This document discusses autoimmune hepatitis and overlap syndromes involving autoimmune hepatitis and primary biliary cholangitis or primary sclerosing cholangitis. It defines autoimmune hepatitis and describes its pathogenesis, epidemiology, and diagnostic criteria. It then discusses variant forms that overlap with primary biliary cholangitis or primary sclerosing cholangitis. These overlap syndromes can be difficult to diagnose and classify. The document compares features of autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. It proposes explanations for overlap syndromes and describes treatment approaches depending on the specific overlap diagnosis and disease severity.

1. Overlap Syndrome;
A Controversial Issue
by
Dr El-Sayed Tharwa M.D.
Professor of Hepatology &
Gastroenterology
NLI – Menoufia University
27th November 2020

2. AUTOIMMUNE HEPATITIS
Chronic hepatitis of unknown etiology
• Can progress to cirrhosis
• Characteristics include:
– presence of autoimmune antibody
– evidence of hepatitis (interface being characteristic)
– elevation of serum globulins
– Continuing / un-resolving hepatocellular
inflammation and necrosis

3. Diagnosis of autoimmune hepatitis requires the
exclusion of other chronic liver diseases that have
similar features, including Wilson’s disease
,chronic viral hepatitis, drug induced liver disease,
non alcoholic fatty liver disease, and the immune
cholangiopathies of primary biliary cholangitis
(PBC) and primary sclerosing cholangitis (PSC).

4. EPIDEMIOLOGY:
• Frequency of AIH among patients with chronic liver
disease in North America is between 11%- 22%.
• It accounts for 5.6% of liver transplants in the US.
• Prevalence is greatest among northern European
white persons.
• Japanese have a lower frequency.
• Women are affected more frequently than
men(3.6:1).

5. PATHOGENESIS:
EVIDENCE SUPPORTING AUTOIMMUNE PATHOGENESIS;
• Histopathological lesions composed of cytotoxic T cells and
plasma cells
• Circulating autoantibodies
• Hyperglobulinemia
• Other autoimmune disorders: thyroiditis, RA , autoimmune
hemolytic anemia, ulcerative colitis, membranoproliferative
glomerulonephritis, diabetes mellitus, celiac disease, Sjogren’s
syndrome
• Histocompatibility haplotypes associations
• Response to steroids and immunosuppression.

6. Exact pathogenesis is unknown.
Predisposition to autoimmunity is inherited, whereas
the liver specificity of this injury is triggered by
environmental factors (Chemical, drugs like
minocycline or viral).
Genetic predisposition is also present (HLA –B1, B8,
DR3,DR4)

7. Cell-mediated immune attack is directed against the
liver cells.
CD4 T lymphocytes are capable of becoming
sensitized to hepatocyte membrane protein and of
destroying liver cells.
Humoral immunity plays a role in extrahepatic
manifestations of arthritis, vasculitis and
glomerulonephritis by immune complex deposition
and complement activation.

8. Interface hepatitis is the hallmark of AIH:

9. Elevated serum AST & Gamma Globulin levels
AST:ALP >3
AMA negative Ceruloplasmin normal
Normal Alpha 1 Antitrypsin
phenotype Normal or near normal
serum iron
HBsAg, Anti HCV, IgM Anti HAV
and Anti HEV negative
LIVER BIOPSY
Interface Hepatitis +/- Lobular Hepatitis

10. Auto immune hepatitis
DEFINITE
Gamma globulin level >=1.5 normal
ANA, SMA, or ANTI LKM1 >=1:80
No exposure to drugs or blood products
Alcohol intake<25 g/day
PROBABLE
Gamma globulin level <1.5 normal ANA,
SMA, or ANTI LKM1<=1:40
Previous exposure to drugs or blood
products
Alcohol Use
Other liver related auto antibodies

12. VARIANT FORMS OF AIH:
• Autoimmune hepatitis + primary biliary cholangitis (PBC).
• Autoimmune hepatitis + primary sclerosing cholangitis(PSC).
• Autoimmune hepatitis + cholestatic features.
• Autoantibody-negative autoimmune hepatitis

13. Hepatic overlap
syndromes

14. Examples of Overlap Syndromes:
- Systemic sclerosis with other CT diseases.
- Myelodysplasia/myeloproliferative disorder
- Atrial arrhythmia and Brugada syndrome.
- Chronic Asthma and chronic obstructive sleep apnea
syndrome
- Functional dyspepsia-IBS syndrome.
- Hepatic overlap syndrome.

16. PBC
Variants of AIH or separate
entities ?
AIH
PSC

17. AIH PBC or PSC
Immune mediated injury
Hepatocytes Bile ducts
Genetic susceptibility and environmental factors
Cellular immunity Humoral immunity
Overlap
syndrome

18. Proposed explanations for overlap syndrome:
- Coexistence or sequential presentation of two independent
diseases in a susceptible patient.
- “Overlap syndromes” represent distinct entities.
- “Overlap syndromes” are in the middle of a wide continuum of
manifestations, ranging from pure hepatitic to pure
cholestatic.
• -“Overlap syndromes” are the result of heterogeneous
manifestations of a primary disorder.

19. Features of AIH, PBC, PSC:
variable AIH PBC PSC
age All ages 30-65 30-50
sex Predominantly
females
Predominantly
females
Predominantly males
AST&ALT Marked elevation Normal or mild
elevation
Normal or mild
elevation
Bilirubin Normal or elevated Normal or elevated Normal or elevated
ALP Normal or mild
elevated
Moderate to marked Moderate to
marked elevation
elevation

20. variable AIH PBC PSC
immunoglobulins Ig G Ig M Ig M & Ig G
ANA 70-80% 30% 8-70%
SMA 50% May be
present
Variable (0-
80%)
LKM 3-4% Negative Negative
SLA 10-30% Yes or no Yes or no

21. variable AIH PBC PSC
AMA Occasionaly
positive in
low titre
90-95% May be present
pANACA 50-96% - 26-94%
Liver histology Interface hepatitis Inflammatory
biliary
injury
Periductal fibrosis
Cholangiogram normal Normal Multifocal stricturing
Treatment
3-10%
Immunosupressives
Very rare
UDKA
80%
No effective TTT

22. Primary biliary cirrhosis - AIH overlap syndrome:
• ALP˃ 2 times or GGT ˃5 times ULN
• Positive AMA
• Histological evidence of bile duct
injury
PBC
• ALT ˃ 5 times ULN
• Ig G ˃2 times ULN or positive SMA
• Liver biopsy: Moderate to severe
Periportal or periseptal inflammation
AIH
Diagnosis require at least 2 out of 3 features in each component of the overlap

23. Autoimmune hepatitis – PSC overlap syndrome
AIH-
PSC
Cholestatic biochemical alteration
Concurrence of IBD
Cholangiographic evidence of intra and
or extrahepatic biliary dilation
Histological evidence of ductpoenia and
bile stasis
ANA or SMA seropositivity
+ Hypergamaglobulinemia +
Interface
hepatitis

25. Treatment:
AIH –PBC
ALK LESS THAN 2
FOLDS ULN
Prednisone or
prednisolone:
• 30 mg 1 week
• 20 mg 1 week
• 15mg 2 weeks
• 10 mg daily
• Combined with
Azathioprine 50 mg
from start
AIH - PBC
• Same +
• Ursodeoxycholic
acid
13-15 mg /kg/day
AIH-PSC
Prednisone or •
prednisolone
combined with
azathioprine 50 -75
mg/day
•Ursodeoxycholic
acid 13-15 mg
/kg/day

26. If you have a patients with AIH and overlap with PBC:
-No follow up changes
-You add a comfortable drug (UDCA) which may slow down
the progression of the disease and reduces mortality.
-Possible reduced life expectancy
Take home:

27. If you have a patients with AIH and overlap with PSC:
-Substancial follow up changes( the patient more liable to
cholangiocarcinoma, hepatoma, or gall bladder carcinoma)
-You add a comfortable drug (UDCA) but possibly
ineffective to slow down the progression of the disease
-Possible reduced life expectancy

28. IF PBC or PSC are preceding , making a diagnosis of AIH
overlap syndrome :
- You will add a uncomfortable but very effective drug
(immunosuppressive) to slow down the progression of the
disease and;
- Dramatically change life expectancy.

29. THANK YOU