Autoimmune Hepatitis

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. 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. 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), 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. 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.

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 antibodies

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 Hepatitis

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.

Sex

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

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. Men may be affected more commonly than women in older age groups.

Treatment

Medical Care

For more than 3 decades, prednisone and azathioprine have been the mainstays of drug therapy for patients with autoimmune hepatitis. 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?

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.⁶ See Table 2.

• Absolute indications for treatment
• • Serum AST – Equal or greater than 10-fold upper limit of normal
  • Serum AST – Equal or greater than 5-fold upper limit of normal and gamma-globulin level equal or greater than twice normal
  • Bridging necrosis or multiacinar necrosis on histologic examination
• Relative indications for treatment
• • Symptoms (eg, fatigue, arthralgia, jaundice)
  • Serum AST and/or gamma-globulin less than absolute criteria
  • Interface hepatitis
• No indication for treatment
• • 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.
• Table 2. Indications for Treatment

Absolute

Relative

Serum AST > 10-fold upper limit of normal

Symptoms (eg, fatigue, arthralgia, jaundice)

Serum AST > 5-fold upper limit of normal

and gamma-globulin level > twice normal

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

Bridging necrosis or multiacinar necrosis on

histologic examination

Interface hepatitis

• The AASLD guidelines suggest 2 potential initial treatment regimens for adults (see Table 3).
• Table 3. Treatment Regimens for Adults

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 until

end point

20

10

50

Reasons for Preference

Cytopenia

Thiopurine

Methyltransferase deficiency

Pregnancy

Malignancy

Short course (£6 mo)

Postmenopausal state

Osteoporosis

Brittle diabetes

Obesity

Acne

Emotional lability

Hypertension

• 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.
• The AASLD guidelines also propose an initial treatment regimen for children (see Table 4).
• Table 4. Treatment Regimens for Children

Initial Regimen

Maintenance Regimen

End Point

Prednisone, 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 daily

b. Azathioprine at constant dose if added initially

c. Continue daily prednisone dose with or without azathioprine or switch to

alternate day prednisone dose adjusted to response with or without azathioprine

a. Normal liver tests for 1-2 years during treatment

b. No flare during entire interval

c. Liver biopsy examination discloses no inflammation

• Treatment endpoints: Patients may achieve 1 of 4 treatment endpoints.
• • Complete remission is indicated by the absence of symptoms, a serum AST level less than 2 times the reference range, and histologic improvement to normal or minimal inflammatory activity on liver biopsy. Patients achieving remission may be able to discontinue azathioprine and be tapered off of prednisone over a 6-week period.
  • Treatment failure is defined as deterioration in a patient's clinical condition, laboratory tests, or histologic features during therapy. Some patients will respond to reinstitution of treatment with high-dose prednisone, with or without combined azathioprine.
  • An incomplete patient response is defined as an improvement that is insufficient to satisfy remission criteria. 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 of 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. Some clinicians 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 still 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 who are resistant to steroids can be treated with cyclosporine or tacrolimus. The use of these medications is supported by a number of small cases series. 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 who were refractory to standard therapy. 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.
  • 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).
  • 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 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.
  • 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
• • 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.
  • The long-term outlook after liver transplantation is excellent, with 5-year survival rates reported at 90% or more. Positive autoantibodies and hypergammaglobulinemia tend to disappear within 2 years of transplantation.
  • 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.

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>1.3 g protein per kg body weight) given the catabolic nature of the disease and patients' high risk for developing muscle wasting.

Activity

Most 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.

Drug Category: Corticosteroids

See 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.

Drug Name	Prednisone (Deltasone, Orasone, Meticorten)
Description	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.
Adult Dose	5-60 mg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve
Pediatric Dose	4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular infections; osteoporosis
Interactions	Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteoporosis and osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Name	Prednisolone (Delta-Cortef, Econopred, Articulose-50)
Description	Decreases autoimmune reactions, possibly by suppressing key components of immune system.
Adult Dose	5-60 mg/d PO/IV/IM in divided doses
Pediatric Dose	0.1-2 mg/kg/d PO/IV/IM qd or divided tid/qid
Contraindications	Documented hypersensitivity; viral, fungal, or tubercular infections; peptic ulcer disease; osteoporosis
Interactions	Decreases effects of salicylates and toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease the effect of corticosteroids
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in hyperthyroidism, osteoporosis, cirrhosis, nonspecific ulcerative colitis, peptic ulcer, diabetes, and myasthenia gravis

Drug Category: Immunosuppressant agents

These agents inhibit immune reactions resulting from diverse stimuli.

Drug Name	Azathioprine (Imuran, Azasan)
Description	Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. May decrease proliferation of immune cells, which results in lower autoimmune activity.
Adult Dose	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 Dose	Initial: 2-5 mg/kg/d PO/IV Maintenance: 1-2 mg/kg/d PO/IV
Contraindications	Documented hypersensitivity; low levels of serum thiopurine methyl transferase (TPMT)
Interactions	Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce severe leukopenia; may increase levels of methotrexate metabolites and decrease effects of anticoagulants, neuromuscular blockers, and cyclosporine
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Increases risk of neoplasia; caution with liver disease and renal impairment; hematologic toxicities may occur; some authors recommend that TPMT level be checked prior to therapy; liver, renal, and hematologic function needs follow-up; pancreatitis rarely associated; see text regarding new data on azathioprine in pregnancy