Clinical manifestations


Asymptomatic disease and early progression. The progression of HCV infection to cirrhosis is often asymptomatic and clinically silent. In chronic hepatitis, the correlation of biochemical liver function test (LFT) values and virological markers with clinical manifestations and progression is poor.10 Patients may report nonspecific fatigue, anorexia, myalgia and arthralgia, symptoms of upper respiratory infection, nausea, intolerance to alcohol and fatty food, right upper quadrant abdominal pain, fever, jaundice, or night sweats. 


Of all the etiologic agents of viral hepatitis, HCV is the one most likely to remain subclinical. Symptoms in early progression are highly variable, and the most common presentation is either no abnormality or mild hepatomegaly.10 Patients report that their disease affects parameters of quality of life in general: mental health perception, physical and social function, and vitality. Successful clearance of HCV improves scores.10

Progression to advanced liver disease. In 15% to 20% of patients in whom chronic HCV infection develops, cirrhosis occurs within 15 to 40 years after the original infection. Among those with cirrhosis, liver failure occurs in 20% to 30% and hepatocellular carcinoma in 10% to 15% over 10 years (Table 3).10

Click to enlarge.

Manifestations of cirrhosis are consistent with a lack of hepatic synthetic function and include the following: hypoalbuminemia with subsequent edema, ascites, and fluid retention; increased lethargy; and coagulopathy due to decreased clotting factor production. Patients report malaise, anorexia, nausea, vomiting, and generalized pruritus resulting from bile salt irritation of the peripheral nerves. The liver may be enlarged or decreased in size with nodularity. In addition, derangement of the hepatic metabolism results in mixed hyperbilirubinemia with jaundice and increased estrogen levels, with resulting palmar erythema, spider nevi, gynecomastia, and testicular atrophy. 


Cirrhosis is the most common cause of portal hypertension, which leads to varices and hepatosplenomegaly. Complications of advanced liver disease and failure, which herald a poor prognosis, include spontaneous bacterial peritonitis, hepatic encephalopathy, variceal bleeding, hepatorenal syndrome, and hepatocellular carcinoma.10 Hepatic encephalopathy should be expected in a patient with a reversal of diurnal sleep patterns, forgetfulness, or inappropriate behavior. 


Extrahepatic manifestations. At least one extrahepatic manifestation develops in approximately 40% to 74% of patients with chronic HCV infection, most commonly affecting the skin, joints, kidneys, and nervous system.2,9,10,11 It is imperative for clinicians to consider the potential range of associated disease processes in HCV infection, particularly because there may not be any obvious manifestations of chronic liver disease in these patients.9 Awareness will facilitate a more prompt diagnosis and timely treatment. 


The disorder most commonly associated with HCV infection is mixed cryoglobulinemia (MC), which is a pathophysiological predecessor of many other associated disorders. HCV infection is present in 50% to 100% of patients with MC, and 10% to 50% of patients with HCV infection develop MC.9 HCV causes the chronic stimulation of lymphocytes, which induces the clonal expansion of B cells and the production of antibodies.9,11 In MC, polyclonal immunoglobulins, which are bound to complement and immune complexes containing HCV, reversibly precipitate in the serum at temperatures below 37°C. These complex immune protein particles deposit in small and medium-size blood vessels, causing vasculitis; they also deposit in other organs, including the skin, kidneys, and peripheral nerves. A variety of disorders seen in chronic HCV infection are related to MC, such as leukocytoclastic vasculitis with palpable purpura, peripheral neuropathies including mononeuritis multiplex, renal disease (27%-60%9,11) and nephrotic syndrome, sicca syndrome, and non-Hodgkin lymphoma9,11; however, these conditions may also occur in HCV infection in the absence of MC. MC is diagnosed through history and the presence of the following: palpable purpura/organ involvement, low levels of complement, circulating cryoglobulins and rheumatoid factor, and vasculitis on histology.9,11

Membranoproliferative glomerulonephritis (MPGN) is the most common HCV-related nephropathy, resulting from the deposition of cryoglobulins in the mesangium and glomerular capillaries. Porphyria cutanea tarda and lichen planus are two skin disorders strongly associated with HCV infection. 


In 40% to 65% of patients with HCV-infection, HCV-mediated B-cell clonal expansion results in the production of antibodies associated with autoimmune disorders. These include the following: antinuclear antibody (ANA); rheumatoid factor (RF); anticardiolipin; anti-smooth muscle; anti-liver, kidney, and microsomal antibodies; anti-thyroid peroxidase; and anti-mitochondrial and/or anti-double-stranded DNA.11,12 In a consideration of autoimmune disorders as the cause of extrahepatic manifestations of HCV infection, it should be noted that the titers of these antibodies will be low, there is no gender predominance, and there is no association with specific HLA-DR genes.11 Arthralgia, fatigue, and fibromyalgia are more common in patients with HCV infection.