Basics
Description
- Autoimmune hepatitis (AIH) is a chronic inflammatory disease of unknown cause, which leads to the progressive destruction of the liver parenchyma.
- Characterized by: Interface hepatitis by histological exam, and/or hypergammaglobulinemia, and/or circulating auto-antibodies
- Type I + antinuclear antibodies (ANA) and/or anti-smooth muscle antibodies (SMA)
- Type II + antiliver/kidney/microsomal antibodies (LKM/LC-1)
- Anti-neutrophilic circulating antibody (pANCA) and soluble liver antibodies (SLA) can be used as surrogate markers in absence of conventional auto antibodies profile.
- Overlapping syndromes
- AIH has features in common (10%) with primary sclerosis cholangitis (PSC), primary biliary cirrhosis (PBC), and autoimmune cholangitis.
Epidemiology
- AIH affects predominantly women of all ages, all ethnic origins.
- 1/2 of the patients with type I classic AIH are women under age of 40.
- Gender ratio: 3.6:1
- Clinical course is more aggressive in children.
- Elderly may have milder disease.
- AIH accounts for 5.6% of all liver transplants in the US.
Incidence
1.9/100,000 white North European population
Prevalence
16.9/100,000 white North European population
Risk Factors
High index of suspicion for patients with autoimmune phenotype and elevated aminotransferases
Genetics
AHI is strongly associated with human leukocyte antigen (HLA) class II alleles DR3 and DR4 in Caucasian and North American patients. HLA alleles influence disease expression and clinical behavior as well as susceptibility.
- AIH Type I DRB1*0301: Younger patients, aggressive disease, less response to therapy
- AIH Type I DRB1*0401: Older patients, better response to therapy
- AHI Type II DRB1*0701: More common in Southern Europe
General Prevention
Early diagnosis and appropriate therapy will prevent progression to end-stage liver disease.
Pathophysiology
The pathogenesis of the disease is only partially understood.
- External factors interacting with host genetic susceptibility trigger immunoreactions targeted to hepatic cells.
- Antibody-dependent and cellular-mediated hepatocyte cytotoxicity
- Targeted antigens in the liver are not known.
- Serum autoantibodies are not involved in the direct damage; useful in diagnosis and monitoring.
- Inflammation causes necrosis and fibrosis deposition in the liver parenchyma.
Etiology
Agent(s) triggering the autoimmune process in classical AIH are unknown (idiopathic)
Can be caused by specific drugs:
- Methyldopa, minocycline, isoniazid, nitrofurantoin, hydralazine
- Drug-induced AIH responds to drug withdrawal.
Associated Conditions
AIH is associated with the full spectrum of autoimmune disorders:
- Diabetes mellitus type1
- Celiac disease
- Rheumatoid arthritis
- Antiphospholipid antibody
- Autoimmune thyroiditis
- Ulcerative colitis
- Vasculitis
- Autoimmune hemolysis
- Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED syndrome)
Diagnosis
Diagnosis is obtained using clinical, laboratory, and histological data.
- Easy to make diagnosis in typical cases
- No pathognomonic features
- Diagnostic criteria have been codified and updated by an international panel (IAHG) and require the presence of characteristic features and exclusion of other known causes of liver disease.
- A scoring system that attributes negative and positive points to clinical and laboratory features is useful in difficult diagnoses (1)[A].
History
- Personal or family history of autoimmune diseases
- History of medications known to cause chronic hepatitis
- Personal history of other liver diseases
- Inquire about alcohol use
- Signs and symptoms:
- Malaise
- Fever
- Arthralgia
- Fatigue
- Right upper quadrant discomfort
- Jaundice
- Acute hepatitis: 30-40% of all cases, usually symptomatic
- Chronic hepatitis: Usually asymptomatic, discovered during routine work-up for abnormal liver function tests (LFTs)
- Cirrhosis: 25% of patients have cirrhosis at time of initial presentation
- 1/2 of children with AIH will present with cirrhosis
Physical Exam
Signs of chronic liver disease may be present:
- Jaundice, muscular wasting, spider angioma
- Hepatosplenomegaly, ascites
- Peripheral edema
- Hyperreflexia, asterixis
Tests
Required to confirm AIH and exclude other liver diseases
Lab
- AST and ALT"‚>5 — normal
- Polyclonal hyperglobulinemia globulin ≥1.5 — normal
- ANA, SMA, SLA, pANCA, LKM1 ≥1:80
- Absent marker of viral infection (EBV, Hep A, B, C)
- Normal alpha-1 antitrypsin phenotype, ceruloplasmin
Imaging
Abdominal ultrasound with Doppler and CT scan with contrast can be useful in ruling out other causes of abnormal LFTs (Budd-Chiari, fatty liver, space-occupying lesions), but are not critical for the diagnosis.
Surgery
A liver biopsy is mandatory for the diagnosis.
Pathological Findings
- Periportal hepatitis (interface hepatitis)
- Predominant lymphocytes, plasma cells often present
- Variable degree of fibrosis
- Absence of biliary changes and granulomas
Differential Diagnosis
- PBC: Autoimmune chronic hepatitis with destruction of biliary epithelia leading to cirrhosis may present with AIH feature
- Cholestatic syndrome
- AMA often present (rarely in AIH)
- Biliary epithelia infiltration, granulomas in liver biopsy
- PSC
- Abnormal endoscopic retrograde cholangiopancreatography
- Predominantly cholestatic picture
- Overlapping syndromes and atypical presentations pose a diagnostic challenge in these cases.
- Order additional antibodies (pANCA, anti-LC-1, anti-SLA, anti-ASGPR)
- HLA type
- Use IAHG score system
- AIH may occur de novo in pregnancy.
- Liver biopsy must be performed if suspected and therapy started.
- AIH might improve during pregnancy (2)[C].
- Pregnant women with AIH have higher frequency of prematurity, low birth weight infants, and fetal losses. Acute fulminant hepatitis has been reported (2)[B].
- Exacerbation of the disease commonly follows delivery.
- Corticosteroids and azathioprine are likely safe in pregnancy but prednisolone alone is the preferred treatment.
Treatment
Once diagnosis is confirmed, treatment should be initiated as soon as possible.
Medication
Goal of therapy is to achieve remission:
- In the first 3 years of therapy, 80% of the patients will achieve biochemical and histological remission (3)[B].
- Long-term remission: 15% after drug withdrawal
- Approximately 85% will relapse after discontinuation of the therapy and require long-term treatment.
- Nonresponders: 20%
- Prompts reevaluation of diagnosis
- Consider an increased dose or change in regimen
- Acute severe hepatitis not responding to therapy should be referred for liver transplant.
- Absolute indication for therapy: AST >10 — normal; AST >5 — upper limit of normal and gamma globulin level >2 — normal; bridging or multilobular necrosis in biopsy (4)[A]
- The benefit of therapy in mild, asymptomatic disease has not been established and should be balanced with the risks of therapy (5)[B].
First Line
- Prednisone alone 60 mg/day or prednisone 30 mg/day + azathioprine 1-2 mg/kg/day (4)[A]
- Use a prednisone tapering schedule to reach the maintenance dose of 10-20 mg/day in 4-6 weeks.
- Clinical and biochemical normalization occurs in first 3-6 months. Histology lags behind.
- The duration of therapy has not been established; however, after initial tapering, maintenance doses should be continued at least for 1 year.
- Repeat liver biopsy 3 months after normalization of laboratories indices is the only confident method to confirm the treatment endpoint (4)[B].
- Relapse: Reinstitute original treatment schedule. Long-term treatment with azathioprine 2 mg/kg/day after complete steroid tapering is preferred treatment after the first exacerbation (4)[B].
Second Line
Other immunosuppressants have been used in nonresponders or in patients intolerant to first-line medications.
- Mycophenolate mofetil, cyclosporine A, tacrolimus
- Budesonide can be used as first line in non-cirrhotic patients to minimize corticosteroid side effects (6)[B].
Additional Treatment
General Measures
Avoid hepatotoxic drugs and alcohol.
Issues for Referral
- Refer to a hepatologist for liver biopsy and initial diagnosis and treatment.
- Refer to transplantation center for decompensated liver disease.
Complementary and Alternative Medicine
- None have been demonstrated effective
- Consider possible hepatotoxicity of herbal preparations
Surgery
- Acute liver failure and decompensated cirrhosis benefit from liver transplant.
- Disease will recur, but is generally mild and does not affect graft survival.
In-Patient Considerations
Initial-Stabilization
- Outpatient treatment is the norm.
- Acute hepatitis may require hospitalization if severe.
- Acute liver failure has been described (rare)
- Monitor coagulopathy and mental status
- A liver transplant is indicated for acute liver failure.
Ongoing Care
Follow-Up Recommendations
The length of therapy is individualized.
- Follow aminotransferases and gamma globulin to normalization
- Long-term therapy with immunosuppressants may be required if remission is not achieved.
- Liver biopsy at 1 year of therapy is required for the diagnosis of sustained remission and the discontinuation of therapy.
Patient Monitoring
Patients need to be followed biannually given the potential of recurrence.
Diet
- Nonrestrictive
- Decompensated liver disease requires dietary modification (salt, water, and animal protein restriction).
Prognosis
Untreated AIH has a poor prognosis.
- Survival at 10 years: 10%
- Improves to 80-93% with corticosteroid treatment (4)[A]
Complications
- Decompensate cirrhosis
- Hepatocellular carcinoma is rare
References
1Alvarez F, Berg PA, Bianchi FB. International Autoimmune Hepatitis Group Report: Review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929-938. [View Abstract]2Schramm C, Herkel J, Beuers U. Pregnancy in autoimmune hepatitis: Outcome and risk factors. Am J Gastroenterol. 2006;101:556-560. [View Abstract]3Czaja AJ. Rapidity of treatment response and outcome in type 1 autoimmune hepatitis. J Hepatol 2009;51:161-167. [View Abstract]4Manns MP, Czaja AJ, Gorham JD. AASLD practice guidelines: Diagnosis and management of autoimmune hepatitis. Hepatology. 2010;51(6):1-31.5Kogan J, Safadi R, Ashur Y. Prognosis of symptomatic versus asymptomatic autoimmune hepatitis: A study of 68 patients. J Clin Gastroenterol. 2002;35:75-81. [View Abstract]6Manns MP, Woynarowski M, Kreisel W. Budesonide induces remission more effectively than prednisone in a controlled trial with autoimmune hepatitis. Gastroenterology. 2010;139(4):1198-1206. [View Abstract]
Additional Reading
1Donaldson PT Genetics of autoimmune and viral liver disease: Understanding the issues. J Hepatol. 2004;41:327-332. [View Abstract]2Talwalxar JA, Keach JC, Anqulo P. Overlap of autoimmune hepatitis and primary biliary cirrhosis: An evaluation of modified scoring system. Am J Gastroenterol. 2002;97:1191-1197.
Codes
ICD9
571.42 Autoimmune hepatitis
ICD10
K75.4 Autoimmune hepatitis
SNOMED
408335007 autoimmune hepatitis (disorder)
Clinical Pearls
- Presents as acute or chronic hepatitis
- More frequent in women
- It is associated with other autoimmune diseases.
- Active disease progresses to end-stage liver disease without treatment.
- Prognosis with treatment is generally good.