Primary sclerosing cholangitis

Last updated: November 30, 2022

Summary

Primary sclerosing cholangitis (PSC) is a progressive chronic inflammation of both the intrahepatic and extrahepatic bile ducts. The exact etiology is unknown but there is a strong association with autoimmune diseases, particularly ulcerative colitis (UC). In the early stages, PSC is often asymptomatic. As the disease progresses, patients may present with right upper quadrant abdominal pain, pruritus, fatigue, and weight loss. Laboratory tests show findings of cholestasis, including elevated alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT). While not recommended for diagnosis, pANCA is positive in up to 80% of cases. Magnetic resonance cholangiopancreatography (MRCP) or endoscopic retrograde cholangiopancreatography (ERCP) is used for diagnostic confirmation. Management is primarily symptomatic, with liver transplantation reserved for end-stage liver disease.

Overview of PSC, PBC, and autoimmune hepatitis

Epidemiology

Sex: : ♂ > ♀ (2:1)
Age: : The median age at diagnosis is ∼ 40.

References:^[1]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

The exact cause is unknown.
Associations
- Chronic inflammatory bowel diseases (IBD)
  - ∼ 90% of patients with PSC have IBD (approx. 87% of these patients have ulcerative colitis) and ∼ 13% have Crohn disease.
  - However, only approx. 5% of patients with UC and < 5% of patients with Crohn disease develop PSC.
- Presence of HLA-B8 and HLA-DR3
- Other autoimmune conditions (e.g., hypergammaglobulinemia IgM)

The majority of patients with PSC also have ulcerative colitis.References:^[1]^[2]

Clinical features

Often initially asymptomatic
Signs of cholestasis
- Jaundice/scleral icterus
- Pruritus
- Pale stool, dark urine
- Fatigue
- Can lead to acute cholangitis (fever, chills, right upper quadrant pain)
Later stages: signs of cirrhosis
- Hepatosplenomegaly
- Portal hypertension
- Liver failure
Symptoms of chronic inflammatory bowel disease, which is frequently associated with PSC, or other associated comorbidities

References:^[2]

Diagnostics

Approach ^[3]^[4]

Suspect PSC in patients with persistently elevated cholestatic enzymes.
Obtain abdominal imaging (e.g., ultrasound) to evaluate for biliary obstruction.
Obtain further studies for diagnostic confirmation.
- No biliary obstruction: MRCP
- Biliary obstruction: therapeutic ERCP
- Consider liver biopsy in select patients.

The diagnosis of PSC is based on persistently elevated cholestatic enzymes, characteristic bile duct strictures seen on MRCP or ERCP, and the exclusion of secondary sclerosing cholangitis. ^[3]

Laboratory studies ^[3]^[4]^[5]

Routine studies

Cholestatic enzymes
- ↑ ALP
- ↑ GGT
- Normal or ↑ conjugated bilirubin
Transaminases: normal or moderately elevated (approx. 2–3× ULN) AST and ALT ^[3]
Lipid profile: ↑ total cholesterol ^[6]
CBC: Thrombocytopenia may be a sign of cirrhosis.

Suspect PSC in patients with a history of inflammatory bowel disease and elevated cholestatic enzymes (ALP, GGT, and conjugated bilirubin).

Serological studies

Findings are typically nonspecific but may help support the diagnosis or differential diagnoses.

Serological studies in patients with suspected PSC ^[3]^[4]
Autoantibodies	Atypical perinuclear anti-neutrophil cytoplasmic antibodies (pANCA): present in up to 80% of patients with PSC. ANAs: present in up to ∼ 75% of patients with PSC ASMAs: presence suggests autoimmune hepatitis Antimitochondrial antibodies: presence supports primary biliary cholangitis
Immunoglobulins	IgM: elevated in ∼ 50% of patients with PSC IgG: elevated in ∼ 60% of patients with PSC IgG4: elevation suggests IgG4-associated cholangitis ^[4]

All patients should be tested for elevated IgG4 at least once, as findings may influence management. ^[3]^[4]

Imaging ^[3]^[4]^[7]

Initial imaging

Obtain abdominal imaging for all patients to evaluate for biliary obstruction.

Modalities: ultrasound, CT scan with contrast, MRI
Supportive findings
- Diffuse thickening of the bile duct walls
- Focal bile duct dilatations
- Possibly gallbladder abnormalities, e.g., thickening, enlargement

Advanced imaging

Obtain for all patients for diagnostic confirmation.

Magnetic resonance cholangiopancreatography
- Method of choice (if there is no biliary obstruction)
- Supportive findings: multifocal intrahepatic and extrahepatic bile duct strictures alternating with dilatation and beading of bile ducts
Endoscopic retrograde cholangiopancreatography
- Should not be used for diagnosis of PSC except in the following scenarios:
  - Need for simultaneous therapeutic intervention for biliary obstruction
  - Contraindications to MRI
- Supportive findings: similar to MRCP

Sclerosing cholangitis in ulcerative colitis Beading of bile ducts in primary sclerosing cholangitis

Liver biopsy ^[4]

Not routinely indicated as part of the workup for PSC
Consider in select patients to evaluate for:
- Small-duct PSC
- Autoimmune hepatitis-PSC overlap syndrome
Finding: concentric periductal onion skin fibrosis (typical but rare)

Pathology

Stage I: inflammatory infiltrate of portal triads and degeneration of the bile duct epithelium
Stage II: periportal inflammation, bridging fibrosis, periportal fibrosis
Stage III: septal fibrosis (from portal triad to another) and bridging necrosis; intrahepatic cholestasis
Stage IV: biliary liver cirrhosis

Differential diagnoses

Differential diagnoses of cholestatic biliary disease
	Primary sclerosing cholangitis	Primary biliary cholangitis	Secondary sclerosing cholangitis ^[8]^[9]
Epidemiology	More common among middle-aged men	More common among middle-aged women	Depends on the underlying condition
Pathophysiology	Progressive chronic inflammation of both intrahepatic and extrahepatic bile ducts	Progressive destruction of only intrahepatic small and medium-sized bile ducts	Develops secondary to an underlying condition, including: Chronic biliary obstruction (e.g., stones, tumors, strictures) Trauma or surgery of the biliary tract Chronic pancreatitis Ischemic injury to the biliary tract (e.g., post-transplantation, critically ill patients) Cholestasis and elevated pressure in intrahepatic bile ducts lead to progressive fibrosis and eventually cirrhosis
Clinical presentation	Pruritus Fatigue Jaundice Hepatomegaly	Similar to PSC Potentially xanthomas and xanthelasma	Similar to PSC Additional symptoms corresponding to the underlying condition Poor prognosis
Laboratory tests	pANCA ↑ ALP, GGT, and conjugated bilirubin	Anti-mitochondrial antibodies (AMA) ↑ ALP, GGT, and conjugated bilirubin	↑ ALP, GGT, and conjugated bilirubin Additional changes corresponding to the underlying condition
Associated conditions	Ulcerative colitis and cholangiocarcinoma	Autoimmune conditions	May lead to ascending cholangitis

Primary sclerosing cholangitis vs. Primary biliary cholangitis

The differential diagnoses listed here are not exhaustive.

Management

General principles ^[3]^[4]

Management is primarily supportive and includes:
- Management of cholestasis-associated pruritus, e.g., with cholestyramine
- Interventional treatment as needed to relieve obstructions
- Monitoring for commonly associated conditions and complications
No medications currently prevent disease progression (e.g., reduced time to liver transplantation). ^[10]
Liver transplantation is the only curative treatment but has a significant risk of disease recurrence.

Pharmacological management ^[3]^[4]^[5]

Ursodeoxycholic acid (UDCA)
- Widely used, but evidence of benefit is mixed. ^[3]^[4]
- May decrease transaminases, ALP, and serum bilirubin
Immunosuppressants (e.g., glucocorticoids); usually reserved for patients with overlap syndromes: ^[3]^[4]
- IgG4-associated cholangitis
- Autoimmune hepatitis-PSC overlap syndrome

Interventional treatment ^[3]^[4]^[5]

Perform as needed in patients with relevant strictures. ^[3]

ERCP with dilation of stenoses
- Indications
  - To relieve symptoms caused by stenosis, e.g., pruritus and/or cholangitis
  - To exclude cholangiocarcinoma
- Stenting may be necessary for severe strictures.
- Provide prophylactic antibiotics to prevent post-ERCP cholangitis .
Percutaneous cholangiography
- Indication: patients who cannot undergo ERCP
- Requires placement of a percutaneous drain

Patients with PSC are at increased risk for post-ERCP cholangitis. ^[4]

Liver transplantation ^[4]^[11]

Refer patients with decompensated cirrhosis and a MELD score > 14.
Additional MELD points may be offered to patients with:
- Recurrent cholangitis with recurrent bacteremia (> 2 episodes) or sepsis (> 1 episode)
- Cholangiocarcinoma < 3 cm in diameter without metastasis
- Intractable pruritus

Screening and monitoring ^[3]^[4]^[7]

Patients with PSC are at increased risk of IBD, progression of liver disease to cirrhosis, osteoporosis, and malignancy.

Screening and monitoring of complications and comorbidities in PSC ^[3]^[4]^[7]
		Modalities	Timing
Inflammatory bowel disease		Ileocolonoscopy	At time of PSC diagnosis, then: Every 1–2 years in patients with IBD Consider every 3–5 years in patients without IBD. ^[4]
Colorectal carcinoma		Ileocolonoscopy
Cholangiocarcinoma		Abdominal ultrasound or MRI Possibly serum CA 19-9 measurements ^[4]	Annually
Gallbladder carcinoma		Abdominal ultrasound	Annually
Progression of liver disease		Liver chemistries Coagulation studies Fibrosis staging with transient elastography or MR elastography Screening for fat-soluble vitamin deficiencies	Obtain at diagnosis then regularly.
Osteoporosis		BMD testing	Screening for osteoporosis at PSC diagnosis and every 2–4 years thereafter ^[4]^[11]
Complications of cirrhosis ^[12]	Hepatocellular carcinoma	Abdominal ultrasound.	Every 6 months
Complications of cirrhosis ^[12]	Esophageal varices	EGD	At cirrhosis diagnosis Then every 2–3 years

Patients with both PSC and UC have a 4–5 times higher risk of developing colorectal dysplasia or cancer than those with UC alone. ^[4]^[11]

Complications

Steatorrhea and deficiency of fat-soluble vitamins
Liver cirrhosis
Bacterial cholangitis
Malignancy
- Cholangiocarcinoma (∼ 10–15% of cases) ^[7]
- Gallbladder carcinoma
- Colorectal carcinoma ^[7]^[13]
- Hepatocellular carcinoma ^[7]
- Pancreatic carcinoma

We list the most important complications. The selection is not exhaustive.

Prognosis

Five-year survival rate after liver transplantation: ∼ 85% ^[14]

References

Abdalian R, Heathcote EJ. Sclerosing cholangitis: A focus on secondary causes. Hepatology. 2006; 44 (5): p.1063-1074.doi: 10.1002/hep.21405 . | Open in Read by QxMD
Ruemmele P, Hofstaedter F, Gelbmann CM. Secondary sclerosing cholangitis. Nature Reviews Gastroenterology & Hepatology. 2009; 6 (5): p.287-295.doi: 10.1038/nrgastro.2009.46 . | Open in Read by QxMD
Kowdley KV. Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/primary-sclerosing-cholangitis-in-adults-clinical-manifestations-and-diagnosis. Last updated: January 4, 2016. Accessed: December 26, 2016.
Kowdley KV. Primary sclerosing cholangitis: Epidemiology and pathogenesis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/primary-sclerosing-cholangitis-epidemiology-and-pathogenesis. Last updated: January 13, 2015. Accessed: December 26, 2016.
Lindor KD, Kowdley KV, Harrison EM. ACG Clinical Guideline: Primary Sclerosing Cholangitis. Am J Gastroenterol. 2015; 110 (5): p.646-659.doi: 10.1038/ajg.2015.112 . | Open in Read by QxMD
Bowlus CL, Arrivé L, Bergquist A, et al. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology. 2022.doi: 10.1002/hep.32771 . | Open in Read by QxMD
Prokopič M, Beuers U. Management of primary sclerosing cholangitis and its complications: an algorithmic approach. Hepatol Int. 2020; 15 (1): p.6-20.doi: 10.1007/s12072-020-10118-x . | Open in Read by QxMD
Lazaridis KN, LaRusso NF. Primary Sclerosing Cholangitis. N Engl J Med. 2016; 375 (12): p.1161-1170.doi: 10.1056/nejmra1506330 . | Open in Read by QxMD
Chapman R, Fevery J, Kalloo A, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology. 2010; 51 (2): p.660-678.doi: 10.1002/hep.23294 . | Open in Read by QxMD
Gochanour E, Jayasekera C, Kowdley K. Primary Sclerosing Cholangitis: Epidemiology, Genetics, Diagnosis, and Current Management. Clin Liver Dis (Hoboken). 2020.
Lemoinne S, Thabut D. Screening for esophageal varices.. Clin liver dis. 2012; 1 (5): p.143-146.doi: 10.1002/cld.101 . | Open in Read by QxMD
Jorgensen RA, Lindor KD, Sartin JS, LaRusso NF, Wiesner RH. Serum Lipid and Fat-Soluble Vitamin Levels in Primary Sclerosing Cholangitis. J Clin Gastroenterol. 1995; 20 (3): p.215-219.doi: 10.1097/00004836-199504000-00011 . | Open in Read by QxMD
Diagnosis and Management of Primary Sclerosing Cholangitis. https://www.aasld.org/sites/default/files/2019-06/PrimarySclerosingCholangitis2010.pdf. Updated: August 31, 2009. Accessed: January 13, 2021.
Ponsioen C. Diagnosis, prognosis, and management of primary sclerosing cholangitis. Gastroenterology & Hepatology. 2013; 9 (7): p.453-65.

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