Review of primary sclerosing cholangitis with increased IgG4 levels

Table 1 Studies evaluating serum IgG4 in primary sclerosing cholangitis patients

Ref.	Study design	Location	No. of PSC patients	Percentage (%) with high serum IgG4	Key findings in PSC high IgG4
Mendes et al[15], 2006	Retrospective case control study	United States	127	9%	Higher bilirubin, ALP and PSC Mayo risk score, lower IBD and shorter time to liver transplantation
Zhang et al[16], 2010	Retrospective cohort study	United States	81	22%	Serum IgG4 levels correlated with tissue IgG4 infiltration in liver explants
Bjornsson et al[17], 2011	Retrospective cohort study with prospective follow-up of PSC high serum IgG4	Sweden	285	12%	Presented with jaundice, both intra and extra hepatic strictures, and pancreatic disorders. 50% had cirrhosis. Biochemical response to steroids (n = 12/18). Steroid side effects (39%)
Alswat et al[18], 2012	Retrospective cohort study	Canada	101	22%	Male gender, High ALP, High PSC Mayo Risk Score, Pancreatitis, Previous biliary intervention, Abnormal pancreatic imaging
Culver et al[19], 2012	Retrospective cohort study with prospective follow-up of PSC high and normal IgG4	United Kingdom	194	14%	14% of 186 patients. Worse clinical outcome including liver transplantation and progression of liver disease
Parhizkar et al[20], 2013	Retrospective cross-sectional study	Iran	34	26.5%	Male and non-smokers. No outcome differences
Navaneethan et al[21], 2013	Retrospective cohort study	United States	50	20%	Elevated serum IgG4 associated with reduced colectomy-free survival in PSC-UC. Shorter time to colectomy from diagnosis of PSC, median time 5 yr (high IgG4) v 12 yr (normal IgG4) P = 0.01
Benito de Valle et al[22], 2014	Retrospective multi-centre (2) cohort study	Sweden and Germany	345	10%	History of pancreatitis combined intrahepatic and extra hepatic biliary involvement, and jaundice. No increased risk of liver transplantation, death or CCA
Taghavi et al[23], 2016	Retrospective cohort study	Iran	73	16%	Higher prevalence of ascites. No clinical outcome differences
Tanaka et al[24], 2017	Questionnaire‐based, multi‐centre, retrospective cohort study	Japan	216	12.5%	Overall mortality and liver transplantation-free survival rate was not different
Muir et al[25], 2018	Phase 2b, dose-ranging, randomized, double-blind, and placebo-controlled study	Northern United States and Europe (61 sites)	234	15%	No difference in fibrosis and progression to cirrhosis in groups stratified by IgG4 level at recruitment

ALP: Alkaline phosphatase; IBD: Inflammatory bowel disease; PSC: Primary sclerosing cholangitis; UC: Ulcerative colitis.

Table 2 Studies evaluating abundant tissue IgG4-positive plasma cells in primary sclerosing cholangitis patients

Ref.	Study design	Location	PSC patients’ number	Percentage (%) with abundant tissue IgG4	Key findings in PSC high IgG4
Koyabu et al[28], 2010	Case series	Japan	3	Biopsy. 2/3 (> 10/HPF)	Infiltration of IgG4-positive plasma cells in portal area of the liver. No improvement in strictures after steroid therapy.
Zhang et al[16], 2010	Retrospective cohort study with paired serum and liver explant tissue	United States	98	Liver explants. 23% (> 10 /HPF)	Shorter time to transplant. More non-cirrhotic at transplant. Higher likelihood of recurrence.
Zen et al[26], 2011	Retrospective cohort study	United Kingdom	41	29% (> 10/HPF). 5% (> 100 /HPF)	Bile duct erosion and xanthogranulomatous reaction.
Fischer et al[27], 2014	Retrospective cohort study	Canada	122	16% (> 50/HPF)	Marked hilar staining significantly associated with dominant biliary strictures and need for biliary stenting. No differences in outcome.

HPF: High power field; PSC: Primary sclerosing cholangitis.

Table 3 HISORt Criteria for IgG4-related sclerosing cholangitis (Adapted from references[32,44])

Histology (Criterion H)	Lymphoplasmacytic infiltrate with > 10 IgG4+ cells per high‐power field within and around bile ducts; obliterative phlebitis; storiform fibrosis
Imaging (Criterion I)	Strictures of the biliary tree including intrahepatic ducts, proximal extra-hepatic ducts, intra-pancreatic ducts; fleeting and migrating biliary strictures
Serology (Criterion S)	Raised serum IgG4 levels (> 1.35 g/L)
Organ involvement (Criterion O)	Extra-biliary manifestations consistent with IgG4-RD, such as: pancreas (focal pancreatic mass/enlargement without pancreatic duct dilatation, multiple pancreatic masses, focal pancreatic duct stricture without upstream dilatation, pancreatic atrophy); retroperitoneal fibrosis; kidney (single or multiple parenchymal low‐attenuation lesions: Round, wedge‐shaped, or diffuse patchy); salivary or lacrimal gland (enlargement)
Response to treatment (Criterion R)	Normalisation of liver enzymes and at least partial stricture resolution after steroid treatment

Definite IgG4-SC: Patient meets criterion H or Criterion S with Criterion I; Probable IgG4-SC: Patient meets 2 of the following criteria: Criterion S, Criterion O, partially meets criterion H, partially meets criterion I. Patients with probable diagnosis can proceed to trial of corticosteroids. If they then meet criterion R, then the diagnosis becomes definite. IgG4-RD: IgG4-related disease; IgG4-SC: IgG4-related sclerosing cholangitis

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.