Autoimmune Hepatitis (AIH) - Causes, Symptoms, and Treatment

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:

1. A hepatic inflammatory pattern of liver enzymes
2. Autoantibodies: Antinuclear antibodies (ANA), smooth muscle antibodies (SMA), liver kidney microsomal antibodies (LKM)
3. Increasing the immunoglobulin G antibody class (IgG)
4. 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.