Professor Catherine Stedman

Momentum is finally gathering around autoimmune hepatitis (AIH) after slow progress compared to the pace of change in other GI conditions such as hepatitis C and IBD.

Delivering the Trans-Tasman Lecture at AGW 2023, Professor Catherine Stedman said relatively small numbers and the lack of prospective RCTs had held back advances in the management of AIH.

However she felt the tide was turning now with a better understanding of its pathogenesis, clarity on therapeutic targets and an increasing role for non-steroid therapies.

Professor Stedman, Director of Gastroenterology at Waitata/Canterbury (NZ) and from the University of Otago in Christchurch, said local data [link here] had shown AIH was increasing in prevalence.

“It’s well established that the incidence of AIH has increased over time compared to primary biliary cholangitis and primary sclerosing cholangitis, the other autoimmune-type liver diseases, which have a relatively stable presence,” she said.

“It will be interesting to see if that increase continues happening as it has with IBD or whether that effect will reach a plateau.”

She noted that while AIH was originally described as a disease of young women, peak incidence was actually in people aged in their 50s and 60s. The female to male ratio was 4:1.

“In terms of understanding pathogenesis, we are well behind IBD but we have some emerging knowledge. We do know that the prevalence does vary quite dramatically depending on ethnic background ….[in New Zealand] we can see a high prevalence in Caucasian population (28/100,000) but lower in Asian (6.8/100,000) and Maori populations (5.1/100,00).”

Risk factors

“We do know from multiple studies that there is a high frequency of certain HLA alleles; particularly DR3 and DR4 have been implicated but these vary in different populations.”

“We have an increasing understanding that there is altered immune tolerance as with most autoimmune diseases and an interplay between that altered immune tolerance and exposure to environmental factors.”

“There are cytotoxic cells such as Th17 that initiate and perpetuate liver injury but there has to be an exposure to some environmental factor to trigger all of this.”

Professor Stedman said an altered intestinal and oral microbiome and an interplay between various viruses and even viral vaccines have been observed.

“Recent data from EASL in the last few years showed quite marked clusters of AIH in geographical locations. There is probably some role for vitamin D and we know that people in Scandinavian countries and New Zealand get more AIH.”

“There’s probably a whole plethora of environmental factors that do come into play. But obviously with the liver the most common environmental risk factor for AIH is drug exposure because the poor old liver gets exposed to everything we ingest.”

“It is well known that certain traditional medications such as minocycline and nitrofurantoin trigger AIH. In the last 10 years there have been others recognised such as atorvastatin, highly active antiretroviral therapy and some of the biologics we use in Crohn’s disease such as adalimumab and infliximab are culprits.”

“So if liver tests go off in your Crohn’s patients, it’s worth thinking about AIH.”

She said anti-inflammatory medications, interferon and complementary medicines can be implicated as well.

“It’s always worth noting that the list of clinical and histopathological features are very similar in drug-induced AIH with de novo AIH with the exception of checkpoint inhibitor immune-mediated hepatitis which is a slightly different subset.”

Professor Stedman said the clinical presentation of AIH has not changed but the nomenclature now included acute AIH for patients presenting with jaundice and acute severe AIH for those presenting with jaundice and coagulopathy +/- encephalopathy.

“We know, consistently in all the studies, about a third of people are cirrhotic at diagnosis so there is still a problem with a delay in diagnosis.”

She said diagnostic criteria had not changed a great deal since the 1950s and was still dependent on the liver histology, hepatitis and a raised IgG.

However there was now a “plethora of autoantibodies” beyond ANA, anti-smooth muscle antibody and anti-LKM1. They included anti-soluble liver antigen, anti-LC1 in paediatric cohorts, pANCA and antimitochondrial antibody.

“It’s worth noting that about 10% of people are autoantibody negative and this is a group we need to remember. Some of them can be negative on diagnosis but become positive on follow-up testing, and the clinical presentations and response to therapy are the same in people who are autoantibody positive.”

She said the higher proportion of autoantibody-negative AIH patients with advanced fibrosis or cirrhosis on presentation probably confirmed a delay in the diagnosis of this patient subset.

Professor Stedman also warned that it was very easy to think that patients with a high BMI had fatty liver disease when some of them may be autoantibody-negative AIH.

Updates in treatment

She said the goal of treatment has become much more clearly defined and is a complete biological response (CBR) – complete normalisation of aminotransferases and IgG below the upper limit of normal.

“Some recent work from EASL shows that those who do achieve CBR are likely to stay non-cirrhotic over a long period of follow up whereas if you don’t achieve CBR you are highly likely to progress to cirrhosis.

“Similarly if you start with cirrhosis, CBR at 6 months leads to improved survival; lack of CBR increases liver-related death and liver transplantation (HR 5.7).”

She added that a recent European cohort showed that only 50% achieve CBR at 6 months and up to 60% at 12 months, “so we have got a way to go in terms of therapy”.

She said the traditional approach to treatment remained steroids but as other autoimmune conditions were moving away from steroids it would be interesting to watch this space.

At present though induction of remission was with prednisone +/- thiopurine and then maintenance with a thiopurine if possible. Second-line drugs included mycophenolate and calcineurin inhibitors

“But there have been some advances and things are starting to change slowly.”

The CAMARO trial [link here], a late-breaker at EASL 2023, found mycophenolate mofetil plus prednisolone was significantly superior to azathioprine plus prednisolone for induction of biochemical remission at 24 weeks in treatment-naïve patients with AIH.

She said this was probably due to intolerance and discontinuation of thiopurines compared to consistent therapy with mycophenolate.

“But it’s very teratogenic so that’s a problem if used in women of childbearing potential,” she said.

As well, despite no significant prospective studies, pooled analyses of observational studies showed that tacrolimus was a very effective therapy with CBR rates of almost 60% in patients who failed first-line therapy.

“Guidelines will increasingly embrace this as an effective therapy for these people,” she said.

Professor Stedman said negative prognostic factors for AIH include cirrhosis at onset, young age at onset, repeated relapses of active disease, those with variant syndromes or concomitant liver disease.

“What we have realised over the last 10 years is that although AIH is a treatable condition, in fact the long term mortality is significant.”

She said the 10-year mortality was 13% and 20-year mortality was 30%.

“We now know that anyone who gets cirrhosis can get HCC,” she added.

While the HCC risk in AIH was lower than in viral hepatitis and alcohol-related liver disease, patients especially those with recurrent relapses, should be screened.