Review of primary sclerosing cholangitis with increased IgG4 levels

Table 4 Features to distinguish primary sclerosing cholangitis with high serum IgG4 from IgG4-related sclerosing cholangitis

				PSC with high IgG4	IgG4-SC
Demographics and history	Gender distribution[46]			Males > Females (7:1)	Males > Females (1.5:1)
	Age distribution[1,44]			< 50 yr	> 60 yr
	Presentation[47-50]			Cholestatic liver biochemistry in patients with IBD. Symptoms of pruritus and fatigue. Jaundice rare (< 5%)	Symptoms of obstructive jaundice, weight loss, abdominal pain. Masses or dysfunction of other organs if systemic disease
	Relationship to IBD[4,51]			Association with IBD, the majority with UC (80%)	Rare association with colitis (5%). Must be in the context of systemic disease
	Pancreatic involvement[52]			Atypical to have co-existent pancreatic disease (< 5%), usually in the context of iatrogenic (azathioprine-induced) acute pancreatitis	Association with autoimmune pancreatitis in the majority (90%-95%)
Laboratory investigations	Autoantibodies[53]			PR3-ANCA present in 40%	No specific autoantibodies
	Serology[18]			Serum IgG4 < equal to 2 × ULN	Serum value of > 5.6 g/L. Serum IgG4:IgG1 ration of > 0.24 has 95% specificity for IgG4-SC. IgG4: IgG RNA ratio. Serum IgE raised in 50% IgG4-SC
	HLA-typing[2,42,54-60]			DRB1*0301, DRB1*1301 and DRB1*1501 in PSC. HLA-B*08 less prevalent in PSC high sIgG4. HLA-B*07 and DRB1*15 more prevalent in PSC high sIgG4	HLA DRB1*0405-DQB1*0401 and HLA-DRB1*0301-DQB1*0201 associated with AIP
Radiology and endoscopy	Cholangiography findings[52,61]			Short band-like strictures, Beaded or prune-tree appearance. Continuous bile duct involvement. CBD wall thickness > 2.5 mm	Long strictures, pre-stenotic bile duct dilation, hilar, intrahepatic and distal CBD involvement, often “skip” lesions
	Cross sectional imaging[36,41,42,47,62,63]			MRCP	Cross-sectional imaging e.g., CT chest abdomen and pelvis or PET-CT to look for masses or fibrosis in other organs
Histology	Hepatobiliary[27,64,65]			(1) Peri-portal sclerosis. And (2)"Onion-skin" fibrosis	(1) Lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells, (2) "Storiform" fibrosis, (3) Obliterative phlebitis, and (4) Eosinophils, variable
	Other organs[42,62,66]			IBD – colitis	Often concurrent masses in other organs e.g., salivary gland, pancreatic. Immunostaining of tissue with IgG4 and IgG; ratio of IgG4:IgG > 40% and IgG4 > 10/HPF
Criteria	Diagnostic Criteria[32,44]			Cholestasis. Abnormal Cholangiogram. High sIgG4. High tIgG4 if biopsy	HISORt for IgG4-SC (Table 3): Histology, imaging, serology, organ involvement, response to steroids
	Moon et al Scoring system[45]			Score of 0-4 PSC. Score 5-6 points, suggest diagnostic steroid trial	Score of 7-9
	Sub-types of disease[5,29,32,50]			Large-duct PSC (classical). Small-duct PSC PSC-AIH overlap	Type 1 IgG4-SC: Distal CBD and pancreas Type 2 IgG4-SC: CHD Type 3 IgG4-SC: CHD with left-right IHD Type 4 IgG4-SC: Hilar
Malignancy	Cancer[7,47]			Increased risk of hepatobiliary malignancy (CCA and gall bladder) and colorectal carcinoma in those with IBD	Increased risk of any malignancy
Management	Treatment[7,29,67]			High-dose corticosteroid trial with biochemical and imaging response can be considered but high-risk side effect. UDCA use controversial: EASL guidelines recommend low-dose (13-15 mg/kg) for chemoprevention role. High-dose (28-30 mg/kg) UDCA toxic in PSC. 3. Liver transplantation	If serology and radiology supportive, with or without histology, and malignancy has been excluded, consider high dose steroid trial for 4 wk e.g., prednisolone 40 mg 2 wk then 30 mg 2 wk and reassess biochemistry and imaging for evidence of response. (1) Corticosteroids first-line (high dose 40 mg 2 wk and taper) with good response in the majority (> 95% with AIP and 2/3 with IgG4-SC). (2) Immunomodulators second line, often azathioprine. And (3) Rituximab for refractory or relapsing disease, and in those with steroid-intolerance
Prognosis		Outcomes[15,19]	Possible rapid progression of disease compared to PSC patients with normal serum IgG4 levels		Excellent response if treated with immunosuppression early before development of fibrotic strictures

AIP: Autoimmune pancreatitis; ALP: Alkaline phosphatase; CBD: Common bile duct; CCA: Cholangiocarcinom; EASL: European Association for the Study of the Liver; IBD: Inflammatory bowel disease; PSC: Primary sclerosing cholangitis; UC: Ulcerative colitis; IgG4-SC: IgG4-related sclerosing cholangitis; MRCP: Magnetic resonance cholangiopancreatography; HLA: Human leukocyte antigen; UDCA: Urseodeoxycholic acid.