Potential Complications

Patients with primary biliary cholangitis (PBC) should be monitored for serious disease-specific and/or cirrhosis-specific complications1


Select complications specific to PBC

Portal hypertension in patients with PBC

Portal hypertension typically occurs when the liver is cirrhotic, though it may develop even sooner.1,3

  • Cirrhosis leads to increased intrahepatic vascular resistance to portal blood flow3
    • Portosystemic collaterals form as a result of portal hypertension3
    • Despite the formation of portosystemic collaterals, portal hypertension persists because of higher resistance in collateral vessels compared with intrahepatic resistance and increased portal venous inflow3
    • As portal pressure increases, varices can form, increasing and growing with time, and potentially leading to variceal hemorrhage3
    • Patients with a platelet count <150,000/mm3, a serum albumin level <40 g/L, and a bilirubin level >20 μmol/L should be screened for esophageal varices4,5

As PBC progresses, it may lead to 2 different metabolic bone diseases1:

  • Osteomalacia, which is associated with calcium malabsorption6,7
    • May respond to supplementation with vitamin D6,7
  • Osteoporosis, which is caused by decreased osteoblastic activity in patients with PBC8
    • Since patients with osteoporosis without fractures have normal alkaline phosphatase (ALP) levels, increased ALP in patients with osteoporosis should raise suspicion of PBC9
    • Liver transplantation may be recommended for select patients with PBC with severe osteoporosis9

Hyperlipidemia in patients with PBC

PBC is associated with the development of hyperlipidemia.1

  • Cardiovascular risk and atherosclerotic signs are not associated with changes in lipid levels in PBC10,11
  • Hyperlipidemia in PBC is not associated with an increase in cardiovascular events10,11

Select complications specific to cirrhosis

Ascites in patients with PBC

Ascites—one of the most common complications of cirrhosis.12

  • 20% of patients with PBC develop ascites within 10 years of diagnosis13
    • Development of esophageal varices may predict appearance of ascites14
  • 1-year probability of survival is 32% for patients with refractory ascites15
  • 5-year probability of survival is 15% for patients with refractory ascites15

Variceal hemorrhage in patients with PBC

About 60% of decompensated and 30% of compensated patients with cirrhosis develop varices.16

  • A retrospective multicenter study of 231 patients with documented variceal bleeding was associated with the following mortality rates17:
    • In-hospital: 14.2%
    • 6-week: 17.5%
    • Overall: 33.5%
  • Patients who survive a first episode of variceal bleeding are at extremely high risk for rebleeding and death16,18,19

Hepatocellular carcinoma in patients with PBC

Hepatocellular carcinoma (HCC)—a complication of cirrhosis.20

  • The number of patients with HCC and concomitant PBC is increasing, with the reported overall incidence ranging from 0.7% to 3.8%21,22
  • In patients with PBC and cirrhosis, the risk of developing HCC exceeds 15% at 10 years of follow-up22
  • Histologic staging of the liver may help in screening for HCC21

Patients with PBC should be screened for HCC if they have any of the following risk factors21,23-26:

  • Advanced histological stage
  • Presence of portal hypertension
  • History of blood transfusion (a significant independent risk factor)
  • Older age (average of 67 at diagnosis of HCC)
  • Nonresponse to ursodeoxycholic acid
  • Male gender (a significant independent risk factor)

Jaundice

The development of jaundice has been associated with decreased survival.27

  • Jaundice is seen late in patients with advanced liver disease28
  • Patients with PBC and jaundice also show abnormal vitamin D metabolism28,29
    • Vitamin D insufficiency is a risk factor for osteoporosis in patients with chronic liver disease30
  • Based on published treatment guidelines, patients should undergo liver tests every 3 to 6 months to assess potential malnutrition28

Liver decompensation

Approximately 25% of patients symptomatic at diagnosis progress to liver failure within 10 years.13,21

  • Antiglycoprotein-210 is an independent risk factor associated with progression to liver failure in PBC31
  • In a cohort of 770 patients diagnosed with PBC, 30 patients underwent liver transplant due to liver decompensation13
  • Approximately 20% to 25% of patients with PBC who undergo liver transplant develop recurrent disease over 10 years28,32

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Which patients with primary biliary cirrhosis or primary sclerosing cholangitis should undergo endoscopic screening for oesophageal varices detection? Gut. 2005;54(3):407-410. doi:10.1136/gut.2004.040832.  6. Bengoa JM, Sitrin MD, Meredith S, et al. Intestinal calcium absorption and vitamin D status in chronic cholestatic liver disease. Hepatology. 1984;4(2):261-265. doi:10.1002/hep.1840040215.  7. Compston JE, Thompson RPH. Intestinal absorption of 25-hydroxyvitamin D and osteomalacia in primary biliary cirrhosis. Lancet. 1977;1(8014);721-724. doi:10.1016/s0140-6736(77)92167-5.  8. Hodgson SF, Dickson ER, Wahner HW, Johnson KA, Mann KG, Riggs BL. Bone loss and reduced osteoblast function in primary biliary cirrhosis. Ann Intern Med. 1985;103(6)(pt 1):855-860. doi:10.7326/0003-4819-103-6-855.  9. Heathcote EJ. Management of primary biliary cirrhosis. Hepatology. 2000;31(4):1005-1013. doi:10.1053/he.2000.5984.  10. Longo M, Crosignani A, Battezzati PM, et al. Hyperlipidaemic state and cardiovascular risk in primary biliary cirrhosis. Gut. 2002;51(2):265-269. doi:10.1136/gut.51.2.265.  11. Allocca M, Crosignani A, Gritti A, et al. Hypercholesterolaemia is not associated with early atherosclerotic lesions in primary biliary cirrhosis. Gut. 2006;55(12):1795-1800. doi:10.1136/gut.2005.079814.  12. Ginés P, Quintero E, Arroyo V, et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology. 1987;7(1):122-128. doi:10.1002/hep.1840070124.  13. Prince M, Chetwynd A, Newman W, Metcalf JV, James OFW. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology. 2002;123(4):1044-1051. doi:10.1053/gast.2002.36027.  14. Silveira MG, Brunt EM, Heathcote J, Gores GJ, Lindor KD, Mayo MJ. American Association for the Study of Liver Diseases endpoints conference: design and endpoints for clinical trials in primary biliary cirrhosis. Hepatology. 2010;52(1):349-359. doi:10.1002/hep.23637.  15. Planas R, Montoliu S, Ballesté B, et al. Natural history of patients hospitalized for management of cirrhotic ascites. Clin Gastroenterol Hepatol. 2006;4(11):1385-1394. doi:10.1016/j.cgh.2006.08.007.  16. D’Amico G, Luca A. Natural history. Clinical-haemodynamic correlations. Prediction of the risk of bleeding. Baillières Clin Gastroenterol. 1997;11(2):243-256. doi:10.1016/s0950-3528(97)90038-5.  17. Chalasani N, Kahi C, Francois F, et al. Improved patient survival after acute variceal bleeding: a multicenter, cohort study. Am J Gastroenterol. 2003;98(3):653-659. doi:10.1016/s0002-9270(02)06016-1.  18. Graham DY, Smith JL. The course of patients after variceal hemorrhage. Gastroenterology. 1981;80(4):800-809.  19. Bosch J, Abraldes JG, Groszmann R. Current management of portal hypertension. J Hepatol. 2003;38(suppl 1):S54-S68. doi:10.1016/S0168-8278(02)00430-0.  20. Nusrat S, Khan MS, Fazili J, Madhoun MF. Cirrhosis and its complications: evidence based treatment. World J Gastroenterol. 2014;20(18):5442-5460. doi:10.3748/wjg.v20.i18.5442.  21. Al-Harthy N, Kumagi N. Natural history and management of primary biliary cirrhosis. Hepat Med. 2012;4:61-71. doi:10.2147/HMER.S25998.  22. Deutsch M, Papatheodoridis GV, Tzakou A, Hadziyannis SJ. Risk of hepatocellular carcinoma and extrahepatic malignancies in primary biliary cirrhosis. Eur J Gastroenterol Hepatol. 2008;20(1):5-9. doi:10.1097/MEG.0b013e3282f163ed.  23. Trivedi PJ, Lammers WJ, van Buuren HR, et al; for Global PBC Study Group. Stratification of hepatocellular risk in primary biliary cirrhosis: a multicentre international study [published online January 7, 2015]. Gut. doi:10.1136/gutjnl-2014-308351.  24. Shibuya A, Tanaka K, Miyakawa H, et al. Hepatocellular carcinoma and survival in patients with primary biliary cirrhosis. Hepatology. 2002;35(5):1172-1178. doi:10.1053/jhep.2002.33157.  25. Silveira MG, Suzuki A, Lindor KD. Surveillance for hepatocellular carcinoma in patients with primary biliary cirrhosis. Hepatology. 2008;48(4):1149-1156. doi:10.1002/hep.22458.  26. Suzuki A, Lymp J, Donlinger J, Mendes F, Angulo P, Lindor K. Clinical predictors for hepatocellular carcinoma in patients with primary biliary cirrhosis. Clin Gastroenterol Hepatol. 2007;5(2):259-264. doi:10.1016/j.cgh.2006.09.031.  27. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353(12):1261-1273. doi:10.1056/NEJMra043898.  28. Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ. Primary biliary cirrhosis. Hepatology. 2009;50(1):291-308. doi:10.1002/hep.22906. (AASLD guidelines)  29. Jung RT, Davie M, Siklos P, Chalmers TM, Hunter JO, Lawson DEM. Vitamin D metabolism in acute and chronic cholestasis. Gut. 1979;20(10):840-847. doi:10.1136/gut.20.10.840.  30. Collier JD, Ninkovic M, Compston JE. Guidelines on the management of osteoporosis associated with chronic liver disease. Gut. 2002;50(suppl 1):i1-i9. doi:10.1136/gut.50.suppl_1.i1.  31. Nakamura M, Kondo H, Mori T, et al. Anti-gp210 and anti-centromere antibodies are different risk factors for the progression of primary biliary cirrhosis. Hepatology. 2007;45(1):118-127. doi:10.1002/hep.21472.  32. Sylvestre PB, Batts KP, Burgart LJ, Poterucha JJ, Wiesner RH. Recurrence of primary biliary cirrhosis after liver transplantation: histologic estimate of incidence and natural history. Liver Transpl. 2003;9(10):1086-1093. doi:10.1053/jlts.2003.50213.