Gastroenterology training and education

What is AIH?

AIH is an unresolving in?ammation of the liver of unknown cause. Women are affected more than men (M: F- 1:3.6) and all ages and ethnic groups are susceptible.
An acute onset of illness is common (40%).

Discuss the diagnosis of AIH?

• Predominant serum aminotransferase abnormality. If alkaline phosphatase is > 3 times elevated, cholangiogram would be needed as PSC histology simulates autoimmune hepatitis Globulin, gamma-globulin or immunoglobulin G level >=1.5 times normal
• Auto antibodies at least in 1:80 titres in adults- ANA, SMA or LKM1 and no AMA
• Periportal hepatitis- limiting plate of portal tract is disrupted by a mononuclear cell infiltrate. This pattern is the hallmark of autoimmune hepatitis-but not specific. No biliary lesions, granulomas, or prominent changes suggestive of another disease
• Absence of-
  • Viral markers (A, B and C)
  • Excessive alcohol consumption (>25 g/day)
  • Recent use of hepatotoxic medicines
  • Normal serum caeruloplasmin, iron, and ferritin levels. Normal A1AT phenotype

Discuss the clinical manifestations of AIH?

Symptoms
Fatigue, jaundice (Bilirubin>4 fold unusual), abdominal discomfort, mild pruritus, anorexia, polymyalgias, diarrhoea, fever
Physical examination
Hepatomegaly, jaundice, splenomegaly, spider, ascites, encephalopathy, concurrent immune diseases. Splenomegaly and spider can occur in absence of cirrhosis.
Investigations
ANA and/or SMA are present in the majority of patients with AIH. Anti-LKM1 typically occurs in the absence of SMA and ANA. pANCA are common in AIH, however, it do not have diagnostic specificity or prognostic implications.

Discuss the natural history of AIH?

Up to 40% of patients with untreated severe disease die within 6 months of diagnosis. Cirrhosis develops in at least 40% of survivors. The 20-year life expectancy for all treated patients exceeds 80%. Untreated patients with interface hepatitis have a 17% probability of cirrhosis within 5 years and normal 5-year life expectancy. The benefit-risk ratio of therapy in such patients may be so low that corticosteroids are unjustified.

Discuss the indications of treatment?

Discuss the treatment options?

Both regimens induce clinical, laboratory, and histologic remission with similar frequency. However, the combination regimen is preferred as it is associated with a lower occurrence of corticosteroid-related side effects. Prednisolone only treatment may be preferable in presence of cytopenias, TPMT deficiency, pregnancy, malignancy or for short courses of treatment (less than 6 months).

Discuss the endpoint of treatment?

The treatment is continued is until remission, treatment failure, incomplete response, or drug toxicity occurs. There is no prescribed minimum or maximum duration of treatment. Adults rarely achieve remission in less than 12 months. Histologic improvement lags behind clinical and laboratory improvement by 3 to 6 months, and treatment should be continued for at least this period

Define remission?

Remission means disappearance of symptoms, improvement of serum aminotransferase levels to less than twice normal, restoration of serum bilirubin and gamma—globulin levels to normal, and improvement of the liver tissue to normal, portal hepatitis, or cirrhosis with minimal or no activity. Sixty-five percent of
patients enter remission within 18 months, and 80% achieve remission within 3 years.
Liver biopsy assessment prior to termination of treatment is preferred, but not essential, in the management of patients who satisfy clinical and laboratory criteria for remission.

Define relapse and its treatment?

Relapse means recurrence of disease activity after induction of remission. It is characterized by an increase in the serum aminotransferase level to more than 3-fold the upper limit of normal and/or increase in the serum gamma-globulin level to more than 2 g/dL. Relapse occurs in from 20% to 100% of patients who enter remission.
Treatment of relapse
First relapse- re institute the same treatment
Second relapse- 2 therapeutic options after induction of remission

Indefinite low dose prednisolone- 7.5-10mg/day. Titrate the dose to lowest level possible to prevent symptoms and to keep aminotransferase levels to less than 5 times normal. The prednisone dose is reduced by 2.5 mg each month until the
lowest dose is reached below which there is clinical and/or biochemical instability. Eighty-seven percent of patients can be managed in this fashion on 10 mg of prednisone daily or less.

Indefinite azathioprine- 2mg/kg/day. The dose of azathioprine is increased to 2
mg/kg daily, and then the dose of prednisone is decreased by 2.5 mg each month until complete withdrawal. Patients taking prednisone only can be switched to the azathioprine schedule by adding azathioprine (2 mg/kg daily) and then reducing the prednisone dose by 2.5 mg each month. Eighty-seven percent of adult patients managed by the indefinite azathioprine strategy remain in remission during
a median observation interval of 67 months

What is incomplete response?

Incomplete response is improvement in all aspects but fail to satisfy remission criteria. Thirteen percent of patients experience this outcome. In these instances, therapy can frequently be maintained in adjusted dose to control disease activity. Inability to induce remission after 4 years of continuous treatment identifies a
subgroup of adults at risk for liver failure. Liver transplantation should be considered in these individuals at the first sign of decompensation. The development of ascites
is the most common indication

Discuss treatment failure?

Treatment failure connotes clinical, laboratory, and histologic worsening despite compliance with conventional treatment schedules, and it occurs in at least 9% of
patient’s. The serum aminotransferase level should increase by at least 67% of the pre-treatment value to qualify for this designation
Management of treatment failure- Stop conventional therapy and start high dose regimens-

1. Prednisolone 60mg/day
2. Pred 30mg/day and azathioprine 150mg/day

The regimen is continued for at least 1 month, and then the dose of prednisone is reduced by 10 mg and the dose of azathioprine is reduced by 50 mg after each month of clinical and laboratory improvement. Dose reduction is continued until conventional maintenance levels of medication are again achieved
Each schedule induces clinical and biochemical remission in 70% within 2 years and survival is preserved. Histologic resolution in 20% only- so long term therapy needed. The development of hepatic encephalopathy, ascites, and/or variceal haemorrhage during therapy for treatment failure is an indication for liver transplantation.
Alternative management strategies for treatment failure in adults have included the administration of cyclosporine, UDCA, budesonide, 6-mercaptopurine, methotrexate, 5 cyclophosphamide, and mycophenolate mofetil. In each instance, experiences have been small and anecdotal, and in most reports, the preliminary results have been encouraging.

Discuss drug toxicity?

Drug toxicity justifies premature withdrawal of medicines or a reduction in dose in 13%, mainly because of intolerable obesity, cosmetic changes or osteoporosis. In these instances, therapy with the tolerated agent (prednisone or azathioprine) can frequently be maintained in adjusted dose to control disease activity.

Discuss liver transplantation?

Liver transplantation is the treatment of choice in patients with end stage autoimmune hepatitis and cirrhosis.
The 5-year patient and graft survival after liver transplantation in adults ranges from 83% to 92%; the actuarial 10- year survival after transplantation is 75%. Autoantibodies and hypergammaglobulinemia disappear within 1 year in most patients; and disease recurrence is typically mild and easily managed.

Patients with histologic cirrhosis respond as well to corticosteroid treatment as patients without cirrhosis. All decompensated patients with severe inflammation should be given a treatment trial of corticosteroids before proceeding with
transplantation. Some individuals with advanced liver disease, ascites, and/or endogenous encephalopathy at presentation will improve with treatment and immediate liver transplantation can be avoided. The likelihood of a significant response to corticosteroid treatment can be determined within 2 weeks.
Resolution of at least one laboratory abnormality, improvement in the pre-treatment hyperbilirubinemia, and/or failure of any test to worsen during the treatment
period indicates that therapy will be effective short term. Conversely, the presence of multiacinar necrosis and a hyperbilirubinemia that does not improve after 2 weeks identifies individuals who will not survive without urgent transplantation.

Ref

1. AASLD Practice Guidelines: Diagnosis and treatment of Autoimmune Hepatitis (archived copy at Webcite)