Case Report Open Access
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 7, 2018; 24(21): 2320-2326
Published online Jun 7, 2018. doi: 10.3748/wjg.v24.i21.2320
Obeticholic acid for severe bile acid diarrhea with intestinal failure: A case report and review of the literature
Christian Lodberg Hvas, Peter Ott, Peter Paine, Simon Lal, Søren Peter Jørgensen, Jens Frederik Dahlerup
Christian Lodberg Hvas, Peter Ott, Søren Peter Jørgensen, Jens Frederik Dahlerup, Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus C 8000, Denmark
Peter Paine, Simon Lal, Department of Gastroenterology, Salford Royal NHS Foundation Trust, Salford, Manchester M6 8HD, United Kingdom
ORCID number: Christian Lodberg Hvas (0000-0001-7973-7184); Peter Ott (0000-0002-3088-1983); Peter Paine (0000-0003-4131-9651); Simon Lal (0000-0002-6245-8864); Søren Peter Jorgensen (0000-0002-6530-6655); Jens Frederik Dahlerup (0000-0002-1587-7636).
Author contributions: Hvas CL treated the intestinal failure in the patient and wrote the first draft of the manuscript; Ott P managed the communications with Intercept Pharmaceuticals, discussed the treatment and drafted the manuscript; Paine P and Lal S discussed the differential diagnoses during the treatment of the patient and revised the manuscript; Jørgensen SP provided expertise on BAD and FXR biology and revised the manuscript; Dahlerup JF was responsible for treating the patient, handled the communication with National Health Authorities, and revised the manuscript; all authors approved the final version of the manuscript.
Informed consent statement: The patient gave oral and written consent for the publication of this case report. A signed informed consent statement has been uploaded with the submission of the manuscript.
Conflict-of-interest statement: Hvas CL reports lecture fees from Takeda, Ferring, Novartis, MSD, and Tillotts. Ott P reports a lecture fee from Intercept Pharmaceuticals. Lal S reports grants from Fresenius Kabi and Shire. Dahlerup JF reports lecture fees from Pharmacosmos, MSD, and Takeda. All other authors declare that they have no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Christian Lodberg Hvas, MD, PhD, Associate Professor, Department of Hepatology and Gastroenterology, Aarhus University Hospital, Nørrebrogade 44, Aarhus C 8000, Denmark.
Telephone: +45-78463895 Fax: +45-78462820
Received: January 20, 2018
Peer-review started: January 22, 2018
First decision: February 26, 2018
Revised: March 8, 2018
Accepted: March 31, 2018
Article in press: March 31, 2018
Published online: June 7, 2018


Bile acid diarrhea results from excessive amounts of bile acids entering the colon due to hepatic overexcretion of bile acids or bile acid malabsorption in the terminal ileum. The main therapies include bile acid sequestrants, such as colestyramine and colesevelam, which may be given in combination with the opioid receptor agonist loperamide. Some patients are refractory to conventional treatments. We report the use of the farnesoid X receptor agonist obeticholic acid in a patient with refractory bile acid diarrhea and subsequent intestinal failure. A 32-year-old woman with quiescent colonic Crohn’s disease and a normal terminal ileum had been diagnosed with severe bile acid malabsorption and complained of watery diarrhea and fatigue. The diarrhea resulted in hypokalemia and sodium depletion that made her dependent on twice weekly intravenous fluid and electrolyte infusions. Conventional therapies with colestyramine, colesevelam, and loperamide had no effect. Second-line antisecretory therapies with pantoprazole, liraglutide, and octreotide also failed. Third-line treatment with obeticholic acid reduced the number of stools from an average of 13 to an average of 7 per 24 h and improved the patient’s quality of life. The fluid and electrolyte balances normalized. The effect was sustained during follow-up for 6 mo with treatment at a daily dosage of 25 mg. The diarrhea worsened shortly after cessation of obeticholic acid. This case report supports the initial report that obeticholic acid may reduce bile acid production and improve symptoms in patients with bile acid diarrhea.

Key Words: Bile acid malabsorption, Diarrhea, Farnesoid X-activated receptor, Crohn’s disease

Core tip: Bile acid diarrhea develops when excessive amounts of bile acids enter the terminal ileum and exceed the intestinal absorptive capacity. The excess bile acids enter the colon and cause secretory diarrhea. We report a patient with multiple potential causes of chronic diarrhea and suggest a systematic strategy for the diagnosis and treatment of this condition. Furthermore, we describe the use of a new treatment for severe bile acid diarrhea, obeticholic acid, which stimulates the farnesoid X receptor of the terminal ileum and increases fibroblast growth factor 19, thereby decreasing hepatic bile acid production via negative feedback.


Chronic secretory diarrhea causes intestinal losses of water, sodium, and potassium[1]. In severe cases, it may negatively affect the fluid and electrolyte balance. Chronic secretory diarrhea may be caused by intestinal inflammation, infection, drug side effects or abuse, neuroendocrine tumors, functional diarrhea, or bile acid diarrhea (BAD). When no cause is identified, the condition is termed diarrhea-predominant irritable bowel syndrome (IBS-D)[2].

BAD occurs when excess amounts of bile acids enter the colon and induce colonic fluid and electrolyte secretion and motility changes[3]. Based on the pathophysiology, BAD is classified as type 1, which is caused by ileal resection, disease, or injury, type 2, which consists of primary or idiopathic BAD, and type 3, which is secondary to other conditions, e.g., cholecystectomy[4-6].

The medical treatments of BAD include the bile acid sequestrants colestyramine and colesevelam[3,7,8]. Antisecretory or antimotility drugs such as loperamide and proton pump inhibitors may be added. Some patients with BAD experience an insufficient effect of the available conventional medical treatments and suffer from an impaired quality of life[9,10].

BAD is proposed to result from defective gut-liver feedback mechanisms. Hepatic bile acid synthesis is inhibited by fibroblast growth factor 19 (FGF19) that is produced by ileal enterocytes upon stimulation by bile acids in the terminal ileum via the farnesoid X receptor (FXR)[5,11]. Decreased circulating FGF19 levels have been reported in patients with primary BAD[12] and in patients with Crohn’s disease and diarrhea[13]. Obeticholic acid, a potent FXR agonist, stimulates ileal FGF19 production and may thereby decrease hepatic bile acid production in BAD[14]. Obeticholic acid is currently used to treat primary biliary cholangitis[15,16] and non-alcoholic steatohepatitis[17,18], but it may also improve BAD[14].

In this case report, we describe the investigations and treatments of a 32-year-old woman with Crohn’s disease who suffered from chronic secretory diarrhea that could be potentially attributed to multiple causal factors. Because no infectious, inflammatory, or metabolic cause was demonstrated other than severe bile acid malabsorption, both type 1 and type 2 BAD were considered. The patient experienced a marked and sustained improvement following treatment with obeticholic acid.


A 32-year-old Caucasian woman was referred to our unit for refractory diarrhea lasting 10 years. She had a 15-year history of recurrent depression and primary tonic-myoclonic epilepsy. Following the onset of diarrhea, she had been diagnosed with colonic Crohn’s disease, and 75selenium homotaurocholic acid test (SeHCAT) scintigraphy[19] performed six years before referral to our unit had revealed a day-7 relative bile acid retention of 0, indicating severe bile acid malabsorption. Conventional treatments for BAD with the bile acid sequestrants colestyramine and colesevelam had a limited or transient effect, and the diarrhea had been unresponsive to antisecretory treatments such as loperamide and codeine phosphate. At the time of referral, the patient received low-dose 6-mercaptopurine for Crohn’s disease, 625 mg colesevelam three times per day, 2-8 mg of loperamide per day for BAD, 1500 mg of levetiracetam per day for depression, and 400 mg of lamotrigine per day for epilepsy. The doses of both levetiracetam and lamotrigine had been optimized using therapeutic drug monitoring. Prior treatments also included 40 mg of escitalopram per day and 225 mg of venlafaxin per day, which led to poor control of the depression and did not affect bowel function. Anti-inflammatory Crohn’s disease treatments with infliximab, adalimumab, natalizumab, and vedolizumab had been provided before referral and did not affect the diarrhea. Crohn’s disease remission had been verified via a colonoscopy and fecal calprotectin measurement. The duodenal biopsies were normal. The patient had not undergone bowel surgery.

During the first admission to our unit, the results from all investigations were reviewed, and a diagnostic workup was planned (Table 1). The patient’s height and weight were 52 kg and 170 cm, respectively. Biochemical analysis revealed severe electrolyte deficiency with low plasma levels of potassium and magnesium. Although the plasma sodium level was normal, sodium depletion was indicated by the urinary sodium being below the detection limit using both single urine measurements and an analysis of a 24-h urine collection. Fecal cultures were negative for Campylobacter, Salmonella, Yersinia, and Shigella species, but a PCR toxin test for Clostridium difficile was positive. A 10-d trial of 125 mg of vancomycin four times per day had a transient effect on the diarrhea, and repeat fecal tests were negative. MRI of the small bowel and pan-enteric double balloon endoscopy revealed endoscopic remission, and duodenal, jejunal, ileal, and colonic biopsies were normal. A laxative screen and markers of systemic infection or metabolic disease were normal (Table 1). All medical treatments were reviewed, and because the diarrhea persisted despite conventional treatment, trials of spironolactone, octreotide, and liraglutide were initiated during the admission but were without effect or produced unacceptable side effects (Table 2). The dose of 6-mercaptopurine was optimized using thiopurine metabolite measurements, revealing a normal TPMT genotype and phenotype, an E-TGN level of 247 nmol/mmol HGB, and an E-MeMP level of 2354 nmol/mmol HGB.

Table 1 Potential causes of chronic diarrhea and their diagnostic investigations and results in a patient with severe bile acid diarrhea and intestinal failure.
Potential cause of diarrheaInvestigationsResults
Excess bile acid production with deficient retentionSeHCAT scintigraphy0 retention, indicating an excess loss of bile acids
Active Crohn’s diseaseSmall bowel imaging; colonoscopy; fecal calprotectinNormal MRI of small bowel and capsule endoscopy; normal colonoscopy with biopsies; fecal calprotectin < 30 mg/kg
Small bowel disease (celiac disease, autoimmune enteropathy)Duodenal and jejunal biopsies; plasma tissue transglutaminase antibodyNormal biopsies; anti-transglutaminase negative
Clostridium difficile infectionClostridium difficile toxin testPositive before fecal transplant; negative repeated tests after fecal transplant
Pathogenic intestinal infectionSalmonella, Shigella, Campylobacter, and Yersinia fecal cultures; PCR for intestinal parasitesNegative
Systemic infectionHIV test; gamma-interferon test for tuberculosisNegative
Small intestinal bacterial overgrowth (SIBO)Hydrogen breath testNegative
Use of antidepressant and antiepileptic medicationsObservation during drug holiday; therapeutic drug monitoringTreatment dose optimized
Laxative useUrine laxative screen repeated with a patient-blinded sampling timeNegative × 2
Neuroendocrine tumorChromogranin A, gastrin, vasoactive intestinal polypeptide, renin, and aldosteroneAll within the reference range
Metabolic diseaseThyroid function test and synacthen testAll within the normal range
Table 2 Anti-diarrheal drug treatments, their mechanisms of action, and their treatment results in a patient with severe bile acid diarrhea and intestinal failure.
DrugMechanism of actionTreatment effect
Colestyramine (Questran®)Bile salt sequestrantLimited effect
Colesevelam (Cholestagel®)Bile salt sequestrantLimited effect
PantoprazoleProton pump inhibitorNo effect
Loperamide (Imodium®)Decreases intestinal motilityNo effect
Codeine phosphateDecreases intestinal motilityNo effect; sedation
SpironolactoneIncreases renal potassium reabsorptionNo effect on potassium deficiency
OctreotideAntisecretoryNo effect; abdominal pain
Liraglutide (Victoza®)Increases glucagon-like peptide 1 (GLP-1)No effect; weight loss of 2 kg to 52 kg
Obeticholic acid (Ocaliva®)Stimulates ileal FGF19 production, thereby inhibiting hepatic bile acid productionMarked reduction of stool volume and fecal electrolyte loss

Due to having persistent dehydration with a passage of up to 5 L of watery stools per day, the patient was considered for long-term intravenous support. The patient’s potassium levels normalized upon infusions of up to 100 mmol of potassium per day, but the urinary sodium became measurable in the 24-h urine samples only after hypertonic NaCl was applied at 2000 mL of 3% NaCl per day. Because intravenous supplementation was necessary to sustain a normal hydration and electrolyte status, the patient was classified as having type III intestinal failure, subtype A3[20]. A scheduled regimen was established with twice weekly infusions of fluids and electrolytes, but the patient remained underweight, had watery diarrhea, and had a poor quality of life.

A trial of obeticholic acid was considered because of the promising initial reports[14]. Following collaboration with Intercept Pharmaceuticals and approval from the National Health Authorities, we were able to start obeticholic acid during admission. In the initial investigation, a repeat Clostridium difficile test was positive, and a fecal transplant using an anonymous donor was performed following a short vancomycin taper. Subsequently, the mean number of bowel passages per 24 h decreased from a mean of 17 to a mean of 13. Obeticholic acid was then started at 10 mg per day and increased to 25 mg per day after 4 d. Importantly, obeticholic acid further reduced the number of bowel movements from a mean of 13 to a mean of 7 per 24 h (Figure 1). When the number of bowel movements during the two weeks of treatment with 25 mg of obeticholic acid per day was compared with that of the two weeks before treatment, the difference was highly statistically significant (P = 0.00001, Mann-Whitney U test). While nightly bowel movements had been a persistent problem before the initiation of treatment, these were reduced from a mean of 3 nightly bowel openings to a mean of 2 nightly bowel openings following treatment, and on occasional nights, the patient did not open her bowel during the night. The patient’s weight increased by 2 kg to 54 kg, and she was weaned off intravenous fluid support. She resumed social activities, including running, although this occasionally induced an increase in the number of bowel movements (Figure 1). She remained sensitive to non-steroid anti-inflammatory drug treatment because a single dose of 400 mg of ibuprofen transiently induced liquid stools (Figure 1). The quality of life was estimated using the Euroqol EQ-5D-3L questionnaire ( Before the treatment, the patient reported an overall wellbeing of 35 on a 0-100 scale. This increased to 85 following two weeks of obeticholic acid treatment and remained at this level for six months of follow-up.

Figure 1
Figure 1 Bowel movement frequencies before and during the initial two months of treatment with 25 mg obeticholic acid once daily for severe bile acid diarrhea with intestinal failure.

To examine whether the effects were specific to obeticholic acid and whether the effect would last without continued treatment, the patient agreed to a treatment pause. Following three days without obeticholic acid, the patient’s condition deteriorated, with an increase in the number of bowel movements in 24 h from 7 to 16 and profound hypokalemia. Shortly after restarting obeticholic acid, the patient’s bowel control was reestablished. During 6 mo of follow-up, we observed no adverse effects, and control of Crohn’s disease, epilepsy, and depression did not change. A single episode of increased serum pancreatic amylase (266 U/L; reference range: 10-65 U/L) necessitated a pause of the 6-mercaptopurine treatment. Ultrasound examination revealed a normal pancreas and bile ducts, and the p-amylase level normalized. A diagnosis of acute pancreatitis could therefore not be confirmed, and treatment was restarted without further episodes or an increase in the pancreatic or liver function tests. The plasma lipids were slightly elevated before the treatment and decreased during the obeticholic acid treatment. Thus, the patient’s total cholesterol decreased from 7.5 to 5.9 mmol/L, and her LDL-cholesterol level decreased from 4.5 to 3.1 mmol/L, while her HDL-cholesterol increased slightly from 2.0 to 2.1 mmol/L. Measurements of fasting serum FGF19 were performed once before and six times during treatment with obeticholic acid, using the Human FGF-19 Quantikine ELISA kit DF 1900 (R&D Systems, Minneapolis, MN, United States). Although the mean FGF19 level increased from 35.7 to 167.0 pg/mL during treatment with 25 mg per day, we observed a marked fluctuation in the serum FGF levels during obeticholic treatment, with serum FGF19 concentrations ranging from 21 pg/mL to 728 mg/mL.


This case report demonstrates the challenges related to the diagnosis and treatment of patients with multifactorial chronic diarrhea. In this patient, a thorough and systematic evaluation of several differential diagnoses was pivotal for understanding the causes of chronic diarrhea in the presence of a severely disrupted electrolyte balance and intestinal failure. Because the SeHCAT retention rate was 0 on day 7, an overproduction of bile acids in combination with severe bile acid malabsorption was indicated. In the absence of other causes of chronic diarrhea, we concluded that the patient had severe BAD. Before treatment with obeticholic acid, the patient had intestinal failure with a dependency on intravenous fluid and electrolyte support. To the best of our knowledge, this is the first report of BAD of such severity.

For patients with chronic diarrhea, the SeHCAT scintigraphy identifies those with BAD and, hence, a treatable cause of diarrhea[8,19,21-23]. It further helps to tailor the treatment. This investigation therefore remains an important tool in the diagnostic workup and should be considered in patients with Crohn’s disease and unresolved diarrhea[6].

While this patient was refractory to conventional therapies for diarrhea, she improved both clinically and biochemically following treatment with obeticholic acid. This adds to the promising data that indicate obeticholic acid may improve BAD via a modulation of negative feedback signaling of FGF19 on hepatic bile acid production[14]. Obeticholic acid is marketed for the treatment of primary biliary cholangitis and has been investigated in dosages of 10 mg to 50 mg daily for 3 mo[15] and up to 10 mg daily for 12 mo[16]. Pruritus was the most common side effect and occurred in up to two-thirds of the treated patients, even at low doses. We observed no side effects in this patient. Because the treatment was well-tolerated, and the improvements of fluid balance and quality of life were sustained during the follow-up, we did not change the treatment dose.

We measured fasting serum FGF19 levels both before and during treatment and found that obeticholic acid increased FGF19 levels, but with substantial variation between samples obtained during treatment. The finding supports that hepatic bile production is inhibited by FGF19 signaling following the obeticholic acid-induced stimulation of FXR in ileal enterocytes[12,24,25]. It also emphasizes that the use of FGF19 measurement should be validated. In general, FGF19 levels depend on renal function, age, and systemic inflammation[26,27]. In patients with Crohn’s disease, FGF19 levels are generally lower than in control patients, and low levels are associated with ileal resection and with active disease, independently of ileal resection[13].

In conclusion, we found that treatment with oral obeticholic acid (25 mg daily) induced a marked and sustained improvement of bowel function, fluid and electrolyte balance, and quality of life in this patient with severe BAD and intestinal failure. Future clinical trials should investigate the long-term clinical effects of obeticholic acid, including safety measures and serum FGF19 dynamics.

Case characteristics

A 32-year-old woman with chronic diarrhea that had multiple potential causes including bile acid diarrhea, Crohn’s disease, and medications for epilepsy and depression.

Clinical diagnosis

Bile acid diarrhea (BAD), diagnosed by selenium homotaurocholic acid test scintigraphy with 0 bile acid retention after seven days.

Laboratory diagnosis

Persistently low plasma levels of sodium and potassium and undetectable 24-h urine sodium excretion, indicating intestinal failure with dependency of intravenous fluid support.

Pathological diagnosis

Normal duodenal, jejunal, ileal, and colonic biopsies, indicating quiescent Crohn’s disease. Positive Clostridium difficile toxin PCR test indicating Clostridium difficile colitis.


Clostridium difficile colitis was treated with vancomycin followed by fecal microbiota transplantation. Bile acid diarrhea was refractory to conventional treatments including colestyramine and colesevelam, and oral obeticholic acid treatment was commenced at 10 mg per day, increasing to 25 mg per day. Upon this, the patient’s bowel habits and quality of life improved.

Related reports

Obeticholic is licensed for primary biliary cholangitis and has been used in non-alcoholic steatohepatitis. It was recently reported that obeticholic acid may improve bile acid diarrhea through induction of fibroblast growth factor 19 that inhibits hepatic bile production.

Term explanation

BAD–bile acid diarrhea, resulting from excess hepatic production and/or deficient ileal reabsorption of bile acids, which in turn induces colonic fluid and electrolyte secretion and leads to chronic secretory diarrhea.

Experiences and lessons

In patients with chronic diarrhea, a thorough and systematic diagnostic workup may help to differentiate between potential causes of diarrhea. Some patients with bile acid diarrhea are refractory to conventional treatments. Obeticholic acid may be of clinical benefit in these patients.


Manuscript source: Unsolicited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Denmark

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CARE checklist (2013) statement: This case report conforms to the CARE checklist (2013), and a fulfilled PDF version of the checklist was attached with the submission of the manuscript.

P- Reviewer: Munck LK, Walters JRF, Wenzl HH S- Editor: Wang XJ L- Editor: A E- Editor: Huang Y

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