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Primary sclerosing cholangitis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Synonyms and keywords: PSC; primary sclerosing cholangitis

Overview

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Overview

Primary sclerosing cholangitis is a relatively rare disease with a progressive nature, characterized by the development of fibrosis and strictures within the intrahepatic and extrahepatic bile ducts. The incidence ranges from 0 to 1.3 per 100,000 cases and prevalence from 0 to 16.2 per 100,000 cases. The disease primarily affects young adult males and the mean age at diagnosis is 41 years. The pathophysiology of primary sclerosing cholangitis is not fully understood, although it is thought to be the result of a combination of genetic as well as environmental factors. The risk of primary sclerosing cholangitis among siblings is estimated to be 9-39 times higher than the general population. The HLA locus on chromosome 6p21 and genes of the IL-2 pathway are associated with increased susceptibility to the development of primary sclerosing cholangitis. Environmental factors associated with increased risk of primary sclerosing cholangitis include exposure to farm animals during childhood and other dietary habits, such as less consumption of coffee and fish than controls. Smoking seems to be a protective factor against the development of primary sclerosing cholangitis. The majority of patients with primary sclerosing cholangitis are asymptomatic and are only diagnosed following abnormal liver function tests. However, those who are symptomatic often present with nonspecific symptoms, such as fever, fatigue, abdominal pain and/or diarrhea, as well as yellowish discoloration of the skin and mucous membranes. The workup in these patients consists of LFTs, serum immunoglobulins, as well as a number of autoantibodies. Patients with primary sclerosing cholangitis typically have an elevated level of ALP, amongst other findings. However, laboratory results in many patients may be normal. ERCP was considered the gold standard for diagnosis of primary sclerosing cholangitis, because it allows visualization of the biliary tree. However, MRCP is now preferred because of its non-invasive nature. Findings on these imaging modalities include alternating areas of strictures and dilatations of the intrahepatic and extra hepatic bile ducts. Liver transplantation is the gold standard for treatment of primary sclerosing cholangitis and there is no effective medical treatment. Ursodeoxycholic acid has been studied as a treatment for the disease. However, there is no proof for its benefit and the American College of Gastroenterology does not support its use in patients with primary sclerosing cholangitis. Unfortunately, there is no screening for primary sclerosis cholangitis and the prognosis is somewhat poor, even with liver transplantation.

Historical Perspective

Due to the rarity of the disease, primary sclerosing cholangitis has not been well studied in the past and cases were reported as individual cases. The first case of primary sclerosing cholangitis was documented in 1924.

Classification

Primary sclerosing cholangitis may be classified according to the size of bile ducts involved, as well as its association with autoimmune hepatitis. The 3 main subtypes are the classic subtype, small ducts subtype and primary sclerosing cholangitis associated with autoimmune hepatitis.

Pathophysiology

 The pathophysiology of primary sclerosing cholangitis is not fully understood, although it is thought to be the result of a combination of genetic as well as environmental factors. The risk of primary sclerosing cholangitis among siblings is estimated to be 9-39 times higher than the general population. The HLA locus on chromosome 6p21 and genes of the IL-2 pathway are associated with increased susceptibility to the development of primary sclerosing cholangitis. Environmental factors associated with increased risk of primary sclerosing cholangitis include exposure to farm animals during childhood and other dietary habits, such as less consumption of coffee and fish than controls. Smoking seems to be a protective factor against the development of primary sclerosing cholangitis.

Causes

The cause of primary sclerosing cholangitis is unclear and not fully understood. However, genetic and environmental factors are thought to contribute to the development of the disease.

Differentiating primary sclerosing cholangitis from Other Diseases

Primary sclerosing cholangitis must be differentiated from causes of secondary sclerosing cholangitis.

Epidemiology and Demographics

Primary sclerosing cholangitis is a relatively rare disease, with the incidence ranging from 0 to 1.3 per 100,000 cases and prevalence of 0 to 16.2 per 100,000 cases. The disease primarily affects young adult males and the mean age at diagnosis is 41 years.

Risk Factors

The most important risk factors associated with primary sclerosing cholangitis include family history and personal history of IBD.

Screening

There are no screening recommendations for primary sclerosing cholangitis.

Natural History, Complications, and Prognosis

Primary sclerosing cholangitis is a progressive disease that often results in death from complications of liver failure, liver transplantation or associated carcinomas. Even with liver transplantation, there is a substantial risk of recurrence of the disease. Complications of primary sclerosing cholangitis include osteoporosis, cholangiocarcinoma and liver failure.

Diagnosis

History and Symptoms

The majority of patients with primary sclerosing cholangitis are asymptomatic and are only diagnosed following an abnormal liver function tests. However, those who are symptomatic often present with nonspecific symptoms, such as fever, fatigue, abdominal pain and/or diarrhea, as well as yellowish discoloration of the skin and mucous membranes.

Physical Examination

Some of the physical examination findings in primary sclerosing cholangitis include hepatomegaly, splenomegaly, ascites, jaundice and fever.

Laboratory Findings

The workup in patients with primary sclerosing cholangitis consists of LFTs, serum immunoglobulins, as well as a number of autoantibodies. Patients with primary sclerosing cholangitis typically have an elevated level of ALP, amongst other findings. However, laboratory results in many patients may be normal.

Electrocardiogram

There are no ECG findings associated with primary sclerosing cholangitis.

X Ray

There are no x-ray findings associated with primary sclerosing cholangitis.

CT Scan

A CT scan of the abdomen is not routinely done as part of the workup for primary sclerosing cholangitis and findings are non-specific. However, findings include: mass lesions, evidence of portal hypertension, such as ascites, splenomegaly and varices, thickening of the bile ducts and bile duct dilatations and abdominal lymphadenopathy.

MRI

In primary sclerosing cholangitis, MRCP rather than standard MRI is used for diagnosis.

Ultrasound

Ultrasound may be done as part of the workup for primary sclerosing cholangitis. However, findings are nonspecific, non-diagnostic and may even be normal. However, approximately 40% of patients have associated gallbladder abnormalities, which may be identified on an abdominal ultrasound. These include thickening of the gallbladder wall, gallbladder enlargement, gallbladder stones (cholelithiasis) and masses and other findings suggestive of cholecystitis.

Other Imaging Findings

ERCP was considered the gold standard for diagnosis of primary sclerosing cholangitis, because it allows visualization of the biliary tree. However, MRCP is now preferred because of its non-invasive nature. Findings on these imaging modalities include alternating areas of strictures and dilatations of the intrahepatic and extra hepatic bile ducts.

Other Diagnostic Studies

A liver biopsy may be performed in patients with primary sclerosing cholangitis, although it is not necessary for diagnosis. The pathognomonic finding of periductal onion-skin fibrosis is rarely seen. However, a liver biopsy may be useful when the small ducts subtype of the primary sclerosing cholangitis or that associated with autoimmune hepatitis are suspected.

Treatment

Medical Therapy

Liver transplantation is the gold standard for treatment of primary sclerosing cholangitis and there is no effective medical treatment. Ursodeoxycholic acid has been studied as a treatment for the disease. However, there is no proof for its benefit and the American College of Gastroenterology does not support its use in patients with primary sclerosing cholangitis.

Surgery

Primary sclerosing cholangitis is a progressive disease that ultimately leads to end-stage liver disease (ESLD). Endoscopic management can be targeted for dominant strictures or as palliative treatment. However, current gold standard of treatment for primary sclerosing cholangitis is liver transplantation. Despite liver transplantation, disease may still recur in 25% of patients.

Primary Prevention

There are no primary preventive measures for primary sclerosing cholangitis.

Secondary Prevention

Secondary prevention in patients with primary sclerosing cholangitis is aimed at screening for complications and coexisting conditions in these patients. These include screening for complications of liver cirrhosis, screening for colon and gallbladder cancers, as well as metabolic bone disease.

References


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Historical Perspective

Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Overview

Due to the rarity of the disease, primary sclerosing cholangitis has not been well studied in the past and cases were reported as individual cases. The first case of primary sclerosing cholangitis was documented in 1924.

Historical Perspective

The following gives a historical perspective on primary sclerosing cholangitis:[1][2]

  • In 1877, Dr. Jean-Martin Charcot at the Salpêtrière hospital in Paris, France was the first to describe cholangitis as a triad of three symptoms: pain, fever, and jaundice.
  • In 1924 the first case of primary sclerosing cholangitis was reported, followed by another case in 1925. Since the disease is rare, cases of primary sclerosing cholangitis were reported as individual cases.
  • In 1971, the first review article on primary sclerosing cholangitis was published.

References

  1. ↑ Tinckler L (1971). “Primary sclerosing cholangitis”. Postgrad Med J. 47 (552): 666–70. PMC 2467318. PMID 4947701.
  2. ↑ Kumar DR, Aslinia F, Yale SH, Mazza JJ (2011). “Jean-Martin Charcot: the father of neurology”. Clin Med Res. 9 (1): 46–9. doi:10.3121/cmr.2009.883. PMC 3064755. PMID 20739583.

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de:Cholangitis sv:Primär skleroserande kolangit


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Classification

Classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Overview

Primary sclerosing cholangitis may be classified according to the size of bile ducts involved, as well as its association with autoimmune hepatitis. The three main subtypes are the classic subtype, small ducts subtype, and primary sclerosing cholangitis associated with autoimmune hepatitis.

Classification

Primary sclerosing cholangitis may be divided into 3 subtypes, according to the type of ducts involved, as well as its association with autoimmune hepatitis:[1][2][3][4]

Subtype Ducts Involved Diagnostic Procedure Histopathology
Classic Small and large bile ducts MRCP, ERCP Mixed inflammatory cells around bile ducts; nonspecific and nondiagnostic finding
Small duct Small bile ducts only Liver biopsy Mixed inflammatory cells around bile ducts; nonspecific and nondiagnostic finding
Associated with autoimmune hepatitis Small and large bile ducts MRCP, ERCP Lymphoplasmacytic infiltrate, associated with interface hepatitis

References

  1. ↑ Lazaridis KN, LaRusso NF (2016). “Primary Sclerosing Cholangitis”. N. Engl. J. Med. 375 (12): 1161–70. doi:10.1056/NEJMra1506330. PMID 27653566.
  2. ↑ Angulo P, Maor-Kendler Y, Lindor KD (2002). “Small-duct primary sclerosing cholangitis: a long-term follow-up study”. Hepatology. 35 (6): 1494–500. doi:10.1053/jhep.2002.33202. PMID 12029635.
  3. ↑ Feldstein AE, Perrault J, El-Youssif M, Lindor KD, Freese DK, Angulo P (2003). “Primary sclerosing cholangitis in children: a long-term follow-up study”. Hepatology. 38 (1): 210–7. doi:10.1053/jhep.2003.50289. PMID 12830004.
  4. ↑ Kaya M, Angulo P, Lindor KD (2000). “Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system”. J. Hepatol. 33 (4): 537–42. PMID 11059857.

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Pathophysiology

Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Overview

The pathophysiology of primary sclerosing cholangitis is not fully understood, although it is thought to be the result of a combination of genetic as well as environmental factors. The risk of primary sclerosing cholangitis among siblings is estimated to be 9-39 times higher than the general population. The HLA locus on chromosome 6p21 and genes of the IL-2 pathway are associated with increased susceptibility to the development of primary sclerosing cholangitis. Environmental factors associated with increased risk of primary sclerosing cholangitis include exposure to farm animals during childhood and other dietary habits, such as less consumption of coffee and fish than controls. Smoking seems to be a protective factor against the development of primary sclerosing cholangitis.

Pathophysiology

Pathogenesis

The pathophysiology of primary sclerosing cholangitis is not fully understood, although it is thought to be the result of a combination of genetic as well as environmental factors.[1]

Environmental Factors

The following environmental factors may be protective or associated with an increased risk of developing primary sclerosing cholangitis:[1]

  • Smoking:
  • Dietary habits:
    • Patients with primary sclerosing cholangitis seem less likely to consume coffee,[2][3] and fish than controls, but more well-done steak and hamburgers.[4]
  • Exposure to farm animals:
    • Patients with primary sclerosing cholangitis were more likely to be exposed to farm animals, but not domestic animals, during their childhood.[2]
  • Use of contraceptive hormones in female patients:
    • Female patients with primary sclerosing cholangitis were less likely to have used contraceptive hormones when compared to female controls.[2]

Genetics

  • Primary sclerosing cholangitis is associated with environmental as well as genetic factors.
  • The risk of primary sclerosing cholangitis among siblings is estimated to be 9-39 times higher than the general population.[5]
  • The HLA-A1, B8, and DR3 locus on chromosome 6p21[6] and genes of the IL-2 pathway[7][8] are associated with increased susceptibility to the development of primary sclerosing cholangitis.
  • In addition, the following 16 gene loci are associated with increased risk of primary sclerosing cholangitis.[6][7][8]
Locus Gene
1p36 MMEL1
2q13 BCL2L11
2q33 CD28
2q37 GPR35
3p21 MST1
4q27 IL2 / IL21
6p21 HLA B
6q15 BACH2
10p15 IL2RA
11q23 SIK2
12q13 HDAC7
12q24 SH2B3
18q21 TCF4
18q22 CD226
19q13 PRKD2
21q22 PSMG1 / ETS2

Associated Conditions

Some of the conditions associated with primary sclerosing cholangitis include:[1][9]

Microscopic Pathology

Histology of primary sclerosing cholangitis (40X) showing inflamed bands [green arrows] and a rare scar at the edge of a triad [black arrow]([ Source: By TexasPathologistMSW (Own work) [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons])
Histology of primary sclerosing cholangitis showing periductal fibrosis [green arrows] and piecemeal necrosis [blue arrow]([ Source: By TexasPathologistMSW (Own work) [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons])

References

  1. ↑ 1.0 1.1 1.2 Lazaridis KN, LaRusso NF (2016). “Primary Sclerosing Cholangitis”. N. Engl. J. Med. 375 (12): 1161–70. doi:10.1056/NEJMra1506330. PMID 27653566.
  2. ↑ 2.0 2.1 2.2 2.3 Andersen IM, Tengesdal G, Lie BA, Boberg KM, Karlsen TH, Hov JR (2014). “Effects of coffee consumption, smoking, and hormones on risk for primary sclerosing cholangitis”. Clin. Gastroenterol. Hepatol. 12 (6): 1019–28. doi:10.1016/j.cgh.2013.09.024. PMID 24076415.
  3. ↑ Lammert C, Juran BD, Schlicht E, Xie X, Atkinson EJ, de Andrade M, Lazaridis KN (2014). “Reduced coffee consumption among individuals with primary sclerosing cholangitis but not primary biliary cirrhosis”. Clin. Gastroenterol. Hepatol. 12 (9): 1562–8. doi:10.1016/j.cgh.2013.12.036. PMC 4101072. PMID 24440215.
  4. ↑ Eaton JE, Juran BD, Atkinson EJ, Schlicht EM, Xie X, de Andrade M, Lammert CS, Luketic VA, Odin JA, Koteish AA, Kowdley KV, Chopra KB, Hirschfield GM, Chalasani NP, Lazaridis KN (2015). “A comprehensive assessment of environmental exposures among 1000 North American patients with primary sclerosing cholangitis, with and without inflammatory bowel disease”. Aliment. Pharmacol. Ther. 41 (10): 980–90. doi:10.1111/apt.13154. PMC 4402146. PMID 25783671.
  5. ↑ Bergquist A, Montgomery SM, Bahmanyar S, Olsson R, Danielsson A, Lindgren S, Prytz H, Hultcrantz R, Lööf LA, Sandberg-Gertzén H, Almer S, Askling J, Ehlin A, Ekbom A (2008). “Increased risk of primary sclerosing cholangitis and ulcerative colitis in first-degree relatives of patients with primary sclerosing cholangitis”. Clin. Gastroenterol. Hepatol. 6 (8): 939–43. doi:10.1016/j.cgh.2008.03.016. PMID 18674735.
  6. ↑ 6.0 6.1 Karlsen TH, Franke A, Melum E, Kaser A, Hov JR, Balschun T, Lie BA, Bergquist A, Schramm C, Weismüller TJ, Gotthardt D, Rust C, Philipp EE, Fritz T, Henckaerts L, Weersma RK, Stokkers P, Ponsioen CY, Wijmenga C, Sterneck M, Nothnagel M, Hampe J, Teufel A, Runz H, Rosenstiel P, Stiehl A, Vermeire S, Beuers U, Manns MP, Schrumpf E, Boberg KM, Schreiber S (2010). “Genome-wide association analysis in primary sclerosing cholangitis”. Gastroenterology. 138 (3): 1102–11. doi:10.1053/j.gastro.2009.11.046. PMID 19944697.
  7. ↑ 7.0 7.1 Melum E, Franke A, Schramm C, Weismüller TJ, Gotthardt DN, Offner FA, Juran BD, Laerdahl JK, Labi V, Björnsson E, Weersma RK, Henckaerts L, Teufel A, Rust C, Ellinghaus E, Balschun T, Boberg KM, Ellinghaus D, Bergquist A, Sauer P, Ryu E, Hov JR, Wedemeyer J, Lindkvist B, Wittig M, Porte RJ, Holm K, Gieger C, Wichmann HE, Stokkers P, Ponsioen CY, Runz H, Stiehl A, Wijmenga C, Sterneck M, Vermeire S, Beuers U, Villunger A, Schrumpf E, Lazaridis KN, Manns MP, Schreiber S, Karlsen TH (2011). “Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci”. Nat. Genet. 43 (1): 17–9. doi:10.1038/ng.728. PMC 4354850. PMID 21151127.
  8. ↑ 8.0 8.1 Liu JZ, Hov JR, Folseraas T, Ellinghaus E, Rushbrook SM, Doncheva NT, Andreassen OA, Weersma RK, Weismüller TJ, Eksteen B, Invernizzi P, Hirschfield GM, Gotthardt DN, Pares A, Ellinghaus D, Shah T, Juran BD, Milkiewicz P, Rust C, Schramm C, Müller T, Srivastava B, Dalekos G, Nöthen MM, Herms S, Winkelmann J, Mitrovic M, Braun F, Ponsioen CY, Croucher PJ, Sterneck M, Teufel A, Mason AL, Saarela J, Leppa V, Dorfman R, Alvaro D, Floreani A, Onengut-Gumuscu S, Rich SS, Thompson WK, Schork AJ, Næss S, Thomsen I, Mayr G, König IR, Hveem K, Cleynen I, Gutierrez-Achury J, Ricaño-Ponce I, van Heel D, Björnsson E, Sandford RN, Durie PR, Melum E, Vatn MH, Silverberg MS, Duerr RH, Padyukov L, Brand S, Sans M, Annese V, Achkar JP, Boberg KM, Marschall HU, Chazouillères O, Bowlus CL, Wijmenga C, Schrumpf E, Vermeire S, Albrecht M, Rioux JD, Alexander G, Bergquist A, Cho J, Schreiber S, Manns MP, Färkkilä M, Dale AM, Chapman RW, Lazaridis KN, Franke A, Anderson CA, Karlsen TH (2013). “Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis”. Nat. Genet. 45 (6): 670–5. doi:10.1038/ng.2616. PMC 3667736. PMID 23603763.
  9. ↑ Vitellas KM, Keogan MT, Freed KS, Enns RA, Spritzer CE, Baillie JM, Nelson RC (2000). “Radiologic manifestations of sclerosing cholangitis with emphasis on MR cholangiopancreatography”. Radiographics. 20 (4): 959–75, quiz 1108–9, 1112. doi:10.1148/radiographics.20.4.g00jl04959. PMID 10903686.
  10. ↑ Molodecky NA, Kareemi H, Parab R, Barkema HW, Quan H, Myers RP, Kaplan GG (2011). “Incidence of primary sclerosing cholangitis: a systematic review and meta-analysis”. Hepatology. 53 (5): 1590–9. doi:10.1002/hep.24247. PMID 21351115.
  11. ↑ Feldstein AE, Perrault J, El-Youssif M, Lindor KD, Freese DK, Angulo P (2003). “Primary sclerosing cholangitis in children: a long-term follow-up study”. Hepatology. 38 (1): 210–7. doi:10.1053/jhep.2003.50289. PMID 12830004.
  12. ↑ Kaya M, Angulo P, Lindor KD (2000). “Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system”. J. Hepatol. 33 (4): 537–42. PMID 11059857.
  13. ↑ Buckles DC, Lindor KD, Larusso NF, Petrovic LM, Gores GJ (2002). “In primary sclerosing cholangitis, gallbladder polyps are frequently malignant”. Am. J. Gastroenterol. 97 (5): 1138–42. doi:10.1111/j.1572-0241.2002.05677.x. PMID 12014717.
  14. ↑ Said K, Glaumann H, Bergquist A (2008). “Gallbladder disease in patients with primary sclerosing cholangitis”. J. Hepatol. 48 (4): 598–605. doi:10.1016/j.jhep.2007.11.019. PMID 18222013.
Causes

Causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Overview

The cause of primary sclerosing cholangitis is unclear and not fully understood. However, genetic and environmental factors are thought to contribute to the development of the disease.

Causes

The cause of primary sclerosing cholangitis is unclear and not fully understood. However, genetic and environmental factors are thought to contribute to the development of the disease.[1][2]

References

  1. ↑ Lazaridis KN, LaRusso NF (2016). “Primary Sclerosing Cholangitis”. N. Engl. J. Med. 375 (12): 1161–70. doi:10.1056/NEJMra1506330. PMID 27653566.
  2. ↑ Geonzon-Gonzales MR (2007). “Primary sclerosing cholangitis”. Gastroenterol Nurs. 30 (2): 102–5, quiz 105–7. doi:10.1097/01.SGA.0000267929.62298.64. PMID 17440311.


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Differentiating Primary sclerosing cholangitis from other Diseases

Differentiating Primary sclerosing cholangitis from other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2] Akshun Kalia M.B.B.S.[3]

Overview

Primary sclerosing cholangitis must be differentiated from causes of secondary sclerosing cholangitis.

Differentiating Primary sclerosing cholangitis from other Diseases

Primary sclerosing cholangitis must be differentiated from causes of secondary sclerosing cholangitis. These include:[1][2]

Primary sclerosing cholangitis must be differentiated from other causes of jaundice and pruritis:

Classification of jaundice based on etiology Disease History and clinical manifestations Diagnosis
Lab Findings Other blood tests Other diagnostic
Family history Fever RUQ Pain Pruritis AST ALT ALK BLR Indirect BLR Direct Viral serology
Cholestatic Jaundice Primary sclerosing cholangitis -/+ + + + N/↑ N/↑ ↑ N ↑ – Beading on MRCP Liver biopsy
Common bile duct stone -/+ -/+ + + N N ↑ N ↑ – Dilated ducts on sono CT/ERCP
Hepatitis A cholestatic type – -/+ + + N N ↑ N ↑ + HAV- AB Abdominal ultrasound
EBV / CMV hepatitis – -/+ + + N N ↑ N ↑ + Positive serology
Primary biliary cirrhosis -/+ – -/+ + N/↑ N/↑ ↑ N ↑ – AMA positive Liver biopsy
Pancreatic carcinoma + – -/+ – N/↑ N/↑ ↑ N ↑ – Mass on ultrasond CT scan for diagnosis

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram


Primary sclerosing cholangitis must be differentiated from other abdominal pain causes:

Disease Clinical manifestations Diagnosis Comments
Symptoms Signs
Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Diarrhea Weight loss Hypo-

tension

Guarding Rebound Tenderness Lab Findings Imaging
Primary sclerosing cholangitis RUQ + − − + − − − − − ERCP and MRCP shows
  • Multiple segmental strictures
  • Mural irregularities
  • Biliary dilatation and diverticula
  • Distortion of biliary tree
  • The risk of cholangiocarcinoma in patients with primary sclerosing cholangitis is 400 times higher than the risk in the general population.
Acute suppurative cholangitis RUQ + + + + − − + + +
  • Abnormal LFT
  • WBC >10,000
  • Ultrasound shows biliary dilatation/stents/tumor
  • Septic shock occurs with features of SIRS
Acute cholangitis RUQ + − − + − − − − −
  • Ultrasound shows biliary dilatation/stents/tumor
  • Biliary drainage (ERCP) + IV antibiotics
Acute cholecystitis RUQ + − + + − − − − − Ultrasound shows:
  • Gallstone
  • Inflammation
Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Diarrhea Weight loss Hypo-

tension

Guarding Rebound Tenderness Lab Findings Imaging Comments
Acute pancreatitis Epigastric + − + ± − − ± − −
  • Ultrasound shows evidence of inflammation
  • CT scan shows severity of pancreatitis
  • Pain radiation to back
Chronic pancreatitis Epigastric − − ± ± + + − − −
  • Increased amylase / lipase
  • Increased stool fat content
  • Pancreatic function test
 CT scan
  • Calcification
  • Pseudocyst
  • Dilation of main pancreatic duct
  • Predisposes to pancreatic cancer
Pancreatic carcinoma Epigastric − − + + + + − − −

Skin manifestations may include:

Primary biliary cirrhosis RUQ/Epigastric − − − + − − − − −
  • Increased AMA level, abnormal LFTs
  • ERCP
  • Pruritis
Cholelithiasis RUQ/Epigastric ± − ± ± − − − − −
  • Fatty food intolerance
Biliary colic RUQ − − + + − − − − −
  • Ultrasound
Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Diarrhea Weight loss Hypo-

tension

Guarding Rebound Tenderness Lab Findings Imaging Comments
Inflammatory bowel disease Diffuse ± − − ± + + − − −

Extra intestinal findings:

Whipple’s disease Diffuse ± − − ± + + ± − − Endoscopy is used to confirm diagnosis.

Images used to find complications

Extra intestinal findings:
Viral hepatitis RUQ + − + + Positive in Hep A and E + Positive in fulminant hepatitis Positive in acute +
  • Abnormal LFTs
  • Viral serology
  • US
  • Hep A and E have fecal-oral route of transmission
  • Hep B and C transmits via blood transfusion and sexual contact.
Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Diarrhea Weight loss Hypo-

tension

Guarding Rebound Tenderness Lab Findings Imaging Comments
Liver abscess RUQ + + + + ± + + + ±
  • US
  • CT
Hepatocellular carcinoma/Metastasis RUQ + − − + − + − − −
  • US
  • CT
  • Liver biopsy

Other symptoms:

Cirrhosis RUQ − − − + − + + − − US
  • Stigmata of liver disease
  • Cruveilhier- Baumgarten murmur
Spontaneous bacterial peritonitis Diffuse + − − Positive in cirrhotic patients + − ± + +
  • Ascitic fluid PMN>250 cells/mm³
  • Culture: Positive for single organism
  • Ultrasound for evaluation of liver cirrhosis

References

  1. ↑ Lazaridis KN, LaRusso NF (2016). “Primary Sclerosing Cholangitis”. N. Engl. J. Med. 375 (12): 1161–70. doi:10.1056/NEJMra1506330. PMID 27653566.
  2. ↑ Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, Gores GJ (2010). “Diagnosis and management of primary sclerosing cholangitis”. Hepatology. 51 (2): 660–78. doi:10.1002/hep.23294. PMID 20101749.


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Epidemiology and Demographics

Epidemiology and Demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Overview

Primary sclerosing cholangitis is a relatively rare disease, with the incidence ranging from 0 to 1.3 per 100,000 cases and prevalence of 0 to 16.2 per 100,000 cases. The disease primarily affects young adult males and the mean age at diagnosis is 41 years.

Epidemiology

The majority of data on the incidence and prevalence of primary sclerosing cholangitis are from North America and Europe. The global incidence of the disease is hard to estimate due to the paucity of studies done in developing countries. Because inflammatory bowel disease is much more prevalent in North America and Europe, and it is strongly associated with primary sclerosing cholangitis, it is thought that data from these regions overestimate the global incidence and prevalence of the disease.[1][2][3][4][5]

Incidence

The incidence of primary sclerosing cholangitis ranges from 0 to 1.3 per 100,000 cases.[1][2]

Prevalence

The prevalence of primary sclerosing cholangitis ranges from 0 to 16.2 per 100,000 cases.[1][2]

Demographics

Age

Primary sclerosing cholangitis is most prevalent between the ages of 35-47 years, with the mean age at diagnosis being 41.[1][2]

Gender

Primary sclerosing cholangitis is more prevalent in males than females, with a male-to-female ratio of 1.70.[1]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Molodecky NA, Kareemi H, Parab R, Barkema HW, Quan H, Myers RP, Kaplan GG (2011). “Incidence of primary sclerosing cholangitis: a systematic review and meta-analysis”. Hepatology. 53 (5): 1590–9. doi:10.1002/hep.24247. PMID 21351115.
  2. ↑ 2.0 2.1 2.2 2.3 Lazaridis KN, LaRusso NF (2016). “Primary Sclerosing Cholangitis”. N. Engl. J. Med. 375 (12): 1161–70. doi:10.1056/NEJMra1506330. PMID 27653566.
  3. ↑ Bambha K, Kim WR, Talwalkar J, Torgerson H, Benson JT, Therneau TM, Loftus EV, Yawn BP, Dickson ER, Melton LJ (2003). “Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community”. Gastroenterology. 125 (5): 1364–9. PMID 14598252.
  4. ↑ Boonstra K, Beuers U, Ponsioen CY (2012). “Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review”. J. Hepatol. 56 (5): 1181–8. doi:10.1016/j.jhep.2011.10.025. PMID 22245904.
  5. ↑ Boberg KM, Aadland E, Jahnsen J, Raknerud N, Stiris M, Bell H (1998). “Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population”. Scand. J. Gastroenterol. 33 (1): 99–103. PMID 9489916.


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Risk Factors

Risk Factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Overview

The most important risk factors associated with primary sclerosing cholangitis include family history and personal history of IBD.

Risk Factors

The most common risk factors associated with the development of primary sclerosing cholangitis are:[1][2][3]

  • IBD: Primary sclerosing cholangitis is more associated with ulcerative colitis than Crohn’s disease.
  • Family history: Those with siblings with primary sclerosing cholangitis are 9-39 times more likely to develop the disease than the general population.

References

  1. ↑ Lazaridis KN, LaRusso NF (2016). “Primary Sclerosing Cholangitis”. N. Engl. J. Med. 375 (12): 1161–70. doi:10.1056/NEJMra1506330. PMID 27653566.
  2. ↑ Boonstra K, de Vries EM, van Geloven N, van Erpecum KJ, Spanier M, Poen AC, van Nieuwkerk CM, Witteman BJ, Tuynman HA, Naber AH, Kingma PJ, Beuers U, Ponsioen CY (2016). “Risk factors for primary sclerosing cholangitis”. Liver Int. 36 (1): 84–91. doi:10.1111/liv.12894. PMID 26077553.
  3. ↑ Geonzon-Gonzales MR (2007). “Primary sclerosing cholangitis”. Gastroenterol Nurs. 30 (2): 102–5, quiz 105–7. doi:10.1097/01.SGA.0000267929.62298.64. PMID 17440311.


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Screening

Screening

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Overview

There are no screening recommendations for primary sclerosing cholangitis.

Screening

There are no screening recommendations for primary sclerosing cholangitis. [1]

References

  1. ↑ U.S. Preventive Services Task Force https://www.uspreventiveservicestaskforce.org/BrowseRec/Search?s=primary+sclerosing+cholangitis Accessed on Dec 12, 2016


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Natural History, Complications and Prognosis

Natural History, Complications and Prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]

Overview

Primary sclerosing cholangitis is a progressive disease that often results in death from complications of liver failure, liver transplantation or associated carcinomas. Even with liver transplantation, there is a substantial risk of recurrence of the disease. Complications of primary sclerosing cholangitis include osteoporosis, cholangiocarcinoma and liver failure.

Natural History

Primary sclerosing cholangitis is a progressive and often fatal disease. Death in patients with primary sclerosing cholangitis often results from complications of liver failure or associated cancers, such as cholangiocarcinoma, hepatocellular carcinoma, and colorectal carcinoma in patients with associated IBD.[1] The median survival from diagnosis to death in patients with primary sclerosing cholangitis ranges between 12-18 years.[2]

Complications

Some of the complications of primary sclerosing cholangitis include:[3]

Prognosis

Primary sclerosing cholangitis is a slowly progressive disease that may ultimately lead to liver failure.[3] Approximately 40% of patients require liver transplantation.[6] Even then, the 1 year survival rate after liver transplantation is 85% and 72% after 5 years. 25% of patients have recurrence of the disease after transplantation.[7]

The following factors are associated with a poorer prognosis in patients with primary sclerosing cholangitis:[3]

The Mayo Score for PSC uses an equation to predict the survival in patients with primary sclerosing cholangitis. The variables in this equation include age, AST levels, total bilirubin levels, serum albumin, as well as variceal bleeding.[13]

References

  1. ↑ Khaderi SA, Sussman NL (2015). “Screening for malignancy in primary sclerosing cholangitis (PSC)”. Curr Gastroenterol Rep. 17 (4): 17. doi:10.1007/s11894-015-0438-0. PMID 25786901.
  2. ↑ 2.0 2.1 Ponsioen CY, Vrouenraets SM, Prawirodirdjo W, Rajaram R, Rauws EA, Mulder CJ, Reitsma JB, Heisterkamp SH, Tytgat GN (2002). “Natural history of primary sclerosing cholangitis and prognostic value of cholangiography in a Dutch population”. Gut. 51 (4): 562–6. PMC 1773389. PMID 12235081.
  3. ↑ 3.0 3.1 3.2 Lazaridis KN, LaRusso NF (2016). “Primary Sclerosing Cholangitis”. N. Engl. J. Med. 375 (12): 1161–70. doi:10.1056/NEJMra1506330. PMID 27653566.
  4. ↑ Angulo P, Grandison GA, Fong DG, Keach JC, Lindor KD, Bjornsson E, Koch A (2011). “Bone disease in patients with primary sclerosing cholangitis”. Gastroenterology. 140 (1): 180–8. doi:10.1053/j.gastro.2010.10.014. PMC 3043598. PMID 20955707.
  5. ↑ 5.0 5.1 Boonstra K, Weersma RK, van Erpecum KJ, Rauws EA, Spanier BW, Poen AC, van Nieuwkerk KM, Drenth JP, Witteman BJ, Tuynman HA, Naber AH, Kingma PJ, van Buuren HR, van Hoek B, Vleggaar FP, van Geloven N, Beuers U, Ponsioen CY (2013). “Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis”. Hepatology. 58 (6): 2045–55. doi:10.1002/hep.26565. PMID 23775876.
  6. ↑ Tischendorf JJ, Hecker H, Krüger M, Manns MP, Meier PN (2007). “Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: A single center study”. Am. J. Gastroenterol. 102 (1): 107–14. doi:10.1111/j.1572-0241.2006.00872.x. PMID 17037993.
  7. ↑ Fosby B, Karlsen TH, Melum E (2012). “Recurrence and rejection in liver transplantation for primary sclerosing cholangitis”. World J. Gastroenterol. 18 (1): 1–15. doi:10.3748/wjg.v18.i1.1. PMC 3251800. PMID 22228965.
  8. ↑ Björnsson E, Olsson R, Bergquist A, Lindgren S, Braden B, Chapman RW, Boberg KM, Angulo P (2008). “The natural history of small-duct primary sclerosing cholangitis”. Gastroenterology. 134 (4): 975–80. doi:10.1053/j.gastro.2008.01.042. PMID 18395078.
  9. ↑ Mendes FD, Jorgensen R, Keach J, Katzmann JA, Smyrk T, Donlinger J, Chari S, Lindor KD (2006). “Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis”. Am. J. Gastroenterol. 101 (9): 2070–5. doi:10.1111/j.1572-0241.2006.00772.x. PMID 16879434.
  10. ↑ Stanich PP, Björnsson E, Gossard AA, Enders F, Jorgensen R, Lindor KD (2011). “Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis”. Dig Liver Dis. 43 (4): 309–13. doi:10.1016/j.dld.2010.12.008. PMC 3057302. PMID 21251891.
  11. ↑ Al Mamari S, Djordjevic J, Halliday JS, Chapman RW (2013). “Improvement of serum alkaline phosphatase to <1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis”. J. Hepatol. 58 (2): 329–34. doi:10.1016/j.jhep.2012.10.013. PMID 23085647.
  12. ↑ Rupp C, Rössler A, Halibasic E, Sauer P, Weiss KH, Friedrich K, Wannhoff A, Stiehl A, Stremmel W, Trauner M, Gotthardt DN (2014). “Reduction in alkaline phosphatase is associated with longer survival in primary sclerosing cholangitis, independent of dominant stenosis”. Aliment. Pharmacol. Ther. 40 (11–12): 1292–301. doi:10.1111/apt.12979. PMID 25316001.
  13. ↑ Mayo Risk Score Calculator http://www.psc-literature.org/mrscalc.htm Accessed on Dec 12, 2016.


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