Treatment of autoimmune hepatitis

Symptomatic patients from the control arms of early treatment trials had mortality rates of approximately 50 percent at five years.  patients with serum aspartate aminotransferase levels at least 10 times ULN or more than 5 times ULN in conjunction with a 2 fold elevation in the gamma globulin level have mortality rates of 60 percent at six months. Finally, over 80 percent of patients with bridging necrosis or multilobular necrosis at presentation progress to cirrhosis and have a five-year mortality rate of approximately 45 percent.

 With regard to asymptomatic patients, some studies suggest that untreated patients have a lower survival rate than treated patients, whereas others suggest that survival is similar

 Referral to a hepatologist should be considered for patients who fail to go into remission with glucocorticoid therapy, who worsen despite therapy, or who have cirrhosis at the time of diagnosis. Patients presenting with fulminant hepatic failure should immediately be admitted to a hospital with liver transplantation capabilities whenever possible


 AASLD 2010 guidelines.  criteria:

• ALT or AST level greater than 10-fold the ULN
• Serum ALT, AST, or gamma globulin level greater than twice ULN if any of the following are present:

• Symptoms
• An elevated conjugated bilirubin or,  even if less than twice the ULN
• Interface hepatitis on biopsy

• Histologic features of bridging necrosis or multiacinar necrosis
• Cirrhosis with any degree of inflammation on biopsy
• Children with autoimmune hepatitis 

 Unclear indications for treatment — Treatment may not be required in asymptomatic patients with normal serum aminotransferase and gamma globulin levels who have minimal necroinflammatory activity on liver biopsy
However, it is reasonable to offer treatment to a patient with histologic evidence of interface hepatitis  particularly if the patient is younger (age less than 50 years) and is unlikely to have severe side effects related to therapy.

 We generally rebiopsy patients who are not receiving treatment to look for histologic evidence of disease progression after two years.

 No indication for treatment —  absence of inflammatory cells on liver biopsy and normal or near-normal serum aminotransferases. The diagnosis of autoimmune hepatitis may be presumed in such patients based upon the clinical setting, the presence of serologic markers of autoimmune hepatitis, and the absence of other causes of liver disease. Such patients may be at increased risk for the development of glucocorticoid-related side effects, and the benefit of treatment is uncertain. However, patients with cirrhosis and active inflammation may be candidates for treatment.
 

Special circumstances —

High risk of drug side effects — The risk of glucocorticoid-related side effects is increased in patients with brittle diabetes, osteoporosis, emotional lability or a history of psychosis, or poorly controlled hypertension. 

not necessarily contraindications but may influence the decision to use azathioprine or 6-mercatopurine or use a lower dose of prednisone. Budesonide may also be in option.

Cirrhosis —  treatment is generally not recommended for patients with cirrhosis and inactive disease. treatment should not be withheld for compensated or decompensated cirrhosis who have active disease. The response to treatment may be excellent, even those with bleeding varices or ascites. Many patients respond when treatment is initiated, and the 10-year survival for treated patients, including those with cirrhosis, exceeds 90 percent

Pregnancy — Women appropriately treated for autoimmune hepatitis can have successful pregnancies. Usual therapy consists of glucocorticoids and/or azathioprine, both of which appear to be safe during pregnancy, though azathioprine is listed as pregnancy class D. Cessation of therapy during pregnancy in such patients has been associated with relapse of the disease  

 -an increased risk of prematurity, low birth weight, and fetal loss 
-monitor during pregnancy and several months post-partum because of the risk of flares in disease activity 

 Children — Autoimmune hepatitis tends to be more severe in children compared with adults,

 Coexisting HCV — treatment should first be directed toward autoimmune hepatitis because of the danger of exacerbating autoimmune hepatitis with interferon-based therapy. Although this approach may result in increased viral levels of HCV, it is the safer initial strategy.

 EXPECTED RESPONSES TO TREATMENT AND PROGNOSIS — The goal of therapy is to achieve a sustained remission without the need for medications- 10 to 40 % of patients. Up to 90% of patients with moderate to severe autoimmune hepatitis will respond to treatment, with a decrease in serum transaminases along with symptom improvement within two weeks. Serum transaminases will fall into the normal range, after 12 or more months of treatment.
 incomplete response in 13 %of patients, and they worsen in 10 %(treatment failure)
 

Risk of treatment failure — :

• Those with established cirrhosis
• Those who develop disease at a younger age or have had a longer duration of disease before therapy
• Those who possess the HLA-B8 and/or HLA-DR3 phenotypes

 Chance of remission — Patients with normalization of their aminotransferase levels are more likely to achieve histologic remission (absence of interface hepatitis), though histologic remission lags behind biochemical remission by several months.  Approximately 65 and 80 percent of patients achieve remission by 18 months and three years, respectively (average of 18 to 24 months). The probability of remission decreases after two years.

Risk of relapse —  50 to 90 % of patients will relapse within 12 months of drug withdrawal. With retreatment, over 80 % of patients will again achieve remission. 13% of patients will achieve a sustained remission when drug withdrawal is again attempted, but the majority will require maintenance therapy.

  Patients who achieve histologic remission have a 20 to 30 percent chance of relapse once treatment is withdrawn, whereas those who have evidence of interface hepatitis have a 75 to 90 percent chance of relapse.

 Risk of cirrhosis — Patients who suffer from multiple relapses are at increased risk for cirrhosis compared with patients with a sustained remission after initial treatment (38 versus 4 percent). They are also at increased risk for death from liver failure or the need for liver transplantation (20 versus 0 percent).

  30 percent of adult patients and almost half of pediatric patients will have cirrhosis at the time of diagnosis and cirrhosis develops in another 30 to 50 percent of patients during follow-up. While 10-year survival is similar to that in patients with autoimmune hepatitis without cirrhosis, survival is lower after 10 to 20 years. Ultimately, 10 to 20 percent of patients will require liver transplantation.  5 percent of patients will develop hepatocellular carcinoma. patients who undergo transplantation, 20 to 30 percent will have a recurrence of autoimmune hepatitis.

 INITIAL THERAPY —  glucocorticoid with or without azathioprine. Patients with fulminant hepatitis and liver failure, will require liver transplantation.

 Fulminant hepatitis and acute liver failure — Patients with fulminant hepatitis and acute liver failure often require liver transplantation. trial of glucocorticoids (for two weeks or less) can then be given while performing the transplant evaluation and closely monitoring the patient's clinical status and Model for End-stage Liver Disease (MELD) score, reserving liver transplantation for patients who do not improve. Steroid in fulminant hepatitis-variable result.




limited data and clinical experience suggest that the two approaches have similar efficacy as initial therapy

 Azathioprine monotherapy is used for maintenance therapy but is not effective for induction therapy. For patients who cannot tolerate prednisone, combination therapy with azathioprine and budesonide may be an alternative

 The AASLD recommends glucocorticoid monotherapy or combination of a glucocorticoid and azathioprine. The BSG guidelines recommend glucocorticoid and azathioprine and do not recommend initial treatment with glucocorticoid monotherapy.

 Because azathioprine is a prodrug of 6-mercaptopurine and, on occasion, toxicity to azathioprine occurs to the prodrug only, we may substitute 6-mercaptopurine at one-half of the azathioprine dosage.

 azathioprine at a dose of 1 to 2 mg/kg daily is often used. Since azathioprine and 6-mercaptopurine have been associated with aplastic anemia in patients lacking TPMT enzyme activity, we obtain TPMT phenotyping prior to initiating therapy

 Serum transaminase, bilirubin, or gamma globulin levels are checked weekly during the taper. If the patient develops recurrent symptoms or worsening laboratory values during the taper, we maintain the patient at the lowest dose that controls symptoms

 When TPMT activity is low, there is an increase in 6-TG, which likely accounts for much of the drugs' toxicity. Measurement of metabolites can also be useful, particularly in patients who have not responded to treatment

 However, toxicity to azathioprine can occur independent of TPMT activity, and some patients intolerant of azathioprine can take 6-mercaptopurine without side effects. In addition, allopurinol, a xanthine oxidase inhibitor, can lead to the increased production of active metabolites and should generally be avoided

 For patients on combination therapy, monitoring includes [11]:

• Weekly liver tests, blood sugar, and blood cell count for four weeks and then every one to three months also including an IgG.
• Bone density testing at the beginning of glucocorticoid therapy and then every one to two years. 
• Screening for glaucoma and cataracts after one year on glucocorticoids.

Remission — defined by :

• Resolution of symptoms
• Normalization of serum aminotransferase levels
• Normalization of serum bilirubin and gamma globulin levels
• Improvement in liver histology to normal or only mild portal hepatitis (or minimal to no activity in patients with cirrhosis) 

- Arthralgias frequently persist despite remission
 -aminotransferase remain elevated in presence of coexisting non-alcoholic fatty liver disease. -gamma globulin levels remain elevated, may be secondary to other chronic inflammatory and/or autoimmune diseases.

 In patients receiving azathioprine for maintenance therapy, 6-thioquanine (6-TG) metabolite levels may predict the ability to maintain remission.  6-TG levels of >220 pmol/[8 x 10⁸ red blood cells] were more likely than those with lower average levels to have normal alanine aminotransferase levels (odds ratio 7.7)

 the presence of normal or near-normal serum aminotransferases does not necessarily indicate histologic normalization

 Withdrawing therapy — Once remission has been established, drug withdrawal can be attempted. The decision to use maintenance azathioprine or to wait for and treat the first relapse depends upon the estimated likelihood of relapse, severity of liver disease, and anticipated side effects. The British Society of Gastroenterology guidelines recommend routine maintenance therapy in younger patients and in patients who are LKM antibody or soluble liver antigen-positive.

 Treatment is generally continued long enough to permit histologic resolution. - at least two years, with normal aminotransferase levels for 18 months. While a liver biopsy may help predict successful drug withdrawal, it has not shown to affect long-term outcomes and not required prior withdraw therapy. However, our preference is to obtain a biopsy prior to withdrawing therapy and to continue treatment if there is significant interface hepatitis or other histologic evidence of active disease.

 We gradually taper the glucocorticoid over a six-week period in patients who achieve clinical remission. We monitor the serum transaminases, total bilirubin, and gamma globulin levels every three weeks during withdrawal and for three months after withdrawal. We then monitor the levels every six months for one year, and yearly thereafter.

 For azathioprine, we generally withdraw it after glucocorticoids have been discontinued. For patients taking 50 mg daily, we simply stop the azathioprine. For patients taking higher doses, we reduce the dose by 50 mg every three months with careful monitoring every three months. In some cases, azathioprine cannot be successfully withdrawn, and patients may need maintenance therapy.

Incomplete response to initial therapy — 13 percent of patients after 36 months 

• Some or no improvement in clinical, laboratory, and histologic features despite compliance with therapy for two to three years
• No worsening of the condition

require long-term maintenance therapy. These patients are managed similarly to those who relapse following remission.

Treatment failure — 10 percent 

• Sustained biochemical and histologic activity, leading to the development or worsening of cirrhosis with eventual complications and death.
• The need for orthotopic liver transplantation. 

 Wilson disease and the overlap syndrome of autoimmune hepatitis/primary sclerosing cholangitis (autoimmune sclerosing cholangitis) should be considered in young patients with treatment failure

 The optimal therapy of resistant disease is not well established. We generally administer azathioprine (2 mg/kg/day up to a maximum dose of 200 mg daily) or 6-mercaptopurine (1 mg/kg/day up to 100 mg daily), while increasing prednisone to 40 to 60 mg/day. In responding patients, we taper the dose of prednisone by 10 mg per month until conventional maintenance doses are reached (10 mg/day) or to the lowest dose associated with clinical improvement (minimum of 10 mg/day). We continue the azathioprine or 6-mercaptopurine for up to one year before considering a dose reduction. After one year of clinical improvement, we taper the dose of azathioprine by 50 mg each month until a dose of 50 mg/day is reached. For patients who enter remission with this regimen, we will consider withdrawing therapy. However, other patients may require long-term maintenance therapy.

 AASLD includes either monotherapy with prednisone (60 mg daily) or combination therapy with prednisone (30 mg daily) and azathioprine (150 mg daily). The regimen is continued for at least one month, after which the dose of prednisone is reduced by 10 mg and the dose of azathioprine reduced by 50 mg after each month of clinical improvement. Dose reduction is continued until conventional maintenance doses are reached.

 Cyclosporine, tacrolimus, budesonide, methotrexate, infliximab, and mycophenolate mofetil have also been used in small numbers of patients who fail or cannot tolerate conventional therapy. AASLD, has been to try mycophenolate mofetil (a total of 2 g daily orally)

 Finally, allopurinol has been tested in patients who are nonresponsive or intolerant to azathioprine or 6-mercaptopurine. When allopurinol is given in conjunction with a thiopurine, the metabolism of the thiopurine is shunted toward increased production of the metabolically active 6-thioguanine and decreased production of the toxic thiopurine metabolites. In a study of eight patients who received allopurinol in conjunction with a thiopurine, biochemical improvements were seen in all eight, with a sustained response in seven. However, if allopurinol (or other xanthine oxidase inhibitors) is used in conjunction with a thiopurine, it is important to monitor thiopurine metabolite levels

 Medication intolerance —  10 percent.
- treat with either glucocorticoids or azathioprine alone (whichever was tolerated) at a dose that controls disease activity.
If there is disease progression on the single agent, alternative therapies, such as mycophenolate mofetil can be considered.

 RELAPSE FOLLOWING SUCCESSFUL DRUG WITHDRAWAL — Relapse may be heralded by the development of fatigue, arthralgias, and anorexia accompanied by a rise in serum aminotransferase levels and/or an increase in serum gamma globulin levels. A rise in serum aminotransferases to more than three times normal or a rise in serum gamma globulins to more than 2 g/dL correlates strongly with the presence of histologic deterioration

 Treatment of relapses — to resume the drug therapy that initially leads to remission at induction doses. Once clinical remission, to withdraw the drug(s), since some patients will achieve a sustained remission despite multiple relapses

 Patients who continue to relapse can be treated with the lowest dose of either azathioprine or prednisone. Both strategies are effective in controlling the disease in the majority of patients. The decision to use azathioprine either as a steroid-sparing agent or as monotherapy involves weighing long-term steroid-induced side effects against those of azathioprine.
 
The following are reasonable approaches to making drug changes in patients taking azathioprine or prednisone for maintenance therapy:
In patients taking combination therapy in whom a prednisone alone strategy is desired, the prednisone dose is typically reduced first to the lowest level that maintains stability of the serum aminotransferases. The dose of prednisone can be decreased by 10 mg per week until a dose of 20 mg/day is reached. Tapering should then be by 5 mg increments per week until a dose of 10 mg/day is reached. At that point, tapering should be done in increments of 2.5 mg per week down to a dose of 5 mg daily. If laboratory tests worsen or symptoms return, the taper should stop and the previous dose resumed.
Azathioprine can then be discontinued by reducing the dose by 50 mg every three months with an increase in the dose of prednisone if needed. A typical maintenance dose of prednisone is less than 10 mg daily. Budesonide may have a role in this setting.

 In patients taking combination therapy in whom maintenance therapy with azathioprine alone is desired, the azathioprine dose can be increased to 2 mg/kg/day, and then the dose of prednisone can be decreased by 2.5 mg each month until complete withdrawal. If 6-mercaptopurine is chosen, the corresponding dose of 1 mg/kg/day is used.

 In patients taking prednisone alone in whom prednisone-free maintenance therapy with azathioprine alone is desired, azathioprine (2 mg/kg/day) or 6-mercaptopurine (1 mg/kg/day) can be added, after which the dose of prednisone can be reduced by 2.5 mg each month.

 Once on a stable dose of medication, we monitor the patient's serum aminotransferases, bilirubin, and gamma globulin levels every six months. In addition, we obtain repeat liver biopsies to assess for disease progression every two years or prior to withdrawing therapy

Partial suppression in frequent relapsers — refers to treating patients to alleviate symptoms and to maintain serum aminotransferase levels that are mildly to moderately elevated. Partial suppression can be achieved with low doses of prednisone, with or without azathioprine
Their long-term outcomes (mean follow-up four years) were similar to those seen in 31 patients receiving conventional treatment. Only 1 of the 22 patients entered sustained remission, while 16 continued therapy. Morbidity was less than in conventionally treated patients since steroid-induced side effects usually resolved with low-dose prednisone.

LIVER TRANSPLANTATION —

We refer patients for a transplantation evaluation if they have:

• Fulminant hepatitis and acute liver failure
• Decompensated cirrhosis with a MELD score ≥15
• Hepatocellular carcinoma meeting criteria for transplantation

 autoimmune hepatitis recurs in 20 to 30 percent of patients

AASLD indications for treatment —

• Immunosuppressive treatment can be considered in adults without symptoms and with mild laboratory and histological changes. The decision should be individualized and balanced against the risks of therapy. Referral of such patients to a hepatologist should be considered.
• 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.
• 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 10⁹/L or platelet counts below 50 X 10⁹/L) or known complete deficiency of thiopurine methyltransferase (TPMT) activity. TPMT activity should be assessed prior to starting azathioprine in a patient with cytopenia.
• Immunosuppressive treatment should be instituted in children at diagnosis regardless of symptoms.

Clinical manifestations and diagnosis of autoimmune hepatitis

Type 1 autoimmune hepatitis – ANA and/or smooth muscle (ASMA);
ASMA with titers of 1:320 or greater generally reflect the presence of AAA.
 ELISA for antiactin antibodies (IgG anti F-actin)

 Type 2 autoimmune hepatitis –
 antibodies to liver/kidney microsomes (ALKM-1) and/or to a liver cytosol antigen (ALC-1)



 EPIDEMIOLOGY — all ethnic groups and can occur at any age, often in 40s or 50s
female to male ratio of 3.6 to 1

 CLINICAL MANIFESTATIONS —  variability in its clinical manifestations, asymptomatic patients, acute liver failure or subclinical disease

 mild or severe nonspecific symptoms, such as fatigue, lethargy, malaise, anorexia, nausea, abdominal pain, and itching, arthralgia small joints

 Diseases commonly seen with autoimmune hepatitis include hemolytic anemia, immune thrombocytopenia (ITP), type 1 diabetes mellitus, thyroiditis, celiac sprue, and ulcerative colitis (which is more often associated with primary sclerosing cholangitis).  polyglandular autoimmune syndrome can occur in children with type 2 autoimmune hepatitis.

 Complications —  progression to carcinoma is less frequent than in chronic viral hepatitis. One report found an increased risk of nonmelanoma skin cancer in patients with autoimmune hepatitis treated with long-term immunosuppression

 AASLD 2010:

• The diagnosis should be made in patients with compatible clinical signs, symptoms, and laboratory abnormalities. Compatible laboratory and histological abnormalities include abnormal liver biochemical tests, an increased total IgG or gamma-globulin levels, serologic markers (ANA, SMA, anti-LKM-1, or anti-LC1), and interface hepatitis. Other conditions that can cause chronic hepatitis should be excluded.
• In unclear cases (such as those who have few or atypical findings), a standardized scoring system should be used in the assessment. 
• In those who are negative for conventional autoantibodies, additional autoantibodies should be sought. At minimum, this should include anti-SLA and atypical pANCA.
• Cholangiographic studies should be considered to exclude primary sclerosing cholangitis in adults who do not respond to corticosteroid therapy after three months.
• In children, cholangiographic studies should be considered to exclude autoimmune sclerosing cholangitis.
• All patients with autoimmune hepatitis and inflammatory bowel disease should undergo cholangiographic studies to exclude primary sclerosing cholangitis.

Laboratory features — aminotransferase elevations

In some cases, however,  cholestatic picture (high levels of conjugated bilirubin and ALP. Extrahepatic obstruction (diagnosed by imaging studies), and cholestatic forms of viral hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and the variant syndromes must be considered.

- elevation in serum globulins, particularly gamma globulins and, generally, IgG. Hyperglobulinemia is generally associated with circulating autoantibodies,
- partial IgA deficiency is seen particularly in children with both type 1 and, more frequently, type 2 disease

Histology — Anonspecific findings:

• A portal mononuclear cell infiltrate, 
• The periportal lesion, sometimes referred to as piecemeal necrosis or interface hepatitis, There may also be centrizonal necrosis.
• Bile duct changes (destructive and nondestructive cholangitis and ductopenia)25%. Granulomas are uncommonly seen.
• An exuberant plasma cell infiltrate, and multinucleated giant cells, may be seen 
• Fibrosis is present in all but the mildest forms of autoimmune hepatitis. Advanced fibrosis connects portal and central areas (bridging), resembles regenerating nodules, results in cirrhosis.

 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. -cryptogenic chronic hepatitis or cryptogenic cirrhosis. A therapeutic response to anti-inflammatory therapy may be the only indication that autoimmune hepatitis is the underlying disease in these patients.

 simplified criteria :.

• Autoantibodies:  one point if the ANA or SMA are 1:40 OR two points if the ANA or SMA are ≥1:80 (OR if the LKM ≥1:40 OR if the SLA is positive).
• IgG:  one point if the IgG is > the upper limit of normal OR  two points if the IgG is >1.10 times the upper limit of normal.
• Liver histology (evidence of hepatitis is a mandatory condition): assign one point if the histological features are compatible with autoimmune hepatitis OR two 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, emperipolesis (active penetration of one cell into and through a large cell), and hepatic rosette formation. Compatible features were defined as a picture of chronic hepatitis with lymphocytic infiltration without all the features considered typical.
• Absence of viral hepatitis: assign two points ,mainly for hepatitis B and C. However, other forms of hepatitis should be considered depending upon the clinical setting.

probable autoimmune hepatitis - six, while a definite diagnosis, points are ≥seven.
study involving 11 international centers, the simplified scoring system had 88 % sensitivity and 97 % specificity

 limitation of scoring system is  lack of standardization of some of the autoantibody tests across testing facilities.

 -difficult to distinguish autoimmune hepatitis from overlap syndromes
 -identify patients with overlap who have a treatable autoimmune component.
 -The validation study did not include patients with differential diagnosis
- The prevalence of ANAs or ASMAs did not correlate with the clinical or histologic severity of autoimmune hepatitis or the response to immunosuppressive therapy














Acute hepatitis —  to distinguish autoimmune  from acute viral hepatitis,  hepatitis C virus RNA (PCR) is required to rule out hepatitis C (Ab up to 6 months)

Chronic hepatitis C — The nonspecific antibody response  in  autoimmune hepatitis may make it difficult to distinguish between autoimmune diseases and chronic hepatitis C- to measure circulating hepatitis C RNA; as a result, patients with autoimmune hepatitis who have false positive hepatitis C antibodies can be identified. chronic hepatitis C may make a variety of autoantibodies including rheumatoid factor and cryoglobulins;



 In addition to clinical features, the magnitude of fatty infiltration, and the presence of polymorphonuclear leukocytes and central fibrosis in the biopsy may point to steatohepatitis.


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. Systemic lupus erythematosus is differentiated from autoimmune hepatitis,by presence of antiribosomal P protein antibodies


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

certain histologic features (eg, portal neutrophils, which are more common in DILI) can help distinguish between drug induces hepatitis and autoimmune

 Iron overload — On occasion, a raised serum ferritin, sometimes accompanied by elevated transferrin saturation, occurs in autoimmune hepatitis or chronic viral hepatitis. Differentiated from genetic hemochromatosis can be excluded by the measurement of hepatic iron concentration and subsequent calculation of the hepatic iron index and HFE mutations

Wilson disease — Almost exclusively a disease of children, Wilson disease can present as a chronic hepatitis or as fatty liver disease