Missed case of group A strep results in amputation of limbs

A 53-YEAR-OLD WOMAN went to the emergency department (ED) with severe abdominal pain, a rapid heartbeat, and a 101.3° F fever. After 9 hours, the ED physician discharged her around midnight with instructions to contact her gynecologist in the morning for “fibroid issues.” Later that day, the patient collapsed at home and was transported back to the hospital. She was treated for septic shock from a group A Streptococcus infection and had all 4 of her limbs amputated.

Older patients with a fever and no definite source of infection must be handled with great caution.

PLAINTIFF’S CLAIM The ED physician, who discharged the patient with a 102.9° F fever, should have spotted the infection and should have spent more time with her—given the complexity of her case. The physician should have given the patient alternative diagnoses, which would have prompted her to pursue other treatment.

THE DEFENSE The defendants denied any negligence.

VERDICT $25.3 million Wisconsin verdict.

COMMENT Although we are not given many details of this case, I suspect there was a fairly thorough work-up with no specific source of infection discovered. While this was an emergency medicine case, it is a strong reminder that older patients with a fever and no definite source of infection must be handled with great caution.

Patient dies following "routine" warfarin change

AN 80-YEAR-OLD WOMAN was taking warfarin for chronic pulmonary emboli. She saw her physician for a follow-up visit after being hospitalized for heart failure and shortness of breath. He ordered lab work, which revealed an elevated international normalized ratio (INR) of 3.7. The physician e-mailed a nurse to contact the patient and tell her to reduce her warfarin dosage. The nurse documented that she told the patient and called in a new prescription. Five days later, the patient was admitted to the hospital with a significantly elevated INR and a spinal bleed that caused paralysis. The patient was transferred to a nursing home, where she died 6 months after her initial follow-up visit.

PLANTIFF’S CLAIM The physician’s instructions were ambiguous, and a repeat INR should have been performed in 2 or 3 days. The nurse did not properly instruct the decedent and should have notified the family and the visiting nurse of the medication change.

THE DEFENSE The instructions the physician gave were correct and the appropriate plan was to repeat the INR in 13 days. The decedent had managed her warfarin through 11 previous dose changes, so there was no reason to notify the family or visiting nurse.

VERDICT $40,000 settlement.

COMMENT This case is a reminder of the difficulties one can encounter with warfarin dose adjustments. In view of the small settlement, it does not appear there was much physician liability. Most patients do not bleed with an INR of 3.7. It certainly would have been prudent to recheck in 2 to 3 days, however.

Severe headache, but no CT scan results in death

A HOSPITALIZED 57-YEAR-OLD MAN complained of a severe headache that he described as a 10 on a scale of 1 to 10. At the time, he was taking warfarin. After 6 days, he died from a brain herniation and hemorrhage.

PLAINTIFF’S CLAIM Despite the patient’s complaint of severe headache, the physician failed to order a computed tomography scan of the head.

THE DEFENSE The patient’s headaches had waxed and waned and were associated with a fever of recent onset. There were no focal neurologic deficits to suggest that there was any problem with the brain. The brain hemorrhage was a sudden and acute event.

VERDICT $250,000 Illinois verdict.

COMMENT Have a high index of suspicion for intracranial hemorrhage in patients taking warfarin with severe headache. What more needs to be said?

Missed case of group A strep results in amputation of limbs

A 53-YEAR-OLD WOMAN went to the emergency department (ED) with severe abdominal pain, a rapid heartbeat, and a 101.3° F fever. After 9 hours, the ED physician discharged her around midnight with instructions to contact her gynecologist in the morning for “fibroid issues.” Later that day, the patient collapsed at home and was transported back to the hospital. She was treated for septic shock from a group A Streptococcus infection and had all 4 of her limbs amputated.

Older patients with a fever and no definite source of infection must be handled with great caution.

PLAINTIFF’S CLAIM The ED physician, who discharged the patient with a 102.9° F fever, should have spotted the infection and should have spent more time with her—given the complexity of her case. The physician should have given the patient alternative diagnoses, which would have prompted her to pursue other treatment.

THE DEFENSE The defendants denied any negligence.

VERDICT $25.3 million Wisconsin verdict.

COMMENT Although we are not given many details of this case, I suspect there was a fairly thorough work-up with no specific source of infection discovered. While this was an emergency medicine case, it is a strong reminder that older patients with a fever and no definite source of infection must be handled with great caution.

Patient dies following "routine" warfarin change

AN 80-YEAR-OLD WOMAN was taking warfarin for chronic pulmonary emboli. She saw her physician for a follow-up visit after being hospitalized for heart failure and shortness of breath. He ordered lab work, which revealed an elevated international normalized ratio (INR) of 3.7. The physician e-mailed a nurse to contact the patient and tell her to reduce her warfarin dosage. The nurse documented that she told the patient and called in a new prescription. Five days later, the patient was admitted to the hospital with a significantly elevated INR and a spinal bleed that caused paralysis. The patient was transferred to a nursing home, where she died 6 months after her initial follow-up visit.

PLANTIFF’S CLAIM The physician’s instructions were ambiguous, and a repeat INR should have been performed in 2 or 3 days. The nurse did not properly instruct the decedent and should have notified the family and the visiting nurse of the medication change.

THE DEFENSE The instructions the physician gave were correct and the appropriate plan was to repeat the INR in 13 days. The decedent had managed her warfarin through 11 previous dose changes, so there was no reason to notify the family or visiting nurse.

VERDICT $40,000 settlement.

COMMENT This case is a reminder of the difficulties one can encounter with warfarin dose adjustments. In view of the small settlement, it does not appear there was much physician liability. Most patients do not bleed with an INR of 3.7. It certainly would have been prudent to recheck in 2 to 3 days, however.

Severe headache, but no CT scan results in death

A HOSPITALIZED 57-YEAR-OLD MAN complained of a severe headache that he described as a 10 on a scale of 1 to 10. At the time, he was taking warfarin. After 6 days, he died from a brain herniation and hemorrhage.

PLAINTIFF’S CLAIM Despite the patient’s complaint of severe headache, the physician failed to order a computed tomography scan of the head.

THE DEFENSE The patient’s headaches had waxed and waned and were associated with a fever of recent onset. There were no focal neurologic deficits to suggest that there was any problem with the brain. The brain hemorrhage was a sudden and acute event.

VERDICT $250,000 Illinois verdict.

COMMENT Have a high index of suspicion for intracranial hemorrhage in patients taking warfarin with severe headache. What more needs to be said?

Missed case of group A strep results in amputation of limbs

A 53-YEAR-OLD WOMAN went to the emergency department (ED) with severe abdominal pain, a rapid heartbeat, and a 101.3° F fever. After 9 hours, the ED physician discharged her around midnight with instructions to contact her gynecologist in the morning for “fibroid issues.” Later that day, the patient collapsed at home and was transported back to the hospital. She was treated for septic shock from a group A Streptococcus infection and had all 4 of her limbs amputated.

Older patients with a fever and no definite source of infection must be handled with great caution.

PLAINTIFF’S CLAIM The ED physician, who discharged the patient with a 102.9° F fever, should have spotted the infection and should have spent more time with her—given the complexity of her case. The physician should have given the patient alternative diagnoses, which would have prompted her to pursue other treatment.

THE DEFENSE The defendants denied any negligence.

VERDICT $25.3 million Wisconsin verdict.

COMMENT Although we are not given many details of this case, I suspect there was a fairly thorough work-up with no specific source of infection discovered. While this was an emergency medicine case, it is a strong reminder that older patients with a fever and no definite source of infection must be handled with great caution.

Patient dies following "routine" warfarin change

AN 80-YEAR-OLD WOMAN was taking warfarin for chronic pulmonary emboli. She saw her physician for a follow-up visit after being hospitalized for heart failure and shortness of breath. He ordered lab work, which revealed an elevated international normalized ratio (INR) of 3.7. The physician e-mailed a nurse to contact the patient and tell her to reduce her warfarin dosage. The nurse documented that she told the patient and called in a new prescription. Five days later, the patient was admitted to the hospital with a significantly elevated INR and a spinal bleed that caused paralysis. The patient was transferred to a nursing home, where she died 6 months after her initial follow-up visit.

PLANTIFF’S CLAIM The physician’s instructions were ambiguous, and a repeat INR should have been performed in 2 or 3 days. The nurse did not properly instruct the decedent and should have notified the family and the visiting nurse of the medication change.

THE DEFENSE The instructions the physician gave were correct and the appropriate plan was to repeat the INR in 13 days. The decedent had managed her warfarin through 11 previous dose changes, so there was no reason to notify the family or visiting nurse.

VERDICT $40,000 settlement.

COMMENT This case is a reminder of the difficulties one can encounter with warfarin dose adjustments. In view of the small settlement, it does not appear there was much physician liability. Most patients do not bleed with an INR of 3.7. It certainly would have been prudent to recheck in 2 to 3 days, however.

Severe headache, but no CT scan results in death

A HOSPITALIZED 57-YEAR-OLD MAN complained of a severe headache that he described as a 10 on a scale of 1 to 10. At the time, he was taking warfarin. After 6 days, he died from a brain herniation and hemorrhage.

PLAINTIFF’S CLAIM Despite the patient’s complaint of severe headache, the physician failed to order a computed tomography scan of the head.

THE DEFENSE The patient’s headaches had waxed and waned and were associated with a fever of recent onset. There were no focal neurologic deficits to suggest that there was any problem with the brain. The brain hemorrhage was a sudden and acute event.

VERDICT $250,000 Illinois verdict.

COMMENT Have a high index of suspicion for intracranial hemorrhage in patients taking warfarin with severe headache. What more needs to be said?

I am a psychiatric nurse and am concerned about the new group of hospitalists who are taking over all the new ED patients:

1. Are signing off to the nursing staff or in the electronic health record (EHR); they do not speak with the attending psychiatrist;
2. Are not monitoring their own medications, including Coumadin or insulin (from what some other nurses have reported);
3. Require that, if we need to speak with one, we are to call the triage hospitalist, who typically says that they can’t do anything because they didn’t start the medication and they don’t know the patient.

Many of our patients are very ill, not only psychiatrically but also medically. We feel the hospital has placed us and the patients in jeopardy. Is this typical? Do other hospitalist groups manage their patients like the ones I have described?

–Sincerely,

Psych Nurse Caught in the Middle

Dr. Hospitalist responds:

Since you mention that the “new group” of hospitalists is caring for “all the new ED patients,” I’m assuming the patients are being assigned to the hospitalist group because they are unassigned and either don’t have a primary care physician (who would direct them to a specific hospitalist) or the group is the only one in the hospital and receives all patients admitted through the ED who require admission to a hospitalist service. After all, if either you or the PCP is dissatisfied with the group and there were other groups to choose from, you would simply call another group.

I’ll address your concerns individually:

Although signing off from a consult in the EHR is fairly common, especially in busy practices, the process is usually mutually agreed upon by the clinicians involved. If the attending psychiatrist would like a call from the hospitalists before they sign off, then he or she should make that known to the group.

On most occasions, the sign-off does not occur until the hospitalist/consultant feels the patient is stable and the clinicians involved can handle “basic medical issues.” There are many patients in the hospital on insulin, Coumadin, and anti-hypertensive medications; if the hospitalist followed all of them throughout their entire hospitalization, there would be no time for the new consults. It is customary to follow patients until they are stable (e.g. the blood sugars are not markedly fluctuating and there is good sliding scale coverage, or the PT/INR [prothrombin time/international normalized ratio] has been relatively unchanged for several days). To do otherwise might also alert the CMS auditors to check the “medical necessity” for the ongoing visits.

While most large hospitalist programs have a designated triage person who receives all the calls from the ED, the other providers, and the transfer service, that person can usually answer basic patient care questions. If the person is very busy, or if the problem is more complex and the original consultant is not available, there is always someone covering for that person or the consult service to answer questions, since this is a very common occurrence.

Consults are meant to answer a specific question or assist with complex medical management issues. In order for the arrangement to work, both parties have to agree to well-defined parameters, and, at some point, there should be mutually agreed upon closure.

If no such arrangement exists, I would discuss the issue with the hospitalist director.

I am a psychiatric nurse and am concerned about the new group of hospitalists who are taking over all the new ED patients:

1. Are signing off to the nursing staff or in the electronic health record (EHR); they do not speak with the attending psychiatrist;
2. Are not monitoring their own medications, including Coumadin or insulin (from what some other nurses have reported);
3. Require that, if we need to speak with one, we are to call the triage hospitalist, who typically says that they can’t do anything because they didn’t start the medication and they don’t know the patient.

Many of our patients are very ill, not only psychiatrically but also medically. We feel the hospital has placed us and the patients in jeopardy. Is this typical? Do other hospitalist groups manage their patients like the ones I have described?

–Sincerely,

Psych Nurse Caught in the Middle

Dr. Hospitalist responds:

Since you mention that the “new group” of hospitalists is caring for “all the new ED patients,” I’m assuming the patients are being assigned to the hospitalist group because they are unassigned and either don’t have a primary care physician (who would direct them to a specific hospitalist) or the group is the only one in the hospital and receives all patients admitted through the ED who require admission to a hospitalist service. After all, if either you or the PCP is dissatisfied with the group and there were other groups to choose from, you would simply call another group.

I’ll address your concerns individually:

Although signing off from a consult in the EHR is fairly common, especially in busy practices, the process is usually mutually agreed upon by the clinicians involved. If the attending psychiatrist would like a call from the hospitalists before they sign off, then he or she should make that known to the group.

On most occasions, the sign-off does not occur until the hospitalist/consultant feels the patient is stable and the clinicians involved can handle “basic medical issues.” There are many patients in the hospital on insulin, Coumadin, and anti-hypertensive medications; if the hospitalist followed all of them throughout their entire hospitalization, there would be no time for the new consults. It is customary to follow patients until they are stable (e.g. the blood sugars are not markedly fluctuating and there is good sliding scale coverage, or the PT/INR [prothrombin time/international normalized ratio] has been relatively unchanged for several days). To do otherwise might also alert the CMS auditors to check the “medical necessity” for the ongoing visits.

While most large hospitalist programs have a designated triage person who receives all the calls from the ED, the other providers, and the transfer service, that person can usually answer basic patient care questions. If the person is very busy, or if the problem is more complex and the original consultant is not available, there is always someone covering for that person or the consult service to answer questions, since this is a very common occurrence.

Consults are meant to answer a specific question or assist with complex medical management issues. In order for the arrangement to work, both parties have to agree to well-defined parameters, and, at some point, there should be mutually agreed upon closure.

If no such arrangement exists, I would discuss the issue with the hospitalist director.

I am a psychiatric nurse and am concerned about the new group of hospitalists who are taking over all the new ED patients:

1. Are signing off to the nursing staff or in the electronic health record (EHR); they do not speak with the attending psychiatrist;
2. Are not monitoring their own medications, including Coumadin or insulin (from what some other nurses have reported);
3. Require that, if we need to speak with one, we are to call the triage hospitalist, who typically says that they can’t do anything because they didn’t start the medication and they don’t know the patient.

Many of our patients are very ill, not only psychiatrically but also medically. We feel the hospital has placed us and the patients in jeopardy. Is this typical? Do other hospitalist groups manage their patients like the ones I have described?

–Sincerely,

Psych Nurse Caught in the Middle

Dr. Hospitalist responds:

Since you mention that the “new group” of hospitalists is caring for “all the new ED patients,” I’m assuming the patients are being assigned to the hospitalist group because they are unassigned and either don’t have a primary care physician (who would direct them to a specific hospitalist) or the group is the only one in the hospital and receives all patients admitted through the ED who require admission to a hospitalist service. After all, if either you or the PCP is dissatisfied with the group and there were other groups to choose from, you would simply call another group.

I’ll address your concerns individually:

Although signing off from a consult in the EHR is fairly common, especially in busy practices, the process is usually mutually agreed upon by the clinicians involved. If the attending psychiatrist would like a call from the hospitalists before they sign off, then he or she should make that known to the group.

On most occasions, the sign-off does not occur until the hospitalist/consultant feels the patient is stable and the clinicians involved can handle “basic medical issues.” There are many patients in the hospital on insulin, Coumadin, and anti-hypertensive medications; if the hospitalist followed all of them throughout their entire hospitalization, there would be no time for the new consults. It is customary to follow patients until they are stable (e.g. the blood sugars are not markedly fluctuating and there is good sliding scale coverage, or the PT/INR [prothrombin time/international normalized ratio] has been relatively unchanged for several days). To do otherwise might also alert the CMS auditors to check the “medical necessity” for the ongoing visits.

While most large hospitalist programs have a designated triage person who receives all the calls from the ED, the other providers, and the transfer service, that person can usually answer basic patient care questions. If the person is very busy, or if the problem is more complex and the original consultant is not available, there is always someone covering for that person or the consult service to answer questions, since this is a very common occurrence.

Consults are meant to answer a specific question or assist with complex medical management issues. In order for the arrangement to work, both parties have to agree to well-defined parameters, and, at some point, there should be mutually agreed upon closure.

If no such arrangement exists, I would discuss the issue with the hospitalist director.

CHICAGO – Progression-free survival for patients with rituximab-refractory indolent non-Hodgkin’s lymphomas was effectively doubled with a combination of obinutuzumab and bendamustine, compared with bendamustine alone.

Dr. Laura Helen Sehn from the British Columbia (Canada) Cancer Agency in Vancouver, says that the study, the GADOLIN trial. “is remarkable, because it does demonstrate the first randomized evidence of a clinical benefit of a novel anti-CD20 monoclonal antibiody for patients who are rituximab refractory.”

She described the study’s key findings at the annual meeting of the American Society of Clinical Oncology.

CHICAGO – Progression-free survival for patients with rituximab-refractory indolent non-Hodgkin’s lymphomas was effectively doubled with a combination of obinutuzumab and bendamustine, compared with bendamustine alone.

Dr. Laura Helen Sehn from the British Columbia (Canada) Cancer Agency in Vancouver, says that the study, the GADOLIN trial. “is remarkable, because it does demonstrate the first randomized evidence of a clinical benefit of a novel anti-CD20 monoclonal antibiody for patients who are rituximab refractory.”

She described the study’s key findings at the annual meeting of the American Society of Clinical Oncology.

CHICAGO – Progression-free survival for patients with rituximab-refractory indolent non-Hodgkin’s lymphomas was effectively doubled with a combination of obinutuzumab and bendamustine, compared with bendamustine alone.

Dr. Laura Helen Sehn from the British Columbia (Canada) Cancer Agency in Vancouver, says that the study, the GADOLIN trial. “is remarkable, because it does demonstrate the first randomized evidence of a clinical benefit of a novel anti-CD20 monoclonal antibiody for patients who are rituximab refractory.”

She described the study’s key findings at the annual meeting of the American Society of Clinical Oncology.

Ruben Mesa, MD

© ASCO/Zach Boyden-Holmes

CHICAGO—The JAK2/FLT3 inhibitor pacritinib may fulfill an unmet need in the treatment of myelofibrosis (MF), according to a speaker at the 2015 ASCO Annual Meeting.

Results of the phase 3 PERSIST-1 trial indicate that pacritinib is safe and effective for MF patients with thrombocytopenia.

“Thrombocytopenia is a common feature in people with advanced [MF], and current treatment options have not been able to concurrently improve splenomegaly symptoms and cytopenias in these patients,” said study investigator Ruben A. Mesa, MD, of the Mayo Clinic Cancer Center in Scottsdale, Arizona.

But PERSIST-1 showed that pacritinib can accomplish this. And the drug proved more effective than best available therapy (BAT), excluding JAK inhibitors, in reducing spleen volume and alleviating MF symptoms in the entire cohort of MF patients.

Dr Mesa presented these results at ASCO as abstract LBA7006. The study was funded by CTI BioPharma Corp., the company developing pacritinib.

The trial included 327 patients who were randomized to receive pacritinib (n=220) or BAT (n=107).

Patients in the BAT arm received therapies that are routinely prescribed off-label for MF, such as erythropoietin-stimulating agents, immunomodulatory drugs, and hydroxyurea. Ruxolitinib was intentionally excluded from this trial because the study included patients with thrombocytopenia.

Dr Mesa said the patients’ baseline characteristics “demonstrate a group of individuals with advanced myelofibrosis, a heavy percentage of those with primary myelofibrosis, the vast majority having intermediate-2 or high-risk disease, with very significant splenomegaly, and the vast majority having the JAK2 mutation.”

“About half the individuals were anemic or transfusion-dependent,” he noted. “And a full third were thrombocytopenic, under 100,000 [platelets/µL], with 16% under 50,000 [platelets/µL]. This was the first phase 3 study of myelofibrosis that allowed individuals with a platelet count of less than 100,000 to be enrolled.”

Fifty-six percent of patients remained on pacritinib at the time of analysis, as did 8% of patients on BAT. Seventy-nine percent of patients crossed over from the BAT arm to the pacritinib arm.

Spleen reduction

The study’s primary endpoint was a reduction in spleen volume of 35% or greater.

In the intent-to-treat (ITT) population, 19.1% of patients in the pacritinib arm met this endpoint, as did 4.7% of patients in the BAT arm (P=0.0003). In the evaluable population—165 patients in the pacritinib arm and 85 patients in the BAT arm—the rates were 25% and 5.9%, respectively (P=0.0001).

Dr Mesa noted that pacritinib was able to reduce spleen volume in all subgroups of patients, including those with thrombocytopenia.

“Both the group [with platelet counts] under 100,000 as well as under 50,000 uniquely responded only on the pacritinib arm, with no responses on the BAT arm,” he said.

In the ITT population, 16.7% of patients with platelet counts under 100,000/µL and 22.9% of patients with platelet counts under 50,000/µL met the primary endpoint. The P values, in the comparison with the BAT arm, were 0.0451 and 0.0086, respectively.

In the evaluable population, 23.5% of patients with platelet counts under 100,000/µL and 33.3% of patients with platelet counts under 50,000/µL met the primary endpoint. The P values were 0.0370 and 0.0072, respectively.

“It is too early to know if pacritinib has an impact on survival, but that is clearly our expectation [based on the spleen responses observed],” Dr Mesa said.

TSS and transfusion

The study’s secondary endpoint was the proportion of patients with a 50% or greater reduction in Total Symptom Score (TSS) from baseline to week 24. TSS was measured by patient responses on the Myeloproliferative Neoplasm Symptom Assessment Form.

In the ITT population, 24.5% of pacritinib-treated patients and 6.5% of BAT-treated patients had a 50% or greater reduction in TSS score (P<0.0001). In the evaluable population, 40.9% and 9.9% of patients, respectively (P<0.0001), met this endpoint.

Dr Mesa also pointed out that 25.7% of pacritinib-treated patients who were severely anemic and transfusion-dependent—requiring at least 6 units of blood in the 90 days prior to study entry—became transfusion independent. But none of the BAT-treated patients did so (P<0.043).

Adverse events

“The most common adverse events [in the pacritinib arm] were consistent with the earlier studies,” Dr Mesa said. “Gastrointestinal toxicities were most common, although typically at low grades.”

“As expected, we saw very few individuals with any significant thrombocytopenia or anemia as drug-emergent. There were individuals who enrolled in the study as a grade 4, so some of those remained.”

The most common adverse events of any grade were diarrhea (53.2% in the pacritinib arm and 12.3% in the BAT arm), nausea (26.8% vs 6.6%), anemia (22.3% vs 19.8%), thrombocytopenia (16.8% vs 13.2%), and vomiting (15.9% vs 5.7%).

Ten percent of patients in the pacritinib arm required dose reductions due to adverse events. Diarrhea prompted dose interruptions in 13 patients and discontinuation in 3 patients. But pacritinib-associated diarrhea typically resolved in a little over a week.

“Based on these preliminary results, pacritinib may represent a very important agent for individuals with advanced disease and may have an impact on the disease course,” Dr Mesa concluded.

Ruben Mesa, MD

© ASCO/Zach Boyden-Holmes

CHICAGO—The JAK2/FLT3 inhibitor pacritinib may fulfill an unmet need in the treatment of myelofibrosis (MF), according to a speaker at the 2015 ASCO Annual Meeting.

Results of the phase 3 PERSIST-1 trial indicate that pacritinib is safe and effective for MF patients with thrombocytopenia.

“Thrombocytopenia is a common feature in people with advanced [MF], and current treatment options have not been able to concurrently improve splenomegaly symptoms and cytopenias in these patients,” said study investigator Ruben A. Mesa, MD, of the Mayo Clinic Cancer Center in Scottsdale, Arizona.

But PERSIST-1 showed that pacritinib can accomplish this. And the drug proved more effective than best available therapy (BAT), excluding JAK inhibitors, in reducing spleen volume and alleviating MF symptoms in the entire cohort of MF patients.

Dr Mesa presented these results at ASCO as abstract LBA7006. The study was funded by CTI BioPharma Corp., the company developing pacritinib.

The trial included 327 patients who were randomized to receive pacritinib (n=220) or BAT (n=107).

Patients in the BAT arm received therapies that are routinely prescribed off-label for MF, such as erythropoietin-stimulating agents, immunomodulatory drugs, and hydroxyurea. Ruxolitinib was intentionally excluded from this trial because the study included patients with thrombocytopenia.

Dr Mesa said the patients’ baseline characteristics “demonstrate a group of individuals with advanced myelofibrosis, a heavy percentage of those with primary myelofibrosis, the vast majority having intermediate-2 or high-risk disease, with very significant splenomegaly, and the vast majority having the JAK2 mutation.”

“About half the individuals were anemic or transfusion-dependent,” he noted. “And a full third were thrombocytopenic, under 100,000 [platelets/µL], with 16% under 50,000 [platelets/µL]. This was the first phase 3 study of myelofibrosis that allowed individuals with a platelet count of less than 100,000 to be enrolled.”

Fifty-six percent of patients remained on pacritinib at the time of analysis, as did 8% of patients on BAT. Seventy-nine percent of patients crossed over from the BAT arm to the pacritinib arm.

Spleen reduction

The study’s primary endpoint was a reduction in spleen volume of 35% or greater.

In the intent-to-treat (ITT) population, 19.1% of patients in the pacritinib arm met this endpoint, as did 4.7% of patients in the BAT arm (P=0.0003). In the evaluable population—165 patients in the pacritinib arm and 85 patients in the BAT arm—the rates were 25% and 5.9%, respectively (P=0.0001).

Dr Mesa noted that pacritinib was able to reduce spleen volume in all subgroups of patients, including those with thrombocytopenia.

“Both the group [with platelet counts] under 100,000 as well as under 50,000 uniquely responded only on the pacritinib arm, with no responses on the BAT arm,” he said.

In the ITT population, 16.7% of patients with platelet counts under 100,000/µL and 22.9% of patients with platelet counts under 50,000/µL met the primary endpoint. The P values, in the comparison with the BAT arm, were 0.0451 and 0.0086, respectively.

In the evaluable population, 23.5% of patients with platelet counts under 100,000/µL and 33.3% of patients with platelet counts under 50,000/µL met the primary endpoint. The P values were 0.0370 and 0.0072, respectively.

“It is too early to know if pacritinib has an impact on survival, but that is clearly our expectation [based on the spleen responses observed],” Dr Mesa said.

TSS and transfusion

The study’s secondary endpoint was the proportion of patients with a 50% or greater reduction in Total Symptom Score (TSS) from baseline to week 24. TSS was measured by patient responses on the Myeloproliferative Neoplasm Symptom Assessment Form.

In the ITT population, 24.5% of pacritinib-treated patients and 6.5% of BAT-treated patients had a 50% or greater reduction in TSS score (P<0.0001). In the evaluable population, 40.9% and 9.9% of patients, respectively (P<0.0001), met this endpoint.

Dr Mesa also pointed out that 25.7% of pacritinib-treated patients who were severely anemic and transfusion-dependent—requiring at least 6 units of blood in the 90 days prior to study entry—became transfusion independent. But none of the BAT-treated patients did so (P<0.043).

Adverse events

“The most common adverse events [in the pacritinib arm] were consistent with the earlier studies,” Dr Mesa said. “Gastrointestinal toxicities were most common, although typically at low grades.”

“As expected, we saw very few individuals with any significant thrombocytopenia or anemia as drug-emergent. There were individuals who enrolled in the study as a grade 4, so some of those remained.”

The most common adverse events of any grade were diarrhea (53.2% in the pacritinib arm and 12.3% in the BAT arm), nausea (26.8% vs 6.6%), anemia (22.3% vs 19.8%), thrombocytopenia (16.8% vs 13.2%), and vomiting (15.9% vs 5.7%).

Ten percent of patients in the pacritinib arm required dose reductions due to adverse events. Diarrhea prompted dose interruptions in 13 patients and discontinuation in 3 patients. But pacritinib-associated diarrhea typically resolved in a little over a week.

“Based on these preliminary results, pacritinib may represent a very important agent for individuals with advanced disease and may have an impact on the disease course,” Dr Mesa concluded.

Ruben Mesa, MD

© ASCO/Zach Boyden-Holmes

CHICAGO—The JAK2/FLT3 inhibitor pacritinib may fulfill an unmet need in the treatment of myelofibrosis (MF), according to a speaker at the 2015 ASCO Annual Meeting.

Results of the phase 3 PERSIST-1 trial indicate that pacritinib is safe and effective for MF patients with thrombocytopenia.

“Thrombocytopenia is a common feature in people with advanced [MF], and current treatment options have not been able to concurrently improve splenomegaly symptoms and cytopenias in these patients,” said study investigator Ruben A. Mesa, MD, of the Mayo Clinic Cancer Center in Scottsdale, Arizona.

But PERSIST-1 showed that pacritinib can accomplish this. And the drug proved more effective than best available therapy (BAT), excluding JAK inhibitors, in reducing spleen volume and alleviating MF symptoms in the entire cohort of MF patients.

Dr Mesa presented these results at ASCO as abstract LBA7006. The study was funded by CTI BioPharma Corp., the company developing pacritinib.

The trial included 327 patients who were randomized to receive pacritinib (n=220) or BAT (n=107).

Patients in the BAT arm received therapies that are routinely prescribed off-label for MF, such as erythropoietin-stimulating agents, immunomodulatory drugs, and hydroxyurea. Ruxolitinib was intentionally excluded from this trial because the study included patients with thrombocytopenia.

Dr Mesa said the patients’ baseline characteristics “demonstrate a group of individuals with advanced myelofibrosis, a heavy percentage of those with primary myelofibrosis, the vast majority having intermediate-2 or high-risk disease, with very significant splenomegaly, and the vast majority having the JAK2 mutation.”

“About half the individuals were anemic or transfusion-dependent,” he noted. “And a full third were thrombocytopenic, under 100,000 [platelets/µL], with 16% under 50,000 [platelets/µL]. This was the first phase 3 study of myelofibrosis that allowed individuals with a platelet count of less than 100,000 to be enrolled.”

Fifty-six percent of patients remained on pacritinib at the time of analysis, as did 8% of patients on BAT. Seventy-nine percent of patients crossed over from the BAT arm to the pacritinib arm.

Spleen reduction

The study’s primary endpoint was a reduction in spleen volume of 35% or greater.

In the intent-to-treat (ITT) population, 19.1% of patients in the pacritinib arm met this endpoint, as did 4.7% of patients in the BAT arm (P=0.0003). In the evaluable population—165 patients in the pacritinib arm and 85 patients in the BAT arm—the rates were 25% and 5.9%, respectively (P=0.0001).

Dr Mesa noted that pacritinib was able to reduce spleen volume in all subgroups of patients, including those with thrombocytopenia.

“Both the group [with platelet counts] under 100,000 as well as under 50,000 uniquely responded only on the pacritinib arm, with no responses on the BAT arm,” he said.

In the ITT population, 16.7% of patients with platelet counts under 100,000/µL and 22.9% of patients with platelet counts under 50,000/µL met the primary endpoint. The P values, in the comparison with the BAT arm, were 0.0451 and 0.0086, respectively.

In the evaluable population, 23.5% of patients with platelet counts under 100,000/µL and 33.3% of patients with platelet counts under 50,000/µL met the primary endpoint. The P values were 0.0370 and 0.0072, respectively.

“It is too early to know if pacritinib has an impact on survival, but that is clearly our expectation [based on the spleen responses observed],” Dr Mesa said.

TSS and transfusion

The study’s secondary endpoint was the proportion of patients with a 50% or greater reduction in Total Symptom Score (TSS) from baseline to week 24. TSS was measured by patient responses on the Myeloproliferative Neoplasm Symptom Assessment Form.

In the ITT population, 24.5% of pacritinib-treated patients and 6.5% of BAT-treated patients had a 50% or greater reduction in TSS score (P<0.0001). In the evaluable population, 40.9% and 9.9% of patients, respectively (P<0.0001), met this endpoint.

Dr Mesa also pointed out that 25.7% of pacritinib-treated patients who were severely anemic and transfusion-dependent—requiring at least 6 units of blood in the 90 days prior to study entry—became transfusion independent. But none of the BAT-treated patients did so (P<0.043).

Adverse events

“The most common adverse events [in the pacritinib arm] were consistent with the earlier studies,” Dr Mesa said. “Gastrointestinal toxicities were most common, although typically at low grades.”

“As expected, we saw very few individuals with any significant thrombocytopenia or anemia as drug-emergent. There were individuals who enrolled in the study as a grade 4, so some of those remained.”

The most common adverse events of any grade were diarrhea (53.2% in the pacritinib arm and 12.3% in the BAT arm), nausea (26.8% vs 6.6%), anemia (22.3% vs 19.8%), thrombocytopenia (16.8% vs 13.2%), and vomiting (15.9% vs 5.7%).

Ten percent of patients in the pacritinib arm required dose reductions due to adverse events. Diarrhea prompted dose interruptions in 13 patients and discontinuation in 3 patients. But pacritinib-associated diarrhea typically resolved in a little over a week.

“Based on these preliminary results, pacritinib may represent a very important agent for individuals with advanced disease and may have an impact on the disease course,” Dr Mesa concluded.

Hypoglycemia

mrfiza/ Shutterstock

A 44-year-old-man with type 1 diabetes mellitus (DM) was transported to the ED via emergency medical services (EMS) with a chief complaint of hypoglycemia. His wife stated the patient had been acting strangely prior to presentation. She further noted that after checking his blood sugar, which was 19 mg/dL, she gave her husband an oral glucose tablet with some water before calling EMS.

Upon arrival to the ED, the patient was triaged and designated as an urgent level III. At that time, he was alert and oriented, with a blood glucose level of 66 mg/dL. The patient was examined by a physician assistant (PA) within 15 minutes of his arrival. When interviewed by the PA, the patient described feelings of weakness, dizziness, and lightheadedness. The PA attributed these symptoms to the patient’s hypoglycemic state and ordered him a food tray. The patient was then observed for approximately 2 hours, during which time repeat blood-glucose testing revealed a level of 438 mg/dL. Approximately 20 minutes later, another blood-glucose test showed a level of 400 mg/dL. The patient felt well, appeared back to baseline, and expressed the desire to go home. At discharge, the PA instructed the patient to reduce his insulin by 20% and to follow up with his primary care physician (PCP) that same week.

Approximately 3 hours after discharge, the patient was found unresponsive by his wife, and EMS was again called. When EMS arrived at the patient’s house, his blood glucose level was 85 mg/dL. At presentation to the ED, the patient was unresponsive and without a pulse. Despite approximately 30 minutes of intensive resuscitative efforts, the code was called and the patient was pronounced dead.

The family sued the hospital, the emergency physician (EP), and the PA. They claimed the triage nurse failed to obtain an adequate history of the patient’s recent glucometer checks, previous hypoglycemic episodes, the amount and time of his last dose of insulin, and when and how much food he had recently ingested. The plaintiff further argued that that PA failed to obtain an electrocardiogram (ECG) to determine if the patient’s heart rhythm had been affected by his hypoglycemic state. The plaintiff also claimed the PA should have notified the patient’s PCP that the patient was in the ED, so that he could be admitted.

The defendants denied any negligence and argued the patient’s death was due to a sudden cardiac event, which was unrelated to the low-blood sugar levels. The defense contended that the patient’s enlarged heart and preexisting cardiovascular disease, hypertension, hypercholesterolemia, poorly controlled type 1 DM, history of alcohol abuse, and documented evidence of medication noncompliance were the cause of death. According to published accounts, a defense verdict was returned.

Discussion

It seems that rarely a shift goes by without a patient presenting with diabetes-associated complications such as hyperglycemia or hypoglycemia. While the jury reached the correct conclusion in this case, it does serve as a reminder that cases of hypoglycemia should not be treated lightly, and the EP must attempt to determine its cause.

The most commonly accepted definition of hypoglycemia is a blood-glucose level <50 mg/dL with associated symptoms. The causes of hypoglycemia in patients treated with insulin typically involves inadequate or no food intake, or accidental administration of too much insulin or the wrong type of insulin.¹

The differential diagnosis, however, needs to be more than just these two conditions. Since insulin is cleared by the kidneys, and patients with DM are at increased risk for kidney disease, acute renal failure should be considered in the differential. Other conditions to consider include infection, acute coronary syndromes, or unusual physical or mental stress.²

As with every patient presenting to the ED, patients with DM require a good history taking and physical examination. Additional testing, such as an ECG, troponin level, and kidney function test, should be performed based on the history and physical examination. Once the cause is determined, the majority of these patients can be treated with either intravenous (IV) or oral medications, observed, and discharged home with follow-up instructions.

Diabetic patients presenting with hypoglycemia due to a sulfonylurea agent or a long-acting insulin are in a completely different category. Because of the longer half-life of these agents, such patients will usually require admission to the hospital for serial glucose monitoring and treatment.² On occasion, patients with diabetic hypoglycemia and who are on a regular form of insulin will also require hospital admission. Those at highest risk are patients with DM aged 80 years and older.¹

Hyperkalemia

A 59-year-old man presented to the ED complaining of generalized weakness, the onset of which he stated had developed gradually over the previous 3 days. He denied chest pain, shortness of breath, or nausea and vomiting. His medical history was significant only for renal insufficiency. The patient was on no medications and denied alcohol or tobacco use.

Monkey Business Images/ Shutterstock

On physical examination, the patient had normal vital signs, including normal pulse oximetry. Similarly, the heart, lung, and abdominal examinations were all normal. On neurological examination, the patient had 5/5 motor strength in all four extremities and exhibited a normal gait.

The EP ordered an ECG, complete blood count (CBC), basic metabolic panel, urinalysis, and a chest X-ray (CXR). Laboratory evaluation showed an elevated potassium level of 6 mEq/L. The results of the CBC, urinalysis, and CXR were all reported as normal. (Unfortunately, there was no published information on the results of the BUN, creatinine, serum bicarbonate, or ECG findings.)

Based on the patient’s elevated potassium level, the EP ordered sodium polystyrene (Kayexalate) orally and arranged for admission to the hospital. The sodium polystyrene was administered to the patient approximately 1 hour after it was ordered.  While waiting for an inpatient bed, the patient experienced a cardiac arrest and died in the ED.

The family sued the EP and hospital for failure to properly respond to the patient’s elevated potassium level. The hospital denied any negligence, and the defense argued that the death was not related to any electrolyte abnormality, but was due to a respiratory arrest that led to the cardiac arrest. The defendants also maintained the sodium polystyrene had been administered in a timely manner. At trial, a defense verdict was returned.

Discussion

Hyperkalemia has been variably defined as serum potassium concentrations >5 mEq/L, >5.5 mEq/L, or >6 mEq/L.¹ Symptoms of hyperkalemia include generalized muscle weakness (as seen in this patient), muscle cramps, paresthesias, nausea, vomiting, and/or diarrhea. However, it is the cardiac manifestations (eg, ventricular arrhythmias, complete heart block, asystole) associated with hyperkalemia that are most concerning.

There are numerous causes of hyperkalemia, including medications, renal failure, digitalis toxicity, and metabolic acidosis. Therefore, it is important for the EP to identify the etiology in order to definitively treat the hyperkalemia.

Traditionally, it has been taught that hyperkalemia only requires treatment if abnormalities on the ECG are noted. Classic findings seen on ECG include prolonged PR interval, peaked T waves,² shortened QT interval, QRS widening, and a sinusoidal wave pattern. Once fictitious or hemolysis has been ruled out as the etiology, most EPs will initiate treatment above a specific threshold value (frequently 6 mEq/L),

Since it is the cardiac effects of hyperkalemia that can result in death, the initial treatment must be directed toward cardiac membrane stabilization. This is best accomplished by the administration of calcium gluconate 10% IV. This medication has a rapid onset of action (typically 1-3 minutes) and helps prevent the development of cardiac arrhythmias. Additional measures, which involve moving potassium intracellullarly, include sodium bicarbonate IV and insulin with glucose IV.

Actual removal of potassium from the body involves either the administration sodium polystyrene sulfonate or hemodialysis. Sodium polystyrene sulfonate, which is an ion-exchange resin designed to exchange sodium for potassium in the colon, can be given either orally or as an enema. Even though sodium polystyrene sulfonate has been approved for the treatment of hyperkalemia since 1958, it does not take effect for 1 to 2 hours after administration; there is also growing evidence questioning its efficacy and safety.³ In addition, sodium polystyrene sulfonate can exacerbate volume overload due to the associated increase in serum sodium. Therefore, hemodialysis is the most effective treatment for hyperkalemia, and is the treatment of choice for unstable patients with hyperkalemia and acute or chronic renal failure.

Hypoglycemia

mrfiza/ Shutterstock

A 44-year-old-man with type 1 diabetes mellitus (DM) was transported to the ED via emergency medical services (EMS) with a chief complaint of hypoglycemia. His wife stated the patient had been acting strangely prior to presentation. She further noted that after checking his blood sugar, which was 19 mg/dL, she gave her husband an oral glucose tablet with some water before calling EMS.

Upon arrival to the ED, the patient was triaged and designated as an urgent level III. At that time, he was alert and oriented, with a blood glucose level of 66 mg/dL. The patient was examined by a physician assistant (PA) within 15 minutes of his arrival. When interviewed by the PA, the patient described feelings of weakness, dizziness, and lightheadedness. The PA attributed these symptoms to the patient’s hypoglycemic state and ordered him a food tray. The patient was then observed for approximately 2 hours, during which time repeat blood-glucose testing revealed a level of 438 mg/dL. Approximately 20 minutes later, another blood-glucose test showed a level of 400 mg/dL. The patient felt well, appeared back to baseline, and expressed the desire to go home. At discharge, the PA instructed the patient to reduce his insulin by 20% and to follow up with his primary care physician (PCP) that same week.

Approximately 3 hours after discharge, the patient was found unresponsive by his wife, and EMS was again called. When EMS arrived at the patient’s house, his blood glucose level was 85 mg/dL. At presentation to the ED, the patient was unresponsive and without a pulse. Despite approximately 30 minutes of intensive resuscitative efforts, the code was called and the patient was pronounced dead.

The family sued the hospital, the emergency physician (EP), and the PA. They claimed the triage nurse failed to obtain an adequate history of the patient’s recent glucometer checks, previous hypoglycemic episodes, the amount and time of his last dose of insulin, and when and how much food he had recently ingested. The plaintiff further argued that that PA failed to obtain an electrocardiogram (ECG) to determine if the patient’s heart rhythm had been affected by his hypoglycemic state. The plaintiff also claimed the PA should have notified the patient’s PCP that the patient was in the ED, so that he could be admitted.

The defendants denied any negligence and argued the patient’s death was due to a sudden cardiac event, which was unrelated to the low-blood sugar levels. The defense contended that the patient’s enlarged heart and preexisting cardiovascular disease, hypertension, hypercholesterolemia, poorly controlled type 1 DM, history of alcohol abuse, and documented evidence of medication noncompliance were the cause of death. According to published accounts, a defense verdict was returned.

Discussion

It seems that rarely a shift goes by without a patient presenting with diabetes-associated complications such as hyperglycemia or hypoglycemia. While the jury reached the correct conclusion in this case, it does serve as a reminder that cases of hypoglycemia should not be treated lightly, and the EP must attempt to determine its cause.

The most commonly accepted definition of hypoglycemia is a blood-glucose level <50 mg/dL with associated symptoms. The causes of hypoglycemia in patients treated with insulin typically involves inadequate or no food intake, or accidental administration of too much insulin or the wrong type of insulin.¹

The differential diagnosis, however, needs to be more than just these two conditions. Since insulin is cleared by the kidneys, and patients with DM are at increased risk for kidney disease, acute renal failure should be considered in the differential. Other conditions to consider include infection, acute coronary syndromes, or unusual physical or mental stress.²

As with every patient presenting to the ED, patients with DM require a good history taking and physical examination. Additional testing, such as an ECG, troponin level, and kidney function test, should be performed based on the history and physical examination. Once the cause is determined, the majority of these patients can be treated with either intravenous (IV) or oral medications, observed, and discharged home with follow-up instructions.

Diabetic patients presenting with hypoglycemia due to a sulfonylurea agent or a long-acting insulin are in a completely different category. Because of the longer half-life of these agents, such patients will usually require admission to the hospital for serial glucose monitoring and treatment.² On occasion, patients with diabetic hypoglycemia and who are on a regular form of insulin will also require hospital admission. Those at highest risk are patients with DM aged 80 years and older.¹

Hyperkalemia

A 59-year-old man presented to the ED complaining of generalized weakness, the onset of which he stated had developed gradually over the previous 3 days. He denied chest pain, shortness of breath, or nausea and vomiting. His medical history was significant only for renal insufficiency. The patient was on no medications and denied alcohol or tobacco use.

Monkey Business Images/ Shutterstock

On physical examination, the patient had normal vital signs, including normal pulse oximetry. Similarly, the heart, lung, and abdominal examinations were all normal. On neurological examination, the patient had 5/5 motor strength in all four extremities and exhibited a normal gait.

The EP ordered an ECG, complete blood count (CBC), basic metabolic panel, urinalysis, and a chest X-ray (CXR). Laboratory evaluation showed an elevated potassium level of 6 mEq/L. The results of the CBC, urinalysis, and CXR were all reported as normal. (Unfortunately, there was no published information on the results of the BUN, creatinine, serum bicarbonate, or ECG findings.)

Based on the patient’s elevated potassium level, the EP ordered sodium polystyrene (Kayexalate) orally and arranged for admission to the hospital. The sodium polystyrene was administered to the patient approximately 1 hour after it was ordered.  While waiting for an inpatient bed, the patient experienced a cardiac arrest and died in the ED.

The family sued the EP and hospital for failure to properly respond to the patient’s elevated potassium level. The hospital denied any negligence, and the defense argued that the death was not related to any electrolyte abnormality, but was due to a respiratory arrest that led to the cardiac arrest. The defendants also maintained the sodium polystyrene had been administered in a timely manner. At trial, a defense verdict was returned.

Discussion

Hyperkalemia has been variably defined as serum potassium concentrations >5 mEq/L, >5.5 mEq/L, or >6 mEq/L.¹ Symptoms of hyperkalemia include generalized muscle weakness (as seen in this patient), muscle cramps, paresthesias, nausea, vomiting, and/or diarrhea. However, it is the cardiac manifestations (eg, ventricular arrhythmias, complete heart block, asystole) associated with hyperkalemia that are most concerning.

There are numerous causes of hyperkalemia, including medications, renal failure, digitalis toxicity, and metabolic acidosis. Therefore, it is important for the EP to identify the etiology in order to definitively treat the hyperkalemia.

Traditionally, it has been taught that hyperkalemia only requires treatment if abnormalities on the ECG are noted. Classic findings seen on ECG include prolonged PR interval, peaked T waves,² shortened QT interval, QRS widening, and a sinusoidal wave pattern. Once fictitious or hemolysis has been ruled out as the etiology, most EPs will initiate treatment above a specific threshold value (frequently 6 mEq/L),

Since it is the cardiac effects of hyperkalemia that can result in death, the initial treatment must be directed toward cardiac membrane stabilization. This is best accomplished by the administration of calcium gluconate 10% IV. This medication has a rapid onset of action (typically 1-3 minutes) and helps prevent the development of cardiac arrhythmias. Additional measures, which involve moving potassium intracellullarly, include sodium bicarbonate IV and insulin with glucose IV.

Actual removal of potassium from the body involves either the administration sodium polystyrene sulfonate or hemodialysis. Sodium polystyrene sulfonate, which is an ion-exchange resin designed to exchange sodium for potassium in the colon, can be given either orally or as an enema. Even though sodium polystyrene sulfonate has been approved for the treatment of hyperkalemia since 1958, it does not take effect for 1 to 2 hours after administration; there is also growing evidence questioning its efficacy and safety.³ In addition, sodium polystyrene sulfonate can exacerbate volume overload due to the associated increase in serum sodium. Therefore, hemodialysis is the most effective treatment for hyperkalemia, and is the treatment of choice for unstable patients with hyperkalemia and acute or chronic renal failure.

Hypoglycemia

mrfiza/ Shutterstock

A 44-year-old-man with type 1 diabetes mellitus (DM) was transported to the ED via emergency medical services (EMS) with a chief complaint of hypoglycemia. His wife stated the patient had been acting strangely prior to presentation. She further noted that after checking his blood sugar, which was 19 mg/dL, she gave her husband an oral glucose tablet with some water before calling EMS.

Upon arrival to the ED, the patient was triaged and designated as an urgent level III. At that time, he was alert and oriented, with a blood glucose level of 66 mg/dL. The patient was examined by a physician assistant (PA) within 15 minutes of his arrival. When interviewed by the PA, the patient described feelings of weakness, dizziness, and lightheadedness. The PA attributed these symptoms to the patient’s hypoglycemic state and ordered him a food tray. The patient was then observed for approximately 2 hours, during which time repeat blood-glucose testing revealed a level of 438 mg/dL. Approximately 20 minutes later, another blood-glucose test showed a level of 400 mg/dL. The patient felt well, appeared back to baseline, and expressed the desire to go home. At discharge, the PA instructed the patient to reduce his insulin by 20% and to follow up with his primary care physician (PCP) that same week.

Approximately 3 hours after discharge, the patient was found unresponsive by his wife, and EMS was again called. When EMS arrived at the patient’s house, his blood glucose level was 85 mg/dL. At presentation to the ED, the patient was unresponsive and without a pulse. Despite approximately 30 minutes of intensive resuscitative efforts, the code was called and the patient was pronounced dead.

The family sued the hospital, the emergency physician (EP), and the PA. They claimed the triage nurse failed to obtain an adequate history of the patient’s recent glucometer checks, previous hypoglycemic episodes, the amount and time of his last dose of insulin, and when and how much food he had recently ingested. The plaintiff further argued that that PA failed to obtain an electrocardiogram (ECG) to determine if the patient’s heart rhythm had been affected by his hypoglycemic state. The plaintiff also claimed the PA should have notified the patient’s PCP that the patient was in the ED, so that he could be admitted.

The defendants denied any negligence and argued the patient’s death was due to a sudden cardiac event, which was unrelated to the low-blood sugar levels. The defense contended that the patient’s enlarged heart and preexisting cardiovascular disease, hypertension, hypercholesterolemia, poorly controlled type 1 DM, history of alcohol abuse, and documented evidence of medication noncompliance were the cause of death. According to published accounts, a defense verdict was returned.

Discussion

It seems that rarely a shift goes by without a patient presenting with diabetes-associated complications such as hyperglycemia or hypoglycemia. While the jury reached the correct conclusion in this case, it does serve as a reminder that cases of hypoglycemia should not be treated lightly, and the EP must attempt to determine its cause.

The most commonly accepted definition of hypoglycemia is a blood-glucose level <50 mg/dL with associated symptoms. The causes of hypoglycemia in patients treated with insulin typically involves inadequate or no food intake, or accidental administration of too much insulin or the wrong type of insulin.¹

The differential diagnosis, however, needs to be more than just these two conditions. Since insulin is cleared by the kidneys, and patients with DM are at increased risk for kidney disease, acute renal failure should be considered in the differential. Other conditions to consider include infection, acute coronary syndromes, or unusual physical or mental stress.²

As with every patient presenting to the ED, patients with DM require a good history taking and physical examination. Additional testing, such as an ECG, troponin level, and kidney function test, should be performed based on the history and physical examination. Once the cause is determined, the majority of these patients can be treated with either intravenous (IV) or oral medications, observed, and discharged home with follow-up instructions.

Diabetic patients presenting with hypoglycemia due to a sulfonylurea agent or a long-acting insulin are in a completely different category. Because of the longer half-life of these agents, such patients will usually require admission to the hospital for serial glucose monitoring and treatment.² On occasion, patients with diabetic hypoglycemia and who are on a regular form of insulin will also require hospital admission. Those at highest risk are patients with DM aged 80 years and older.¹

Hyperkalemia

A 59-year-old man presented to the ED complaining of generalized weakness, the onset of which he stated had developed gradually over the previous 3 days. He denied chest pain, shortness of breath, or nausea and vomiting. His medical history was significant only for renal insufficiency. The patient was on no medications and denied alcohol or tobacco use.

Monkey Business Images/ Shutterstock

On physical examination, the patient had normal vital signs, including normal pulse oximetry. Similarly, the heart, lung, and abdominal examinations were all normal. On neurological examination, the patient had 5/5 motor strength in all four extremities and exhibited a normal gait.

The EP ordered an ECG, complete blood count (CBC), basic metabolic panel, urinalysis, and a chest X-ray (CXR). Laboratory evaluation showed an elevated potassium level of 6 mEq/L. The results of the CBC, urinalysis, and CXR were all reported as normal. (Unfortunately, there was no published information on the results of the BUN, creatinine, serum bicarbonate, or ECG findings.)

Based on the patient’s elevated potassium level, the EP ordered sodium polystyrene (Kayexalate) orally and arranged for admission to the hospital. The sodium polystyrene was administered to the patient approximately 1 hour after it was ordered.  While waiting for an inpatient bed, the patient experienced a cardiac arrest and died in the ED.

The family sued the EP and hospital for failure to properly respond to the patient’s elevated potassium level. The hospital denied any negligence, and the defense argued that the death was not related to any electrolyte abnormality, but was due to a respiratory arrest that led to the cardiac arrest. The defendants also maintained the sodium polystyrene had been administered in a timely manner. At trial, a defense verdict was returned.

Discussion

Hyperkalemia has been variably defined as serum potassium concentrations >5 mEq/L, >5.5 mEq/L, or >6 mEq/L.¹ Symptoms of hyperkalemia include generalized muscle weakness (as seen in this patient), muscle cramps, paresthesias, nausea, vomiting, and/or diarrhea. However, it is the cardiac manifestations (eg, ventricular arrhythmias, complete heart block, asystole) associated with hyperkalemia that are most concerning.

There are numerous causes of hyperkalemia, including medications, renal failure, digitalis toxicity, and metabolic acidosis. Therefore, it is important for the EP to identify the etiology in order to definitively treat the hyperkalemia.

Traditionally, it has been taught that hyperkalemia only requires treatment if abnormalities on the ECG are noted. Classic findings seen on ECG include prolonged PR interval, peaked T waves,² shortened QT interval, QRS widening, and a sinusoidal wave pattern. Once fictitious or hemolysis has been ruled out as the etiology, most EPs will initiate treatment above a specific threshold value (frequently 6 mEq/L),

Since it is the cardiac effects of hyperkalemia that can result in death, the initial treatment must be directed toward cardiac membrane stabilization. This is best accomplished by the administration of calcium gluconate 10% IV. This medication has a rapid onset of action (typically 1-3 minutes) and helps prevent the development of cardiac arrhythmias. Additional measures, which involve moving potassium intracellullarly, include sodium bicarbonate IV and insulin with glucose IV.

Actual removal of potassium from the body involves either the administration sodium polystyrene sulfonate or hemodialysis. Sodium polystyrene sulfonate, which is an ion-exchange resin designed to exchange sodium for potassium in the colon, can be given either orally or as an enema. Even though sodium polystyrene sulfonate has been approved for the treatment of hyperkalemia since 1958, it does not take effect for 1 to 2 hours after administration; there is also growing evidence questioning its efficacy and safety.³ In addition, sodium polystyrene sulfonate can exacerbate volume overload due to the associated increase in serum sodium. Therefore, hemodialysis is the most effective treatment for hyperkalemia, and is the treatment of choice for unstable patients with hyperkalemia and acute or chronic renal failure.

Case

A previously healthy 4-month-old girl was brought into the ED for concerns of alcohol ingestion. Reportedly, the infant’s father reconstituted 4 ounces of powdered formula using what he thought was water from an unmarked bottle in his refrigerator. He later realized that the bottle contained rum, although he still let the child finish the 4 ounces of formula in the hopes that she would vomit—which did not occur.

Upon arrival to the ED, the infant’s vital signs were: blood pressure, 100/61 mm Hg; heart rate, 155 beats/minute; respiratory rate, 36 breaths/minute; and temperature, normal. Oxygen saturation was 98% on room air. A rapid bedside blood glucose test was 89 mg/dL. The infant’s physical examination was unremarkable. She appeared active but hungry, had a strong cry, and had a developmentally appropriate gross neurological examination.

How does ethanol exposure in children typically occur?

Recent reports from the American Association of Poison Control Centers’ National Poison Data System demonstrate that ethanol exposures comprise 1% to 3% of total exposures in children aged ≤5 years.

The most common sources are ethanol-containing beverages, mouthwash, and cologne/perfume.¹ Ethanol can also be found as a solvent for certain pediatric liquid medications (eg, ranitidine) or in flavor extracts (eg, vanilla extract, orange extract). Any clear alcohol (eg, vodka, gin, rum) stored in an accessible site, such as a refrigerator, may be mistaken for water. In many reports, a caregiver unintentionally used the alcohol to reconstitute formula; however, intentional provision of alcohol to toddlers, usually as a sedative, is a recurring concern.²

What are the clinical concerns in children with ethanol intoxication?

Under usual conditions, a normal serum glucose concentration is maintained from ingested carbohydrates and via glycogenolysis of hepatic glycogen stores. Such glycogen reserves can sustain normal blood glucose concentrations for several hours in adults but for a shorter period in children. Once glycogen is depleted, as is common after an overnight fast, glucose can be generated through gluconeogenesis.

However, in the presence of ethanol (Figure), the excessive reducing potential (ie, NADH) that results from ethanol metabolism shunts pyruvate away from the gluconeogenic pathway (toward lactate), inhibiting glucose production. Unlike adults, children and infants, who have relatively low glycogen reserves, are at significant risk for hypoglycemia following ethanol exposure. This represents the largest contributor to morbidity and mortality of children with ethanol intoxication.³ Patients with hypoglycemia can have a highly variable clinical presentation including agitation, seizures, focality, or coma.⁴

Case Continuation

Intravenous (IV) access was obtained, and the patient was placed on a dextrose-containing fluid at 1.5 times the maintenance flow rate. Pertinent laboratory studies revealed a serum glucose level of 90 mg/dL, normal electrolyte panel, and an initial blood alcohol concentration of 337 mg/dL (approximately 30 minutes postingestion).

How do children with ethanol intoxication present?

While there is some variation in clinical effects among nontolerant adults, acute ethanol intoxication with a serum concentration >250 mg/dL is frequently associated with stupor, respiratory depression, and hypotension. A concentration >400 mg/dL may be associated with coma or apnea. Although similar clinical effects are expected in adolescents and children, infants often have counterintuitive clinical findings.

To date, eight cases of significant infant ethanol exposure exist in the literature (age range, 29 days to 9 months; ethanol concentration, 183-524 mg/dL). Respiratory depression was absent in all cases.^5-9 In all but two cases, the neurological examination revealed only subtle decreases in interaction or tone. The remaining two children were described as obtunded and flaccid (ethanol levels, 405 mg/dL and 524 mg/dL, respectively) and were intubated for airway protection despite normal respiratory rates.^7,10

The incongruence between the clinical findings (both the neurological examination and respiratory effects) and the ethanol concentration is difficult to explain. It may be due to age-related neurological immaturity or a limited ability to perform the required detailed neurological examinations in children. In particular, the relatively preserved level of consciousness, despite an otherwise coma-inducing ethanol concentration, is unique to infants. Accordingly, there should be a low threshold to check ethanol concentrations in infants presenting with apparent life-threatening events, altered mental status, decreased tone, or unexplained hypoglycemia or hypothermia.

What is the estimated time to sobriety in infants?

Ethanol is eliminated via a hepatic enzymatic oxidation pathway that becomes saturated at low serum levels. In nontolerant adults, this results in a zero-order kinetic elimination pattern with an ethanol elimination rate of approximately 20 mg/dL per hour. Anecdotally, it had been thought that children clear ethanol at roughly double this rate via unclear mechanisms. However, a review of published kinetic data suggests the actual rate of clearance may not differ substantially from adults (range, 19-34 mg/dL per hour).^5-7,10,11

Case Conclusion

The patient was transferred to a tertiary care pediatric hospital for continued management, where the markedly elevated serum ethanol concentration was confirmed.  She was maintained on a dextrose-containing IV fluid and observed overnight without development of any complications. Serial serum ethanol concentrations were performed and complete clearance was achieved approximately 20 hours postingestion, suggesting a metabolic rate of 16 mg/dL per hour. The infant was discharged home with supervision by child protective services.

Dr Boroughf is a toxicology fellow, department of emergency medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board. Dr Henretig is an attending toxicologist, department of emergency medicine, Children’s Hospital of Philadelphia, Pennsylvania.

Case

A previously healthy 4-month-old girl was brought into the ED for concerns of alcohol ingestion. Reportedly, the infant’s father reconstituted 4 ounces of powdered formula using what he thought was water from an unmarked bottle in his refrigerator. He later realized that the bottle contained rum, although he still let the child finish the 4 ounces of formula in the hopes that she would vomit—which did not occur.

Upon arrival to the ED, the infant’s vital signs were: blood pressure, 100/61 mm Hg; heart rate, 155 beats/minute; respiratory rate, 36 breaths/minute; and temperature, normal. Oxygen saturation was 98% on room air. A rapid bedside blood glucose test was 89 mg/dL. The infant’s physical examination was unremarkable. She appeared active but hungry, had a strong cry, and had a developmentally appropriate gross neurological examination.

How does ethanol exposure in children typically occur?

Recent reports from the American Association of Poison Control Centers’ National Poison Data System demonstrate that ethanol exposures comprise 1% to 3% of total exposures in children aged ≤5 years.

The most common sources are ethanol-containing beverages, mouthwash, and cologne/perfume.¹ Ethanol can also be found as a solvent for certain pediatric liquid medications (eg, ranitidine) or in flavor extracts (eg, vanilla extract, orange extract). Any clear alcohol (eg, vodka, gin, rum) stored in an accessible site, such as a refrigerator, may be mistaken for water. In many reports, a caregiver unintentionally used the alcohol to reconstitute formula; however, intentional provision of alcohol to toddlers, usually as a sedative, is a recurring concern.²

What are the clinical concerns in children with ethanol intoxication?

Under usual conditions, a normal serum glucose concentration is maintained from ingested carbohydrates and via glycogenolysis of hepatic glycogen stores. Such glycogen reserves can sustain normal blood glucose concentrations for several hours in adults but for a shorter period in children. Once glycogen is depleted, as is common after an overnight fast, glucose can be generated through gluconeogenesis.

However, in the presence of ethanol (Figure), the excessive reducing potential (ie, NADH) that results from ethanol metabolism shunts pyruvate away from the gluconeogenic pathway (toward lactate), inhibiting glucose production. Unlike adults, children and infants, who have relatively low glycogen reserves, are at significant risk for hypoglycemia following ethanol exposure. This represents the largest contributor to morbidity and mortality of children with ethanol intoxication.³ Patients with hypoglycemia can have a highly variable clinical presentation including agitation, seizures, focality, or coma.⁴

Case Continuation

Intravenous (IV) access was obtained, and the patient was placed on a dextrose-containing fluid at 1.5 times the maintenance flow rate. Pertinent laboratory studies revealed a serum glucose level of 90 mg/dL, normal electrolyte panel, and an initial blood alcohol concentration of 337 mg/dL (approximately 30 minutes postingestion).

How do children with ethanol intoxication present?

While there is some variation in clinical effects among nontolerant adults, acute ethanol intoxication with a serum concentration >250 mg/dL is frequently associated with stupor, respiratory depression, and hypotension. A concentration >400 mg/dL may be associated with coma or apnea. Although similar clinical effects are expected in adolescents and children, infants often have counterintuitive clinical findings.

To date, eight cases of significant infant ethanol exposure exist in the literature (age range, 29 days to 9 months; ethanol concentration, 183-524 mg/dL). Respiratory depression was absent in all cases.^5-9 In all but two cases, the neurological examination revealed only subtle decreases in interaction or tone. The remaining two children were described as obtunded and flaccid (ethanol levels, 405 mg/dL and 524 mg/dL, respectively) and were intubated for airway protection despite normal respiratory rates.^7,10

The incongruence between the clinical findings (both the neurological examination and respiratory effects) and the ethanol concentration is difficult to explain. It may be due to age-related neurological immaturity or a limited ability to perform the required detailed neurological examinations in children. In particular, the relatively preserved level of consciousness, despite an otherwise coma-inducing ethanol concentration, is unique to infants. Accordingly, there should be a low threshold to check ethanol concentrations in infants presenting with apparent life-threatening events, altered mental status, decreased tone, or unexplained hypoglycemia or hypothermia.

What is the estimated time to sobriety in infants?

Ethanol is eliminated via a hepatic enzymatic oxidation pathway that becomes saturated at low serum levels. In nontolerant adults, this results in a zero-order kinetic elimination pattern with an ethanol elimination rate of approximately 20 mg/dL per hour. Anecdotally, it had been thought that children clear ethanol at roughly double this rate via unclear mechanisms. However, a review of published kinetic data suggests the actual rate of clearance may not differ substantially from adults (range, 19-34 mg/dL per hour).^5-7,10,11

Case Conclusion

The patient was transferred to a tertiary care pediatric hospital for continued management, where the markedly elevated serum ethanol concentration was confirmed.  She was maintained on a dextrose-containing IV fluid and observed overnight without development of any complications. Serial serum ethanol concentrations were performed and complete clearance was achieved approximately 20 hours postingestion, suggesting a metabolic rate of 16 mg/dL per hour. The infant was discharged home with supervision by child protective services.

Dr Boroughf is a toxicology fellow, department of emergency medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board. Dr Henretig is an attending toxicologist, department of emergency medicine, Children’s Hospital of Philadelphia, Pennsylvania.

Case

A previously healthy 4-month-old girl was brought into the ED for concerns of alcohol ingestion. Reportedly, the infant’s father reconstituted 4 ounces of powdered formula using what he thought was water from an unmarked bottle in his refrigerator. He later realized that the bottle contained rum, although he still let the child finish the 4 ounces of formula in the hopes that she would vomit—which did not occur.

Upon arrival to the ED, the infant’s vital signs were: blood pressure, 100/61 mm Hg; heart rate, 155 beats/minute; respiratory rate, 36 breaths/minute; and temperature, normal. Oxygen saturation was 98% on room air. A rapid bedside blood glucose test was 89 mg/dL. The infant’s physical examination was unremarkable. She appeared active but hungry, had a strong cry, and had a developmentally appropriate gross neurological examination.

How does ethanol exposure in children typically occur?

Recent reports from the American Association of Poison Control Centers’ National Poison Data System demonstrate that ethanol exposures comprise 1% to 3% of total exposures in children aged ≤5 years.

The most common sources are ethanol-containing beverages, mouthwash, and cologne/perfume.¹ Ethanol can also be found as a solvent for certain pediatric liquid medications (eg, ranitidine) or in flavor extracts (eg, vanilla extract, orange extract). Any clear alcohol (eg, vodka, gin, rum) stored in an accessible site, such as a refrigerator, may be mistaken for water. In many reports, a caregiver unintentionally used the alcohol to reconstitute formula; however, intentional provision of alcohol to toddlers, usually as a sedative, is a recurring concern.²

What are the clinical concerns in children with ethanol intoxication?

Under usual conditions, a normal serum glucose concentration is maintained from ingested carbohydrates and via glycogenolysis of hepatic glycogen stores. Such glycogen reserves can sustain normal blood glucose concentrations for several hours in adults but for a shorter period in children. Once glycogen is depleted, as is common after an overnight fast, glucose can be generated through gluconeogenesis.

However, in the presence of ethanol (Figure), the excessive reducing potential (ie, NADH) that results from ethanol metabolism shunts pyruvate away from the gluconeogenic pathway (toward lactate), inhibiting glucose production. Unlike adults, children and infants, who have relatively low glycogen reserves, are at significant risk for hypoglycemia following ethanol exposure. This represents the largest contributor to morbidity and mortality of children with ethanol intoxication.³ Patients with hypoglycemia can have a highly variable clinical presentation including agitation, seizures, focality, or coma.⁴

Case Continuation

Intravenous (IV) access was obtained, and the patient was placed on a dextrose-containing fluid at 1.5 times the maintenance flow rate. Pertinent laboratory studies revealed a serum glucose level of 90 mg/dL, normal electrolyte panel, and an initial blood alcohol concentration of 337 mg/dL (approximately 30 minutes postingestion).

How do children with ethanol intoxication present?

While there is some variation in clinical effects among nontolerant adults, acute ethanol intoxication with a serum concentration >250 mg/dL is frequently associated with stupor, respiratory depression, and hypotension. A concentration >400 mg/dL may be associated with coma or apnea. Although similar clinical effects are expected in adolescents and children, infants often have counterintuitive clinical findings.

To date, eight cases of significant infant ethanol exposure exist in the literature (age range, 29 days to 9 months; ethanol concentration, 183-524 mg/dL). Respiratory depression was absent in all cases.^5-9 In all but two cases, the neurological examination revealed only subtle decreases in interaction or tone. The remaining two children were described as obtunded and flaccid (ethanol levels, 405 mg/dL and 524 mg/dL, respectively) and were intubated for airway protection despite normal respiratory rates.^7,10

The incongruence between the clinical findings (both the neurological examination and respiratory effects) and the ethanol concentration is difficult to explain. It may be due to age-related neurological immaturity or a limited ability to perform the required detailed neurological examinations in children. In particular, the relatively preserved level of consciousness, despite an otherwise coma-inducing ethanol concentration, is unique to infants. Accordingly, there should be a low threshold to check ethanol concentrations in infants presenting with apparent life-threatening events, altered mental status, decreased tone, or unexplained hypoglycemia or hypothermia.

What is the estimated time to sobriety in infants?

Ethanol is eliminated via a hepatic enzymatic oxidation pathway that becomes saturated at low serum levels. In nontolerant adults, this results in a zero-order kinetic elimination pattern with an ethanol elimination rate of approximately 20 mg/dL per hour. Anecdotally, it had been thought that children clear ethanol at roughly double this rate via unclear mechanisms. However, a review of published kinetic data suggests the actual rate of clearance may not differ substantially from adults (range, 19-34 mg/dL per hour).^5-7,10,11

Case Conclusion

The patient was transferred to a tertiary care pediatric hospital for continued management, where the markedly elevated serum ethanol concentration was confirmed.  She was maintained on a dextrose-containing IV fluid and observed overnight without development of any complications. Serial serum ethanol concentrations were performed and complete clearance was achieved approximately 20 hours postingestion, suggesting a metabolic rate of 16 mg/dL per hour. The infant was discharged home with supervision by child protective services.

Dr Boroughf is a toxicology fellow, department of emergency medicine, Albert Einstein Medical Center, Philadelphia, Pennsylvania. Dr Nelson, editor of “Case Studies in Toxicology,” is a professor in the department of emergency medicine and director of the medical toxicology fellowship program at the New York University School of Medicine and the New York City Poison Control Center. He is also associate editor, toxicology, of the EMERGENCY MEDICINE editorial board. Dr Henretig is an attending toxicologist, department of emergency medicine, Children’s Hospital of Philadelphia, Pennsylvania.

Nevertheless, careful attention to the ST-T and QRS-complex configurations often allows diagnosis of the cause of ST elevation (Figure 1, Table 1). This paper discusses the differential diagnosis of ST elevation.

MEASURED AT THE J POINT OR LATER

ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION

A diagnosis of STEMI that mandates emergency reperfusion requires ST elevation equaling or exceeding the following cut-points, in at least two contiguous leads (using the standardization of 1.0 mV = 10 mm)^4,5:

• 1 mm in all standard leads other than V₂ and V₃
• 2.5 mm in leads V₂ and V₃ in men younger than age 40, 2 mm in leads V₂ and V₃ in men age 40 and older, and 1.5 mm in these leads in women
• 0.5 mm in the posterior chest leads V₇ to V₉; ST elevation is attenuated in the posterior leads because of their greater distance from the heart, explaining the lower cut-point.⁶

While ST elevation that falls below these cut-points may be a normal variant, any ST elevation or depression (≥ 0.5 mm) may be abnormal and may necessitate further evaluation for ischemia, particularly when the clinical setting or the ST morphology suggests ischemia or when other signs of ischemia such as T-wave abnormalities, Q waves, or reciprocal ST-segment changes are also present on the electrocardiogram.

Conversely, ST elevation that exceeds these cut-points may not represent STEMI. In an analysis of patients with chest pain manifesting ST elevation, only 15% were eventually diagnosed with STEMI.⁷ In addition to size, careful attention to the morphology of the ST segment and the associated features is critical (Figure 1).

Other features of STEMI

Four other features characteristic of STEMI may be present (Figures 2 and 3):

• Concomitant T-wave abnormalities (wide, ample, or inverted T waves)
• Q waves
• ST depression in the reciprocal leads. Reciprocal ST depression is seen in all inferior STEMIs and in 70% of anterior STEMIs.^11,12 Diffuse ST elevation mimicking pericarditis may be seen with midvessel occlusion of a left anterior descending artery that wraps around the apex and supplies part of the inferior wall.

• 

  ST or T-wave amplitude may approximate or exceed the QRS amplitude in at least one lead.^3,13,14 This finding is characteristic of STEMI, in which the QRS “shrinks” as the infarcted area becomes electrically neutral, whereas the ST-T segments become ample.^3,13 In fact, early STEMI may be characterized by a small R wave that seems to be “pulled up” by the elevated ST segment. A small or absent R wave along with an ample, convex ST segment that fuses with the T wave and exceeds the height of the remaining R wave is called “tombstoning” (Figure 3). Tombstoning is most commonly seen with anterior infarction and implies more extensive myocardial damage and a worse prognosis than STEMI without tombstoning.¹⁵

Note that ST elevation may not be acute STEMI but an old STEMI with a chronically dysfunctional myocardium (dyskinetic or aneurysmal myocardium). In fact, an old STEMI may manifest as a chronic, persistent ST elevation along with Q waves, and T waves may be inverted or upright, but not ample.¹⁴ A history of an old MI, old electrocardiograms, if available, and quick bedside echocardiography may allow the diagnosis. In the case of an old dyskinetic infarct, echocardiography shows a thin, bright (scarred), and possibly aneurysmal myocardium, whereas in acute STEMI, the myocardium is neither thin nor scarred yet. If the patient does not report a history of MI, if the T wave is ample (> 75% the size of QRS), or if the patient presents with atypical ongoing angina, presume it is acute STEMI.

EARLY REPOLARIZATION

Early repolarization is a normal variant of ST elevation that equals or exceeds 1 mm (measured at the J point). It is highly prevalent in people under age 40 and remains prevalent in middle-aged people.

Two distinct and sometimes coexistent forms of early repolarization have been described: (1) ST elevation in the anterior leads V₁ to V₃,^16–19 and (2) ST elevation in the lateral leads (V₄ to V₆, I, aVL) or inferior leads.^18–22 The prevalence of the first form—ie, ST elevation of 1 mm or more in any of the leads V₁ through V₃—is 60% to 90% in men  age 45 and younger, 20% to 40% in men over age 45, and about 10% in women of any age.¹⁶ Thus, this form of early repolarization is called “normal male pattern.”

Even early repolarization that involves the lateral or inferior leads is common, with a prevalence of about 15% in people ages 30 to 40 and about 5% to 10% in those 40 to 65.^20–23 It is two to four times more prevalent in men and three times more prevalent in African Americans. It is also highly prevalent in athletes younger than 25 (about 30% to 40%).²²

• The ST segment is concave upward, and the J point is well demarcated and may be notched or slurred (Figure 1).
• ST elevation is usually no more than 3 mm.
• ST elevation may be limited to the anterior leads or, in many instances, may extend to the inferior or lateral leads. Early repolarization is very rarely limited to the limb leads, and involvement of some precordial leads is the rule.^18,19 The ST segment is depressed in lead aVR in 50% of patients.^18,19

• 

  The T wave is usually ample and may be more than 10 mm tall in the precordial leads in one-third of patients,¹⁷ but as opposed to the ample T wave of STEMI, it is not broad and remains smaller than the QRS complex. The ample T wave distinguishes early repolarization from pericarditis, and explains the low ST-T ratio in lead V₆. In up to 10% of young black men, the T wave has a terminal inversion in leads V₃ to V₅, and occasionally in V₁ and V₂, mimicking infarction (Figure 5).²⁴
• The QRS complex tends to have prominent precordial voltage, in sharp contrast to STEMI, in which QRS shrinking occurs.^3,17,22

The early repolarization pattern may be intermittent, may vary among serial electrocardiograms, may decrease with a rise in sympathetic tone, as observed during exercise, and may increase with a rise in vagal tone.^18,19,25,26  Although it is usually a benign finding, the early repolarization pattern in leads other than V₁ to V₃ has been associated with an increased risk of sudden death, particularly when the ST elevation is horizontal-descending rather than upsloping and, possibly, when early repolarization involves the inferior leads with a J point that is notched or elevated 2 mm or more.^20,22

PERICARDITIS

Transient PR depression greater than 1 mm is often seen, particularly in leads II, aVF, and V₄ to V₆, and represents atrial subepicardial injury. PR depression in those leads is always associated with PR elevation in lead aVR and sometimes V₁. PR changes often coexist with ST changes but may be isolated and may precede ST changes.³⁰ PR depression is characteristic of pericarditis but may be seen in early repolarization, where it is less marked than in pericarditis (< 0.8 mm) and implies early repolarization of the atrial tissue,³¹ and in MI, where it implies atrial infarction with atrial injury pattern.

Classically, it is said that in pericarditis, unlike in STEMI, the T wave does not invert until the ST elevation subsides. In reality, up to 40% of patients develop a notched or biphasic positive-negative T wave before full return of the ST segment to the baseline.^27,32 And if T-wave inversion antedates pericarditis, concomitant ST elevation and T-wave inversion may be seen once pericarditis develops. However, the T wave inverts less deeply and less completely than in STEMI, and the corrected QT interval remains normal even when the T wave inverts.

Three criteria distinguish pericarditis from early repolarization (but not from STEMI):

• PR depression greater than 1 mm
• ST-segment depression in lead V₁
• A ratio of ST-segment height to T-wave height of at least 25% in lead V₆, V₅, V₄, or I. This feature distinguishes pericarditis from early repolarization with a high sensitivity and specificity. In pericarditis, the T waves have normal or reduced amplitude, and the ST-T ratio is therefore high,³³ whereas in early repolarization the T waves are tall, so the ST-T ratio is less than 25%.

Widespread ST elevation may be seen with both pericarditis and early repolarization. ST elevation limited to the anterior leads is more likely to be early repolarization than pericarditis.

LEFT BUNDLE BRANCH BLOCK

The following findings imply MI:

• 

  ST elevation or depression that is concordant with the QRS complex. Moreover, since ST deviation is mandatory with left bundle branch block, a “normal-looking” ST segment implies ischemia.
• Inverted T waves concordant with the QRS in more than one lead, or biphasic T waves in more than one lead (eg, V₁ to V₃). Across the precordial leads, T waves may transition from positive to negative one lead earlier or later than the QRS and ST transition. Therefore, even in the absence of ischemia, the T wave may be inverted in lead V₃, in which the QRS is deeply negative and the ST is still elevated (negative T-wave concordance in one lead). Also, the T wave may be upright in leads V₅, V₆, and I where QRS is upright and the ST segment is depressed (positive T-wave concordance does not imply ischemia).

• 

  In addition to concordance, a discordant ST segment or T wave that is very large may imply ischemia. For example, a discordant ST segment or T wave that is larger than the QRS height implies ischemia. A discordant ST elevation greater than 5 mm has been suggested by Sgarbossa et al³⁵ as a diagnostic feature of STEMI; however, this feature is seen in 10% of control patients with left bundle branch block and no STEMI, and it is thus poorly specific and also poorly sensitive, frequently missing STEMI.^35–37 Smith et al³⁶ have suggested that a discordant ST elevation of at least 25% of the S-wave depth is a far more sensitive and accurate feature but one that may still be found in up to 10% of control patients.³⁶

LEFT VENTRICULAR HYPERTROPHY

In left ventricular hypertrophy, a deep S wave is seen in leads V₁ to V₃, with ST elevation and T waves that are discordant with the QRS complex. Rarely, ST elevation may be straight or convex. The following findings imply MI:

• ST elevation or depression that is concordant with the QRS.
• Inverted T waves that are concordant with the QRS in more than one lead, or biphasic T waves in more than one lead (eg, V₁ to V₃).
• A discordant ST segment or a T wave that is very large may imply ischemia. In left ventricular hypertrophy, ST elevation is usually less than 2.5 mm in leads V₁ to V₃ and is rarely seen in the inferior leads, where it would be less than 1 mm.³⁴ When ST elevation is seen in leads V₁ to V₃ in left ventricular hypertrophy, an ST magnitude of 25% or more of the total QRS voltage has a 91% specificity for STEMI.³⁴

On another note, right ventricular hypertrophy and right bundle branch block may lead to ST-segment depression and T-wave inversion, but not to ST elevation. Thus, ST elevation occurring with right ventricular hypertrophy or right bundle branch block implies STEMI. While only left bundle branch block poses a diagnostic challenge, both types of bundle branch block, if secondary to STEMI, represent equally high-risk categories.³⁸

PREEXCITATION

HYPERKALEMIA

OTHER CAUSES OF ST-SEGMENT ELEVATION

Takotsubo cardiomyopathy

Takotsubo cardiomyopathy mimics all electrocardiographic features of anteroapical STEMI. ST elevation may extend to the inferior leads but cannot be isolated in the inferior leads.³⁹ As in apical STEMI, reciprocal ST depression is uncommon. Within 24 to 48 hours, ST elevation evolves into deep anterior T-wave inversion and a prolonged QT interval. Transient Q waves may be seen.

Myocarditis

Myocarditis may have one of two electrocardiographic patterns: a pericarditis pattern, or a typical STEMI pattern with Q waves sometimes localized to one area.⁴⁰

Atrial flutter waves

Large pulmonary embolism

A large pulmonary embolism may be associated with T-wave inversion in the anterior leads or the inferior leads, or both, reflective of cor pulmonale. Less commonly, ST elevation in the anterior or inferior leads is seen. In fact, changes of both anterior and inferior ischemia should always suggest a pulmonary embolism.^41,42

Brugada syndrome

Hyperkalemia, Brugada syndrome, and sometimes pulmonary embolism are characterized by an ST elevation that slopes downward (Figures 11 and 13), which contrasts with the upsloping, convex ST elevation of STEMI.

Nevertheless, careful attention to the ST-T and QRS-complex configurations often allows diagnosis of the cause of ST elevation (Figure 1, Table 1). This paper discusses the differential diagnosis of ST elevation.

MEASURED AT THE J POINT OR LATER

ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION

A diagnosis of STEMI that mandates emergency reperfusion requires ST elevation equaling or exceeding the following cut-points, in at least two contiguous leads (using the standardization of 1.0 mV = 10 mm)^4,5:

• 1 mm in all standard leads other than V₂ and V₃
• 2.5 mm in leads V₂ and V₃ in men younger than age 40, 2 mm in leads V₂ and V₃ in men age 40 and older, and 1.5 mm in these leads in women
• 0.5 mm in the posterior chest leads V₇ to V₉; ST elevation is attenuated in the posterior leads because of their greater distance from the heart, explaining the lower cut-point.⁶

While ST elevation that falls below these cut-points may be a normal variant, any ST elevation or depression (≥ 0.5 mm) may be abnormal and may necessitate further evaluation for ischemia, particularly when the clinical setting or the ST morphology suggests ischemia or when other signs of ischemia such as T-wave abnormalities, Q waves, or reciprocal ST-segment changes are also present on the electrocardiogram.

Conversely, ST elevation that exceeds these cut-points may not represent STEMI. In an analysis of patients with chest pain manifesting ST elevation, only 15% were eventually diagnosed with STEMI.⁷ In addition to size, careful attention to the morphology of the ST segment and the associated features is critical (Figure 1).

Other features of STEMI

Four other features characteristic of STEMI may be present (Figures 2 and 3):

• Concomitant T-wave abnormalities (wide, ample, or inverted T waves)
• Q waves
• ST depression in the reciprocal leads. Reciprocal ST depression is seen in all inferior STEMIs and in 70% of anterior STEMIs.^11,12 Diffuse ST elevation mimicking pericarditis may be seen with midvessel occlusion of a left anterior descending artery that wraps around the apex and supplies part of the inferior wall.

• 

  ST or T-wave amplitude may approximate or exceed the QRS amplitude in at least one lead.^3,13,14 This finding is characteristic of STEMI, in which the QRS “shrinks” as the infarcted area becomes electrically neutral, whereas the ST-T segments become ample.^3,13 In fact, early STEMI may be characterized by a small R wave that seems to be “pulled up” by the elevated ST segment. A small or absent R wave along with an ample, convex ST segment that fuses with the T wave and exceeds the height of the remaining R wave is called “tombstoning” (Figure 3). Tombstoning is most commonly seen with anterior infarction and implies more extensive myocardial damage and a worse prognosis than STEMI without tombstoning.¹⁵

Note that ST elevation may not be acute STEMI but an old STEMI with a chronically dysfunctional myocardium (dyskinetic or aneurysmal myocardium). In fact, an old STEMI may manifest as a chronic, persistent ST elevation along with Q waves, and T waves may be inverted or upright, but not ample.¹⁴ A history of an old MI, old electrocardiograms, if available, and quick bedside echocardiography may allow the diagnosis. In the case of an old dyskinetic infarct, echocardiography shows a thin, bright (scarred), and possibly aneurysmal myocardium, whereas in acute STEMI, the myocardium is neither thin nor scarred yet. If the patient does not report a history of MI, if the T wave is ample (> 75% the size of QRS), or if the patient presents with atypical ongoing angina, presume it is acute STEMI.

EARLY REPOLARIZATION

Early repolarization is a normal variant of ST elevation that equals or exceeds 1 mm (measured at the J point). It is highly prevalent in people under age 40 and remains prevalent in middle-aged people.

Two distinct and sometimes coexistent forms of early repolarization have been described: (1) ST elevation in the anterior leads V₁ to V₃,^16–19 and (2) ST elevation in the lateral leads (V₄ to V₆, I, aVL) or inferior leads.^18–22 The prevalence of the first form—ie, ST elevation of 1 mm or more in any of the leads V₁ through V₃—is 60% to 90% in men  age 45 and younger, 20% to 40% in men over age 45, and about 10% in women of any age.¹⁶ Thus, this form of early repolarization is called “normal male pattern.”

Even early repolarization that involves the lateral or inferior leads is common, with a prevalence of about 15% in people ages 30 to 40 and about 5% to 10% in those 40 to 65.^20–23 It is two to four times more prevalent in men and three times more prevalent in African Americans. It is also highly prevalent in athletes younger than 25 (about 30% to 40%).²²

• The ST segment is concave upward, and the J point is well demarcated and may be notched or slurred (Figure 1).
• ST elevation is usually no more than 3 mm.
• ST elevation may be limited to the anterior leads or, in many instances, may extend to the inferior or lateral leads. Early repolarization is very rarely limited to the limb leads, and involvement of some precordial leads is the rule.^18,19 The ST segment is depressed in lead aVR in 50% of patients.^18,19

• 

  The T wave is usually ample and may be more than 10 mm tall in the precordial leads in one-third of patients,¹⁷ but as opposed to the ample T wave of STEMI, it is not broad and remains smaller than the QRS complex. The ample T wave distinguishes early repolarization from pericarditis, and explains the low ST-T ratio in lead V₆. In up to 10% of young black men, the T wave has a terminal inversion in leads V₃ to V₅, and occasionally in V₁ and V₂, mimicking infarction (Figure 5).²⁴
• The QRS complex tends to have prominent precordial voltage, in sharp contrast to STEMI, in which QRS shrinking occurs.^3,17,22

The early repolarization pattern may be intermittent, may vary among serial electrocardiograms, may decrease with a rise in sympathetic tone, as observed during exercise, and may increase with a rise in vagal tone.^18,19,25,26  Although it is usually a benign finding, the early repolarization pattern in leads other than V₁ to V₃ has been associated with an increased risk of sudden death, particularly when the ST elevation is horizontal-descending rather than upsloping and, possibly, when early repolarization involves the inferior leads with a J point that is notched or elevated 2 mm or more.^20,22

PERICARDITIS

Transient PR depression greater than 1 mm is often seen, particularly in leads II, aVF, and V₄ to V₆, and represents atrial subepicardial injury. PR depression in those leads is always associated with PR elevation in lead aVR and sometimes V₁. PR changes often coexist with ST changes but may be isolated and may precede ST changes.³⁰ PR depression is characteristic of pericarditis but may be seen in early repolarization, where it is less marked than in pericarditis (< 0.8 mm) and implies early repolarization of the atrial tissue,³¹ and in MI, where it implies atrial infarction with atrial injury pattern.

Classically, it is said that in pericarditis, unlike in STEMI, the T wave does not invert until the ST elevation subsides. In reality, up to 40% of patients develop a notched or biphasic positive-negative T wave before full return of the ST segment to the baseline.^27,32 And if T-wave inversion antedates pericarditis, concomitant ST elevation and T-wave inversion may be seen once pericarditis develops. However, the T wave inverts less deeply and less completely than in STEMI, and the corrected QT interval remains normal even when the T wave inverts.

Three criteria distinguish pericarditis from early repolarization (but not from STEMI):

• PR depression greater than 1 mm
• ST-segment depression in lead V₁
• A ratio of ST-segment height to T-wave height of at least 25% in lead V₆, V₅, V₄, or I. This feature distinguishes pericarditis from early repolarization with a high sensitivity and specificity. In pericarditis, the T waves have normal or reduced amplitude, and the ST-T ratio is therefore high,³³ whereas in early repolarization the T waves are tall, so the ST-T ratio is less than 25%.

Widespread ST elevation may be seen with both pericarditis and early repolarization. ST elevation limited to the anterior leads is more likely to be early repolarization than pericarditis.

LEFT BUNDLE BRANCH BLOCK

The following findings imply MI:

• 

  ST elevation or depression that is concordant with the QRS complex. Moreover, since ST deviation is mandatory with left bundle branch block, a “normal-looking” ST segment implies ischemia.
• Inverted T waves concordant with the QRS in more than one lead, or biphasic T waves in more than one lead (eg, V₁ to V₃). Across the precordial leads, T waves may transition from positive to negative one lead earlier or later than the QRS and ST transition. Therefore, even in the absence of ischemia, the T wave may be inverted in lead V₃, in which the QRS is deeply negative and the ST is still elevated (negative T-wave concordance in one lead). Also, the T wave may be upright in leads V₅, V₆, and I where QRS is upright and the ST segment is depressed (positive T-wave concordance does not imply ischemia).

• 

  In addition to concordance, a discordant ST segment or T wave that is very large may imply ischemia. For example, a discordant ST segment or T wave that is larger than the QRS height implies ischemia. A discordant ST elevation greater than 5 mm has been suggested by Sgarbossa et al³⁵ as a diagnostic feature of STEMI; however, this feature is seen in 10% of control patients with left bundle branch block and no STEMI, and it is thus poorly specific and also poorly sensitive, frequently missing STEMI.^35–37 Smith et al³⁶ have suggested that a discordant ST elevation of at least 25% of the S-wave depth is a far more sensitive and accurate feature but one that may still be found in up to 10% of control patients.³⁶

LEFT VENTRICULAR HYPERTROPHY

In left ventricular hypertrophy, a deep S wave is seen in leads V₁ to V₃, with ST elevation and T waves that are discordant with the QRS complex. Rarely, ST elevation may be straight or convex. The following findings imply MI:

• ST elevation or depression that is concordant with the QRS.
• Inverted T waves that are concordant with the QRS in more than one lead, or biphasic T waves in more than one lead (eg, V₁ to V₃).
• A discordant ST segment or a T wave that is very large may imply ischemia. In left ventricular hypertrophy, ST elevation is usually less than 2.5 mm in leads V₁ to V₃ and is rarely seen in the inferior leads, where it would be less than 1 mm.³⁴ When ST elevation is seen in leads V₁ to V₃ in left ventricular hypertrophy, an ST magnitude of 25% or more of the total QRS voltage has a 91% specificity for STEMI.³⁴

On another note, right ventricular hypertrophy and right bundle branch block may lead to ST-segment depression and T-wave inversion, but not to ST elevation. Thus, ST elevation occurring with right ventricular hypertrophy or right bundle branch block implies STEMI. While only left bundle branch block poses a diagnostic challenge, both types of bundle branch block, if secondary to STEMI, represent equally high-risk categories.³⁸

PREEXCITATION

HYPERKALEMIA

OTHER CAUSES OF ST-SEGMENT ELEVATION

Takotsubo cardiomyopathy

Takotsubo cardiomyopathy mimics all electrocardiographic features of anteroapical STEMI. ST elevation may extend to the inferior leads but cannot be isolated in the inferior leads.³⁹ As in apical STEMI, reciprocal ST depression is uncommon. Within 24 to 48 hours, ST elevation evolves into deep anterior T-wave inversion and a prolonged QT interval. Transient Q waves may be seen.

Myocarditis

Myocarditis may have one of two electrocardiographic patterns: a pericarditis pattern, or a typical STEMI pattern with Q waves sometimes localized to one area.⁴⁰

Atrial flutter waves

Large pulmonary embolism

A large pulmonary embolism may be associated with T-wave inversion in the anterior leads or the inferior leads, or both, reflective of cor pulmonale. Less commonly, ST elevation in the anterior or inferior leads is seen. In fact, changes of both anterior and inferior ischemia should always suggest a pulmonary embolism.^41,42

Brugada syndrome

Hyperkalemia, Brugada syndrome, and sometimes pulmonary embolism are characterized by an ST elevation that slopes downward (Figures 11 and 13), which contrasts with the upsloping, convex ST elevation of STEMI.

Nevertheless, careful attention to the ST-T and QRS-complex configurations often allows diagnosis of the cause of ST elevation (Figure 1, Table 1). This paper discusses the differential diagnosis of ST elevation.

MEASURED AT THE J POINT OR LATER

ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION

A diagnosis of STEMI that mandates emergency reperfusion requires ST elevation equaling or exceeding the following cut-points, in at least two contiguous leads (using the standardization of 1.0 mV = 10 mm)^4,5:

• 1 mm in all standard leads other than V₂ and V₃
• 2.5 mm in leads V₂ and V₃ in men younger than age 40, 2 mm in leads V₂ and V₃ in men age 40 and older, and 1.5 mm in these leads in women
• 0.5 mm in the posterior chest leads V₇ to V₉; ST elevation is attenuated in the posterior leads because of their greater distance from the heart, explaining the lower cut-point.⁶

While ST elevation that falls below these cut-points may be a normal variant, any ST elevation or depression (≥ 0.5 mm) may be abnormal and may necessitate further evaluation for ischemia, particularly when the clinical setting or the ST morphology suggests ischemia or when other signs of ischemia such as T-wave abnormalities, Q waves, or reciprocal ST-segment changes are also present on the electrocardiogram.

Conversely, ST elevation that exceeds these cut-points may not represent STEMI. In an analysis of patients with chest pain manifesting ST elevation, only 15% were eventually diagnosed with STEMI.⁷ In addition to size, careful attention to the morphology of the ST segment and the associated features is critical (Figure 1).

Other features of STEMI

Four other features characteristic of STEMI may be present (Figures 2 and 3):

• Concomitant T-wave abnormalities (wide, ample, or inverted T waves)
• Q waves
• ST depression in the reciprocal leads. Reciprocal ST depression is seen in all inferior STEMIs and in 70% of anterior STEMIs.^11,12 Diffuse ST elevation mimicking pericarditis may be seen with midvessel occlusion of a left anterior descending artery that wraps around the apex and supplies part of the inferior wall.

• 

  ST or T-wave amplitude may approximate or exceed the QRS amplitude in at least one lead.^3,13,14 This finding is characteristic of STEMI, in which the QRS “shrinks” as the infarcted area becomes electrically neutral, whereas the ST-T segments become ample.^3,13 In fact, early STEMI may be characterized by a small R wave that seems to be “pulled up” by the elevated ST segment. A small or absent R wave along with an ample, convex ST segment that fuses with the T wave and exceeds the height of the remaining R wave is called “tombstoning” (Figure 3). Tombstoning is most commonly seen with anterior infarction and implies more extensive myocardial damage and a worse prognosis than STEMI without tombstoning.¹⁵

Note that ST elevation may not be acute STEMI but an old STEMI with a chronically dysfunctional myocardium (dyskinetic or aneurysmal myocardium). In fact, an old STEMI may manifest as a chronic, persistent ST elevation along with Q waves, and T waves may be inverted or upright, but not ample.¹⁴ A history of an old MI, old electrocardiograms, if available, and quick bedside echocardiography may allow the diagnosis. In the case of an old dyskinetic infarct, echocardiography shows a thin, bright (scarred), and possibly aneurysmal myocardium, whereas in acute STEMI, the myocardium is neither thin nor scarred yet. If the patient does not report a history of MI, if the T wave is ample (> 75% the size of QRS), or if the patient presents with atypical ongoing angina, presume it is acute STEMI.

EARLY REPOLARIZATION

Early repolarization is a normal variant of ST elevation that equals or exceeds 1 mm (measured at the J point). It is highly prevalent in people under age 40 and remains prevalent in middle-aged people.

Two distinct and sometimes coexistent forms of early repolarization have been described: (1) ST elevation in the anterior leads V₁ to V₃,^16–19 and (2) ST elevation in the lateral leads (V₄ to V₆, I, aVL) or inferior leads.^18–22 The prevalence of the first form—ie, ST elevation of 1 mm or more in any of the leads V₁ through V₃—is 60% to 90% in men  age 45 and younger, 20% to 40% in men over age 45, and about 10% in women of any age.¹⁶ Thus, this form of early repolarization is called “normal male pattern.”

Even early repolarization that involves the lateral or inferior leads is common, with a prevalence of about 15% in people ages 30 to 40 and about 5% to 10% in those 40 to 65.^20–23 It is two to four times more prevalent in men and three times more prevalent in African Americans. It is also highly prevalent in athletes younger than 25 (about 30% to 40%).²²

• The ST segment is concave upward, and the J point is well demarcated and may be notched or slurred (Figure 1).
• ST elevation is usually no more than 3 mm.
• ST elevation may be limited to the anterior leads or, in many instances, may extend to the inferior or lateral leads. Early repolarization is very rarely limited to the limb leads, and involvement of some precordial leads is the rule.^18,19 The ST segment is depressed in lead aVR in 50% of patients.^18,19

• 

  The T wave is usually ample and may be more than 10 mm tall in the precordial leads in one-third of patients,¹⁷ but as opposed to the ample T wave of STEMI, it is not broad and remains smaller than the QRS complex. The ample T wave distinguishes early repolarization from pericarditis, and explains the low ST-T ratio in lead V₆. In up to 10% of young black men, the T wave has a terminal inversion in leads V₃ to V₅, and occasionally in V₁ and V₂, mimicking infarction (Figure 5).²⁴
• The QRS complex tends to have prominent precordial voltage, in sharp contrast to STEMI, in which QRS shrinking occurs.^3,17,22

The early repolarization pattern may be intermittent, may vary among serial electrocardiograms, may decrease with a rise in sympathetic tone, as observed during exercise, and may increase with a rise in vagal tone.^18,19,25,26  Although it is usually a benign finding, the early repolarization pattern in leads other than V₁ to V₃ has been associated with an increased risk of sudden death, particularly when the ST elevation is horizontal-descending rather than upsloping and, possibly, when early repolarization involves the inferior leads with a J point that is notched or elevated 2 mm or more.^20,22

PERICARDITIS

Transient PR depression greater than 1 mm is often seen, particularly in leads II, aVF, and V₄ to V₆, and represents atrial subepicardial injury. PR depression in those leads is always associated with PR elevation in lead aVR and sometimes V₁. PR changes often coexist with ST changes but may be isolated and may precede ST changes.³⁰ PR depression is characteristic of pericarditis but may be seen in early repolarization, where it is less marked than in pericarditis (< 0.8 mm) and implies early repolarization of the atrial tissue,³¹ and in MI, where it implies atrial infarction with atrial injury pattern.

Classically, it is said that in pericarditis, unlike in STEMI, the T wave does not invert until the ST elevation subsides. In reality, up to 40% of patients develop a notched or biphasic positive-negative T wave before full return of the ST segment to the baseline.^27,32 And if T-wave inversion antedates pericarditis, concomitant ST elevation and T-wave inversion may be seen once pericarditis develops. However, the T wave inverts less deeply and less completely than in STEMI, and the corrected QT interval remains normal even when the T wave inverts.

Three criteria distinguish pericarditis from early repolarization (but not from STEMI):

• PR depression greater than 1 mm
• ST-segment depression in lead V₁
• A ratio of ST-segment height to T-wave height of at least 25% in lead V₆, V₅, V₄, or I. This feature distinguishes pericarditis from early repolarization with a high sensitivity and specificity. In pericarditis, the T waves have normal or reduced amplitude, and the ST-T ratio is therefore high,³³ whereas in early repolarization the T waves are tall, so the ST-T ratio is less than 25%.

Widespread ST elevation may be seen with both pericarditis and early repolarization. ST elevation limited to the anterior leads is more likely to be early repolarization than pericarditis.

LEFT BUNDLE BRANCH BLOCK

The following findings imply MI:

• 

  ST elevation or depression that is concordant with the QRS complex. Moreover, since ST deviation is mandatory with left bundle branch block, a “normal-looking” ST segment implies ischemia.
• Inverted T waves concordant with the QRS in more than one lead, or biphasic T waves in more than one lead (eg, V₁ to V₃). Across the precordial leads, T waves may transition from positive to negative one lead earlier or later than the QRS and ST transition. Therefore, even in the absence of ischemia, the T wave may be inverted in lead V₃, in which the QRS is deeply negative and the ST is still elevated (negative T-wave concordance in one lead). Also, the T wave may be upright in leads V₅, V₆, and I where QRS is upright and the ST segment is depressed (positive T-wave concordance does not imply ischemia).

• 

  In addition to concordance, a discordant ST segment or T wave that is very large may imply ischemia. For example, a discordant ST segment or T wave that is larger than the QRS height implies ischemia. A discordant ST elevation greater than 5 mm has been suggested by Sgarbossa et al³⁵ as a diagnostic feature of STEMI; however, this feature is seen in 10% of control patients with left bundle branch block and no STEMI, and it is thus poorly specific and also poorly sensitive, frequently missing STEMI.^35–37 Smith et al³⁶ have suggested that a discordant ST elevation of at least 25% of the S-wave depth is a far more sensitive and accurate feature but one that may still be found in up to 10% of control patients.³⁶

LEFT VENTRICULAR HYPERTROPHY

In left ventricular hypertrophy, a deep S wave is seen in leads V₁ to V₃, with ST elevation and T waves that are discordant with the QRS complex. Rarely, ST elevation may be straight or convex. The following findings imply MI:

• ST elevation or depression that is concordant with the QRS.
• Inverted T waves that are concordant with the QRS in more than one lead, or biphasic T waves in more than one lead (eg, V₁ to V₃).
• A discordant ST segment or a T wave that is very large may imply ischemia. In left ventricular hypertrophy, ST elevation is usually less than 2.5 mm in leads V₁ to V₃ and is rarely seen in the inferior leads, where it would be less than 1 mm.³⁴ When ST elevation is seen in leads V₁ to V₃ in left ventricular hypertrophy, an ST magnitude of 25% or more of the total QRS voltage has a 91% specificity for STEMI.³⁴

On another note, right ventricular hypertrophy and right bundle branch block may lead to ST-segment depression and T-wave inversion, but not to ST elevation. Thus, ST elevation occurring with right ventricular hypertrophy or right bundle branch block implies STEMI. While only left bundle branch block poses a diagnostic challenge, both types of bundle branch block, if secondary to STEMI, represent equally high-risk categories.³⁸

PREEXCITATION

HYPERKALEMIA

OTHER CAUSES OF ST-SEGMENT ELEVATION

Takotsubo cardiomyopathy

Takotsubo cardiomyopathy mimics all electrocardiographic features of anteroapical STEMI. ST elevation may extend to the inferior leads but cannot be isolated in the inferior leads.³⁹ As in apical STEMI, reciprocal ST depression is uncommon. Within 24 to 48 hours, ST elevation evolves into deep anterior T-wave inversion and a prolonged QT interval. Transient Q waves may be seen.

Myocarditis

Myocarditis may have one of two electrocardiographic patterns: a pericarditis pattern, or a typical STEMI pattern with Q waves sometimes localized to one area.⁴⁰

Atrial flutter waves

Large pulmonary embolism

A large pulmonary embolism may be associated with T-wave inversion in the anterior leads or the inferior leads, or both, reflective of cor pulmonale. Less commonly, ST elevation in the anterior or inferior leads is seen. In fact, changes of both anterior and inferior ischemia should always suggest a pulmonary embolism.^41,42

Brugada syndrome

Hyperkalemia, Brugada syndrome, and sometimes pulmonary embolism are characterized by an ST elevation that slopes downward (Figures 11 and 13), which contrasts with the upsloping, convex ST elevation of STEMI.

Since 1963, when Starzl et al performed the first successful liver transplantation,¹ outcomes of this life-saving procedure have continued to improve. Long-term survival rates have increased markedly: the current 5-year rate is 73.8% and the 10-year rate is 60%.²

This success means that internists will be caring for a greater number of liver transplant recipients and managing their long-term problems, such as hypertension, diabetes mellitus, dyslipidemia, obesity, metabolic syndrome, cardiovascular disease, renal insufficiency, osteoporosis, cancer, and gout.

This review will discuss these complications, focusing on the role the primary care physician assumes beyond the first year after transplantation.

ROLE OF THE PRIMARY CARE PHYSICIAN

Hepatologists, primary care physicians, and surgeons share the care of transplant recipients. The first several weeks after transplantation require close follow-up by the hepatologist and transplantation team, with particular attention paid to the patient’s overall health and well-being, medication compliance, and biochemical and immunosuppression monitoring.

After the first year, the primary care physician assumes a greater role, becoming the main provider of the patient’s care.^3,4 Good communication between the transplant center and the primary care physician should lead to a smooth transition.⁴ Although the hepatologist continues to manage immunosuppressive drugs, allograft rejections, and biliary complications, the primary care physician manages most of the long-term complications and thus needs to be aware of the common ones and feel comfortable managing them. Aims during visits are to screen for and detect common complications and manage them appropriately, in addition to performing annual physical examinations and routine health care. A reasonable interval for liver transplant recipients to visit their primary care physician is every 6 months.

IMMUNOSUPPRESSANT MEDICATIONS

Multiple agents are used for immunosuppression after liver transplantation:

• Calcineurin inhibitors (cyclosporine and tacrolimus)
• Antimetabolites (mycophenolate mofetil, azathioprine, and mycophenolate sodium)
• Mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus)
• Corticosteroids.

Table 1 lists their common side effects.

Most centers use a combination of two to four immunosuppressants as induction therapy in the immediate posttransplant period, then taper the doses and eliminate all but a calcineurin inhibitor and an antimetabolite. For example, some start with a combination of tacrolimus, mycophenolate mofetil, and a corticosteroid. The choice in the immediate posttransplant period is frequently made by the transplant center in cooperation with the hepatologist. By the time primary care physicians see these patients, they usually are on a calcineurin inhibitor alone or a calcineurin inhibitor plus mycophenolate mofetil.

Calcineurin inhibitors

Cyclosporine is metabolized by the cytochrome CYP3A4 pathway. With an average half-life of 15 hours, it is given orally, usually every 12 hours.

The dosage is adjusted according to the trough level. Higher levels are needed in the initial posttransplant period to prevent graft rejection, whereas lower levels are preferred later to decrease the occurrence and severity of adverse effects. Typical long-term trough levels are 50 to 100 ng/mL. Levels should be checked more often if an acute illness develops or the patient starts taking a potentially interfering drug.

Of importance: the dosage should be based on trough levels and not on random levels. Levels are often falsely high if blood samples are not drawn at the trough level. Repeating the measurement and making sure the sample is drawn at the trough level, ie, 12 hours after the last dose, is advised in this condition.

Cyclosporine causes widespread vasoconstriction resulting in decreased renal blood flow and systemic hypertension, often within a few days of starting it. Other important adverse effects include renal insufficiency, dyslipidemia, neurotoxicity (headache, tremor, seizure), and diabetes.

Tacrolimus is superior to cyclosporine in terms of survival, graft loss, acute rejection, and steroid-resistant rejection in the first year.⁵ Currently, it is the agent used most often for maintenance immunosuppression after liver transplantation.

Like cyclosporine, tacrolimus is metabolized in the liver by CYP3A4. Satisfactory trough levels after 1 year are 4 to 6 ng/mL.

The adverse effects of tacrolimus are similar to those of cyclosporine, but diabetes mellitus is more common with tacrolimus. Bone marrow suppression may occur more often with tacrolimus as well.

Antimetabolites

Antimetabolites are generally not potent enough to be used alone.

Mycophenolate mofetil causes adverse effects that include bone marrow suppression and gastrointestinal symptoms such as gastritis, diarrhea, and abdominal pain.

Azathioprine, infrequently used in transplantation in the United States, is nevertheless sometimes substituted for mycophenolate mofetil in pregnant women, as it seems safer for use in pregnancy.

Serum levels of azathioprine and mycophenolate mofetil are not routinely monitored.

mTOR inhibitors

Sirolimus and everolimus are mTOR inhibitors, inhibiting proliferation of lymphocytes.^6,7

Unlike calcineurin inhibitors, mTOR inhibitors are not associated with nephrotoxicity, neurotoxicity, renal dysfunction, hypertension, or diabetes. Sirolimus is considered an alternative to calcineurin inhibitors or, in some instances, used as add-on-therapy to lower the dose of the calcineurin inhibitor.

Sirolimus carries a black-box warning about hepatic artery thrombosis

However, sirolimus carries a potential risk of hepatic artery thrombosis, a life-threatening complication.⁸ This has led the US Food and Drug Administration (FDA) to require sirolimus to carry a black-box warning, and most transplant centers avoid using it in the first 30 days after transplantation.

Dyslipidemia is perhaps the most common adverse effect of sirolimus. Others include dose-related cytopenia and wound dehiscence.⁹

Everolimus has yet to be established for use in liver transplantation, although safety trials have been published.^10,11 The FDA currently recommends against using it in the first 30 days after liver transplantation.

Both sirolimus and everolimus are metabolized by CYP3A4, which is the same metabolic pathway used by cyclosporine and tacrolimus. Hence, drugs that inhibit CYP3A4 may significantly impair clearance of both sirolimus and everolimus.

Corticosteroids

Corticosteroids have been the cornerstone of immunosuppression and remain the first line of treatment for acute allograft rejection. High intravenous doses of corticosteroids are usually started in the peritransplant period and are then switched to oral doses, which are tapered and continued with a fixed dose such as 20 mg of prednisone daily for 3 to 6 months after transplantation. However, some transplant centers keep patients on prednisone 5 mg/day indefinitely.

Adverse effects of corticosteroids include diabetes, salt and fluid retention, hypertension, hyperlipidemia, cosmetic changes (acne, cervical fat pad or “buffalo hump”), delayed wound healing, susceptibility to infection, cataracts, osteopenia, and potential adrenal suppression.¹² There is concern that the use of these drugs may increase hepatitis C virus replication in patients who received a liver transplant for hepatitis C cirrhosis. Randomized trials have yielded conflicting results.^13–15

Drug interactions

Certain drugs can affect the metabolism of calcineurin inhibitors and mTOR inhibitors by inducing CYP3A4, which results in decreasing the levels of the immunosuppressive drugs, or by inhibiting CYP3A4, which has the opposite effect.

Medications that can decrease the levels of calcineurin inhibitors and mTOR inhibitors:

• Anticonvulsants (carbamazepine, phenobarbital, phenytoin)
• Antibiotics (rifampin, isoniazid)
• St John’s wort.

Medications that can increase the levels of calcineurin inhibitors and mTOR inhibitors:

• Antifungals (fluconazole, ketoconazole, itraconazole, voriconazole, aspofungin)
• Antibiotics (azithromycin, erythromycin, clarithromycin)
• Nondihydropyridine calcium channel blockers (diltiazem, verapamil).¹⁶

Selected antibiotics are generally well tolerated, such as penicillins, cephalosporins, quinolones, sulfonamides, and topical antifungal agents.

LONG-TERM COMPLICATIONS

Figure 1 summarizes the common long-term complications of liver transplantation.

Hypertension

The prevalence of hypertension after liver transplantation is 40% to 85%, which is markedly higher than in patients with chronic liver disease before liver transplantation.^17,18

One of the factors contributing to this increase is the use of immunosuppressive medications. Of these drugs, cyclosporine seems to be the one that most often causes an increase in both the incidence and the severity of hypertension, as it produces widespread vasoconstriction.¹⁹ Corticosteroids cause hypertension through their mineralocorticoid effects.

The diagnostic cutoffs for hypertension (ie, 140/90 mm Hg) and the treatment goals in posttransplant patients are similar to those in the general population. However, at our institution we target a blood pressure of less than 130/80 mm Hg in transplant patients because they have a high prevalence of other cardiovascular risk factors such as diabetes, obesity, and renal insufficiency.²⁰

Dihydropyridine calcium channel blockers such as amlodipine and nifedipine are considered the best first-line agents because they dilate renal afferent arterioles, an effect that may counteract the vasoconstriction mediated by calcineurin inhibitors. Nondihydropyridine calcium channel blockers such as diltiazem and verapamil tend to have more marked negative inotropic effects and are not recommended in liver transplant recipients because they increase the levels of calcineurin inhibitors.²¹

Diuretics (eg, furosemide) might be the second-line agents, especially in patients with peripheral edema.¹⁶ One should be vigilant for hyperuricemia if thiazide agents are used.

Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are typically avoided in the early posttransplant period, but they can be started later and have additional benefits in patients with diabetes and congestive heart failure. Starting ACE inhibitors is acceptable in these patients unless there is a contraindication such as allergy to ACE inhibitors, hypotension, history of bilateral renal artery stenosis, significant hyperkalemia, or acute kidney injury. Monitor the serum potassium level closely for hyperkalemia in patients concurrently using calcineurin inhibitors.

Alpha-blockers and beta-blockers can be used as add-on therapy in patients with uncontrolled hypertension with the exception of carvedilol, because it increases the levels of calcineurin inhibitors.²²

Blood pressure monitoring by the primary care physician is recommended every 6 months after the early posttransplant period, or more frequently when changes in treatment are being considered.

If hypertension continues to be inadequately controlled despite treatment, changing the immunosuppressive drugs or decreasing the doses can be considered, but the transplant hepatologist must be involved in this decision.^23,24

Diabetes mellitus

The prevalence of diabetes mellitus is higher in liver transplant recipients than in the general population, reaching 30% to 40%.^17,25 In addition to preexisting diabetes, 15% of liver transplant recipients develop new-onset diabetes.^26,27

Risk factors for developing diabetes after liver transplantation include African American or Hispanic ethnicity, obesity, family history, pretransplant diabetes, hepatitis C virus infection, use of corticosteroids, and use of calcineurin inhibitors (tacrolimus more than cyclosporine) and sirolimus.²⁶

In addition to increasing the risk of cardiovascular disease and other diseases, diabetes decreases both patient and graft survival after liver transplantation.²⁸

The management of diabetes and the treatment target after transplantation should follow the American Diabetes Association guidelines for the treatment of type 2 diabetes mellitus.²⁹ Lifestyle modifications, diet, and exercise are as important for transplant patients as for the nontransplant population. Insulin therapy is usually needed in the early posttransplant period to control blood glucose levels well, especially with the high doses of corticosteroids used during the first few weeks. No trials to date have compared oral agents in posttransplant patients. Therefore, the choice of oral hypoglycemic agents should be individualized on the basis of the patient’s characteristics and comorbidities.

Screen all liver transplant recipients for diabetes regardless of their pretransplant status

We recommend that primary care providers screen all liver transplant recipients for diabetes regardless of their pretransplant status. This can be done by obtaining regular fasting blood glucose levels or a hemoglobin A_1c level every 6 months. Additionally, liver transplant recipients diagnosed with diabetes require annual eye examinations to look for cataracts and diabetes-related changes.³⁰

Dyslipidemia

On November 12, 2013, the American College of Cardiology and the American Heart Association (ACC/AHA) released new clinical practice guidelines for treating blood cholesterol levels.^31,32 According to these new guidelines, there are four groups of patients for whom treatment with statins is clearly indicated:

• Patients with cardiovascular disease
• Patients with low-density lipoprotein cholesterol (LDL-C) levels ≥ 190 mg/dL
• Patients 40 to 75 years old with type 2 diabetes
• Patients 40 to 75 years old with an estimated 10-year risk of cardiovascular disease of 7.5% or greater.

Liver transplant recipients should be evaluated on an individual basis to see if they fit in any of the four groups and if statin treatment therefore needs to be initiated.

A few things need to be kept in mind. First, the incidence of dyslipidemia after liver transplantation is estimated to be 45% to 69%. Risk factors include obesity, diabetes mellitus, cholestatic liver disease, and immunosuppressant medications.³³ Sirolimus has a significant and well-documented association with dyslipidemia. Cyclosporine and corticosteroids are also strongly associated with dyslipidemia. Tacrolimus has a minor effect, and mycophenolate mofetil and azathioprine have no significant effects on serum lipid levels.¹⁶

Second, of the seven currently marketed statins, pravastatin and fluvastatin are preferred in liver transplant recipients because they are not metabolized by the same cytochrome CYP3A4 pathway that metabolizes calcineurin inhibitors and sirolimus.³⁴ The doses of 40 to 80 mg daily of pravastatin or 40 mg twice daily of fluvastatin lower low-density lipoprotein cholesterol (LDL-C) levels by approximately 30% to 35%. However, these two agents are considered “moderate-intensity” statins according to the new ACC/AHA guidelines. The only two “high-intensity” statins are atorvastatin (40–80 mg) and rosuvastatin (20–40 mg), but they are both metabolized by CYP3A4. Therefore it is prudent to avoid them with the concurrent use of a calcineurin inhibitor or tacrolimus.

Gemfibrozil does not lower LDL-C and should not be used concomitantly with statins due to unacceptable risk of rhabdomyolysis and myopathy. Fenofibrates are usually avoided due to potential nephrotoxicity in patients receiving cyclosporine. Bile acid sequestrants (cholestyramine, colestipol, colesevelam) can decrease plasma mycophenolate mofetil levels by 35%.^16,35 Thus, these agents should be avoided if mycophenolate mofetil is used.

It is reasonable to screen all liver transplant recipients with a fasting lipid profile at 3, 6, and 12 months after transplantation and annually thereafter. Creatine kinase should be measured if the patient complains of severe muscle pain or weakness but not on a routine basis.

Obesity

Approximately one-third of patients who are of normal weight at the time of transplantation will become obese afterward.^18,25 Corticosteroid use is an important risk factor for posttransplant obesity, and tapering these drugs helps reduce weight.³⁶ Patients treated with cyclosporine are more likely to gain weight than those who receive tacrolimus.³⁷

Of importance: nonalcoholic fatty liver disease, currently the most common cause of chronic liver disease in adults, is rapidly increasing as an indication for liver transplantation. In fact, the proportion of liver transplantation procedures for nonalcoholic steatohepatitis-related cirrhosis increased from 1.2% in 2001 to 9.7% in 2009, and nonalcoholic steatohepatitis is expected to become the leading indication for liver transplantation in the next 20 years. And because nonalcoholic fatty liver disease is directly linked to obesity, the prevalence of obesity as a complication of liver transplantation will most likely increase in the near future.

Overweight liver transplant recipients may have great difficulty losing weight. Treatment starts with patient education on caloric restriction and exercise. If traditional measures fail to result in adequate weight loss, additional options include switching from cyclosporine to tacrolimus.²³

Bariatric surgery may become an option for posttransplant patients. In a recent case series from the University of Minnesota, Al-Nowaylati et al³⁸ reported their experience with seven patients who underwent orthotopic liver transplantation and then open Roux-en-Y gastric bypass. After bariatric surgery, the patients’ mean body mass index declined significantly, and glycemic control and high-density lipoprotein cholesterol (HDL-C) levels improved. However, one patient died of multiple organ failure, to which the bariatric surgery might have contributed.³⁸

Heimbach et al³⁹ conducted a study in patients referred for liver transplantation for whom a rigorous noninvasive weight-loss program before transplantation had failed. The researchers performed combined liver transplantation and sleeve gastrectomy in seven carefully selected patients who had failed to achieve weight loss to a body mass index less than 35 kg/m² before transplantation. All seven patients lost weight, decreasing their mean body mass index from 49 kg/m² before the procedure to 29 kg/m² at last follow-up, and none of them developed posttransplant diabetes or steatosis.

At this time, there is not enough evidence to recommend concurrent orthotopic liver transplantation plus bariatric surgery, or combined orthotopic liver transplantation and sleeve gastrectomy. More study is needed to further evaluate these advanced approaches.

Posttransplant metabolic syndrome

Metabolic syndrome is common after liver transplantation and is strongly associated with increased morbidity in this patient population.^40,41 The general definition of metabolic syndrome includes a combination of at least three of the following: hypertension, insulin resistance, hypertriglyceridemia, low HDL-C, and obesity.

The prevalence of metabolic syndrome is higher in patients after liver transplantation than in nontransplant patients. In a review of 252 liver transplant recipients, 52% were diagnosed with posttransplant metabolic syndrome, but only 5% had had it pretransplant.⁴²

Careful screening for posttransplant metabolic syndrome and early recognition of risk factors are important. Nevertheless, the treatment of this condition depends on treating its components according to recommended guidelines.⁴¹

Cardiovascular disease

The incidence of cardiovascular morbidity and death is increased after liver transplantation.²⁴ In addition, after liver transplantation, cardiovascular disease is a major cause of death unrelated to liver disease. It accounts for 12% to 16% of deaths and is the third most common cause of late mortality after liver transplantation.⁴³ Of note, a recent study by our group demonstrated that patients undergoing liver transplantation for nonalcoholic steatohepatitis had a significantly higher risk of a cardiovascular event during the 3 years after transplantation than patients undergoing liver transplantation for cholestatic liver disease.⁴⁴

Risk factors for cardiovascular disease after liver transplantation include older age at transplantation, male sex, posttransplant diabetes, posttransplant hypertension, and the use of mycophenolate mofetil.⁴⁴ Modifying the risk factors is essential in decreasing the risk of cardiovascular events.

It is reasonable to perform dobutamine stress testing every 3 to 5 years in patients with multiple risk factors for cardiovascular disease, or more frequently in those with preexisting coronary artery disease.^45,46

Malignancy

The risk of several malignancies increases after liver transplantation. Liver transplant recipients have an incidence of cancer 2.1 to 4.3 times greater than age- and sex-matched controls.^24,47–49

Skin cancers are the most common and account for almost 40% of malignancies in organ transplant recipients.⁵⁰ Whereas basal cell carcinoma is more common in the general population, squamous cell carcinoma is equally common in liver transplant recipients.

Multiple clinical studies have linked calcineurin inhibitors and azathioprine to the development of skin cancer. Annual skin examinations in addition to avoiding other risk factors such as smoking and sun exposure are generally recommended. Changing the immunosuppressants to sirolimus in high-risk patients may lower their chance of developing skin cancer.^51,52

Patients with ulcerative colitis who undergo liver transplantation because of sclerosing cholangitis are at higher risk of colon cancer and require annual colonoscopy with surveillance biopsies. Patients who undergo transplantation for alcoholic liver disease seem to have a higher risk of pulmonary and oropharyngeal cancers.^53,54

It is important that transplant patients adhere to recommended cancer screening guidelines, in view of their increased risk. Studies have shown improved overall survival in liver transplant recipients who underwent intensive cancer surveillance.⁵⁵

Renal insufficiency

Renal insufficiency is a well-recognized complication of liver transplantation and is associated with an increased long-term death rate.^56,57

The incidence of renal insufficiency increases dramatically over time. Ojo et al,⁵⁷ in a study of almost 37,000 liver transplant recipients, found that the incidence of chronic kidney disease (defined as an estimated glomerular filtration rate < 30 mL/min/1.73 m²) was 13.9% at 3 years, 18% at 5 years, and approximately 26% at 10 years.

Risk factors include the use of calcineurin inhibitors (both cyclosporine and tacrolimus), older age, female sex, lower pretransplant glomerular filtration rate, postoperative acute renal failure, diabetes, hypertension, hepatitis C virus infection, and transplantation before 1998.^58,59 Replacing a calcineurin inhibitor with mycophenolate mofetil or sirolimus may be considered with communication with the transplant center, as mycophenolate mofetil or sirolimus are associated with a lower risk of renal injury.^60–64

All liver transplant recipients should avoid nonsteroidal anti-inflammatory drugs and nephrotoxic medications

Starting 1 year after liver transplantation, primary care providers should screen for renal dysfunction by obtaining kidney function tests every 6 months, including urinalysis and microalbuminuria assessment. Equations for estimating the glomerular filtration rate used in practice, such as the Modification of Diet in Renal Disease Study equation, rely mainly on serum creatinine, which may lead to overestimating renal function in some circumstances. Therefore, other equations can be used to confirm the estimated glomerular filtration rate measured by creatinine clearance, and to more accurately evaluate kidney function. Calculators are available at www.kidney.org/professionals/kdoqi/gfr_calculator.

All liver transplant recipients should avoid nonsteroidal anti-inflammatory drugs and nephrotoxic medications, and should have their hypertension and diabetes adequately controlled.

Bone diseases

Osteopenia is another major complication of liver transplantation. One-third of liver transplant recipients have a bone mineral density below the fracture threshold.⁶⁵

Multiple factors contribute to increased bone loss after transplantation, including use of corticosteroids, use of calcineurin inhibitors (cyclosporine, tacrolimus), poor nutrition, vitamin D deficiency, immobility, sarcopenia (reduced muscle mass), hypogonadism, smoking, and alcohol abuse.⁶⁶ Even at low doses of less than 7.5 mg per day, corticosteroids inhibit osteoblast activity and increase bone resorption.

Studies have reported rapid bone loss at around 6 months after transplantation.^67–69 However, long-term follow-up of bone mineral density up to 15 years after transplantation revealed an improvement mainly in the 2nd postoperative year, with no deterioration afterward.⁶⁵

High-risk patients need to be identified early with appropriate screening and evaluation. Evaluation includes dual-energy x-ray absorptiometry and serum levels of calcium, phosphorous, parathyroid hormone, testosterone (men), estradiol (women), and alpha-25-hydroxyvitamin D. These tests are typically done before transplantation and then every other year afterward.

We recommend a daily dose of calcitriol and a calcium supplement to all our liver transplant patients.⁷⁰ If osteoporosis (a T-score 2.5 or more standard deviations below the mean) or a fragility fracture occurs, then the patient may benefit from an oral bisphosphonate. Calcitonin has also been shown to improve bone mineral density in patients with osteoporosis after liver transplantation.⁷¹

Hyperuricemia and gout

Although hyperuricemia is common in liver transplant recipients (reported in approximately 47%), the development of clinical gout is less common (6%).⁷² Asymptomatic hyperuricemia requires observation only and is not usually treated in liver transplant recipients.

Acute attacks of gout are typically managed with colchicine 0.6 mg every 2 hours, up to five doses. Prednisone can be considered if symptoms persist despite treatment with colchicine. Allopurinol in an initial dose of 100 mg daily is used as maintenance therapy to reduce production of uric acid.⁷³ However, because of the potential for drug interactions, the combination of azathioprine and allopurinol should be avoided.

Psychiatric complications and quality of life

Depression is common in liver transplant recipients, significantly more so in patients who received a transplant because of hepatitis C.⁷⁴ The type of immunosuppressant is not associated with the incidence of depression. When indicated, the internist may start the patient on a selective serotonin reuptake inhibitor such as citalopram 20 mg daily, as these medications are usually effective and well tolerated in liver transplant patients.⁷³

Liver transplantation has a major positive effect on quality of life. Most patients with end-stage liver disease have poor quality of life before transplantation, but this seems to improve notably afterward. A meta-analysis showed significant improvement in posttransplant physical health, sexual functioning, daily activities, and social functioning compared with before transplantation.⁷⁵

Alcohol abuse and smoking

Patients who underwent liver transplantation because of alcoholic liver disease should be advised to abstain from alcohol.¹⁹ Patients who underwent the procedure for a different indication are advised to avoid excessive alcohol intake, as it is proven to lower the survival rate.²⁰ Alcohol recidivism and smoking (including marijuana) are major problems, and internists are best positioned to address these issues and treat them.

Vaccinations

All liver transplant recipients should be vaccinated against influenza, pneumococcal infection, and tetanus. Hepatitis A and B vaccines are typically given before transplantation. In general, live vaccines such as measles-mumps-rubella and varicella are not recommended after any solid organ transplant.⁷⁶

A study in Germany showed that immunization rates were too low in solid-organ transplant recipients, and almost 90% of patients were not adequately informed about immunizations.⁷⁷ Hence, there may be room for improvement, and primary care providers should take the lead toward better outcomes in this regard.

Recurrence of the primary liver disease after transplantation

Different primary liver diseases recur with different frequencies.

Hepatitis C has the highest rate of recurrence of the liver diseases.^78,79 Reinfection with hepatitis C virus after liver transplantation is almost universal and can follow different patterns. One of the most aggressive patterns is fibrosing cholestatic hepatitis, which frequently leads to graft failure and death, and hence necessitates urgent detection and treatment.

Hepatocellular carcinoma also has a high recurrence rate.⁸⁰ Surveillance with liver ultrasonography or computed tomography is required every 6 months for the first 5 years after liver transplantation.

Other liver diseases. Nonalcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, and hepatitis B infection also tend to recur after liver transplantation.^46,81 On the other hand, alpha-1 antitrypsin deficiency, Wilson disease, hemochromatosis, and metabolic disorders are “cured” after liver transplantation.

It is important to detect any increase in liver enzymes above baseline. An elevation of 1.5 times the upper limit of normal or more should trigger further investigation.

Allograft dysfunction

A number of complications can develop in the liver allograft and result in abnormal liver function tests and, if not treated, graft failure. The most common causes of late graft dysfunction include recurrence of primary liver disease, biliary complications, and chronic rejection.⁴⁶

Vascular complications include hepatic artery thrombosis and stenosis and are usually evaluated by liver ultrasonography and Doppler scan of the hepatic artery and venous structures.²⁴

Biliary strictures give a cholestatic picture, with elevated bilirubin and greater elevation of alkaline phosphatase than of alanine aminotransferase and aspartate aminotransferase. Strictures are usually treated by endoscopic dilation and stenting, but they may eventually require surgery.

Late acute cellular rejections occur in 10% to 20% of cases and are a risk factor for chronic rejection. Liver biopsy is needed to make the diagnosis, and pulsed doses of corticosteroids remain the backbone of treatment therapy.

Chronic rejection is not common, occurring in 3% to 4% of liver transplant recipients.⁴⁶ Treatment is based on increasing immunosuppression and ensuring compliance with prescribed medications. However, chronic rejection may not respond well, and repeat transplantation may be the last resort for some patients.

WHEN TO REFER TO THE HEPATOLOGIST

Some situations require referral to the hepatologist or the transplant center. In general, the following are best managed by a hepatologist: adjustment of immunosuppressive drugs and dosages, allograft dysfunction, vascular and biliary complications, progressing renal dysfunction, and recurrence of primary liver disease. Early communication with a hepatologist and the transplant center is recommended in these cases.

Since 1963, when Starzl et al performed the first successful liver transplantation,¹ outcomes of this life-saving procedure have continued to improve. Long-term survival rates have increased markedly: the current 5-year rate is 73.8% and the 10-year rate is 60%.²

This success means that internists will be caring for a greater number of liver transplant recipients and managing their long-term problems, such as hypertension, diabetes mellitus, dyslipidemia, obesity, metabolic syndrome, cardiovascular disease, renal insufficiency, osteoporosis, cancer, and gout.

This review will discuss these complications, focusing on the role the primary care physician assumes beyond the first year after transplantation.

ROLE OF THE PRIMARY CARE PHYSICIAN

Hepatologists, primary care physicians, and surgeons share the care of transplant recipients. The first several weeks after transplantation require close follow-up by the hepatologist and transplantation team, with particular attention paid to the patient’s overall health and well-being, medication compliance, and biochemical and immunosuppression monitoring.

After the first year, the primary care physician assumes a greater role, becoming the main provider of the patient’s care.^3,4 Good communication between the transplant center and the primary care physician should lead to a smooth transition.⁴ Although the hepatologist continues to manage immunosuppressive drugs, allograft rejections, and biliary complications, the primary care physician manages most of the long-term complications and thus needs to be aware of the common ones and feel comfortable managing them. Aims during visits are to screen for and detect common complications and manage them appropriately, in addition to performing annual physical examinations and routine health care. A reasonable interval for liver transplant recipients to visit their primary care physician is every 6 months.

IMMUNOSUPPRESSANT MEDICATIONS

Multiple agents are used for immunosuppression after liver transplantation:

• Calcineurin inhibitors (cyclosporine and tacrolimus)
• Antimetabolites (mycophenolate mofetil, azathioprine, and mycophenolate sodium)
• Mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus)
• Corticosteroids.

Table 1 lists their common side effects.

Most centers use a combination of two to four immunosuppressants as induction therapy in the immediate posttransplant period, then taper the doses and eliminate all but a calcineurin inhibitor and an antimetabolite. For example, some start with a combination of tacrolimus, mycophenolate mofetil, and a corticosteroid. The choice in the immediate posttransplant period is frequently made by the transplant center in cooperation with the hepatologist. By the time primary care physicians see these patients, they usually are on a calcineurin inhibitor alone or a calcineurin inhibitor plus mycophenolate mofetil.

Calcineurin inhibitors

Cyclosporine is metabolized by the cytochrome CYP3A4 pathway. With an average half-life of 15 hours, it is given orally, usually every 12 hours.

The dosage is adjusted according to the trough level. Higher levels are needed in the initial posttransplant period to prevent graft rejection, whereas lower levels are preferred later to decrease the occurrence and severity of adverse effects. Typical long-term trough levels are 50 to 100 ng/mL. Levels should be checked more often if an acute illness develops or the patient starts taking a potentially interfering drug.

Of importance: the dosage should be based on trough levels and not on random levels. Levels are often falsely high if blood samples are not drawn at the trough level. Repeating the measurement and making sure the sample is drawn at the trough level, ie, 12 hours after the last dose, is advised in this condition.

Cyclosporine causes widespread vasoconstriction resulting in decreased renal blood flow and systemic hypertension, often within a few days of starting it. Other important adverse effects include renal insufficiency, dyslipidemia, neurotoxicity (headache, tremor, seizure), and diabetes.

Tacrolimus is superior to cyclosporine in terms of survival, graft loss, acute rejection, and steroid-resistant rejection in the first year.⁵ Currently, it is the agent used most often for maintenance immunosuppression after liver transplantation.

Like cyclosporine, tacrolimus is metabolized in the liver by CYP3A4. Satisfactory trough levels after 1 year are 4 to 6 ng/mL.

The adverse effects of tacrolimus are similar to those of cyclosporine, but diabetes mellitus is more common with tacrolimus. Bone marrow suppression may occur more often with tacrolimus as well.

Antimetabolites

Antimetabolites are generally not potent enough to be used alone.

Mycophenolate mofetil causes adverse effects that include bone marrow suppression and gastrointestinal symptoms such as gastritis, diarrhea, and abdominal pain.

Azathioprine, infrequently used in transplantation in the United States, is nevertheless sometimes substituted for mycophenolate mofetil in pregnant women, as it seems safer for use in pregnancy.

Serum levels of azathioprine and mycophenolate mofetil are not routinely monitored.

mTOR inhibitors

Sirolimus and everolimus are mTOR inhibitors, inhibiting proliferation of lymphocytes.^6,7

Unlike calcineurin inhibitors, mTOR inhibitors are not associated with nephrotoxicity, neurotoxicity, renal dysfunction, hypertension, or diabetes. Sirolimus is considered an alternative to calcineurin inhibitors or, in some instances, used as add-on-therapy to lower the dose of the calcineurin inhibitor.

Sirolimus carries a black-box warning about hepatic artery thrombosis

However, sirolimus carries a potential risk of hepatic artery thrombosis, a life-threatening complication.⁸ This has led the US Food and Drug Administration (FDA) to require sirolimus to carry a black-box warning, and most transplant centers avoid using it in the first 30 days after transplantation.

Dyslipidemia is perhaps the most common adverse effect of sirolimus. Others include dose-related cytopenia and wound dehiscence.⁹

Everolimus has yet to be established for use in liver transplantation, although safety trials have been published.^10,11 The FDA currently recommends against using it in the first 30 days after liver transplantation.

Both sirolimus and everolimus are metabolized by CYP3A4, which is the same metabolic pathway used by cyclosporine and tacrolimus. Hence, drugs that inhibit CYP3A4 may significantly impair clearance of both sirolimus and everolimus.

Corticosteroids

Corticosteroids have been the cornerstone of immunosuppression and remain the first line of treatment for acute allograft rejection. High intravenous doses of corticosteroids are usually started in the peritransplant period and are then switched to oral doses, which are tapered and continued with a fixed dose such as 20 mg of prednisone daily for 3 to 6 months after transplantation. However, some transplant centers keep patients on prednisone 5 mg/day indefinitely.

Adverse effects of corticosteroids include diabetes, salt and fluid retention, hypertension, hyperlipidemia, cosmetic changes (acne, cervical fat pad or “buffalo hump”), delayed wound healing, susceptibility to infection, cataracts, osteopenia, and potential adrenal suppression.¹² There is concern that the use of these drugs may increase hepatitis C virus replication in patients who received a liver transplant for hepatitis C cirrhosis. Randomized trials have yielded conflicting results.^13–15

Drug interactions

Certain drugs can affect the metabolism of calcineurin inhibitors and mTOR inhibitors by inducing CYP3A4, which results in decreasing the levels of the immunosuppressive drugs, or by inhibiting CYP3A4, which has the opposite effect.

Medications that can decrease the levels of calcineurin inhibitors and mTOR inhibitors:

• Anticonvulsants (carbamazepine, phenobarbital, phenytoin)
• Antibiotics (rifampin, isoniazid)
• St John’s wort.

Medications that can increase the levels of calcineurin inhibitors and mTOR inhibitors:

• Antifungals (fluconazole, ketoconazole, itraconazole, voriconazole, aspofungin)
• Antibiotics (azithromycin, erythromycin, clarithromycin)
• Nondihydropyridine calcium channel blockers (diltiazem, verapamil).¹⁶

Selected antibiotics are generally well tolerated, such as penicillins, cephalosporins, quinolones, sulfonamides, and topical antifungal agents.

LONG-TERM COMPLICATIONS

Figure 1 summarizes the common long-term complications of liver transplantation.

Hypertension

The prevalence of hypertension after liver transplantation is 40% to 85%, which is markedly higher than in patients with chronic liver disease before liver transplantation.^17,18

One of the factors contributing to this increase is the use of immunosuppressive medications. Of these drugs, cyclosporine seems to be the one that most often causes an increase in both the incidence and the severity of hypertension, as it produces widespread vasoconstriction.¹⁹ Corticosteroids cause hypertension through their mineralocorticoid effects.

The diagnostic cutoffs for hypertension (ie, 140/90 mm Hg) and the treatment goals in posttransplant patients are similar to those in the general population. However, at our institution we target a blood pressure of less than 130/80 mm Hg in transplant patients because they have a high prevalence of other cardiovascular risk factors such as diabetes, obesity, and renal insufficiency.²⁰

Dihydropyridine calcium channel blockers such as amlodipine and nifedipine are considered the best first-line agents because they dilate renal afferent arterioles, an effect that may counteract the vasoconstriction mediated by calcineurin inhibitors. Nondihydropyridine calcium channel blockers such as diltiazem and verapamil tend to have more marked negative inotropic effects and are not recommended in liver transplant recipients because they increase the levels of calcineurin inhibitors.²¹

Diuretics (eg, furosemide) might be the second-line agents, especially in patients with peripheral edema.¹⁶ One should be vigilant for hyperuricemia if thiazide agents are used.

Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are typically avoided in the early posttransplant period, but they can be started later and have additional benefits in patients with diabetes and congestive heart failure. Starting ACE inhibitors is acceptable in these patients unless there is a contraindication such as allergy to ACE inhibitors, hypotension, history of bilateral renal artery stenosis, significant hyperkalemia, or acute kidney injury. Monitor the serum potassium level closely for hyperkalemia in patients concurrently using calcineurin inhibitors.

Alpha-blockers and beta-blockers can be used as add-on therapy in patients with uncontrolled hypertension with the exception of carvedilol, because it increases the levels of calcineurin inhibitors.²²

Blood pressure monitoring by the primary care physician is recommended every 6 months after the early posttransplant period, or more frequently when changes in treatment are being considered.

If hypertension continues to be inadequately controlled despite treatment, changing the immunosuppressive drugs or decreasing the doses can be considered, but the transplant hepatologist must be involved in this decision.^23,24

Diabetes mellitus

The prevalence of diabetes mellitus is higher in liver transplant recipients than in the general population, reaching 30% to 40%.^17,25 In addition to preexisting diabetes, 15% of liver transplant recipients develop new-onset diabetes.^26,27

Risk factors for developing diabetes after liver transplantation include African American or Hispanic ethnicity, obesity, family history, pretransplant diabetes, hepatitis C virus infection, use of corticosteroids, and use of calcineurin inhibitors (tacrolimus more than cyclosporine) and sirolimus.²⁶

In addition to increasing the risk of cardiovascular disease and other diseases, diabetes decreases both patient and graft survival after liver transplantation.²⁸

The management of diabetes and the treatment target after transplantation should follow the American Diabetes Association guidelines for the treatment of type 2 diabetes mellitus.²⁹ Lifestyle modifications, diet, and exercise are as important for transplant patients as for the nontransplant population. Insulin therapy is usually needed in the early posttransplant period to control blood glucose levels well, especially with the high doses of corticosteroids used during the first few weeks. No trials to date have compared oral agents in posttransplant patients. Therefore, the choice of oral hypoglycemic agents should be individualized on the basis of the patient’s characteristics and comorbidities.

Screen all liver transplant recipients for diabetes regardless of their pretransplant status

We recommend that primary care providers screen all liver transplant recipients for diabetes regardless of their pretransplant status. This can be done by obtaining regular fasting blood glucose levels or a hemoglobin A_1c level every 6 months. Additionally, liver transplant recipients diagnosed with diabetes require annual eye examinations to look for cataracts and diabetes-related changes.³⁰

Dyslipidemia

On November 12, 2013, the American College of Cardiology and the American Heart Association (ACC/AHA) released new clinical practice guidelines for treating blood cholesterol levels.^31,32 According to these new guidelines, there are four groups of patients for whom treatment with statins is clearly indicated:

• Patients with cardiovascular disease
• Patients with low-density lipoprotein cholesterol (LDL-C) levels ≥ 190 mg/dL
• Patients 40 to 75 years old with type 2 diabetes
• Patients 40 to 75 years old with an estimated 10-year risk of cardiovascular disease of 7.5% or greater.

Liver transplant recipients should be evaluated on an individual basis to see if they fit in any of the four groups and if statin treatment therefore needs to be initiated.

A few things need to be kept in mind. First, the incidence of dyslipidemia after liver transplantation is estimated to be 45% to 69%. Risk factors include obesity, diabetes mellitus, cholestatic liver disease, and immunosuppressant medications.³³ Sirolimus has a significant and well-documented association with dyslipidemia. Cyclosporine and corticosteroids are also strongly associated with dyslipidemia. Tacrolimus has a minor effect, and mycophenolate mofetil and azathioprine have no significant effects on serum lipid levels.¹⁶

Second, of the seven currently marketed statins, pravastatin and fluvastatin are preferred in liver transplant recipients because they are not metabolized by the same cytochrome CYP3A4 pathway that metabolizes calcineurin inhibitors and sirolimus.³⁴ The doses of 40 to 80 mg daily of pravastatin or 40 mg twice daily of fluvastatin lower low-density lipoprotein cholesterol (LDL-C) levels by approximately 30% to 35%. However, these two agents are considered “moderate-intensity” statins according to the new ACC/AHA guidelines. The only two “high-intensity” statins are atorvastatin (40–80 mg) and rosuvastatin (20–40 mg), but they are both metabolized by CYP3A4. Therefore it is prudent to avoid them with the concurrent use of a calcineurin inhibitor or tacrolimus.

Gemfibrozil does not lower LDL-C and should not be used concomitantly with statins due to unacceptable risk of rhabdomyolysis and myopathy. Fenofibrates are usually avoided due to potential nephrotoxicity in patients receiving cyclosporine. Bile acid sequestrants (cholestyramine, colestipol, colesevelam) can decrease plasma mycophenolate mofetil levels by 35%.^16,35 Thus, these agents should be avoided if mycophenolate mofetil is used.

It is reasonable to screen all liver transplant recipients with a fasting lipid profile at 3, 6, and 12 months after transplantation and annually thereafter. Creatine kinase should be measured if the patient complains of severe muscle pain or weakness but not on a routine basis.

Obesity

Approximately one-third of patients who are of normal weight at the time of transplantation will become obese afterward.^18,25 Corticosteroid use is an important risk factor for posttransplant obesity, and tapering these drugs helps reduce weight.³⁶ Patients treated with cyclosporine are more likely to gain weight than those who receive tacrolimus.³⁷

Of importance: nonalcoholic fatty liver disease, currently the most common cause of chronic liver disease in adults, is rapidly increasing as an indication for liver transplantation. In fact, the proportion of liver transplantation procedures for nonalcoholic steatohepatitis-related cirrhosis increased from 1.2% in 2001 to 9.7% in 2009, and nonalcoholic steatohepatitis is expected to become the leading indication for liver transplantation in the next 20 years. And because nonalcoholic fatty liver disease is directly linked to obesity, the prevalence of obesity as a complication of liver transplantation will most likely increase in the near future.

Overweight liver transplant recipients may have great difficulty losing weight. Treatment starts with patient education on caloric restriction and exercise. If traditional measures fail to result in adequate weight loss, additional options include switching from cyclosporine to tacrolimus.²³

Bariatric surgery may become an option for posttransplant patients. In a recent case series from the University of Minnesota, Al-Nowaylati et al³⁸ reported their experience with seven patients who underwent orthotopic liver transplantation and then open Roux-en-Y gastric bypass. After bariatric surgery, the patients’ mean body mass index declined significantly, and glycemic control and high-density lipoprotein cholesterol (HDL-C) levels improved. However, one patient died of multiple organ failure, to which the bariatric surgery might have contributed.³⁸

Heimbach et al³⁹ conducted a study in patients referred for liver transplantation for whom a rigorous noninvasive weight-loss program before transplantation had failed. The researchers performed combined liver transplantation and sleeve gastrectomy in seven carefully selected patients who had failed to achieve weight loss to a body mass index less than 35 kg/m² before transplantation. All seven patients lost weight, decreasing their mean body mass index from 49 kg/m² before the procedure to 29 kg/m² at last follow-up, and none of them developed posttransplant diabetes or steatosis.

At this time, there is not enough evidence to recommend concurrent orthotopic liver transplantation plus bariatric surgery, or combined orthotopic liver transplantation and sleeve gastrectomy. More study is needed to further evaluate these advanced approaches.

Posttransplant metabolic syndrome

Metabolic syndrome is common after liver transplantation and is strongly associated with increased morbidity in this patient population.^40,41 The general definition of metabolic syndrome includes a combination of at least three of the following: hypertension, insulin resistance, hypertriglyceridemia, low HDL-C, and obesity.

The prevalence of metabolic syndrome is higher in patients after liver transplantation than in nontransplant patients. In a review of 252 liver transplant recipients, 52% were diagnosed with posttransplant metabolic syndrome, but only 5% had had it pretransplant.⁴²

Careful screening for posttransplant metabolic syndrome and early recognition of risk factors are important. Nevertheless, the treatment of this condition depends on treating its components according to recommended guidelines.⁴¹

Cardiovascular disease

The incidence of cardiovascular morbidity and death is increased after liver transplantation.²⁴ In addition, after liver transplantation, cardiovascular disease is a major cause of death unrelated to liver disease. It accounts for 12% to 16% of deaths and is the third most common cause of late mortality after liver transplantation.⁴³ Of note, a recent study by our group demonstrated that patients undergoing liver transplantation for nonalcoholic steatohepatitis had a significantly higher risk of a cardiovascular event during the 3 years after transplantation than patients undergoing liver transplantation for cholestatic liver disease.⁴⁴

Risk factors for cardiovascular disease after liver transplantation include older age at transplantation, male sex, posttransplant diabetes, posttransplant hypertension, and the use of mycophenolate mofetil.⁴⁴ Modifying the risk factors is essential in decreasing the risk of cardiovascular events.

It is reasonable to perform dobutamine stress testing every 3 to 5 years in patients with multiple risk factors for cardiovascular disease, or more frequently in those with preexisting coronary artery disease.^45,46

Malignancy

The risk of several malignancies increases after liver transplantation. Liver transplant recipients have an incidence of cancer 2.1 to 4.3 times greater than age- and sex-matched controls.^24,47–49

Skin cancers are the most common and account for almost 40% of malignancies in organ transplant recipients.⁵⁰ Whereas basal cell carcinoma is more common in the general population, squamous cell carcinoma is equally common in liver transplant recipients.

Multiple clinical studies have linked calcineurin inhibitors and azathioprine to the development of skin cancer. Annual skin examinations in addition to avoiding other risk factors such as smoking and sun exposure are generally recommended. Changing the immunosuppressants to sirolimus in high-risk patients may lower their chance of developing skin cancer.^51,52

Patients with ulcerative colitis who undergo liver transplantation because of sclerosing cholangitis are at higher risk of colon cancer and require annual colonoscopy with surveillance biopsies. Patients who undergo transplantation for alcoholic liver disease seem to have a higher risk of pulmonary and oropharyngeal cancers.^53,54

It is important that transplant patients adhere to recommended cancer screening guidelines, in view of their increased risk. Studies have shown improved overall survival in liver transplant recipients who underwent intensive cancer surveillance.⁵⁵

Renal insufficiency

Renal insufficiency is a well-recognized complication of liver transplantation and is associated with an increased long-term death rate.^56,57

The incidence of renal insufficiency increases dramatically over time. Ojo et al,⁵⁷ in a study of almost 37,000 liver transplant recipients, found that the incidence of chronic kidney disease (defined as an estimated glomerular filtration rate < 30 mL/min/1.73 m²) was 13.9% at 3 years, 18% at 5 years, and approximately 26% at 10 years.

Risk factors include the use of calcineurin inhibitors (both cyclosporine and tacrolimus), older age, female sex, lower pretransplant glomerular filtration rate, postoperative acute renal failure, diabetes, hypertension, hepatitis C virus infection, and transplantation before 1998.^58,59 Replacing a calcineurin inhibitor with mycophenolate mofetil or sirolimus may be considered with communication with the transplant center, as mycophenolate mofetil or sirolimus are associated with a lower risk of renal injury.^60–64

All liver transplant recipients should avoid nonsteroidal anti-inflammatory drugs and nephrotoxic medications

Starting 1 year after liver transplantation, primary care providers should screen for renal dysfunction by obtaining kidney function tests every 6 months, including urinalysis and microalbuminuria assessment. Equations for estimating the glomerular filtration rate used in practice, such as the Modification of Diet in Renal Disease Study equation, rely mainly on serum creatinine, which may lead to overestimating renal function in some circumstances. Therefore, other equations can be used to confirm the estimated glomerular filtration rate measured by creatinine clearance, and to more accurately evaluate kidney function. Calculators are available at www.kidney.org/professionals/kdoqi/gfr_calculator.

All liver transplant recipients should avoid nonsteroidal anti-inflammatory drugs and nephrotoxic medications, and should have their hypertension and diabetes adequately controlled.

Bone diseases

Osteopenia is another major complication of liver transplantation. One-third of liver transplant recipients have a bone mineral density below the fracture threshold.⁶⁵

Multiple factors contribute to increased bone loss after transplantation, including use of corticosteroids, use of calcineurin inhibitors (cyclosporine, tacrolimus), poor nutrition, vitamin D deficiency, immobility, sarcopenia (reduced muscle mass), hypogonadism, smoking, and alcohol abuse.⁶⁶ Even at low doses of less than 7.5 mg per day, corticosteroids inhibit osteoblast activity and increase bone resorption.

Studies have reported rapid bone loss at around 6 months after transplantation.^67–69 However, long-term follow-up of bone mineral density up to 15 years after transplantation revealed an improvement mainly in the 2nd postoperative year, with no deterioration afterward.⁶⁵

High-risk patients need to be identified early with appropriate screening and evaluation. Evaluation includes dual-energy x-ray absorptiometry and serum levels of calcium, phosphorous, parathyroid hormone, testosterone (men), estradiol (women), and alpha-25-hydroxyvitamin D. These tests are typically done before transplantation and then every other year afterward.

We recommend a daily dose of calcitriol and a calcium supplement to all our liver transplant patients.⁷⁰ If osteoporosis (a T-score 2.5 or more standard deviations below the mean) or a fragility fracture occurs, then the patient may benefit from an oral bisphosphonate. Calcitonin has also been shown to improve bone mineral density in patients with osteoporosis after liver transplantation.⁷¹

Hyperuricemia and gout

Although hyperuricemia is common in liver transplant recipients (reported in approximately 47%), the development of clinical gout is less common (6%).⁷² Asymptomatic hyperuricemia requires observation only and is not usually treated in liver transplant recipients.

Acute attacks of gout are typically managed with colchicine 0.6 mg every 2 hours, up to five doses. Prednisone can be considered if symptoms persist despite treatment with colchicine. Allopurinol in an initial dose of 100 mg daily is used as maintenance therapy to reduce production of uric acid.⁷³ However, because of the potential for drug interactions, the combination of azathioprine and allopurinol should be avoided.

Psychiatric complications and quality of life

Depression is common in liver transplant recipients, significantly more so in patients who received a transplant because of hepatitis C.⁷⁴ The type of immunosuppressant is not associated with the incidence of depression. When indicated, the internist may start the patient on a selective serotonin reuptake inhibitor such as citalopram 20 mg daily, as these medications are usually effective and well tolerated in liver transplant patients.⁷³

Liver transplantation has a major positive effect on quality of life. Most patients with end-stage liver disease have poor quality of life before transplantation, but this seems to improve notably afterward. A meta-analysis showed significant improvement in posttransplant physical health, sexual functioning, daily activities, and social functioning compared with before transplantation.⁷⁵

Alcohol abuse and smoking

Patients who underwent liver transplantation because of alcoholic liver disease should be advised to abstain from alcohol.¹⁹ Patients who underwent the procedure for a different indication are advised to avoid excessive alcohol intake, as it is proven to lower the survival rate.²⁰ Alcohol recidivism and smoking (including marijuana) are major problems, and internists are best positioned to address these issues and treat them.

Vaccinations

All liver transplant recipients should be vaccinated against influenza, pneumococcal infection, and tetanus. Hepatitis A and B vaccines are typically given before transplantation. In general, live vaccines such as measles-mumps-rubella and varicella are not recommended after any solid organ transplant.⁷⁶

A study in Germany showed that immunization rates were too low in solid-organ transplant recipients, and almost 90% of patients were not adequately informed about immunizations.⁷⁷ Hence, there may be room for improvement, and primary care providers should take the lead toward better outcomes in this regard.

Recurrence of the primary liver disease after transplantation

Different primary liver diseases recur with different frequencies.

Hepatitis C has the highest rate of recurrence of the liver diseases.^78,79 Reinfection with hepatitis C virus after liver transplantation is almost universal and can follow different patterns. One of the most aggressive patterns is fibrosing cholestatic hepatitis, which frequently leads to graft failure and death, and hence necessitates urgent detection and treatment.

Hepatocellular carcinoma also has a high recurrence rate.⁸⁰ Surveillance with liver ultrasonography or computed tomography is required every 6 months for the first 5 years after liver transplantation.

Other liver diseases. Nonalcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, and hepatitis B infection also tend to recur after liver transplantation.^46,81 On the other hand, alpha-1 antitrypsin deficiency, Wilson disease, hemochromatosis, and metabolic disorders are “cured” after liver transplantation.

It is important to detect any increase in liver enzymes above baseline. An elevation of 1.5 times the upper limit of normal or more should trigger further investigation.

Allograft dysfunction

A number of complications can develop in the liver allograft and result in abnormal liver function tests and, if not treated, graft failure. The most common causes of late graft dysfunction include recurrence of primary liver disease, biliary complications, and chronic rejection.⁴⁶

Vascular complications include hepatic artery thrombosis and stenosis and are usually evaluated by liver ultrasonography and Doppler scan of the hepatic artery and venous structures.²⁴

Biliary strictures give a cholestatic picture, with elevated bilirubin and greater elevation of alkaline phosphatase than of alanine aminotransferase and aspartate aminotransferase. Strictures are usually treated by endoscopic dilation and stenting, but they may eventually require surgery.

Late acute cellular rejections occur in 10% to 20% of cases and are a risk factor for chronic rejection. Liver biopsy is needed to make the diagnosis, and pulsed doses of corticosteroids remain the backbone of treatment therapy.

Chronic rejection is not common, occurring in 3% to 4% of liver transplant recipients.⁴⁶ Treatment is based on increasing immunosuppression and ensuring compliance with prescribed medications. However, chronic rejection may not respond well, and repeat transplantation may be the last resort for some patients.

WHEN TO REFER TO THE HEPATOLOGIST

Some situations require referral to the hepatologist or the transplant center. In general, the following are best managed by a hepatologist: adjustment of immunosuppressive drugs and dosages, allograft dysfunction, vascular and biliary complications, progressing renal dysfunction, and recurrence of primary liver disease. Early communication with a hepatologist and the transplant center is recommended in these cases.

Since 1963, when Starzl et al performed the first successful liver transplantation,¹ outcomes of this life-saving procedure have continued to improve. Long-term survival rates have increased markedly: the current 5-year rate is 73.8% and the 10-year rate is 60%.²

This success means that internists will be caring for a greater number of liver transplant recipients and managing their long-term problems, such as hypertension, diabetes mellitus, dyslipidemia, obesity, metabolic syndrome, cardiovascular disease, renal insufficiency, osteoporosis, cancer, and gout.

This review will discuss these complications, focusing on the role the primary care physician assumes beyond the first year after transplantation.

ROLE OF THE PRIMARY CARE PHYSICIAN

Hepatologists, primary care physicians, and surgeons share the care of transplant recipients. The first several weeks after transplantation require close follow-up by the hepatologist and transplantation team, with particular attention paid to the patient’s overall health and well-being, medication compliance, and biochemical and immunosuppression monitoring.

After the first year, the primary care physician assumes a greater role, becoming the main provider of the patient’s care.^3,4 Good communication between the transplant center and the primary care physician should lead to a smooth transition.⁴ Although the hepatologist continues to manage immunosuppressive drugs, allograft rejections, and biliary complications, the primary care physician manages most of the long-term complications and thus needs to be aware of the common ones and feel comfortable managing them. Aims during visits are to screen for and detect common complications and manage them appropriately, in addition to performing annual physical examinations and routine health care. A reasonable interval for liver transplant recipients to visit their primary care physician is every 6 months.

IMMUNOSUPPRESSANT MEDICATIONS

Multiple agents are used for immunosuppression after liver transplantation:

• Calcineurin inhibitors (cyclosporine and tacrolimus)
• Antimetabolites (mycophenolate mofetil, azathioprine, and mycophenolate sodium)
• Mammalian target of rapamycin (mTOR) inhibitors (sirolimus and everolimus)
• Corticosteroids.

Table 1 lists their common side effects.

Most centers use a combination of two to four immunosuppressants as induction therapy in the immediate posttransplant period, then taper the doses and eliminate all but a calcineurin inhibitor and an antimetabolite. For example, some start with a combination of tacrolimus, mycophenolate mofetil, and a corticosteroid. The choice in the immediate posttransplant period is frequently made by the transplant center in cooperation with the hepatologist. By the time primary care physicians see these patients, they usually are on a calcineurin inhibitor alone or a calcineurin inhibitor plus mycophenolate mofetil.

Calcineurin inhibitors

Cyclosporine is metabolized by the cytochrome CYP3A4 pathway. With an average half-life of 15 hours, it is given orally, usually every 12 hours.

The dosage is adjusted according to the trough level. Higher levels are needed in the initial posttransplant period to prevent graft rejection, whereas lower levels are preferred later to decrease the occurrence and severity of adverse effects. Typical long-term trough levels are 50 to 100 ng/mL. Levels should be checked more often if an acute illness develops or the patient starts taking a potentially interfering drug.

Of importance: the dosage should be based on trough levels and not on random levels. Levels are often falsely high if blood samples are not drawn at the trough level. Repeating the measurement and making sure the sample is drawn at the trough level, ie, 12 hours after the last dose, is advised in this condition.

Cyclosporine causes widespread vasoconstriction resulting in decreased renal blood flow and systemic hypertension, often within a few days of starting it. Other important adverse effects include renal insufficiency, dyslipidemia, neurotoxicity (headache, tremor, seizure), and diabetes.

Tacrolimus is superior to cyclosporine in terms of survival, graft loss, acute rejection, and steroid-resistant rejection in the first year.⁵ Currently, it is the agent used most often for maintenance immunosuppression after liver transplantation.

Like cyclosporine, tacrolimus is metabolized in the liver by CYP3A4. Satisfactory trough levels after 1 year are 4 to 6 ng/mL.

The adverse effects of tacrolimus are similar to those of cyclosporine, but diabetes mellitus is more common with tacrolimus. Bone marrow suppression may occur more often with tacrolimus as well.

Antimetabolites

Antimetabolites are generally not potent enough to be used alone.

Mycophenolate mofetil causes adverse effects that include bone marrow suppression and gastrointestinal symptoms such as gastritis, diarrhea, and abdominal pain.

Azathioprine, infrequently used in transplantation in the United States, is nevertheless sometimes substituted for mycophenolate mofetil in pregnant women, as it seems safer for use in pregnancy.

Serum levels of azathioprine and mycophenolate mofetil are not routinely monitored.

mTOR inhibitors

Sirolimus and everolimus are mTOR inhibitors, inhibiting proliferation of lymphocytes.^6,7

Unlike calcineurin inhibitors, mTOR inhibitors are not associated with nephrotoxicity, neurotoxicity, renal dysfunction, hypertension, or diabetes. Sirolimus is considered an alternative to calcineurin inhibitors or, in some instances, used as add-on-therapy to lower the dose of the calcineurin inhibitor.

Sirolimus carries a black-box warning about hepatic artery thrombosis

However, sirolimus carries a potential risk of hepatic artery thrombosis, a life-threatening complication.⁸ This has led the US Food and Drug Administration (FDA) to require sirolimus to carry a black-box warning, and most transplant centers avoid using it in the first 30 days after transplantation.

Dyslipidemia is perhaps the most common adverse effect of sirolimus. Others include dose-related cytopenia and wound dehiscence.⁹

Everolimus has yet to be established for use in liver transplantation, although safety trials have been published.^10,11 The FDA currently recommends against using it in the first 30 days after liver transplantation.

Both sirolimus and everolimus are metabolized by CYP3A4, which is the same metabolic pathway used by cyclosporine and tacrolimus. Hence, drugs that inhibit CYP3A4 may significantly impair clearance of both sirolimus and everolimus.

Corticosteroids

Corticosteroids have been the cornerstone of immunosuppression and remain the first line of treatment for acute allograft rejection. High intravenous doses of corticosteroids are usually started in the peritransplant period and are then switched to oral doses, which are tapered and continued with a fixed dose such as 20 mg of prednisone daily for 3 to 6 months after transplantation. However, some transplant centers keep patients on prednisone 5 mg/day indefinitely.

Adverse effects of corticosteroids include diabetes, salt and fluid retention, hypertension, hyperlipidemia, cosmetic changes (acne, cervical fat pad or “buffalo hump”), delayed wound healing, susceptibility to infection, cataracts, osteopenia, and potential adrenal suppression.¹² There is concern that the use of these drugs may increase hepatitis C virus replication in patients who received a liver transplant for hepatitis C cirrhosis. Randomized trials have yielded conflicting results.^13–15

Drug interactions

Certain drugs can affect the metabolism of calcineurin inhibitors and mTOR inhibitors by inducing CYP3A4, which results in decreasing the levels of the immunosuppressive drugs, or by inhibiting CYP3A4, which has the opposite effect.

Medications that can decrease the levels of calcineurin inhibitors and mTOR inhibitors:

• Anticonvulsants (carbamazepine, phenobarbital, phenytoin)
• Antibiotics (rifampin, isoniazid)
• St John’s wort.

Medications that can increase the levels of calcineurin inhibitors and mTOR inhibitors:

• Antifungals (fluconazole, ketoconazole, itraconazole, voriconazole, aspofungin)
• Antibiotics (azithromycin, erythromycin, clarithromycin)
• Nondihydropyridine calcium channel blockers (diltiazem, verapamil).¹⁶

Selected antibiotics are generally well tolerated, such as penicillins, cephalosporins, quinolones, sulfonamides, and topical antifungal agents.

LONG-TERM COMPLICATIONS

Figure 1 summarizes the common long-term complications of liver transplantation.

Hypertension

The prevalence of hypertension after liver transplantation is 40% to 85%, which is markedly higher than in patients with chronic liver disease before liver transplantation.^17,18

One of the factors contributing to this increase is the use of immunosuppressive medications. Of these drugs, cyclosporine seems to be the one that most often causes an increase in both the incidence and the severity of hypertension, as it produces widespread vasoconstriction.¹⁹ Corticosteroids cause hypertension through their mineralocorticoid effects.

The diagnostic cutoffs for hypertension (ie, 140/90 mm Hg) and the treatment goals in posttransplant patients are similar to those in the general population. However, at our institution we target a blood pressure of less than 130/80 mm Hg in transplant patients because they have a high prevalence of other cardiovascular risk factors such as diabetes, obesity, and renal insufficiency.²⁰

Dihydropyridine calcium channel blockers such as amlodipine and nifedipine are considered the best first-line agents because they dilate renal afferent arterioles, an effect that may counteract the vasoconstriction mediated by calcineurin inhibitors. Nondihydropyridine calcium channel blockers such as diltiazem and verapamil tend to have more marked negative inotropic effects and are not recommended in liver transplant recipients because they increase the levels of calcineurin inhibitors.²¹

Diuretics (eg, furosemide) might be the second-line agents, especially in patients with peripheral edema.¹⁶ One should be vigilant for hyperuricemia if thiazide agents are used.

Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are typically avoided in the early posttransplant period, but they can be started later and have additional benefits in patients with diabetes and congestive heart failure. Starting ACE inhibitors is acceptable in these patients unless there is a contraindication such as allergy to ACE inhibitors, hypotension, history of bilateral renal artery stenosis, significant hyperkalemia, or acute kidney injury. Monitor the serum potassium level closely for hyperkalemia in patients concurrently using calcineurin inhibitors.

Alpha-blockers and beta-blockers can be used as add-on therapy in patients with uncontrolled hypertension with the exception of carvedilol, because it increases the levels of calcineurin inhibitors.²²

Blood pressure monitoring by the primary care physician is recommended every 6 months after the early posttransplant period, or more frequently when changes in treatment are being considered.

If hypertension continues to be inadequately controlled despite treatment, changing the immunosuppressive drugs or decreasing the doses can be considered, but the transplant hepatologist must be involved in this decision.^23,24

Diabetes mellitus

The prevalence of diabetes mellitus is higher in liver transplant recipients than in the general population, reaching 30% to 40%.^17,25 In addition to preexisting diabetes, 15% of liver transplant recipients develop new-onset diabetes.^26,27

Risk factors for developing diabetes after liver transplantation include African American or Hispanic ethnicity, obesity, family history, pretransplant diabetes, hepatitis C virus infection, use of corticosteroids, and use of calcineurin inhibitors (tacrolimus more than cyclosporine) and sirolimus.²⁶

In addition to increasing the risk of cardiovascular disease and other diseases, diabetes decreases both patient and graft survival after liver transplantation.²⁸

The management of diabetes and the treatment target after transplantation should follow the American Diabetes Association guidelines for the treatment of type 2 diabetes mellitus.²⁹ Lifestyle modifications, diet, and exercise are as important for transplant patients as for the nontransplant population. Insulin therapy is usually needed in the early posttransplant period to control blood glucose levels well, especially with the high doses of corticosteroids used during the first few weeks. No trials to date have compared oral agents in posttransplant patients. Therefore, the choice of oral hypoglycemic agents should be individualized on the basis of the patient’s characteristics and comorbidities.

Screen all liver transplant recipients for diabetes regardless of their pretransplant status

We recommend that primary care providers screen all liver transplant recipients for diabetes regardless of their pretransplant status. This can be done by obtaining regular fasting blood glucose levels or a hemoglobin A_1c level every 6 months. Additionally, liver transplant recipients diagnosed with diabetes require annual eye examinations to look for cataracts and diabetes-related changes.³⁰

Dyslipidemia

On November 12, 2013, the American College of Cardiology and the American Heart Association (ACC/AHA) released new clinical practice guidelines for treating blood cholesterol levels.^31,32 According to these new guidelines, there are four groups of patients for whom treatment with statins is clearly indicated:

• Patients with cardiovascular disease
• Patients with low-density lipoprotein cholesterol (LDL-C) levels ≥ 190 mg/dL
• Patients 40 to 75 years old with type 2 diabetes
• Patients 40 to 75 years old with an estimated 10-year risk of cardiovascular disease of 7.5% or greater.

Liver transplant recipients should be evaluated on an individual basis to see if they fit in any of the four groups and if statin treatment therefore needs to be initiated.

A few things need to be kept in mind. First, the incidence of dyslipidemia after liver transplantation is estimated to be 45% to 69%. Risk factors include obesity, diabetes mellitus, cholestatic liver disease, and immunosuppressant medications.³³ Sirolimus has a significant and well-documented association with dyslipidemia. Cyclosporine and corticosteroids are also strongly associated with dyslipidemia. Tacrolimus has a minor effect, and mycophenolate mofetil and azathioprine have no significant effects on serum lipid levels.¹⁶

Second, of the seven currently marketed statins, pravastatin and fluvastatin are preferred in liver transplant recipients because they are not metabolized by the same cytochrome CYP3A4 pathway that metabolizes calcineurin inhibitors and sirolimus.³⁴ The doses of 40 to 80 mg daily of pravastatin or 40 mg twice daily of fluvastatin lower low-density lipoprotein cholesterol (LDL-C) levels by approximately 30% to 35%. However, these two agents are considered “moderate-intensity” statins according to the new ACC/AHA guidelines. The only two “high-intensity” statins are atorvastatin (40–80 mg) and rosuvastatin (20–40 mg), but they are both metabolized by CYP3A4. Therefore it is prudent to avoid them with the concurrent use of a calcineurin inhibitor or tacrolimus.

Gemfibrozil does not lower LDL-C and should not be used concomitantly with statins due to unacceptable risk of rhabdomyolysis and myopathy. Fenofibrates are usually avoided due to potential nephrotoxicity in patients receiving cyclosporine. Bile acid sequestrants (cholestyramine, colestipol, colesevelam) can decrease plasma mycophenolate mofetil levels by 35%.^16,35 Thus, these agents should be avoided if mycophenolate mofetil is used.

It is reasonable to screen all liver transplant recipients with a fasting lipid profile at 3, 6, and 12 months after transplantation and annually thereafter. Creatine kinase should be measured if the patient complains of severe muscle pain or weakness but not on a routine basis.

Obesity

Approximately one-third of patients who are of normal weight at the time of transplantation will become obese afterward.^18,25 Corticosteroid use is an important risk factor for posttransplant obesity, and tapering these drugs helps reduce weight.³⁶ Patients treated with cyclosporine are more likely to gain weight than those who receive tacrolimus.³⁷

Of importance: nonalcoholic fatty liver disease, currently the most common cause of chronic liver disease in adults, is rapidly increasing as an indication for liver transplantation. In fact, the proportion of liver transplantation procedures for nonalcoholic steatohepatitis-related cirrhosis increased from 1.2% in 2001 to 9.7% in 2009, and nonalcoholic steatohepatitis is expected to become the leading indication for liver transplantation in the next 20 years. And because nonalcoholic fatty liver disease is directly linked to obesity, the prevalence of obesity as a complication of liver transplantation will most likely increase in the near future.

Overweight liver transplant recipients may have great difficulty losing weight. Treatment starts with patient education on caloric restriction and exercise. If traditional measures fail to result in adequate weight loss, additional options include switching from cyclosporine to tacrolimus.²³

Bariatric surgery may become an option for posttransplant patients. In a recent case series from the University of Minnesota, Al-Nowaylati et al³⁸ reported their experience with seven patients who underwent orthotopic liver transplantation and then open Roux-en-Y gastric bypass. After bariatric surgery, the patients’ mean body mass index declined significantly, and glycemic control and high-density lipoprotein cholesterol (HDL-C) levels improved. However, one patient died of multiple organ failure, to which the bariatric surgery might have contributed.³⁸

Heimbach et al³⁹ conducted a study in patients referred for liver transplantation for whom a rigorous noninvasive weight-loss program before transplantation had failed. The researchers performed combined liver transplantation and sleeve gastrectomy in seven carefully selected patients who had failed to achieve weight loss to a body mass index less than 35 kg/m² before transplantation. All seven patients lost weight, decreasing their mean body mass index from 49 kg/m² before the procedure to 29 kg/m² at last follow-up, and none of them developed posttransplant diabetes or steatosis.

At this time, there is not enough evidence to recommend concurrent orthotopic liver transplantation plus bariatric surgery, or combined orthotopic liver transplantation and sleeve gastrectomy. More study is needed to further evaluate these advanced approaches.

Posttransplant metabolic syndrome

Metabolic syndrome is common after liver transplantation and is strongly associated with increased morbidity in this patient population.^40,41 The general definition of metabolic syndrome includes a combination of at least three of the following: hypertension, insulin resistance, hypertriglyceridemia, low HDL-C, and obesity.

The prevalence of metabolic syndrome is higher in patients after liver transplantation than in nontransplant patients. In a review of 252 liver transplant recipients, 52% were diagnosed with posttransplant metabolic syndrome, but only 5% had had it pretransplant.⁴²

Careful screening for posttransplant metabolic syndrome and early recognition of risk factors are important. Nevertheless, the treatment of this condition depends on treating its components according to recommended guidelines.⁴¹

Cardiovascular disease

The incidence of cardiovascular morbidity and death is increased after liver transplantation.²⁴ In addition, after liver transplantation, cardiovascular disease is a major cause of death unrelated to liver disease. It accounts for 12% to 16% of deaths and is the third most common cause of late mortality after liver transplantation.⁴³ Of note, a recent study by our group demonstrated that patients undergoing liver transplantation for nonalcoholic steatohepatitis had a significantly higher risk of a cardiovascular event during the 3 years after transplantation than patients undergoing liver transplantation for cholestatic liver disease.⁴⁴

Risk factors for cardiovascular disease after liver transplantation include older age at transplantation, male sex, posttransplant diabetes, posttransplant hypertension, and the use of mycophenolate mofetil.⁴⁴ Modifying the risk factors is essential in decreasing the risk of cardiovascular events.

It is reasonable to perform dobutamine stress testing every 3 to 5 years in patients with multiple risk factors for cardiovascular disease, or more frequently in those with preexisting coronary artery disease.^45,46

Malignancy

The risk of several malignancies increases after liver transplantation. Liver transplant recipients have an incidence of cancer 2.1 to 4.3 times greater than age- and sex-matched controls.^24,47–49

Skin cancers are the most common and account for almost 40% of malignancies in organ transplant recipients.⁵⁰ Whereas basal cell carcinoma is more common in the general population, squamous cell carcinoma is equally common in liver transplant recipients.

Multiple clinical studies have linked calcineurin inhibitors and azathioprine to the development of skin cancer. Annual skin examinations in addition to avoiding other risk factors such as smoking and sun exposure are generally recommended. Changing the immunosuppressants to sirolimus in high-risk patients may lower their chance of developing skin cancer.^51,52

Patients with ulcerative colitis who undergo liver transplantation because of sclerosing cholangitis are at higher risk of colon cancer and require annual colonoscopy with surveillance biopsies. Patients who undergo transplantation for alcoholic liver disease seem to have a higher risk of pulmonary and oropharyngeal cancers.^53,54

It is important that transplant patients adhere to recommended cancer screening guidelines, in view of their increased risk. Studies have shown improved overall survival in liver transplant recipients who underwent intensive cancer surveillance.⁵⁵

Renal insufficiency

Renal insufficiency is a well-recognized complication of liver transplantation and is associated with an increased long-term death rate.^56,57

The incidence of renal insufficiency increases dramatically over time. Ojo et al,⁵⁷ in a study of almost 37,000 liver transplant recipients, found that the incidence of chronic kidney disease (defined as an estimated glomerular filtration rate < 30 mL/min/1.73 m²) was 13.9% at 3 years, 18% at 5 years, and approximately 26% at 10 years.

Risk factors include the use of calcineurin inhibitors (both cyclosporine and tacrolimus), older age, female sex, lower pretransplant glomerular filtration rate, postoperative acute renal failure, diabetes, hypertension, hepatitis C virus infection, and transplantation before 1998.^58,59 Replacing a calcineurin inhibitor with mycophenolate mofetil or sirolimus may be considered with communication with the transplant center, as mycophenolate mofetil or sirolimus are associated with a lower risk of renal injury.^60–64

All liver transplant recipients should avoid nonsteroidal anti-inflammatory drugs and nephrotoxic medications

Starting 1 year after liver transplantation, primary care providers should screen for renal dysfunction by obtaining kidney function tests every 6 months, including urinalysis and microalbuminuria assessment. Equations for estimating the glomerular filtration rate used in practice, such as the Modification of Diet in Renal Disease Study equation, rely mainly on serum creatinine, which may lead to overestimating renal function in some circumstances. Therefore, other equations can be used to confirm the estimated glomerular filtration rate measured by creatinine clearance, and to more accurately evaluate kidney function. Calculators are available at www.kidney.org/professionals/kdoqi/gfr_calculator.

All liver transplant recipients should avoid nonsteroidal anti-inflammatory drugs and nephrotoxic medications, and should have their hypertension and diabetes adequately controlled.

Bone diseases

Osteopenia is another major complication of liver transplantation. One-third of liver transplant recipients have a bone mineral density below the fracture threshold.⁶⁵

Multiple factors contribute to increased bone loss after transplantation, including use of corticosteroids, use of calcineurin inhibitors (cyclosporine, tacrolimus), poor nutrition, vitamin D deficiency, immobility, sarcopenia (reduced muscle mass), hypogonadism, smoking, and alcohol abuse.⁶⁶ Even at low doses of less than 7.5 mg per day, corticosteroids inhibit osteoblast activity and increase bone resorption.

Studies have reported rapid bone loss at around 6 months after transplantation.^67–69 However, long-term follow-up of bone mineral density up to 15 years after transplantation revealed an improvement mainly in the 2nd postoperative year, with no deterioration afterward.⁶⁵

High-risk patients need to be identified early with appropriate screening and evaluation. Evaluation includes dual-energy x-ray absorptiometry and serum levels of calcium, phosphorous, parathyroid hormone, testosterone (men), estradiol (women), and alpha-25-hydroxyvitamin D. These tests are typically done before transplantation and then every other year afterward.

We recommend a daily dose of calcitriol and a calcium supplement to all our liver transplant patients.⁷⁰ If osteoporosis (a T-score 2.5 or more standard deviations below the mean) or a fragility fracture occurs, then the patient may benefit from an oral bisphosphonate. Calcitonin has also been shown to improve bone mineral density in patients with osteoporosis after liver transplantation.⁷¹

Hyperuricemia and gout

Although hyperuricemia is common in liver transplant recipients (reported in approximately 47%), the development of clinical gout is less common (6%).⁷² Asymptomatic hyperuricemia requires observation only and is not usually treated in liver transplant recipients.

Acute attacks of gout are typically managed with colchicine 0.6 mg every 2 hours, up to five doses. Prednisone can be considered if symptoms persist despite treatment with colchicine. Allopurinol in an initial dose of 100 mg daily is used as maintenance therapy to reduce production of uric acid.⁷³ However, because of the potential for drug interactions, the combination of azathioprine and allopurinol should be avoided.

Psychiatric complications and quality of life

Depression is common in liver transplant recipients, significantly more so in patients who received a transplant because of hepatitis C.⁷⁴ The type of immunosuppressant is not associated with the incidence of depression. When indicated, the internist may start the patient on a selective serotonin reuptake inhibitor such as citalopram 20 mg daily, as these medications are usually effective and well tolerated in liver transplant patients.⁷³

Liver transplantation has a major positive effect on quality of life. Most patients with end-stage liver disease have poor quality of life before transplantation, but this seems to improve notably afterward. A meta-analysis showed significant improvement in posttransplant physical health, sexual functioning, daily activities, and social functioning compared with before transplantation.⁷⁵

Alcohol abuse and smoking

Patients who underwent liver transplantation because of alcoholic liver disease should be advised to abstain from alcohol.¹⁹ Patients who underwent the procedure for a different indication are advised to avoid excessive alcohol intake, as it is proven to lower the survival rate.²⁰ Alcohol recidivism and smoking (including marijuana) are major problems, and internists are best positioned to address these issues and treat them.

Vaccinations

All liver transplant recipients should be vaccinated against influenza, pneumococcal infection, and tetanus. Hepatitis A and B vaccines are typically given before transplantation. In general, live vaccines such as measles-mumps-rubella and varicella are not recommended after any solid organ transplant.⁷⁶

A study in Germany showed that immunization rates were too low in solid-organ transplant recipients, and almost 90% of patients were not adequately informed about immunizations.⁷⁷ Hence, there may be room for improvement, and primary care providers should take the lead toward better outcomes in this regard.

Recurrence of the primary liver disease after transplantation

Different primary liver diseases recur with different frequencies.

Hepatitis C has the highest rate of recurrence of the liver diseases.^78,79 Reinfection with hepatitis C virus after liver transplantation is almost universal and can follow different patterns. One of the most aggressive patterns is fibrosing cholestatic hepatitis, which frequently leads to graft failure and death, and hence necessitates urgent detection and treatment.

Hepatocellular carcinoma also has a high recurrence rate.⁸⁰ Surveillance with liver ultrasonography or computed tomography is required every 6 months for the first 5 years after liver transplantation.

Other liver diseases. Nonalcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, and hepatitis B infection also tend to recur after liver transplantation.^46,81 On the other hand, alpha-1 antitrypsin deficiency, Wilson disease, hemochromatosis, and metabolic disorders are “cured” after liver transplantation.

It is important to detect any increase in liver enzymes above baseline. An elevation of 1.5 times the upper limit of normal or more should trigger further investigation.

Allograft dysfunction

A number of complications can develop in the liver allograft and result in abnormal liver function tests and, if not treated, graft failure. The most common causes of late graft dysfunction include recurrence of primary liver disease, biliary complications, and chronic rejection.⁴⁶

Vascular complications include hepatic artery thrombosis and stenosis and are usually evaluated by liver ultrasonography and Doppler scan of the hepatic artery and venous structures.²⁴

Biliary strictures give a cholestatic picture, with elevated bilirubin and greater elevation of alkaline phosphatase than of alanine aminotransferase and aspartate aminotransferase. Strictures are usually treated by endoscopic dilation and stenting, but they may eventually require surgery.

Late acute cellular rejections occur in 10% to 20% of cases and are a risk factor for chronic rejection. Liver biopsy is needed to make the diagnosis, and pulsed doses of corticosteroids remain the backbone of treatment therapy.

Chronic rejection is not common, occurring in 3% to 4% of liver transplant recipients.⁴⁶ Treatment is based on increasing immunosuppression and ensuring compliance with prescribed medications. However, chronic rejection may not respond well, and repeat transplantation may be the last resort for some patients.

WHEN TO REFER TO THE HEPATOLOGIST

Some situations require referral to the hepatologist or the transplant center. In general, the following are best managed by a hepatologist: adjustment of immunosuppressive drugs and dosages, allograft dysfunction, vascular and biliary complications, progressing renal dysfunction, and recurrence of primary liver disease. Early communication with a hepatologist and the transplant center is recommended in these cases.

A 40-year-old man with end-stage renal disease on intermittent hemodialysis presented to the emergency department with a 1-week history of pain affecting his left lower back, left flank, and left lower abdomen, diagnosed as zoster prodrome.

Of note, both corneas were cloudy, most severely in the limbus (Figure 1). His visual acuity and findings on funduscopic examination were normal.

CORNEAL OPACITY

The finding of corneal opacity should prompt an immediate ophthalmologic evaluation by the internist as well as an ophthalmologist. The initial examination should include visual acuity testing; gross examination with the naked eye; penlight examination of the pupil, conjunctiva, and anterior chamber; funduscopic examination to at least confirm a red reflex; and fluorescein examination of the cornea. Fluorescein testing is done last, as the dye may interfere with the other initial tests.¹

A number of causes of opacity

A number of conditions can cause corneal opacity. Several genetic conditions can cause developmental anomalies of the cornea, leading to corneal defects present at birth.² Causes of secondary corneal opacity in early infancy include infections such as herpes, iatrogenic injury during amniocentesis or forceps delivery, and infantile congenital glaucoma.²

Later in life, causes of corneal opacity include cataract, glaucoma, chemical exposure, foreign body injury, irradiation, infection (eg, syphilis, herpes, chlamydia), endophthalmitis, and metabolic genetic disorders such as Fabry disease, trisomy 18 syndrome, and lecithin-cholesterol acyltransferase (LCAT) deficiency.³

LCAT DEFICIENCY

LCAT is a key protein in reverse transport of cholesterol from the systemic circulation to the liver for excretion into the bile. Its deficiency results in low serum concentrations of high-density lipoprotein cholesterol (HDL-C).⁴ About 80 different mutations in the LCAT gene have been linked to LCAT deficiency.⁵

LCAT deficiency varies in severity. Patients with complete deficiency can have nearly undetectable levels of HDL-C, eruptive xanthoma, hepatosplenomegaly, and premature coronary artery disease (ie, by age 40).5,6 Features of coronary atherosclerosis can be lacking in patients with partial deficiency.

Regardless of the degree of LCAT deficiency, most patients have corneal opacification that is most severe near the limbus (thus, the term “fish eye syndrome”) and anemia.⁷ Although corneal opacification presents early in life and persists, it does not seem to affect vision.⁵ The anemia is associated with enhanced fractional clearance of red blood cells secondary to hypersplenism.⁸

LCAT deficiency and the kidneys

LCAT deficiency has its most devastating effect on the kidney. Renal disease begins early in life with mild proteinuria and microscopic hematuria. With increasing age, renal function deteriorates and proteinuria and hematuria worsen.⁹

Renal biopsy study may reveal foam cells in the glomerular tufts, arterioles with thickened intima and narrowed lumens, and subendothelial deposits of lipids in the renal arteries and arterioles.¹⁰ Some studies have suggested that kidney disease is most likely initiated by lipid deposition or cellular uptake of lipoproteins in the glomerular basement membrane, mesangium, and capillary subendothelium.

Treatment

There are few treatment options for patients with LCAT deficiency. Control of hypertension, if present, may halt or slow renal deterioration.⁵ Many patients eventually require dialysis, and some undergo renal transplantation, but the renal disease can recur.

OUR PATIENT

Our patient had a known diagnosis of LCAT deficiency. Five years before this presentation at our emergency department, he developed malignant hypertension, followed shortly by renal disease. Over the next 4 years, his kidney function deteriorated, culminating in the need for dialysis; his corneal opacities manifested and gradually worsened; and after extensive studies including kidney biopsies, he was finally diagnosed with LCAT deficiency.

He also exhibited a chronically low level of HDL-C (2 to 5 mg/dL) and significant coronary artery disease. Although unrelated, his zoster pain was treated with renally dosed acyclovir and gabapentin. He never demonstrated the characteristic rash, and his pain improved significantly within 5 days of treatment.

A 40-year-old man with end-stage renal disease on intermittent hemodialysis presented to the emergency department with a 1-week history of pain affecting his left lower back, left flank, and left lower abdomen, diagnosed as zoster prodrome.

Of note, both corneas were cloudy, most severely in the limbus (Figure 1). His visual acuity and findings on funduscopic examination were normal.

CORNEAL OPACITY

The finding of corneal opacity should prompt an immediate ophthalmologic evaluation by the internist as well as an ophthalmologist. The initial examination should include visual acuity testing; gross examination with the naked eye; penlight examination of the pupil, conjunctiva, and anterior chamber; funduscopic examination to at least confirm a red reflex; and fluorescein examination of the cornea. Fluorescein testing is done last, as the dye may interfere with the other initial tests.¹

A number of causes of opacity

A number of conditions can cause corneal opacity. Several genetic conditions can cause developmental anomalies of the cornea, leading to corneal defects present at birth.² Causes of secondary corneal opacity in early infancy include infections such as herpes, iatrogenic injury during amniocentesis or forceps delivery, and infantile congenital glaucoma.²

Later in life, causes of corneal opacity include cataract, glaucoma, chemical exposure, foreign body injury, irradiation, infection (eg, syphilis, herpes, chlamydia), endophthalmitis, and metabolic genetic disorders such as Fabry disease, trisomy 18 syndrome, and lecithin-cholesterol acyltransferase (LCAT) deficiency.³

LCAT DEFICIENCY

LCAT is a key protein in reverse transport of cholesterol from the systemic circulation to the liver for excretion into the bile. Its deficiency results in low serum concentrations of high-density lipoprotein cholesterol (HDL-C).⁴ About 80 different mutations in the LCAT gene have been linked to LCAT deficiency.⁵

LCAT deficiency varies in severity. Patients with complete deficiency can have nearly undetectable levels of HDL-C, eruptive xanthoma, hepatosplenomegaly, and premature coronary artery disease (ie, by age 40).5,6 Features of coronary atherosclerosis can be lacking in patients with partial deficiency.

Regardless of the degree of LCAT deficiency, most patients have corneal opacification that is most severe near the limbus (thus, the term “fish eye syndrome”) and anemia.⁷ Although corneal opacification presents early in life and persists, it does not seem to affect vision.⁵ The anemia is associated with enhanced fractional clearance of red blood cells secondary to hypersplenism.⁸

LCAT deficiency and the kidneys

LCAT deficiency has its most devastating effect on the kidney. Renal disease begins early in life with mild proteinuria and microscopic hematuria. With increasing age, renal function deteriorates and proteinuria and hematuria worsen.⁹

Renal biopsy study may reveal foam cells in the glomerular tufts, arterioles with thickened intima and narrowed lumens, and subendothelial deposits of lipids in the renal arteries and arterioles.¹⁰ Some studies have suggested that kidney disease is most likely initiated by lipid deposition or cellular uptake of lipoproteins in the glomerular basement membrane, mesangium, and capillary subendothelium.

Treatment

There are few treatment options for patients with LCAT deficiency. Control of hypertension, if present, may halt or slow renal deterioration.⁵ Many patients eventually require dialysis, and some undergo renal transplantation, but the renal disease can recur.

OUR PATIENT

Our patient had a known diagnosis of LCAT deficiency. Five years before this presentation at our emergency department, he developed malignant hypertension, followed shortly by renal disease. Over the next 4 years, his kidney function deteriorated, culminating in the need for dialysis; his corneal opacities manifested and gradually worsened; and after extensive studies including kidney biopsies, he was finally diagnosed with LCAT deficiency.

He also exhibited a chronically low level of HDL-C (2 to 5 mg/dL) and significant coronary artery disease. Although unrelated, his zoster pain was treated with renally dosed acyclovir and gabapentin. He never demonstrated the characteristic rash, and his pain improved significantly within 5 days of treatment.

A 40-year-old man with end-stage renal disease on intermittent hemodialysis presented to the emergency department with a 1-week history of pain affecting his left lower back, left flank, and left lower abdomen, diagnosed as zoster prodrome.

Of note, both corneas were cloudy, most severely in the limbus (Figure 1). His visual acuity and findings on funduscopic examination were normal.

CORNEAL OPACITY

The finding of corneal opacity should prompt an immediate ophthalmologic evaluation by the internist as well as an ophthalmologist. The initial examination should include visual acuity testing; gross examination with the naked eye; penlight examination of the pupil, conjunctiva, and anterior chamber; funduscopic examination to at least confirm a red reflex; and fluorescein examination of the cornea. Fluorescein testing is done last, as the dye may interfere with the other initial tests.¹

A number of causes of opacity

A number of conditions can cause corneal opacity. Several genetic conditions can cause developmental anomalies of the cornea, leading to corneal defects present at birth.² Causes of secondary corneal opacity in early infancy include infections such as herpes, iatrogenic injury during amniocentesis or forceps delivery, and infantile congenital glaucoma.²

Later in life, causes of corneal opacity include cataract, glaucoma, chemical exposure, foreign body injury, irradiation, infection (eg, syphilis, herpes, chlamydia), endophthalmitis, and metabolic genetic disorders such as Fabry disease, trisomy 18 syndrome, and lecithin-cholesterol acyltransferase (LCAT) deficiency.³

LCAT DEFICIENCY

LCAT is a key protein in reverse transport of cholesterol from the systemic circulation to the liver for excretion into the bile. Its deficiency results in low serum concentrations of high-density lipoprotein cholesterol (HDL-C).⁴ About 80 different mutations in the LCAT gene have been linked to LCAT deficiency.⁵

LCAT deficiency varies in severity. Patients with complete deficiency can have nearly undetectable levels of HDL-C, eruptive xanthoma, hepatosplenomegaly, and premature coronary artery disease (ie, by age 40).5,6 Features of coronary atherosclerosis can be lacking in patients with partial deficiency.

Regardless of the degree of LCAT deficiency, most patients have corneal opacification that is most severe near the limbus (thus, the term “fish eye syndrome”) and anemia.⁷ Although corneal opacification presents early in life and persists, it does not seem to affect vision.⁵ The anemia is associated with enhanced fractional clearance of red blood cells secondary to hypersplenism.⁸

LCAT deficiency and the kidneys

LCAT deficiency has its most devastating effect on the kidney. Renal disease begins early in life with mild proteinuria and microscopic hematuria. With increasing age, renal function deteriorates and proteinuria and hematuria worsen.⁹

Renal biopsy study may reveal foam cells in the glomerular tufts, arterioles with thickened intima and narrowed lumens, and subendothelial deposits of lipids in the renal arteries and arterioles.¹⁰ Some studies have suggested that kidney disease is most likely initiated by lipid deposition or cellular uptake of lipoproteins in the glomerular basement membrane, mesangium, and capillary subendothelium.

Treatment

There are few treatment options for patients with LCAT deficiency. Control of hypertension, if present, may halt or slow renal deterioration.⁵ Many patients eventually require dialysis, and some undergo renal transplantation, but the renal disease can recur.

OUR PATIENT

Our patient had a known diagnosis of LCAT deficiency. Five years before this presentation at our emergency department, he developed malignant hypertension, followed shortly by renal disease. Over the next 4 years, his kidney function deteriorated, culminating in the need for dialysis; his corneal opacities manifested and gradually worsened; and after extensive studies including kidney biopsies, he was finally diagnosed with LCAT deficiency.

He also exhibited a chronically low level of HDL-C (2 to 5 mg/dL) and significant coronary artery disease. Although unrelated, his zoster pain was treated with renally dosed acyclovir and gabapentin. He never demonstrated the characteristic rash, and his pain improved significantly within 5 days of treatment.

A 24-year-old woman from northern India came to our medical center because of lower back pain for the past 2 years. The pain was initially a dull, continuous ache and did not radiate. She had no fever, night sweats, weight loss, or other constitutional symptoms.

In addition, she had seen her local practitioner 1 year earlier because of burning during urination and occasional frequency. She had been found to have an 8-mm calculus in the lower calyx of the left kidney, for which she underwent two sessions of shock-wave lithotripsy, but she did not pass any stone fragments. Because her back pain continued, she sought medical treatment at our center.

On evaluation at our facility, she was found to have paraspinal muscle spasm and scoliosis. Her gait was antalgic. Sensations were normal over both lower limbs in all dermatomes. Power was grade 5 throughout, and deep tendon reflexes were normal. The straight-leg-raising test was positive for reproducible pain in the lower back and sciatic pain radiating down the back of both legs.

Laboratory testing showed that her hemoglobin was low at 9.7 g/dL (reference range 11.5–15.5), but the rest of the complete blood cell count was within normal limits. C-reactive protein was elevated at 70.7 mg/L (reference range < 6 mg/L). An enzyme-linked immunosorbent assay was negative for human immunodeficiency virus (HIV).

Nonenhanced computed tomography of the abdomen revealed destruction of vertebral body end plates and disks from the L2 lower end plate to the L5 superior end plate. The left transverse processes of the L3, L4, and L5 vertebral bodies were also destroyed. The scan also revealed bilateral psoas abscesses larger than 10 by 10 cm (Figure 1), with the right side larger than the left, and confirmed a stone in the left lower renal calyx (Figure 2).

She underwent bilateral ultrasonographically guided drainage of the abscesses. Culture of the thick pus that was aspirated grew Mycobacterium tuberculosis. Tuberculosis therapy was started with isoniazid, rifampicin, pyrazinamide, and ethambutol. Her condition improved rapidly over the next 2 to 3 months. She completed 18 months of tuberculosis therapy.

Because her spine was stable, with no collapse of vertebrae, she did not require orthopedic intervention.

SPINAL TUBERCULOSIS

Spinal tuberculosis, or Pott disease, is still a common cause of back pain in areas where the infection is rampant, such as northern India.¹Mycobacterium infections continue to be a problem, especially coexisting with HIV infection.^2,3 In fact, the World Health Organization and the United States Agency for International Development have referred to this as a twin epidemic.⁴

Early diagnosis and prompt treatment can prevent or minimize spinal deformity and permanent neurologic disability.⁵ Rapidly progressive and significant neurologic involvement requires surgical management. On the other hand, Patil et al⁶ reported a series of 50 cases in which early radiologic evidence of spinal cord compression from tuberculosis was managed nonoperatively.

When evaluating back pain, symptoms that should ring the alarm include weight loss, constitutional symptoms, no change in pain status after 6 weeks of treatment with a nonsteroidal anti-inflammatory drug, pain at night or at rest, and neurologic symptoms. Our patient had no relief of pain and thus sought treatment.

An important take-home message is that small, nonobstructive renal calculi almost never cause back pain, and when incidentally detected, as in this patient, should not be considered the cause of back pain.

A 24-year-old woman from northern India came to our medical center because of lower back pain for the past 2 years. The pain was initially a dull, continuous ache and did not radiate. She had no fever, night sweats, weight loss, or other constitutional symptoms.

In addition, she had seen her local practitioner 1 year earlier because of burning during urination and occasional frequency. She had been found to have an 8-mm calculus in the lower calyx of the left kidney, for which she underwent two sessions of shock-wave lithotripsy, but she did not pass any stone fragments. Because her back pain continued, she sought medical treatment at our center.

On evaluation at our facility, she was found to have paraspinal muscle spasm and scoliosis. Her gait was antalgic. Sensations were normal over both lower limbs in all dermatomes. Power was grade 5 throughout, and deep tendon reflexes were normal. The straight-leg-raising test was positive for reproducible pain in the lower back and sciatic pain radiating down the back of both legs.

Laboratory testing showed that her hemoglobin was low at 9.7 g/dL (reference range 11.5–15.5), but the rest of the complete blood cell count was within normal limits. C-reactive protein was elevated at 70.7 mg/L (reference range < 6 mg/L). An enzyme-linked immunosorbent assay was negative for human immunodeficiency virus (HIV).

Nonenhanced computed tomography of the abdomen revealed destruction of vertebral body end plates and disks from the L2 lower end plate to the L5 superior end plate. The left transverse processes of the L3, L4, and L5 vertebral bodies were also destroyed. The scan also revealed bilateral psoas abscesses larger than 10 by 10 cm (Figure 1), with the right side larger than the left, and confirmed a stone in the left lower renal calyx (Figure 2).

She underwent bilateral ultrasonographically guided drainage of the abscesses. Culture of the thick pus that was aspirated grew Mycobacterium tuberculosis. Tuberculosis therapy was started with isoniazid, rifampicin, pyrazinamide, and ethambutol. Her condition improved rapidly over the next 2 to 3 months. She completed 18 months of tuberculosis therapy.

Because her spine was stable, with no collapse of vertebrae, she did not require orthopedic intervention.

SPINAL TUBERCULOSIS

Spinal tuberculosis, or Pott disease, is still a common cause of back pain in areas where the infection is rampant, such as northern India.¹Mycobacterium infections continue to be a problem, especially coexisting with HIV infection.^2,3 In fact, the World Health Organization and the United States Agency for International Development have referred to this as a twin epidemic.⁴

Early diagnosis and prompt treatment can prevent or minimize spinal deformity and permanent neurologic disability.⁵ Rapidly progressive and significant neurologic involvement requires surgical management. On the other hand, Patil et al⁶ reported a series of 50 cases in which early radiologic evidence of spinal cord compression from tuberculosis was managed nonoperatively.

When evaluating back pain, symptoms that should ring the alarm include weight loss, constitutional symptoms, no change in pain status after 6 weeks of treatment with a nonsteroidal anti-inflammatory drug, pain at night or at rest, and neurologic symptoms. Our patient had no relief of pain and thus sought treatment.

An important take-home message is that small, nonobstructive renal calculi almost never cause back pain, and when incidentally detected, as in this patient, should not be considered the cause of back pain.

A 24-year-old woman from northern India came to our medical center because of lower back pain for the past 2 years. The pain was initially a dull, continuous ache and did not radiate. She had no fever, night sweats, weight loss, or other constitutional symptoms.

In addition, she had seen her local practitioner 1 year earlier because of burning during urination and occasional frequency. She had been found to have an 8-mm calculus in the lower calyx of the left kidney, for which she underwent two sessions of shock-wave lithotripsy, but she did not pass any stone fragments. Because her back pain continued, she sought medical treatment at our center.

On evaluation at our facility, she was found to have paraspinal muscle spasm and scoliosis. Her gait was antalgic. Sensations were normal over both lower limbs in all dermatomes. Power was grade 5 throughout, and deep tendon reflexes were normal. The straight-leg-raising test was positive for reproducible pain in the lower back and sciatic pain radiating down the back of both legs.

Laboratory testing showed that her hemoglobin was low at 9.7 g/dL (reference range 11.5–15.5), but the rest of the complete blood cell count was within normal limits. C-reactive protein was elevated at 70.7 mg/L (reference range < 6 mg/L). An enzyme-linked immunosorbent assay was negative for human immunodeficiency virus (HIV).

Nonenhanced computed tomography of the abdomen revealed destruction of vertebral body end plates and disks from the L2 lower end plate to the L5 superior end plate. The left transverse processes of the L3, L4, and L5 vertebral bodies were also destroyed. The scan also revealed bilateral psoas abscesses larger than 10 by 10 cm (Figure 1), with the right side larger than the left, and confirmed a stone in the left lower renal calyx (Figure 2).

She underwent bilateral ultrasonographically guided drainage of the abscesses. Culture of the thick pus that was aspirated grew Mycobacterium tuberculosis. Tuberculosis therapy was started with isoniazid, rifampicin, pyrazinamide, and ethambutol. Her condition improved rapidly over the next 2 to 3 months. She completed 18 months of tuberculosis therapy.

Because her spine was stable, with no collapse of vertebrae, she did not require orthopedic intervention.

SPINAL TUBERCULOSIS

Spinal tuberculosis, or Pott disease, is still a common cause of back pain in areas where the infection is rampant, such as northern India.¹Mycobacterium infections continue to be a problem, especially coexisting with HIV infection.^2,3 In fact, the World Health Organization and the United States Agency for International Development have referred to this as a twin epidemic.⁴

Early diagnosis and prompt treatment can prevent or minimize spinal deformity and permanent neurologic disability.⁵ Rapidly progressive and significant neurologic involvement requires surgical management. On the other hand, Patil et al⁶ reported a series of 50 cases in which early radiologic evidence of spinal cord compression from tuberculosis was managed nonoperatively.

When evaluating back pain, symptoms that should ring the alarm include weight loss, constitutional symptoms, no change in pain status after 6 weeks of treatment with a nonsteroidal anti-inflammatory drug, pain at night or at rest, and neurologic symptoms. Our patient had no relief of pain and thus sought treatment.

An important take-home message is that small, nonobstructive renal calculi almost never cause back pain, and when incidentally detected, as in this patient, should not be considered the cause of back pain.