IN THE NAME OF GOD. DR. N. ALETAHA MD Autoimmune hepatitis.

IN THE NAME OF GOD

DR. N. ALETAHA MD

Autoimmune hepatitis

INTRODUCTION

Autoimmune hepatitis is a chronic hepatitis of unknown etiology that occurs in children and adults of all ages.

It is characterized by autoimmune features, hyperglobulinemia, and the presence of circulating auto antibodies.

CLASSIFICATION

Two major forms have been described, type 1 and type 2.

Type 1 autoimmune hepatitis — Type 1 or

classic autoimmune hepatitis is characterized by circulating antibodies to nuclei (ANA) and/or smooth muscle (ASMA); the latter are anti actin antibodies (AAA).

 Type 2 autoimmune hepatitis — Type 2 autoimmune hepatitis is defined by the presence of antibodies to liver/kidney microsomes (ALKM-1) and/or to a liver cytosol antigen (ALC-1) .

Epidemiology

Incidence 1.9 cases per 100,000 persons annually

among white northern Europeans Prevalence In the U.S. ~100,000 to 200,000 cases Accounts for 5.9% of cases in the National

Institutes of Health liver transplantation database

Seen in 11–23% of people with chronic liver disease in North America

Epidemiology

Age Autoimmune hepatitis (AIH) type I Classic syndrome in young women AIH type II Often seen in children and more

common in Mediterranean populations Subdivided by some authorities: AIH type IIa: young women AIH type IIb: older men

Epidemiology

Sex Female preponderance AIH type I Female to male ratio of 3-4:1 AIH type II Female-to-male ratio of 8-9:1 Race/ethnicity Highest frequency in white northern

Europeans All races are susceptible.

CLASSIFICATION

Classic (type 1) autoimmune hepatitis occurs predominantly in women in all age groups, while ALKM-1 (type 2) autoimmune hepatitis is generally a disease of girls and young women.

Overlap syndromes — Patients with variant forms of autoimmune hepatitis have clinical and serologic findings of autoimmune hepatitis plus features of other forms of chronic liver disease, particularly primary biliary cirrhosis or primary sclerosing cholangitis.

CLINICAL MANIFESTATIONS

Autoimmune hepatitis has a heterogeneous and fluctuating nature

Asymptomatic patientsConsiderable and sometimes debilitating

symptoms Fulminant hepatic failure. Finding of an elevated aminotransferase levelIdentification of liver abnormality during

surgerySometimes frankly cirrhotic-appearing liver.

CLINICAL MANIFESTATIONS

Mild or severe nonspecific symptoms, such as fatiguability, lethargy, malaise, anorexia, nausea, abdominal pain, and itching.

Arthralgia involving the small joints is a characteristic clinical feature.

Physical findings range from a normal physical examination to the presence of hepatomegaly, splenomegaly, stigmata of chronic liver disease, and/or deep jaundice.

Extrahepatic manifestations

Diseases commonly seen with autoimmune hepatitis include hemolytic anemia, idiopathic thrombocytopenic purpura, type 1 diabetes mellitus, thyroiditis, celiac sprue, and ulcerative colitis (which is more often associated with primary sclerosing cholangitis), Proliferative glomerulonephritis, Sjögren’s syndrome .

The liver disease may antedate the appearance of colitis in both disorders.

Complications

Primary hepatocellular carcinoma is thought to be a natural consequence of the chronic hepatitis-cirrhosis disease progression.

Autoimmune hepatitis is not an exception to this hypothesis, although progression to carcinoma is less frequent than in chronic viral hepatitis.

DIAGNOSIS

 Diagnosis is based upon characteristic serologic and histologic findings and the exclusion of other forms of chronic liver disease.

The diagnosis should be made in patients with compatible clinical signs, symptoms, and laboratory abnormalities.

DIAGNOSIS

Compatible laboratory and histological abnormalities include Abnormal liver biochemical tests Increased total IgG or gamma-globulin levels serologic markers (ANA, SMA, anti-LKM-1, or anti-

LC1) interface hepatitis.

Other conditions that can cause chronic hepatitis should be excluded.

Laboratory features

As a general rule, aminotransferase elevations are more striking in autoimmune hepatitis than those of bilirubin and alkaline phosphatase.

In some cases, autoimmune hepatitis has a cholestatic picture marked by high levels of conjugated bilirubin and alkaline phosphatase.

Histology

A portal mononuclear cell infiltrate, generally lymphoplasmacytic, often with occasional eosinophils, surrounding the portal triad and the surrounding lobule (periportal infiltrate) and beyond

The periportal lesion (piecemeal necrosis or interface hepatitis), There may also be centrizonal necrosis

Histology

Bile duct changes (destructive and nondestructive cholangitis and ductopenia) are present in approximately 25 percent of patients

Fibrosis is present in all but the mildest forms of autoimmune hepatitis.

Advanced fibrosis connects portal and central areas (bridging) which ultimately, by architectural distortion of the hepatic lobule and the appearance of regenerating nodules, results in cirrhosis.

Autoantibodies

Approximately 10 percent of patients with type 1 autoimmune hepatitis have antibodies directed against a soluble liver antigen (anti SLA/LP).

Autoantibodies

Atypical perinuclear antineutrophil cytoplasmic antibodies (P-ANCA), which are found in high frequency in primary sclerosing cholangitis and idiopathic ulcerative colitis, are also common in type 1 autoimmune hepatitis.

Autoantibodies

There are some patients who present with all the features of autoimmune hepatitis, but lack circulating ANA, ASMA, anti SLA/LP, ANCA, or ALKM-1 antibodies.

At present, they are considered to have cryptogenic chronic hepatitis or cryptogenic cirrhosis.

A therapeutic response to antiinflammatory therapy may be the only indication that autoimmune hepatitis is the underlying disease in these patients.

Scoring systems

Simplified scoring systemis based upon titers of autoantibodies, IgG levels, liver histology, and exclusion of viral hepatitis.

Autoantibodies: assign 1 point if the ANA or SMA are 1:40 OR assign 2 points if the ANA or SMA are ≥1:80 (OR if the LKM ≥1:40 OR if the SLA is positive).

 IgG: assign 1 point if the IgG is > the upper limit of normal OR assign 2 points if the IgG is >1.10 times the upper limit of normal.

Scoring systems

Liver histology (evidence of hepatitis is a mandatory condition): assign 1 point if the histological features are compatible with autoimmune hepatitis OR 2 points if the histological features are typical of autoimmune hepatitis.

Typical histologic features were defined as the presence of interface hepatitis, lymphocytic/lymphoplasmacytic infiltrates in the portal tracts and extending into the lobule, and hepatic rosette formation.

Scoring systems

Compatible features were defined as a picture of chronic hepatitis with lymphocytic infiltration without all the features considered typical.

Absence of viral hepatitis: assign 2 points if viral hepatitis has been excluded. In the validation study, patients were mainly tested for hepatitis B and C.

Scoring systems

However, other forms of hepatitis should be considered depending upon the clinical setting.

A probable diagnosis of autoimmune hepatitis is made if the total points are 6 while a definite diagnosis is made if the total points are ≥7.

DIFFERENTIAL DIAGNOSIS 

Primary biliary cirrhosis and primary sclerosing cholangitis

liver biopsy: commonly have features involving bile duct paucity, inflammation and/or damage, or periductular fibrosis that are not seen in autoimmune hepatitis

Although antimitochondrial antibodies (AMA) can occur in association with other autoantibodies in autoimmune hepatitis, the isolated presence of AMA almost always signifies primary biliary cirrhosis

DIFFERENTIAL DIAGNOSIS

Acute hepatitisIn the acute setting, it is necessary to

distinguish autoimmune hepatitis from acute viral hepatitis secondary to hepatitis A to D, hepatitis E in some parts of the world, cytomegalovirus, Epstein-Barr virus, and herpes viruses.

DIFFERENTIAL DIAGNOSIS

Chronic hepatitis C patients with autoimmune hepatitis who have

false positive hepatitis C antibodies can be identified.

On the other hand, patients with chronic hepatitis C may make a variety of autoantibodies including rheumatoid factor and cryoglobulins; the presence of these autoantibodies does not imply the existence of autoimmune liver disease.

In rare instances, chronic viral hepatitis and autoimmune hepatitis coexist

DIFFERENTIAL DIAGNOSIS

Diagnosing autoimmune hepatitis in patients with underlying nonalcoholic steatohepatitis may be difficult, especially in the presence of a positive ANA presence of polymorphonuclear leukocytes and central fibrosis in the biopsy may point to steatohepatitis.

liver disease associated with lupus. Although ANA can be seen in both conditions, ASMA and AMA are rare in lupus; thus, their presence suggests that the patient has autoimmune hepatitis

DIFFERENTIAL DIAGNOSIS

It is probable that autoimmune hepatitis also accounts for some cases of cryptogenic chronic hepatitis or cirrhosis in which autoantibodies are absent, or will eventually become detectable.

Iron overload  On occasion, a raised serum ferritin, sometimes

accompanied by an elevated transferrin saturation, occurs in autoimmune hepatitis or chronic viral hepatitis. Significant iron overload from genetic hemochromatosis can be excluded in this setting by the measurement of hepatic iron concentration and subsequent calculation of the hepatic iron index and HFE mutations.

Treatment

INDICATIONS FOR TREATMENTAASLD recommendations • Immunosuppressive treatment should be

instituted in patients with serum aminotransferases greater than 10-fold

the upper limit of normalserum aminotransferases at least five-fold the upper

limit of normal in conjunction with serum gamma-globulin levels at least two-fold the upper limit of normal

and/or histologic features of bridging necrosis or multilobular necrosis.

Treatment

 • Immunosuppressive treatment should NOT be instituted in patients with minimal or no disease activity or inactive cirrhosis, but such patients should be followed every three to six months.

Treatment

 • Immunosuppressive treatment should NOT be instituted in patients with serious preexisting comorbid conditions (vertebral compression, psychosis, brittle diabetes, uncontrolled hypertension) or previous known intolerances to prednisone unless the disease is severe and progressive and adequate control measures for the comorbid conditions can be instituted.

 • Azathioprine should NOT be started in patients with severe pretreatment cytopenia (white blood cell counts below 2.5 X 10(9)/L or platelet counts below 50 X 10(9)/L) or known complete deficiency of thiopurine methyltransferase activity.

 • Immunosuppressive treatment should be instituted in children at diagnosis regardless of symptoms.

CHOICE OF INITIAL THERAPY

 Glucocorticoids are the mainstay of antiinflammatory/immunosuppressive therapy in autoimmune hepatitis.

However, steroid-sparing with azathioprine is frequently used. Combination regimens permit the use of lower doses of glucocorticoids thereby reducing glucocorticoid-related side effects.

CHOICE OF INITIAL THERAPY

A regimen of glucocorticoids alone may be preferred in settings in which there is a concern related to exposing the patient to azathioprine such as in patients with preexisting cytopenias, malignancy, and thiopurine methyltransferase deficiency.

A regimen of azathioprine alone may be considered in patients at increased risk for glucocorticoid side effects.

CHOICE OF INITIAL THERAPY

Combination therapy is generally preferable because of the convincing data documenting efficacy of glucocorticoids as initial treatment.

Patients at increased risk for glucocorticoid side effects include postmenopausal women, and those with osteoporosis, brittle diabetes, obesity, acne, emotional lability, and hypertension.

CHOICE OF INITIAL THERAPY

AASLD recommendations 

• Two initial treatment regimens are considered to be equally effective in severe AIH: prednisone (60 mg daily) alone or lower dose prednisone (30 mg daily) in combination with azathioprine (50 mg daily is used most commonly in the United States, while in Europe the dose is often given as 1 to 2 mg/kg body weight)

 • The combination regimen is associated with a significantly lower rate of glucocorticoid-related side-effects.

AASLD recommendations

 • Prednisone should be tapered to an individual level sufficient to maintain remission. Tapering should be done by 5 mg increments per week once patients are at a 20 mg dose. Once they are at a 10 mg/day dose, tapering should be done in increments of 2.5 mg/week up to 5 mg daily.

 • Patients should be vaccinated against hepatitis A and B if not already immune, possibly even before immunosuppression is started.

CHOICE OF INITIAL THERAPY

Cyclosporine may be a reasonable initial alternative in children in whom compliance can be a particular problem because side-effects of glucocorticoids may be unacceptable.

CHOICE OF INITIAL THERAPY

Patients not treated — Patients in whom treatment is not initiated should be monitored carefully, including performance of repeat liver biopsies for evidence of disease progression. We generally rebiopsy such patients no longer than two years after diagnosis, although the optimal management of such patients is unclear.

THE END