Autoimmune Hepatitis

AUTOIMMUNE LIVER DISEASE

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Autoimmune Hepatitis

• Three different patterns of circulating autoantibodies have been described in patients with autoimmune hepatitis; most of the antigens against which they are directed have been identified • Despite these advances, factors that trigger the development of autoimmune hepatitis remain unclear • Progression of liver disease to cirrhosis is most common in patients with continuing liver inflammation despite treatment; close clinical monitoring is mandatory throughout treatment • Relapse of disease is now recognized to be common after immunosuppressive therapy is stopped; long-term treatment is therefore often required

Michael J P Arthur

Autoimmune hepatitis is a liver disease associated with: • hyperglobulinaemia • autoantibodies in the serum • a history of other autoimmune disorders. It was previously known as ‘chronic active hepatitis’, but this term is now outmoded, in recognition of the acute presentation in some cases. It typically occurs in young women (age at onset 20–40 years), but it may develop at any age in either sex. Three subtypes of autoimmune hepatitis can currently be identified (Figure 1), though the existence of type 3 as a separate entity is disputed; it is clinically indistinguishable from type 1 but is associated with different autoantibodies (antisoluble liver antigen/liver–pancreas – anti-SLA/LP). Some patients present with anti-SLA/LP in the absence of the more characteristic autoantibodies found in type 1 autoimmune hepatitis. It is important to consider and diagnose this third entity, because it usually responds to corticosteroid therapy (see below).

cytes. In these circumstances, cell lysis could occur via complement fixation or by antibody-directed cell-mediated cytotoxicity. Cellular immune responses are likely to be of major importance because most infiltrating lymphocytes in ‘interface hepatitis’ are T-helper cells, which have been demonstrated experimentally to proliferate in response to target antigens such as recombinant cytochrome P450IID6. In type 2 autoimmune hepatitis, characteristic antiliver–kidney microsomal (anti-LKM) antibodies are also directed against cytochrome P450IID6, but the trigger for the development of these antibodies is unclear. Recent studies have demonstrated that anti-SLA/LP antibodies are directed against a cellular protein called UGA-suppressor tRNA-associated protein, but again this has not led to any new insights into the true cause of the disease. These studies highlight the complexity of the immunopathogenesis and the likely heterogeneity of the underlying aetiology.

Aetiology, immunopathogenesis and heterogeneity The aetiology of autoimmune hepatitis is unknown. The importance of autoimmunity in the pathogenesis is suggested by the strong association with other autoimmune diseases, hyperglobulinaemia and autoantibodies. The autoantibodies per se are not clearly implicated in the immunopathogenesis. A possible mechanism by which autoantibodies could mediate liver injury is through binding to their respective antigens (which would have to be located on the cell surface) on hepato-

Clinical features Patients with autoimmune hepatitis often have a history or family history of other autoimmune disorders. Classic type 1 autoimmune hepatitis may present insidiously with anorexia, malaise, nausea and fatigue. Physical examination may reveal few clinical signs of chronic liver disease, but most patients have palmar erythema and spider naevi. Jaundice is uncommon in mild disease. Some patients develop mooned facies, a buffalo hump, truncal obesity and abdominal striae

Michael J P Arthur is Professor of Medicine at the University of Southampton and Honorary Consultant Physician at Southampton University Hospitals, Southampton, UK.

Types of autoimmune hepatitis Autoantibodies

Target antigen

Clinical features

Response to corticosteroids Yes

Type 1

Antinuclear antibodies Smooth muscle antibodies

Not known F-actin

Classic chronic hepatitis ± cirrhosis May present as severe acute hepatitis

Type 2

Antiliver–kidney microsomal antibodies

Cytochrome P450IID6

Commonly presents in childhood More common in continental Europe

Yes

Type 3

Antisoluble liver antigen/ liver–pancreas

UGA-suppressor tRNA-associated protein

As for type 1

Yes

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AUTOIMMUNE LIVER DISEASE

Case history Prednisolone

60 mg

40 mg

Reducing dose

10 mg

5 mg

4 mg

1400

350

1200

300

1000

250

600

400

200

0

Alanine aminotransferase Bilirubin

Positive antinuclear antibody Positive smooth muscle antibody

800

26 January

200

150

Bilirubin

Alanine aminotransferase

Azathioprine, 50 mg b.d.

100

50

0

1415 1720 1 22 February March

1 May

10 January July

1995

1996

Liver biopsy Severe autoimmune hepatitis

July

October

1997

March

1998

Repeat liver biopsy Controlled remission

A 58-year-old woman presented with a 3-month history of malaise and lethargy followed by jaundice. Serology indicated autoimmune hepatitis, which was confirmed by liver biopsy. The graph shows the dramatic response to immunosuppressive treatment and the way in which treatment was altered relative to biochemical and histological remission. Prednisolone treatment was stopped in late 1998 and the patient remains in remission on long-term azathioprine therapy. 2

(before corticosteroid treatment), but this clinical presentation is now rare. Mild-to-moderate elevations of serum transaminases are usually observed. In contrast, onset is relatively rapid in some patients, resembling acute viral hepatitis. Such patients are usually jaundiced and have multiple spider naevi, tender hepatomegaly, splenomegaly and ascites. Laboratory findings indicate severe liver disease with hypoalbuminaemia, gross elevation of serum transaminases and prolongation of prothrombin time (Figure 2). This florid presentation can lead to extensive hepatic necrosis and onset of liver failure. In more than 60% of patients with classic autoimmune hepatitis, there is evidence of involvement of other organs or coexisting autoimmune disease such as keratoconjunctivitis sicca (35% of patients), renal tubular acidosis (24%), peripheral neuropathy (10%), Hashimoto’s thyroiditis (7%), ulcerative colitis (4%) and rheumatoid arthritis (2%). Autoimmune hepatitis may have a relapsing and remitting course or may progress slowly, resulting ultimately in cirrhosis. Alternatively, established cirrhosis may be found at presentation. Type 2 autoimmune hepatitis occurs most commonly in children and is more common in continental Europe than in the UK. Presentation is usually acute or fulminant, with rapid progression to severe liver disease and cirrhosis. It is associated

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with autoimmune thyroid disease, type 1 diabetes mellitus and vitiligo. Type 3 autoimmune hepatitis has clinical features similar to those of type 1 disease.

Laboratory findings and diagnosis Liver biopsy is the most important diagnostic test for autoimmune hepatitis (Figure 3). Indications for liver biopsy are: • raised transaminases and other abnormalities of liver function, if relevant serum autoantibody markers are detected (Figure 1) • a more florid acute presentation (resembling acute viral hepatitis), if there are no other diagnostic markers (for hepatitis A, B, C, D or E, Epstein–Barr virus or cytomegalovirus infection), particularly when autoantibodies are detected • persistently elevated transaminases (above twice normal levels) of uncertain cause, particularly when there is no local access to testing for anti-SLA/LP. Other laboratory findings (Figure 4) demonstrate the degree of liver damage and suggest an underlying autoimmune aetiology. Non-organ-specific autoantibodies are a cardinal feature of autoimmune hepatitis (Figure 1) and are important in establishing the diagnosis. Serological testing for anti-LKM1 and anti-SLA/LP

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AUTOIMMUNE LIVER DISEASE

Management The mainstay of treatment of autoimmune hepatitis is immunosuppression with corticosteroids and/or azathioprine. Corticosteroid treatment is usually given as prednisolone, 60 mg/day initially reduced after about 2 weeks to 40 mg/day. Subsequent reduction of the corticosteroid dose depends on the clinical response; maintenance doses of 10–20 mg/day are usually required for several months before the dose can be reduced to less than 10 mg/day. Azathioprine, 1.0–1.5 mg/kg/day p.o., is used as an adjunct to corticosteroid therapy (predominantly as a corticosteroid-

3 Liver histology in autoimmune hepatitis. A lymphocytic and plasma cell infiltrate extends from the portal tract (left) into the liver parenchyma and encircles degenerating hepatocytes. Conditions that can mimic autoimmune hepatitis histologically include primary biliary cirrhosis, sclerosing cholangitis, alcoholic liver disease, non-alcoholic steatohepatitis (fatty liver) and α1-antitrypsin deficiency; these conditions may also cause other types of liver injury that are easily distinguishable from autoimmune hepatitis. (H and E stain.)

Laboratory findings in autoimmune hepatitis • Raised bilirubin in 25–50% of patients at presentation • Raised serum transaminases are usually found at clinical presentation, but may vary from slightly elevated (about twofold) to massively elevated (> 20-fold) in severe disease • Alkaline phosphatase may be normal or slightly elevated; gross elevation is seldom seen • Serum albumin is decreased in severe disease • Haematological abnormalities include raised ESR, normochromic, normocytic anaemia, features of hypersplenism (in those with cirrhosis and portal hypertension) and, in severe disease, prolonged prothrombin ratio • Hyperglobulinaemia is a typical feature of autoimmune hepatitis and usually results from elevated serum IgG without significant changes in levels of IgA or IgM; occasionally, hyperglobulinaemia may be sufficiently severe to cause hyperviscosity syndrome • Positive tests for lupus erythematosus cells are described in 10–15% of patients with type 1 autoimmune hepatitis; this has led to the use of the clinical term ‘lupoid hepatitis’ (lupoid hepatitis is not associated with or caused by the classical autoimmune disease systemic lupus erythematosus) • Classic type 1 autoimmune hepatitis is associated with antinuclear antibodies in about 40–70% of patients and with smooth muscle antibodies in about 60%; many patients have both antinuclear and smooth muscle antibodies in their serum • Type 2 autoimmune hepatitis is characterized by antiliver–kidney microsomal antibody 1 directed against a liver and kidney microsomal antigen (cytochrome P450IID6); these sera are usually negative for antinuclear and smooth muscle antibodies, but some patients have these autoantibodies in addition to antiliver–kidney microsomal antibody 1 • Type 3 autoimmune hepatitis is characterized by antibodies directed against a soluble liver (and pancreas) antigen identified as UGA-suppressor tRNA-associated protein; these antibodies may occur in isolation or in combination with antinuclear and smooth muscle antibodies • The incidence of the HLA haplotype A1 B8 DR3 is greater in autoimmune hepatitis (38% compared with 11% of controls in the UK), but this association is geographically heterogeneous; there is also an association with the DR4 haplotype

is important, because these other subtypes of autoimmune hepatitis respond to treatment with immunosuppressive therapy. Differential diagnosis: a drug and alcohol history must be taken, and tests to exclude other causes of chronic hepatitis must be performed in all cases (Figure 5). The following conditions should be excluded. Chronic viral hepatitis may be differentiated from autoimmune hepatitis by demonstrating the presence of viral antigens or antibody markers in the patient’s serum. Particular care should be taken in interpreting the significance of autoantibodies in patients with hepatitis C virus (HCV) infection. Many different autoantibodies have been described, including antinuclear and smooth muscle antibodies; anti-LKM antibodies are particularly important. Most HCV-positive patients with coexisting autoantibodies respond well to standard antiviral therapy, but careful monitoring and the possibility of autoimmune liver damage must be considered if liver function deteriorates. Wilson’s disease – hepatic manifestations usually occur in children or adolescents, but occasionally in the over-25s. α1-antitrypsin deficiency is diagnosed at liver biopsy and confirmed by analysis of the α1-antitrypsin phenotype in peripheral blood. Alcoholic liver disease seldom gives a histological picture of chronic hepatitis resembling autoimmune disease. Primary biliary cirrhosis (PBC) – in PBC, liver histology may reveal features similar to those of autoimmune hepatitis. A high titre (> 1:80 or > 100 IU/litre) of antimitochondrial antibodies or demonstration of specific anti-M2 mitochondrial antibodies indicates primary biliary cirrhosis. Sclerosing cholangitis has typical cholangiographic findings of strictured and beaded intrahepatic and extrahepatic bile ducts. These appearances are increasingly diagnosed by MRI of the liver. A high index of suspicion should be maintained in patients who complain of chronic lower gastrointestinal symptoms or frank colitis. 4 MEDICINE

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Prognosis and follow-up

Laboratory tests in the differential diagnosis of autoimmune hepatitis

The most important prognostic factors are the presence of complications at presentation and the response to immunosuppressive treatment. In a large series at the Mayo Clinic, Rochester, USA, 10-year survival in patients who presented without cirrhosis, portal hypertension or signs of hepatic failure was 98%, compared with 65% in patients presenting with established cirrhosis and its complications. In 10–20% of patients, corticosteroid therapy can be stopped after 1–2 years without relapse. In the remaining 80–90%, relapse usually occurs within 3 years. Prolonged follow-up is therefore essential. Patients who remain on long-term immunosuppressive therapy with low-dose corticosteroids or azathioprine seldom relapse. ‹

Virology • Hepatitis B surface antigen • Hepatitis B e antigen • IgM anti-hepatitis B core1 • Hepatitis B virus DNA1 • Anti-hepatitis C virus antibody • Hepatitis C virus RNA1 • Anti-hepatitis D virus1 • IgM anti-hepatitis E virus Immunology • Antimitochondrial antibodies (anti-M2) Biochemistry • Serum ceruloplasmin • 24-hour urinary copper excretion • Serum α1-antitrypsin • α1-antitrypsin phenotype

FURTHER READING Ben-Ari Z, Czaja A J. Autoimmune Hepatitis and its Variant Syndromes. Gut 2001: 49: 589–94. (Overlap and variant syndromes of autoimmune hepatitis and the various autoimmune biliary diseases, and how to differentiate them.) Henegan M A, McFarlane I G. Current and Novel Immunosuppressive Therapy for Autoimmune Hepatitis. Hepatology 2002; 35: 7–13. Kita H, Mackay I R, Van De Water J, Gerschwin M E. The Lymphoid Liver: Considerations on Pathways to Autoimmune Liver Injury. Gastroenterology 2001; 120: 1485–501. Manns M P, Strassburg C P. Autoimmune Hepatitis: Clinical Challenges. Gastroenterology 2001; 120: 1502–17. (A comprehensive review of the aetiology, diagnosis and treatment of autoimmune hepatitis from a leading researcher and authority.)

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These tests are usually performed as second-line investigations after initial serological results are positive

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sparing agent). Azathioprine alone is ineffective in treating the acute phase of autoimmune hepatitis but can be used in maintaining remission. Histological remission of the inflammatory process may take 18 months or longer. In patients with severe autoimmune hepatitis (transaminases increased more than tenfold and bridging hepatic necrosis on liver biopsy), corticosteroid therapy (with or without azathioprine) reduces mortality from 30% to 6%. In milder forms of the disease, the benefit of corticosteroid treatment is less clear. However, many centres treat patients with moderate elevations of transaminases and interface hepatitis on liver biopsy. There is evidence that patients who progress to cirrhosis are those who have continuing inflammatory activity on repeat liver biopsy (at 1–2 years) despite treatment. If this is found, immunosuppressive treatment should be increased (e.g. increase azathioprine to 1.5–2.0 mg/kg/day and adjust prednisolone therapy). In patients who are intolerant of azathioprine or who do not respond to combined prednisolone and azathioprine, ciclosporin, 3–6 mg/kg/day, may be used. Treatment should be titrated against ciclosporin levels in the blood, and blood pressure and renal function should be reviewed carefully. Other drug treatments used in difficult cases include tacrolimus, 3 mg b.d. aiming for trough drug levels of 0.6–1.0 ng/ml, mycophenolate mofetil, 2 g/day, and cyclophosphamide, 1–1.5 mg/kg/day. Reported use of these third-line drugs is limited to single case reports or small case series only. In general, immunosuppressive therapy is not used in asymptomatic patients or in established cirrhosis with no evidence of an active inflammatory process and ongoing liver cell necrosis. Liver transplantation is now the treatment of choice in patients with end-stage autoimmune hepatitis and cirrhosis. In patients with autoimmune hepatitis who undergo liver transplantation, 5-year survival is more than 80%. Recurrent autoimmune hepatitis has been reported in the transplanted liver.

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Practice points • Autoimmune hepatitis is an important clinical diagnosis because effective immunosuppressive treatment reduces mortality • Autoimmune hepatitis can present as an acute illness resembling severe acute viral hepatitis • Effective immunosuppression is essential to prevent development of cirrhosis; relapse of disease is common in patients in whom treatment is withdrawn • Liver transplantation is the treatment of choice in advanced disease with complications of cirrhosis and/or liver failure

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