Primary Sclerosing Cholangitis

Definition and EtiologyTop

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease related to chronic inflammation with fibrosis and strictures. It leads to damage and narrowing of intrahepatic and extrahepatic bile ducts.

Clinical Features and Natural HistoryTop

PSC is asymptomatic in 15% to 45% of patients. Signs and symptoms include chronic fatigue, pruritus, weight loss, and symptoms of recurrent cholangitis (episodes of jaundice, fever, and right upper abdominal quadrant pain). Clinical examination reveals jaundice of the skin and mucous membranes as well as scratch marks. In advanced stages symptoms of cirrhosis and its complications may be seen. Ulcerative colitis or less commonly Crohn disease coexists in ~70% of patients. Other frequent comorbidities include pancreatitis (10%-25%), diabetes mellitus (5%-15%), and other autoimmune diseases. Within 10 to 15 years of diagnosis, >50% of patients require liver transplant.

DiagnosisTop

Diagnostic Tests

1. Laboratory tests:

1) Blood biochemical tests: Elevated serum alkaline phosphatase (ALP) levels and/or gamma-glutamyl transferase (GGT) levels (usually 3-10 × upper limit of normal [ULN]), as well as elevated serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels (usually 2-4 × ULN), serum bilirubin levels (although in ~60% of patients bilirubin levels are normal at diagnosis), and hypergammaglobulinemia (elevated IgG and IgM levels in 45%-80% of patients).

2) Immunologic studies: Positive antinuclear antibody (ANA) and smooth muscle antibody (SMA) (in 20%-50% of patients) as well as perinuclear antineutrophil cytoplasmic antibody (p-ANCA) (30%-80%).

2. Magnetic resonance cholangiopancreatography (MRCP) is the practical diagnostic gold standard, as it has comparable accuracy to endoscopic retrograde cholangiopancreatography (ERCP), is less invasive, and results in cost savings when used as the initial test strategy for diagnosing PSC.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of some data. Lindor KD, Kowdley KV, Harrison ME; American College of Gastroenterology. ACG Clinical Guideline: Primary Sclerosing Cholangitis. Am J Gastroenterol. 2015 May;110(5):646-59; quiz 660. doi: 10.1038/ajg.2015.112. Epub 2015 Apr 14. PMID: 25869391. Talwalkar JA, Angulo P, Johnson CD, Petersen BT, Lindor KD. Cost-minimization analysis of MRC versus ERCP for the diagnosis of primary sclerosing cholangitis. Hepatology. 2004 Jul;40(1):39-45. PMID: 15239084. Berstad AE, Aabakken L, Smith HJ, Aasen S, Boberg KM, Schrumpf E. Diagnostic accuracy of magnetic resonance and endoscopic retrograde cholangiography in primary sclerosing cholangitis. Clin Gastroenterol Hepatol. 2006 Apr;4(4):514-20. PMID: 16616358. It reveals typical strictures with downstream dilatation of the bile ducts; the strictures may be found both in intrahepatic and extrahepatic bile ducts.

3. ERCP is an invasive test. It should be performed only if the diagnosis cannot be confirmed by MRCP or in clinical situations that require immediate therapeutic intervention (sphincterotomy, biliary stenting) and collection of cytologic specimens because of suspected cholangiocarcinoma.Evidence 2Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of some data. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009 Aug;51(2):237-67. doi: 10.1016/j.jhep.2009.04.009. Epub 2009 Jun 6. PubMed PMID: 19501929. Lindor KD, Kowdley KV, Harrison ME; American College of Gastroenterology. ACG Clinical Guideline: Primary Sclerosing Cholangitis. Am J Gastroenterol. 2015 May;110(5):646-59; quiz 660. doi: 10.1038/ajg.2015.112. Epub 2015 Apr 14. PMID: 25869391. Angulo P, Pearce DH, Johnson CD, et al. Magnetic resonance cholangiography in patients with biliary disease: its role in primary sclerosing cholangitis. J Hepatol. 2000 Oct;33(4):520-7. PMID: 11059855.

4. Liver biopsy is indicated if small-duct PSC is suspected (this variant cannot be confirmed by imaging studies), if autoimmune hepatitis overlaps with PSC and diagnosis based on MRCP or ERCP is uncertain, and in patients with clinically suspected cirrhosis (confirmation of advanced fibrosis has significant clinical implications).

Diagnostic Criteria

Typical features of bile ducts consistent with PSC found on ERCP or MRCP. If results of these studies are normal and clinical features suggest PSC, perform histologic examination of liver biopsy specimens (in patients with histologic features typical for PSC, a PSC variant involving only the fine bile ducts is diagnosed).Evidence 3Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational/retrospective nature of data. Burak KW, Angulo P, Lindor KD. Is there a role for liver biopsy in primary sclerosing cholangitis? Am J Gastroenterol. 2003 May;98(5):1155-8. PMID: 12809842. Lindor KD, Kowdley KV, Harrison ME; American College of Gastroenterology. ACG Clinical Guideline: Primary Sclerosing Cholangitis. Am J Gastroenterol. 2015 May;110(5):646-59; quiz 660. doi: 10.1038/ajg.2015.112. Epub 2015 Apr 14. PMID: 25869391.

Differential Diagnosis

Cholangitis caused by IgG4 antibodies (a manifestation of IgG4-related disease), other chronic liver diseases with cholestasis (eg, primary biliary cholangitis, vanishing bile duct syndrome, eosinophilic cholangitis), secondary sclerosing cholangitis (eg, due to iatrogenic injury of bile ducts or their vasculature), congenital bile duct abnormalities (eg, Alagille syndrome: hypoplasia of intrahepatic bile ducts; Caroli disease: cystic dilatation of intrahepatic bile ducts), infective cholangiopathies (eg, in patients with AIDS or infestation with Clonorchis sinensis [the Chinese liver fluke]).

TreatmentTop

Pharmacotherapy

1. Oral ursodiol (INN ursodeoxycholic acid) 13 to 15 mg/kg/d; ursodiol is not routinely recommended, its effects on clinically important outcomes are unclear, and it may be harmful in higher doses.Evidence 4Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to some heterogeneity among mostly observational studies. Saffioti F, Gurusamy KS, Hawkins N, et al. Pharmacological interventions for primary sclerosing cholangitis: an attempted network meta-analysis. Cochrane Database Syst Rev. 2017 Mar 28;3:CD011343. doi: 10.1002/14651858.CD011343.pub2. PMID: 28417463. Lindor KD, Kowdley KV, Harrison ME; American College of Gastroenterology. ACG Clinical Guideline: Primary Sclerosing Cholangitis. Am J Gastroenterol. 2015 May;110(5):646-59; quiz 660. doi: 10.1038/ajg.2015.112. Epub 2015 Apr 14. PMID: 25869391. Martin P, DiMartini A, Feng S, Brown R Jr, Fallon M. Evaluation for liver transplantation in adults: 2013 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Hepatology. 2014 Mar;59(3):1144-65. PMID: 24716201. Eaton JE, Silveira MG, Pardi DS, et al. High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol. 2011 Sep;106(9):1638-45. doi: 10.1038/ajg.2011.156. Epub 2011 May 10. PMID: 21556038; PMCID: PMC3168684.

2. Treatment of pruritus.

3. Prevention and treatment of osteoporosis.

Invasive Treatment

1. Endoscopic treatment: In patients with dominant biliary duct stenosis, endoscopic balloon dilatation and stenting of the biliary ducts may be performed (the success rate is 60%-90%).Evidence 5Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational/retrospective nature of data. Chapman R, Fevery J, Kalloo A, et al; American Association for the Study of Liver Diseases. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010 Feb;51(2):660-78. doi: 10.1002/hep.23294. PMID: 20101749. May GR, Bender CE, LaRusso NF, Wiesner RH. Nonoperative dilatation of dominant strictures in primary sclerosing cholangitis. AJR Am J Roentgenol. 1985 Nov;145(5):1061-4. PMID: 3876737. Gluck M, Cantone NR, Brandabur JJ, Patterson DJ, Bredfeldt JE, Kozarek RA. A twenty-year experience with endoscopic therapy for symptomatic primary sclerosing cholangitis. J Clin Gastroenterol. 2008 Oct;42(9):1032-9. doi: 10.1097/MCG.0b013e3181646713. PMID: 18580600.

2. Liver transplant: Indications include recurrent episodes of acute cholangitis, no improvement after pharmacologic and endoscopic treatment of advanced biliary duct stenosis, features of end-stage liver failure refractory to medical treatment, and refractory pruritus. In such situations liver transplant may be the only effective therapeutic option for patients with very advanced primary sclerosing cholangitis and should be explored.Evidence 6Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the lack of experimental data. de Vries EM, Wang J, Williamson KD, et al. A novel prognostic model for transplant-free survival in primary sclerosing cholangitis. Gut. 2018 Oct;67(10):1864-1869. doi: 10.1136/gutjnl-2016-313681. Epub 2017 Jul 24. PMID: 28739581. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009 Aug;51(2):237-67. doi: 10.1016/j.jhep.2009.04.009. Epub 2009 Jun 6. PMID: 19501929. LaRusso NF, Shneider BL, Black D, et al. Primary sclerosing cholangitis: summary of a workshop. Hepatology. 2006 Sep;44(3):746-64. Review. PMID: 16941705. Five-year survival rates in patients treated with liver transplant are ~80%. Patients after transplant may have recurrences of PSC in the transplanted liver.

ComplicationsTop

1. Increased risk of malignancy: Cholangiocarcinoma (in 10%-20% of patients), hepatocellular carcinoma (risk increased in patients with cirrhosis), pancreatic cancer (risk 14 times higher than in the general population), colorectal cancer (PSC additionally increases the risk associated with ulcerative colitis), gallbladder cancer (in 2% of patients).

2. Episodes of acute cholangitis (see Acute Cholangitis).