Applied Evidence

How best to manage chronic cholestasis

J Fam Pract. 2018 July;67(7):E9-E15

From The Journal of Family Practice | 2018;67(7):E9-E15.

References

1. Kremer AE, Namer B, Bolier R, et al. Pathogenesis and management of pruritus in PBC and PSC. Dig Dis. 2015;33(suppl 2):164-175.

2. Deska Pagana K, Pagana TJ. Mosby’s Diagnostic and Laboratory Test Reference. 13th ed. St. Louis, MO: Elsevier; 2017.

3. Sapey T, Mendler MH, Guyader D, et al. Respective value of alkaline phosphatase, gamma-glutamyl transpeptidase and 5’ nucleotidase serum activity in the diagnosis of cholestasis: a prospective study of 80 patients. J Clin Gastroenterol. 2000;30:259-263.

4. European Association for the Study of the Liver. EASL Clinical practice guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51:237-267.

5. Lammers WJ, van Buuren HR, Hirschfield GM, et al; Global PBC Study Group. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology. 2014;147:1338-1349.

6. Trivedi PJ, Corpechot C, Pares A, et al. Risk stratification in autoimmune cholestatic liver diseases: opportunities for clinicians and trialists. Hepatology. 2016;63:644-659.

7. Lammers WJ, Hirschfield GM, Corpechot C, et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology. 2015;149:1804-1812.

8. Johnston DE. Special considerations in interpreting liver function tests. Am Fam Physician. 1999;59:2223-2230.

9. Assy N, Jacob G, Spira G, et al. Diagnostic approach to patients with cholestatic jaundice. World J Gastroenterol. 1999;5:252-262.

10. Padda MS, Sanchez M, Akhtar AJ, et al. Drug-induced cholestasis. Hepatology. 2011;53:1377-1387.

11. US Food and Drug Administration. Food. Consumer advisory: kava-containing dietary supplements may be associated with severe liver injury. March 25, 2002. Available at: http://wayback.archive-it.org/7993/20171114232640/https://www.fda.gov/Food/RecallsOutbreaksEmergencies/SafetyAlertsAdvisories/ucm085482.htm. Accessed June 19, 2018.

12. Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology. 2002;123:1367-1384.

13. Rogoveanu I, Gheonea DI, Saftoiu A, et al. The role of imaging methods in identifying the causes of extrahepatic cholestasis. J Gastrointestin Liver Dis. 2006;15:265-271.

14. Gotthardt DN, Rudolph G, Klöters-Plachky P, et al. Endoscopic dilation of dominant stenoses in primary sclerosing cholangitis: outcome after long-term treatment. Gastrointest Endosc. 2010;71:527-534.

15. Fitzmorris P, Singal AK. Surveillance and diagnosis of hepatocellular carcinoma. Gastroenterol Hepatol (NY). 2015;11:38-46.

16. Bruix J, Sherman M. Management of hepatocellular carcinoma: an update. Hepatology. 2011;53:1020-1022.

17. Pinzani M, Vizzutti F, Arena U, et al. Technology insight: noninvasive assessment of liver fibrosis by biochemical scores and elastography. Nat Clin Pract Gastroenterol Hepatol. 2008;5:95-106.

18. Castéra L, Vergniol J, Foucher J, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005;128:343-350.

19. Van Gossum A, Pironi L, Messing B, et al. Transient elastography (FibroScan) is not correlated with liver fibrosis but with cholestasis in patients with long-term home parenteral nutrition. JPEN. 2015;39:719-724.

20. Millonig G, Reimann FM, Friedrich S, et al. Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis. Hepatology. 2008;48:1718-1723.

21. European Association for the Study of the Liver. EASL clinical practice guidelines: the diagnosis and management of patients with primary biliary cholangitis. J Hepatol. 2017;67:145-172.

22. Ozaslan E, Efe C, Gokbulut Ozaslan N. The diagnosis of antimitochondrial antibody-negative primary biliary cholangitis. Clin Res Hepatol Gastroenterol. 2016;40:553-561.

23. Lindor KD, Gershwin ME, Poupon R, et al; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology. 2009;50:291-308.

24. Hov JR, Boberg KM, Karlsen TH. Autoantibodies in primary sclerosing cholangitis. World J Gastroenterol. 2008;14:3781-3791.

25. Dilger K, Hohenester S, Winkler-Budenhofer U, et al. Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health. J Hepatol. 2012;57:133-140.

26. Invernizzi P, Setchell KD, Crosignani A, et al. Differences in the metabolism and disposition of ursodeoxycholic acid and of its taurine-conjugated species in patients with primary biliary cirrhosis. Hepatology. 1999;29:320-327.

27. Jorgensen R, Angulo P, Dickson ER, et al. Results of long-term ursodiol treatment for patients with primary biliary cirrhosis. Am J Gastroenterol. 2002;97:2647-2650.

28. Parés A, Caballería L, Rodés J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology. 2006;130:715-720.

29. Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology. 2008;48:871-877.

30. Levine JS, Burakoff R. Extraintestinal manifestations of inflammatory bowel disease. Gastroenterol Hepatol (NY). 2011;7:235-241.

31. Rodriguez HJ, Bass NM. Primary sclerosing cholangitis. Semin Gastrointest Dis. 2003;14:189-198.

32. Tajiri K, Shimizu Y. Recent advances in the management of pruritus in chronic liver diseases. World J Gastroenterol. 2017;23:3418-3426.

33. Kremer AE, Namer B, Bolier R, et al. Pathogenesis and management of pruritus in PBC and PSC. Dig Dis. 2015;33(suppl 2):164-175.

34. Buyse S, Durand F, Joly F. Nutritional assessment in cirrhosis. Gastroenterol Clin Biol. 2008;32:265-273.

35. Fagiuoli S, Colli A, Bruno R, et al; 2011 AISF Single Topic Group. Management of infections pre- and post-liver transplantation: report of an AISF consensus conference. J Hepatol. 2014;60:1075-1089.

36. Kanaan Z, Antaki F. Magnetic resonance cholangiopancreatography still plays a role in the preoperative evaluation of choledocholithiasis and biliary pathology. J Am Coll Surg. 2016;222:325-326.

37. McMahon CJ. The relative roles of magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound in diagnosis of common bile duct calculi: a critically appraised topic. Abdom Imaging. 2008;33:6-9.

38. Njei B, McCarty TR, Varadarajulu S, et al. Systematic review with meta-analysis: endoscopic retrograde cholangiopancreatography-based modalities for the diagnosis of cholangiocarcinoma in primary sclerosing cholangitis. Aliment Pharmacol Ther. 2016;44:1139-1151.

39. Wimalawansa SJ, Razzaque DMS, Al-Daghri NM. Calcium and vitamin D in human health: hype or real? J Steroid Biochem Mol Biol. 2017. doi: 10.1016/j.jsbmb.2017.12.009.

40. Yadav A, Carey EJ. Osteoporosis in chronic liver disease. Nutr Clin Pract. 2013;28:52-64.

Mildly elevated gGT and/or alkaline phosphatase (ALP) (0.5-2.5 times the upper normal limit [UNL] or 19-95 U/L and 60-300 U/L, respectively²) in the presence of normal transaminase levels (<20 U/L) in an asymptomatic patient can indicate chronic liver disease. Signs suggestive of significant liver disease have been reported in many patients with gGT or ALP elevation with good sensitivity (65%) and specificity (83%) for a diagnosis of intrahepatic cholestasis.³ However, because abnormal gGT values are common and often resolve spontaneously, family physicians (FPs) may pay little attention to this finding, thus missing an opportunity for early identification and treatment.

That’s why it’s important to schedule follow-up testing within 6 months for asymptomatic patients with abnormal laboratory findings. Persistent elevation of gGT alone or accompanied by ALP and ALT elevation (ALT >0.5 times the UNL or >18 U/L) is the most common feature of a chronic (>6 months) cholestatic condition.⁴ (In particular, elevated ALP levels appear to be associated with more aggressive disease and predict risk of liver transplantation or death in patients with primary biliary cholangitis (PBC).^5,6 Lowering ALP levels is associated with improved disease outcomes, including transplant-free survival rates.^5,7)

Elevated serum aminotransferase levels (aspartate aminotransferase [AST] >0.5 times the UNL or 17.5 U/L; ALT >0.5 times the UNL or >18 U/L) and bilirubin (>1.1 mg/dL), with predominance of the conjugated form (TABLE 1⁸), suggest possible cholestasis. In light of such findings, a clinician’s next step should be to distinguish intrahepatic from extrahepatic conditions. (For a detailed list of the causes of intra- and extrahepatic cholestasis, see TABLES 2⁴ and 3.⁹)

Patient’s history can provide important clues

A thorough patient history is especially important when cholestasis is suspected. Details about the patient’s occupation, environment, and lifestyle are key, as are the specifics of prescribed or over-the-counter medications and supplements that could be hepatotoxic (TABLE 4¹⁰). A number of exogenous substances can cause liver injury, and the use of some herbal products (senna, black cohosh, greater celandine, kava) have been linked to hepatitis and cholestasis.¹¹ Ask patients about alcohol use and history of conditions associated with liver disease, such as diabetes, hyperlipidemia, and thyroid disorders.

Continue to: Indicators pointing to cholestasis? It's time for ultrasonography