Gastroenterology Hepatology

Autoimmune hepatitis

How can I be sure that the patient has autoimmune hepatitis?

The diagnosis of autoimmune hepatitis (AIH) should be considered in patients with acute or chronic hepatitis of undetermined cause. Nonspecific symptoms as fatigue, anorexia, nausea, jaundice, abdominal pain, or arthralgias are often the first symptoms. However, the spectrum ranges from asymptomatic patients to patients with acute liver failure. A sudden onset is common. Liver cirrhosis is present in 30% at time of diagnosis. Women are affected more frequently than men (3.6:1). An association with extrahepatic autoimmune diseases is common. Biochemical evaluation typically reveals an elevation of aminotransferases and imunoglobulins. Alkaline phosphatase and bilirubin are normal or elevated to a lesser extent. Characteristic antibody pattern is discussed later.

A tabular or chart listing of features and signs and symptoms

See Table I for a listimg of AIH symptoms.

Table I.

Symptoms of autoimmune hepatitis
Symptoms Examples for alternative diagnose Ways to distinguish
Fatigue Malignant disease Tumor search: X-ray/CT, endoscopy
Other autoimmune diseases Autoantibodies, organ biopsy
Anemia Blood count
Infectious diseases Microbiological examination of eligible specimens, serological tests
Other liver diseases Ultrasound, exclusion of viral hepatitis, hereditary/metabolic disorders, toxic liver disease
Anorexia and nausea Malignant disease Tumor search: X-ray/CT, endoscopy
Gastrointestinal diseases Endoscopy, ultrasound
Other liver diseases (See above)
Autoimmune disease (See above)
Infectious diseases (See above)
Jaundice Other liver diseases: PBC, PSC, gallstones, tumors Ultrasound, ERCP, serological tests
Chronic abdominal pain Gastric/intestinal ulcers Endoscopy
Abdominal tumors Ultrasound/CT/MRI
Ulcerative colitis/ Crohn's disease Endoscopy
Pancreatitis Ultrasound
Signs of severe liver disease: hemorrhagias, ascites, encephalopathy Other reasons for acute or chronic liver failure Exclusion of viral or toxic hepatitis, NASH/ASH, M. Wilson
Arthralgia All forms of arthritis,arthrosis Pattern of affected joints, anamnesis,X-ray/MRI,serological tests

How can I confirm the diagnosis?

Different clinical and laboratory findings are required to diagnose AIH. No single parameter is sensitive or specific enough to diagnose or preclude AIH. Typical findings are elevation of aminotransferases, bilirubin, and γ-globulins and the presence of autoantibodies. ANA and SMA are found in AIH type 1; anti-LKM-1 antibodies are the hallmark antibody of AIH type 2, which is typically found in children and young adults. AIH can be diagnosed only when other reasons for chronic hepatitis (e.g., viral or toxic hepatitis, metabolic disorders) are excluded. A liver biopsy is recommended for diagnosing AIH. Main histological findings are interface hepatitis and plasma cell infiltration.

To confirm the diagnosis of AIH, the first assessment should include the following:

  • – Levels of serum alanine (ALT) or aspartate (AST) transferase (expected to be elevated; can be normal in advanced cirrhosis)

  • – Alkaline phosphatase (AP) (not expected to be markedly elevated)

  • – Albumin (low in advanced disease)

  • – Total or γ-globulin, IgG (typically elevated >1.5 fold of ULN in AIH)

  • – Bilirubin

  • – ANA, SMA, and anti-LKM-1 antibodies (titres of 1:40 are considered significant in adults, titres of 1:20 are significant in children)

To diagnose AIH, other types of chronic hepatitis must be precluded. The following investigations should be undertaken:

  • – AMA to rule out PBC and overlap syndromes

  • – To exclude hepatitis A, B, or C virus infection (Hepatitis A: anti-HAV IgG and IgM; Hepatitis B: HBs-antigen, anti-HBc; when HBs-antigen and anti-HBc are positive, determination/quantification of HBV-DNA replicates; Hepatitis C: anti-HCV IgG and when positive, HCV-RNA)

  • – In immunocompromised patients, the exclusion of opportunistic and rare infections, e.g., CMV, HSV, or VZV hepatitis (serological tests, final diagnosis via biopsy) or hepatitis E virus infection.

  • – Wilson's disease must be ruled out by normal serum ceruloplasmin levels and normal urinary copper excretion. Wilson's disease is probable in patients with neurologic symptoms and the presence of a Kayser Fleischer ring and serum ceruloplasmin levels of less than 20 mg/dL. In patients without neurologic symptoms and Kayser-Fleischer ring, a hepatic copper concentration of more than 250 mg/g of dry weight in conjunction with low ceruloplasmin levels establish the diagnosis. The urinary copper excretion usually is more than 100 mg/d in symptomatic patients. A normal hepatic copper concentration rules out Wilson's disease.

  • – When hereditary hemochromatosis is suspected (high transferrin saturation, elevated ferritin, positive family history), it should be assessed via biopsy and a test for a mutation in the HFE-gene.

  • – Alpha1-antitrypsin levels should be assessed to rule out alpha1-antitrypsin deficiency.

  • – Ultrasound should be performed to assess for a steatohepatosis and biliary diseases (e.g., PSC).

  • – The possibility of toxic hepatitis (alcohol, drugs, herbs) has to be ruled out carefully.

Finally, to confirm the diagnosis, to have the possibility of follow-up disease activity and progress and to clarify the diagnosis in case of inconclusive results:

  • – Liver biopsy should be performed. In AIH, interface hepatitis and plasma cell infiltrates are expected. In all but the mildest forms, fibrosis is present. In advanced cases, bridging fibrosis or cirrhosis is seen. Steatohepatits, granulomas, bile duct affection, and iron overload indicate alternative liver diseases.

In case of uncertainty concerning the diagnosis:

  • – When titres for ANA, SMA, and anti-LKM-1 are not significantly elevated, a positivity of anti-LC-1, anti-LKM-3, anti-actin, ANCA, and anti-SLA,/LPantibodies can point to the diagnosis of AIH, and the positivity of anti-PDH-E2antibodies detected by ELISA or immunoblot can confirm a AMA negative PBC.

  • – A serological overlap occurs in some cases (see Table II).

  • – For difficult diagnostic cases, the revised original score of the International Autoimmune Hepatitis Group(see Table II below) can facilitate the diagnostic decision.

The revised original score of the International Autoimmune Hepatitis Group (IAIHG) is shown in Table II.

Table II.

The revised original score of the International Autoimmune Hepatitis Group
Sex Female +2 HLA DR3 or DR4 +1
AP:AST(or ALT) ratio >3<1.5 -2+2 Immune disease Yes +2
ANA, SMA or anti-LKM1 titres >1:801:801:40<1:40 +3+2+10 Other markers Anti-SLA, anti-actin, anti LC1, pANCA +2
γ-globulin or IgG above ULN >21.5-2.01.0-1.5<1.0 +3+2+10 Histological feature Interface hepatitis,plasmacytic,rosettes,none of above,biliary changes,others +3+1+1-5-3-3
AMA Positive -4 Treatment response Completerelapse +2+3
Viral markers PositiveNegative -3+3
Drugs YesNo -4+1 Pretreatment aggregate score Definite diagnosis,probable diagnosis >1510-15
Alcohol <25g/day>60d/day +2-2 Post-treatment aggregate score Definite diagnosis,probable diagnosis >1712-17

Auto-antibodies in AIH

ANA, SMA, anti-LKM-1, and anti-LC-1 are the conventional antibodies found in AIH. According to the antibody-pattern, AIH type 1 with positivity of ANA and/or SMA can be distinguished from AIH type 2, which is characterized by positivity of anti-LKM1 or anti-LC1. Type 2 AIH is primarily seen in children and young adults. (See Table III.)

Table III.

Autoantibodies in AIH
Autoantibody Target antigen Liver disease Clinical implication for AIH
ANA Multiple targets, e.g., chromatin, ribonucleoproteins AIH, PBC, PSC, drug-induced hepatitis, chronic hepatitis C and B Diagnosis of type 1 AIH
SMA Microfilaments and intermediate filaments Same as ANA Diagnosis of type 1 AIH
LKM-1 CYP2D6 Type 2 AIH, chronic hepatitis C Diagnosis of type 2 AIH
LC-1 FTCD Type 2 AIH, chronic hepatitis C Diagnosis of type 2 AIH
Atypical pANCA Nuclear lamina proteins AIH, PSC Diagnosis of type 1 AIH, re-classification of cryptogenic chronic hepatitis as AIH
SLA tRNP(SER)Sec AIH, chronic hepatitis C Diagnosis of AIH, prognostic marker for severe disease and relapse
LKM-3 UGT1A Type 2 AIH, chronic hepatitis D Diagnosis of type 2 AIH
LM CYP1A2 Dihydralazine-induced hepatitis, APECED hepatitis Diagnosis of APECED hepatitis
ASGPR Asialoglycoprotein receptor AIH, PBC, drug-induced hepatitis Prognostic marker for severe disease , histological activity, and relapse

Most patients with AIH develop these antibodies – sometimes being negative at the onset of symptoms but positive during the course of the disease. Significant antibody-titres (1:40 in adults, 1:20 in children) do not prove AIH and negative antibody-titres do not preclude AIH.

Overlap forms

In some patients, the diagnostic tests may reveal findings fitting to more than one autoimmune liver disease. Serological overlaps with the detection of antibodies matching different diseases are, for instance, the simultaneous presence of SMA, ANA, and AMA, which can be interpreted as a serological overlap between type 1 AIH and PBC.

On the other hand, patients with PBC may be AMA-negative but positive for ANA or SMA. In other patients, an AIH-typical antibody pattern is combined with PSC-characteristic cholangiography. Liver biopsy is an important tool to establish the correct diagnosis in these patients. AIH-patients can be AMA-positive without ever showing clinical or histological features of PBC.

The simultaneous presence of diagnostic criteria sufficient to diagnose AIH on the one hand and a PSC-typical cholangiogram on the other hand is also called autoimmune cholangitis (AIC), and is often diagnosed in children. Especially coexisting inflammatory bowel disease may predispose for PSC/AIH-overlap.

It is important to note that there is no definite diagnostic criterion for overlap syndromes. The international autoimmune hepatitis group recommends categorizing patients according to the predominating features as AIH, PBC, or PSC and not to define new disease entities. Furthermore, other liver diseases, such as viral hepatitis, NASH, or the intake of drugs (minocycline, diclofenac, infliximab, propylthiouracil, atorvastatin, nitrofurantoin, methyl dopa, isoniazid) can mimic AIH, including the presence of autoantibodies.

What other diseases, conditions, or complications should I look for in patients with autoimmune hepatitis?

Patients with AIH need to be followed closely. Fibrosis is present in all but the mildest forms of AIH, and progression of the disease may result in the development of cirrhosis.

At diagnosis, cirrhosis is already present in about 25%. In advanced cirrhosis, current complications are the development of ascites and spontaneous bacterial peritonitis, hemorrhages (for instance due to coagulopathy and variceal bleeding), and hepatic encephalopathy. All cirrhotic patients are at risk to develop an HCC in the course of the disease. According to a recent study, liver decompensation at presentation, cirrhosis at any time, failure to normalize serum ALT levels within 1 year, and more than four relapses per decade are associated with liver-related death or transplant.

Furthermore, patients with AIH can suffer from therapy-related disease. The chronic intake of steroids may result in osteoporosis, diabetes, hypertension, cosmetic problems due to steroid acne, weight gain and dorsal hump formation, psychic alterations, and more. Azathioprine can cause cytopenia and as a complication of this may support the susceptibility for opportunistic infections. Under the therapy with azathioprine, pancreatitis can occur. Last but not least, azathioprine is a cytotoxic agent and can enhance the risk for future cancer

Patients with AIH often suffer from other autoimmune diseases, including autoimmune thyroid disease, synovitis, celiac disease, and ulcerative colitis.

What is the right therapy for a patient with autoimmune hepatitis?

AIH can be treated very effectively with immunosuppressive agents. The gold standard is the treatment with prednisone (or prednisolone in Europe) alone or in combination with azathioprine.

The indication for starting an immunosuppressive treatment has to be evaluated, and the treatment strategy must be adjusted to the patient's individual risk for developing adverse events of either corticosteroids or azathioprine. For instance, in obese patients, patients with osteoporosis, or patients with brittle diabetes, the steroid dose should be as low as possible, whereas in patients with cytopenia, azathioprine should be avoided (see below for details).

Patients with refractory disease and "burned out" cirrhosis may be candidates for liver transplantation. Alternative immunosuppressive agents are not well established in AIH, but the promising agents with the most empiric use are mycophenolate mofetil and cyclosporine.

Indications for treatment of AIH

Absolute indication for starting an immunosuppressive treatment in patients with AIH include the following:

  • – An elevation of ALT >10 fold ULN

  • – A more than 5-fold ULN elevated ALT in conjunction with a more than twofold-elevated gamma globulin

  • – Bridging necrosis or multiacinar necrosis in the histological picture

  • – Cases of severe and intolerable symptoms

Patients with absolute indications for treatment have a poor prognosis without immunosuppressive therapy.

Relative indication for starting an immunosuppressive treatment include the following:

  • – A symptomatic patient (all AIH-related symptoms)

  • – An elevation of ALT or gamma globulin levels lower than required for the absolute criteria

  • – The histological picture of interface hepatitis

  • – When patients with the need for therapy of AIH present relative contraindications for treatment with either steroids or azathioprine

The following patients will not benefit from immunosuppressive treatment:

  • – Patients without clinical, laboratory, or histological signs of inflammation (asymptomatic patients with normal or near-normal ALT and gamma globulin levels and without histological signs of inflammation)

  • – Patients with inactive cirrhosis. Patients with "burned out" cirrhosis are at higher risk of drug-induced adverse events.

Randomized controlled trials are lacking for patients with mild disease or inactive cirrhosis. Thus, treatment indication is uncertain in these patients and must be individualized according to the particular risk profile and course of the disease. Notably, it is challenging to detect the patients who do not require immunosuppression, and asymptomatic patients without treatment may have a worse outcome than treated asymptomatic patients.

Instrtion

What is the most effective initial therapy?

The gold standard for initial therapy is prednisone (or prednisolone) with or without azathioprine. Both regimens have shown to be effective. Usual initial doses are 60 mg prednisone when given as monotherapy or 30 mg prednisone in conjunction with 50 mg azathioprine (alternatively, 1-2 mg/kg body weight).

Listing of usual initial therapeutic options, including guidelines for use, along with expected result of therapy.

The monotherapy with prednisone, or prednisolone in equivalent doses, is instituted with 60 mg per day and is tapered down until maintenance dosage is achieved. The maintenance dosage is individual and is the lowest sufficient dose to hold a remission. (See Table IV.)

Table IV.

Monotherapy with prednisone in mg/day
Week Prednisone dose (mg/day)
1 60
2 40
3 30
4 30
5 20
6 20
7 15

From the daily dose of 20 mg onward, the reduction steps should not exceed 5 mg per week and below 10 mg, 2.5 mg-steps are recommended. The lowest dose to maintain the remission is continued. A reason to prefer the monotherapy over the combination of prednisone and azathioprine is a contraindication for azathioprine or a high risk of azathioprine-related side effects. In particular, in cytopenia (white blood cell counts <2.5 x 109/L or platelet counts below 50 x 109/L) or deficiency of thiopurine methyltransferase, the application of azathioprine is prohibited. Other reasons for not using azathioprine are pregnancy, malignancies, or when only a short period of treatment is planned.

The combination therapy of prednisone (initial dose 30 mg) and azathioprine (50 mg daily or in Europe 1-2 mg/kg daily) is as effective as the monotherapy of prednisone alone. Prednisone can be reduced according to the regimen of the monotherapy. The advantage of the combination therapy is the lower occurrence of corticosteroid-related side effects. This is especially important for patients with high individual risks of developing steroid-related side effects – that is, patients with brittle diabetes, obese patients, postmenopausal women, or other patients with osteoporosis, as well as patients with psychological problems. For all patients without contraindications for azathioprine, the combination regimen is the preferred treatment strategy. (See Table V.)

Table V.

Combination therapy: prednisone plus azathioprine in mg/d
Week Prednisone Azathioprine
1 30 50 or 1 mg/kg bodyweight
2 20 50 or 1 mg/kg bodyweight
3 15 50 or 1 mg/kg bodyweight
4 15 50 or 1 mg/kg bodyweight
5 10 50

What are the expected effects of treatment?

Within 2 weeks, the levels of ALT, gamma globulins, and bilirubin improve in the vast majority of patients. The complete resolution of all laboratory and histological pathologies takes more than 1 year in most patients. Notably, histological improvement takes 3 to 8 months longer than biochemical improvement. If remission is not achieved after 2 years of effective treatment, the probability of complete remission in the future is low.

What is remission?

Remission is defined by normal serum aminotransferases, bilirubin and gamma globulin levels, the disappearance of AIH-related symptoms, and the histological absence of inflammation.

For how long is the treatment continued?

The treatment goal is to achieve a complete biochemical and histological remission. Notably, the resolution of histological changes takes longer than the resolution of biochemical changes. Liver biopsy will reveal interface hepatitis in up to 50% of patients with normal serum aminotransferases and immunoglobulins. These patients are at high risk to relapse after discontinuation of therapy. In contrast, patients with complete biochemical and histological remission are at low risk to relapse. Thus, discontinuation of treatment should primarily be considered in patients without any biochemical and histological signs of inflammation. The recommended overall treatment duration is at least 2 years.

What does relapse mean and how is it managed?

Relapse is defined as a recrudescence of disease activity after having achieved a period of remission and termination of treatment. The serum ALT level is typically increased to more than threefold the ULN and the serum gamma globulins to more than 2 g/dL. These laboratory changes are characteristic for a new onset of inflammatory activity. Thus, a liver biopsy to confirm relapse is not required in this situation.

The management of relapse is to restart treatment with prednisone and azathioprine until the normalization of serum aminotransferases and gamma globulins. Thereafter, it is recommended to eliminate prednisone when possible and to increase the dose of azathioprine to 2 mg/kg/day. Azathioprine is then continued as a maintenance therapy. Alternatively, prednisone is administered in the lowest possible dose to guarantee normal or less than threefold the ULN elevated serum aminotransferases. Long-term doses of less than 10 mg prednisone daily are generally well tolerated.

Gradual withdrawal from either azathioprine or prednisone should only be attempted when serum aminotransferases and gamma globulins are normal and not before 24 months of treatment. The risk of relapse in higher in patients with a previous relapse.

A listing of a subset of second-line therapies, including guidelines for choosing and using these salvage therapies

What should be done in case of incomplete response and treatment failure?

Incomplete response is present when remission is not achieved after 36 months. These patients require continuous low-dose corticosteroid treatment or treatment with azathioprine as 2 mg/kg bodyweight in individuals that do not tolerate prednisone. The adjustment of the prednisone dose should be handled carefully and with small reduction steps of 2.5 mg per week as long as the serum aminotransferases remain stable.

Treatment failure means a worsening of inflammation despite treatment, including the possibility of developing severe complications of advanced liver disease. This condition requires institution of high-dose prednisone (60 mg) or a lower dose of prednisone (30 mg) in conjunction with azathioprine as 2 mg/kg bodyweight per day for at least 4 weeks. In case of an amelioration of symptoms and biochemical results, prednisone dose can be reduced by 10 mg and azathioprine by 50mg each month. Patients who do not benefit from this therapy and in particular those who develop encephalopathy, ascites, or variceal hemorrhages are candidates for liver transplantation (see below).

Other (nonstandard) agents used in the management of AIH

Alternative drugs for the management of AIH should only be used if the standard treatment regimen for initial treatment, relapse, incomplete remission, or treatment failure was not successful. The following drugs have been administered empirically, and randomized controlled studies are lacking for most agents.

Mycophenolate mofetil is one of the nonstandard agents with the broadest use and promising results. A biochemical improvement is documented in 39% to 84%, but the rate of withdrawal because of side effects is relatively high. Common adverse events are nausea, vomiting, diarrhea, pancreatitis, rash, alopecia, and deep vein thrombosis. Further attempts as salvage therapies were undertaken with cyclosporine, tacrolimus, methotrexate, cyclophosphamide, 6-mercaptopurine, ursodeoxycholic acid, and budesonide. Ursodeoxycholic acid and budesonide were not successful as salvage therapies in randomized controlled trials.

However, even though budesonide is not appropriate as salvage therapy, the promising results of a controlled randomized prospective study has shown that in noncirrhotic patients, budesonide induces remission at a higher percentage than prednisone (both tested in conjunction with azathioprine). At the same time, less corticosteroid-related side effects occur because of the high first-pass effect of budesonide with resulting low-systemic drug concentrations.

Liver transplantation

Indications for liver transplantation can be acute liver failure (often as first manifestation of the disease), decompensated liver cirrhosis, and HCC if meeting the transplant criteria.

The need for transplantation of patients with decompensated liver cirrhosis can be assessed with the MELD-score (Model of End-Stage Liver Disease), which calculates the estimated mortality rate by using the parameters INR, bilirubin, and creatinin. The prognosis after liver transplantation due to AIH is very good, with a 10-year survival rate of approximately 75%. After liver transplantation, AIH-recurrence may occur in up to 30% within 5 years.

Whether cyclosporine or tacrolimus is chosen as immunosuppressant after transplantation has no influence on the probability of a recurrence of AIH, but it is clearly associated with a discontinuation of prednisone. Thus, treatment includes a reinstitution of prednison – respectively, an increase of the dose and an optimization of calcineurin inhibitor dose. In case of failure of this regimen, mycophenolate mofetil can be added. Alternatively, a combination of prednisone and azathioprine can be considered.

Which treatment-related side effects must be taken into account?

Both, prednisone and azathioprine are associated with side effects justifying discontinuation of treatment in 13%. The patient should be informed of the possible and drug-specific adverse events before the treatment is instituted.

Corticosteroid-related side effects have a wide variety. In the majority, cosmetic changes occur, including facial rounding, dorsal hump formation, acne, facial hirsutism, and striae distensae. Chronic use of steroids is very often accompanied by weight gain, one of the leading causes of termination of therapy. The glucose homeostasis is impaired regularly and in particular in patients with preexisting glucose intolerance, a steroid- induced diabetes can become manifest. In addition, severe side effects span osteopenia with vertebral compression, psychosis, opportunistic infections, and pancreatitis, cataract and glaucoma, labile hypertension, and, finally, malignancies. Patients with an especially high risk of developing one of these complications should be monitored very closely, and the lowest prednisone dose should be applied. The combination therapy with azathioprine is the preferred therapy regimen in this patient group. To prevent, or at least to alleviate, the development of osteoporosis, an adjunctive treatment with vitamin D and calcium supplementation, regular weight baring exercise program, and, for individual patients, the application of bisphosphonates is appropriate.

Azathioprine is well tolerated in most patients. The most relevant side effect of azathioprine is cytopenia and it can culminate in bone marrow failure in severe cases. Cytopenia is a current preexisting finding in patients with AIH-related cirrhosis, mostly caused by hypersplenism. The drug should be avoided in patients with severe cytopenia (leukocytes <2.5 × 109/L, thrombocytes <50 × 109/L).

Azathioprine-related side effects include early adverse events that may require termination of therapy as nausea and vomiting, arthralgias, fever, skin rash, or pancreatitis. All aforementioned reactions can also occur in the course of treatment. Furthermore, cholestatic hepatitis, opportunistic infections, and malignancies (1.4-fold increased risk greater than normal of developing malignancy) are complications of treatment with azathioprine. Finally, a rare but important possible side effect is a diarrheal syndrome with accompanying small villus atrophy and malabsorption.

The overall frequency of azathioprine related side effects is 10%. Often, therapy can be continued after a reduction of the dose. In individual patients – for instance, those who develop cytopenia during treatment or if the administration of higher-than-conventional doses of azathioprine is planned – the measurement of erythrocyte concentration of thiopurine methyltransferase activity can be justified. Routine screening is not recommended. Patients with a decreased thiopurine methyltransferase activity most often tolerate low doses of azathioprine, whereas in the seldom case of a severe enzyme deficiency, the administration of azathioprine should be avoided.

Azathioprine has a category D pregnancy rating by the FDA. Teratogenicity under the treatment of azathioprine must be considered theoretically, albeit there exists no report of increased birth defects in children with azathioprine-treated mothers. In general, the immunosuppressive treatment in pregnant women should be as low as possible. It is important to note that postpartal disease exacerbations are frequent and, therefore, standard therapy should be restarted 2 weeks before delivery.

How should I monitor the patient with AIH?

Patients with AIH have to be monitored lifelong. It is necessary to consider the following:

  • – Disease activity

  • – Treatment-related side effects

  • – Development of other autoimmune diseases

  • – Development of long-term complications

When discontinuation of treatment is intended, serum aminotransferases, bilirubin, and gamma globulin need to be closely observed during the process of drug withdrawal. During that period, these should be tested every 3 weeks, including the first 3 months after drug withdrawal. In the following year, ALT, bilirubin, and gamma globulins should be assessed every 6 months and, thereafter, once a year lifelong.

In case of reoccurrence or in the setting of uncontrolled disease activity, monitoring has to be adapted to the individual patient and situation. A delay of treatment onset or change can fatally worsen the prognosis. In general, new adjustments of treatment require narrow follow ups, and testing intervals should be increased in case of stable disease.

During treatment with azathioprine, patients must be monitored for leukopenia and thrombocytopenia at 6-month intervals. Patients who receive prednisone should be monitored for bone disease at base line and then annually by bone densitometry measurement. Furthermore, they should undergo eye examinations periodically to detect glaucoma or cataracts.

A certain percentage of patients will show symptoms of correlated autoimmune diseases during the course of the disease, requiring adequate further diagnostic steps.

AIH patients with cirrhosis should undergo ultrasonographic examination and AFP monitoring concerning the development of hepatocellular carcinoma every 6 months. The 10-year probability for HCC is 2.9%, with higher risks in individuals with advanced cirrhosis.

Patients with portal hypertension should be screened for esophageal varices. As in hepatopathies of other causes, vaccination against hepatitis A virus and hepatitis B virus is highly recommended. (See Table VI.)

Table VI.

Endpoints of initial therapy and course of action
Endpoint Characteristics Course of Action
Remission – No symptoms– Normal ALT, bilirubin, gamma globulins– Histology: normal liver tissue or inactive cirrhosis Gradual withdrawal of immunosuppressants over a 6-week period. Control of serum ALT, gamma globulins, and bilirubin every 3 weeks until 3 months after drug withdrawal
Incomplete response No or insufficient improvement in clinical, laboratory and histological features after 36 months of adequate treatment Reduction of prednisone dose by 2.5 mg/month until the lowest possible dose for maintaining ALT levels is reached, ORAzathioprine 2 mg/kg/day as a monotherapy
Treatment failure Worsening of symptoms, laboratory and histological features,development of complications (jaundice, ascites, encephalopathy) Prednisone 60 mg/d as a monotherapyORprednisone 30 mg/d + azathioprine 150 mg/d for at least 1 month
Drug toxicity Development of intolerable drug-related side effects Reduction in dose or discontinuation

What is the Evidence?

Soloway, RD, Summerskill, WH, Baggenstoss, AH. "Clinical, biochemical, and histological remission of severe chronic active liver disease: a controlled study of treatments and early prognosis". Gastroenterology. vol. 63. 1972. pp. 820-33.

Hennes, EM, Oo, YH, Schramm, C. "Mycophenolate mofetil as second-line therapy in autoimmune hepatitis". Am J Gastroenterol. vol. 103. 2008. pp. 3063-70.

Manns, MP, Woynarowski, M, Kreisel, W. "Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis". Gastroenterology. vol. 139. 2010. pp. 1198-206.

Boberg, KM, Chapman, RW, Hirschfield, GM. "Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue". H Hepatol. vol. 54. 2011. pp. 374-85.

Hoeroldt, B, McFarlane, E, Dube, A. "Long-term outcomes of patients with autoimmune hepatitis managed at a nontransplant center". Gastroenterology. vol. 140. 2011. pp. 1980-9.

Czaja, AJ. "Safety issues in the management of autoimmune hepatitis". Expert Opin Drug Safety. vol. 7. 2008. pp. 319-33.

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