Original articles report and assess current issues of concern in gastroenterology

Cryoglobulinemia and Other Extrahepatic Manifestations of Chronic Hepatitis C Including Diabetes and Lymphoma

Sanjiv Chopra, MD
December 6, 2000

In addition to causing both acute and chronic hepatitis, cirrhosis and primary hepatocellular carcinoma, chronic HCV infection may be associated with several extrahepatic diseases. These include the following:

  • Hematological disorders such as essential mixed cryoglobulinemia, monoclonal gammopathies and lymphoma
  • Renal disease, most commonly membranoproliferative glomerulonephritis
  • Dermatological disorders such as porphyria cutanea tarda, leukocytoclastic vasculitis and lichen planus
  • Autoimmune disorders such as thyroid disease, sialoadenitis, autoimmune ITP and diabetes mellitus

These extrahepatic manifestations can on occasion be responsible for significant morbidity and even mortality while the liver disease per se in such individuals may not be present at an advanced stage.

Essential Mixed Cryoglobulinemia (EMC): EMC is a lymphoproliferative disorder that can lead to deposition of circulating immune complexes in small- to medium-sized blood vessels. The classical triad consists of palpable purpura, arthralgias and weakness. Patients can also have involvement of the kidneys, peripheral nerves and brain.

Chronic HCV infection appears to play an etiological role in most patients with EMC. Three studies of 101 patients with this disorder found that 95% had polyclonal IgG anti-HCV antibodies within the cryoprecipitate and HCV RNA in the plasma and particularly in the cryoprecipitate. The association of EMC and chronic HCV may be linked to the ability of the virus to bind to B lymphocytes via CD81. Binding may lower the activation thresholds of these cells thereby promoting the production of autoantibodies.

Anti-HCV antibodies can be detected in the vessel walls of skin biopsies from patients with EMC and cutaneous vasculitis. When patients respond to treatment with interferon alpha the skin lesions and symptoms improve together with a drop in the cryoglobulin levels.

Cryoglobulins can also be found in patients with other forms of chronic liver disease. In a study that prospectively evaluated the prevalence of cryoglobulins in more than 200 patients with chronic liver disease, cryoglobulins were detected in 15% of chronic HBV positive patients and 32% of those with other chronic liver disorders. Cryoglobulinemia was more likely if the patients had cirrhosis.

Renal disease in patients with mixed cryoglobulinemia is present in approximately 20% of patients at the time of diagnosis and eventually occurs in 35–60% of patients with Type II disease. Histological examination reveals thickening of the glomerular basement membrane and cellular infiltration, intraluminal thrombi and diffuse IgM deposition. Subendothelial deposits with a characteristic fingerprint pattern are seen at electronmicroscopy.

The kidney disease usually becomes clinically evident after appearance of purpura. Most patients have asymptomatic hematuria and proteinuria. Acute renal failure and/or the nephrotic syndrome occur in some patients.

The diagnosis of cryoglobulinemia is typically made from the history, presence of purpura, low complement levels and demonstration of circulating cryoglobulins. To assess for cyroglobulins, 20 ml. of blood should be drawn in the fasting state into a tube not treated with an anticoagulant. The tubes should be placed in warm water (37° C) and transported to the laboratory. The serum is separated by centrifugation and placed in a 4° C refrigerator to see if precipitation occurs over the next 48–72 hours.

Renal biopsy should be reserved for patients with progressive disease or in whom the diagnosis is in doubt. Aggressive therapy in mixed cryoglobulinemia is generally reserved for patients with acute severe disease, as manifested by distal necroses requiring amputation, advanced neuropathy, or progressive renal failure. Although there are no controlled studies, a recommended regimen often includes plasmapharesis (which removes the circulating cryoglobulins) in conjunction with steroids and cyclophosphamide. Renal function most often stabilizes with this regimen.

Antiviral therapy has been employed using interferon alpha and can result in improvement in cutaneous vasculitis, plasma creatinine concentration and lead to a drop in the cryocrit.

Currently there are no studies published concerning the effectiveness of interferon plus ribavirin in patients with HCV induced cryoglobulinemia.

In a recent report, the authors examine the prognosis of 105 patients with cryoglobulinemia and renal involvement, of whom 85% were hepatitis C virus antibody positive, prior to treatment with interferon. Fifteen years after the diagnosis, survival was 50%, with most deaths due to hepatic or cardiovascular disease or infection. Only 14% developed end-stage renal disease at 10 years after renal biopsy.

Renal transplantation has been successfully performed in patients with essential mixed cryoglobulinemia. Unfortunately, clinically significant disease can recur in 50–70% of patients with affected patients presenting with purpura, hematuria, proteinuria, renal insufficiency and hypocomplementemia.

Lymphoma: Several reports have described an association between chronic HCV and B cell non-Hodgkin's lymphoma (NHL). In one study, 32% of 50 Italian patients with NHL had HCV viremia. By comparison, HCV seropositivity was present in only 1.3% of healthy controls and 3% of patients with Hodgkin's lymphoma.


HCV RNA has been isolated from the involved lymph nodes of patients with immunocytoma, a low-grade malignancy previously linked to cryoglobulinemia.

In a study from Toronto, 24 patients with chronic HCV infection and clinically significant cryoglobulinemia were identified within a population of approximately 1500 patients with chronic HCV. Sixteen of these 24 patients agreed to undergo bone marrow aspirates and biopsies which were subjected to molecular genetic testing and flow cytometric analysis. Nine (56%) had abnormal bone marrow morphology, including 7 (44%) highly suspicious for lymphoma and 2 (13%) consistent with non-Hodgkin's lymphoma. None of the patients had systemic symptoms.

The association with HCV and lymphoma has not been detected in all published studies. Nevertheless, the development of lymphadenopathy or progressive or unexplained anemia in a patient with chronic hepatitis C should raise concern about the possibility of an underlying lymphoproliferative disorder. It is not known whether treatment of the chronic hepatitis C infection is of benefit in such patients.

Diabetes Mellitus: Chronic HCV has been linked to diabetes mellitus in at least half a dozen epidemiological studies. In a retrospective analysis of 1,117 patients with chronic viral hepatitis, diabetes was noted in significantly more patients with chronic HCV compared to chronic HBV (21 vs. 12%). Furthermore, the prevalence of HCV infection was significantly higher among patients with diabetes mellitus compared to patients with thyroid disease (4.2 vs. 1.6%).

There is anecdotal information suggesting a high rate of abnormal glucose tolerance tests in patients with chronic hepatitis C. Additionally, on rare occasions, the diabetes mellitus significantly abates following successful treatment of chronic hepatitis C virus infection. The pathophysiology is not known but could conceivably be a consequence of insulin resistance secondary to increased levels of tumor necrosis factor.

Porphyria Cutanea Tarda (PCT): PCT is a skin disease caused by a reduction of hepatic uroporphyrinogen decarboylase activity. The syndrome is characterized by photosensitivity, skin fragility, bruising and vesicles or bullae. In three studies that examined 209 patients, hepatitis C virus antibodies were detected in 75% of patients with sporadic PCT. Patients with PCT positive for hepatitis C also tend to have more advanced liver disease than those without chronic hepatitis C infection.

Currently it is recommended that all patients with PCT be tested for HCV infection in addition to other potential precipitating factors. Reasonable guidelines for treatment include phlebotomy, followed by antiviral treatment.


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