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Cryoglobulins in nonalcoholic Fatty-liver disease: what is the association?

The history of cryoglobulinemia dates back to the 1930s, when it was first described in a patient with multiple myeloma.1 The modern era of cryoglobulinemia dates to 1966, when it was described by Meltzer and colleagues in a group of 9 patients presenting with a clinical triad of purpura, arthralgias, and weakness.2 Mixed cryoglobulinemia has been better characterized since 1990, after the discovery of the hepatitis C virus (HCV).3 
 
The exact pathogenesis of cryoglobulinemia is unclear. It is hypothesized that cryoglobulinemia is the result of a disturbed immune cascade with elevated B-cell activity, and the condition often progresses smoothly to non-Hodgkin lymphoma.4,5 Mixed cryoglobulinemias are associated with chronic inflammatory states such as systemic lupus erythematosus, Sjogren syndrome, and viral infections, particularly HCV infection.3,6 The variable manifestations of cryoglobulinemia are due to ischemia of tissues caused by occlusion of the vessel lumen. Symptoms, when present, range from a mixed cryoglobulin syndrome (eg, purpura, arthralgias, and asthenia) to more serious systemic vasculitis with neurologic and/or renal involvement. The prevalence of symptomatic cryoglobulinemia is estimated at 1:100,000. However, the overall prevalence of patients with circulating cryoglobulins is difficult to ascertain and is probably underestimated due to the overall prevalence of HCV infection worldwide. 
 
Studies have well established that the prevalence of nonalcoholic fatty-liver disease (NAFLD) in developed countries is increasing, paralleling the increasing incidence of obesity and metabolic syndrome.7 NAFLD has become the most prevalent cause of chronic liver disease worldwide. NAFLD can affect individuals of any age, race, and/or ethnicity. NAFLD is estimated to affect 1 in 3 adults, resulting in over 70 million adult Americans with this condition. Additionally, it is believed that 1 in 10 children/adolescents in the United States are affected by NAFLD.7 
 
The case reported by Giangreco and colleagues presents a 44-year-old male patient with a history of hypertension, hyperlipidemia, and fasting glucose intolerance who initially presented with elevated liver enzyme levels and a 6-week history of an erythematous macular/papular rash involving the trunk with sparring of the palms and soles.8 This presentation was associated with fever, chills, and arthralgias. Initially, the patient was diagnosed with contact dermatitis and treated with steroids. Subsequently, the patient had total resolution of symptoms for 6 weeks. However, symptoms then recurred, again associated with myalgias and fever. 
 
At that time, laboratory evaluation with regard to elevated liver enzyme levels revealed a largely negative serologic work-up for chronic liver disease, including negative results for serum viral hepatitis testing. Serologic work-up for hemochromatosis, Wilson disease, a-1 antitrypsin deficiency, and autoimmune hepatitis was negative, and HCV RNA was undetectable. Rheumatologic serologic work-up was also conducted and revealed a positive rheumatoid factor (RF; 51 IU/mL), low-titer positive antinuclear antibody (ANA) and anti—smooth muscle antibody at 1:40, decreased complement 4 levels, and normal complement 3 levels. Results of an extractable nuclear antigen panel—including ribonucleoprotein-smith, anti—Sjogren syndrome A, anti—Sjogren syndrome B, SCL-70, and anti—Jo-1 —were negative, as were peripheral antineutrophil cytoplasmic antibody testing results and anticardiolipins. Immunoglobulins, light chains, and serum protein electrophoresis were normal. Serum tested positive for the presence of cryoglobulins with a pattern consistent with type III cryoglobulinemia. 
 
A biopsy of the left thigh revealed superficial acute leukocytoclastic vasculitis. A liver biopsy revealed mixed microvesicular and macrovesicular steatosis involving 80% of the hepatic parenchyma with bridging fibrosis, mild portal chronic inflammation, and balloon-cell changes consistent with nonalcoholic steatohepatitis (NASH). Symptoms responded to immunosuppression but recurred 1 year after self-discontinuation of treatment. Rash responded again with reinitiation of mycophenolate mofetil.