Skip to main content
Top
Published in: Digestive Diseases and Sciences 6/2022

07-08-2021 | Cholecystectomy | Original Article

Bile Acid Malabsorption in Patients with Neuroendocrine Tumors

Authors: Lehar Khanna, Thorvardur R. Halfdanarson, Mohamad B. Sonbol, Rachel Eiring, Teresa Prond, Michael Camilleri

Published in: Digestive Diseases and Sciences | Issue 6/2022

Login to get access

Abstract

Background

Chronic diarrhea in patients with neuroendocrine tumors (NET) may be caused by bioactive products of NET, bile acid malabsorption (BAM), ileal resection (IR) or steatorrhea.

Aim

To quantitate BA and fat malabsorption in NET with diarrhea.

Methods

Part of evaluation in medical oncology clinical practice, 67 patients [42F, 25 M; median age 64.0 y (17.0 IQR)] with well-differentiated NET and diarrhea underwent clinically indicated measurements of 48-h fecal BA [(FBA), fecal weight (normal < 400 g/48 h), fecal fat (normal < 7 g/day) in n = 52] and fasting serum 7αC4 (marker of hepatic BA synthesis, n = 30) between 01/2018 and 11/2020. IR had been performed in 45 patients. BAM diagnosis was based on FBA criteria: elevated total FBA (> 2337 µmol/48 h) or > 10% primary FBA or combination > 4% primary FBA plus > 1000 µmol total FBA/48 h. We also measured fecal elastase (for pancreatic insufficiency) in 13 patients.

Results

BAM was present in 48/52 (92%) patients with NET. There were significant correlations between total FBA and 48-h fecal weight (Rs = 0.645, P < 0.001). Mean length of IR was 47 cm; in patients with IR < 25 cm, total FBA was elevated in 85% and primary FBA > 10% in 69%. In 22 patients with no IR, 13/15 tested (87%) had BAM. Among 6 patients with pancreatic NET and no IR, 80% had BAM. Fecal fat was ≥ 15 g/day in 18/42 (43%). In 4/17 (24%) with IR < 25 cm and 8/19 (42%) patients with IR > 25 cm fecal fat was 44.0 (40.5) and 38.0 (38.0)g/day, respectively.

Conclusion

A majority of patients with NET and diarrhea had BAM, even with < 25 cm or no IR.
Literature
1.
go back to reference Eads JR, Reidy-Lagunes D, Soares HP et al. Differential diagnosis of diarrhea in patients with neuroendocrine tumors. Pancreas 2020;49:1123–1130.CrossRef Eads JR, Reidy-Lagunes D, Soares HP et al. Differential diagnosis of diarrhea in patients with neuroendocrine tumors. Pancreas 2020;49:1123–1130.CrossRef
2.
go back to reference Naraev BG, Halland M, Halperin DM et al. Management of diarrhea in patients with carcinoid syndrome. Pancreas 2019;48:961–972.CrossRef Naraev BG, Halland M, Halperin DM et al. Management of diarrhea in patients with carcinoid syndrome. Pancreas 2019;48:961–972.CrossRef
3.
go back to reference Dasari A, Joish VN, Perez-Olle R et al. Work productivity burden and indirect costs associated with carcinoid syndrome diarrhea. Expert Rev Pharmacoecon Outcomes Res. 2020;20:507–511.CrossRef Dasari A, Joish VN, Perez-Olle R et al. Work productivity burden and indirect costs associated with carcinoid syndrome diarrhea. Expert Rev Pharmacoecon Outcomes Res. 2020;20:507–511.CrossRef
4.
go back to reference Broder MS, Chang E, Romanus D, Cherepanov D, Neary MP. Healthcare and economic impact of diarrhea in patients with carcinoid syndrome. World J Gastroenterol. 2016;22:2118–2125.CrossRef Broder MS, Chang E, Romanus D, Cherepanov D, Neary MP. Healthcare and economic impact of diarrhea in patients with carcinoid syndrome. World J Gastroenterol. 2016;22:2118–2125.CrossRef
5.
go back to reference Dasari A, Joish VN, Perez-Olle R et al. Direct costs of carcinoid syndrome diarrhea among adults in the United States. World J Gastroenterol. 2019;25:6857–6865.CrossRef Dasari A, Joish VN, Perez-Olle R et al. Direct costs of carcinoid syndrome diarrhea among adults in the United States. World J Gastroenterol. 2019;25:6857–6865.CrossRef
6.
go back to reference Hofmann AF. Quantifying the complexities of bile acid metabolism in man: Continued progress. Cell Mol Gastroenterol Hepatol. 2020;10:201–202.CrossRef Hofmann AF. Quantifying the complexities of bile acid metabolism in man: Continued progress. Cell Mol Gastroenterol Hepatol. 2020;10:201–202.CrossRef
7.
go back to reference Wong BS, Camilleri M, Carlson P et al. Increased bile acid biosynthesis is associated with irritable bowel syndrome with diarrhea. Clin Gastroenterol Hepatol. 2012;10:1009-1015.e3.CrossRef Wong BS, Camilleri M, Carlson P et al. Increased bile acid biosynthesis is associated with irritable bowel syndrome with diarrhea. Clin Gastroenterol Hepatol. 2012;10:1009-1015.e3.CrossRef
9.
go back to reference Khan MS, Walter T, Buchanan-Hughes A et al. Differential diagnosis of diarrhoea in patients with neuroendocrine tumours: A systematic review. World J Gastroenterol. 2020;26:4537–4556.CrossRef Khan MS, Walter T, Buchanan-Hughes A et al. Differential diagnosis of diarrhoea in patients with neuroendocrine tumours: A systematic review. World J Gastroenterol. 2020;26:4537–4556.CrossRef
10.
go back to reference Pusceddu S, Rossi RE, Torchio M et al. Differential diagnosis and management of diarrhea in patients with neuroendocrine tumors. J Clin Med. 2020;9:2468.CrossRef Pusceddu S, Rossi RE, Torchio M et al. Differential diagnosis and management of diarrhea in patients with neuroendocrine tumors. J Clin Med. 2020;9:2468.CrossRef
11.
go back to reference Poley JR, Hofmann AF. Role of fat maldigestion in pathogenesis of steatorrhea in ileal resection. Gastroenterology 1976;71:38–44.CrossRef Poley JR, Hofmann AF. Role of fat maldigestion in pathogenesis of steatorrhea in ileal resection. Gastroenterology 1976;71:38–44.CrossRef
12.
go back to reference Hofmann AF, Poley JR. Cholestyramine treatment of diarrhea associated with ileal resection. N Engl J Med. 1969;281:397–402.CrossRef Hofmann AF, Poley JR. Cholestyramine treatment of diarrhea associated with ileal resection. N Engl J Med. 1969;281:397–402.CrossRef
13.
go back to reference Camilleri M, Vijayvargiya P. The role of bile acids in chronic ciarrhea. Am J Gastroenterol. 2020;115:1596–1603.CrossRef Camilleri M, Vijayvargiya P. The role of bile acids in chronic ciarrhea. Am J Gastroenterol. 2020;115:1596–1603.CrossRef
14.
go back to reference Bampton PA, Dinning PG, Kennedy ML et al. The proximal colonic motor response to rectal mechanical and chemical stimulation. Am J Physiol Gastrointest Liver Physiol. 2002;282:G443–G449.CrossRef Bampton PA, Dinning PG, Kennedy ML et al. The proximal colonic motor response to rectal mechanical and chemical stimulation. Am J Physiol Gastrointest Liver Physiol. 2002;282:G443–G449.CrossRef
15.
go back to reference Alemi F, Poole DP, Chiu J et al. The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology 2013;144:145–154.CrossRef Alemi F, Poole DP, Chiu J et al. The receptor TGR5 mediates the prokinetic actions of intestinal bile acids and is required for normal defecation in mice. Gastroenterology 2013;144:145–154.CrossRef
16.
go back to reference Fromm H, Malavolti M. Bile acid-induced diarrhoea. Clin Gastroenterol. 1986;15:567–582.CrossRef Fromm H, Malavolti M. Bile acid-induced diarrhoea. Clin Gastroenterol. 1986;15:567–582.CrossRef
17.
go back to reference von der Ohe MR, Camilleri M, Kvols LK et al. Motor dysfunction of the small bowel and colon in patients with the carcinoid syndrome and diarrhea. N Engl J Med. 1993;329:1073–1078.CrossRef von der Ohe MR, Camilleri M, Kvols LK et al. Motor dysfunction of the small bowel and colon in patients with the carcinoid syndrome and diarrhea. N Engl J Med. 1993;329:1073–1078.CrossRef
18.
go back to reference Vijayvargiya P, Camilleri M. Current practice in the diagnosis of bile acid diarrhea. Gastroenterology 2019;156:1233–1238.CrossRef Vijayvargiya P, Camilleri M. Current practice in the diagnosis of bile acid diarrhea. Gastroenterology 2019;156:1233–1238.CrossRef
19.
go back to reference Vijayvargiya P, Camilleri M, Taylor A et al. Combined fasting serum C4 and primary bile acids from a single stool sample to diagnose bile acid diarrhea. Gastroenterology 2020;159:1952-1954.e2.CrossRef Vijayvargiya P, Camilleri M, Taylor A et al. Combined fasting serum C4 and primary bile acids from a single stool sample to diagnose bile acid diarrhea. Gastroenterology 2020;159:1952-1954.e2.CrossRef
20.
go back to reference Tagliacozzi D, Mozzi AF, Casetta B et al. Quantitative analysis of bile acids in human plasma by liquid chromatography-electrospray tandem mass spectrometry: A simple and rapid one-step method. Clin Chem Lab Med. 2003;41:1633–1641.CrossRef Tagliacozzi D, Mozzi AF, Casetta B et al. Quantitative analysis of bile acids in human plasma by liquid chromatography-electrospray tandem mass spectrometry: A simple and rapid one-step method. Clin Chem Lab Med. 2003;41:1633–1641.CrossRef
21.
go back to reference Vijayvargiya P, Camilleri M, Chedid V et al. Analysis of fecal primary bile acids detects increased stool weight and colonic transit in patients with chronic functional diarrhea. Clin Gastroenterol Hepatol. 2019;17:922-929.e2.CrossRef Vijayvargiya P, Camilleri M, Chedid V et al. Analysis of fecal primary bile acids detects increased stool weight and colonic transit in patients with chronic functional diarrhea. Clin Gastroenterol Hepatol. 2019;17:922-929.e2.CrossRef
22.
go back to reference Hammer HF, Santa Ana CA, Schiller LR et al. Studies of osmotic diarrhea induced in normal subjects by ingestion of polyethylene glycol and lactulose. J Clin Invest. 1989;84:1056–1062.CrossRef Hammer HF, Santa Ana CA, Schiller LR et al. Studies of osmotic diarrhea induced in normal subjects by ingestion of polyethylene glycol and lactulose. J Clin Invest. 1989;84:1056–1062.CrossRef
23.
go back to reference Camilleri M, Nadeau A, Tremaine WJ et al. Measurement of serum 7α-hydroxy-4-cholesten-3-one (or 7αC4), a surrogate test for bile acid malabsorption in health, ileal disease and irritable bowel syndrome using liquid chromatography-tandem mass spectrometry. Neurogastroenterol Motil. 2009;21:734-e43.CrossRef Camilleri M, Nadeau A, Tremaine WJ et al. Measurement of serum 7α-hydroxy-4-cholesten-3-one (or 7αC4), a surrogate test for bile acid malabsorption in health, ileal disease and irritable bowel syndrome using liquid chromatography-tandem mass spectrometry. Neurogastroenterol Motil. 2009;21:734-e43.CrossRef
24.
go back to reference Skouras T, Dodd S, Prasad Y et al. Brief report: length of ileal resection correlates with severity of bile acid malabsorption in Crohn’s disease. Int J Colorectal Dis. 2019;34:185–188.CrossRef Skouras T, Dodd S, Prasad Y et al. Brief report: length of ileal resection correlates with severity of bile acid malabsorption in Crohn’s disease. Int J Colorectal Dis. 2019;34:185–188.CrossRef
25.
go back to reference Camilleri M, Busciglio I, Acosta A et al. Effect of increased bile acid synthesis or fecal excretion in irritable bowel syndrome-diarrhea. Am J Gastroenterol. 2014;109:1621–1630.CrossRef Camilleri M, Busciglio I, Acosta A et al. Effect of increased bile acid synthesis or fecal excretion in irritable bowel syndrome-diarrhea. Am J Gastroenterol. 2014;109:1621–1630.CrossRef
26.
go back to reference Watanabe H, Akasaka D, Ogasawara H et al. Peripheral serotonin enhances lipid metabolism by accelerating bile acid turnover. Endocrinology 2010;151:4776–4786.CrossRef Watanabe H, Akasaka D, Ogasawara H et al. Peripheral serotonin enhances lipid metabolism by accelerating bile acid turnover. Endocrinology 2010;151:4776–4786.CrossRef
27.
go back to reference Bijvelds MJC, Jorna H, Verkade HJ et al. Activation of CFTR by ASBT-mediated bile salt absorption. Am J Physiol Gastrointest Liver Physiol. 2005;289:G870–G879.CrossRef Bijvelds MJC, Jorna H, Verkade HJ et al. Activation of CFTR by ASBT-mediated bile salt absorption. Am J Physiol Gastrointest Liver Physiol. 2005;289:G870–G879.CrossRef
28.
go back to reference Gregersen T, Grønbæk H, Worsøe J et al. Effects of sandostatin LAR on gastrointestinal motility in patients with neuroendocrine tumors. Scand J Gastroenterol. 2011;46:895–902.CrossRef Gregersen T, Grønbæk H, Worsøe J et al. Effects of sandostatin LAR on gastrointestinal motility in patients with neuroendocrine tumors. Scand J Gastroenterol. 2011;46:895–902.CrossRef
29.
go back to reference Saslow SB, Camilleri M, Thomforde GM et al. Relation between fat malabsorption and transit abnormalities in human carcinoid diarrhea. Gastroenterology 1996;110:405–410.CrossRef Saslow SB, Camilleri M, Thomforde GM et al. Relation between fat malabsorption and transit abnormalities in human carcinoid diarrhea. Gastroenterology 1996;110:405–410.CrossRef
30.
go back to reference Saslow SB, O’Brien MD, Camilleri M et al. Octreotide inhibition of flushing and colonic motor dysfunction in carcinoid syndrome. Am J Gastroenterol. 1997;92:2250–2256.PubMed Saslow SB, O’Brien MD, Camilleri M et al. Octreotide inhibition of flushing and colonic motor dysfunction in carcinoid syndrome. Am J Gastroenterol. 1997;92:2250–2256.PubMed
31.
go back to reference Vijayvargiya P, Camilleri M, Burton D et al. Bile and fat excretion are biomarkers of clinically significant diarrhoea and constipation in irritable bowel syndrome. Aliment Pharmacol Ther. 2019;49:744–758.CrossRef Vijayvargiya P, Camilleri M, Burton D et al. Bile and fat excretion are biomarkers of clinically significant diarrhoea and constipation in irritable bowel syndrome. Aliment Pharmacol Ther. 2019;49:744–758.CrossRef
32.
go back to reference Schiller LR, Bilhartz LE, Santa Ana CA et al. Comparison of endogenous and radiolabeled bile acid excretion in patients with idiopathic chronic diarrhea. Gastroenterology 1990;98:1036–1043.CrossRef Schiller LR, Bilhartz LE, Santa Ana CA et al. Comparison of endogenous and radiolabeled bile acid excretion in patients with idiopathic chronic diarrhea. Gastroenterology 1990;98:1036–1043.CrossRef
33.
go back to reference Muhammad WS, Alicia R, Melissa HS et al. Chronic use of long-acting somatostatin analogues (SSAs) and exocrine pancreatic insufficiency (EPI) in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs): An under-recognized adverse effect. Cancer Med J. 2020;3:75–84.CrossRef Muhammad WS, Alicia R, Melissa HS et al. Chronic use of long-acting somatostatin analogues (SSAs) and exocrine pancreatic insufficiency (EPI) in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs): An under-recognized adverse effect. Cancer Med J. 2020;3:75–84.CrossRef
34.
go back to reference Thomas LA. Octreotide induced prolongation of colonic transit increases faecal anaerobic bacteria, bile acid metabolising enzymes, and serum deoxycholic acid in patients with acromegaly. Gut 2005;54:630–635.CrossRef Thomas LA. Octreotide induced prolongation of colonic transit increases faecal anaerobic bacteria, bile acid metabolising enzymes, and serum deoxycholic acid in patients with acromegaly. Gut 2005;54:630–635.CrossRef
Metadata
Title
Bile Acid Malabsorption in Patients with Neuroendocrine Tumors
Authors
Lehar Khanna
Thorvardur R. Halfdanarson
Mohamad B. Sonbol
Rachel Eiring
Teresa Prond
Michael Camilleri
Publication date
07-08-2021
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 6/2022
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-021-07189-7

Other articles of this Issue 6/2022

Digestive Diseases and Sciences 6/2022 Go to the issue

Editorial

BAM ≢ BAD