Evolving epidemiology

Autoimmune hepatitis (AIH) is a genetic disease that requires interplay among genetic, immunologic, and environmental factors. It is variable by geography and prevalence of associated risk factors in studies populations. Most data come from Europe, where the incidence and prevalence of AIH are rising, with a current 50% increase in prevalence. Moderating the incidence and prevalence rate are factors that include but are not limited to intake of oral contraceptives and hormone replacement therapy; pregnancies; smoking; recurrent urinary tract infections; and incident of herpes simplex virus, Epstein-Barr virus, and measles. Interestingly, populations living at more northern latitudes have higher incidence and prevalence of AIH.

Optimizing immunosuppression in patients with autoimmune hepatitis

According to the Scientific Registry of Transplant Recipients (SRTR) and the Adult Living Donor Liver Transplantation Studies (A2ALL), 6% of the liver transplants (LT) correspond to autoimmune hepatitis (AIH). Unfortunately, there are few data guiding the optimization of immunosuppression in patients with AIH after LT. Any type of rejection, even if the rejection occurs within the first 6 months after transplant, increases the risk of death, particularly in recipients with chronic rejection.

There is an 8-12% risk of rejection within the first year and up to 70% within 5 years. The median recurrence is 2.5 years; recurrence significantly worsens patient and graft survival. The diagnosis of rejection is suspected when there is hypergammaglobulinemia and positive antinuclear antibody (ANA)/smooth muscle antibody (SMA). Also, the histology could be similar to pretransplant AIH. However, rejection features could also be present.

Risk factors for rejection include:

• High titers of autoantibodies, IgG at liver transplant
• Other autoimmune disorders
• HLA-DR3/DR4 and sex mismatch
• Severe necroinflammatory activity in the explant
• Young recipients
• Early corticosteroid withdrawal. Use of mycophenolate mofetil (MMF) on recent studies, even though those are not robust studies just associations.

Utility of immunosuppression for patients with AIH on waitlist

The treatment goals for patients with AIH on transplant waitlists are complete normalization of liver chemistries and IgG; resolution of symptoms; and prevention of disease progression.

Unfortunately, 40 – 50% of patients fail to achieve remission with standard of care, especially younger patients, those who have acute presentation, or those with higher bilirubin or a MELD score > 12 at the time of diagnosis.

Indications for LT in AIH are acute or fulminant liver failure; decompensated liver disease; and hepatocellular carcinoma.

Among patients with AIH who receive LT, 81% survive for 5 years and 77% survive at 10 years. Disease recurrence posttransplant ranges widely, from less than 8% up to 68% at 10 year posttransplant.

These patients show increased frequency of acute cellular rejection and chronic ductopenic rejection.

Steroid withdrawal vs maintenance steroids after LT

Steroid use after LT has lowest recurrence of AIH at 7%. However, there are increased rates of infections and osteoporosis. Studies have showed more rejection with steroid withdrawal but lower incidence of diabetes and hypertension. The truth is most steroid withdrawals are successful, but reintroduction is required in approximately 20% due to acute cellular rejection, recurrent AIH, and complication of calcineurin inhibitor.

Steroid withdrawal should have an individualized approach: patients more likely to be discontinued are those with low risk of recurrence and optimally controlled activity before LT.

Fatal infections are more common in the first 3 months post-LT. The risk could be reduced by minimizing the use of high-dose steroids pre-LT and immediate post-LT, especially in patients with acute liver failure or severe AIH.

The latest AASLD 2019 guidelines by Mack CL et al. showed limited data that support long-term corticosteroids use to prevent posttransplant rejection, graft loss, and recurrent AIH. They also suggest that a gradual withdrawal of glucocorticoids should be considered.

The International Liver Transplantation Society recommends maintaining low-dose steroids for the long term or adding azathioprine (AZA), MMF or mycophenolic acid (MPA) to facilitate steroid weaning.

Recurrent AIH management: Similar to pretransplant

Among patients with recurrent AIH posttransplant who have a mild presentation, the best approach is to increase immunosuppression and emphasize compliance with treatment regimens. Some data support switching from cyclosporin to tacrolimus.

In more moderate to severe cases, recurrent AIH should be treated aggressively, as if the patient were in rejection. Treatment options include high-dose prednisone with a slow taper down to 5-10 within 1-2 months; increase or add agents such as AZA, everolimus, MMF, or rituximab.

Retransplantation is required in 33-60% of patients with severe recurrent AIH.

It’s extremely important to differentiate between recurrence and de novo AIH. The latter occurs when patients without AIH received LT for a different disease and then develop AIH after. It is more common in children and rejection is less likely than recurrent AIH.

Clinical pearls in managing immunosuppression in AIH:

• Regular laboratory testing
• Clinician awareness of ongoing risk
• Patient education to seek medical advice:
  • Viral syndromes, vaccination
  • Illness affecting medicinal absorption
  • Addition of new medication

References:
Cholestatic & Autoimmune Liver Diseases SIG and Liver Transplant & Surgery SIG Program: Optimizing Pre- and Post-Transplant Management of Immune Mediated Liver Disease. Speakers: Monica Tincopa, Cynthia Levy, Josh Levitsky. The Liver Meeting, AASLD 2022.