Guest guest Posted December 12, 2008 Report Share Posted December 12, 2008 Hepatitis - Wikipedia, the free encyclopedia Hepatitis (plural hepatitides) implies injury to liver characterized by presence of inflammatory cells in the liver tissue. Etymologically from ancient Greek hepar (ηÏ?αÏ) or hepato - (ηÏ?Î±Ï " ο-), meaning 'liver,' and suffix -itis, denoting 'inflammation' (c. 1727). The condition can be self limiting, healing on its own, or can progress to scarring of the liver.Causes · Signs and symptoms · Types of hepatitishu.wikipedia.org/wiki/en:Hepatitis · Cached page http://emedicine.medscape.com/article/172356-overview C Wolf, MD, FACP, FACG, AGAF, Medical Director of Liver Transplantation, Westchester Medical Center, Professor of Clinical Medicine, Division of Gastroenterology and Hepatobiliary Diseases, Department of Medicine, New York Medical College Unnithan V Raghuraman, MD, FRCP, FACG, FACP, Consulting Staff, Department of Gastroenterology, St Medical Center Contributor Information and Disclosures Updated: Jul 31, 2008 a.. Print This b.. Email This a.. Overview b.. Differential Diagnoses & Workup c.. Treatment & Medication d.. Follow-up a.. References b.. Keywords Introduction Background During the past 30 years, remarkable advances have occurred in the understanding of the epidemiology, natural history, and pathogenesis of chronic hepatitis. The development of viral serologic tests has permitted hepatologists to differentiate chronic viral hepatitis from other types of chronic liver disease, including autoimmune hepatitis. Autoimmune hepatitis is now accepted as a chronic disease of unknown cause, characterized by continuing hepatocellular inflammation and necrosis, which tends to progress to cirrhosis. Immune serum markers frequently are present, and the disease often is associated with other autoimmune diseases. Autoimmune hepatitis cannot be explained on the basis of chronic viral infection, alcohol consumption, or exposure to hepatotoxic medications or chemicals. In 1950, Waldenstrom first described a form of chronic hepatitis in young women.1 This condition was characterized by cirrhosis, plasma cell infiltration of the liver, and marked hypergammaglobulinemia. Kunkel, in 1950, and Bearn, in 1956, described other features of the disease, including hepatosplenomegaly, jaundice, acne, hirsutism, cushingoid facies, pigmented abdominal striae, obesity, arthritis, and amenorrhea.2, 3 In 1955, Joske first reported the association of the lupus erythematosus (LE) cell phenomenon in active chronic viral hepatitis.4 This association led to the introduction of the term lupoid hepatitis by Mackay and associates in 1956.5 Researchers currently know that no direct link exists between systemic lupus erythematosus (SLE) syndrome and autoimmune hepatitis; thus, lupoid hepatitis is not associated with SLE. Autoimmune hepatitis now is recognized as a multisystem disorder that can occur in males and females of all ages. This condition can coexist with other liver diseases (eg, chronic viral hepatitis) and also may be triggered by certain viral infections (eg, hepatitis A) and chemicals (eg, minocycline). The histopathologic description of autoimmune hepatitis has undergone several revisions over the years. In 1992, an international panel codified the diagnostic criteria.6 The term autoimmune hepatitis was selected to replace terms such as autoimmune liver disease and autoimmune chronic active hepatitis. The panel waived the requirement of 6 months of disease activity to establish chronicity, expanded the histologic spectrum to include lobular hepatitis, and reaffirmed the nonviral nature of the disease. The panel also designated incompatible histologic features, such as cholestatic histology, the presence of bile duct injury, and ductopenia. Pathophysiology Evidence suggests that liver injury in a patient with autoimmune hepatitis is the result of a cell-mediated immunologic attack. This attack is directed against genetically predisposed hepatocytes. Aberrant display of human leukocyte antigen (HLA) class II on the surface of hepatocytes facilitates the presentation of normal liver cell membrane constituents to antigen-processing cells. These activated cells, in turn, stimulate the clonal expansion of autoantigen-sensitized cytotoxic T lymphocytes. Cytotoxic T lymphocytes infiltrate liver tissue, release cytokines, and help to destroy liver cells. The reasons for the aberrant HLA display are unclear. It may be initiated or triggered by genetic factors, viral infections (eg, acute hepatitis A or B, Epstein-Barr virus infection),7 and chemical agents (eg, interferon, melatonin, alpha methyldopa, oxyphenisatin, nitrofurantoin, tienilic acid). The asialoglycoprotein receptor and the cytochrome mono-oxygenase P-450 IID6 are proposed as the triggering autoantigens. Some patients appear to be genetically susceptible to developing autoimmune hepatitis. This condition is associated with the complement allele C4AQO and with the HLA haplotypes B8, B14, DR3, DR4, and Dw3. C4A gene deletions are associated with the development of autoimmune hepatitis in younger patients.8 HLA DR3-positive patients are more likely than other patients to have aggressive disease, which is less responsive to medical therapy; these patients are younger than other patients at the time of their initial presentation. HLA DR4-positive patients are more likely to develop extrahepatic manifestations of their disease.9 Evidence for an autoimmune pathogenesis includes the following: a.. Hepatic histopathologic lesions composed predominantly of cytotoxic T cells and plasma cells b.. Circulating autoantibodies (ie, nuclear, smooth muscle, thyroid, liver-kidney microsomal, soluble liver antigen, hepatic lectin) c.. Association with hypergammaglobulinemia and the presence of a rheumatoid factor d.. Association with other autoimmune diseases e.. Response to steroid and/or immunosuppressive therapy The autoantibodies described in these patients include the following: a.. Antinuclear antibody (ANA), primarily in a homogenous pattern b.. Anti-smooth muscle antibody (ASMA) directed at actin c.. Anti-liver-kidney microsomal antibody (anti-LKM-1) d.. Antibodies against soluble liver antigen (anti-SLA) directed at cytokeratins types 8 and 18 e.. Antibodies to liver-specific asialoglycoprotein receptor or hepatic lectin f.. Antimitochondrial antibody (AMA) - AMA is the sine qua non of primary biliary cirrhosis (PBC) but may be observed in the so-called overlap syndrome with autoimmune hepatitis. g.. Antiphospholipid antibodies10 Based on autoantibody markers, autoimmune hepatitis is recognized as a heterogeneous disorder and has been subclassified into 3 types. The distinguishing features of these types are noted in Table 1. Table 1. Clinical Characteristics of Autoimmune Hepatitis11 Open table in new window [ CLOSE WINDOW ] Table Clinical Features Type 1 Type 2 Type 3 Diagnostic autoantibodies ASMA ANA Antiactin Anti-LKM P-450 IID6 Synthetic core motif peptides 254-271 Soluble liver-kidney antigen Cytokeratins 8 and 18 Age 10 y-elderly Pediatric (2-14 y) Rare in adults Adults (30-50 y) Women (%) 78 89 90 Concurrent immune disease (%) 41 34 58 Gamma globulin elevation +++ + ++ Low IgA* No Occasional No HLA association B8, DR3, DR4 B14, Dr3, C4AQO Uncertain Steroid response +++ ++ +++ Progression to cirrhosis (%) 45 82 75 Clinical Features Type 1 Type 2 Type 3 Diagnostic autoantibodies ASMA ANA Antiactin Anti-LKM P-450 IID6 Synthetic core motif peptides 254-271 Soluble liver-kidney antigen Cytokeratins 8 and 18 Age 10 y-elderly Pediatric (2-14 y) Rare in adults Adults (30-50 y) Women (%) 78 89 90 Concurrent immune disease (%) 41 34 58 Gamma globulin elevation +++ + ++ Low IgA* No Occasional No HLA association B8, DR3, DR4 B14, Dr3, C4AQO Uncertain Steroid response +++ ++ +++ Progression to cirrhosis (%) 45 82 75 *Immunoglobulin A Frequency United States The frequency of autoimmune hepatitis among patients with chronic liver disease ranges from 11-23%. The disease accounts for about 6% of liver transplantations in the United States. International The incidence of type 1 autoimmune hepatitis is estimated to be 0.1-1.9 cases per 100,000 persons per year in Caucasian populations. The incidence is lower in Japan. Type 2 autoimmune hepatitis is more commonly described in southern Europe than in northern Europe, the United States, or Japan. Articles describe the prevalence of autoimmune hepatitis in Europe as being in the range of 11.6-16.9 cases per 100,000 persons. This is approximately the same prevalence as PBC and twice as high as the prevalence of primary sclerosing cholangitis (PSC). Autoimmune hepatitis accounts for about 3% of liver transplantations in Europe. Mortality/Morbidity Without treatment, nearly 50% of patients with severe autoimmune hepatitis die in approximately 5 years. Race The disease is most common in Caucasians of northern European ancestry with a high frequency of HLA-DR3 and HLA-DR4 markers. The Japanese population has a low frequency of HLA-DR3 markers. In Japan, autoimmune hepatitis is associated with HLA-DR4.12, 13 Sex Women are affected more often than men (70-80% of patients are women).14 Age Classic descriptions of type 1 autoimmune hepatitis spoke of a bimodal age distribution (10-30 y and 40-50 y). However, more recent work shows that infants, young children, and older adults may be affected. The diagnosis should not be overlooked in individuals older than 70 years.15 Men may be affected more commonly than women in older age groups. Clinical History a.. Clinical features of autoimmune hepatitis a.. Autoimmune hepatitis may present as acute hepatitis, chronic hepatitis, or well-established cirrhosis. b.. Approximately one third of patients present with symptoms of acute hepatitis marked by fever, hepatic tenderness, and jaundice. In some patients, the acute illness may appear to resolve spontaneously; however, patients invariably develop signs and symptoms of chronic liver disease. Other patients experience rapid progression of the disease to acute liver failure, as marked by coagulopathy and jaundice. Ascites and hepatic encephalopathy also may ensue. c.. Clinicians must consider the diagnosis of autoimmune hepatitis when confronted with a patient who has acute hepatitis or acute liver failure (defined by the new onset of coagulopathy). The workup of such patients should include testing for serum ANA, ASMA, anti-LKM, serum protein electrophoresis (SPEP), and quantitative immunoglobulins. Urgent liver biopsy, transjugular if appropriate, may help to confirm the clinical suspicion of acute autoimmune hepatitis. Rapid institution of treatment with high-dose corticosteroids may rescue patients whose disease ultimately would have progressed to either fulminant hepatic failure or cirrhosis. Other patients continue to deteriorate in spite of immunosuppressant therapy. Accordingly, a low threshold should exist for transferring patients with acute liver failure to tertiary care hospitals that are capable of performing emergent liver transplantation. d.. The chronic hepatitis associated with autoimmune hepatitis may range in severity from a subclinical illness without symptoms and with abnormal results on liver chemistries to a disabling chronic liver disease. Symptoms and physical examination findings may stem from the various extrahepatic diseases associated with autoimmune hepatitis. Common symptoms include the following: a.. Fatigue b.. Upper abdominal discomfort c.. Mild pruritus d.. Anorexia e.. Myalgia f.. Diarrhea g.. Cushingoid features h.. Arthralgias i.. Skin rashes (including acne) j.. Edema k.. Hirsutism l.. Amenorrhea m.. Chest pain from pleuritis n.. Weight loss and intense pruritus (unusual) e.. Without therapy, most patients die within 10 years of disease onset.16 Treatment with corticosteroids has been shown to improve the chances for survival significantly. Indeed, the life expectancy of patients in clinical remission is similar to that of the general population. f.. Many patients have histologic evidence of cirrhosis at the onset of symptoms. This is true both for patients with an initial presentation of acute hepatitis and for patients with chronic hepatitis. Thus, subclinical disease often precedes the onset of symptoms. g.. As many as 20% of patients present initially with signs of decompensated cirrhosis. In other patients, chronic hepatitis progresses to cirrhosis after years of unsuccessful immunosuppressant therapy marked by multiple disease relapses. This is said to occur in 20-40% of patients. Patients with cirrhosis may experience classic symptoms of portal hypertension, namely variceal bleeding, ascites, and hepatic encephalopathy. Patients with complications of cirrhosis should be referred for consideration of liver transplantation. b.. Disease associations: Autoimmune hepatitis, especially type 2, is associated with a wide variety of other disorders. Involvement of other systems may present at disease onset or may develop during the course of active liver disease. These conditions, most of which are immunologic in origin, include the following: a.. Hematologic complications a.. Hematologic manifestations of hypersplenism b.. Autoimmune hemolytic anemia c.. Coombs-positive hemolytic anemia d.. Pernicious anemia e.. Idiopathic thrombocytopenic purpura f.. Eosinophilia b.. Gastrointestinal complications a.. Inflammatory bowel disease (6%): The presence of ulcerative colitis in patients with autoimmune hepatitis should prompt performance of cholangiography to exclude PSC. b.. Celiac disease: One recent study of 140 pediatric patients with autoimmune hepatitis, autoimmune cholangitis, and overlap syndrome identified 23 patients with celiac disease.17 c.. Proliferative glomerulonephritis d.. Fibrosing alveolitis e.. Pericarditis and myocarditis f.. Endocrinologic complications a.. Graves disease (6%) and autoimmune thyroiditis (12%) b.. Juvenile diabetes mellitus g.. Rheumatologic complications a.. Rheumatoid arthritis and Felty syndrome b.. Sjögren syndrome c.. Systemic sclerosis d.. Mixed connective-tissue disease e.. Erythema nodosum f.. Leukocytoclastic vasculitis: Patients may present with symptoms of leg ulcers. h.. Febrile panniculitis i.. Lichen planus j.. Uveitis c.. The hepatitis C connection a.. The hepatitis C virus (HCV) has several important associations with autoimmune hepatitis. The prevalence rate of HCV infection in patients with autoimmune hepatitis is similar to that in the general population. This implies that HCV is not an important factor in the etiology of autoimmune hepatitis; however, patients who are seropositive for anti-LKM-1 frequently are infected with HCV. These patients have predominant features of chronic viral hepatitis and frequently lack antibodies to P-450 IID6. Such patients respond to treatment with interferon. They should be distinguished from anti-LKM-1-positive patients who have a positive anti-P-450 IID6, are seronegative for anti-HCV, and are responsive to steroid therapy.18 b.. False-positive results on anti-HCV enzyme-linked immunoassay (ELISA) tests are described in the setting of hypergammaglobulinemia, including that observed in patients with autoimmune hepatitis. In patients with ANA and/or ASMA seropositivity and a positive anti-HCV, a false-positive reaction to HCV should be excluded by performing a test for HCV RNA using the polymerase chain reaction (PCR). In general, patients with definite autoimmune hepatitis have median serum titers of ASMA and ANA of 1:160 and 1:320, respectively. In contrast, these titers may be in the range of 1:80 or less in patients with true chronic viral hepatitis. c.. Although autoimmune hepatitis and chronic HCV have similar histologic features, moderate-to-severe plasma cell infiltration of the portal tracts is more common in patients with autoimmune hepatitis. Portal lymphoid aggregates, steatosis, and bile duct damage are more common in patients with chronic HCV. d.. See related CME at Optimizing Outcomes in Hepatitis C. d.. Overlap syndromes: Patients with autoimmune hepatitis may present with features that overlap those classically associated with patients with PBC and PSC. a.. About 7% of patients with autoimmune hepatitis have a disease that overlaps with PBC. They may have a detectable AMA (usually in low titer), histologic findings of bile duct injury and/or destruction, and the presence of hepatic copper. The natural history of the disease tends to echo type 1 autoimmune hepatitis. a.. Patients with the autoimmune hepatitis-PBC overlap syndrome may improve with steroid therapy. b.. Recently, one group of authors compared the progression of hepatic fibrosis in patients with autoimmune hepatitis-PBC treated with ursodiol monotherapy with patients treated with ursodiol in combination with immunosuppressants.19 The mean duration of follow-up was 7.5 years. In noncirrhotic patients, fibrosis progression was seen in 4 of 8 patients treated with ursodiol monotherapy, as compared to 0 of 6 patients treated with combination therapy (P = 0.04). Thus, treatment combining ursodiol and immunosuppressants may be advisable in patients with the autoimmune hepatitis-PBC overlap syndrome. b.. About 6% of patients with autoimmune hepatitis have a disease that overlaps with PSC. Patients with the autoimmune hepatitis-PSC overlap syndrome frequently have concurrent inflammatory bowel disease. The liver biopsy findings reveal bile duct injury. Findings from cholangiograms are abnormal. Such patients usually have mixed hepatocellular and cholestatic liver chemistries and typically are resistant to steroid therapy. Treatment with ursodiol should be considered. a.. The natural history of autoimmune hepatitis-PSC is not well studied. b.. One recent article assessed 41 consecutive patients with PSC, 34 patients with classical PSC and 7 patients with the autoimmune hepatitis-PSC overlap syndrome.20 The mean follow-up period was 14 years. Patients with autoimmune hepatitis-PSC tended to present at a younger age and had more elevated aminotransferases and serum IgG measurements than patients with classical PSC. They also appeared to have a better chance for transplant-free survival. One case of cholangiocarcinoma, no deaths, and 1 transplant were reported among the 7 patients with autoimmune hepatitis-PSC, as compared to 5 cases of cholangiocarcinoma, 9 deaths, and 6 transplants among the 34 patients with classical PSC. e.. Autoimmune cholangitis is characterized by mixed hepatic and cholestatic liver chemistries, positive ANA and/or ASMA, negative AMA, antibodies to carbonic anhydrase, and histology that resembles PBC. Some authors contend that this condition is AMA-negative PBC. Patients may have an unpredictable response to therapy with steroids or ursodiol. f.. Cryptogenic autoimmune hepatitis is characterized by a clinical picture that is indistinguishable from autoimmune hepatitis. Here, the diagnosis is made by liver biopsy. ANA, ASMA, and anti-LKM-1 are negative at disease onset and may appear late in the disease course, as might anti-SLA. The disease usually is responsive to steroid therapy. Physical a.. Common findings on physical examination are as follows: a.. Hepatomegaly (83%) b.. Jaundice (69%) c.. Splenomegaly (32%) d.. Spider angiomata (58%) e.. Ascites (20%) f.. Encephalopathy (14%) b.. All of these findings may be observed in patients with disease that has progressed to the point of cirrhosis with ensuing portal hypertension; however, hepatomegaly, jaundice, splenomegaly, and spider angiomata also may be observed in patients who do not have cirrhosis. Causes Autoimmune hepatitis is a chronic disease of unknown etiology. Some cases of drug-induced liver disease have an immune-mediated basis. A number of drugs, including methyldopa, nitrofurantoin, and minocycline, can produce an illness with the clinical features of autoimmune hepatitis. Although most cases improve when the drug is stopped, chronic cases of autoimmune hepatitis may be seen, even after drug withdrawal.21 ____________________________________________________________ TOP Chart Ringtones Get top ringtones on your cell phone. Click here now! http://thirdpartyoffers.netzero.net/TGL2241/fc/u4MuSdTsFEclZxC8zVbKA1WYxwu5FuyzC\ dAsJI0qN7lBuLqSRUVOp/ Quote Link to comment Share on other sites More sharing options...
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