicion that the diagnosis is actually Crohn’s disease, enteral feeding is preferred for UC patients even if they may have significant food aversion. The early involvement of a registered dietitian is valuable to guide dietary choices and recommend appropriate enteral nutrition supplements. During acute flares, patients may find a low-residue diet to be less stimulating to their gut while their acute flare is being treated. Electrolyte abnormalities should be repleted and consistently monitored during the hospitalization. Providing parenteral intravenous iron for anemic patients will expedite correction of the anemia alongside treatment of the underlying UC.

Day 3 – Assessing response to corticosteroids

In addition to daily symptom assessments, a careful abdominal exam should be performed every day with the understanding that steroids (and also narcotics) may mask perforation or pain. Any abrupt decrease or cessation of bowel movements, increasing abdominal distention, or a sudden increase in abdominal pain or tenderness may require abdominal imaging to ensure no interim perforation or severe colonic dilation has occurred while receiving steroid therapy. In these circumstances, the addition of broad spectrum intravenous antibiotics should be considered, particularly if hemodynamic instability (such as tachycardia) is present.

Patients should be assessed for response to intravenous steroid therapy after 3 days of treatment. A meaningful response to corticosteroids is present if the patient has had more than 50% improvement in symptoms, particularly rectal bleeding and stool frequency. A more than 75% improvement in CRP should also be noted from admission to day 3 with an overall trend of improvement.^2,21 Additionally, patients should be afebrile, require minimal to no narcotic usage, tolerating oral intake, and be ambulatory. If the patient has met all these parameters, it is reasonable to transition to oral corticosteroids, such as prednisone 40-60 mg daily after a course of 3-5 days of intravenous corticosteroids. Ideally, patients should be observed for 24-48 hours in the hospital after transitioning to oral corticosteroids to make sure that symptoms do not worsen with the switch.

Patients with more than eight bowel movements per day, CRP greater than 4.5 g/dL, deep ulcers on endoscopy, or albumin less than 3.0 g/dL have a higher likelihood of failing intravenous corticosteroid therapy, and these patients should be prepared for rescue therapy.^2,21 A patient has failed intravenous corticosteroids by day 3 if they have sustained fever in the absence of an infection, continued CRP elevation or lack of CRP decrease, or ongoing high stool frequency, bleeding, and pain with less than 50% improvement from baseline on admission.⁸ In the setting of nonresponse to intravenous corticosteroids, it is prudent to involve colorectal surgery to discuss colectomy as an option of equal merit to medical salvage therapies such as infliximab or cyclosporine.

Infliximab is the most readily available rescue therapy for steroid-refractory patients and has been shown to increase colectomy-free survival in patients with ASUC.⁸ However, patients with the same predictors for intravenous steroid failures (low albumin, high CRP, and/or deep ulcers on endoscopy) are also at the highest risk for infliximab nonresponse. These factors are important to discuss with the patients and colorectal surgery teams when providing the options of treatment strategy, particularly with medication dosing. ASUC with more severe disease biochemically (low albumin, elevated CRP, possibly bandemia) benefit from a higher dose of infliximab at 10 mg/kg, given the likelihood of increased drug clearance in this situation.^22,23

From a practical standpoint, it is important to confirm the patient’s insurance status prior to medication administration to make sure therapy can be continued after hospital discharge. Early involvement of the social workers and case coordinators is key to ensuring timely administration of the next dose of treatment. Patients who receive infliximab rescue therapy should be monitored for an additional 1-2 days after administration to ensure they are responding to this therapy with continued monitoring of CRP and symptoms during this period. If there is no response at this point, an additional dose of infliximab may be considered but surgery should not be delayed if there is no meaningful response after the first dose.

Another option for intravenous corticosteroid nonresponders is intravenous cyclosporine because treatment failure rates for cyclosporine and infliximab were similar in head-to-head studies.²⁴ However, patient selection is key to successful utilization of this agent. Unlike infliximab, cyclosporine is primarily an induction agent for steroid nonresponders rather than a maintenance strategy. Therefore, in patients in whom cyclosporine is being considered, thiopurines or vedolizumab are potential options for maintenance therapy. If the patient has poor renal function, low cholesterol, advanced age, significant comorbidities, or a history of nonadherence to therapy, cyclosporine should not be given. Additionally, clinical experience with intravenous cyclosporine administration and monitoring both during inpatient and outpatient care settings should be factored into the decision making for infliximab versus cyclosporine.⁸
 

Day 5 and beyond – Discharge planning

Patients who have responded to the initial intravenous steroid course by hospital day 5 should have successfully transitioned to oral steroids with plans to start an appropriate steroid-sparing therapy shortly after discharge. Treatment planning should commence prior to discharge and should be communicated with the outpatient GI team to ensure a smooth transition to the ambulatory care setting, primarily to begin insurance authorizations as soon as possible. If the patient has had a meaningful response to infliximab rescue therapy (improvement by more than 50% in bowel frequency, amount of blood, abdominal pain), discharge planning needs to prioritize obtaining authorization for the second dose within 2 weeks of the initial infusion. These patients are high risk for readmission, and close outpatient follow-up by the ambulatory GI care team is necessary to help direct the tapering of steroids and monitor response to treatment.

If the patient has not responded to intravenous steroid therapy, infliximab, or cyclosporine by day 5-7, then surgery should be strongly considered. Delaying surgery may worsen outcomes as patients become more malnourished, anemic, and continue to receive intravenous steroids. Additional preoperative optimization may be required depending on the patient’s course up to this point (Table 2).
 

Summary

The cornerstones of inpatient UC management center on a thorough initial evaluation including imaging and endoscopy as appropriate, establishment of baseline parameters, and daily assessment of response to therapy through a combination of patient-reported outcomes and biomarkers of inflammation. With this strategy in mind, practitioners and care teams can manage these complex patients using a consistent strategy focusing on multidisciplinary, evidence-based care.

References

1. Truelove SC et al. Br Med J. 1955 Oct 23;2(4947):1041-8.

2. Ho GT et al. Aliment Pharmacol Ther. 2004 May 15;19(10):1079-87.


3. Tinsley A et al. Scand J Gastroenterol. 2015;50(9):1103-9.

4. Issa M et al. Clin Gastroenterol Hepatol. 2007 Mar;5(3):345-51.

5. Ananthakrishnan AN et al. Gut. 2008 Feb;57(2):205-10.

6. Negron ME et al. Am J Gastroenterol. 2016 May;111(5):691-704.

7. Taylor KN et al. Gynecol Oncol. 2017 Feb;144(2):428-37.

8. Rubin DT et al. Am J Gastroenterol. 2019 Mar;114(3):384-413.

9. Jalan KN et al. Gastroenterology. 1969 Jul;57(1):68-82.

10. Gan SI et al. Am J Gastroenterol. 2003 Nov;98(11):2363-71.

11. Makkar R et al. Gastroenterol Hepatol (N Y). 2013 Sep;9(9):573-83.

12. Hindryckx P et al. Nat Rev Gastroenterol Hepatol. 2016 Nov;13(11):654-64.

13. Yerushalmy-Feler A et al. Curr Infect Dis Rep. 2019 Feb 15;21(2):5.

14. Shukla T et al. J Clin Gastroenterol. 2017 May/Jun;51(5):394-401.

15. McCurdy JD et al. Clin Gastroenterol Hepatol. 2015 Jan;13(1):131-7; quiz e7.

16. Cottone M et al. Am J Gastroenterol. 2001 Mar;96(3):773-5.

17. Nguyen GC et al. Gastroenterology. 2014 Mar;146(3):835-48 e6.

18. Limsrivilai J et al. Clin Gastroenterol Hepatol. 2017 Mar;15(3):385-92 e2.

19. Targownik LE et al. Am J Gastroenterol. 2014 Oct;109(10):1613-20.

20. Takeuchi K et al. Clin Gastroenterol Hepatol. 2006 Feb;4(2):196-202.

21. Travis SP et al. Gut. 1996 Jun;38(6):905-10.

22. Syal G et al. Mo1891 - Gastroenterology. 2018;154:S841.

23. Ungar B et al. Aliment Pharmacol Ther. 2016 Jun;43(12):1293-9.

24. Laharie D et al. Lancet 2012 Dec 1;380(9857):1909-15.
 

Dr. Chiplunker is an advanced inflammatory bowel disease fellow; Dr. Ha is associate professor of medicine at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center, Los Angeles.

Introduction

Inpatient management of acute ulcerative colitis (UC) flares can be challenging because of the multiple patient and disease-related factors influencing therapeutic decision making. The clinical course during the first 24-72 hours of the hospitalization will likely guide the decision between rescue medical and surgical therapy. Using available evidence from clinical practice guidelines, we present a day-by-day guide to managing most hospitalized UC patients.

Day 0 – The emergency department (ED)

When an UC patient presents to the ED for evaluation, the initial assessments should focus on the acuity and severity of the flare. Key clinical features of disease severity include the presence of fever, tachycardia, hypotension, or weight loss in addition to worsened gastrointestinal symptoms of stool frequency relative to baseline, rectal bleeding, and abdominal pain. Acute severe ulcerative colitis (ASUC) is often defined using the modified Truelove and Witts criteria.¹ A patient meets criteria for ASUC if they have at least six bloody stools per day and at least one sign of systemic toxicity, such as heart rate greater than 90 bpm, temperature at or above 37.8° C, hemoglobin level below 10.5 g/dL, or elevated inflammatory markers.

Initial laboratory assessments should include complete blood counts to identify anemia, potential superimposed infection, or toxicity and a comprehensive metabolic profile to evaluate for dehydration, electrolyte abnormalities, hepatic injury or hypoalbuminemia (an important predictor of surgery), as well as assessment of response to treatment and readmission.^2,3 An evaluation at admission of C-reactive protein (CRP) is crucial because changes from the initial value will determine steroid response and predict need for surgical intervention or rescue therapy. A baseline fecal calprotectin can serve as a noninvasive marker that can be followed after discharge to monitor response to therapy.

Clostridioides difficile infection (CDI) must be ruled out in all patients presenting with ASUC regardless of history of antibiotic use or prior negative testing. Concomitant UC and CDI are associated with a four- to sixfold increased risk of in-hospital mortality and a two- to sixfold increased risk of bowel surgery.^4-6 Immunoassay testing is inexpensive and fast with a high specificity but has low sensitivity; nucleic acid amplification testing with polymerase chain reaction has a high sensitivity and specificity.⁷ Knowing which testing algorithm the hospital lab uses helps guide interpretation of results.

For patients meeting criteria for ASUC, obtaining at least an abdominal x-ray is important to assess for colonic dilation to further stratify the patient by risk. Colonic dilation, defined as a transverse colon diameter greater than 5.5 cm, places the patient in the category of fulminant colitis and colorectal surgical consultation should be obtained.⁸ A CT scan is often ordered first because it can provide a rapid assessment of intra-abdominal processes but is not routinely needed unless hemodynamic instability, an acute abdomen, or markedly abnormal laboratory testing (specifically white blood cell count with bandemia) is present as these can be indicators of toxic megacolon or perforation.^8-10

Day 1 – Assess disease severity and assemble the team

Obtaining a thorough clinical history is essential to classify disease severity and identify potential triggers for the acute exacerbation. Potential triggers may include infections, new medications, recent antibiotic use, recent travel, sick contacts, or cessation of treatments. Standard questions include asking about the timing of onset of symptoms, bowel movements during a 24-hour period, and particularly the presence of nocturnal bowel movements. If patients report bloody stools, inquire how often they see blood relative to the total number of bowel movements. The presence and nature of abdominal pain should be elicited, particularly changes in abdominal pain and comparison with previous disease flares. These clinical parameters are used to assess response to treatment; therefore, ask patients to keep a log of their stool frequency, consistency, rectal urgency, and bleeding each day to report to the team during daily rounds.

Once disease severity has been determined, intravenous corticosteroid therapy may be initiated, ideally once CDI and CMV have been excluded. The recommended dosing of intravenous corticosteroids is methylprednisolone 20 mg IV every 8 hours or equivalent. There is no evidence to support additional benefit for doses exceeding these amounts.⁸ Prior to starting parenteral corticosteroids, it is important to keep in mind the possible need for rescue therapy during the admission. Recommended testing includes hepatitis B surface antigen and antibody, hepatitis B core antibody and tuberculosis testing if there is no documented negative testing within the past 6-12 months. These labs should be drawn prior to steroid treatment to avoid delays in care and indeterminate results. Finally, a lipid profile is recommended for patients who may be cyclosporine candidates pending response to intravenous corticosteroids. Unless the patient has been admitted with a bowel obstruction, which should raise the suspicion that the diagnosis is actually Crohn’s disease, enteral feeding is preferred for UC patients even if they may have significant food aversion. The early involvement of a registered dietitian is valuable to guide dietary choices and recommend appropriate enteral nutrition supplements. During acute flares, patients may find a low-residue diet to be less stimulating to their gut while their acute flare is being treated. Electrolyte abnormalities should be repleted and consistently monitored during the hospitalization. Providing parenteral intravenous iron for anemic patients will expedite correction of the anemia alongside treatment of the underlying UC.

Day 3 – Assessing response to corticosteroids

In addition to daily symptom assessments, a careful abdominal exam should be performed every day with the understanding that steroids (and also narcotics) may mask perforation or pain. Any abrupt decrease or cessation of bowel movements, increasing abdominal distention, or a sudden increase in abdominal pain or tenderness may require abdominal imaging to ensure no interim perforation or severe colonic dilation has occurred while receiving steroid therapy. In these circumstances, the addition of broad spectrum intravenous antibiotics should be considered, particularly if hemodynamic instability (such as tachycardia) is present.

Patients should be assessed for response to intravenous steroid therapy after 3 days of treatment. A meaningful response to corticosteroids is present if the patient has had more than 50% improvement in symptoms, particularly rectal bleeding and stool frequency. A more than 75% improvement in CRP should also be noted from admission to day 3 with an overall trend of improvement.^2,21 Additionally, patients should be afebrile, require minimal to no narcotic usage, tolerating oral intake, and be ambulatory. If the patient has met all these parameters, it is reasonable to transition to oral corticosteroids, such as prednisone 40-60 mg daily after a course of 3-5 days of intravenous corticosteroids. Ideally, patients should be observed for 24-48 hours in the hospital after transitioning to oral corticosteroids to make sure that symptoms do not worsen with the switch.

Patients with more than eight bowel movements per day, CRP greater than 4.5 g/dL, deep ulcers on endoscopy, or albumin less than 3.0 g/dL have a higher likelihood of failing intravenous corticosteroid therapy, and these patients should be prepared for rescue therapy.^2,21 A patient has failed intravenous corticosteroids by day 3 if they have sustained fever in the absence of an infection, continued CRP elevation or lack of CRP decrease, or ongoing high stool frequency, bleeding, and pain with less than 50% improvement from baseline on admission.⁸ In the setting of nonresponse to intravenous corticosteroids, it is prudent to involve colorectal surgery to discuss colectomy as an option of equal merit to medical salvage therapies such as infliximab or cyclosporine.

Infliximab is the most readily available rescue therapy for steroid-refractory patients and has been shown to increase colectomy-free survival in patients with ASUC.⁸ However, patients with the same predictors for intravenous steroid failures (low albumin, high CRP, and/or deep ulcers on endoscopy) are also at the highest risk for infliximab nonresponse. These factors are important to discuss with the patients and colorectal surgery teams when providing the options of treatment strategy, particularly with medication dosing. ASUC with more severe disease biochemically (low albumin, elevated CRP, possibly bandemia) benefit from a higher dose of infliximab at 10 mg/kg, given the likelihood of increased drug clearance in this situation.^22,23

From a practical standpoint, it is important to confirm the patient’s insurance status prior to medication administration to make sure therapy can be continued after hospital discharge. Early involvement of the social workers and case coordinators is key to ensuring timely administration of the next dose of treatment. Patients who receive infliximab rescue therapy should be monitored for an additional 1-2 days after administration to ensure they are responding to this therapy with continued monitoring of CRP and symptoms during this period. If there is no response at this point, an additional dose of infliximab may be considered but surgery should not be delayed if there is no meaningful response after the first dose.

Another option for intravenous corticosteroid nonresponders is intravenous cyclosporine because treatment failure rates for cyclosporine and infliximab were similar in head-to-head studies.²⁴ However, patient selection is key to successful utilization of this agent. Unlike infliximab, cyclosporine is primarily an induction agent for steroid nonresponders rather than a maintenance strategy. Therefore, in patients in whom cyclosporine is being considered, thiopurines or vedolizumab are potential options for maintenance therapy. If the patient has poor renal function, low cholesterol, advanced age, significant comorbidities, or a history of nonadherence to therapy, cyclosporine should not be given. Additionally, clinical experience with intravenous cyclosporine administration and monitoring both during inpatient and outpatient care settings should be factored into the decision making for infliximab versus cyclosporine.⁸
 

Day 5 and beyond – Discharge planning

Patients who have responded to the initial intravenous steroid course by hospital day 5 should have successfully transitioned to oral steroids with plans to start an appropriate steroid-sparing therapy shortly after discharge. Treatment planning should commence prior to discharge and should be communicated with the outpatient GI team to ensure a smooth transition to the ambulatory care setting, primarily to begin insurance authorizations as soon as possible. If the patient has had a meaningful response to infliximab rescue therapy (improvement by more than 50% in bowel frequency, amount of blood, abdominal pain), discharge planning needs to prioritize obtaining authorization for the second dose within 2 weeks of the initial infusion. These patients are high risk for readmission, and close outpatient follow-up by the ambulatory GI care team is necessary to help direct the tapering of steroids and monitor response to treatment.

If the patient has not responded to intravenous steroid therapy, infliximab, or cyclosporine by day 5-7, then surgery should be strongly considered. Delaying surgery may worsen outcomes as patients become more malnourished, anemic, and continue to receive intravenous steroids. Additional preoperative optimization may be required depending on the patient’s course up to this point (Table 2).
 

Summary

The cornerstones of inpatient UC management center on a thorough initial evaluation including imaging and endoscopy as appropriate, establishment of baseline parameters, and daily assessment of response to therapy through a combination of patient-reported outcomes and biomarkers of inflammation. With this strategy in mind, practitioners and care teams can manage these complex patients using a consistent strategy focusing on multidisciplinary, evidence-based care.

References

1. Truelove SC et al. Br Med J. 1955 Oct 23;2(4947):1041-8.

2. Ho GT et al. Aliment Pharmacol Ther. 2004 May 15;19(10):1079-87.


3. Tinsley A et al. Scand J Gastroenterol. 2015;50(9):1103-9.

4. Issa M et al. Clin Gastroenterol Hepatol. 2007 Mar;5(3):345-51.

5. Ananthakrishnan AN et al. Gut. 2008 Feb;57(2):205-10.

6. Negron ME et al. Am J Gastroenterol. 2016 May;111(5):691-704.

7. Taylor KN et al. Gynecol Oncol. 2017 Feb;144(2):428-37.

8. Rubin DT et al. Am J Gastroenterol. 2019 Mar;114(3):384-413.

9. Jalan KN et al. Gastroenterology. 1969 Jul;57(1):68-82.

10. Gan SI et al. Am J Gastroenterol. 2003 Nov;98(11):2363-71.

11. Makkar R et al. Gastroenterol Hepatol (N Y). 2013 Sep;9(9):573-83.

12. Hindryckx P et al. Nat Rev Gastroenterol Hepatol. 2016 Nov;13(11):654-64.

13. Yerushalmy-Feler A et al. Curr Infect Dis Rep. 2019 Feb 15;21(2):5.

14. Shukla T et al. J Clin Gastroenterol. 2017 May/Jun;51(5):394-401.

15. McCurdy JD et al. Clin Gastroenterol Hepatol. 2015 Jan;13(1):131-7; quiz e7.

16. Cottone M et al. Am J Gastroenterol. 2001 Mar;96(3):773-5.

17. Nguyen GC et al. Gastroenterology. 2014 Mar;146(3):835-48 e6.

18. Limsrivilai J et al. Clin Gastroenterol Hepatol. 2017 Mar;15(3):385-92 e2.

19. Targownik LE et al. Am J Gastroenterol. 2014 Oct;109(10):1613-20.

20. Takeuchi K et al. Clin Gastroenterol Hepatol. 2006 Feb;4(2):196-202.

21. Travis SP et al. Gut. 1996 Jun;38(6):905-10.

22. Syal G et al. Mo1891 - Gastroenterology. 2018;154:S841.

23. Ungar B et al. Aliment Pharmacol Ther. 2016 Jun;43(12):1293-9.

24. Laharie D et al. Lancet 2012 Dec 1;380(9857):1909-15.
 

Dr. Chiplunker is an advanced inflammatory bowel disease fellow; Dr. Ha is associate professor of medicine at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center, Los Angeles.

Introduction

Inpatient management of acute ulcerative colitis (UC) flares can be challenging because of the multiple patient and disease-related factors influencing therapeutic decision making. The clinical course during the first 24-72 hours of the hospitalization will likely guide the decision between rescue medical and surgical therapy. Using available evidence from clinical practice guidelines, we present a day-by-day guide to managing most hospitalized UC patients.

Day 0 – The emergency department (ED)

When an UC patient presents to the ED for evaluation, the initial assessments should focus on the acuity and severity of the flare. Key clinical features of disease severity include the presence of fever, tachycardia, hypotension, or weight loss in addition to worsened gastrointestinal symptoms of stool frequency relative to baseline, rectal bleeding, and abdominal pain. Acute severe ulcerative colitis (ASUC) is often defined using the modified Truelove and Witts criteria.¹ A patient meets criteria for ASUC if they have at least six bloody stools per day and at least one sign of systemic toxicity, such as heart rate greater than 90 bpm, temperature at or above 37.8° C, hemoglobin level below 10.5 g/dL, or elevated inflammatory markers.

Initial laboratory assessments should include complete blood counts to identify anemia, potential superimposed infection, or toxicity and a comprehensive metabolic profile to evaluate for dehydration, electrolyte abnormalities, hepatic injury or hypoalbuminemia (an important predictor of surgery), as well as assessment of response to treatment and readmission.^2,3 An evaluation at admission of C-reactive protein (CRP) is crucial because changes from the initial value will determine steroid response and predict need for surgical intervention or rescue therapy. A baseline fecal calprotectin can serve as a noninvasive marker that can be followed after discharge to monitor response to therapy.

Clostridioides difficile infection (CDI) must be ruled out in all patients presenting with ASUC regardless of history of antibiotic use or prior negative testing. Concomitant UC and CDI are associated with a four- to sixfold increased risk of in-hospital mortality and a two- to sixfold increased risk of bowel surgery.^4-6 Immunoassay testing is inexpensive and fast with a high specificity but has low sensitivity; nucleic acid amplification testing with polymerase chain reaction has a high sensitivity and specificity.⁷ Knowing which testing algorithm the hospital lab uses helps guide interpretation of results.

For patients meeting criteria for ASUC, obtaining at least an abdominal x-ray is important to assess for colonic dilation to further stratify the patient by risk. Colonic dilation, defined as a transverse colon diameter greater than 5.5 cm, places the patient in the category of fulminant colitis and colorectal surgical consultation should be obtained.⁸ A CT scan is often ordered first because it can provide a rapid assessment of intra-abdominal processes but is not routinely needed unless hemodynamic instability, an acute abdomen, or markedly abnormal laboratory testing (specifically white blood cell count with bandemia) is present as these can be indicators of toxic megacolon or perforation.^8-10

Day 1 – Assess disease severity and assemble the team

Obtaining a thorough clinical history is essential to classify disease severity and identify potential triggers for the acute exacerbation. Potential triggers may include infections, new medications, recent antibiotic use, recent travel, sick contacts, or cessation of treatments. Standard questions include asking about the timing of onset of symptoms, bowel movements during a 24-hour period, and particularly the presence of nocturnal bowel movements. If patients report bloody stools, inquire how often they see blood relative to the total number of bowel movements. The presence and nature of abdominal pain should be elicited, particularly changes in abdominal pain and comparison with previous disease flares. These clinical parameters are used to assess response to treatment; therefore, ask patients to keep a log of their stool frequency, consistency, rectal urgency, and bleeding each day to report to the team during daily rounds.

Once disease severity has been determined, intravenous corticosteroid therapy may be initiated, ideally once CDI and CMV have been excluded. The recommended dosing of intravenous corticosteroids is methylprednisolone 20 mg IV every 8 hours or equivalent. There is no evidence to support additional benefit for doses exceeding these amounts.⁸ Prior to starting parenteral corticosteroids, it is important to keep in mind the possible need for rescue therapy during the admission. Recommended testing includes hepatitis B surface antigen and antibody, hepatitis B core antibody and tuberculosis testing if there is no documented negative testing within the past 6-12 months. These labs should be drawn prior to steroid treatment to avoid delays in care and indeterminate results. Finally, a lipid profile is recommended for patients who may be cyclosporine candidates pending response to intravenous corticosteroids. Unless the patient has been admitted with a bowel obstruction, which should raise the suspicion that the diagnosis is actually Crohn’s disease, enteral feeding is preferred for UC patients even if they may have significant food aversion. The early involvement of a registered dietitian is valuable to guide dietary choices and recommend appropriate enteral nutrition supplements. During acute flares, patients may find a low-residue diet to be less stimulating to their gut while their acute flare is being treated. Electrolyte abnormalities should be repleted and consistently monitored during the hospitalization. Providing parenteral intravenous iron for anemic patients will expedite correction of the anemia alongside treatment of the underlying UC.

Day 3 – Assessing response to corticosteroids

In addition to daily symptom assessments, a careful abdominal exam should be performed every day with the understanding that steroids (and also narcotics) may mask perforation or pain. Any abrupt decrease or cessation of bowel movements, increasing abdominal distention, or a sudden increase in abdominal pain or tenderness may require abdominal imaging to ensure no interim perforation or severe colonic dilation has occurred while receiving steroid therapy. In these circumstances, the addition of broad spectrum intravenous antibiotics should be considered, particularly if hemodynamic instability (such as tachycardia) is present.

Patients should be assessed for response to intravenous steroid therapy after 3 days of treatment. A meaningful response to corticosteroids is present if the patient has had more than 50% improvement in symptoms, particularly rectal bleeding and stool frequency. A more than 75% improvement in CRP should also be noted from admission to day 3 with an overall trend of improvement.^2,21 Additionally, patients should be afebrile, require minimal to no narcotic usage, tolerating oral intake, and be ambulatory. If the patient has met all these parameters, it is reasonable to transition to oral corticosteroids, such as prednisone 40-60 mg daily after a course of 3-5 days of intravenous corticosteroids. Ideally, patients should be observed for 24-48 hours in the hospital after transitioning to oral corticosteroids to make sure that symptoms do not worsen with the switch.

Patients with more than eight bowel movements per day, CRP greater than 4.5 g/dL, deep ulcers on endoscopy, or albumin less than 3.0 g/dL have a higher likelihood of failing intravenous corticosteroid therapy, and these patients should be prepared for rescue therapy.^2,21 A patient has failed intravenous corticosteroids by day 3 if they have sustained fever in the absence of an infection, continued CRP elevation or lack of CRP decrease, or ongoing high stool frequency, bleeding, and pain with less than 50% improvement from baseline on admission.⁸ In the setting of nonresponse to intravenous corticosteroids, it is prudent to involve colorectal surgery to discuss colectomy as an option of equal merit to medical salvage therapies such as infliximab or cyclosporine.

Infliximab is the most readily available rescue therapy for steroid-refractory patients and has been shown to increase colectomy-free survival in patients with ASUC.⁸ However, patients with the same predictors for intravenous steroid failures (low albumin, high CRP, and/or deep ulcers on endoscopy) are also at the highest risk for infliximab nonresponse. These factors are important to discuss with the patients and colorectal surgery teams when providing the options of treatment strategy, particularly with medication dosing. ASUC with more severe disease biochemically (low albumin, elevated CRP, possibly bandemia) benefit from a higher dose of infliximab at 10 mg/kg, given the likelihood of increased drug clearance in this situation.^22,23

From a practical standpoint, it is important to confirm the patient’s insurance status prior to medication administration to make sure therapy can be continued after hospital discharge. Early involvement of the social workers and case coordinators is key to ensuring timely administration of the next dose of treatment. Patients who receive infliximab rescue therapy should be monitored for an additional 1-2 days after administration to ensure they are responding to this therapy with continued monitoring of CRP and symptoms during this period. If there is no response at this point, an additional dose of infliximab may be considered but surgery should not be delayed if there is no meaningful response after the first dose.

Another option for intravenous corticosteroid nonresponders is intravenous cyclosporine because treatment failure rates for cyclosporine and infliximab were similar in head-to-head studies.²⁴ However, patient selection is key to successful utilization of this agent. Unlike infliximab, cyclosporine is primarily an induction agent for steroid nonresponders rather than a maintenance strategy. Therefore, in patients in whom cyclosporine is being considered, thiopurines or vedolizumab are potential options for maintenance therapy. If the patient has poor renal function, low cholesterol, advanced age, significant comorbidities, or a history of nonadherence to therapy, cyclosporine should not be given. Additionally, clinical experience with intravenous cyclosporine administration and monitoring both during inpatient and outpatient care settings should be factored into the decision making for infliximab versus cyclosporine.⁸
 

Day 5 and beyond – Discharge planning

Patients who have responded to the initial intravenous steroid course by hospital day 5 should have successfully transitioned to oral steroids with plans to start an appropriate steroid-sparing therapy shortly after discharge. Treatment planning should commence prior to discharge and should be communicated with the outpatient GI team to ensure a smooth transition to the ambulatory care setting, primarily to begin insurance authorizations as soon as possible. If the patient has had a meaningful response to infliximab rescue therapy (improvement by more than 50% in bowel frequency, amount of blood, abdominal pain), discharge planning needs to prioritize obtaining authorization for the second dose within 2 weeks of the initial infusion. These patients are high risk for readmission, and close outpatient follow-up by the ambulatory GI care team is necessary to help direct the tapering of steroids and monitor response to treatment.

If the patient has not responded to intravenous steroid therapy, infliximab, or cyclosporine by day 5-7, then surgery should be strongly considered. Delaying surgery may worsen outcomes as patients become more malnourished, anemic, and continue to receive intravenous steroids. Additional preoperative optimization may be required depending on the patient’s course up to this point (Table 2).
 

Summary

The cornerstones of inpatient UC management center on a thorough initial evaluation including imaging and endoscopy as appropriate, establishment of baseline parameters, and daily assessment of response to therapy through a combination of patient-reported outcomes and biomarkers of inflammation. With this strategy in mind, practitioners and care teams can manage these complex patients using a consistent strategy focusing on multidisciplinary, evidence-based care.

References

1. Truelove SC et al. Br Med J. 1955 Oct 23;2(4947):1041-8.

2. Ho GT et al. Aliment Pharmacol Ther. 2004 May 15;19(10):1079-87.


3. Tinsley A et al. Scand J Gastroenterol. 2015;50(9):1103-9.

4. Issa M et al. Clin Gastroenterol Hepatol. 2007 Mar;5(3):345-51.

5. Ananthakrishnan AN et al. Gut. 2008 Feb;57(2):205-10.

6. Negron ME et al. Am J Gastroenterol. 2016 May;111(5):691-704.

7. Taylor KN et al. Gynecol Oncol. 2017 Feb;144(2):428-37.

8. Rubin DT et al. Am J Gastroenterol. 2019 Mar;114(3):384-413.

9. Jalan KN et al. Gastroenterology. 1969 Jul;57(1):68-82.

10. Gan SI et al. Am J Gastroenterol. 2003 Nov;98(11):2363-71.

11. Makkar R et al. Gastroenterol Hepatol (N Y). 2013 Sep;9(9):573-83.

12. Hindryckx P et al. Nat Rev Gastroenterol Hepatol. 2016 Nov;13(11):654-64.

13. Yerushalmy-Feler A et al. Curr Infect Dis Rep. 2019 Feb 15;21(2):5.

14. Shukla T et al. J Clin Gastroenterol. 2017 May/Jun;51(5):394-401.

15. McCurdy JD et al. Clin Gastroenterol Hepatol. 2015 Jan;13(1):131-7; quiz e7.

16. Cottone M et al. Am J Gastroenterol. 2001 Mar;96(3):773-5.

17. Nguyen GC et al. Gastroenterology. 2014 Mar;146(3):835-48 e6.

18. Limsrivilai J et al. Clin Gastroenterol Hepatol. 2017 Mar;15(3):385-92 e2.

19. Targownik LE et al. Am J Gastroenterol. 2014 Oct;109(10):1613-20.

20. Takeuchi K et al. Clin Gastroenterol Hepatol. 2006 Feb;4(2):196-202.

21. Travis SP et al. Gut. 1996 Jun;38(6):905-10.

22. Syal G et al. Mo1891 - Gastroenterology. 2018;154:S841.

23. Ungar B et al. Aliment Pharmacol Ther. 2016 Jun;43(12):1293-9.

24. Laharie D et al. Lancet 2012 Dec 1;380(9857):1909-15.
 

Dr. Chiplunker is an advanced inflammatory bowel disease fellow; Dr. Ha is associate professor of medicine at the Inflammatory Bowel Disease Center at Cedars-Sinai Medical Center, Los Angeles.