Federal Practitioner

Histology is the gold standard for cirrhosis diagnosis. However, a combination of clinical history, physical examination findings, and supportive laboratory and radiographic features is generally sufficient to make the diagnosis. Routine ultrasound and computed tomography (CT) imaging often identifies a nodular liver contour with sequelae of portal hypertension, including splenomegaly, varices, and ascites, which can suggest cirrhosis when supported by laboratory parameters and clinical features. As a result, the diagnosis is typically made clinically.¹ Many patients with compensated cirrhosis go undetected. The presence of a decompensation event (ascites, spontaneous bacterial peritonitis, variceal hemorrhage, or hepatic encephalopathy) often leads to index diagnosis when patients were previously compensated. When a patient presents with suspected decompensated cirrhosis, it is important to consider other diagnoses with similar presentations and ensure that multiple disease processes are not contributing to the symptoms.

CASE PRESENTATION

A 64-year-old male with a history of intravenous (IV) methamphetamine use and prior incarceration presented with a 3-week history of progressively worsening generalized swelling. Prior to the onset of his symptoms, the patient injured his right lower extremity (RLE) in a bicycle accident, resulting in edema that progressed to bilateral lower extremity (BLE) edema and worsening fatigue, despite resolution of the initial injury. The patient gained weight though he could not quantify the amount. He experienced progressive hunger, thirst, and fatigue as well as increased sleep. Additionally, the patient experienced worsening dyspnea on exertion and orthopnea. He started using 2 pillows instead of 1 pillow at night.

The patient reported no fevers, chills, sputum production, chest pain, or paroxysmal nocturnal dyspnea. He had no known history of sexually transmitted infections, no significant history of alcohol use, and occasional tobacco and marijuana use. He had been incarcerated > 10 years before and last used IV methamphetamine 3 years before. He did not regularly take any medications.

The patient’s vital signs included a temperature of 98.2 °F; 78/min heart rate; 15/min respiratory rate; 159/109 mm Hg blood pressure; and 98% oxygen saturation on room air. He had gained 20 lbs in the past 4 months. He had pitting edema in both legs and arms, as well as periorbital swelling, but no jugular venous distention, abnormal heart sounds, or murmurs. Breath sounds were distant but clear to auscultation. His abdomen was distended with normal bowel sounds and no fluid wave; mild epigastric tenderness was present, but no intra-abdominal masses were palpated. He had spider angiomata on the upper chest but no other stigmata of cirrhosis, such as caput medusae or jaundice. Tattoos were noted.

Laboratory test results showed a platelet count of 178 x 10³/μL (reference range, 140- 440 ~ 10³μL).Creatinine was 0.80 mg/dL (reference range, < 1.28 mg/dL), with an estimated glomerular filtration rate (eGFR) of 99 mL/min/1.73 m² using the Chronic Kidney Disease-Epidemiology equation (reference range, > 60 mL/min/1.73 m²), (reference range, > 60 mL/min/1.73 m²), and Cystatin C was 1.14 mg/L (reference range, < 1.15 mg/L). His electrolytes and complete blood count were within normal limits, including sodium, 134 mmol/L; potassium, 4.4 mmol/L; chloride, 108 mmol/L; and carbon dioxide, 22.5 mmol/L.

Additional test results included alkaline phosphatase, 126 U/L (reference range, < 94 U/L); alanine transaminase, 41 U/L (reference range, < 45 U/L); aspartate aminotransferase, 70 U/L (reference range, < 35 U/L); total bilirubin, 0.6 mg/dL (reference range, < 1 mg/dL); albumin, 1.8 g/dL (reference range, 3.2-4.8 g/dL); and total protein, 6.3 g/dL (reference range, 5.9-8.3 g/dL). The patient’s international normalized ratio was 0.96 (reference range, 0.8-1.1), and brain natriuretic peptide was normal at 56 pg/mL. No prior laboratory results were available for comparison.

Urine toxicology was positive for amphetamines. Urinalysis demonstrated large occult blood, with a red blood cell count of 26/ HPF (reference range, 0/HPF) and proteinuria (100 mg/dL; reference range, negative), without bacteria, nitrites, or leukocyte esterase. Urine white blood cell count was 10/ HPF (reference range, 0/HPF), and fine granular casts and hyaline casts were present.

A noncontrast CT of the abdomen and pelvis in the emergency department showed an irregular liver contour with diffuse nodularity, multiple portosystemic collaterals, moderate abdominal and pelvic ascites, small bilateral pleural effusions with associated atelectasis, and anasarca consistent with cirrhosis (Figure 1). The patient was admitted to the internal medicine service for workup and management of newly diagnosed cirrhosis.

Paracentesis revealed straw-colored fluid with an ascitic fluid neutrophil count of 17/μL, a protein level of < 3 g/dL and albumin level of < 1.5 g/dL. Gram stain of the ascitic fluid showed a moderate white blood cell count with no organisms. Fluid culture showed no microbial growth.

Initial workup for cirrhosis demonstrated a positive total hepatitis A antibody. The patient had a nonreactive hepatitis B surface antigen and surface antibody, but a reactive hepatitis B core antibody; a hepatitis B DNA level was not ordered. He had a reactive hepatitis C antibody with a viral load of 4,490,000 II/mL (genotype 1a). The patient’s iron level was 120 μg/dL, with a calculated total iron-binding capacity (TIBC) of 126.2 μg/dL. His transferrin saturation (TSAT) (serum iron divided by TIBC) was 95%. The patient had nonreactive antinuclear antibody and antimitochondrial antibody tests and a positive antismooth muscle antibody test with a titer of 1:40. His α-fetoprotein (AFP) level was 505 ng/mL (reference range, < 8 ng/mL).

Follow-up MRI of the abdomen and pelvis showed cirrhotic morphology with large volume ascites and portosystemic collaterals, consistent with portal hypertension. Additionally, it showed multiple scattered peripheral sub centimeter hyperenhancing foci, most likely representing benign lesions.

The patient's spot urine protein-creatinine ratio was 3.76. To better quantify proteinuria, a 24-hour urine collection was performed and revealed 12.8 g/d of urine protein (reference range, 0-0.17 g/d). His serum triglyceride level was 175 mg/dL (reference range, 40-60 mg/dL); total cholesterol was 177 mg/ dL (reference range, ≤ 200 mg/dL); low density lipoprotein cholesterol was 98 mg/ dL (reference range, ≤ 130 mg/dL); and highdensity lipoprotein cholesterol was 43.8 mg/ dL (reference range, ≥ 40 mg/dL); C3 complement level was 71 mg/dL (reference range, 82-185 mg/dL); and C4 complement level was 22 mg/dL (reference range, 15-53 mg/ dL). His rheumatoid factor was < 14 IU/mL. Tests for rapid plasma reagin and HIV antigen- antibody were nonreactive, and the phospholipase A2 receptor antibody test was negative. The patient tested positive for QuantiFERON-TB Gold and qualitative cryoglobulin, which indicated a cryocrit of 1%.

A renal biopsy was performed, revealing diffuse podocyte foot process effacement and glomerulonephritis with low-grade C3 and immunoglobulin (Ig) G deposits, consistent with early membranoproliferative glomerulonephritis (MPGN) (Figures 2 and 3).

The patient was initially diuresed with IV furosemide without significant urine output. He was then diuresed with IV 25% albumin (total, 25 g), followed by IV furosemide 40 mg twice daily, which led to significant urine output and resolution of his anasarca. Given the patient’s hypoalbuminemic state, IV albumin was necessary to deliver furosemide to the proximal tubule. He was started on lisinopril for renal protection and discharged with spironolactone and furosemide for fluid management in the context of cirrhosis.

The patient was evaluated by the Liver Nodule Clinic, which includes specialists from hepatology, medical oncology, radiation oncology, interventional radiology, and diagnostic radiology. The team considered the patient’s medical history and characteristics of the nodules on imaging. Notable aspects of the patient’s history included hepatitis C virus (HCV) infection and an elevated AFP level, although imaging showed no lesion concerning for malignancy. Given these findings, the patient was scheduled for a liver biopsy to establish a tissue diagnosis of cirrhosis. Hepatology, nephrology, and infectious disease specialists coordinated to plan the management and treatment of latent tuberculosis (TB), chronic HCV, MPGN, compensated cirrhosis, and suspicious liver lesions.

The patient chose to handle management and treatment as an outpatient. He was discharged with furosemide and spironolactone for anasarca management, and amlodipine and lisinopril for his hypertension and MPGN. Follow-up appointments were scheduled with infectious disease for management of latent TB and HCV, nephrology for MPGN, gastroenterology for cirrhosis, and interventional radiology for liver biopsy. Unfortunately, the patient was unhoused with limited access to transportation, which prevented timely follow-up. Given these social factors, immunosuppression was not started. Additionally, he did not start on HCV therapy because the viral load was still pending at time of discharge.

DISCUSSION

The diagnosis of decompensated cirrhosis was prematurely established, resulting in a diagnostic delay, a form of diagnostic error. However, on hospital day 2, the initial hypothesis of decompensated cirrhosis as the sole driver of the patient’s presentation was reconsidered due to the disconnect between the severity of hypoalbuminemia and diffuse edema (anasarca), and the absence of laboratory evidence of hepatic decompensation (normal international normalized ratio, bilirubin, and low but normal platelet count). Although image findings supported cirrhosis, laboratory markers did not indicate hepatic decompensation. The severity of hypoalbuminemia and anasarca, along with an indeterminate Serum-Ascites Albumin Gradient, prompted the patient’s care team to consider other causes, specifically, nephrotic syndrome.

The patien’s spot protein-to-creatinine ratio was 3.76 (reference range < 0.2 mg/mg creatinine), but a 24-hour urine protein collection was 12.8 g/day (reference range < 150 mg/day). While most spot urine protein- to-creatinine ratios (UPCR) correlate with a 24-hour urine collection, discrepancies can occur, as in this case. It is important to recognize that the spot UPCR assumes that patients are excreting 1000 mg of creatinine daily in their urine, which is not always the case. In addition, changes in urine osmolality can lead to different values. The gold standard for proteinuria is a 24-hour urine collection for protein and creatinine.

The patient’s nephrotic-range proteinuria and severe hypoalbuminemia are not solely explained by cirrhosis. In addition, the patient’s lower extremity edema pointed to nephrotic syndrome. The differential diagnosis for nephrotic syndrome includes both primary and secondary forms of membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, and MPGN, a histopathological diagnosis that requires distinguishing between immune complex-mediated and complement-mediated forms. Other causes of nephrotic syndrome that do not fit in any of these buckets include amyloidosis, IgA nephropathy, and diabetes mellitus (DM). Despite DM being a common cause of nephrotic range proteinuria, it rarely leads to full nephrotic syndrome.

When considering the diagnosis, we reframed the patient’s clinical syndrome as compensated cirrhosis plus nephrotic syndrome. This approach prioritized identifying a cause that could explain both cirrhosis (from any cause) leading to IgA nephropathy or injection drug use serving as a risk factor for cirrhosis and nephrotic syndrome through HCV or AA amyloidosis, respectively. This problem representation guided us to the correct diagnosis. There are multiple renal diseases associated with HCV infection, including MPGN, membranous nephropathy, focal segmental glomerulosclerosis, and IgA nephropathy.² MPGN and mixed cryoglobulinemia are the most common. In the past, MPGN was classified as type I, II, and III.

The patient’s urine toxicology revealed recent amphetamine use, which can also lead to acute kidney injury through rhabdomyolysis or acute interstitial nephritis (AIN).³ In the cases of rhabdomyolysis, urinalysis would show positive heme without any red blood cell on microscopic analysis, which was not present in this case. AIN commonly manifests as acute kidney injury, pyuria, and proteinuria but without a decrease in complement levels.⁴ While the patient’s urine sediment included white blood cell (10/high-power field), the presence of microscopic hematuria, decreased complement levels, and proteinuria in the context of HCV positivity makes MPGN more likely than AIN.

Recently, there has been greater emphasis on using immunofluorescence for kidney biopsies. MPGN is now classified into 2 main categories: MPGN with mesangial immunoglobulins and C3 deposits in the capillary walls, and MPGN with C3 deposits but without Ig.⁵ MPGN with Ig-complement deposits is seen in autoimmune diseases and infections and is associated with dysproteinemias.

The renal biopsy in this patient was consistent with MPGN with immunofluorescence, a common finding in patients with infection. By synthesizing these data, we concluded that the patient represented a case of chronic HCV infection that led to MPGN with cryoglobulinemia. The normal C4 and negative RF do not suggest cryoglobulinemic crisis. Compensated cirrhosis was seen on imaging, pending liver biopsy.

Treatment

The management of MPGN secondary to HCV infection relies on the treatment of the underlying infection and clearance of viral load. Direct-acting antivirals have been used successfully in the treatment of HCV-associated MPGN. When cryoglobulinemia is present, immunosuppressive therapy is recommended. These regimens commonly include rituximab and steroids.⁵ Rituximab is also used for nephrotic syndrome associated with MPGN, as recommended in the 2018 Kidney Disease: Improving Global Outcomes guidelines.⁶

When initiating rituximab therapy in a patient who tests positive for hepatitis B (HBcAb positive or HBsAb positive), it is recommended to follow the established guidelines, which include treating them with entecavir for prophylaxis to prevent reactivation or a flare of hepatitis B.⁷ The patient in this case needed close follow-up in the nephrology and hepatology clinic. Immunosuppressive therapy was not pursued while the patient was admitted to the hospital due to instability with housing, transportation, and difficulty in ensuring close follow-up.

CONCLUSIONS

Clinicians should maintain a broad differential even in the face of confirmatory imaging and other objective findings. In the case of anasarca, nephrotic syndrome should be considered. Key causes of nephrotic syndromes include MPGN, membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis. MPGN is a histopathological diagnosis, and it is essential to identify if it is secondary to immune complexes or only complement mediated because Ig-complement deposits are seen in autoimmune disease and infection. The management of MPGN due to HCV infection relies on antiviral therapy. In the presence of cryoglobulinemia, immunosuppressive therapy is recommended.

Histology is the gold standard for cirrhosis diagnosis. However, a combination of clinical history, physical examination findings, and supportive laboratory and radiographic features is generally sufficient to make the diagnosis. Routine ultrasound and computed tomography (CT) imaging often identifies a nodular liver contour with sequelae of portal hypertension, including splenomegaly, varices, and ascites, which can suggest cirrhosis when supported by laboratory parameters and clinical features. As a result, the diagnosis is typically made clinically.¹ Many patients with compensated cirrhosis go undetected. The presence of a decompensation event (ascites, spontaneous bacterial peritonitis, variceal hemorrhage, or hepatic encephalopathy) often leads to index diagnosis when patients were previously compensated. When a patient presents with suspected decompensated cirrhosis, it is important to consider other diagnoses with similar presentations and ensure that multiple disease processes are not contributing to the symptoms.

CASE PRESENTATION

A 64-year-old male with a history of intravenous (IV) methamphetamine use and prior incarceration presented with a 3-week history of progressively worsening generalized swelling. Prior to the onset of his symptoms, the patient injured his right lower extremity (RLE) in a bicycle accident, resulting in edema that progressed to bilateral lower extremity (BLE) edema and worsening fatigue, despite resolution of the initial injury. The patient gained weight though he could not quantify the amount. He experienced progressive hunger, thirst, and fatigue as well as increased sleep. Additionally, the patient experienced worsening dyspnea on exertion and orthopnea. He started using 2 pillows instead of 1 pillow at night.

The patient reported no fevers, chills, sputum production, chest pain, or paroxysmal nocturnal dyspnea. He had no known history of sexually transmitted infections, no significant history of alcohol use, and occasional tobacco and marijuana use. He had been incarcerated > 10 years before and last used IV methamphetamine 3 years before. He did not regularly take any medications.

The patient’s vital signs included a temperature of 98.2 °F; 78/min heart rate; 15/min respiratory rate; 159/109 mm Hg blood pressure; and 98% oxygen saturation on room air. He had gained 20 lbs in the past 4 months. He had pitting edema in both legs and arms, as well as periorbital swelling, but no jugular venous distention, abnormal heart sounds, or murmurs. Breath sounds were distant but clear to auscultation. His abdomen was distended with normal bowel sounds and no fluid wave; mild epigastric tenderness was present, but no intra-abdominal masses were palpated. He had spider angiomata on the upper chest but no other stigmata of cirrhosis, such as caput medusae or jaundice. Tattoos were noted.

Laboratory test results showed a platelet count of 178 x 10³/μL (reference range, 140- 440 ~ 10³μL).Creatinine was 0.80 mg/dL (reference range, < 1.28 mg/dL), with an estimated glomerular filtration rate (eGFR) of 99 mL/min/1.73 m² using the Chronic Kidney Disease-Epidemiology equation (reference range, > 60 mL/min/1.73 m²), (reference range, > 60 mL/min/1.73 m²), and Cystatin C was 1.14 mg/L (reference range, < 1.15 mg/L). His electrolytes and complete blood count were within normal limits, including sodium, 134 mmol/L; potassium, 4.4 mmol/L; chloride, 108 mmol/L; and carbon dioxide, 22.5 mmol/L.

Additional test results included alkaline phosphatase, 126 U/L (reference range, < 94 U/L); alanine transaminase, 41 U/L (reference range, < 45 U/L); aspartate aminotransferase, 70 U/L (reference range, < 35 U/L); total bilirubin, 0.6 mg/dL (reference range, < 1 mg/dL); albumin, 1.8 g/dL (reference range, 3.2-4.8 g/dL); and total protein, 6.3 g/dL (reference range, 5.9-8.3 g/dL). The patient’s international normalized ratio was 0.96 (reference range, 0.8-1.1), and brain natriuretic peptide was normal at 56 pg/mL. No prior laboratory results were available for comparison.

Urine toxicology was positive for amphetamines. Urinalysis demonstrated large occult blood, with a red blood cell count of 26/ HPF (reference range, 0/HPF) and proteinuria (100 mg/dL; reference range, negative), without bacteria, nitrites, or leukocyte esterase. Urine white blood cell count was 10/ HPF (reference range, 0/HPF), and fine granular casts and hyaline casts were present.

A noncontrast CT of the abdomen and pelvis in the emergency department showed an irregular liver contour with diffuse nodularity, multiple portosystemic collaterals, moderate abdominal and pelvic ascites, small bilateral pleural effusions with associated atelectasis, and anasarca consistent with cirrhosis (Figure 1). The patient was admitted to the internal medicine service for workup and management of newly diagnosed cirrhosis.

Paracentesis revealed straw-colored fluid with an ascitic fluid neutrophil count of 17/μL, a protein level of < 3 g/dL and albumin level of < 1.5 g/dL. Gram stain of the ascitic fluid showed a moderate white blood cell count with no organisms. Fluid culture showed no microbial growth.

Initial workup for cirrhosis demonstrated a positive total hepatitis A antibody. The patient had a nonreactive hepatitis B surface antigen and surface antibody, but a reactive hepatitis B core antibody; a hepatitis B DNA level was not ordered. He had a reactive hepatitis C antibody with a viral load of 4,490,000 II/mL (genotype 1a). The patient’s iron level was 120 μg/dL, with a calculated total iron-binding capacity (TIBC) of 126.2 μg/dL. His transferrin saturation (TSAT) (serum iron divided by TIBC) was 95%. The patient had nonreactive antinuclear antibody and antimitochondrial antibody tests and a positive antismooth muscle antibody test with a titer of 1:40. His α-fetoprotein (AFP) level was 505 ng/mL (reference range, < 8 ng/mL).

Follow-up MRI of the abdomen and pelvis showed cirrhotic morphology with large volume ascites and portosystemic collaterals, consistent with portal hypertension. Additionally, it showed multiple scattered peripheral sub centimeter hyperenhancing foci, most likely representing benign lesions.

The patient's spot urine protein-creatinine ratio was 3.76. To better quantify proteinuria, a 24-hour urine collection was performed and revealed 12.8 g/d of urine protein (reference range, 0-0.17 g/d). His serum triglyceride level was 175 mg/dL (reference range, 40-60 mg/dL); total cholesterol was 177 mg/ dL (reference range, ≤ 200 mg/dL); low density lipoprotein cholesterol was 98 mg/ dL (reference range, ≤ 130 mg/dL); and highdensity lipoprotein cholesterol was 43.8 mg/ dL (reference range, ≥ 40 mg/dL); C3 complement level was 71 mg/dL (reference range, 82-185 mg/dL); and C4 complement level was 22 mg/dL (reference range, 15-53 mg/ dL). His rheumatoid factor was < 14 IU/mL. Tests for rapid plasma reagin and HIV antigen- antibody were nonreactive, and the phospholipase A2 receptor antibody test was negative. The patient tested positive for QuantiFERON-TB Gold and qualitative cryoglobulin, which indicated a cryocrit of 1%.

A renal biopsy was performed, revealing diffuse podocyte foot process effacement and glomerulonephritis with low-grade C3 and immunoglobulin (Ig) G deposits, consistent with early membranoproliferative glomerulonephritis (MPGN) (Figures 2 and 3).

The patient was initially diuresed with IV furosemide without significant urine output. He was then diuresed with IV 25% albumin (total, 25 g), followed by IV furosemide 40 mg twice daily, which led to significant urine output and resolution of his anasarca. Given the patient’s hypoalbuminemic state, IV albumin was necessary to deliver furosemide to the proximal tubule. He was started on lisinopril for renal protection and discharged with spironolactone and furosemide for fluid management in the context of cirrhosis.

The patient was evaluated by the Liver Nodule Clinic, which includes specialists from hepatology, medical oncology, radiation oncology, interventional radiology, and diagnostic radiology. The team considered the patient’s medical history and characteristics of the nodules on imaging. Notable aspects of the patient’s history included hepatitis C virus (HCV) infection and an elevated AFP level, although imaging showed no lesion concerning for malignancy. Given these findings, the patient was scheduled for a liver biopsy to establish a tissue diagnosis of cirrhosis. Hepatology, nephrology, and infectious disease specialists coordinated to plan the management and treatment of latent tuberculosis (TB), chronic HCV, MPGN, compensated cirrhosis, and suspicious liver lesions.

The patient chose to handle management and treatment as an outpatient. He was discharged with furosemide and spironolactone for anasarca management, and amlodipine and lisinopril for his hypertension and MPGN. Follow-up appointments were scheduled with infectious disease for management of latent TB and HCV, nephrology for MPGN, gastroenterology for cirrhosis, and interventional radiology for liver biopsy. Unfortunately, the patient was unhoused with limited access to transportation, which prevented timely follow-up. Given these social factors, immunosuppression was not started. Additionally, he did not start on HCV therapy because the viral load was still pending at time of discharge.

DISCUSSION

The diagnosis of decompensated cirrhosis was prematurely established, resulting in a diagnostic delay, a form of diagnostic error. However, on hospital day 2, the initial hypothesis of decompensated cirrhosis as the sole driver of the patient’s presentation was reconsidered due to the disconnect between the severity of hypoalbuminemia and diffuse edema (anasarca), and the absence of laboratory evidence of hepatic decompensation (normal international normalized ratio, bilirubin, and low but normal platelet count). Although image findings supported cirrhosis, laboratory markers did not indicate hepatic decompensation. The severity of hypoalbuminemia and anasarca, along with an indeterminate Serum-Ascites Albumin Gradient, prompted the patient’s care team to consider other causes, specifically, nephrotic syndrome.

The patien’s spot protein-to-creatinine ratio was 3.76 (reference range < 0.2 mg/mg creatinine), but a 24-hour urine protein collection was 12.8 g/day (reference range < 150 mg/day). While most spot urine protein- to-creatinine ratios (UPCR) correlate with a 24-hour urine collection, discrepancies can occur, as in this case. It is important to recognize that the spot UPCR assumes that patients are excreting 1000 mg of creatinine daily in their urine, which is not always the case. In addition, changes in urine osmolality can lead to different values. The gold standard for proteinuria is a 24-hour urine collection for protein and creatinine.

The patient’s nephrotic-range proteinuria and severe hypoalbuminemia are not solely explained by cirrhosis. In addition, the patient’s lower extremity edema pointed to nephrotic syndrome. The differential diagnosis for nephrotic syndrome includes both primary and secondary forms of membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, and MPGN, a histopathological diagnosis that requires distinguishing between immune complex-mediated and complement-mediated forms. Other causes of nephrotic syndrome that do not fit in any of these buckets include amyloidosis, IgA nephropathy, and diabetes mellitus (DM). Despite DM being a common cause of nephrotic range proteinuria, it rarely leads to full nephrotic syndrome.

When considering the diagnosis, we reframed the patient’s clinical syndrome as compensated cirrhosis plus nephrotic syndrome. This approach prioritized identifying a cause that could explain both cirrhosis (from any cause) leading to IgA nephropathy or injection drug use serving as a risk factor for cirrhosis and nephrotic syndrome through HCV or AA amyloidosis, respectively. This problem representation guided us to the correct diagnosis. There are multiple renal diseases associated with HCV infection, including MPGN, membranous nephropathy, focal segmental glomerulosclerosis, and IgA nephropathy.² MPGN and mixed cryoglobulinemia are the most common. In the past, MPGN was classified as type I, II, and III.

The patient’s urine toxicology revealed recent amphetamine use, which can also lead to acute kidney injury through rhabdomyolysis or acute interstitial nephritis (AIN).³ In the cases of rhabdomyolysis, urinalysis would show positive heme without any red blood cell on microscopic analysis, which was not present in this case. AIN commonly manifests as acute kidney injury, pyuria, and proteinuria but without a decrease in complement levels.⁴ While the patient’s urine sediment included white blood cell (10/high-power field), the presence of microscopic hematuria, decreased complement levels, and proteinuria in the context of HCV positivity makes MPGN more likely than AIN.

Recently, there has been greater emphasis on using immunofluorescence for kidney biopsies. MPGN is now classified into 2 main categories: MPGN with mesangial immunoglobulins and C3 deposits in the capillary walls, and MPGN with C3 deposits but without Ig.⁵ MPGN with Ig-complement deposits is seen in autoimmune diseases and infections and is associated with dysproteinemias.

The renal biopsy in this patient was consistent with MPGN with immunofluorescence, a common finding in patients with infection. By synthesizing these data, we concluded that the patient represented a case of chronic HCV infection that led to MPGN with cryoglobulinemia. The normal C4 and negative RF do not suggest cryoglobulinemic crisis. Compensated cirrhosis was seen on imaging, pending liver biopsy.

Treatment

The management of MPGN secondary to HCV infection relies on the treatment of the underlying infection and clearance of viral load. Direct-acting antivirals have been used successfully in the treatment of HCV-associated MPGN. When cryoglobulinemia is present, immunosuppressive therapy is recommended. These regimens commonly include rituximab and steroids.⁵ Rituximab is also used for nephrotic syndrome associated with MPGN, as recommended in the 2018 Kidney Disease: Improving Global Outcomes guidelines.⁶

When initiating rituximab therapy in a patient who tests positive for hepatitis B (HBcAb positive or HBsAb positive), it is recommended to follow the established guidelines, which include treating them with entecavir for prophylaxis to prevent reactivation or a flare of hepatitis B.⁷ The patient in this case needed close follow-up in the nephrology and hepatology clinic. Immunosuppressive therapy was not pursued while the patient was admitted to the hospital due to instability with housing, transportation, and difficulty in ensuring close follow-up.

CONCLUSIONS

Clinicians should maintain a broad differential even in the face of confirmatory imaging and other objective findings. In the case of anasarca, nephrotic syndrome should be considered. Key causes of nephrotic syndromes include MPGN, membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis. MPGN is a histopathological diagnosis, and it is essential to identify if it is secondary to immune complexes or only complement mediated because Ig-complement deposits are seen in autoimmune disease and infection. The management of MPGN due to HCV infection relies on antiviral therapy. In the presence of cryoglobulinemia, immunosuppressive therapy is recommended.

Histology is the gold standard for cirrhosis diagnosis. However, a combination of clinical history, physical examination findings, and supportive laboratory and radiographic features is generally sufficient to make the diagnosis. Routine ultrasound and computed tomography (CT) imaging often identifies a nodular liver contour with sequelae of portal hypertension, including splenomegaly, varices, and ascites, which can suggest cirrhosis when supported by laboratory parameters and clinical features. As a result, the diagnosis is typically made clinically.¹ Many patients with compensated cirrhosis go undetected. The presence of a decompensation event (ascites, spontaneous bacterial peritonitis, variceal hemorrhage, or hepatic encephalopathy) often leads to index diagnosis when patients were previously compensated. When a patient presents with suspected decompensated cirrhosis, it is important to consider other diagnoses with similar presentations and ensure that multiple disease processes are not contributing to the symptoms.

CASE PRESENTATION

A 64-year-old male with a history of intravenous (IV) methamphetamine use and prior incarceration presented with a 3-week history of progressively worsening generalized swelling. Prior to the onset of his symptoms, the patient injured his right lower extremity (RLE) in a bicycle accident, resulting in edema that progressed to bilateral lower extremity (BLE) edema and worsening fatigue, despite resolution of the initial injury. The patient gained weight though he could not quantify the amount. He experienced progressive hunger, thirst, and fatigue as well as increased sleep. Additionally, the patient experienced worsening dyspnea on exertion and orthopnea. He started using 2 pillows instead of 1 pillow at night.

The patient reported no fevers, chills, sputum production, chest pain, or paroxysmal nocturnal dyspnea. He had no known history of sexually transmitted infections, no significant history of alcohol use, and occasional tobacco and marijuana use. He had been incarcerated > 10 years before and last used IV methamphetamine 3 years before. He did not regularly take any medications.

The patient’s vital signs included a temperature of 98.2 °F; 78/min heart rate; 15/min respiratory rate; 159/109 mm Hg blood pressure; and 98% oxygen saturation on room air. He had gained 20 lbs in the past 4 months. He had pitting edema in both legs and arms, as well as periorbital swelling, but no jugular venous distention, abnormal heart sounds, or murmurs. Breath sounds were distant but clear to auscultation. His abdomen was distended with normal bowel sounds and no fluid wave; mild epigastric tenderness was present, but no intra-abdominal masses were palpated. He had spider angiomata on the upper chest but no other stigmata of cirrhosis, such as caput medusae or jaundice. Tattoos were noted.

Laboratory test results showed a platelet count of 178 x 10³/μL (reference range, 140- 440 ~ 10³μL).Creatinine was 0.80 mg/dL (reference range, < 1.28 mg/dL), with an estimated glomerular filtration rate (eGFR) of 99 mL/min/1.73 m² using the Chronic Kidney Disease-Epidemiology equation (reference range, > 60 mL/min/1.73 m²), (reference range, > 60 mL/min/1.73 m²), and Cystatin C was 1.14 mg/L (reference range, < 1.15 mg/L). His electrolytes and complete blood count were within normal limits, including sodium, 134 mmol/L; potassium, 4.4 mmol/L; chloride, 108 mmol/L; and carbon dioxide, 22.5 mmol/L.

Additional test results included alkaline phosphatase, 126 U/L (reference range, < 94 U/L); alanine transaminase, 41 U/L (reference range, < 45 U/L); aspartate aminotransferase, 70 U/L (reference range, < 35 U/L); total bilirubin, 0.6 mg/dL (reference range, < 1 mg/dL); albumin, 1.8 g/dL (reference range, 3.2-4.8 g/dL); and total protein, 6.3 g/dL (reference range, 5.9-8.3 g/dL). The patient’s international normalized ratio was 0.96 (reference range, 0.8-1.1), and brain natriuretic peptide was normal at 56 pg/mL. No prior laboratory results were available for comparison.

Urine toxicology was positive for amphetamines. Urinalysis demonstrated large occult blood, with a red blood cell count of 26/ HPF (reference range, 0/HPF) and proteinuria (100 mg/dL; reference range, negative), without bacteria, nitrites, or leukocyte esterase. Urine white blood cell count was 10/ HPF (reference range, 0/HPF), and fine granular casts and hyaline casts were present.

A noncontrast CT of the abdomen and pelvis in the emergency department showed an irregular liver contour with diffuse nodularity, multiple portosystemic collaterals, moderate abdominal and pelvic ascites, small bilateral pleural effusions with associated atelectasis, and anasarca consistent with cirrhosis (Figure 1). The patient was admitted to the internal medicine service for workup and management of newly diagnosed cirrhosis.

Paracentesis revealed straw-colored fluid with an ascitic fluid neutrophil count of 17/μL, a protein level of < 3 g/dL and albumin level of < 1.5 g/dL. Gram stain of the ascitic fluid showed a moderate white blood cell count with no organisms. Fluid culture showed no microbial growth.

Initial workup for cirrhosis demonstrated a positive total hepatitis A antibody. The patient had a nonreactive hepatitis B surface antigen and surface antibody, but a reactive hepatitis B core antibody; a hepatitis B DNA level was not ordered. He had a reactive hepatitis C antibody with a viral load of 4,490,000 II/mL (genotype 1a). The patient’s iron level was 120 μg/dL, with a calculated total iron-binding capacity (TIBC) of 126.2 μg/dL. His transferrin saturation (TSAT) (serum iron divided by TIBC) was 95%. The patient had nonreactive antinuclear antibody and antimitochondrial antibody tests and a positive antismooth muscle antibody test with a titer of 1:40. His α-fetoprotein (AFP) level was 505 ng/mL (reference range, < 8 ng/mL).

Follow-up MRI of the abdomen and pelvis showed cirrhotic morphology with large volume ascites and portosystemic collaterals, consistent with portal hypertension. Additionally, it showed multiple scattered peripheral sub centimeter hyperenhancing foci, most likely representing benign lesions.

The patient's spot urine protein-creatinine ratio was 3.76. To better quantify proteinuria, a 24-hour urine collection was performed and revealed 12.8 g/d of urine protein (reference range, 0-0.17 g/d). His serum triglyceride level was 175 mg/dL (reference range, 40-60 mg/dL); total cholesterol was 177 mg/ dL (reference range, ≤ 200 mg/dL); low density lipoprotein cholesterol was 98 mg/ dL (reference range, ≤ 130 mg/dL); and highdensity lipoprotein cholesterol was 43.8 mg/ dL (reference range, ≥ 40 mg/dL); C3 complement level was 71 mg/dL (reference range, 82-185 mg/dL); and C4 complement level was 22 mg/dL (reference range, 15-53 mg/ dL). His rheumatoid factor was < 14 IU/mL. Tests for rapid plasma reagin and HIV antigen- antibody were nonreactive, and the phospholipase A2 receptor antibody test was negative. The patient tested positive for QuantiFERON-TB Gold and qualitative cryoglobulin, which indicated a cryocrit of 1%.

A renal biopsy was performed, revealing diffuse podocyte foot process effacement and glomerulonephritis with low-grade C3 and immunoglobulin (Ig) G deposits, consistent with early membranoproliferative glomerulonephritis (MPGN) (Figures 2 and 3).

The patient was initially diuresed with IV furosemide without significant urine output. He was then diuresed with IV 25% albumin (total, 25 g), followed by IV furosemide 40 mg twice daily, which led to significant urine output and resolution of his anasarca. Given the patient’s hypoalbuminemic state, IV albumin was necessary to deliver furosemide to the proximal tubule. He was started on lisinopril for renal protection and discharged with spironolactone and furosemide for fluid management in the context of cirrhosis.

The patient was evaluated by the Liver Nodule Clinic, which includes specialists from hepatology, medical oncology, radiation oncology, interventional radiology, and diagnostic radiology. The team considered the patient’s medical history and characteristics of the nodules on imaging. Notable aspects of the patient’s history included hepatitis C virus (HCV) infection and an elevated AFP level, although imaging showed no lesion concerning for malignancy. Given these findings, the patient was scheduled for a liver biopsy to establish a tissue diagnosis of cirrhosis. Hepatology, nephrology, and infectious disease specialists coordinated to plan the management and treatment of latent tuberculosis (TB), chronic HCV, MPGN, compensated cirrhosis, and suspicious liver lesions.

The patient chose to handle management and treatment as an outpatient. He was discharged with furosemide and spironolactone for anasarca management, and amlodipine and lisinopril for his hypertension and MPGN. Follow-up appointments were scheduled with infectious disease for management of latent TB and HCV, nephrology for MPGN, gastroenterology for cirrhosis, and interventional radiology for liver biopsy. Unfortunately, the patient was unhoused with limited access to transportation, which prevented timely follow-up. Given these social factors, immunosuppression was not started. Additionally, he did not start on HCV therapy because the viral load was still pending at time of discharge.

DISCUSSION

The diagnosis of decompensated cirrhosis was prematurely established, resulting in a diagnostic delay, a form of diagnostic error. However, on hospital day 2, the initial hypothesis of decompensated cirrhosis as the sole driver of the patient’s presentation was reconsidered due to the disconnect between the severity of hypoalbuminemia and diffuse edema (anasarca), and the absence of laboratory evidence of hepatic decompensation (normal international normalized ratio, bilirubin, and low but normal platelet count). Although image findings supported cirrhosis, laboratory markers did not indicate hepatic decompensation. The severity of hypoalbuminemia and anasarca, along with an indeterminate Serum-Ascites Albumin Gradient, prompted the patient’s care team to consider other causes, specifically, nephrotic syndrome.

The patien’s spot protein-to-creatinine ratio was 3.76 (reference range < 0.2 mg/mg creatinine), but a 24-hour urine protein collection was 12.8 g/day (reference range < 150 mg/day). While most spot urine protein- to-creatinine ratios (UPCR) correlate with a 24-hour urine collection, discrepancies can occur, as in this case. It is important to recognize that the spot UPCR assumes that patients are excreting 1000 mg of creatinine daily in their urine, which is not always the case. In addition, changes in urine osmolality can lead to different values. The gold standard for proteinuria is a 24-hour urine collection for protein and creatinine.

The patient’s nephrotic-range proteinuria and severe hypoalbuminemia are not solely explained by cirrhosis. In addition, the patient’s lower extremity edema pointed to nephrotic syndrome. The differential diagnosis for nephrotic syndrome includes both primary and secondary forms of membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, and MPGN, a histopathological diagnosis that requires distinguishing between immune complex-mediated and complement-mediated forms. Other causes of nephrotic syndrome that do not fit in any of these buckets include amyloidosis, IgA nephropathy, and diabetes mellitus (DM). Despite DM being a common cause of nephrotic range proteinuria, it rarely leads to full nephrotic syndrome.

When considering the diagnosis, we reframed the patient’s clinical syndrome as compensated cirrhosis plus nephrotic syndrome. This approach prioritized identifying a cause that could explain both cirrhosis (from any cause) leading to IgA nephropathy or injection drug use serving as a risk factor for cirrhosis and nephrotic syndrome through HCV or AA amyloidosis, respectively. This problem representation guided us to the correct diagnosis. There are multiple renal diseases associated with HCV infection, including MPGN, membranous nephropathy, focal segmental glomerulosclerosis, and IgA nephropathy.² MPGN and mixed cryoglobulinemia are the most common. In the past, MPGN was classified as type I, II, and III.

The patient’s urine toxicology revealed recent amphetamine use, which can also lead to acute kidney injury through rhabdomyolysis or acute interstitial nephritis (AIN).³ In the cases of rhabdomyolysis, urinalysis would show positive heme without any red blood cell on microscopic analysis, which was not present in this case. AIN commonly manifests as acute kidney injury, pyuria, and proteinuria but without a decrease in complement levels.⁴ While the patient’s urine sediment included white blood cell (10/high-power field), the presence of microscopic hematuria, decreased complement levels, and proteinuria in the context of HCV positivity makes MPGN more likely than AIN.

Recently, there has been greater emphasis on using immunofluorescence for kidney biopsies. MPGN is now classified into 2 main categories: MPGN with mesangial immunoglobulins and C3 deposits in the capillary walls, and MPGN with C3 deposits but without Ig.⁵ MPGN with Ig-complement deposits is seen in autoimmune diseases and infections and is associated with dysproteinemias.

The renal biopsy in this patient was consistent with MPGN with immunofluorescence, a common finding in patients with infection. By synthesizing these data, we concluded that the patient represented a case of chronic HCV infection that led to MPGN with cryoglobulinemia. The normal C4 and negative RF do not suggest cryoglobulinemic crisis. Compensated cirrhosis was seen on imaging, pending liver biopsy.

Treatment

The management of MPGN secondary to HCV infection relies on the treatment of the underlying infection and clearance of viral load. Direct-acting antivirals have been used successfully in the treatment of HCV-associated MPGN. When cryoglobulinemia is present, immunosuppressive therapy is recommended. These regimens commonly include rituximab and steroids.⁵ Rituximab is also used for nephrotic syndrome associated with MPGN, as recommended in the 2018 Kidney Disease: Improving Global Outcomes guidelines.⁶

When initiating rituximab therapy in a patient who tests positive for hepatitis B (HBcAb positive or HBsAb positive), it is recommended to follow the established guidelines, which include treating them with entecavir for prophylaxis to prevent reactivation or a flare of hepatitis B.⁷ The patient in this case needed close follow-up in the nephrology and hepatology clinic. Immunosuppressive therapy was not pursued while the patient was admitted to the hospital due to instability with housing, transportation, and difficulty in ensuring close follow-up.

CONCLUSIONS

Clinicians should maintain a broad differential even in the face of confirmatory imaging and other objective findings. In the case of anasarca, nephrotic syndrome should be considered. Key causes of nephrotic syndromes include MPGN, membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis. MPGN is a histopathological diagnosis, and it is essential to identify if it is secondary to immune complexes or only complement mediated because Ig-complement deposits are seen in autoimmune disease and infection. The management of MPGN due to HCV infection relies on antiviral therapy. In the presence of cryoglobulinemia, immunosuppressive therapy is recommended.

Primary care practitioners (PCPs) in the US Department of Veterans Affairs (VA) provide care for patients with higher rates of many diseases—diabetes, heart disease, cancer, chronic obstructive pulmonary disease (COPD), and stroke—compared to the nonveteran population. ¹ Due to the medical complexities of these diseases, they are often misdiagnosed or not diagnosed at all.

COPD is hiding in plain sight, impacting quality of life and burdening US health care systems.² Research has yielded new treatments and evidence-based guidelines; however, COPD remains underdiagnosed. Only 13 million of the estimated 79 million US adults with COPD aged 20 to 79 years have been formally diagnosed.³ By the time patients are diagnosed, the disease is often advanced, and therapies are less effective. In 2 large studies of patients with COPD symptoms, later diagnosis was associated with worse outcomes.^4,5

Veterans have a higher prevalence of COPD (8%-19%) than nonveterans (6%), likely due to higher rates of smoking and service-related exposures, especially among veterans of post-9/11 conflicts.^6,7 Veterans do not always report symptoms and PCPs may not ask about symptoms, leading to underdiagnosis.⁸ The combination of high likelihood and underdetection of COPD presents a challenge and a target for VA quality improvement (QI).

The US Preventive Services Task Force (USPSTF) recommends against screening asymptomatic patients for COPD. However, both the USPSTF and the Global Initiative for Chronic Obstructive Lung Disease Report advocate for active case finding in primary care clinics to determine whether high-risk patients, such as smokers, experience COPD symptoms and warrant spirometry. ^9,10 To make early COPD diagnoses, clinicians may use questionnaires alone or in combination with handheld peak expiratory flow rate measurements.^11,12 Formal spirometry, considered the gold standard for COPD diagnosis, is ordered for patients who report COPD symptoms (ie, shortness of breath with exertion) or who have both COPD symptoms and reduced peak flow rates.

A systematic review and meta-analysis found that while the combination of questionnaires and peak flows was the more effective strategy overall, questionnaires alone were also valuable for identifying patients with possible COPD.¹³ Implementation of either screening method in primary care practices would be challenging. In a simulation study that applied chronic disease and preventive care guidelines to hypothetical patient panels, the time required for PCPs to provide guideline-recommended chronic and preventive care in addition to acute care far exceeded 8 hours per day, even in team-based settings.¹⁴ Overburdened PCPs are therefore unlikely to accept additional tasks like COPD case finding.

Why don’t patients report their pulmonary symptoms? Patients may not recognize the symptoms as evidence of COPD. Others may be afraid of a COPD diagnosis or the stigma that is associated with it.¹⁵ Perhaps they believe COPD treatment is ineffective because of lung damage from smoking. Some patients may not want to know if they have COPD, while others reduce activity levels to avoid symptoms.¹⁶

QUALITY IMPROVEMENT PROJECT

Given the high prevalence of COPD among veterans and the potential for underdiagnosis, VA Northeast Ohio Healthcare System (VANEOHS) internal medicine residents and faculty assessed the state of COPD diagnosis in its primary care clinic with a QI project in 2022. Patients in the clinic between August 1, 2015, and November 30, 2022, with an International Classification of Diseases-10 (ICD-10) COPD diagnosis code (J44) in the electronic health record were included. Of 157 included patients, 105 patients who had prior spirometry testing were excluded. Of the 52 patients with diagnosed COPD and no spirometry testing, 30 patients had computed tomography (CT) findings consistent with COPD (ie, airway thickening, emphysema, air trapping) that was performed for CT lung cancer screening (LCS).¹⁷ Twenty-three of these 30 patients were contacted by phone. All 23 were ever smokers and 13 reported COPD symptoms. The PCPs of the symptomatic patients were then contacted. Spirometry was ordered for all 13 patients and completed by 7. Three spirometry tests confirmed the COPD diagnosis. One PCP initiated inhaler therapy for a patient with newly diagnosed COPD.

All 11 PCPs of symptomatic patients were interviewed (many had > 1 symptomatic patient). They reported being unaware of patients’ COPD symptoms because the patients did not mention them, noting that screening for COPD was not a priority.

Role of Lung Cancer Screening

VA PCPs use electronic health record clinical reminders to track tests, consults, chronic disease education, cancer screenings, and routine health maintenance. A clinical reminder already exists (based on USPSTF recommendations) for LCS for patients aged 50 to 80 years who have a smoking history of 20 pack years. Patients who meet these criteria would also be considered high risk for COPD.

The VANEOHS QI project suggests that previously undiagnosed patients with findings of COPD on LCS may also have symptoms of COPD. Therefore, we wondered whether the LCS clinical reminder could serve a second purpose by prompting PCPs to ask veterans who meet LCS criteria about their COPD symptoms.

In 2022, about 13 million patients were eligible for LCS.¹⁸ Patients who qualify for LCS are at high risk for other cardiopulmonary disorders, such as COPD and coronary artery disease. Lung cancer is detected in only 1% of patients screened with CT at baseline. However, more often LCS yields evidence of additional cardiopulmonary disorders, such as emphysema or coronary artery calcifications. The International Early Lung Cancer Program (I-ELCAP) and the National Lung Cancer Screening Trial (NLST), which included > 79,000 patients, found evidence of emphysema on CT imaging in 24% and 31% of cases, respectively.^19,20 In both cohorts, > 80% of patients with emphysema on CT imaging had no prior history of COPD.

In a 2022 article summarizing the potential impact of CT LCS on COPD diagnosis, Mulshine et al suggest that detection of emphysema on CT LCS provides “earlier recognition for PCPs to identify patients who would benefit from detailed symptom screening to prompt spirometry for COPD detection” and additional motivation for tobacco cessation.²¹ The VANEOHS QI project was developed and implemented prior to I-ELCAP or NLST reporting results but reinforces the value of CT LCS for COPD diagnosis.

Early diagnosis of COPD remains challenging because PCPs do not ask, patients do not tell, and symptoms can easily be dismissed. However, earlier diagnosis of COPD in symptomatic patients improves outcomes.^3,4 To bridge this gap, VA PCPs and primary care patient aligned care teams (PACTs) need to commit to probing high-risk patients for COPD symptoms and ordering spirometry for those who are symptomatic. To accomplish this task, primary care teams need help.

The VANEOHS QI project confirmed that some patients with evidence of COPD on CT have symptoms of COPD that they did not share with their PCPs and suggests that LCS can be used as a dual action case finding method to screen both for lung cancer and COPD. We propose that patients who are eligible for LCS should also be probed for COPD symptoms at their clinic visits; for symptomatic patients, spirometry should be ordered, and COPD evidence-based management should be initiated when spirometry results are consistent with COPD. Annual probing for COPD symptoms could be considered in asymptomatic patients with ongoing tobacco use or emphysema on CT, since they may develop symptoms in the future. This new case-finding method bypasses the need for time-prohibitive questionnaires or peak flow measurements.

Future Opportunities

VA PCPs juggle many priorities and despite the simplicity of this new case finding COPD method, it may be unintentionally overlooked. PCPs often run out of time or may forget to ask patients about COPD symptoms when ordering LCS.

Future innovations to increase COPD diagnosis could include the creation of a yearly VA clinical reminder linked to the tobacco use reminder that has check boxes asking about symptoms of COPD in current and prior smokers. If patients have COPD symptoms, the reminder can prompt the ordering of spirometry. Similar reminders could be implemented to identify veterans with exposures to burn pits or other military environmental exposures who may have COPD symptoms. Another possible way to increase COPD diagnosis would be a partnership between primary care and the VA LCS program where patients receiving screening are asked about COPD symptoms during their LCS interviews and PACTs are alerted to order spirometry for symptomatic patients.

Elusive no longer! We can pull the veil back on COPD diagnosis and identify patients with possible COPD earlier in their course using their eligibility for LCS as a yearly reminder to probe them for symptoms. While not all patients who undergo LCS—even those with evidence of COPD on CT—will have COPD symptoms, symptoms may develop over time. LCS provides the possibility of 2 diagnoses from 1 test. This is an opportunity we cannot afford to miss.

Primary care practitioners (PCPs) in the US Department of Veterans Affairs (VA) provide care for patients with higher rates of many diseases—diabetes, heart disease, cancer, chronic obstructive pulmonary disease (COPD), and stroke—compared to the nonveteran population. ¹ Due to the medical complexities of these diseases, they are often misdiagnosed or not diagnosed at all.

COPD is hiding in plain sight, impacting quality of life and burdening US health care systems.² Research has yielded new treatments and evidence-based guidelines; however, COPD remains underdiagnosed. Only 13 million of the estimated 79 million US adults with COPD aged 20 to 79 years have been formally diagnosed.³ By the time patients are diagnosed, the disease is often advanced, and therapies are less effective. In 2 large studies of patients with COPD symptoms, later diagnosis was associated with worse outcomes.^4,5

Veterans have a higher prevalence of COPD (8%-19%) than nonveterans (6%), likely due to higher rates of smoking and service-related exposures, especially among veterans of post-9/11 conflicts.^6,7 Veterans do not always report symptoms and PCPs may not ask about symptoms, leading to underdiagnosis.⁸ The combination of high likelihood and underdetection of COPD presents a challenge and a target for VA quality improvement (QI).

The US Preventive Services Task Force (USPSTF) recommends against screening asymptomatic patients for COPD. However, both the USPSTF and the Global Initiative for Chronic Obstructive Lung Disease Report advocate for active case finding in primary care clinics to determine whether high-risk patients, such as smokers, experience COPD symptoms and warrant spirometry. ^9,10 To make early COPD diagnoses, clinicians may use questionnaires alone or in combination with handheld peak expiratory flow rate measurements.^11,12 Formal spirometry, considered the gold standard for COPD diagnosis, is ordered for patients who report COPD symptoms (ie, shortness of breath with exertion) or who have both COPD symptoms and reduced peak flow rates.

A systematic review and meta-analysis found that while the combination of questionnaires and peak flows was the more effective strategy overall, questionnaires alone were also valuable for identifying patients with possible COPD.¹³ Implementation of either screening method in primary care practices would be challenging. In a simulation study that applied chronic disease and preventive care guidelines to hypothetical patient panels, the time required for PCPs to provide guideline-recommended chronic and preventive care in addition to acute care far exceeded 8 hours per day, even in team-based settings.¹⁴ Overburdened PCPs are therefore unlikely to accept additional tasks like COPD case finding.

Why don’t patients report their pulmonary symptoms? Patients may not recognize the symptoms as evidence of COPD. Others may be afraid of a COPD diagnosis or the stigma that is associated with it.¹⁵ Perhaps they believe COPD treatment is ineffective because of lung damage from smoking. Some patients may not want to know if they have COPD, while others reduce activity levels to avoid symptoms.¹⁶

QUALITY IMPROVEMENT PROJECT

Given the high prevalence of COPD among veterans and the potential for underdiagnosis, VA Northeast Ohio Healthcare System (VANEOHS) internal medicine residents and faculty assessed the state of COPD diagnosis in its primary care clinic with a QI project in 2022. Patients in the clinic between August 1, 2015, and November 30, 2022, with an International Classification of Diseases-10 (ICD-10) COPD diagnosis code (J44) in the electronic health record were included. Of 157 included patients, 105 patients who had prior spirometry testing were excluded. Of the 52 patients with diagnosed COPD and no spirometry testing, 30 patients had computed tomography (CT) findings consistent with COPD (ie, airway thickening, emphysema, air trapping) that was performed for CT lung cancer screening (LCS).¹⁷ Twenty-three of these 30 patients were contacted by phone. All 23 were ever smokers and 13 reported COPD symptoms. The PCPs of the symptomatic patients were then contacted. Spirometry was ordered for all 13 patients and completed by 7. Three spirometry tests confirmed the COPD diagnosis. One PCP initiated inhaler therapy for a patient with newly diagnosed COPD.

All 11 PCPs of symptomatic patients were interviewed (many had > 1 symptomatic patient). They reported being unaware of patients’ COPD symptoms because the patients did not mention them, noting that screening for COPD was not a priority.

Role of Lung Cancer Screening

VA PCPs use electronic health record clinical reminders to track tests, consults, chronic disease education, cancer screenings, and routine health maintenance. A clinical reminder already exists (based on USPSTF recommendations) for LCS for patients aged 50 to 80 years who have a smoking history of 20 pack years. Patients who meet these criteria would also be considered high risk for COPD.

The VANEOHS QI project suggests that previously undiagnosed patients with findings of COPD on LCS may also have symptoms of COPD. Therefore, we wondered whether the LCS clinical reminder could serve a second purpose by prompting PCPs to ask veterans who meet LCS criteria about their COPD symptoms.

In 2022, about 13 million patients were eligible for LCS.¹⁸ Patients who qualify for LCS are at high risk for other cardiopulmonary disorders, such as COPD and coronary artery disease. Lung cancer is detected in only 1% of patients screened with CT at baseline. However, more often LCS yields evidence of additional cardiopulmonary disorders, such as emphysema or coronary artery calcifications. The International Early Lung Cancer Program (I-ELCAP) and the National Lung Cancer Screening Trial (NLST), which included > 79,000 patients, found evidence of emphysema on CT imaging in 24% and 31% of cases, respectively.^19,20 In both cohorts, > 80% of patients with emphysema on CT imaging had no prior history of COPD.

In a 2022 article summarizing the potential impact of CT LCS on COPD diagnosis, Mulshine et al suggest that detection of emphysema on CT LCS provides “earlier recognition for PCPs to identify patients who would benefit from detailed symptom screening to prompt spirometry for COPD detection” and additional motivation for tobacco cessation.²¹ The VANEOHS QI project was developed and implemented prior to I-ELCAP or NLST reporting results but reinforces the value of CT LCS for COPD diagnosis.

Early diagnosis of COPD remains challenging because PCPs do not ask, patients do not tell, and symptoms can easily be dismissed. However, earlier diagnosis of COPD in symptomatic patients improves outcomes.^3,4 To bridge this gap, VA PCPs and primary care patient aligned care teams (PACTs) need to commit to probing high-risk patients for COPD symptoms and ordering spirometry for those who are symptomatic. To accomplish this task, primary care teams need help.

The VANEOHS QI project confirmed that some patients with evidence of COPD on CT have symptoms of COPD that they did not share with their PCPs and suggests that LCS can be used as a dual action case finding method to screen both for lung cancer and COPD. We propose that patients who are eligible for LCS should also be probed for COPD symptoms at their clinic visits; for symptomatic patients, spirometry should be ordered, and COPD evidence-based management should be initiated when spirometry results are consistent with COPD. Annual probing for COPD symptoms could be considered in asymptomatic patients with ongoing tobacco use or emphysema on CT, since they may develop symptoms in the future. This new case-finding method bypasses the need for time-prohibitive questionnaires or peak flow measurements.

Future Opportunities

VA PCPs juggle many priorities and despite the simplicity of this new case finding COPD method, it may be unintentionally overlooked. PCPs often run out of time or may forget to ask patients about COPD symptoms when ordering LCS.

Future innovations to increase COPD diagnosis could include the creation of a yearly VA clinical reminder linked to the tobacco use reminder that has check boxes asking about symptoms of COPD in current and prior smokers. If patients have COPD symptoms, the reminder can prompt the ordering of spirometry. Similar reminders could be implemented to identify veterans with exposures to burn pits or other military environmental exposures who may have COPD symptoms. Another possible way to increase COPD diagnosis would be a partnership between primary care and the VA LCS program where patients receiving screening are asked about COPD symptoms during their LCS interviews and PACTs are alerted to order spirometry for symptomatic patients.

Elusive no longer! We can pull the veil back on COPD diagnosis and identify patients with possible COPD earlier in their course using their eligibility for LCS as a yearly reminder to probe them for symptoms. While not all patients who undergo LCS—even those with evidence of COPD on CT—will have COPD symptoms, symptoms may develop over time. LCS provides the possibility of 2 diagnoses from 1 test. This is an opportunity we cannot afford to miss.

Primary care practitioners (PCPs) in the US Department of Veterans Affairs (VA) provide care for patients with higher rates of many diseases—diabetes, heart disease, cancer, chronic obstructive pulmonary disease (COPD), and stroke—compared to the nonveteran population. ¹ Due to the medical complexities of these diseases, they are often misdiagnosed or not diagnosed at all.

COPD is hiding in plain sight, impacting quality of life and burdening US health care systems.² Research has yielded new treatments and evidence-based guidelines; however, COPD remains underdiagnosed. Only 13 million of the estimated 79 million US adults with COPD aged 20 to 79 years have been formally diagnosed.³ By the time patients are diagnosed, the disease is often advanced, and therapies are less effective. In 2 large studies of patients with COPD symptoms, later diagnosis was associated with worse outcomes.^4,5

Veterans have a higher prevalence of COPD (8%-19%) than nonveterans (6%), likely due to higher rates of smoking and service-related exposures, especially among veterans of post-9/11 conflicts.^6,7 Veterans do not always report symptoms and PCPs may not ask about symptoms, leading to underdiagnosis.⁸ The combination of high likelihood and underdetection of COPD presents a challenge and a target for VA quality improvement (QI).

The US Preventive Services Task Force (USPSTF) recommends against screening asymptomatic patients for COPD. However, both the USPSTF and the Global Initiative for Chronic Obstructive Lung Disease Report advocate for active case finding in primary care clinics to determine whether high-risk patients, such as smokers, experience COPD symptoms and warrant spirometry. ^9,10 To make early COPD diagnoses, clinicians may use questionnaires alone or in combination with handheld peak expiratory flow rate measurements.^11,12 Formal spirometry, considered the gold standard for COPD diagnosis, is ordered for patients who report COPD symptoms (ie, shortness of breath with exertion) or who have both COPD symptoms and reduced peak flow rates.

A systematic review and meta-analysis found that while the combination of questionnaires and peak flows was the more effective strategy overall, questionnaires alone were also valuable for identifying patients with possible COPD.¹³ Implementation of either screening method in primary care practices would be challenging. In a simulation study that applied chronic disease and preventive care guidelines to hypothetical patient panels, the time required for PCPs to provide guideline-recommended chronic and preventive care in addition to acute care far exceeded 8 hours per day, even in team-based settings.¹⁴ Overburdened PCPs are therefore unlikely to accept additional tasks like COPD case finding.

Why don’t patients report their pulmonary symptoms? Patients may not recognize the symptoms as evidence of COPD. Others may be afraid of a COPD diagnosis or the stigma that is associated with it.¹⁵ Perhaps they believe COPD treatment is ineffective because of lung damage from smoking. Some patients may not want to know if they have COPD, while others reduce activity levels to avoid symptoms.¹⁶

QUALITY IMPROVEMENT PROJECT

Given the high prevalence of COPD among veterans and the potential for underdiagnosis, VA Northeast Ohio Healthcare System (VANEOHS) internal medicine residents and faculty assessed the state of COPD diagnosis in its primary care clinic with a QI project in 2022. Patients in the clinic between August 1, 2015, and November 30, 2022, with an International Classification of Diseases-10 (ICD-10) COPD diagnosis code (J44) in the electronic health record were included. Of 157 included patients, 105 patients who had prior spirometry testing were excluded. Of the 52 patients with diagnosed COPD and no spirometry testing, 30 patients had computed tomography (CT) findings consistent with COPD (ie, airway thickening, emphysema, air trapping) that was performed for CT lung cancer screening (LCS).¹⁷ Twenty-three of these 30 patients were contacted by phone. All 23 were ever smokers and 13 reported COPD symptoms. The PCPs of the symptomatic patients were then contacted. Spirometry was ordered for all 13 patients and completed by 7. Three spirometry tests confirmed the COPD diagnosis. One PCP initiated inhaler therapy for a patient with newly diagnosed COPD.

All 11 PCPs of symptomatic patients were interviewed (many had > 1 symptomatic patient). They reported being unaware of patients’ COPD symptoms because the patients did not mention them, noting that screening for COPD was not a priority.

Role of Lung Cancer Screening

VA PCPs use electronic health record clinical reminders to track tests, consults, chronic disease education, cancer screenings, and routine health maintenance. A clinical reminder already exists (based on USPSTF recommendations) for LCS for patients aged 50 to 80 years who have a smoking history of 20 pack years. Patients who meet these criteria would also be considered high risk for COPD.

The VANEOHS QI project suggests that previously undiagnosed patients with findings of COPD on LCS may also have symptoms of COPD. Therefore, we wondered whether the LCS clinical reminder could serve a second purpose by prompting PCPs to ask veterans who meet LCS criteria about their COPD symptoms.

In 2022, about 13 million patients were eligible for LCS.¹⁸ Patients who qualify for LCS are at high risk for other cardiopulmonary disorders, such as COPD and coronary artery disease. Lung cancer is detected in only 1% of patients screened with CT at baseline. However, more often LCS yields evidence of additional cardiopulmonary disorders, such as emphysema or coronary artery calcifications. The International Early Lung Cancer Program (I-ELCAP) and the National Lung Cancer Screening Trial (NLST), which included > 79,000 patients, found evidence of emphysema on CT imaging in 24% and 31% of cases, respectively.^19,20 In both cohorts, > 80% of patients with emphysema on CT imaging had no prior history of COPD.

In a 2022 article summarizing the potential impact of CT LCS on COPD diagnosis, Mulshine et al suggest that detection of emphysema on CT LCS provides “earlier recognition for PCPs to identify patients who would benefit from detailed symptom screening to prompt spirometry for COPD detection” and additional motivation for tobacco cessation.²¹ The VANEOHS QI project was developed and implemented prior to I-ELCAP or NLST reporting results but reinforces the value of CT LCS for COPD diagnosis.

Early diagnosis of COPD remains challenging because PCPs do not ask, patients do not tell, and symptoms can easily be dismissed. However, earlier diagnosis of COPD in symptomatic patients improves outcomes.^3,4 To bridge this gap, VA PCPs and primary care patient aligned care teams (PACTs) need to commit to probing high-risk patients for COPD symptoms and ordering spirometry for those who are symptomatic. To accomplish this task, primary care teams need help.

The VANEOHS QI project confirmed that some patients with evidence of COPD on CT have symptoms of COPD that they did not share with their PCPs and suggests that LCS can be used as a dual action case finding method to screen both for lung cancer and COPD. We propose that patients who are eligible for LCS should also be probed for COPD symptoms at their clinic visits; for symptomatic patients, spirometry should be ordered, and COPD evidence-based management should be initiated when spirometry results are consistent with COPD. Annual probing for COPD symptoms could be considered in asymptomatic patients with ongoing tobacco use or emphysema on CT, since they may develop symptoms in the future. This new case-finding method bypasses the need for time-prohibitive questionnaires or peak flow measurements.

Future Opportunities

VA PCPs juggle many priorities and despite the simplicity of this new case finding COPD method, it may be unintentionally overlooked. PCPs often run out of time or may forget to ask patients about COPD symptoms when ordering LCS.

Future innovations to increase COPD diagnosis could include the creation of a yearly VA clinical reminder linked to the tobacco use reminder that has check boxes asking about symptoms of COPD in current and prior smokers. If patients have COPD symptoms, the reminder can prompt the ordering of spirometry. Similar reminders could be implemented to identify veterans with exposures to burn pits or other military environmental exposures who may have COPD symptoms. Another possible way to increase COPD diagnosis would be a partnership between primary care and the VA LCS program where patients receiving screening are asked about COPD symptoms during their LCS interviews and PACTs are alerted to order spirometry for symptomatic patients.

Elusive no longer! We can pull the veil back on COPD diagnosis and identify patients with possible COPD earlier in their course using their eligibility for LCS as a yearly reminder to probe them for symptoms. While not all patients who undergo LCS—even those with evidence of COPD on CT—will have COPD symptoms, symptoms may develop over time. LCS provides the possibility of 2 diagnoses from 1 test. This is an opportunity we cannot afford to miss.

The landmark Crossing the Quality Chasm report from the National Academy of Medicine identified patient- centered care as essential to health care quality. The report defines patientcentered care as “respectful of and responsive to individual patient preferences, needs, and values.”¹ Many health care systems, including the Veterans Health Administration, are transforming to a patient-centered model of care.² The US Department of Veterans Affairs (VA) Whole Health System of Care initiative is a system-wide, cultural transformation. Within whole health, what matters most to the patient—including their preferences, needs, and values—is foundational to health care and meant to be essential in every clinical encounter. Whole health implementation includes a progressive rollout with health care practitioner (HCP) trainings across the VA.²

Shared decision-making (SDM) is a different but aligned patient-centered care concept. SDM is a process through which a decision or care plan, based on patients’ preferences, needs, and values, is made or developed.^3-5 SDM is ideal in situations with equipoise (decisions with equivalent choices), individualized risks, and/or greater uncertainty of the net benefit, such as with lung cancer screening (LCS).³ SDM for LCS is required by the US Centers for Medicare and Medicaid Services and has been adopted by many US health care systems, including the VA.^6,7 Early detection of lung cancer can reduce death by 20% at the population level.⁸ However, at the patient level there is wide variation in the risk of developing lung cancer and a range of potential harms.⁸ LCS follow-up procedures may be more invasive than with other cancer screenings. Thus, there is concern about the risk of false-positive results leading to unnecessary care or complications.⁸ Given this balance between benefit and harm and the differing patient value on the trade-offs of LCS, an individualized, patient-centered approach is essential when deciding whether LCS is the right choice for a specific patient.

Despite the importance of LCS SDM, observational studies have shown poor implementation in clinical encounters.^9,10 HCP barriers include competing demands, limited time, lack of familiarity with and training in SDM, and beliefs biasing screening over no screening.^11-13 Additionally, HCPs may assume that patients want them to make the decision. However, research has shown that patients actually want to be more involved in their health care decisions.¹⁴ One suggested strategy to overcome these barriers is aligning SDM for LCS within an organization’s broader patient-centered initiatives.¹⁵

This project sought to align the need for SDM for LCS and the broader VA whole health initiative as part of a multilevel strategy to implement SDM for LCS across Veterans Integrated Service Network (VISN) 1.¹⁶

This article addresses HCP-level barriers. HCPs targeted are those typically involved in LCS. The VA utilizes LCS coordinators (LCSCs) in both centralized or consult models (in which LCSCs are involved in all aspects of screening) and hybrid models (in which primary care practitioners and LCSCs are both engaged in LCS tasks). The goal of this program was to generate areas of conceptual alignment between SDM and whole health as a first step in integrating these VA initiatives. This work was conducted as a foundation for an SDM for lung cancer HCP training and consultation initiative.

ALIGNMENT PROCESS

We reviewed relevant literature and resources for SDM and whole health. In reviewing the SDM literature, we included a sample of the most widely cited literature on the topic, and focused primarily on the systematic review by Bomhof-Roordink et al.^4,5,17,18 This review provided a synthesis of SDM elements across SDM models and identified 53 different elements clustered into 24 components.⁴ The most common components were present in at least half of all SDM published models, including: make the decision, patient preferences, tailor information, deliberate, create choice awareness, and learn about the patient. Bomhof-Roordink et al provided the guiding framework for this conceptualization of SDM because that study included the available recent published SDM models.⁴

Second, published literature on VA whole health along with supplemental promotional and training materials were reviewed. The whole health materials included 2 sets of training slides developed for VA HCPs (available to VA employees): Implementing Whole Health in Clinical Care, which is focused on HCPs’ work with patients, and Whole Health for You and Me, which is about HCPs’ personal well-being.¹⁹ We also reviewed a publication describing the history of whole health and patient-facing online whole health tools.^2,19

Each document was reviewed for key elements related to SDM, patient-centered care, and whole health. Using the 53 elements identified by Bomhof-Roordink et al, we reviewed and compared each element to the whole health materials to create the integrated model of SDM and whole health. We iteratively discussed and organized the elements until we reached consensus.

SDM and Whole Health Alignment

We created an integrated model of SDM for LCS within the context of the VA whole health initiative. This integrated model is directed at HCPs who would likely engage patients in discussions of LCS, including primary care practitioners and nurse coordinators. The model includes 3 steps for HCPs to follow that align SDM within whole health: (1) frame the conversation and partner with the patient; (2) share clinical perspective and elicit patient values; and (3) deliberate and decide together. For each step, the SDM elements, whole health elements, and integration of SDM and whole health are provided. Table 1 provides an overview of the similarities and differences between SDM and whole health. Example phrases that merge SDM and whole health for HCPs to use in patient conversations about LCS are included in Table 2.

STEP 1. FRAME THE CONVERSATION AND PARTNER WITH THE PATIENT

Shared decision-making. Traditional SDM literature includes an initial step of letting patients know that there is a choice to be made between ≥ 2 clinical options.⁴ Ancillary elements of this first step include asking patients their preferences about the degree to which they want to be involved in SDM and about how they like to receive information (eg, verbal, written, video). These steps open the SDM conversation and ensure the patient and HCP are on the same page before moving forward. For example, the US Agency for Healthcare Research and Quality SHARE model’s first step is for HCPs to communicate that choices exist and to invite the patient to be involved in decisions.²⁰ Similarly, Elwyn’s 3-step SDM model begins with establishing that a choice exists and inviting patient input on making that choice.¹⁷

Whole health. Patients are encouraged to play an active role in their health care. Through whole health programs such as Taking Charge of My Life and Health, patients explore their values and set self-care goals.²¹ HCP whole health trainings teach and reinforce communication skills, including SDM, listening skills, and motivational interviewing.¹⁹

Shared decision-making/whole health integration. SDM and whole health both prioritize respect, compassion, and patients’ expertise. They focus on the patient-HCP relationship with an emphasis on fostering egalitarian interactions. HCPs frame the SDM conversation and partner with the patient so they know what to expect and who will be involved. This conversation is framed from the outset as a collaborative discussion. HCPs empower the patient to play an active role in decision-making and help them understand why their engagement is critical.

STEP 2. SHARE CLINICAL PERSPECTIVE AND ELICIT PATIENT VALUES

Shared decision-making. HCPs share clinical perspective on LCS tailored to individual patients while explicitly inviting the patient to share their preferences and values when thinking about whether to undergo LCS. HCPs give a balanced description of LCS, including the benefits and harms, tailored to the patient’s unique information needs and questions. Sharing clinical perspective also includes describing treatment options, the most common element across SDM models.⁴ Decision aids, which provide unbiased information and include a values clarification exercise, may be helpful in sharing clinical perspectives and clarifying patient values related to the trade-offs of LCS.²² For example, the VA National Center for Health Promotion and Disease Prevention developed a LCS decision aid to be used for SDM for LCS.

Whole health. The conversation shifts from “What is the matter with you?” to “What matters to you?” starting with the patient’s goals and priorities rather than disease prevention, diagnosis, and treatment.² Several whole health tools exist, including the Personal Health Inventory, used to identify what matters most to patients and understand their current well-being and self-care.²³ Using the inventory, the patient and their health care team develop the patient’s personal health plan.²⁴ Additionally, whole health trains HCPs to reflect on their own attitudes and biases when providing clinical care.

Shared decision-making/whole health integration. The LCS conversation can build on other whole health-related conversations with a HCP or other team members. HCPs can reference the patient’s personal health plan for documentation of the patient’s preferences, values, and goals in the electronic medical record. During this process, HCPs can give space for patients to discuss factors in their life and experiences that impact their perspective and decision-making. For example, patient concerns could be explored here, including fear of a cancer diagnosis, stigma around smoking, and fears around the screening and/or treatment process. HCPs may ask, “What matters most to you when making this decision?” Finally, by sharing clinical information, HCPs will focus on patient values to help overcome their own biases toward a desire for LCS. HCPs, similar to the rest of the US public, tend to hold highly favorable attitudes toward cancer screening as well as misconceptions about the magnitude of benefits from screening.¹³

STEP 3. DELIBERATE AND DECIDE TOGETHER

Shared decision-making. Decision-making is almost always considered the last SDM step.⁴ In the final step, the patient and HCP discuss the options (ie, to screen or not to screen) considering the patient’s values and preferences, and patients decide with their HCP whether they will undergo LCS. Patients may decide they need more time to think about these options. As part of deliberation, HCPs assess what other information patients may need to arrive at a decision. Family members, friends, or peers may be included in making the final decision.

Whole health. In Whole health, decisions also may include the entire health care team and other individuals important to the patient (eg, family, friends). Integration across different health care settings is also considered a key whole health element. Finally, whole health focuses on long-term relationships with patients; thus, the LCS SDM process is situated within longer term relationship building and patient empowerment, both of which will facilitate partnering with the patient in future conversations about other decisions.

Shared decision-making/whole health integration. Both SDM and whole health emphasize partnership with the patient in making a final decision. There is also focus on decision-making as an ongoing process. Deciding whether LCS is the best choice might include naming and addressing emotions, voicing questions not raised, and exploring whether screening fits the patient’s goals, values, and life context. HCPs may give guidance, but patients retain the authority to make decisions. The goal is to empower patients to know that the only right decision is the one right for them and they will be supported.

Limitations

This article describes a VA practice program and was not a formal research study. Further work is needed to evaluate the presented strategies. Additionally, we did not conduct a systematic literature review and thus elements of SDM and whole health may not be exhaustive.

CONCLUSIONS

This article describes the alignment of 2 distinct VA initiatives, whole health and SDM for LCS. The goal was to reduce known barriers to SDM, such as competing demands, limited time, and lack of familiarity with and training in SDM.^11-13 These concepts are well aligned. This integrated model is the first step in informing the development of a HCP training program and materials as part of a multilevel strategy that our team is using to implement SDM for LCS in VISN 1.16 The final training and materials resulting from this work were delivered to LCSCs in 3 ways: (1) a series of 3 interactive group training sessions, including didactic elements, role play, and time for open discussion; (2) 1-on-1 academic detailing; and (3) educational handouts. In academic detailing, a member of the research team trained in academic detailing met virtually with each nurse coordinator, identified that individual’s barriers to SDM, and used the training materials to highlight messages to overcome those barriers; follow-up calls provided a forum for discussing progress and overcoming additional challenges. Although this article focused specifically on whole health and SDM, the conceptual alignment process strategy can be applied to other implementations of multiple initiatives.

The landmark Crossing the Quality Chasm report from the National Academy of Medicine identified patient- centered care as essential to health care quality. The report defines patientcentered care as “respectful of and responsive to individual patient preferences, needs, and values.”¹ Many health care systems, including the Veterans Health Administration, are transforming to a patient-centered model of care.² The US Department of Veterans Affairs (VA) Whole Health System of Care initiative is a system-wide, cultural transformation. Within whole health, what matters most to the patient—including their preferences, needs, and values—is foundational to health care and meant to be essential in every clinical encounter. Whole health implementation includes a progressive rollout with health care practitioner (HCP) trainings across the VA.²

Shared decision-making (SDM) is a different but aligned patient-centered care concept. SDM is a process through which a decision or care plan, based on patients’ preferences, needs, and values, is made or developed.^3-5 SDM is ideal in situations with equipoise (decisions with equivalent choices), individualized risks, and/or greater uncertainty of the net benefit, such as with lung cancer screening (LCS).³ SDM for LCS is required by the US Centers for Medicare and Medicaid Services and has been adopted by many US health care systems, including the VA.^6,7 Early detection of lung cancer can reduce death by 20% at the population level.⁸ However, at the patient level there is wide variation in the risk of developing lung cancer and a range of potential harms.⁸ LCS follow-up procedures may be more invasive than with other cancer screenings. Thus, there is concern about the risk of false-positive results leading to unnecessary care or complications.⁸ Given this balance between benefit and harm and the differing patient value on the trade-offs of LCS, an individualized, patient-centered approach is essential when deciding whether LCS is the right choice for a specific patient.

Despite the importance of LCS SDM, observational studies have shown poor implementation in clinical encounters.^9,10 HCP barriers include competing demands, limited time, lack of familiarity with and training in SDM, and beliefs biasing screening over no screening.^11-13 Additionally, HCPs may assume that patients want them to make the decision. However, research has shown that patients actually want to be more involved in their health care decisions.¹⁴ One suggested strategy to overcome these barriers is aligning SDM for LCS within an organization’s broader patient-centered initiatives.¹⁵

This project sought to align the need for SDM for LCS and the broader VA whole health initiative as part of a multilevel strategy to implement SDM for LCS across Veterans Integrated Service Network (VISN) 1.¹⁶

This article addresses HCP-level barriers. HCPs targeted are those typically involved in LCS. The VA utilizes LCS coordinators (LCSCs) in both centralized or consult models (in which LCSCs are involved in all aspects of screening) and hybrid models (in which primary care practitioners and LCSCs are both engaged in LCS tasks). The goal of this program was to generate areas of conceptual alignment between SDM and whole health as a first step in integrating these VA initiatives. This work was conducted as a foundation for an SDM for lung cancer HCP training and consultation initiative.

ALIGNMENT PROCESS

We reviewed relevant literature and resources for SDM and whole health. In reviewing the SDM literature, we included a sample of the most widely cited literature on the topic, and focused primarily on the systematic review by Bomhof-Roordink et al.^4,5,17,18 This review provided a synthesis of SDM elements across SDM models and identified 53 different elements clustered into 24 components.⁴ The most common components were present in at least half of all SDM published models, including: make the decision, patient preferences, tailor information, deliberate, create choice awareness, and learn about the patient. Bomhof-Roordink et al provided the guiding framework for this conceptualization of SDM because that study included the available recent published SDM models.⁴

Second, published literature on VA whole health along with supplemental promotional and training materials were reviewed. The whole health materials included 2 sets of training slides developed for VA HCPs (available to VA employees): Implementing Whole Health in Clinical Care, which is focused on HCPs’ work with patients, and Whole Health for You and Me, which is about HCPs’ personal well-being.¹⁹ We also reviewed a publication describing the history of whole health and patient-facing online whole health tools.^2,19

Each document was reviewed for key elements related to SDM, patient-centered care, and whole health. Using the 53 elements identified by Bomhof-Roordink et al, we reviewed and compared each element to the whole health materials to create the integrated model of SDM and whole health. We iteratively discussed and organized the elements until we reached consensus.

SDM and Whole Health Alignment

We created an integrated model of SDM for LCS within the context of the VA whole health initiative. This integrated model is directed at HCPs who would likely engage patients in discussions of LCS, including primary care practitioners and nurse coordinators. The model includes 3 steps for HCPs to follow that align SDM within whole health: (1) frame the conversation and partner with the patient; (2) share clinical perspective and elicit patient values; and (3) deliberate and decide together. For each step, the SDM elements, whole health elements, and integration of SDM and whole health are provided. Table 1 provides an overview of the similarities and differences between SDM and whole health. Example phrases that merge SDM and whole health for HCPs to use in patient conversations about LCS are included in Table 2.

STEP 1. FRAME THE CONVERSATION AND PARTNER WITH THE PATIENT

Shared decision-making. Traditional SDM literature includes an initial step of letting patients know that there is a choice to be made between ≥ 2 clinical options.⁴ Ancillary elements of this first step include asking patients their preferences about the degree to which they want to be involved in SDM and about how they like to receive information (eg, verbal, written, video). These steps open the SDM conversation and ensure the patient and HCP are on the same page before moving forward. For example, the US Agency for Healthcare Research and Quality SHARE model’s first step is for HCPs to communicate that choices exist and to invite the patient to be involved in decisions.²⁰ Similarly, Elwyn’s 3-step SDM model begins with establishing that a choice exists and inviting patient input on making that choice.¹⁷

Whole health. Patients are encouraged to play an active role in their health care. Through whole health programs such as Taking Charge of My Life and Health, patients explore their values and set self-care goals.²¹ HCP whole health trainings teach and reinforce communication skills, including SDM, listening skills, and motivational interviewing.¹⁹

Shared decision-making/whole health integration. SDM and whole health both prioritize respect, compassion, and patients’ expertise. They focus on the patient-HCP relationship with an emphasis on fostering egalitarian interactions. HCPs frame the SDM conversation and partner with the patient so they know what to expect and who will be involved. This conversation is framed from the outset as a collaborative discussion. HCPs empower the patient to play an active role in decision-making and help them understand why their engagement is critical.

STEP 2. SHARE CLINICAL PERSPECTIVE AND ELICIT PATIENT VALUES

Shared decision-making. HCPs share clinical perspective on LCS tailored to individual patients while explicitly inviting the patient to share their preferences and values when thinking about whether to undergo LCS. HCPs give a balanced description of LCS, including the benefits and harms, tailored to the patient’s unique information needs and questions. Sharing clinical perspective also includes describing treatment options, the most common element across SDM models.⁴ Decision aids, which provide unbiased information and include a values clarification exercise, may be helpful in sharing clinical perspectives and clarifying patient values related to the trade-offs of LCS.²² For example, the VA National Center for Health Promotion and Disease Prevention developed a LCS decision aid to be used for SDM for LCS.

Whole health. The conversation shifts from “What is the matter with you?” to “What matters to you?” starting with the patient’s goals and priorities rather than disease prevention, diagnosis, and treatment.² Several whole health tools exist, including the Personal Health Inventory, used to identify what matters most to patients and understand their current well-being and self-care.²³ Using the inventory, the patient and their health care team develop the patient’s personal health plan.²⁴ Additionally, whole health trains HCPs to reflect on their own attitudes and biases when providing clinical care.

Shared decision-making/whole health integration. The LCS conversation can build on other whole health-related conversations with a HCP or other team members. HCPs can reference the patient’s personal health plan for documentation of the patient’s preferences, values, and goals in the electronic medical record. During this process, HCPs can give space for patients to discuss factors in their life and experiences that impact their perspective and decision-making. For example, patient concerns could be explored here, including fear of a cancer diagnosis, stigma around smoking, and fears around the screening and/or treatment process. HCPs may ask, “What matters most to you when making this decision?” Finally, by sharing clinical information, HCPs will focus on patient values to help overcome their own biases toward a desire for LCS. HCPs, similar to the rest of the US public, tend to hold highly favorable attitudes toward cancer screening as well as misconceptions about the magnitude of benefits from screening.¹³

STEP 3. DELIBERATE AND DECIDE TOGETHER

Shared decision-making. Decision-making is almost always considered the last SDM step.⁴ In the final step, the patient and HCP discuss the options (ie, to screen or not to screen) considering the patient’s values and preferences, and patients decide with their HCP whether they will undergo LCS. Patients may decide they need more time to think about these options. As part of deliberation, HCPs assess what other information patients may need to arrive at a decision. Family members, friends, or peers may be included in making the final decision.

Whole health. In Whole health, decisions also may include the entire health care team and other individuals important to the patient (eg, family, friends). Integration across different health care settings is also considered a key whole health element. Finally, whole health focuses on long-term relationships with patients; thus, the LCS SDM process is situated within longer term relationship building and patient empowerment, both of which will facilitate partnering with the patient in future conversations about other decisions.

Shared decision-making/whole health integration. Both SDM and whole health emphasize partnership with the patient in making a final decision. There is also focus on decision-making as an ongoing process. Deciding whether LCS is the best choice might include naming and addressing emotions, voicing questions not raised, and exploring whether screening fits the patient’s goals, values, and life context. HCPs may give guidance, but patients retain the authority to make decisions. The goal is to empower patients to know that the only right decision is the one right for them and they will be supported.

Limitations

This article describes a VA practice program and was not a formal research study. Further work is needed to evaluate the presented strategies. Additionally, we did not conduct a systematic literature review and thus elements of SDM and whole health may not be exhaustive.

CONCLUSIONS

This article describes the alignment of 2 distinct VA initiatives, whole health and SDM for LCS. The goal was to reduce known barriers to SDM, such as competing demands, limited time, and lack of familiarity with and training in SDM.^11-13 These concepts are well aligned. This integrated model is the first step in informing the development of a HCP training program and materials as part of a multilevel strategy that our team is using to implement SDM for LCS in VISN 1.16 The final training and materials resulting from this work were delivered to LCSCs in 3 ways: (1) a series of 3 interactive group training sessions, including didactic elements, role play, and time for open discussion; (2) 1-on-1 academic detailing; and (3) educational handouts. In academic detailing, a member of the research team trained in academic detailing met virtually with each nurse coordinator, identified that individual’s barriers to SDM, and used the training materials to highlight messages to overcome those barriers; follow-up calls provided a forum for discussing progress and overcoming additional challenges. Although this article focused specifically on whole health and SDM, the conceptual alignment process strategy can be applied to other implementations of multiple initiatives.

The landmark Crossing the Quality Chasm report from the National Academy of Medicine identified patient- centered care as essential to health care quality. The report defines patientcentered care as “respectful of and responsive to individual patient preferences, needs, and values.”¹ Many health care systems, including the Veterans Health Administration, are transforming to a patient-centered model of care.² The US Department of Veterans Affairs (VA) Whole Health System of Care initiative is a system-wide, cultural transformation. Within whole health, what matters most to the patient—including their preferences, needs, and values—is foundational to health care and meant to be essential in every clinical encounter. Whole health implementation includes a progressive rollout with health care practitioner (HCP) trainings across the VA.²

Shared decision-making (SDM) is a different but aligned patient-centered care concept. SDM is a process through which a decision or care plan, based on patients’ preferences, needs, and values, is made or developed.^3-5 SDM is ideal in situations with equipoise (decisions with equivalent choices), individualized risks, and/or greater uncertainty of the net benefit, such as with lung cancer screening (LCS).³ SDM for LCS is required by the US Centers for Medicare and Medicaid Services and has been adopted by many US health care systems, including the VA.^6,7 Early detection of lung cancer can reduce death by 20% at the population level.⁸ However, at the patient level there is wide variation in the risk of developing lung cancer and a range of potential harms.⁸ LCS follow-up procedures may be more invasive than with other cancer screenings. Thus, there is concern about the risk of false-positive results leading to unnecessary care or complications.⁸ Given this balance between benefit and harm and the differing patient value on the trade-offs of LCS, an individualized, patient-centered approach is essential when deciding whether LCS is the right choice for a specific patient.

Despite the importance of LCS SDM, observational studies have shown poor implementation in clinical encounters.^9,10 HCP barriers include competing demands, limited time, lack of familiarity with and training in SDM, and beliefs biasing screening over no screening.^11-13 Additionally, HCPs may assume that patients want them to make the decision. However, research has shown that patients actually want to be more involved in their health care decisions.¹⁴ One suggested strategy to overcome these barriers is aligning SDM for LCS within an organization’s broader patient-centered initiatives.¹⁵

This project sought to align the need for SDM for LCS and the broader VA whole health initiative as part of a multilevel strategy to implement SDM for LCS across Veterans Integrated Service Network (VISN) 1.¹⁶

This article addresses HCP-level barriers. HCPs targeted are those typically involved in LCS. The VA utilizes LCS coordinators (LCSCs) in both centralized or consult models (in which LCSCs are involved in all aspects of screening) and hybrid models (in which primary care practitioners and LCSCs are both engaged in LCS tasks). The goal of this program was to generate areas of conceptual alignment between SDM and whole health as a first step in integrating these VA initiatives. This work was conducted as a foundation for an SDM for lung cancer HCP training and consultation initiative.

ALIGNMENT PROCESS

We reviewed relevant literature and resources for SDM and whole health. In reviewing the SDM literature, we included a sample of the most widely cited literature on the topic, and focused primarily on the systematic review by Bomhof-Roordink et al.^4,5,17,18 This review provided a synthesis of SDM elements across SDM models and identified 53 different elements clustered into 24 components.⁴ The most common components were present in at least half of all SDM published models, including: make the decision, patient preferences, tailor information, deliberate, create choice awareness, and learn about the patient. Bomhof-Roordink et al provided the guiding framework for this conceptualization of SDM because that study included the available recent published SDM models.⁴

Second, published literature on VA whole health along with supplemental promotional and training materials were reviewed. The whole health materials included 2 sets of training slides developed for VA HCPs (available to VA employees): Implementing Whole Health in Clinical Care, which is focused on HCPs’ work with patients, and Whole Health for You and Me, which is about HCPs’ personal well-being.¹⁹ We also reviewed a publication describing the history of whole health and patient-facing online whole health tools.^2,19

Each document was reviewed for key elements related to SDM, patient-centered care, and whole health. Using the 53 elements identified by Bomhof-Roordink et al, we reviewed and compared each element to the whole health materials to create the integrated model of SDM and whole health. We iteratively discussed and organized the elements until we reached consensus.

SDM and Whole Health Alignment

We created an integrated model of SDM for LCS within the context of the VA whole health initiative. This integrated model is directed at HCPs who would likely engage patients in discussions of LCS, including primary care practitioners and nurse coordinators. The model includes 3 steps for HCPs to follow that align SDM within whole health: (1) frame the conversation and partner with the patient; (2) share clinical perspective and elicit patient values; and (3) deliberate and decide together. For each step, the SDM elements, whole health elements, and integration of SDM and whole health are provided. Table 1 provides an overview of the similarities and differences between SDM and whole health. Example phrases that merge SDM and whole health for HCPs to use in patient conversations about LCS are included in Table 2.

STEP 1. FRAME THE CONVERSATION AND PARTNER WITH THE PATIENT

Shared decision-making. Traditional SDM literature includes an initial step of letting patients know that there is a choice to be made between ≥ 2 clinical options.⁴ Ancillary elements of this first step include asking patients their preferences about the degree to which they want to be involved in SDM and about how they like to receive information (eg, verbal, written, video). These steps open the SDM conversation and ensure the patient and HCP are on the same page before moving forward. For example, the US Agency for Healthcare Research and Quality SHARE model’s first step is for HCPs to communicate that choices exist and to invite the patient to be involved in decisions.²⁰ Similarly, Elwyn’s 3-step SDM model begins with establishing that a choice exists and inviting patient input on making that choice.¹⁷

Whole health. Patients are encouraged to play an active role in their health care. Through whole health programs such as Taking Charge of My Life and Health, patients explore their values and set self-care goals.²¹ HCP whole health trainings teach and reinforce communication skills, including SDM, listening skills, and motivational interviewing.¹⁹

Shared decision-making/whole health integration. SDM and whole health both prioritize respect, compassion, and patients’ expertise. They focus on the patient-HCP relationship with an emphasis on fostering egalitarian interactions. HCPs frame the SDM conversation and partner with the patient so they know what to expect and who will be involved. This conversation is framed from the outset as a collaborative discussion. HCPs empower the patient to play an active role in decision-making and help them understand why their engagement is critical.

STEP 2. SHARE CLINICAL PERSPECTIVE AND ELICIT PATIENT VALUES

Shared decision-making. HCPs share clinical perspective on LCS tailored to individual patients while explicitly inviting the patient to share their preferences and values when thinking about whether to undergo LCS. HCPs give a balanced description of LCS, including the benefits and harms, tailored to the patient’s unique information needs and questions. Sharing clinical perspective also includes describing treatment options, the most common element across SDM models.⁴ Decision aids, which provide unbiased information and include a values clarification exercise, may be helpful in sharing clinical perspectives and clarifying patient values related to the trade-offs of LCS.²² For example, the VA National Center for Health Promotion and Disease Prevention developed a LCS decision aid to be used for SDM for LCS.

Whole health. The conversation shifts from “What is the matter with you?” to “What matters to you?” starting with the patient’s goals and priorities rather than disease prevention, diagnosis, and treatment.² Several whole health tools exist, including the Personal Health Inventory, used to identify what matters most to patients and understand their current well-being and self-care.²³ Using the inventory, the patient and their health care team develop the patient’s personal health plan.²⁴ Additionally, whole health trains HCPs to reflect on their own attitudes and biases when providing clinical care.

Shared decision-making/whole health integration. The LCS conversation can build on other whole health-related conversations with a HCP or other team members. HCPs can reference the patient’s personal health plan for documentation of the patient’s preferences, values, and goals in the electronic medical record. During this process, HCPs can give space for patients to discuss factors in their life and experiences that impact their perspective and decision-making. For example, patient concerns could be explored here, including fear of a cancer diagnosis, stigma around smoking, and fears around the screening and/or treatment process. HCPs may ask, “What matters most to you when making this decision?” Finally, by sharing clinical information, HCPs will focus on patient values to help overcome their own biases toward a desire for LCS. HCPs, similar to the rest of the US public, tend to hold highly favorable attitudes toward cancer screening as well as misconceptions about the magnitude of benefits from screening.¹³

STEP 3. DELIBERATE AND DECIDE TOGETHER

Shared decision-making. Decision-making is almost always considered the last SDM step.⁴ In the final step, the patient and HCP discuss the options (ie, to screen or not to screen) considering the patient’s values and preferences, and patients decide with their HCP whether they will undergo LCS. Patients may decide they need more time to think about these options. As part of deliberation, HCPs assess what other information patients may need to arrive at a decision. Family members, friends, or peers may be included in making the final decision.

Whole health. In Whole health, decisions also may include the entire health care team and other individuals important to the patient (eg, family, friends). Integration across different health care settings is also considered a key whole health element. Finally, whole health focuses on long-term relationships with patients; thus, the LCS SDM process is situated within longer term relationship building and patient empowerment, both of which will facilitate partnering with the patient in future conversations about other decisions.

Shared decision-making/whole health integration. Both SDM and whole health emphasize partnership with the patient in making a final decision. There is also focus on decision-making as an ongoing process. Deciding whether LCS is the best choice might include naming and addressing emotions, voicing questions not raised, and exploring whether screening fits the patient’s goals, values, and life context. HCPs may give guidance, but patients retain the authority to make decisions. The goal is to empower patients to know that the only right decision is the one right for them and they will be supported.

Limitations

This article describes a VA practice program and was not a formal research study. Further work is needed to evaluate the presented strategies. Additionally, we did not conduct a systematic literature review and thus elements of SDM and whole health may not be exhaustive.

CONCLUSIONS

This article describes the alignment of 2 distinct VA initiatives, whole health and SDM for LCS. The goal was to reduce known barriers to SDM, such as competing demands, limited time, and lack of familiarity with and training in SDM.^11-13 These concepts are well aligned. This integrated model is the first step in informing the development of a HCP training program and materials as part of a multilevel strategy that our team is using to implement SDM for LCS in VISN 1.16 The final training and materials resulting from this work were delivered to LCSCs in 3 ways: (1) a series of 3 interactive group training sessions, including didactic elements, role play, and time for open discussion; (2) 1-on-1 academic detailing; and (3) educational handouts. In academic detailing, a member of the research team trained in academic detailing met virtually with each nurse coordinator, identified that individual’s barriers to SDM, and used the training materials to highlight messages to overcome those barriers; follow-up calls provided a forum for discussing progress and overcoming additional challenges. Although this article focused specifically on whole health and SDM, the conceptual alignment process strategy can be applied to other implementations of multiple initiatives.

New data suggest that glucagon-like peptide 1 (GLP-1) receptor agonists, used to treat diabetes and obesity, may also help guard against obesity-related cancers.

In a large observational study, new GLP-1 agonist users with obesity and diabetes had a significantly lower risk for 14 obesity-related cancers than similar individuals who received dipeptidyl peptidase-4 (DPP-4) inhibitors, which are weight-neutral.

This study provides a “reassuring safety signal” showing that GLP-1 drugs are linked to a modest drop in obesity-related cancer risk, and not a higher risk for these cancers, said lead investigator Lucas Mavromatis, medical student at NYU Grossman School of Medicine in New York City, during a press conference at American Society of Clinical Oncology (ASCO) 2025 annual meeting.

However, there were some nuances to the findings. The protective effect of GLP-1 agonists was only significant for colon and rectal cancers and for women, Mavromatis reported. And although GLP-1 users had an 8% lower risk of dying from any cause, the survival benefit was also only significant for women.

Still, the overall “message to patients is GLP-1 receptor treatments remain a strong option for patients with diabetes and obesity and may have an additional, small favorable benefit in cancer,” Mavromatis explained at the press briefing.

'Intriguing Hypothesis'

Obesity is linked to an increased risk of developing more than a dozen cancer types, including esophageal, colon, rectal, stomach, liver, gallbladder, pancreatic, kidney, postmenopausal breast, ovarian, endometrial and thyroid, as well as multiple myeloma and meningiomas.

About 12% of Americans have been prescribed a GLP-1 medication to treat diabetes and/or obesity. However, little is known about how these drugs affect cancer risk.

To investigate, Mavromatis and colleagues used the Optum healthcare database to identify 170,030 adults with obesity and type 2 diabetes from 43 health systems in the United States.

Between 2013 and 2023, half started a GLP-1 agonist and half started a DPP-4 inhibitor, with propensity score matching used to balance characteristics of the two cohorts.

Participants were a mean age of 56.8 years, with an average body mass index of 38.5; more than 70% were White individuals and more than 14% were Black individuals.

During a mean follow-up of 3.9 years, 2501 new obesity-related cancers were identified in the GLP-1 group and 2671 in the DPP-4 group — representing a 7% overall reduced risk for any obesity-related cancer in the GLP-1 group (hazard ratio [HR], 0.93).

When analyzing each of the 14 obesity-related cancers separately, the protective link between GLP-1 use and cancer was primarily driven by colon and rectal cancers. GLP-1 users had a 16% lower risk for colon cancer (HR, 0.84) and a 28% lower risk for rectal cancer (HR, 0.72).

“No other cancers had statistically significant associations with GLP-1 use,” Mavromatis told briefing attendees. But “importantly, no cancers had statistically significant adverse associations with GLP-1 use,” he added.

Experts have expressed some concern about a possible link between GLP-1 use and pancreatic cancer given that pancreatitis is a known side effect of GLP-1 use. However, “this is not borne out by epidemiological data,” Mavromatis said.

“Additionally, we were not able to specifically assess medullary thyroid cancer, which is on the warning label for several GLP-1 medications, but we did see a reassuring lack of association between GLP-1 use and thyroid cancer as a whole,” he added.

During follow-up, there were 2783 deaths in the GLP-1 group and 2961 deaths in the DPP-4 group — translating to an 8% lower risk for death due to any cause among GLP-1 users (HR, 0.92; P = .001).

Mavromatis and colleagues observed sex differences as well. Women taking a GLP-1 had an 8% lower risk for obesity-related cancers (HR, 0.92; P = .01) and a 20% lower risk for death from any cause (HR, 0.80; P < .001) compared with women taking a DPP-4 inhibitor.

Among men, researchers found no statistically significant difference between GLP-1 and DPP-4 use for obesity-related cancer risk (HR, 0.95; P = .29) or all-cause mortality (HR, 1.04; P = .34).

Overall, Mavromatis said, it’s important to note that the absolute risk reduction seen in the study is “small and the number of patients that would need to be given one of these medications to prevent an obesity-related cancer, based on our data, would be very large.”

Mavromatis also noted that the length of follow-up was short, and the study assessed primarily older and weaker GLP-1 agonists compared with newer agents on the market. Therefore, longer-term studies with newer GLP-1s are needed to confirm the effects seen as well as safety.

In a statement, ASCO President Robin Zon, MD, said this trial raises the “intriguing hypothesis” that the increasingly popular GLP-1 medications might offer some benefit in reducing the risk of developing cancer.

Zon said she sees many patients with obesity, and given the clear link between cancer and obesity, defining the clinical role of GLP-1 medications in cancer prevention is “important.”

This study “leads us in the direction” of a potential protective effect of GLP-1s on cancer, but “there are a lot of questions that are generated by this particular study, especially as we move forward and we think about prevention of cancers,” Zon told the briefing.

This study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. Mavromatis reported no relevant disclosures. Zon reported stock or ownership interests in Oncolytics Biotech, TG Therapeutics, Select Sector SPDR Health Care, AstraZeneca, CRISPR, McKesson, and Berkshire Hathaway.

A version of this article first appeared on Medscape.com.

New data suggest that glucagon-like peptide 1 (GLP-1) receptor agonists, used to treat diabetes and obesity, may also help guard against obesity-related cancers.

In a large observational study, new GLP-1 agonist users with obesity and diabetes had a significantly lower risk for 14 obesity-related cancers than similar individuals who received dipeptidyl peptidase-4 (DPP-4) inhibitors, which are weight-neutral.

This study provides a “reassuring safety signal” showing that GLP-1 drugs are linked to a modest drop in obesity-related cancer risk, and not a higher risk for these cancers, said lead investigator Lucas Mavromatis, medical student at NYU Grossman School of Medicine in New York City, during a press conference at American Society of Clinical Oncology (ASCO) 2025 annual meeting.

However, there were some nuances to the findings. The protective effect of GLP-1 agonists was only significant for colon and rectal cancers and for women, Mavromatis reported. And although GLP-1 users had an 8% lower risk of dying from any cause, the survival benefit was also only significant for women.

Still, the overall “message to patients is GLP-1 receptor treatments remain a strong option for patients with diabetes and obesity and may have an additional, small favorable benefit in cancer,” Mavromatis explained at the press briefing.

'Intriguing Hypothesis'

Obesity is linked to an increased risk of developing more than a dozen cancer types, including esophageal, colon, rectal, stomach, liver, gallbladder, pancreatic, kidney, postmenopausal breast, ovarian, endometrial and thyroid, as well as multiple myeloma and meningiomas.

About 12% of Americans have been prescribed a GLP-1 medication to treat diabetes and/or obesity. However, little is known about how these drugs affect cancer risk.

To investigate, Mavromatis and colleagues used the Optum healthcare database to identify 170,030 adults with obesity and type 2 diabetes from 43 health systems in the United States.

Between 2013 and 2023, half started a GLP-1 agonist and half started a DPP-4 inhibitor, with propensity score matching used to balance characteristics of the two cohorts.

Participants were a mean age of 56.8 years, with an average body mass index of 38.5; more than 70% were White individuals and more than 14% were Black individuals.

During a mean follow-up of 3.9 years, 2501 new obesity-related cancers were identified in the GLP-1 group and 2671 in the DPP-4 group — representing a 7% overall reduced risk for any obesity-related cancer in the GLP-1 group (hazard ratio [HR], 0.93).

When analyzing each of the 14 obesity-related cancers separately, the protective link between GLP-1 use and cancer was primarily driven by colon and rectal cancers. GLP-1 users had a 16% lower risk for colon cancer (HR, 0.84) and a 28% lower risk for rectal cancer (HR, 0.72).

“No other cancers had statistically significant associations with GLP-1 use,” Mavromatis told briefing attendees. But “importantly, no cancers had statistically significant adverse associations with GLP-1 use,” he added.

Experts have expressed some concern about a possible link between GLP-1 use and pancreatic cancer given that pancreatitis is a known side effect of GLP-1 use. However, “this is not borne out by epidemiological data,” Mavromatis said.

“Additionally, we were not able to specifically assess medullary thyroid cancer, which is on the warning label for several GLP-1 medications, but we did see a reassuring lack of association between GLP-1 use and thyroid cancer as a whole,” he added.

During follow-up, there were 2783 deaths in the GLP-1 group and 2961 deaths in the DPP-4 group — translating to an 8% lower risk for death due to any cause among GLP-1 users (HR, 0.92; P = .001).

Mavromatis and colleagues observed sex differences as well. Women taking a GLP-1 had an 8% lower risk for obesity-related cancers (HR, 0.92; P = .01) and a 20% lower risk for death from any cause (HR, 0.80; P < .001) compared with women taking a DPP-4 inhibitor.

Among men, researchers found no statistically significant difference between GLP-1 and DPP-4 use for obesity-related cancer risk (HR, 0.95; P = .29) or all-cause mortality (HR, 1.04; P = .34).

Overall, Mavromatis said, it’s important to note that the absolute risk reduction seen in the study is “small and the number of patients that would need to be given one of these medications to prevent an obesity-related cancer, based on our data, would be very large.”

Mavromatis also noted that the length of follow-up was short, and the study assessed primarily older and weaker GLP-1 agonists compared with newer agents on the market. Therefore, longer-term studies with newer GLP-1s are needed to confirm the effects seen as well as safety.

In a statement, ASCO President Robin Zon, MD, said this trial raises the “intriguing hypothesis” that the increasingly popular GLP-1 medications might offer some benefit in reducing the risk of developing cancer.

Zon said she sees many patients with obesity, and given the clear link between cancer and obesity, defining the clinical role of GLP-1 medications in cancer prevention is “important.”

This study “leads us in the direction” of a potential protective effect of GLP-1s on cancer, but “there are a lot of questions that are generated by this particular study, especially as we move forward and we think about prevention of cancers,” Zon told the briefing.

This study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. Mavromatis reported no relevant disclosures. Zon reported stock or ownership interests in Oncolytics Biotech, TG Therapeutics, Select Sector SPDR Health Care, AstraZeneca, CRISPR, McKesson, and Berkshire Hathaway.

A version of this article first appeared on Medscape.com.

New data suggest that glucagon-like peptide 1 (GLP-1) receptor agonists, used to treat diabetes and obesity, may also help guard against obesity-related cancers.

In a large observational study, new GLP-1 agonist users with obesity and diabetes had a significantly lower risk for 14 obesity-related cancers than similar individuals who received dipeptidyl peptidase-4 (DPP-4) inhibitors, which are weight-neutral.

This study provides a “reassuring safety signal” showing that GLP-1 drugs are linked to a modest drop in obesity-related cancer risk, and not a higher risk for these cancers, said lead investigator Lucas Mavromatis, medical student at NYU Grossman School of Medicine in New York City, during a press conference at American Society of Clinical Oncology (ASCO) 2025 annual meeting.

However, there were some nuances to the findings. The protective effect of GLP-1 agonists was only significant for colon and rectal cancers and for women, Mavromatis reported. And although GLP-1 users had an 8% lower risk of dying from any cause, the survival benefit was also only significant for women.

Still, the overall “message to patients is GLP-1 receptor treatments remain a strong option for patients with diabetes and obesity and may have an additional, small favorable benefit in cancer,” Mavromatis explained at the press briefing.

'Intriguing Hypothesis'

Obesity is linked to an increased risk of developing more than a dozen cancer types, including esophageal, colon, rectal, stomach, liver, gallbladder, pancreatic, kidney, postmenopausal breast, ovarian, endometrial and thyroid, as well as multiple myeloma and meningiomas.

About 12% of Americans have been prescribed a GLP-1 medication to treat diabetes and/or obesity. However, little is known about how these drugs affect cancer risk.

To investigate, Mavromatis and colleagues used the Optum healthcare database to identify 170,030 adults with obesity and type 2 diabetes from 43 health systems in the United States.

Between 2013 and 2023, half started a GLP-1 agonist and half started a DPP-4 inhibitor, with propensity score matching used to balance characteristics of the two cohorts.

Participants were a mean age of 56.8 years, with an average body mass index of 38.5; more than 70% were White individuals and more than 14% were Black individuals.

During a mean follow-up of 3.9 years, 2501 new obesity-related cancers were identified in the GLP-1 group and 2671 in the DPP-4 group — representing a 7% overall reduced risk for any obesity-related cancer in the GLP-1 group (hazard ratio [HR], 0.93).

When analyzing each of the 14 obesity-related cancers separately, the protective link between GLP-1 use and cancer was primarily driven by colon and rectal cancers. GLP-1 users had a 16% lower risk for colon cancer (HR, 0.84) and a 28% lower risk for rectal cancer (HR, 0.72).

“No other cancers had statistically significant associations with GLP-1 use,” Mavromatis told briefing attendees. But “importantly, no cancers had statistically significant adverse associations with GLP-1 use,” he added.

Experts have expressed some concern about a possible link between GLP-1 use and pancreatic cancer given that pancreatitis is a known side effect of GLP-1 use. However, “this is not borne out by epidemiological data,” Mavromatis said.

“Additionally, we were not able to specifically assess medullary thyroid cancer, which is on the warning label for several GLP-1 medications, but we did see a reassuring lack of association between GLP-1 use and thyroid cancer as a whole,” he added.

During follow-up, there were 2783 deaths in the GLP-1 group and 2961 deaths in the DPP-4 group — translating to an 8% lower risk for death due to any cause among GLP-1 users (HR, 0.92; P = .001).

Mavromatis and colleagues observed sex differences as well. Women taking a GLP-1 had an 8% lower risk for obesity-related cancers (HR, 0.92; P = .01) and a 20% lower risk for death from any cause (HR, 0.80; P < .001) compared with women taking a DPP-4 inhibitor.

Among men, researchers found no statistically significant difference between GLP-1 and DPP-4 use for obesity-related cancer risk (HR, 0.95; P = .29) or all-cause mortality (HR, 1.04; P = .34).

Overall, Mavromatis said, it’s important to note that the absolute risk reduction seen in the study is “small and the number of patients that would need to be given one of these medications to prevent an obesity-related cancer, based on our data, would be very large.”

Mavromatis also noted that the length of follow-up was short, and the study assessed primarily older and weaker GLP-1 agonists compared with newer agents on the market. Therefore, longer-term studies with newer GLP-1s are needed to confirm the effects seen as well as safety.

In a statement, ASCO President Robin Zon, MD, said this trial raises the “intriguing hypothesis” that the increasingly popular GLP-1 medications might offer some benefit in reducing the risk of developing cancer.

Zon said she sees many patients with obesity, and given the clear link between cancer and obesity, defining the clinical role of GLP-1 medications in cancer prevention is “important.”

This study “leads us in the direction” of a potential protective effect of GLP-1s on cancer, but “there are a lot of questions that are generated by this particular study, especially as we move forward and we think about prevention of cancers,” Zon told the briefing.

This study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. Mavromatis reported no relevant disclosures. Zon reported stock or ownership interests in Oncolytics Biotech, TG Therapeutics, Select Sector SPDR Health Care, AstraZeneca, CRISPR, McKesson, and Berkshire Hathaway.

A version of this article first appeared on Medscape.com.

Veterans enrolled in the US Department of Veterans Affairs (VA) who have been referred to Community Care no longer need a second review from a VA clinician according to a new policy. The provision implements language from the Senator Elizabeth Dole 21st Century Veterans Healthcare and Benefits Improvement Act. VA officials hope that it will speed up access to community care.

The move expands on the 2019 MISSION Act, which allows eligible veterans to access health care from non-VA clinicians that is paid for by the VA when it is in their “best medical interest.” Those decisions, however, were not considered final until reviewed by a second VA doctor.

The Dole Act prohibits VA administrators from overriding a VA doctor’s referral for a patient to receive outside care. According to the law, the ban on administrative review will remain in place for 2 years, after which the VA must report on its effects to Congress. The VA announced it would begin training employees to ensure the community care referral process is followed in compliance with the Dole Act. 

Analysis from the Veterans Healthcare Policy Institute claims the best medical interest criterion “is to be considered when a veteran's health and/or well-being would be compromised if they were not able to be seen in the community for the requested clinical service.”

During a March hearing, Rep. Julia Brownley (D-CA), ranking Democrat on the House Veterans’ Affairs subcommittee on health, said any veteran who seeks residential treatment should get it, but noted the VA has not developed a fee schedule for community treatment centers. In at least 1 case, she said, the department was charged up to $6000 a day for 1 patient. Brownley also noted that the VA doesn't track the timeliness or quality of medical care in community residential treatment facilities.

“We have no way of knowing the level of treatment or support they are getting,” she said. “We must find a balance between community care and VA direct care. In my opinion, we have not found that balance when it comes to residential rehabilitation treatment facilities.”

At the same hearing, chair of the House Veterans Affairs health subcommittee Rep. Mariannette Miller-Meeks (R-IA) said more change is needed—specifically to ensure that veterans also can access private residential substance abuse treatment centers. Some, she said, “are told they cannot access community care unless a VA facility fails to meet a 20-day threshold—forcing them to wait, even when immediate, alternative options exist."

The House of Representatives passed H.R. 1969, the No Wrong Door for Veterans Act, in May, which expands the VA suicide prevention grant program. However, the Senate has yet to take up the legislation. “I’ve seen firsthand how difficult it can be for veterans in crisis to navigate a complicated system when every second counts,” Miller-Meeks said. “The No Wrong Door for Veterans Act ensures that our heroes are never turned away or left without help. It streamlines access, strengthens coordination, and reaffirms our promise to those who served.”

Veterans enrolled in the US Department of Veterans Affairs (VA) who have been referred to Community Care no longer need a second review from a VA clinician according to a new policy. The provision implements language from the Senator Elizabeth Dole 21st Century Veterans Healthcare and Benefits Improvement Act. VA officials hope that it will speed up access to community care.

The move expands on the 2019 MISSION Act, which allows eligible veterans to access health care from non-VA clinicians that is paid for by the VA when it is in their “best medical interest.” Those decisions, however, were not considered final until reviewed by a second VA doctor.

The Dole Act prohibits VA administrators from overriding a VA doctor’s referral for a patient to receive outside care. According to the law, the ban on administrative review will remain in place for 2 years, after which the VA must report on its effects to Congress. The VA announced it would begin training employees to ensure the community care referral process is followed in compliance with the Dole Act. 

Analysis from the Veterans Healthcare Policy Institute claims the best medical interest criterion “is to be considered when a veteran's health and/or well-being would be compromised if they were not able to be seen in the community for the requested clinical service.”

During a March hearing, Rep. Julia Brownley (D-CA), ranking Democrat on the House Veterans’ Affairs subcommittee on health, said any veteran who seeks residential treatment should get it, but noted the VA has not developed a fee schedule for community treatment centers. In at least 1 case, she said, the department was charged up to $6000 a day for 1 patient. Brownley also noted that the VA doesn't track the timeliness or quality of medical care in community residential treatment facilities.

“We have no way of knowing the level of treatment or support they are getting,” she said. “We must find a balance between community care and VA direct care. In my opinion, we have not found that balance when it comes to residential rehabilitation treatment facilities.”

At the same hearing, chair of the House Veterans Affairs health subcommittee Rep. Mariannette Miller-Meeks (R-IA) said more change is needed—specifically to ensure that veterans also can access private residential substance abuse treatment centers. Some, she said, “are told they cannot access community care unless a VA facility fails to meet a 20-day threshold—forcing them to wait, even when immediate, alternative options exist."

The House of Representatives passed H.R. 1969, the No Wrong Door for Veterans Act, in May, which expands the VA suicide prevention grant program. However, the Senate has yet to take up the legislation. “I’ve seen firsthand how difficult it can be for veterans in crisis to navigate a complicated system when every second counts,” Miller-Meeks said. “The No Wrong Door for Veterans Act ensures that our heroes are never turned away or left without help. It streamlines access, strengthens coordination, and reaffirms our promise to those who served.”

Veterans enrolled in the US Department of Veterans Affairs (VA) who have been referred to Community Care no longer need a second review from a VA clinician according to a new policy. The provision implements language from the Senator Elizabeth Dole 21st Century Veterans Healthcare and Benefits Improvement Act. VA officials hope that it will speed up access to community care.

The move expands on the 2019 MISSION Act, which allows eligible veterans to access health care from non-VA clinicians that is paid for by the VA when it is in their “best medical interest.” Those decisions, however, were not considered final until reviewed by a second VA doctor.

The Dole Act prohibits VA administrators from overriding a VA doctor’s referral for a patient to receive outside care. According to the law, the ban on administrative review will remain in place for 2 years, after which the VA must report on its effects to Congress. The VA announced it would begin training employees to ensure the community care referral process is followed in compliance with the Dole Act. 

Analysis from the Veterans Healthcare Policy Institute claims the best medical interest criterion “is to be considered when a veteran's health and/or well-being would be compromised if they were not able to be seen in the community for the requested clinical service.”

During a March hearing, Rep. Julia Brownley (D-CA), ranking Democrat on the House Veterans’ Affairs subcommittee on health, said any veteran who seeks residential treatment should get it, but noted the VA has not developed a fee schedule for community treatment centers. In at least 1 case, she said, the department was charged up to $6000 a day for 1 patient. Brownley also noted that the VA doesn't track the timeliness or quality of medical care in community residential treatment facilities.

“We have no way of knowing the level of treatment or support they are getting,” she said. “We must find a balance between community care and VA direct care. In my opinion, we have not found that balance when it comes to residential rehabilitation treatment facilities.”

At the same hearing, chair of the House Veterans Affairs health subcommittee Rep. Mariannette Miller-Meeks (R-IA) said more change is needed—specifically to ensure that veterans also can access private residential substance abuse treatment centers. Some, she said, “are told they cannot access community care unless a VA facility fails to meet a 20-day threshold—forcing them to wait, even when immediate, alternative options exist."

The House of Representatives passed H.R. 1969, the No Wrong Door for Veterans Act, in May, which expands the VA suicide prevention grant program. However, the Senate has yet to take up the legislation. “I’ve seen firsthand how difficult it can be for veterans in crisis to navigate a complicated system when every second counts,” Miller-Meeks said. “The No Wrong Door for Veterans Act ensures that our heroes are never turned away or left without help. It streamlines access, strengthens coordination, and reaffirms our promise to those who served.”