Get your own Free Home PageAUTOIMMUNE LIVER DISEASE( overview )
Serum gamma-globulin and immunoglobulin-G show mild to moderate degree of elevation, and in case of autoimmune hepatitis it is usually highly elevated - serum hypergammaglobulinemia. HLA types predominantly B8, DR3, DR4. Patients losing immunological tolerance of liver itself. Various factors as environment, varied contagious agents trigger the disease. Female predominance. Frequently associated with autoimmune diseases such as: thyroiditis, ulcerative colitis, Sjogren's syndrome. With chracteristic serum autoimmune antibodies such as: ANA, Anti-LKM antibody, anti-smooth muscle antobody, anti-soluble liver antigen antibody,anti-liver-pancreas antigen antibody, anti-asialoglycoprotein receptor antibody, anti-heptocyte plasma membrane antigen antibody. Absence of serum markers of HBV, HCV and HDV infections and anti-mitochrondrial antibody. Well respond to corticosteroid and/or immunosuppressive therapy.
Subgroups of autoimmune hepatitis:
Autoimmune hepatitis type 1: high titers of ANA or SMA.
Autoimmune hepatitis type 2: presence of anti-LKM-1 directed against cytochrome P-450 IID6.
Autoimmune hepatitis type 3: presence of soluble liver antigen antobodies in the absence of ANA or anti-LKM.
THE INTERNATIONAL AUTOIMMUNE HEPATITIS SCORE IN CHRONIC HEPATITIS C.
Dickson RC; Gaffey MJ; Ishitani MB; Roarty TP; Driscoll CJ; Caldwell SH; Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville 22908, USA. J Viral Hepat, 1997 Mar, 4:2, 121-8
Clinical and laboratory findings of autoimmunity are common in chronic hepatitis C. Autoimmune hepatitis (AIH), a disease of unknown cause, has been defined by use of the International Autoimmune Hepatitis Group Score (AIH score), which quantifies clinical and laboratory parameters. To further validate the specificity of the International AIH score and investigate the similarities between hepatitis C and AIH, we measured the International Autoimmune Hepatitis Group Score in patients with well-defined chronic hepatitis C. Thirty consecutive non-cirrhotic patients with chronic hepatitis C were evaluated. Scoring was performed using both components of the AIH score: a set of minimum required parameters including laboratory and historical data and a second set of additional parameters dominated by histological criteria. Autoantibodies were positive in 21 of 30 hepatitis C patients and associated (patient or first-degree relative) autoimmune diseases were present in eight of 30 patients. Histologically, chronic active hepatitis with periportal piecemeal necrosis was seen in 24 of 30 patients and lymphoid follicles in 16 of 30 patients. No patient scored as probable or definite AIH using the minimum required parameters of the AIH score. When histological parameters were included, four of 30 patients scored as probable AIH but none as definite AIH. Therefore, AIH was excluded by the minimal and additional criteria of the AIH score in 86% of patients with hepatitis C despite a high prevalence of autoantibodies in these patients. We conclude that the criteria set forth by the International AIH scoring system defines a distinct disease although it shares some features with chronic hepatitis C. Modification of the AIH scoring system to include other commonly accepted risk factors for hepatitis C and additional histological parameters would further improve its specificity.
AUTOIMMUNE CHRONIC ACTIVE HEPATITIS
Renner EL; Institut für klinische Pharmakologie, Universität Bern. Ther Umsch, 1993 Feb, 50:2, 100-9
Autoimmune chronic active hepatitis is a rare type of chronic active hepatitis which occurs with a bimodal age distribution (10 to 30 or > or = 50 years) most frequently in women. It is characterized by negative markers for other possible (e.g. viral) etiologies, hypergammaglobulinemia and a number of circulating autoantibodies. According to the latter, several subgroups can be discriminated today. Histology shows chronic active hepatitis with chronic, sometimes plasma-cell-rich infiltration of portal tracts and piece-meal necroses. Symptoms and signs are classically non-specific and include general malaise, lethargy and fatigue. Accompanying autoimmune diseases may be present. The disease is today, however, also frequently diagnosed in an early, asymptomatic stage. Cause(s) and pathogenetic mechanism(s) of the increasingly heterogeneous appearing disease remain unknown. Recent observations seem to indicate that as yet undetermined (exogenous) substance(s) and the hepatitis C virus may, at least in certain subgroups, trigger autoimmune reactions, which may then perpetuate on the basis of a permissive (immuno)genetic background. Untreated, the disease is, in general, progressive, leads to cirrhosis and shows a mortality of up to > or = 50% in 2 to 4 years. Signs potentially indicating a nonfavorable prognosis include high inflammatory activity and the presence of cirrhosis at diagnosis. Typically, immunosuppressive therapy with corticosteroids (with or without azathioprine) results in remission of inflammatory, but usually not fibro-genetic activity with its potential for cirrhosis. Exacerbations after cessation of treatment are not infrequent (> or = 50%), and indefinite therapy is required in a number of patients, despite its potential for unwanted effects (e.g. osteopenia). Such therapy may increase the 5-year survival rate to > 80%. Liver transplantation remains the sole therapeutic option in end stage disease.
THE VARIANT FORMS OF AUTOIMMUNE HEPATITIS.
Czaja AJ, Mayo Clinic, Rochester, Minnesota, USA. Ann Intern Med, 1996 Oct 1, 125:7, 588-98
OBJECTIVES: To review the diagnostic criteria for autoimmune hepatitis,
to characterize the variant forms of autoimmune hepatitis, and
to indicate appropriate therapies for this condition.
DATA SOURCES: A MEDLINE search (1990 to 1995) of the English-language
literature, review of a personal library of journals and reprints
(1975 to 1995), and review of references selected from the bibliographies
of identified articles. Terms used in the MEDLINE search included
the names of all autoimmune liver diseases, viral hepatitis and
autoimmunity, cryptogenic hepatitis, and overlap syndromes.
STUDY SELECTION: All articles that discussed atypical clinical
features, mixed diagnostic findings, and variations in treatment
response were selected.
DATA EXTRACTION:Data were selected from 548 articles.
DATA SYNTHESIS: Standardized criteria permit the confident diagnosis
of autoimmune hepatitis, but they exclude many patients who have
features suggesting autoimmunity. Such patients have findings
indicative of both autoimmune hepatitis and another disorder (overlap
syndromes) or findings that are inconsistent with the classic
definition of autoimmune hepatitis (outlier syndromes). Overlap
syndromes include combinations of autoimmune hepatitis and primary
biliary cirrhosis, primary sclerosing cholangitis, or chronic
viral hepatitis. Treatment of these syndromes requires identification
of the predominant disorder and selection of the most appropriate
drug regimen. Outlier syndromes include autoimmune cholangitis
and cryptogenic chronic hepatitis. Corticosteroids or ursodeoxycholic
acid are treatment options for patients with autoimmune cholangitis;
corticosteroids can also benefit patients with cryptogenic chronic
hepatitis. Grading each clinical feature and developing a composite
score can permit comparison of the variants and a determination
of the similarity between the variants and autoimmune hepatitis.
CONCLUSIONS: Variant forms of autoimmune hepatitis are common.
Recognition of them is important in assessing common pathogenic
mechanisms, developing effective treatment strategies, and refining
classification schemes.
AUTOIMMUNE LIVER DISEASE
Albert J. Czaja, MD; Current Opinion in Gastroenterology 1997 13 : 248-256.
The diagnostic criteria of autoimmune hepatitis have been codified, and concepts of autoantibody expression, genetic predisposition, immunopathogenesis, disease behavior, and treatment have been extended. A scoring system quantitates the net strength of the diagnosis, but it does not sufficiently downgrade laboratory and histologic features of cholestasis to be used generally. Antibodies to asialoglycoprotein receptor identify patients who are prone to relapse after corticosteroid withdrawal, and antibodies to actin characterize patients with a poorer immediate treatment response than seronegative counterparts. These antibodies may ultimately supplant conventional markers that lack prognostic implication. Antibodies to heat shock proteins have promise as indices of disease activity, and antineutrophil cytoplasmic antibodies have similar frequencies of low titer seropositivity in primary sclerosing cholangitis and autoimmune hepatitis. These latter antibodies also have similar immunoglobulin G subclasses, and they may have a common target antigen. The same genetic risk factors for autoimmune hepatitis are associated with immune manifestations in other chronic liver diseases, and the host predisposition rather than the nature of the liver disease may be the critical determinant of the immune response. Corticosteroid-treated patients with severe autoimmune hepatitis have the same 10-year survival as age- and gender-matched normal subjects and histologic cirrhosis at presentation does not diminish the immediate response to treatment or lower the 10-year life expectancy. 6-Mercaptopurine can enhance the efficacy of a prednisone regimen in patients in whom therapy with azathioprine has failed.
IDIOPATHIC AUTOIMMUNE CHRONIC ACTIVE HEPATITIS (IACAH)
The syndrome chronic active hepatitis (CAH) is characterized histologically by periportal piecemeal necrosis and prominent plasma cell infiltration of the portal tracts and persistence of symptoms or signs for more that 6 months. However, it is unequivocally heterogenous with regard to etiology.
Infections with hepatitis B, delta, and C are the most clearly defined etiologic agents, but CAH is also a recognized feature of other primary liver disease (Wilson's disease and alpha one antitrypsin deficiency) and may arise as an adverse reaction to certain therapeutic drugs. The term "autoimmune" CAH has no generally accepted definition but most authorities agree that it includes those cases in which all known etiologic factors have been excluded. The definition has lead to terms such as "idiopathic", "cryptogenic", or "presumed" autoimmune CAH. Additionally, some authorities require the presence of immunologic features, particularly high titers (usually more than 1:40) of certain non organic specific autoantibodies and polyclonal hyperglobulinemia. In this more stringent classification, the diagnosis is established positively, rather than entirely by exclusion. The term "cryptogenic" therefore becomes reserved to those with no detectable conventional autoantibodies.
The cause of IACAH is unknown, therefore the designation idiopathic. The possibility that a viral agent may trigger the onset of autoimmune chronic active hepatitis has been extensively considered, although at present there are no strongly supported candidate agents. The apparent predisposition of individuals with HLA-B8 and DR3 haplotypes to develop IACAH suggests that genetically conditioned abnormalities may have a role in pathogenesis.
Patients with IACAH most often present with insidious onset of malaise, anorexia, fever and fatigue. Approximately 75% of these patients are female with the most frequent ages of onset between 10-40 years. However, IACAH may occur at any age and in both sexes. The most typical course for patients is to have evidence of mild to moderate disease pursuing a gradual but usually relentless deteriorating course. At the other end of the spectrum are patients with advanced disease and cirrhosis who present with ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, or bleeding form esophageal varices. Occasionally, a patient may present with an apparent acute hepatitis and jaundice. The correct diagnosis may be established only after the patient is observed to have continuing and often worsening hepatitis over several months and is found to have markedly elevated serum gamma globulin levels and autoantibodies. The apparent acute hepatitis-like onset may represent an episode of activation of an underlying chronic process that has been previously silent.
IACAH is divided into three types. Type I or classic autoimmune CAH is the most prevalent, characterized by the presence of antismooth muscle (antiactin) antibodies in 100% of patients and ANA in 33% of patients. In addition, these patients may have arthralgia, oligomenorrhea, fluctuating jaundice and cushingoid appearance with striae, hirsutism and acne. Other "autoimmune" disease such as hyperthyroidism and Coomb's positive hemolytic anemia are seen in 10% of patients.
Type II autoimmune CAH is characterized by the presence of antiliver-kidney microsomal antibodies (anti-LKM) which are found in the absence of ANA or antiactin antibodies. It is much less prevalent than type I in all age groups but tends to present predominantly in the pediatric age group and is more often associated with "autoimmune" disorders such as insulin-dependent diabetes, autoimmune thyroid disease and vitiligo. The presentation is often acute, even fulminant, with severe histologic features and a marked propensity to progress rapidly to cirrhosis.
Type III autoimmune CAH is characterized by the presence of anti-soluble liver antigen (SLA) antibodies. This group has been less fully studied than the other two groups.
The goals of therapy in IACAH are to decrease mortality, diminish hepatic inflammation and to prevent progression to cirrhosis. Mortality figures in placebo groups of major controlled studies have showed that more than half of the untreated patients died within 3-5 years. There is considerable evidence that corticosteroids and other immunosuppressive therapy lead to decreased mortality but there is less evidence that progression to cirrhosis is slowed or prevented.
Several randomized controlled studies established that corticosteroid not only prolong life but decrease the symptoms and signs of fatigue, loss of appetite and fever. Corticosteroid therapy also lead to improvement in biochemical abnormalities (decrease bilirubin and aminotransferase level and increase albumin) as well as decrease in the inflammatory component found on liver biopsy. There is no evidence that the presence of LE cells or any other individual antibody affects the likelihood of response to therapy. There is no difference in outcome when prednisone therapy was compared to prednisone therapy.
Since therapy is immunosuppressive rather than specifically directed toward the basic cause of the disease, treatment usually needs to be continued indefinitely with gradual tapering using the level of serum aminotransferase and clinical status as guides. Azathioprine is sometimes used as an adjunctive therapy. Cyclosporine was reported to be effective in treating patients with IACAH who were refractory to therapy with corticosteroids. Alpha interferon used in viral hepatitis is known to induce exacerbation of various autoimmune disorders.
Patients with autoimmune CAH that were erroneously diagnosed as chronic hepatitis C and received alpha interferon suffered from aggravation of liver disease. However, improvement followed discontinuation of alpha interferon and institution of corticosteroid therapy. The positive anti-HVC antibody common in patients with IACAH is caused by disease related hypergammaglobulinemia and steroid therapy usually leads to decrease in gamma globulin level and elimination of positive anti-HCV. However, the new recombinant immunoblot assay (RIBA-II) which increases the specificity of anti-HCV by testing for four separate regions of the hepatitis C virus is less frequently positive and therefore is important for differential diagnosis especially that alpha interferon that is beneficial in viral hepatitis could be detrimental in IACAH.
Finally, liver transplantation is considered now at earlier stages
of the disorder before multiple severe complication develop. However,
with this new modality we will be facing the challenge of recurrence
in liver graft. Therefore, an issue for the future will be to
determine the likelihood for recurrence in the host or grafted
liver.
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