Pediatric autoimmune hepatitis (AIH) is a progressive liver inflammatory disorder predominantly affecting females, typically presenting with hypergammaglobulinemia and autoantibodies. It can lead to liver failure if not treated promptly and can be classified into two main types based on autoantibody profiles. Effective treatment involves immunosuppressive therapies, and patients may require liver transplantation in severe cases.

1. Pediatric
Autoimmune Hepatitis
W. P. Rivindu H. Wickramanayake
Group no. 04a
6th Year 1st Semester – 2020 April
Tbilisi State Medical University, Georgia

2. ● A progressive inflammatory hepatopathy.
● The most typical features of AIH are
- Female preponderance,
- Hypergammaglobulinemia/increased immunoglobulin G (IgG),
- Seropositivity for circulating autoantibodies, and
- A picture of interface hepatitis on histology.
● AIH responds to immunosuppressive treatment in the majority of cases.
Treatment should be instituted promptly upon diagnosis.
● If left untreated, AIH usually progresses to liver failure requiring
transplantation.
● Two types of AIH are distinguished according to serological profile:
- Type 1 AIH (AIH-1) - ANA and/or anti-smith muscle antibody (SMA),
- Type 2 AIH (AIH-2) - anti-liver kidney microsomal type 1
antibody(anti-LKM-1) and/or for anti-liver cytosol type 1 antibody (anti-LC-1).

3. ● Is unknown. Several factors (eg, viral infection, drugs,
environmental agents) may trigger an autoimmune response and
autoimmune disease.
● In a few patients with AIH, illness onset follows acute hepatitis
A, hepatitis B, or Epstein-Barr virus infections.
● Autoantibodies - in patients with chronic HCV infection, liver-
kidney microsomal type 1 (LKM-1) antibody.
Etiology

4. ● Some cases of drug-induced liver disease have an immune-
mediated basis. A number of drugs (eg, methyldopa,
nitrofurantoin, minocycline, adalimumab, infliximab) can
produce an illness with the clinical features of AIH.
● Although most cases improve when the drug is stopped,
chronic cases of AIH may be seen, even after drug withdrawal.
● Casswall et al found Helicobacter species DNA in 50% of liver
biopsies from patients with AIH and ulcerative colitis.

5. ● Current evidence suggests that liver injury in a patient with
autoimmune hepatitis is the result of a cell-mediated immunologic
attack.
● Aberrant display of human leukocyte antigen (HLA) class II on the
surface of hepatocytes facilitates the exposure of normal liver cell
membrane constituents to antigen-presenting cells (APCs).
● and helper T lymphocytes interact at the ligand-ligand level, which, in
turn, activates TH 0. This activation is followed by functional
differentiation into helper T cell 1(TH1)/ helper T cell 2(TH2), according
to the cytokines prevailing in the tissue & the nature of the antigen.
Pathogenesis

6. ● TH 1 primarily secretes interleukin 2 (IL-2) and interferon gamma,
which activate macrophages and enhance the expression of HLA
classes I and II, thus perpetuating the immune recognition cycle.
● TH 2 cells primarily produce interleukins 4, 5, and 10, which
stimulate autoantibody production by B lymphocytes.
● The asialoglycoprotein receptor and the cytochrome mono-
oxygenase P-450 IID6 are proposed as the triggering autoantigens.
● Physiologically, TH 1 and TH 2 cells antagonize each other.
Regulatory mechanisms strictly control the autoantigen recognition
process; their failure perpetuates an autoimmune attack.

7. ●Liver cell injury can be caused by the action of cytotoxic lymphocytes
that are stimulated by IL-2, complement activation, engagement of
natural killer lymphocytes by the autoantibody bound to the hepatocyte
surface, or reaction of autoantibodies with liver-specific antigens
expressed on hepatocyte surfaces.
●Autoantibody-coated hepatocytes from patients with autoimmune
hepatitis are killed when incubated with autologous allogenic
lymphocytes.
●The effector cell was shown to be an Fc receptor-positive mononuclear
cell.
●It is shown that T-cell clones from liver biopsy specimens in children
with autoimmune hepatitis who express the γ/δ T-cell receptor are
preferentially cytotoxic to liver-derived cells.

8. Epidemiology
● Prevalence in Europe - 11.6-16.9 cases per 100,000 persons.
- most common in whites of northern European ancestry
- with a high frequency of HLA-DR3 and HLA-DR4 markers.
● Prevalence in Japan - 0.08-0.015 cases per 100,000 persons.
- More associated with HLA-DR4.
● Women > Men (70%-80% of patients are women).
● AIH has a bimodal age distribution, with a first peak of incidence
at age 10-20 years and a second at age 45-70 years.
● Approx. one half of the affected individuals are younger than 20
years;
● Incidence peaks in premenstrual girls.
● Patients with AIH-2 tend to be younger; 80% are children.

9. Classification
● Based on
autoantibody
markers, AIH is
recognized as a
heterogeneous
disorder
● Sub-classified into
3 types.

11. Pediatric Presentation
● An acute presentation of mimicking acute viral hepatitis (ie,
abdominal discomfort, vomiting, nausea, jaundice).
● Fulminant hepatic failure - more common in patients with AIH-2.
● Insidious presentation was characterized by intermittent jaundice or
nonspecific symptoms.
● Routine blood analysis - abnormal liver enzymes.
● Patients with autoimmune hepatitis developed cirrhosis and portal
hypertension.
● AIH-2 can be part of autoimmune polyendocrinopathy-candidiasis-
ectodermal dystrophy (APECED), an autosomal recessive genetic
disorder in which liver disease is reportedly present in about 20% of
cases.

12. ● Often occur in children with AIH.
● In children with AIH-1:
- Ulcerative colitis
- Sclerosing cholangitis
- Vasculitis
- Arthritis
- Glomerulonephritis
- Diabetes mellitus
Additional Autoimmune Disorders

13. ●In children with AIH-2 :
- Polyendocrinopathy
- Alopecia areata
- Diabetes mellitus
- Thyroiditis
●Acute liver failure occurs primarily between the ages of 13 months
and 4 years in children with AIH-2.
●It typically occurs after puberty in patients with AIH-1.

14. ● Common findings on physical examination are as follows:
- Hepatomegaly
- Jaundice
- Splenomegaly
- Spider angiomata
- Ascites
- Encephalopathy
● All of these findings may be observed in patients with disease that has
progressed to cirrhosis with ensuing portal hypertension.
● However, hepatomegaly, jaundice, splenomegaly, and spider
angiomata also may be observed in patients who do not have cirrhosis.

15. ● Cirrhosis and complications of cirrhosis;
- Ascites,
- Coagulopathy,
- Hepatic coma
● Portal hypertension
● Esophageal varices
● Malnutrition (with poor growth in children)
● Overlap Syndrome[Tx. - Ursodiol + Immunosuppressants]
Complications

16. ● Many causes of chronic liver diseases including;
- α1 -antitrypsin deficiency,
- Wilson disease,
- Viral hepatitis,
- Hepatotoxic drugs,
- Excessive alcohol consumption
- Autoimmune polyendocrine syndrome type I (APS-1),
- Autoimmunity in hepatitis C virus (HCV) infection,
- Immune-mediated drug-induced hepatitis,,
- Cryptogenic hepatitis,
- Overlap syndrome [primary biliary cirrhosis (PBC)
and primary sclerosing cholangitis (PSC)]
Differential Diagnoses

17. Diagnosis
● Laboratory findings in autoimmune hepatitis include the following:
- Elevated serum aminotransferase levels (1.5-50 times
reference values)
- Elevated serum immunoglobulin levels, primarily
immunoglobulin G (IgG)
- Seropositive results for ANAs, SMAs, or LKM-1 or anti–
liver cytosol 1 (anti-LC1) antibodies
- Decreased albumin levels
- Prolonged prothombin time
● Urgent liver biopsy, transjugular if appropriate, may help to
confirm the clinical suspicion of autoimmune hepatitis.

18. ● Assays;
- Serum antinuclear antibody (ANA)
- Anti–smooth muscle antibody (ASMA)
- Liver-kidney microsomal type 1 (LKM-1) antibody
- Serum protein electrophoresis (SPEP)
- Quantitative immunoglobulins
● Autoantibody tests;
- AIH-1 - ASMA and ANA
- AIH-2 - Anti–LKM-1 antibody
- AIH-3 - Antibodies to soluble liver antigen (anti-SLA)

19. ● Hematologic abnormalities may include the following:
- Mild leukopenia
- Normochromic anemia
- Coombs-positive hemolytic anemia
- Thrombocytopenia
- Elevated erythrocyte sedimentation rate
● Autoimmune hepatitis has even been described as the sole
presenting feature of idiopathic hypereosinophilic syndrome.

20. ● The presence of heterogeneous hepatic echotexture on abdominal
ultrasound or abnormal contrast enhancement on abdominal CT
imaging may suggest the presence of active inflammation or
necrosis.
● The appearance of an irregular nodular liver may confirm the
presence of cirrhosis.
● Endoscopic retrograde cholangiopancreatography (ERCP) to rule
out coexisting primary sclerosing cholangitis (PSC) [When alkaline
phosphatase levels are 7-8 times reference values or gamma glutamyl
transferase levels are 2-3 times reference values + a patient with autoimmune
hepatitis and ulcerative colitis]

21. Indications for Treatment of AIH in Adults

22. Treatment Regimens for Adults

23. Treatment for Adults Cont;

24. Treatment Regimens for Children

25. ● Prednisolone rather than prednisone may be used, at a dosage of 2
mg/kg/d (not to exceed 60 mg/d).
● Taper over 4-8 weeks, if testing of transaminase levels
demonstrates gradual improvement, then administer the minimum
maintenance dose required to sustain reference levels of liver
enzymes.
● If liver enzyme levels do not return to the reference values during
the first 4-8 weeks of treatment or if improvement requires high
doses of steroids, initiate azathioprine administration at 0.5 mg/kg/d
and gradually increase to 2 mg/kg/d until transaminase levels return
to the reference values.

26. ● An effective form of therapy for patients in whom medical therapy
has failed, or those with decompensated cirrhosis caused by AIH.
● Liver transplantation also may be used to rescue patients who
present with fulminant hepatic failure secondary to AIH.
● Approximately 10%-20% of patients require liver transplantation.
● The long-term outlook after liver transplantation is excellent, with
10-year survival rates reported as greater than 70%.
● Positive autoantibodies and hypergammaglobulinemia tend to
disappear within 2 years of transplantation.
Liver Transplantation

27. ● Should perform liver function tests in patients with autoimmune
hepatitis (AIH) weekly during the first 6-8 weeks of treatment
and then every 2-3 months, based on the results.
● Scheduling regular follow-up visits to assess disease activity
and to search for signs and symptoms of chronic liver disease.
● Surveillance abdominal imaging studies (eg, ultrasound, CT,
MRI) and alpha-fetoprotein testing are typically performed
every 6 months in patients with most types of cirrhosis.
Long-Term Monitoring

28. Prognosis
● In children with AIH, 70% require treatment until adulthood.
● Many patients already have cirrhosis at the time of diagnosis.
● Almost 20-25% of children with Autoimmune hepatitis die or
require liver transplantation.
● Young patients with AIH should receive immunosuppressive
treatment to prevent or delay cirrhosis, even if they do not meet other
treatment criteria.

29. ● HLA status affects treatment outcome.
Eg. - HLA DR3-positive patients - active disease & less
responsive to therapy than patients with other HLA types & require
liver transplantation.
● Spontaneous resolution in 13%-20% of patients, regardless of the
inflammatory activity, an unpredictable event.
● In general, the following factors are associated with a worse
prognosis:
• Young age at presentation
• AIH-2
• Coagulopathy
• Severe initial histologic activity

30. Questions
1. Which one of the following statements regarding AIH is true?
1. An acute onset of illness is common (40%)- TRUE
2. Women are affected more than men (M: F- 1:2)
3. Predominant serum alkaline phosphatase abnormality
4. Immunoglobulin level is usually normal
5. Splenomegaly and spider naevi never occurs in absence of cirrhosis
2. Which one of the following statements regarding AIH is/are true?
1. Auto antibodies at least in 1:80 titres in adults- ANA, SMA or LKM1 and no
AMA
2. Bilirubin >4fold increase is unusual
3. Anti-LKM1 typically occurs in the absence of SMA and ANA
4. Bridging necrosis is an indication of treatment
5. All above

31. 3. Which one of the following statements regarding AIH is false?
1. Relapse is characterized by an increase in the serum aminotransferase level to more
than 3-fold the upper limit of normal and/or increase in the serum gamma-globulin level to
more than 2 g/dL
2. Indefinite low dose treatment is given after second relapse
3. Relapse occurs in from 20% to 100% of patients who enter remission.
4. After first relapse long term treatment is needed
5. Biochemical remission means serum aminotransferase levels to less than twice
normal, restoration of serum bilirubin and gammaglobulin levels to normal
4. Which one of the following statements regarding AIH is false?
1. Both steroid only and steroid and azathioprine are approved treatment options
2. Adults rarely achieve remission in less than 12 months
3. Histologic improvement lags behind clinical and laboratory improvement by 3 to 6
months
4. Sixty-five percent of patients enter remission within 18 months
5. Biochemical remission is defined as serum aminotransferase to normal