Autoimmune Hepatitis

Introduction

BackgroundDuring 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.

PathophysiologyEvidence 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.7

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),8 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.9 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.10

Evidence for an autoimmune pathogenesis includes the following:

Hepatic histopathologic lesions composed predominantly of cytotoxic T cells and plasma cells Circulating autoantibodies (ie, nuclear, smooth muscle, thyroid, liver-kidney microsomal, soluble liver

antigen, hepatic lectin) Association with hypergammaglobulinemia and the presence of a rheumatoid factor Association with other autoimmune diseases Response to steroid and/or immunosuppressive therapy

The autoantibodies described in these patients include the following:

Antinuclear antibody (ANA), primarily in a homogenous pattern Anti–smooth muscle antibody (ASMA) directed at actin Anti–liver-kidney microsomal antibody (anti–LKM-1) Antibodies against soluble liver antigen (anti-SLA) directed at cytokeratins types 8 and 18 Antibodies to liver-specific asialoglycoprotein receptor or hepatic lectin 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. Antiphospholipid antibodies11

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 Hepatitis12

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Clinical Features Type 1 Type 2 Type 3

Diagnostic autoantibodies ASMAANAAntiactin

Anti-LKMP-450 IID6Synthetic core motif peptides 254-271

Soluble liver-kidney antigenCytokeratins 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

Clinical Features Type 1 Type 2 Type 3

Diagnostic autoantibodies ASMAANAAntiactin

Anti-LKMP-450 IID6Synthetic core motif peptides 254-271

Soluble liver-kidney antigenCytokeratins 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

FrequencyUnited 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.

In an analysis of data from 33,379 patients with liver cirrhosis, Michitaka et al concluded that autoimmune hepatitis is the etiologic agent in 1.9% of such cases in Japan.13 (Hepatitis C virus was the most prevalent etiologic agent, being associated with approximately 61% of cases of liver cirrhosis.)

Mortality/MorbidityWithout treatment, nearly 50% of patients with severe autoimmune hepatitis die in approximately 5 years.

RaceThe 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-DR4.14,15,16

SexWomen are affected more often than men (70-80% of patients are women).17

AgeClassic descriptions of type 1 autoimmune hepatitis spoke of a bimodal age distribution (10-30 y and 40-50 y). However, subsequent work has shown that infants, young children, and older adults may be affected.16,18,19 The diagnosis should not be overlooked in individuals older than 70 years.20 Men may be affected more commonly than women in older age groups.

Clinical

HistoryClinical features of autoimmune hepatitis

Autoimmune hepatitis may present as acute hepatitis, chronic hepatitis, or well-established cirrhosis.

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.

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.

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:

Fatigue Upper abdominal discomfort Mild pruritus Anorexia Myalgia Diarrhea Cushingoid features Arthralgias Skin rashes (including acne) Edema Hirsutism Amenorrhea Chest pain from pleuritis Weight loss and intense pruritus (unusual)

Without therapy, most patients die within 10 years of disease onset.21 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.

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.

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.

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:

Hematologic complications - Hematologic manifestations of hypersplenism, autoimmune hemolytic anemia, Coombs-positive hemolytic anemia, pernicious anemia, idiopathic thrombocytopenic purpura, eosinophilia

Gastrointestinal complications - Inflammatory bowel disease (6%): The presence of ulcerative colitis in patients with autoimmune hepatitis should prompt performance of cholangiography to exclude PSC. Celiac disease: A study of 140 pediatric patients with autoimmune hepatitis, autoimmune cholangitis, and overlap syndrome identified 23 patients with celiac disease.22

Proliferative glomerulonephritis Fibrosing alveolitis Pericarditis and myocarditis

Endocrinologic complications - Graves disease (6%) and autoimmune thyroiditis (12%), juvenile diabetes mellitus

Rheumatologic complications - Rheumatoid arthritis and Felty syndrome, Sjögren syndrome, systemic sclerosis, mixed connective-tissue disease, erythema nodosum, leukocytoclastic vasculitis: Patients may present with symptoms of leg ulcers.

Febrile panniculitis Lichen planus Uveitis

The hepatitis C connection

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.23

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.

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.

Overlap syndromes

Patients with autoimmune hepatitis may present with features that overlap those classically associated with patients with PBC and PSC.

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.

Patients with the autoimmune hepatitis-PBC overlap syndrome may improve with steroid therapy.

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.24 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.

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. The natural history of autoimmune hepatitis-PSC is not well studied.

One article assessed 41 consecutive patients with PSC, 34 patients with classical PSC and 7 patients with the autoimmune hepatitis-PSC overlap syndrome.25 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 immunoglobulin G (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.

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.

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.

PhysicalCommon findings on physical examination are as follows:

Hepatomegaly (83%) Jaundice (69%) Splenomegaly (32%) Spider angiomata (58%) Ascites (20%) Encephalopathy (14%)

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.

CausesAutoimmune 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.26

Differential Diagnoses

Hepatitis AHepatitis BHepatitis CHepatitis DHepatitis EHepatitis, Viral

Workup

Laboratory StudiesAutoantibodies

Autoimmune hepatitis is characterized by positive findings on autoantibody tests (see Pathophysiology). Autoimmune hepatitis type 1 is characterized by positive test results for ASMA and ANA. Type 2 disease is observed infrequently in the United States, but it is well characterized in Europe. Type 2 disease is marked by a positive test result for anti–LKM-1 antibody. Type 3 disease also is observed infrequently in the United States. Type 3 is marked by a positive test result for anti-SLA antibody.

Serum protein electrophoresis and quantitative immunoglobulins

An IgG-predominant polyclonal hypergammaglobulinemia is a common finding in patients with untreated autoimmune hepatitis. Gamma globulin values typically range from 3-4 g/dL and frequently are as high as 5-6 g/dL. Cases of hyperviscosity syndrome secondary to high IgG levels are reported. Autoimmune hepatitis is an unlikely diagnosis in patients who have acute hepatitis without hypergammaglobulinemia.

The gamma globulin or the IgG level may be followed on a regular basis as a marker of disease responsiveness to therapy.

Aminotransferases

Serum aminotransferases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) are elevated in 100% of patients at initial presentation, with average values of 200-300 U/L. Aminotransferase values correlate poorly with the degree of hepatic necrosis; however, values in the thousands may indicate acute hepatitis or a severe flare of preexisting disease.

Continued elevation of the aminotransferases in the face of ongoing therapy is a reliable marker for ongoing inflammatory activity in the liver. Normalization of the aminotransferase levels during therapy is an encouraging sign, but active liver inflammation is present in more than 50% of patients with normalized liver chemistries. Indeed, biochemical remission may precede true histologic remission by 3-6 months. Typically, patients are treated for at least 1 year after documentation of normal liver chemistries. Liver biopsy is recommended by some experts to confirm that the patient is in histologic remission. Drug withdrawal may be attempted at this time (see Treatment).

Worsening of aminotransferase levels in a patient undergoing treatment or in a patient who is in remission may signal a resurgence of disease activity.

Other liver chemistries

Serum bilirubin and alkaline phosphatase values are mildly to moderately increased in 80-90% of patients. A sharp increase in the alkaline phosphatase values during the course of autoimmune disease might reflect the development of PSC or the onset of hepatocellular carcinoma as a complication of cirrhosis.

Hypoalbuminemia and prolongation of prothrombin time are markers of severe hepatic synthetic dysfunction, which may be observed in active disease or decompensated cirrhosis.

Other laboratory abnormalities

Mild leukopenia Normochromic anemia Coombs-positive hemolytic anemia Thrombocytopenia Elevated erythrocyte sedimentation rate Eosinophilia (uncommon, but counts ranging from 9% to 48% are described) Autoimmune hepatitis has even been described as the sole presenting feature of idiopathic

hypereosinophilic syndrome.

Imaging StudiesImaging studies, in general, are not helpful in reaching a definitive diagnosis of autoimmune hepatitis; however, the presence of heterogeneous echotexture on abdominal ultrasound or abnormal contrast enhancement on abdominal CT imaging may suggest the presence of active inflammation or necrosis. The appearance of an irregular nodular liver may confirm the presence of cirrhosis. Furthermore, these imaging studies may be used to rule out the presence of hepatocellular carcinoma, a potential complication of autoimmune hepatitis–induced cirrhosis.

ProceduresLiver biopsy

Liver biopsy is the most important diagnostic procedure in patients with autoimmune hepatitis. This procedure can be performed percutaneously, with or without ultrasound guidance, or by the transjugular route. The latter is preferred if the patient has coagulopathy or severe thrombocytopenia. A transjugular liver biopsy also may be preferable if ascites is present or if the liver is small, shrunken, and difficult to reach percutaneously. Liver biopsy routinely is performed in the outpatient setting to investigate abnormal liver chemistries. Liver biopsy should be performed as early as possible in patients with acute hepatitis who are thought to have autoimmune hepatitis. Confirmation of the diagnosis enables initiation of treatment at an early stage in the disease process.

The role of biopsy in patients presenting with well-established cirrhosis secondary to autoimmune hepatitis is less clear. As an example, the initiation of treatment in a patient with cirrhosis, normal aminotransferase levels, and a minimally elevated gamma globulin level is not expected to influence the disease outcome.

Endoscopic retrograde cholangiopancreatography

Occasionally, a patient with autoimmune hepatitis and ulcerative colitis may require endoscopic retrograde cholangiopancreatography (ERCP) to rule out coexisting PSC.

Histologic Findings

Autoimmune hepatitis is characterized by a chronic inflammatory cell infiltrate. Plasma cells are the prominent cell type. Biopsies may show evidence for interface hepatitis (ie, piecemeal necrosis), bridging necrosis, and fibrosis. Lobular collapse, best identified by reticulin staining, is a common finding.

Interface hepatitis does not predict a progressive disease course. By contrast, a strong likelihood exists that cirrhosis will develop when bridging necrosis is present. The presence or absence of cirrhosis on liver biopsy is an important determinant of the patient's prognosis.

Liver biopsy findings can help to differentiate autoimmune hepatitis from chronic HCV infection, alcohol-induced hepatitis, drug-induced liver disease, PBC, and PSC.27

In 1999, the International Autoimmune Hepatitis Group established a scoring system that is particularly helpful in establishing the diagnosis of autoimmune hepatitis in problematic cases.28,29

Treatment

Medical CareFor more than 3 decades, prednisone and azathioprine have been the mainstays of drug therapy for patients with autoimmune hepatitis.30 Considerable variation in practice style exists when answering the following common clinical questions:

How high a dose of prednisone should be used when initiating therapy? When should azathioprine be added to the patient's treatment regimen? When should a reduction in steroid dosing be considered? How long should treatment continue beyond a patient's biochemical remission? Should liver biopsy be performed in order to document histologic remission, prior to attempting to

withdraw immunosuppression? Should patients receive life-long low-dose maintenance therapy with azathioprine?

Initial therapy for adults

Approximately 65% of patients respond to initial therapy and enter histological remission; however, 80% of these patients relapse after drug withdrawal.

The practice guideline of the American Association for the Study of Liver Diseases (AASLD) provides recommendations for therapy.{Ref45} See Table 2, below.

Table 2. Indications for Treatment

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Absolute Relative

Serum AST 10-fold or more greater than the upper limit of normal Symptoms (eg, fatigue, arthralgia, jaundice)

Serum AST 5-fold or more greater than the upper limit of normal and gamma-globulin level 2-fold or more greater than normal

Serum AST and/or gamma-globulin less than absolute criteria

Bridging necrosis or multiacinar necrosis onhistologic examination

Interface hepatitis

AST = aspartate aminotransferase.

Absolute Relative

Serum AST 10-fold or more greater than the upper limit of normal Symptoms (eg, fatigue, arthralgia, jaundice)

Serum AST 5-fold or more greater than the upper limit of normal and gamma-globulin level 2-fold or more greater than normal

Serum AST and/or gamma-globulin less than absolute criteria

Bridging necrosis or multiacinar necrosis onhistologic examination

Interface hepatitis

AST = aspartate aminotransferase.

Treatment might not be necessary in patients with inactive cirrhosis, preexistent comorbid conditions, or drug intolerances.

Treatment might not be appropriate in patients with decompensated liver disease. Such individuals might be better served by undergoing liver transplantation.

The AASLD guidelines suggest 2 potential initial treatment regimens for adults (see Table 3, below).

Table 3. Treatment Regimens for Adults

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Prednisone only (mg/d)

Combination

Prednisone (mg/d) Azathioprine (mg/d)

Week 1 60 30 50

Week 2 40 20 50

Week 3 30 15 50

Week 4 30 15 50

Maintenance untilend point

20 10 50

Reasons for Preference CytopeniaThiopurineMethyltransferase deficiencyPregnancyMalignancyShort course (6 mo or less)

Postmenopausal stateOsteoporosisBrittle diabetesObesityAcneEmotional labilityHypertension

Prednisone only (mg/d)

Combination

Prednisone (mg/d) Azathioprine (mg/d)

Week 1 60 30 50

Week 2 40 20 50

Week 3 30 15 50

Week 4 30 15 50

Maintenance untilend point

20 10 50

Reasons for Preference CytopeniaThiopurineMethyltransferase deficiencyPregnancyMalignancyShort course (6 mo or less)

Postmenopausal stateOsteoporosisBrittle diabetesObesityAcneEmotional labilityHypertension

Budesonide may offer an alternative to prednisone. Recently, Manns et al conducted a prospective, double-blind randomized trial comparing budesonide 3 mg three times daily or twice daily to prednisone.31 The initial prednisone dose was 40 mg daily, tapered to 10 mg daily. Patients also received azathioprine 1-2 mg/kg/d. Six months after initiating treatment, 60% of the budesonide-treated patients had normalized liver chemistries, compared with 39% of the prednisone-treated patients.31 Furthermore, steroid-specific side effects were seen in only 28% of the budesonide-treated patients relative to 53% of the prednisone-treated patients. Longer term follow-up is need to better assess the efficacy and safety of budesonide.

Patients whose liver chemistries normalize after initial therapy then require maintenance therapy. In the authors' opinions, prednisone dosing can be further reduced after achieving normalization of liver chemistries. The authors commonly use azathioprine alone as a maintenance drug. Azathioprine therapy is withdrawn approximately 1 year after the patient's liver chemistries have normalized.

Initial therapy for children

The AASLD guidelines also propose an initial treatment regimen for children (see Table 4, below).

Table 4. Treatment Regimens for Children

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Initial Regimen Maintenance Regimen End Point

Prednisone, 1-2 mg/kg/d (up to 60 mg/d),for 2 weeks, either alone or in combination with azathioprine, 1-2 mg/kg/d

a. Prednisone taper over 6-8 weeks to 0.1-0.2 mg/kg daily or 5 mg dailyb. Azathioprine at constant dose if added initiallyc. Continue daily prednisone dose with

a. Normal liver tests for 1-2 years during treatmentb. No flare during entire intervalc. Liver biopsy examination

or without azathioprine or switch toalternate day prednisone dose adjusted to response with or without azathioprine

discloses no inflammation

Initial Regimen Maintenance Regimen End Point

Prednisone, 1-2 mg/kg/d (up to 60 mg/d),for 2 weeks, either alone or in combination with azathioprine, 1-2 mg/kg/d

a. Prednisone taper over 6-8 weeks to 0.1-0.2 mg/kg daily or 5 mg dailyb. Azathioprine at constant dose if added initiallyc. Continue daily prednisone dose with or without azathioprine or switch toalternate day prednisone dose adjusted to response with or without azathioprine

a. Normal liver tests for 1-2 years during treatmentb. No flare during entire intervalc. Liver biopsy examination discloses no inflammation

Treatment endpoints

Patients may achieve 1 of 4 treatment endpoints.32

Remission is indicated by the absence of symptoms, normalization of aminotransferases, and histologic improvement to normal or minimal inflammatory activity on liver biopsy. Patients achieving remission may be able to taper off prednisone over a 6-week period. Azathioprine can be discontinued subsequent to the withdrawal of prednisone.

Treatment failure is defined as deterioration in a patient's clinical condition, laboratory tests, or histologic features during therapy. This is seen in approximately 9% of patients.32 Some patients will have a response to reinstitution of treatment with high-dose prednisone, with or without combined azathioprine.

Incomplete response is defined as an improvement that is insufficient to satisfy remission criteria. It is estimated to occur in 13% of patients.32 Many such patients will require indefinite treatment with as low an immunosuppressant dose as is needed to prevent clinical deterioration.

Drug toxicity may occur. Patients must be tapered off from the culprit medication. Some patients successfully achieve treatment goals on alternative medications.

Treatment results and duration of therapy

It has been clear for many years that immunosuppressant therapy improves survival for patients with autoimmune hepatitis. The 10-year life expectancies for treated patients with and without cirrhosis at presentation are 89% and 90%, respectively.

There are no firm guidelines regarding the duration of therapy in either adults or children. However, relatively long courses of immunosuppressant therapy are needed for most patients. It is common for treatment to continue for 1.5-2 years or longer before an attempt is made to withdraw medications. Indeed, adults infrequently achieve clinical, laboratory, and histologic remission in less than 12 months. Immunosuppressant therapy can achieve remission in 65% of patients within 18 months and in 80% of patients by 3 years.

Histologic remission tends to lag behind clinical and laboratory remission by 3-6 months. Many clinicians—and the current practice guidelines of the AASLD32 —recommend that a follow-up liver biopsy be performed. This is done in an effort to avoid medication withdrawal in a patient who is not yet in histologic remission.

Patients with a histologic diagnosis of cirrhosis may respond well to therapy and should be offered treatment in an attempt to slow disease progression.

Patients with severe disease (eg, acute liver failure due to autoimmune hepatitis) have a high short-term mortality rate if they fail to show normalization of at least 1 laboratory parameter after starting prednisone-based therapy or if pretreatment hyperbilirubinemia fails to improve during a 2-week treatment trial. Early liver transplantation should be considered in such individuals. In contrast, patients in acute liver failure whose liver chemistries improve rapidly after starting prednisone have an excellent short-term prognosis. Many such patients ultimately achieve clinical remission on immunosuppressant therapy.

Treatment failures and incomplete responses

Nine percent of patients experience treatment failure with standard therapy. Treatment with high-dose prednisone (60 mg/d) alone or prednisone (30 mg/d) plus azathioprine (150 mg/d) is an alternative approach to therapy.

Patients whose condition is resistant to steroids can be treated with cyclosporine or tacrolimus. The use of these medications is supported by a number of small cases series.33,34,35 However, the potential toxicity of these calcineurin inhibitors must be assessed carefully before initiating treatment.

Similarly, a few studies have supported the use of mycophenolate mofetil in patients whose disease was refractory to standard therapy.36,37,38,39 In these studies, a dose of 1 g orally twice per day was employed initially. The authors have seen a number of patients who experienced treatment failure with prednisone plus azathioprine but achieved treatment success with low-dose prednisone plus mycophenolate mofetil. However, mycophenolate mofetil has not been subjected to a randomized trial in patients with autoimmune hepatitis. Furthermore, there are no clear guidelines as to how mycophenolate mofetil should be tapered if a therapeutic response has been achieved. The authors have used doses as low as 500 mg twice per day to maintain patients in a drug-induced remission.

Budesonide has been has been used with variable success in patients who had treatment failures.40,41

Thirteen percent of patients improve with standard therapy but do not achieve remission criteria. A low-dose, long-term prednisone schedule, similar to that used after relapse (10 mg/d), is reasonable. The goal of therapy is to control disease activity on the lowest dose of medication possible. Azathioprine may help to serve as a steroid-sparing agent.

Patients should be referred for consideration of liver transplantation if they manifest signs of hepatic decompensation (eg, new onset of hypoalbuminemia, coagulopathy, variceal bleeding, ascites, hepatic encephalopathy).

Relapse after drug withdrawal

Relapse occurs in 50% of patients within 6 months of treatment withdrawal and in 80% of patients within 3 years of treatment. Reinstitution of the original treatment regimen usually induces another remission; however,

relapse commonly recurs after a second attempt at terminating therapy. The major consequence of relapse and re-treatment is the development of drug-related complications, which occurs in 70% of patients.

Patients who relapse twice require indefinite therapy with either prednisone or azathioprine. The dose is titrated as low as possible in order to prevent symptoms and to maintain AST 5-fold below the reference range. The median dose of prednisone required to achieve this is 7.5 mg/d.

Some authors advocate indefinite treatment with azathioprine only. One article assessed long-term therapy with azathioprine at a dose of 2 mg/kg/d; 60 (83%) of the 72 patients remained in remission under such immunosuppression, with a median follow-up period of 67 months (range, 12-128 mo).42

Patients should be cautioned against premature withdrawal of drug therapy. Abrupt discontinuation of medical therapy is not infrequently complicated by an acute flare of disease activity. Such flares may be severe and potentially life-threatening.

Treatment of adverse effects

Cushingoid features, acne, and hirsutism develop in 80% of patients after 2 years of prednisone-based therapy. Osteoporosis with vertebral compression, diabetes, cataracts, severe emotional lability, and hypertension may develop in patients who are treated with prolonged courses of high-dose prednisone. Premature treatment withdrawal is justified in patients who develop intolerable obesity, cosmetic changes, or osteoporosis.

Azathioprine can function as a steroid-sparing agent. The authors have had great success and minimal drug-related adverse effects using a regimen of prednisone 10 mg/d plus azathioprine 50 mg/d. Patients should be co-treated with calcium and vitamin D in order to prevent the development of steroid-induced osteoporosis. Regular exercise should be encouraged. Bone densitometry performed every 1-2 years should be used to monitor patients. Signs of early osteoporosis may warrant the institution of treatment with alendronate.

Azathioprine therapy can be complicated by cholestatic hepatotoxicity, nausea, vomiting, rash, cytopenia, and pancreatitis. These complications occur in fewer than 10% of patients treated with azathioprine at 50 mg/d.

Azathioprine is metabolized to 6-mercaptopurine. One of the enzymes responsible for metabolizing 6-mercaptopurine is thiopurine methyltransferase (TPMT). About 0.3% of the population possesses mutations of the genes coding for TPMT. These individuals, with low or no TPMT activity, may develop excess levels of the metabolite 6-thioguanine. High 6-thioguanine levels, in turn, may predispose the patient to bone marrow suppression. Some authors recommend that patients undergo TPMT genotyping prior to the initiation of azathioprine therapy.43

To date, most studies of azathioprine efficacy in autoimmune hepatitis have used a dose of 50 mg/d. In contrast, many authors in the field of inflammatory bowel disease (IBD) suggest that azathioprine (or 6-mercaptopurine) dosing be individualized so that patients can achieve a desired 6-thioguanine level of 230-400 pmol/8x108 erythrocytes.44 This level has been associated with optimal clinical outcomes for patients with IBD. It remains to be determined whether such an approach should be applied to azathioprine dosing in patients with autoimmune hepatitis.

Cytopenias, particularly leukopenia, may occur at any time after the initiation of azathioprine therapy. All patients undergoing treatment with azathioprine should undergo routine interval testing of the complete blood count.

Teratogenicity has been ascribed to treatment with azathioprine; however, the gastroenterology literature is replete with references that describe the safe use of azathioprine and 6-mercaptopurine in pregnant women with inflammatory bowel disease. Whether this observation can be extended to pregnant women with autoimmune hepatitis and whether azathioprine can be employed safely in these patients is unclear.

Hematologic malignancy has been reported in patients undergoing treatment with azathioprine; however, the risk of malignancy is thought to be low in patients with autoimmune hepatitis who are treated with low doses of the drug.

Surgical Care

Liver transplantation o This procedure is an effective form of therapy for patients with decompensated cirrhosis

caused by autoimmune hepatitis. This procedure also may be used to rescue patients who present with fulminant hepatic failure secondary to autoimmune hepatitis.

o The long-term outlook after liver transplantation is excellent, with 10-year survival rates reported as greater than 70%.45 Positive autoantibodies and hypergammaglobulinemia tend to disappear within 2 years of transplantation.46

o Recurrence of autoimmune hepatitis is described after liver transplantation. It has been reported primarily in inadequately immunosuppressed patients. It may occur more often in HLA DR3-positive recipients of HLA DR3-negative donors. Recurrent disease is seen in 10-35% of patients undergoing transplant for autoimmune hepatitis. Although such recurrences are often mild events, one paper described a need for retransplantation in one half of patients experiencing recurrent disease.45,47,48

o In a study of autoimmune hepatitis recurrence following liver transplantation, Montano-Loza et al concluded that recurrence risk factors include concomitant autoimmune disease and high levels of aspartate aminotransferase, alanine aminotransferase, and IgG prior to the transplant.48 The presence of moderate to severe inflammatory activity or plasma cell infiltration in the liver explant also was said to increase the recurrence risk. According to the authors, their findings suggest that incomplete suppression of disease activity before liver transplantation promotes autoimmune hepatitis recurrence.

Diet

Patients with acute autoimmune hepatitis and symptoms of nausea and vomiting may require intravenous fluids and even total parenteral nutrition; however, most patients can tolerate a regular diet. A high caloric intake is desirable.

Patients with cirrhosis secondary to autoimmune hepatitis may develop ascites. A low-salt diet (generally <2000 mg of sodium per d) is mandatory in these individuals. Patients should continue to consume protein (ie, >1.3 g protein per kg body weight) given the catabolic nature of the disease and patients' high risk for developing muscle wasting.

ActivityMost patients do not need hospitalization, although this may be required for clinically severe illness. Forced and prolonged bed rest is unnecessary, but patients may feel better with restricted physical activity.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Medications used include prednisone, prednisolone, and azathioprine.

CorticosteroidsSee Treatment. Rapid institution of treatment with high-dose corticosteroids may rescue patients whose disease ultimately would have progressed to either fulminant hepatic failure or cirrhosis. Treatment with corticosteroids has been shown to improve the chances for survival significantly.

Prednisone (Sterapred)

Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production.

Dosing

Interactions

Contraindications

Precautions

Adult

5-60 mg/d PO qd.

Pediatric

4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO qD.

Dosing

Interactions

Contraindications

Precautions

Dosing

Interactions

Contraindications

Precautions

Dosing

Interactions

Contraindications

Precautions

Prednisolone (Delta-Cortef, Econopred, Articulose-50)

Decreases autoimmune reactions, possibly by suppressing key components of immune system.

Dosing

Interactions

Contraindications

Precautions

Adult

5-60 mg/d PO/IV/IM in divided doses

Pediatric

0.1-2 mg/kg/d PO/IV/IM qd or divided tid/qid

Dosing

Interactions

Contraindications

Precautions

Dosing

Interactions

Contraindications

Precautions

Dosing

Interactions

Contraindications

Precautions Immunosuppressant agentsThese agents inhibit immune reactions resulting from diverse stimuli.

Azathioprine (Imuran, Azasan)

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.

Dosing

Interactions

Contraindications

Precautions

Adult

1 mg/kg/d PO for 6-8 wk; increase by 0.5 mg/kg q4wk until response or dose reaches 2.5 mg/kg/d

Pediatric

Initial: 2-5 mg/kg/d PO/IVMaintenance: 1-2 mg/kg/d PO/IV

Follow-up

Transfer

A low threshold should exist for transferring patients with acute liver failure to tertiary care hospitals that are capable of performing emergent liver transplantation.

Complications

See the information on disease associations, in the History section, for a discussion of complications.

Prognosis

Role of liver inflammation: The prognosis of autoimmune hepatitis depends primarily on the severity of liver inflammation. Patients with a severe initial presentation tend to have a worse long-term outlook than patients whose initial disease is mild. Similarly, the inability to enter remission or the development of multiple relapses, either during therapy or after treatment withdrawal, implies a worse long-term prognosis.

The role of HLA type: HLA status reflects treatment outcome. As an example, HLA DR3-positive patients are more likely to have active disease and are less responsive to therapy than patients with other HLA types. These patients also are more likely to require liver transplantation at some point.

Spontaneous remission: Spontaneous resolution of disease is observed in 13-20% of patients, regardless of the inflammatory activity. This is an unpredictable event.

Hepatocellular carcinoma (HCC) is less common in patients with autoimmune hepatitis–induced cirrhosis than in cirrhosis caused by other factors; however, HCC is not a rare event in autoimmune hepatitis. Surveillance abdominal imaging studies (eg, ultrasound, CT, MRI) and alpha-fetoprotein testing are typically performed every 6 months in patients with most types of cirrhosis. The optimal interval for surveillance and the best type of abdominal imaging study have not yet been determined for patients with autoimmune hepatitis-induced cirrhosis. Detection of a small HCC on imaging studies should prompt immediate referral for consideration of liver transplantation.

Patient Education

For patient education information, see Hepatitis Center and Liver, Gallbladder, and Pancreas Center, as well as Hepatitis A, Hepatitis B, Hepatitis C, and Cirrhosis.

Miscellaneous

Medicolegal Pitfalls

Because autoimmune hepatitis is a potentially treatable condition, a missed diagnosis can have serious consequences. The diagnosis should be considered in all patients with hepatitis, especially females. Untreated autoimmune hepatitis can result in death due to liver failure.

Similarly, a wrong diagnosis of autoimmune hepatitis can expose the patient to unnecessary complications of immunosuppressant therapy, which can be serious and life threatening.