Autoimmune hepatitis (AIH) is a chronic, progressive autoimmune disorder affecting the liver. It is associated with the production of antinuclear (ANA) and smooth muscle (SMA) antibodies and high serum immunoglobulin, alongside raised transaminase levels. AIH occurs more commonly in women and onset is typically between 20-40 years old. It has a prevalence of around 1-2/100000 persons per year affected. Patients typically, if symptomatic, present with jaundice, malaise, and up to a third have cirrhosis. AIH is managed with steroid treatment in symptomatic patients with raised transaminase levels. 10-year survival for AIH is around 82%, with the prognosis being worse if cirrhosis is detected on the initial biopsy.

Autoimmune hepatitis has been classified into three distinct types based upon the immunological findings:

• Type 1 - positive for ANA and/or SMA, which may also be associate with perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA). Accounts for the majority of cases.
• Type 2 is associated with either anti-liver kidney microsomal-1 (LKM-1) or anti-liver cytosolic-1 (LC-1) antibodies. Type 2 AIH accounts for less than 10% of all cases. Type 2 is generally more severe, patients are younger at diagnosis and the disease is usually more advanced at presentation. Patients will also classically have higher levels of bilirubin, ALT, and AST than patients with type 1 AIH.
• Type 3 is associated with autoantibodies against soluble liver antigens (anti-SLA) or liver-pancreas antigen (anti-LP). There is a suggestion that anti-SLA autoantibodies don't define a subgroup but in fact, belong to AIH type 1.

The fact that there is such variation in the autoantibodies associated with AIH may suggest that the condition isn't one disease but instead a group of diseases with a similar clinical presentation.

Human leukocyte antigen (HLA) genes, specifically HLA-DR, have shown a strong correlation with AIH, particularly of type 1 AIH. The genetic links of type 2 AIH are currently unknown.

There is a strong suggestion that exposure to pathogens may cause loss of tolerance to hepatocyte antigens by molecular mimicry, where similarities between the pathogenic antigens and self-antigens are sufficient to cause cross-reactivity and production of T or B cells against the self-antigens. There are many pathogens that may be implicated, including:

• Hepatitis A
• Hepatitis B
• Hepatitis C
• Epstein-Barr virus
• Measles virus.

There are other risk factors that are present for primary biliary cirrhosis and are thought to possibly be associated with AIH. These include:

• Recurrent UTIs
• Being post-partum (causes disease flares)
• Smoking
• Family history

In a person who is genetically susceptible to AIH, an environmental factor can trigger an immunological cascade that results in an inflammatory reaction against the liver. There is no clearly identified infectious agent that is thought to cause AIH, but there is evidence that some environmental agents may be involved in trigger AIH. Such environmental factors may include:

• Viruses e.g. hepatitis B, hepatitis C, measles.
• Drugs e.g. nitrofurantoin, anti-tumor necrosis factor-alpha agents.
• Toxins e.g. trichloroethylene, smoking

The liver is an extremely tolerant organ so the development of immunological injury is rare and surprising. It is regularly exposed to high levels and a wide variety of antigenic compounds and so requires high levels of tolerance. It is not entirely clear how this tolerance is overcome in AIH, but it is thought that hepatitis viruses may be implicated in the development of autoimmunity, possible due to mechanisms such as molecular mimicry, the formation of neoantigens, and inflammatory processes revealing otherwise hidden self-antigens.

This exposure and development of autoantigens then result in the activation of CD8+ and CD4+ T cells. Some experiments have suggested that these T cells may be primed, activated, and attack self-cells all within the liver. These cellular responses, along with direct cytokine actions and apoptosis result in progressive tissue damage, which may result in the further unmasking of self-antigens or the creation of neoantigens, propagating the disease even more.

The presentation of AIH can vary, with up to 25% of patients being asymptomatic at diagnosis, even some of those with cirrhosis. Up to 50% of patients may be clinically jaundiced, and about 30% have cirrhosis at presentation. Some clinical features include:

• Non-specific symptoms including fatigue, anorexia, weight loss, abdominal pain amenorrhoea.
• Features of cirrhosis including ascites, variceal bleeding etc.
• Pruritus.
• Arthralgias.
• Maculopapular rash.
• Pyrexia of unknown origin.
• Raised transaminase levels and immunoglobulin G (IgG).

The classical picture of AIH is as a chronic disease with raised transaminase levels for at least three months. However, in about 40% of patients AIH may present acutely, sometimes preceded by a flu like illness.

AIH is commonly associated with other autoimmune diseases, and co-presentation with coeliac disease is an important presentation to recognise. This is because in patients with coeliac disease there may be malabsorption of the immunosuppressive medication that is required to treat AIH. The most common autoimmune disorder that AIH is associated with is autoimmune thyroid disease, but it also may be associated with type 1 diabetes, rheumatoid arthritis, vitiligo, ulcerative colitis, etc.

The diagnosis of AIH relies on a combination of a clinical history and appropriate features on examination, compatible investigation results and the exclusion of other liver diseases. The diagnosis is often not straightforward and requires expert clinical input.

The key laboratory findings for AIH are:

• Raised serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
• Raised serum immunoglobulins, particularly IgG.
• Negative serum tests for viral hepatitis
• High titers of circulating autoantibodies. A study published in the Annals of Hepatology noted that ANA was positive in around 60% of patients, and anti-SMA was positive in around 70% of patients. It's important to note that the absence of autoantibodies doesn't completely exclude the diagnosis.

Serum ALP will be normal or only slightly raised.

Biochemical and immunological blood tests and are insufficient for a definitive diagnosis of AIH, and so Liver biopsy must be used. Typical features of AIH on liver biopsy include:

• Interface hepatitis - Inflammation of the hepatocytes at the junction of the portal tract and the hepatic parenchyma
• Periportal lymphocytic inflammation
• Hepatocyte swelling
• Necrosis

A set of simplified diagnostic criteria for AIH was published in Hepatology, which are as follows:

There is a maximum of 2 points for all autoantibodies and a maximum of two points for IgG. A score of ≥6 is classified as probable AIH. and a score of ≥7 is classified as definite AIH.

AIH can mimic many other liver conditions and it can be difficult to differentiate from other conditions. There are no clear pathognomonic features and so diagnosis is often based on the exclusion of other diseases. Some differential diagnoses include:

• Alcoholic liver disease (ALD). Clinical presentation can often be very similar, with similarly high levels of aminotransferases. However, in ALD, patients will have a strong history of alcohol abuse, there will not be any evidence of autoantibodies, and histological signs will be different.
• Non-alcoholic fatty liver disease (NAFLD). It can be difficult to distinguish between NAFLD and AIH as neither has laboratory tests or clinical features that are pathognomonic. However, the presence of autoantibodies will strongly suggest AIH over NAFLD as a diagnosis.
• Chronic hepatitis C infection. Clinical presentation may be similar, and there may likewise be an elevation of LFTs and rarely patients may also have raised autoimmune antibodies. However, the diagnosis of hepatitis C can be excluded with a viral hepatology screen. On histology, hepatitis C classically features ground-glass hepatocytes which will not be present in AIH.

The mainstay of treatment for AIH is immunosuppressive therapy. AIH is typically managed under the expertise of a hepatologist or a gastroenterologist. Patients with AIH and moderate to severe inflammation should be offered treatment, as well as symptomatic patients and younger patients who are more at risk of developing cirrhosis later in life. Moderate to severe inflammation is suggested by:

• AST >5 times the normal serum level
• Immunoglobulins >2 times the normal serum level
• Liver biopsy showing necrosis The mainstay of treatment is prednisolone, sometimes in combination with azathioprine as well.

In adjunct to this, patients should be vaccinated against hepatitis A and B infection, receive calcium and vitamin D supplementation, and have regular DEXA scans and screening for glaucoma and cataracts.

About 10-20% of patients will require liver transplantation during their lifetime, indicated by either severe acute AIH resulting in liver failure, decompensated liver disease or hepatocellular carcinoma.

Patients who are diagnosed with AIH will need regular follow up and monitoring of disease progression. Most patients with AIH will have a degree of fibrosis within the liver and will be at risk of progression to cirrhosis. Cirrhosis, in turn, can lead to the development of:

• Ascites
• Spontaneous bacterial peritonitis
• Haemorrhages (e.g. due to variceal bleeding)
• Hepatic encephalopathy
• Hepatocellular carcinoma

Patients can also suffer from iatrogenic complications related to steroid treatment, including osteoporosis, diabetes, hypertension, and opportunistic infections.