Hepatitis: Musculoskeletal ManifestationsDz

ICD-9 Codes: Hepatitis A, 070.1; hepatitis B, 070.30; acute hepatitis C, 070.51; chronic hepatitis C, 070.54; lupoid hepatitis, 571.49; chronic active hepatitis, 571.49; drug-induced hepatitis, 573.3.

Definition: A variety of musculoskeletal disorders may be associated with hepatitis A virus (HAV), hepatitis B virus (HBV), or hepatitis C virus (HCV).

Etiology: The arthritis associated with acute HBV infection involves a serum sickness syndrome, with formation of circulating immune complexes. Immune complexes are deposited in joints and other parts of the body when the quantity of viral antigens approximates that of the antiviral antibodies. This is often transient, occurring as antigen levels fall and antibody levels rise, typically in the prodromal phase of clinical infection. In addition to arthritis, maculopapular rash, urticaria, and renal disease may result from formation of circulating immune complexes. In chronic HBV and HCV infections, formation of cryoglobulins (especially HCV) or induction of PAN can further lead to arthritic symptoms. Intermittent viremia may be responsible for chronic arthritis reported in both HBV and HCV infection. A direct viral cytopathogenic effect on the synovium has also been postulated in HBV infection.

Demographics
—HAV: Infection is transmitted enterally. The precise number of cases is not known; 30,000 cases/year are reported by the Centers for Disease Control and Prevention. Actual numbers are likely much higher because the illness is frequently subclinical (30%–50% of adults have serologic evidence of past exposure to HAV, but only 3%–5% recall a clinically compatible acute illness). Transient arthralgia has been reported in 10% of patients and is twice as frequent in icteric patients. Arthritis rarely occurs in HAV infection.
—HBV: Transmitted parenterally, sexually, and vertically, 200,000 cases of HBV occur annually in the United States, with 6% to 10% becoming chronic. Most cases occur in young adults, especially in high-risk groups such as parenteral drug users and some immigrant groups from endemic regions. Arthralgias develop in 25% of patients and frank arthritis in 10%; there is a slight male preponderance (1.5:1 male:female ratio).
—HCV: Antibodies to HCV are detected in 1.4% of the U.S. population. Prevalence is higher in developing countries (>3%). Transmission is primarily via contaminated blood. Risk factors include parenteral drug use, tattooing, blood transfusions, and hemodialysis. In 40% to 50%, no risk factors can be identified. Persistent infection occurs in 50% to 60% of patients. HCV-associated arthritis is uncommon. Arthritic syndromes associated with type II cryoglobulinemia are more commonly symptomatic.

Cardinal Findings
—HAV: Transient arthralgias may occur in acute infection. A transient serum sickness-like syndrome uncommonly occurs.
—HBV: The most common rheumatic syndrome in acute HBV infection is abrupt onset of a severe, symmetric polyarthritis in the prodromal phase. Simultaneous joint involvement is the usual pattern; occasionally a migratory or additive pattern is observed. The arthritis and rash are often short-lived and typically disappear with the onset of jaundice. Urticaria, petechiae, and maculopapular eruptions commonly accompany the arthritis. A similar syndrome, after HBV vaccination, has been reported. In 1% of cases of chronic HBV infection, PAN may occur with necrotizing vasculitis, mononeuritis multiplex, and fever. HBV-associated glomerulonephritis is a variant of this condition.
—HCV: As many as one-third of patients with chronic HCV will have rheumatic complaints that may include an acute arthritis (rare), chronic RA-like arthritis affecting small joints and associated with lowtiter positive RF and ESR elevations, and an intermittent mono/oligoarthritis (usually with cryoglobulins) of large and medium-sized joints. RA-like arthritis is typically nonerosive. Mixed cryoglobulinemia (type II cryoglobulins) has been strongly associated with chronic HCV infection (30%–90%) with associated membranoproliferative glomerulonephritis. Chronic HCV infection has been associated with Sjögren’s syndrome, psoriasis, or psoriatic arthritis, with sporadic reports occurring after interferon treatment.

Uncommon Findings
—HAV: Rarely, cryoglobulinemia may occur with purpura and arthritis. There are rare reports of inflammatory reactive arthritis after HAV vaccination.
—HBV: Cryoglobulinemia may occur. In persistent HBV infection, chronic polyarthritis may occur.
—HCV: Anti-HCV antibodies have been detected in 14% of patients with PAN.

Diagnostic Tests: See Hepatitis: Serologic Tests for more information.
—HAV accounts for approximately 20% of cases of acute viral hepatitis in the United States. Anti-HAV IgM is found in acute HAV infection. Anti-HAV IgG indicates previous exposure to HAV. Serum transaminases rise in the prodromal phase and peak by the time jaundice develops. Other findings include leukopenia. In the icteric phase, many liver function abnormalities are noted, including hyperbilirubinemia and a prolonged prothrombin time, depending on the severity of the illness.
—HBV causes approximately 60% of cases of acute viral hepatitis in the United States. HBsAg is the first serologic marker to appear; anti-HBsAg follows. In chronic HBV infection, HBsAg (hepatitis B surface antigen) is detectable; anti-HBsAg is not. Serum transaminase levels vary and are often less than twice normal. Hyperbilirubinemia, if present, is usually mild. Serologic tests for ANA, RF, and native DNA are frequently positive in patients with acute or chronic HBV infection.
—HCV causes approximately 20% of cases of acute viral hepatitis in the United States (but HCV is responsible for 90% of posttransfusion hepatitis). IgG anti-HCV antibody is usually not seen until 2 to 6 months after acute infection. Biochemical abnormalities are typically mild; transaminase levels often wax and wane. More sensitive assays for HCV infection include ELISA, recombinant immunoblot assay, polymerase chain reaction (PCR), and branched DNA assay. Patients with HCV may be RF positive (75%) or ANA positive (>20%) or have anti–smooth muscle antibodies (>60%).

Differential Diagnosis
—Acute arthritis: Because arthritis occurs in the prodromal preicteric phase of hepatitis, clues to the correct diagnosis are few. Serum transaminases are frequently elevated, but the diagnosis is often made retrospectively, after jaundice develops. Nonetheless, acute polyarthritis, especially when accompanied by a serum sickness-like syndrome, should raise suspicion of acute viral hepatitis. Other viral infections presenting in a similar manner include rubella, mumps, Parvovirus B19, herpesviruses, HIV, enteroviruses, and a variety of arboviruses. At the outset, acute HBV infection may be mistaken for RA, SLE, rheumatic fever, Still’s disease, or gonococcal or reactive arthritis.
—Cryoglobulinemia: Detection of cryoglobulins should prompt testing for viral hepatitis (HBV, HCV). Other causes of cryoglobulinemia include connective tissue diseases and myeloproliferative and lymphoproliferative disorders.
—PAN: Ten to 25% of cases of classic PAN are associated with chronic HBV or HCV infection.

Keys to Diagnosis: The availability of sensitive and specific assays for viral hepatitis has greatly simplified diagnosis. A high index of suspicion, especially when such risk factors for viral hepatitis as household exposure, blood transfusion, hemodialysis, and parenteral drug use are present, is the main key to establishing the correct diagnosis.

Therapy
—Arthritis: Acute arthritis is managed symptomatically with analgesics or NSAIDs. Chronic or intermittent arthritis may require additional measures. Many DMARDs cannot be used owing to hepatotoxic effects. Gold, hydroxychloroquine, and corticosteroids have been used with modest success. Recent studies suggest that TNF inhibitors may be used safely in patients with HCV and without flare of HCV infection, but further studies are needed. There are reports of HBV exacerbation and fulminant hepatitis occurring with TNF inhibitor use.
—Cryoglobulinemia: Interferon alpha has been used successfully in the management of HCV infection. In patients with HCV-associated cryoglobulinemia, interferon alpha can decrease the cryocrit and improve purpura, but symptoms often rebound after discontinuation of therapy. Purpura and arthritis can be managed with NSAIDs. If visceral organs such as the kidney and lung are involved, corticosteroids and cyclophosphamide may be required. Plasma exchange also has a role as a supplementary measure, especially with fulminant disease. Liver transplantation may be indicated in selected patients with chronic HCV infection.
—PAN: PAN associated with HBV infection is often problematic to treat because interferon alpha has immunostimulatory effects and glucocorticoid therapy can exacerbate HBV infection. Corticosteroids are often used initially for rapid control of the most life-threatening manifestations of PAN. This can be followed by antiviral regimens of vidarabine or interferon alpha combined with cyclophosphamide, with plasma exchange playing a supplementary role.

Prognosis
—HAV: Arthritis is usually transient and self-limited.
—HBV: Arthritis is usually self-limited but may occasionally become chronic with persistent HBV infection. HBV-associated PAN, when treated, had an 83% survival rate in one series, compared with an untreated 5-year survival rate of 13%.
—HCV: Arthritis is usually transient; rarely, it is chronic. HCV-associated cryoglobulinemia has a 70% 10 year survival rate overall; it is lower in patients who develop renal disease.

BIBLIOGRAPHY

Olivieri I, Palazzi C, Padula A. Hepatitis C virus and arthritis. Rheum Dis Clin North Am 2003;29:111–122. PMID:12635503

Pyrsopoulos NT, Reddy KR. Extrahepatic manifestations of chronic viral hepatitis. Curr Gastroenterol Rep 200;3:71–78.PMID:11177698