Definition
AIH is a chronic inflammatory
autoimmune liver disease. In principle, for every patient with a picture of
hepatitis, AIH should be included in the differential diagnosis
It was first described in the 1950s as "lupoid hepatitis" in young women.
Affected at any age, the most
common is the clinical first manifestation, however, in middle adulthood with a
peak between 40 and 70 years.
Ratio of women: men 3-4: 1.
Incidence of about 1-3 per 100,000
a year.
Pathogenesis
- Break in immune tolerance by external noxae in genetically predisposed individuals
- Genetic predisposition: Alleles of major histocompatibility complex (MHC) class II molecules contribute most to the genetic risk. In Europe, mainly HLA-DRB1 *0301 and HLA-DRB1 *0401 are predisposing alleles.
- External noxae: may be, for example, infections with hepatotropic viruses, such as hepatitis A, hepatitis E or herpes viruses, or drugs, such as nitrofurantoin, minocycline or infliximab.
- Immune tolerance: The adaptive immune system, and especially the T and B lymphocytes, is believed to play a crucial role in the pathophysiology of AIH. Whether autoantibodies or the increased immunoglobulins play a role has not yet been clarified. Finally, a lack of regulatory T cells, which has long been thought to cause AIH, could not be confirmed. Deficiency of interleukin-2 in the inflamed liver before and during therapy is discussed. Interleukin-2 is essential for regulatory T cells.
Clinical picture
The symptoms vary from mild cases
with incidental finding of elevated liver enzymes, acute or acute-to-chronic
courses to liver failure.
There are similar symptoms to
other hepatitis
- fatigue
- upper abdominal complaints
- jaundice
- One-third of patients already show signs of liver cirrhosis when first diagnosed
- Extrahepatic manifestations, for example with joint and muscle complaints occur frequently
Extrahepatic autoimmune diseases
up to 40% of cases, e.g. (DM I, thyroiditis, CED, RA)
Overlap with autoimmune
cholangitis in 20% of cases (PSC, PBC)
Diagnostics
AIH is an exclusion diagnosis
because it lacks pathognomonic findings. It typically shows the following
findings constellation:
- A hepatic inflammatory pattern of liver enzymes
- Autoantibodies: Antinuclear antibodies (ANA), smooth muscle antibodies (SMA), liver kidney microsomal antibodies (LKM)
- Increasing the immunoglobulin G antibody class (IgG)
- Histological findings
Exclusion diagnosis? :
- Viral hepatitis. Hepatitis A-E, herpes simplex, varicella-zoster (VZV), cytomegalovirus (CMV) and Epstein-Barr virus (EPV); in adolescence also human herpesvirus 6 (HHV6) and parvovirus B19.
- Abdominal ultrasound for the assessment of perfusion disorders, cholestasis, and liver room demands is obligatory.
- Anamnesis of ingestion of obligate and potentially toxic substances such as alcohol, medicines, drugs, food and nutritional supplements.
- Metabolic causes: α1-antitrypsin deficiency, Wilson's disease or hemochromatosis.
- With a worldwide increase in nonalcoholic fatty liver hepatitis (NAFLD), in purely statistical terms, AIH manifestations in the fatty liver are to be expected so that a liver steatosis should not lead to the immediate exclusion of the differential diagnosis AIH. In experimental mouse models, liver adiposity even enhances AIH
Autoantibodies:
- AIH type 1 (most commonly 70%): SMA, ANA, and pANCA, antibodies to the soluble liver antigen (SLA)
- AIH type 2 (mainly in children, rarely 10%): antibodies to liver-kidney microsomes (LKM1-AK/LKM3-AK) and liver cytosol antibodies [LC-1]
- Quantitative determination of IgG/IgM
- 20%
negative
- IgG serum levels and anti-actin autoantibody titers (SMA) may correlate with AIH activity
Histological findings: Liver biopsy:
To confirm the diagnosis, a liver
biopsy should be performed. Recommendation, Strong consensus
After already initiated therapy,
the significance of histology for the diagnosis of AIH is considered limited.
Strong consensus
The simplified AIH score evaluates
interface hepatitis, emperipolesis, and rosetting, all three being required for
the diagnosis of "AIH-typical." Chronic hepatitis with lymphocytic
infiltrate is considered to be compatible with AIH without any other typical
changes
![]() |
Normal liver Lobule |
AIH Typical histological findings:
![]() |
AIH with portal and intra-acinar inflammation, interface activity, regenerative hyperplasia |
![]() |
Emperipolese |
![]() |
AIH with pseudorosets |
In often difficult distinction to
toxic hepatitis, a probative treatment with steroids can be tried. There is a
prompt response with relapse after stopping the steroids for an AIH.
Treatment response to steroids
is considered an indication of AIH, but is not conclusive!
simplified AIH score:
![]() |
simplified Autoimmunhepatitis score |
The diagnosis of AIH is possible
without positive detection of autoantibodies - especially in cases of fulminant
autoimmune hepatitis both autoantibodies and IgG elevation may be absent!
International autoimmune hepatitis
group revised diagnostic scoring system (IAHG)
Interpretation:
Before therapy initiation
> 15 points: "definitive"
autoimmune hepatitis
10-15 points: "Probable"
autoimmune hepatitis
After therapy initiation
> 17 points: "definitive"
autoimmune hepatitis
12-17 points: "Probable"
autoimmune hepatitis
![]() |
International autoimmune hepatitis group revised diagnostic scoring system IAHG |
Therapy
The goal of the therapy:
- Liver fibrosis does not progress.
- free of complaints
- Few side effects of the therapy.
- The concrete therapeutic goal is a complete normalization of the liver enzymes AST and ALT as well as γ-globulins or IgG.
Histological remission:
- Hepatitis Activity Index (HAI) of ≤3
- Absence of interface hepatitis
- Any AIH patient who does not meet these criteria will have a treatment indication
Standard therapy:
- Remission induction therapy
- Remission maintenance therapy
- Biochemical remission at 80% and above
![]() |
Autoimmune hepatitis Therapie |
Prednisolone vs budesonide
A randomized, controlled study on
remission induction at AIH 2010 showed that budesonide in combination with
azathioprine is at least on par with standard therapy with prednisolone and
azathioprine in patients without liver cirrhosis with significantly reduced
steroid-related side effects.
Due to the risk of severe side
effects such as thromboembolic events and the reduced first-pass effect in
cirrhotic bypasses, budesonide should only be used in patients without liver
cirrhosis.
In a recent retrospective monocentric
study from Hamburg (60 women, 2001-2016) it was also shown that the bone
density under long-term use of budesonide only rarely worsens further.
With long-term use of budesonide,
the rate of biochemical remission (even in difficult to treat patients) could
be doubled to 40%
Therapy side effects
Under the immunosuppressive
therapy.
- In up to 80% of patients, steroid-related side effects occur
- in up to 50% of patients with azathioprine changes in blood counts
![]() |
Autoimmune hepatitis Therapy side effects |
End standard therapy
After at least 2 years of
maintenance therapy with biochemical remission, an omission attempt of the
immunosuppressants with the patient can be discussed.
The risk of a relapse can be
estimated more accurately with a previous liver biopsy.
- Persistent histological disease activity (HAI≥4)
- Interface hepatitis
- higher risk of relapse
Surveillance biopsy of this kind
is also gaining additional importance due to data from a large retrospective
monocentric study from England (2015). In this study, poorer long-term survival
of patients with persistent HAI≥4 was found despite biochemical response
Therapy not successful?
For all cases in which the biochemical response is not achieved, should:
- questioned the diagnosis
- Connection to a specialized center are considered
If there is evidence of an onset
of liver failure (acute, acute on chronic, or even chronic), the connection to
a transplantation center should be made immediately
Second-line treatment
Data is poor, no medication of the Second-line treatment of AIH is approved
So far, only interim results of a
randomized, controlled trial comparing ciclosporin with prednisolone as a
first-line therapy are published in 2013
![]() |
The conclusion of the meta-analysis on the second-line therapy of the AIH (02/2018) |
In the meta-analysis mentioned
above, only mycophenolate mofetil and calcineurin inhibitors were considered,
but not biologics, such as antibodies against tumor necrosis factor-α (TNF-α)
or CD20, and also no mammalian target-of-rapamycin (mTOR) inhibitors. Regarding
these, in small monocentric case series an improvement in inflammatory activity
has been reported, but partly with non-negligible infectious complications.
Because of this, some authors also classify these drugs as potential third-line
therapeutics
The national and international
professional societies, therefore, recommend the following with the current data:
- Mycophenolate mofetil more likely for patients with intolerance to azathioprine
- Tacrolimus is currently the most likely to be preferred if therapy response to standard therapy is insufficient
The first randomized,
placebo-controlled multicenter second-line study in AIH is currently in the
pipeline (AMBER study, ClinicalTrials.gov identifier NCT03217422). Here, the
antibody VAY736 against the B-cell activating factor (BAFF) receptor on B cells
is to be investigated.
conclusion for practice
- AIH is a differential diagnosis for all unclear hepatitis.
- Diagnosis is based on the combination of autoantibodies, histology and the exclusion of more likely liver disease.
- Standard therapy with prednisolone ± azathioprine improves patient survival.
- For patients without cirrhosis, there is the side-effect less therapeutic alternative in the combination of budesonide + azathioprine.
- The data available for the choice of second-line therapies is insufficient. So far, no second-line therapy has been approved for AIH.
- The therapeutic goal is a complete normalization of ALT, AST, IgG/γ globulins and histological findings.
- Despite good treatment response, most patients require lifelong maintenance therapy.
- The good medical care of the AIH also includes vaccinations according to the recommendations of the Standing Committee on Vaccination (STIKO), prevention of osteoporosis with prednisolone medication> 5 mg/day, early diagnosis of tumors and counseling in family planning.
Written by: Ayman Zoaa
I’m a resident doctor living in Bremerhaven-Germany, my goal here is to explain medical stuff as easy and practical as possible. My second purpose is to help those who are trying to begin specializing in Germany.
About my profession, I’m 30 years old, was born in Syria on 1989, I studied medicine at the University of Aleppo between 2007 and 2013, then I traveled to Germany and began my actual work before about 3 Years. I have got my medicine certificate recognized in Germany after I had made the recognition test and the medical language test.
I’m specializing in internal medicine, and then I’ll proceed to gastroenterology, and hopefully endocrinology.
I find writing interesting, and it also helps me to keep my information up to date, what we- medical people - need.
Let us keep in touch through singing up, and through the contact-from, i will answer your Questions gladly.
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