Autoimmune Hepatitis (AIH)

Definition

• AIH is an immune mediated inflammatory liver disease of uncertain cause

Background

• All ages, genders, race/ethnicity effected but manifestations may vary
• 2 peaks for age at diagnosis: 10-20 (50% of all diagnoses) & (45-70)
• Female Predominance, more significant in adults (71-95%) vs pediatrics (60-76%)
• Prevalence 2.4-9.9 per 100,000 persons
• Incidence increasing
  
• Complex disease in genetically susceptible individuals (genetic, epigenetic, immunologic, and environmental factors)
• Exception is rare AR mutation in autoimmune regulator gene on chromosome 21q22.3 - assoc w/ Autoimmune polyglandular syndrome type 1 (APS-1)
• Environmental factors and exposures (microbio) act as triggers for loss of tolerance to autoantigens
• Pathogenesis
• "Current concepts of the immunopathogenesis of AIH. Current knowledge supports a multistep working model of the immunopathogenesis of AIH, in which a break in self‐tolerance to hepatocyte autoantigens initiates immunological responses causing progressive hepatic necroinflammation and fibrogenesis." (2)

Clinical Manifestations

• Range
• Asymptomatic
• Chronic illness
• Acute liver failure
  

Diagnosis

• Requires:
• Interface hepatitis on liver biopsy - histopathology
• Elevated transaminases (AST, ALT) and serum IgG
  
• Presence of one or more characteristic autoantibodies
• Exclusion of other diseases which may cause liver injury (Viral Hepatitis, Drug induced liver injury, Wilson's, Hereditary hemochromatosis)
• Per AASLD: diagnosis of AIH cannot be made without liver biopsy

• 2 main types

• Autoantibody titers may roughly reflect disease severity and treatment response but are not validated biomarkers
• SLA associated with more severe disease and relapse after drug withdrawal
• Reacting to both Anti-actin and anti-alpha-actin is associated with severe acute AIH, incomplete treatment response, and relapse

• No individual histological finding is specific for AIH, but the following findings are considered typical of AIH:
• Interface hepatitis with portal lymphocytic or lymphoplasmacytic cells extending into the lobule
• Emperipolesis (Emperipolesis is the penetration of one intact cell into another intact cell, with both cells retaining viability, as opposed to phagocytosis)
• Rosettes
• Interface hepatitis is the histological hallmark of AIH, accompanied by
  
• Plasma cell infiltration in 66%
• Lobular hepatitis in 47%.
• Centrilobular necrosis in 29%
  
• Emperipolesis is present in 65%
• Hepatocyte rosettes in 33%.
  
• Cirrhosis is present in 38% of children (33% of adults , esp elderly)
  

Treatment

AASLD recommendations/Guidelines:

• The diagnosis of AIH requires compatible histological findings and is further supported by the following features:
  
• (1) elevated serum aminotransaminase levels;
  
• (2) elevated serum IgG level and/or positive serological marker(s);
  
• (3) exclusion of viral, hereditary, metabolic, cholestatic, and drug‐induced diseases that may resemble AIH.
• Initial serological testing should include determinations of ANA and SMA in adults and ANA, SMA, and anti‐LKM1 in children; consider additional autoantibody tests if warranted to secure the diagnosis.
• Diagnostically challenging cases should be reviewed by or referred to an experienced liver center prior to initiating therapy
• The diagnosis of AIH must be considered in all patients presenting with acute or chronic liver disease, including patients with asymptomatic liver test abnormalities, ALF, and autoantibody‐negative hepatitis

• AIH patients should be screened for celiac and thyroid diseases at diagnosis
• AIH patients should be assessed for rheumatoid arthritis, IBD, autoimmune hemolytic anemia, diabetes, and other extrahepatic autoimmune diseases based on symptomatology and medical provider concern

• Patients with AIH, cholestatic laboratory/histological findings consistent with PBC, and a positive AMA should be considered to have AIH–PBC overlap syndrome
• Patients with AIH, cholestatic laboratory findings, histological features of bile duct injury or loss, and concurrent chronic UC should be evaluated for large‐duct PSC by cholangiography to determine whether they have the AIH–PSC overlap syndrome.
  
• The Paris criteria can aid in diagnosing the AIH–PBC overlap syndrome, but the criteria may exclude patients with AIH–PBC who have less severe cholestatic features.
• Neither the revised nor the simplified IAIHG diagnostic scoring systems for AIH should be used for assessing overlap syndromes.
• Note (note in guidelines): New studies suggest MR-Cholangiography in select group of children with cholestatic features, inflammatory bowel disease and in those who showed poor response to immunosuppression instead of all children with AIH (3)
  

• Drug‐induced AIH‐like liver injury must always be considered in the differential diagnosis of AIH.
• The offending agent must be withdrawn and monitoring maintained to ensure laboratory resolution.
• Glucocorticoid therapy for drug‐induced AIH‐like injury should be instituted when symptoms or disease activity are severe (e.g., fulfill Hy’s law) or if symptoms and laboratory tests fail to improve or worsen after discontinuation of the offending drug.
• Laboratory flare after glucocorticoid withdrawal suggests underlying AIH and the need for immunosuppressive therapy.

• Serum‐based biomarker panels for hepatic fibrosis are unestablished in AIH and should not be used.
• VCTE can identify advanced fibrosis or cirrhosis in patients with AIH with reasonable accuracy, but it should be deferred for at least 6 months after successful treatment of AIH in order to avoid the confounding effects of hepatic inflammation.

• Consider screening patients with AIH for absent or near‐absent TPMT activity prior to initiating treatment with AZA.

• Vaccines should be administered to all susceptible patients with AIH according to the age‐specific guidelines of the Centers for Disease Control and Prevention (https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/immunocompetence.html)
• Patients unprotected against HAV and HBV infection should undergo vaccination, preferably before immunosuppressive therapy.Patients with AIH who are HBsAg‐negative/anti‐HBc‐positive during the diagnostic phase of their evaluation should undergo periodic serological testing (HBsAg, HBV DNA) during conventional therapy with prednisone or prednisolone in conjunction with AZA to detect HBV reactivation and the need for on‐demand antiviral therapy.
• Patients with serological evidence of previous HBV infection who are treated with high‐dose glucocorticoids or other immune modulators, especially B cell–depleting agents, are at moderate risk for HBV reactivation and should be considered for preemptive antiviral therapy.

• Bone mineral densitometry should be performed at baseline in all adult patients with AIH who have risk factors for osteoporosis, and it should be repeated every 2‐3 years of continuous glucocorticoid treatment.
• Serum levels of 25‐hydroxyvitamin D should be determined at diagnosis and annually thereafter.
• Supplementation with elemental calcium (1,000‐1,200 mg daily) and vitamin D (at least 400‐800 IU daily) should be provided while on glucocorticoid therapy and supplemented as clinically indicated in patients with vitamin D insufficiency.
• Bisphosphonate therapy is indicated for patients with AIH and documented osteoporosis.
• Assessment for all features of metabolic syndrome should be performed prior to and during therapy, and its presence may require individualized treatment adjustments and lifestyle modifications.

• Potential barriers to long‐term medication compliance should be identified proactively and addressed at the start of treatment and monitored thereafter.
• Manifestations of depression and changes in the quality of life should be monitored throughout management of AIH, and they can be assessed objectively by structured, validated questionnaires.

• Family planning should include the goal of achieving biochemical remission of AIH for 1 year prior to conception.
• Women of reproductive potential should receive prenatal counseling on the significant adverse effect of active AIH on pregnancy and the risk of flares during and after pregnancy.
• Maintenance doses of glucocorticoids and/or AZA should be continued throughout pregnancy.
• MMF is contraindicated during pregnancy, and women should be counseled about the adverse effects of MMF on pregnancy prior to initiating MMF treatment.
• Women with cirrhosis who are pregnant or plan to become pregnant within the next year should be screened for varices by endoscopy either prior to conception or during the second trimester of gestation and treated with band ligation.
• Women with AIH should be monitored closely for the first 6 months postpartum for early detection of a flare.

• For children and adults who present with AIH who do not have cirrhosis or acute severe AIH, the AASLD suggests that budesonide and AZA or prednisone/prednisolone and AZA be used as first-line treatment.
• For children and adults with AIH who have cirrhosis or who present with acute severe AIH, the AASLD suggests that budesonide not be used (conditional recommendation, very low certainty).

• Patients with acute severe AIH should receive a treatment trial with prednisone or prednisolone alone, whereas patients with AIH and ALF should be evaluated directly for LT.
• Patients with acute severe AIH who do not improve laboratory tests or clinically worsen within 1‐2 weeks of glucocorticoid therapy should be evaluated for LT.

• Drug withdrawal and achievement of a long‐term treatment‐free remission of AIH are possible in a minority of patients and should be considered in patients who have normalized serum aminotransferase and IgG levels for at least 2 years.
• Liver tissue examination prior to drug withdrawal is valuable in excluding unsuspected inflammation and reducing the frequency of relapse, but it is not mandatory in adults.
• Patients must be closely monitored for relapse with regular laboratory assessments during the first 12 months after treatment withdrawal and annually thereafter to cover for lifelong risk.
• Relapse requires prompt reinstitution of the original treatment until biochemical remission and subsequent transition to a long‐term maintenance regimen.

• In children or adults with AIH who have treatment failure, incomplete response, or drug intolerance to first‐line agents, the AASLD suggests the use of MMF or TAC to achieve and maintain biochemical remission (conditional recommendation, low certainty).
• Based on a superior ease of use and side‐effect profile, the AASLD suggests a trial of MMF over TAC as the initial second‐line agent in patients with AIH (conditional recommendation, very low certainty).

• In children or adults with AIH who have nonresponse to first‐line treatment, the accuracy of the original diagnosis and medication adherence should be reevaluated.
• Anti‐TNF and anti‐CD20 are possible alternative therapies after first‐line and second‐line regimens have failed, but the data supporting their use are limited.

• Consider adding UDCA to prednisone or prednisolone in combination with AZA in adults and children with AIH and overlap syndromes.

• Cancer surveillance should include hepatic ultrasonography, with or without serum AFP level, every 6 months in patients with cirrhosis and adherence to standard guidelines for detection of extrahepatic malignancy.

• Based on limited data to support long‐term administration of glucocorticoids to prevent posttransplant rejection, graft loss, recurrent AIH, and reduced patient and graft survival in adults, the AASLD suggests that a gradual withdrawal of glucocorticoids be considered after LT (conditional recommendation, very low certainty).
• Recurrent AIH or de novo AIH and plasma cell hepatitis/rejection must be suspected in LT recipients with laboratory changes of allograft injury.
• Liver biopsy, serum IgG level, and autoantibodies should be obtained to distinguish immune‐mediated disease from other causes of allograft dysfunction.
• Predniso(lo)ne with AZA should be added to the calcineurin inhibitor to achieve biochemical remission in recurrent AIH or de novo AIH.

References

1. AASLD - Autoimmune Hepatitis Clinical Practice Guidelines. https://www.aasld.org/practice-guidelines/management-autoimmune-hepatitis
   
2. Floreani A, Restrepo‐Jimenez P, Secchi MF, De Martin S, Leung PSC, Krawitt E, et al. Etiopathogenesis of autoimmune hepatitis. J Autoimmun 2018;95:133‐143.
3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007839/