Etiopathogenesis of primary sclerosing cholangitis

Table 1 Causes and mimics of secondary sclerosing cholangitis (SSC)

	SSC
Causes	Surgical trauma to bile ducts
	Ischaemic injury eg after transplantation
	Hepatic arterial chemotherapy eg floxuridine
	Intraductal gallstones[3]
	Viral or bacterial infection eg CMV or cryptosporidiosis
	Caustic injury eg formalin treatment of hydatid disease
	Congenital abnormalities eg cystic fibrosis
Conditions mimicking sclerosing cholangitis on imaging	Malignancy eg metastatic carcinoma
	Hypereosinophilic syndrome
	Choledochal cyst

Table 2 The features of primary sclerosing cholangitis compared with classical autoimmune disease

Characteristic	Classical autoimmune disease	Immune-mediated inflammatory disease (such as IBD, psoriasis)	Primary sclerosing cholangitis
Age	Children and adults	Children and adults	Children and adults
Sex	Female predominance	No gender predilection	Male predominance
Autoantigens	Yes	No	No
Autoantibodies	Yes (pathogenic)	Yes (markers)	Yes (probably markers)
Associated autoimmune disease	Yes	Yes	Yes
HLA associations (class I and II)	Yes	Yes	Yes
Response to immunosuppression	Usually good	Often good	Good in children
			Poor in adults

Table 3 Autoantibody prevalence in primary sclerosing cholangitis

Antibody	Prevalence (%)
Anti-nuclear antibody (ANA)	7-77
Anti-smooth muscle antibody (ASMA)	13-20
Anti-endothelial cell antibody (AECA)	35
Anti-cardiolipin antibody	4-66
Thyroperoxidase	7-16
Thyroglobulin	4
Rheumatoid factor	15

Anti-mitochondrial antibody is only rarely detected in PSC (< 10%). This is useful in differentiating PSC from primary biliary cirrhosis (PBC). Data taken from Angulo et al[12].

Table 4 Key HLA haplotypes in PSC[27]

	HLA haplotypes	Odds ratio
3 HLA haplotypes associated with an increased risk	B8-MICA*008-TNFA*2-DRB3*0101-DRB1*0301-DQB1*0201	2.69
	DRB3*0101-DRB1*1301-DQA1*0103-DQB1*0603	3.8
	MICA*008-DRB5*0101-DRB1*1501-DQA1*0102-DQB1*0602	1.52
3 HLA haplotypes associated with reduced risk (protective)	DRB4*0103-DRB4*0401-DQA1*03-DQB1*0302	0.26
	DRB4*0103-DRB1*0701-DQA1*0201-DQB1*0303	0.15
	MICA*002	0.12

Table 5 Comparison of PSC and AIP-SC

	PSC	AIP-SC
Gender	M:F = 2:1	Probably some male predominance[818587]
Clinical presentation	Usually insidious. Sometimes with obstructive jaundice secondary to cholangiocarcinoma.	Mild abdo/Back pain
		Sometimes with short history of obstructive jaundice due to CBD stricture
Associated inflammatory bowel disease	Yes	No
Cholangiographic findings	Diffuse changes throughout intra- and extrahepatic bile ducts. Abnormalities in pancreatic duct common.	Pancreatic duct strictures or narrowing. Often stricture of distal 1/3 of common bile duct. Intrahepatic duct changes less common.
Blood chemistry data	Often cholestatic but bilirubin usually near normal.	May be cholestatic. Bilirubin often high
Autoantibodies	Atypical pANCA plus range of others	Antibodies to carbonic anhydrase II plus range of others[808184]
Immunoglobulins	IgG4 levels normal	IgG4 levels usually elevated[82]
Histology	Absence of plasma cells positive for IgG4 on immunostaining	IgG4 positive plasma cells present in bile ducts and portal tracts[79]
Liver biopsy staging	Range of Ludwig staging including higher stages eg III or IV	Ludwig staging usually only I or II[86]
Treatment	Ursodeoxycholic acid ± biliary drainage for dominant strictures	Systemic steroid therapy usually leads to complete resolution of symptoms and signs of disease. Occasionally patients relapse and require longer courses of steroids

Table 6 Evidence for the influence of immune mechanisms on the aetiology of PSC

	Evidence for the influence of immune mechanisms
Humoral immunity	Increased circulating immune complexes
	Elevated immunoglobulin levels (IgG and IgM)
	Low titres of non-organ specific autoantibodies (ANA and SMA)
	High titres of antineutrophil nuclear antibody (ANNA)
Cell mediated immunity	Decreased levels of circulating peripheral CD8+ve Tcells
	Portal T cell and NK cell infiltrate
	Increased activated and memory T cells
	Restricted T cell receptor repertoire (Vβ3)
	Aberrant expression of HLA-DR on BEC
	Coexpression of costimulatory molecules and HLA-DR on BECs
	Abnormal expression of adhesion molecules on biliary epithelial cells
	Abnormal expression of chemokine ligands on biliary epithelial cells
Immune effector mechanisms	Enhanced cytokine expression in the liver
Immunogenetic mechanisms	HLA associations