1) Bile acid malabsorption (BAM) results from dysregulation of the enterohepatic recycling of bile acids and is a common but underrecognized cause of chronic diarrhea. 2) BAM should be considered as a potential cause of chronic diarrhea, especially in patients with a history of ileal disease or resection due to conditions like Crohn's disease. 3) While diagnostic tests exist for BAM, access may be limited, so treatment with bile acid binders can be tried empirically if BAM is suspected as the cause of chronic diarrhea.

1. Gastroenterology & Hepatology: Open Access 2016

2. • Bile acid malabsorption (BAM) results from
dysregulation of the enterohepatic recycling of
bile acids &bile acid production.
• Often regarded as a rare phenomenon
• The most common clinical presentation is chronic
diarrhea, approximately 1/3 of new patients
presented this symptom.
Introduction

3. • The primary bile acids are cholic acid (CA) &
chenodeoxycholic acid (CDCA); synthesized from
cholesterol in the liver, conjugated with glycine or
taurine to increase their water solubility&
secreted to bile.
• Secondary bile acid are deoxycholic acid (DCA) &
lithocholic acid, derived from primary bile acids as
a result of as deconjugation, 7-dehydroxylation by
intestinal bacteria, toincrease passive absorption
of secondary bile acids in the colon.
EHC Of BAs:

4. • 95% of primary bile acids are reabsorbed by the
distal ileum through active uptake by the apical
sodium-dependent bile acid transporter (ASBT),
returned to the liver via the portal circulation &
taken up by hepatocytes.
• A small % entering the colon can be passively
absorbed, resulting in an overall net loss of 1- 3%.
• The conservation of the bile acid pool is altered by
more rapid intestinal transit & changes in gut flora
because of the different types of dieting,
medications or other factors.
EHC Of BAs:

5. • Approximately 0.5 g of bile acids are synthesized
in the liver per day, the total bile acid pool is
approximately 3 g, of which 95% is reclaimed from
the ileum & a small amount of unconjugated bile
acids is recaptured in the colon via passive non
ionic diffusion.
• The cycle repeats for almost 4 - 12 times per day,
resulting in an estimated loss of 0.2 g-0.6g/day in
the feces&must be replaced with bile acid
synthesized by the hepatocytes.
EHC Of BAs:

6. Chenodeoxycholic acid Deoxycholic acidCholic acid
Bile Acids
Lithocholic acid
What are Bile Acids?
• “Digestive Detergents”
• Important role in absorbing Fats

7. Bile Acids: What do they do?
TI absorption reduced
Excess BA spills into colon
Reduces calcium-
mediated water &
electrolyte absorption:
Net fluid loss
Watery diarrhoea
Courtesy of KD Bardhan, Emeritus Professor, Rotherham
• Released into the small intestine
• After function performed – recycled
back to the liver
97%
Gallbladder
Liver
Ileum
3%
• Released into the small intestine
• After function performed – recycled
back to the liver

8. TI absorption reduced
Excess BA spills into colon
Reduces calcium-
mediated water &
electrolyte absorption:
Net fluid loss
Watery diarrhoea
• Role in Fat Digestion
• Secreted into the small intestine
• After function performed – recycled
back to the liver
Reabsorption reduced
Excess BA spills into colon
Watery diarrhoea
Salt and Water Secretion
<<97%
Gallbladder
Liver
Diarrhoea
Bile Acid Malabsorption (BAM)
1. Active inflammation of the
Terminal Ileum (Crohn’s)
2. Surgically removed
Ileum
>>3%
Problems with Bile Acids

10. Epidemiology:
• Common under-recognized cause of chronic diarrhea.
• Frequently not considered as a possible cause.
• Prevalence of 4-5%.
• > 90% OF Resected CD & 12-52% of un-resected CD.
• 1/3 IN IBS-D.

11. Epidemiology: Types
1.Type 1: Ileal dysfunction & impaired reabsorption such as
Crohn’s disease.
2.Type 2: Primary, or idiopathic, BAM produces a similar
picture of increased fecal BAs, watery diarrhea&response to
BA sequestrants in the absence of ileal or other obvious GI
disease.
3. Type 3: Other GI disorders such as small intestinal
bacteria overgrowth, celiac disease, or chronic pancreatitis.
4. Excessive hepatic BA synthesis, from the use of
hypoglycemic drugs (metformin).

12. Epidemiology: Diseases
• Ileal disease: Following ileal resection, typically due to
Crohn’s disease, BAs are not absorbed normally, which
leads to BAM.
• A complication of Crohn’s ileitis without resection can
result in alteration of bile acid absorption.

13. Epidemiology: diseases
• Type 3 BAM include conditions such as pancreatic
insufficiency, cholecystectomy & small intestinal bacterial
overgrowth.
• Malignant tumors may have had radiation ileitis,
pancreatitis, resection &bacterial overgrowth.

14. Epidemiology: diseases
• 1/3 of patients with a diagnosis of IBS-D have BAM.
• 10% presented severe BAM
• 32% moderate BAM
• 26% some degree of BAM (mild, moderate or severe).

15. Epidemiology: diseases
• BAM is associated to altered bicarbonate secretion in
chronic pancreatitis.
• In celiac disease, caused by impairments in gall bladder
motor function&atrophy of the small intestinal mucosa.

16. Epidemiology: T2BAM
A. Defective feedback inhibition of bile acid biosynthesis by
FGF- 19: FGF-19 is produced in the ileum to regulate
hepatic BA synthesis, in response to their absorption.
B. Genetic mutations in the apical sodium-bile acid
transporter (ASBT): extremely rare.
C. Accelerated small bowel transit bypassing active bile acid
transport in the ileum:

17. Epidemiology: T2BAM
D. Genetic variations in the proteins involved in feedback
regulation of bile acid synthesis, KlothoB gene & fibroblast
growth factor 4 gene: This theory is based on the association
of SNP rs17618244 in the KlothoB gene with colonic transit
in IBS-D. Pharmacogenetic studies suggest that variations in
the KlothoB gene may result in bowel response to BAM.
E. Upregulation of the membrane bound bile acid receptor
(GPBAR1): GPBAR1 is a member of the G protein-coupled
receptor family that works as a surface receptor for BA.
variations in GPBAR1 may predispose to quantitative changes in the
excretion of BA.

18. Epidemiology: Features
• Bile acid malabsorption usually manifests as a chronic,
watery diarrhea.
• In type 2 BAM this can be the only symptom the patient
refers, but gastroenterologists often do not relate the
condition as a possible cause for chronic diarrhea.
• BAM should be clinical suspected & investigated in the
presence of chronic diarrhea following a resection in
Crohn’s disease or associated to other conditions such as
pancreatitis.

19. More than BAM
• Seen :
– After gallbladder surgery (cholecystectomy)
– After radiation treatment (Radiation enteritis)
– With Microscopic Colitis/ Coeliac Disease
– 40% is idiopathic
• BILE ACID DIARRHOEA (BAD)
– Excessive Bile Acids
– Increased Gut Movements

20. Diarrhoea – Bread & Butter
• One of the commonest
reasons for referral to a
Gastroenterologist
• Estimated that 4-5% of the
general population have
chronic diarrhoea
• Associated with reduced
quality of life.

21. Causes of Diarrhoea
• Inflammatory bowel disease
• Coeliac disease
• Colorectal cancer
• Microscopic colitis
• Pancreatic insufficiency
• GI infections and infestations
• Bacterial overgrowth
• Lactose intolerance
• Functional diarrhoea
• Diarrhoea-predominant irritable bowel syndrome (IBS-D)
• Drugs (including laxative abuse)
• Bile Acid Diarrhoea (BAD)

23. How common is Bile Acid Diarrhoea in
the UK?
1:100,000
1:10,000 1:1,000
1:100

24. Wheat Field with Sheaves, 1888 Vincent Van Gogh
Coeliac Disease – 1%

25. Guidelines on Diarrhoea
British Society of Gastroenterology
Guidelines, 2003

26. Diagnosis of BAD
In the UK, Europe and Canada
• 23-Seleno-25-homo-tauro-cholic acid (SeHCAT)
scanning.
• Uses 370KBq capsule of 75Se homocholyltaurine
• Normal - ≥15% retention at day 7
• 15 CXRs
However, limited access in some centres, and in
the USA, SeHCAT scanning is not available
Other potential methods include:
• Serum 7α-hydroxy-4cholesten-3-one (also known as C4)
• Faecal bile acid measurement
• Trial of a bile acid sequestrant, with response used as a
positive test for BAM

27. Diagnosis of BAD
– The four main diagnostic tests
– C-glycocholate breath & stool test
– Selenium HomotauroCholic Acid Test (SeHCAT)
– Serum 7 α-hydroxy-4-cholesten-3-one (C4)
– Measurement of bile acids in feces.
– More practical are SeHCAT & C4

28. Diagnosis of BAD
• C-glycocholate breath and stool test:
• determine bacterial dependent deconjugation that happens in the
digestive tract due to BAM or other causes.
• The C-glycocholate solution is administered orally & mixes with the
pool of BAs.
• Bacteria in GIT sever the bond between glycine - cholic acid. C-glycine
is released, metabolized &exhaled as CO2.
• If early breath excretion of CO2 is detected, this is highly suggestive of
bacterial overgrowth in the small intestine.
• If not, it is inferred that the solution entered the large intestine & will
be metabolized by colonic bacteria. A small part is excreted in stool&a
stool collection after the breath test can detect BAM.
• These disadvantages &development of more practical/ improved
diagnostic tests, many centers discontinue the C-glycocholate breath /
stool test.

29. Diagnosis of BAD
• Selenium homotaurocholic acid test (SeHCAT):
• most commonly used test for diagnosis of BAM.
• The test uses a synthetic BA (selenium homotaurocholic)
that resists passive diffusion & bacterial degradation.
• The bile acid is administered orally via capsule and the
retention is measured through a gamma camera after a
week.
• A retention <10% is considered abnormal& indicates BAM.
The test has sensitivity for BAM of 80-90% & specificity of
70-100%.
• Retention of =>15% normal, 10-15% mild,5-10%
moderate,<5% severe.

30. Diagnosis of BAD
• C4 serum level:
• BA synthesis is regulated by the enzyme cholesterol
7αhydroxylase (CYP7A1).
• C4 is a product of CYP7A1.
• Serum C4 consists of a simple blood test in the morning
after an overnight fasting, followed by isolation of C4
through liquid chromatography-tandem mass spectrometry.
• An elevated serum C4 concentration is >60.7ng/mL.
• The C4 test has a high sensitivity & specificity (90 and 79%)
& negative / positive predictive values of 98% and 74%,
respectively, in comparison to the SeHCAT test.

31. Diagnosis of BAD
• Fecal BA
• Indirect, since they measure BA synthesis or retention.
• Increased total fecal BA is reported in chronic diarrhea
& in IBS-D.
• It is an arduous technique,complex & needs the
expertise /skill.
• Even though in the future it may become the gold
standard test, it is not available in every center.

32. Not just chronic diarrhoea

33. Not just chronic diarrhoea

34. Under-recognised and Under-
utilised
Survey of 436 UK Gastroenterologists:
– 34% of all new patients seen had chronic diarrhoea
– BAM was considered as a possible cause in only 22%
– 72% of Gastroenterologists only considered after other
investigations negative
– Estimated 184 new diagnoses of BAM per month
– Equates to 5 cases per Gastroenterologist per year
– 50% of all SeHCAT scans in the UK come from 10
hospitals
– <80 of the 250 departments in the UK equipped to
perform SeHCAT do so
Khalid et al. Clin Medicine 2010;10:124-126

35. Testing may be improving
0
20
40
60
80
100
120
2005 2006 2007 2008 2009 2010 2011
Year
Negative
Positive
Proportion of patients with a positive test in each year did not vary significantly
(χ2 for trend = 1.46, P = 0.96)
Gracie et al. Neurogastroenterol Motil 2012;24:983-e538

36. Coeliac Disease
• 1988: 273 publications
• 1993: 332 publications
• 1998: 470 publications
• 2003: 658 publications
• 2008: 908 publications
• 2013: 972 publications
Bile Acid Malabsorption
• 1988: 27 publications
• 1993: 18 publications
• 1998: 31 publications
• 2003: 26 publications
• 2008: 11 publications
• 2013: 23 publications
• SeHCAT = 87 in total
Why the difference between coeliac
disease and bile acid malabsorption??!!

37. Treatment:
• BA sequestrants:
• Cholestyramine,colestepole &colesevelam.
• Effective.
• Lower cholesterol too.
• No systemic side effects.
• Cholestyramine has unpleasant taste,constipation, Flatulence,
borborygmi, abdominal pain and nausea.
• Both cholestyramine &colestipol can interact with other drugs such
as thiazide diuretics, digoxin, beta-blockers & thyroid hormones,
reducing their absorption & serum concentrations so dministered 2
hours before the bile acid binders.
• Response to cholestyramine was detected in 96% of patients with
<5% retention in the SeHCAT, 80% at <10% & 70% at <15%.

38. Treatment:
Colesevelam more effective binder, better tolarated & is oral tabs
without unpleasant taste.ome Messages

39. Take Home Messages
• BAD is common/under-recognised
• Diagnosing BAD can reduce
misdiagnosis, inappropriate
treatments & potentially improve
QOL

40. Take Home Messages

41. BAM is a frequently ignored DD in patients with chronic diarrhea.
Even uncommon, GEs fail to assess their patients for it.
BAM should always be suspected in patients with chronic, watery
diarrhea, particularly in patients with history of ileal disease, bowel
resection due to Crohn’s disease or other related GIT pathologies.
Take Home Messages

42. • Type 2 BAM or idiopathic BAM, can also be a contributing factor in
causing diarrhea in one-third of patients with IBS-D.
The etiology of idiopathic BAM is still not entirely understood but it
is believed alterations in the enterohepatic circulation, lowered
FGF19 levels
Take Home Messages

43. • Since diagnostic tests like SeHCAT or C4 are not readily available in
all medical centers & gastroenterology practices.
It is recommended to provide an empirical treatment with bile acid
binders, such as cholestyramine, in case BAM is the cause of chronic
diarrhea, as currently recommended by AGA & BSG guidelines.
Take Home Messages