Regarding autoimmune hepatitis, you need to master these | Clinical Essentials

Autoimmune hepatitis (AIH) is a type of liver parenchymal inflammation mediated by autoimmune response to liver cells, with positive serum autoantibodies, high immunoglobulin G and/or γ-globulinemia, The liver histology is characterized by the presence of interface hepatitis, which can often lead to cirrhosis and liver failure if left untreated.

This article will combine the latest guidelines to discuss the clinical manifestations, diagnosis, differential diagnosis, and treatment management of AIH.

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The clinical manifestations of AIH The clinical manifestations of AIH are diverse.
Generally, they are chronic and insidious onset, but they can also be acute onset, or even cause acute liver failure, with varying degrees of severity.

The most common symptoms include drowsiness, fatigue, and general malaise.

Physical examination can reveal signs of hepatomegaly, splenomegaly, ascites, and occasionally peripheral edema.

Asymptomatic patients usually see a doctor because of an elevated level of transaminase found on physical examination.

Acute onset patients may have acute liver failure, severe jaundice and prolonged prothrombin time.

In addition, most patients have non-specific symptoms of varying severity, such as fatigue, lethargy, fatigue, and anorexia.

Multi-articular pain involving small joints but not accompanied by arthritis has a greater suggestive significance for this disease [7].

 The AIH diagnosis process is shown in the following figure: Figure 1 AIH diagnosis flow chart Note: ANA=antinuclear antibody; SMA=smooth muscle antibody; LKM1=liver kidney microsomal antibody type 1; SLA=anti-soluble liver antigen; pANCA=perinuclear Type anti-neutrophil cytoplasmic antibody; tTG=anti-tissue transglutaminase; AMA=anti-mitochondrial antibody; PBC=primary biliary cholangitis; PSC=primary sclerosing cholangitis; NASH=non-alcohol Steatohepatitis; NAFLD = non-alcoholic fatty liver disease.

 According to the "Practical Guidelines for the Diagnosis and Treatment of Autoimmune Hepatitis" issued by the American Society for the Study of Liver Diseases (AASLD), AIH diagnostic criteria are as follows: ➤ AIH diagnosis requires consistent histological results and meets the following characteristics: (1) Serum Elevated AST/ALT levels; (2) Elevated serum IgG levels and/or positive for one or more autoantibodies; (3) Excluded other causes of chronic hepatitis: viral, hereditary, metabolic, cholestasis Sex and drug sex, etc.

 ➤ The initial serological examination should include: (1) Adults: ANA and SMA; (2) Children: ANA, SMA and anti-LKM1.

If necessary, consider additional autoantibody testing to ensure diagnosis.

 ➤ All patients with acute or chronic liver disease, including asymptomatic liver function test abnormalities, acute liver failure, and routine autoantibody-negative hepatitis patients, must consider the diagnosis of AIH.

 ➤ It is common for patients with AIH to have autoimmune diseases, and should be screened for celiac disease and thyroid disease at the time of diagnosis.

 ➤ AIH patients should be evaluated for rheumatoid arthritis, inflammatory bowel disease (IBD), autoimmune hemolytic anemia, diabetes, and other extrahepatic autoimmune diseases based on symptoms.

 Differential diagnosis of AIH 1.
The reason why it is difficult to distinguish drug-induced liver injury (DILI) is that both DILI and AIH can be manifested as liver cell injury; AIH is mainly chronic, but 10% is acute.
DILI is acute.
Mainly, but long-term medication can also cause chronic damage; some DILI drugs can induce autoantibody production.

 Both DILI and AIH lack specific clinical manifestations and diagnostic markers, especially the onset of chronic liver injury caused by drugs is relatively insidious, making differential diagnosis difficult.

In recent years, different research groups have tried to distinguish the two purely from histology.

Both interface hepatitis, focal necrosis, and portal area inflammation can be seen, but AIH is more serious than DILI.

The characteristic histological manifestations of AIH include plasma cell infiltration, "rose rosette"-like structure and penetrating phenomenon; while the portal area neutrophils, eosinophil infiltration, granuloma formation, intrahepatic cholestasis and fatty change are more common in DILI .

In addition, DILI fibrosis is lighter than AIH.

 2.
Non-alcoholic steatohepatitis (NASH) At present, liver biopsy is still the gold standard for diagnosing NASH and assessing the degree of liver fibrosis [31].

Non-alcoholic fatty liver disease (NAFLD) activity scores often use the NAS system to assess the disease activity grading, for the presence of serum ferritin greater than 1.
5 times the upper limit of normal (indicating NASH and advanced liver fibrosis), splenomegaly, and blood cells Reduced patients over 45 years of age with obesity or diabetes should consider liver biopsy.

For asymptomatic patients with elevated liver enzymes and NASH patients, abdominal ultrasound is the most common and economical method of choice.

Some patients with NASH may have low titers of serum autoantibodies.
It is recommended that liver biopsy be performed if necessary to confirm the presence of AIH [32].

 3.
Hepatolenticular degeneration (Wilson disease) Clinically, the liver histological examination and serum immunological characteristics of Wilson disease patients can be similar to AIH, which is easy to cause misdiagnosis.

Patients with unexplained liver injury and cirrhosis should pay attention to the investigation of Wilson disease.

Recent studies have shown that the exchangeable copper determination method to calculate the relative exchangeable copper can directly and accurately determine the copper overload, which can be used as a new tool for the diagnosis of Wilson disease.

The KF ring is a classic ophthalmological manifestation of Wilson's disease and can be checked by a slit lamp.

For patients with unknown diagnosis, liver puncture can be used to determine the liver copper content.
The liver copper content> 250 μg/g (dry liver weight) plays a key role in the diagnosis of Wilson's disease.

Patients who have been diagnosed with Wilson disease should be regularly followed up for evaluation.

 4.
Other serum virological indicators can identify viral hepatitis. Elevated serum iron levels and moderately increased intrahepatic iron concentrations can be seen in AIH patients, and differential diagnosis should be made with hemochromatosis patients who can occasionally detect autoantibodies.

Saturated transferrin in serum and chemical determination of iron in liver tissue and calculation of iron index can help distinguish.

Some systemic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, affect the liver, but the extent, scope, and pathological manifestations of the liver are not the same as those of AIH, making it easier to distinguish.

 AIH treatment strategy First-line treatment For untreated children and adults with AIH, if not cirrhosis or acute severe disease, AASLD recommends budesonide combined with azathioprine, or prednisone (long) combined with azathioprine as the initial first-line Treatment plan (conditional recommendation, low certainty).

For children and adult AIH patients with liver cirrhosis or acute severe AIH, AASLD does not recommend the use of budesonide (conditional recommendation, very low certainty).

Figure 2 AIH first-line treatment and second-line treatment For children or adult patients with AIH who have failed, incompletely responded to or intolerated the first-line drug therapy, AASLD recommends the use of mycophenolate mofetil (MMF) or tacrolimus to achieve and maintain biochemical remission (conditional) Recommended, low certainty).

 After the routine treatment of autoimmune hepatitis patients is discontinued, relapses are common.

Immunosuppressant therapy should be continued for at least 3 years, and transaminase and IgG will be completely normal after at least 2 years.

For patients who have achieved biochemical remission for more than 2 years, liver biopsy should be considered before stopping the drug.

 ※Remission of biochemical level is defined as normalization of IgG and transaminase, and histological remission is defined as normal histology or minimized hepatitis (HAI<4 or equivalent).

 Liver transplantation Liver transplantation is used for AIH patients with fulminant liver failure or patients who have progressed to end-stage liver disease.

The latter is more likely when cirrhosis is diagnosed or when there is a long history of liver disease before treatment begins.

After transplantation, approximately 20% of cases describe recurrent AIH, and juvenile AIH-2 is more likely to relapse than AIH-1.

The diagnosis of recurrence is based on biochemical abnormalities, the presence of autoantibodies, interface hepatitis on liver histology, and steroid dependence.

Recurrence may occur even a few years after transplantation, so it is recommended to maintain a small dose of steroids (2.
5-5 mg/d).

The recurrence of AIH usually does not affect the outcome after transplantation, and the 5-year survival rate exceeds 90%.

 Conclusion Although AIH related research has made great progress in recent years, it still faces many problems and challenges.

The diagnosis of AIH is more complicated, and it is a comprehensive diagnosis based on the exclusion diagnosis.
The lack of specific diagnostic markers is the main problem in the diagnosis of AIH.

With the rapid development of immunology, molecular biology and other technologies, it is expected that new markers will be discovered, which will be more helpful to the understanding of diagnosis or pathogenesis, and improve the level of diagnosis and treatment.

 In general, the management of patients with autoimmune hepatitis varies greatly.

In addition, there is still a lack of consensus among liver disease experts regarding the initial treatment and follow-up of patients with autoimmune hepatitis.

Although there is a lack of good quality evidence, there is more experience in the second-line and third-line treatment of patients with refractory autoimmune hepatitis.

Future prospective research should focus on solving these problems.
In this way, the management of patients with autoimmune hepatitis can shift from treatment based on expert experience to individualized evidence-based management.  References: [1] Cara LM, David A, David NA, et al.
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Liver histopathological diagnosis of autoimmune hepatitis[J].
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