Question
I am currently caring for a 74-year-old man with a 2-month history of progressive nephrotic syndrome and cholestatic jaundice. What are the most likely diagnoses to consider?
Response from Mark E. Williams, MD
This is a challenging clinical situation involving the differential diagnosis of cholestatic jaundice and rapidly evolving nephrotic syndrome in a 74-year-old man. The analysis described below presumes that the past medical history is unrevealing (for example, no previous hepatitis B or C virus [HBV and HCV]) and that there are no obvious findings on physical examination, such as purpura, lymphadenopathy, or splenomegaly. It also assumes that the basic laboratory findings were negative, including no evidence of thrombocytopenia. The following response focuses on the conditions that are easy to overlook.
Response from Mark E. Williams, MD
Amyloidosis is a systemic disease in which amorphous material (called "amyloid" by Rudolph Virchow because liver biopsy specimens, when viewed microscopically, resembled starch) is deposited in body tissues. All amyloid proteins produce apple green birefringence under polarized light and stain with Congo red. The usual presentation of renal amyloid is heavy proteinuria and nephrotic syndrome. Renal failure is the leading cause of death in systemic amyloidosis, occurring in up to 50% of patients.[1] Over 90% of patients with systemic amyloidosis have liver involvement and many have hepatomegaly. Jaundice is caused by intrahepatic cholestasis. If ascites is present, it is usually caused by an associated nephrotic syndrome rather than by portal hypertension. Light-chain deposition disease, a variant of multiple myeloma and related to amyloid, also produces nephrotic syndrome and commonly affects the liver.[2]
Response from Mark E. Williams, MD
Nephrotic syndrome is sometimes associated with malignancy, including solid tumors and lymphoma. Membranous nephropathy is the cause in two thirds of patients with nephrotic syndrome and carcinomas (especially of the lung and colon). It results from immune complex-mediated injury (eg, by the carcinoembryonic antigen).[3] The presence of jaundice would favor colon cancer with liver metastasis in this patient.
Hodgkin's disease, and less often non-Hodgkin's lymphoma or leukemia, can also be associated with nephrotic syndrome due to minimal-change disease or focal glomerulosclerosis. The activity of minimal-change nephropathy often parallels the activity of the underlying lymphoma.
Response from Mark E. Williams, MD
Henoch-Schönlein purpura is a leukocytoclastic vasculitis with the deposition of immune complexes containing immunoglobulin (Ig)A. It commonly affects the skin, joints, and gastrointestinal (GI) tract. Renal involvement is common (45% to 85% of cases), and the long-term prognosis depends on severity. In 1 series, mortality was high and was secondary to malignancy involving the upper respiratory and digestive tracts.[4] The pathophysiology of Henoch-Schönlein purpura has been attributed to abnormal IgA clearance, and interestingly, the mucosa of the lungs and GI tract both secrete IgA.
Response from Mark E. Williams, MD
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder that commonly involves the kidney. Lupus nephritis is a frequent and serious complication of SLE. It is the strongest predictor of prognosis. Its prevalence ranges from 29% to 75%. Clinical manifestations of renal involvement can range from mild abnormalities of the urinary sediment to fulminant nephrotic syndrome that rapidly progresses to renal failure. Diffuse proliferative or membranous glomerulonephritis (GN) is the most common underlying pathology.
Liver involvement is uncommon, but mildly abnormal levels of liver enzymes frequently are observed, especially in patients who have active disease or who are taking nonsteroidal anti-inflammatory drugs. A patient who develops acute right upper quadrant pain and ascites suggests Budd-Chiari syndrome, which is related to the presence of lupus anticoagulant.[5] These symptoms may represent the first presentation of SLE.
Response from Mark E. Williams, MD
IgA is produced by the GI tract and upper respiratory mucosa, and in healthy individuals, mucosal IgA is not found in the systemic circulation. In patients with cirrhosis, reduced clearance and impaired immune function lead to the increased production and systemic circulation of IgA. Most patients with alcoholic cirrhosis and IgA nephropathy are asymptomatic (from a renal standpoint) with microscopic hematuria being the most common finding. Nephrotic syndrome is unusual, occurring in about 5% of patients, but may be heralded by the development of systemic hypertension. Patients with cirrhosis and portal hypertension rarely have systemic arterial hypertension, so the presence of systemic arterial hypertension suggests GN.
Response from Mark E. Williams, MD
Various glomerular lesions have been described in HBV infection with a prevalence of 2% to 16%.[6] The most common are membranous GN and membranoproliferative GN; IgA nephropathy, focal glomerulosclerosis, and minimal change disease are less likely, but not rare. Patients usually present with nephrotic syndrome, gross peripheral edema, and fatigue. HBV-associated vasculitis due to polyarteritis nodosa or essential mixed cryoglobulinemia is less likely a cause of nephrotic syndrome.
Response from Mark E. Williams, MD
HCV infection can produce renal impairment through immune mechanisms. Membranoproliferative GN is the most common abnormality.[7] Approximately half of patients with HCV infection and renal involvement have some degree of renal insufficiency. Patients with membranous GN usually present with nephrotic syndrome.[8]
Response from Mark E. Williams, MD
Sarcoidosis is an idiopathic disease characterized by the presence of noncaseating granulomas. The lungs are most often affected, although any organs can be involved. Liver involvement is common, but clinical and symptomatic liver disease is unusual. Hepatic sarcoidosis may mimic primary biliary cirrhosis and be accompanied by severe cholestasis with jaundice, pruritus, and hypercholesterolemia.[9]
Renal sarcoidosis is usually related to hypercalcemia and nephrolithiasis. However, some patients with sarcoidosis can have granulomatous interstitial nephritis. These patients typically present with mild edema and proteinuria.
Response from Mark E. Williams, MD
Many pharmacologic agents have the potential to cause liver and renal damage. Drug-induced liver disease is an important cause of jaundice, and is the most common cause of fulminant hepatic failure. Some pharmaceuticals, such as acetaminophen, can have a dose-dependent hepatotoxic effect so that the damage is often predictable, especially in large doses. Other drugs can have more unpredictable effects that are immunologically mediated and are often associated with extrahepatic manifestations of hypersensitivity.
Renal toxicity is frequently related to the accumulation of toxins that can injure the tubules and interstitium. The urinary concentrating mechanism can markedly increase the levels of toxins, especially in the medullary and the papillary nephrons. Hypersensitivity reactions can also impair the kidney, producing glomerulonephropathies.
Medscape Internal Medicine. 2004;6(1) © 2004 Medscape
Cite this: Mark E Williams. Elderly Man With Progressive Nephrotic Syndrome and Jaundice - Medscape - Jun 11, 2004.
