They were intrigued by the patient's many extra-hepatic manifestations -- vascular lesions on the lower limbs, acute pain in the joints, intense tingling of the fingers, and extreme labor-impairing fatigue. They were also intrigued by the presence of cryoglobulins in the patient's blood. Two years later, the patient developed enlarged lymph nodes on the neck. When one of the nodes was histologically tested, the patient was found to have lymphoma.

This case spurred the interest of the investigators in the extra-hepatic manifestations and complications of HCV infection, and for over a decade they studied the links between HCV infection, cryoglobulinemia, and lymphoma.

A research article published on December 28, 2007 in the World Journal of Gastroenterology addresses this problem. In a study of 136 Bulgarian patients with HCV, the team of Tchernev and Petrova found 76.5% of the patients had extra-hepatic manifestations. Common manifestations were fatigue (59.6%), renal impairment (25%), type 2 diabetes (22.8%), paresthesia (19.9%), arthralgia (18.4%), and purpura predominantly of the lower limbs (17.6%). Over 37% of the patients had cryoglobulins, and 8.8% had B-cell lymphoma.

The study found positive links between the presence of extra-hepatic manifestations and age, female gender, duration of the infection, infection by transfusion of blood and blood products, and extensive liver fibrosis. Therefore, elderly women with chronic HCV and advanced liver fibrosis, who were infected by transfusion during childbirth, are at the highest risk of developing extra-hepatic manifestations of HCV infection.

The study also showed most extra-hepatic manifestations of HCV infection are associated with the presence of cryoglobulins. In particular, the risks of developing B-cell non-Hodgkin lymphoma are much higher in cryoglobulin-positive than in cryoglobulin-negative patients. In the study, 17.6% of cryoglobulin-positive patients had lymphoma, whereas only 3.5% of cryoglobulin-negative patients did.

Given the prevalence of HCV around the world, it is important for physicians to recognize the extra-hepatic signs and symptoms of HCV infection. Patients who exhibit such manifestations should be tested for HCV infection. This can lead to prompt diagnosis and effective treatment of the infection before the development of cryoglobulinemia, when treatment gives poor results or is ineffective.

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