doi:10.1111/codi.12932
Original article
Are bile acid malabsorption and bile acid diarrhoea important causes of loose stool complicating cancer therapy? F. Phillips, A. C. G. Muls, A. Lalji and H. J. N. Andreyev The GI unit, The Department of Medicine, The Royal Marsden Hospital, London, UK Received 8 October 2014; accepted 22 December 2014; Accepted Article online 28 February 2015
Abstract Aim Gastrointestinal (GI) symptoms during and after cancer therapy can significantly affect quality of life and interfere with treatment. This study assessed whether bile acid malabsorption (BAM) or bile acid diarrhoea (BAD) are important causes of diarrhoea associated with cancer treatment. Method A retrospective analysis was carried out of consecutive patients assessed for BAM using (75Se) Selenium homocholic acid taurocholate (SeHCAT) scanning, after reporting any episodes of loose stool, attending a gastroenterology clinic in a cancer centre. Results Between 2009 and 2013, 506 consecutive patients (54.5% male; age range: 20–91 years), were scanned. BAM/BAD was diagnosed in 215 (42.5%). It was mild in 25.6%, moderate in 29.3% and severe in 45.1%. Pelvic chemoradiation had induced BAM in > 50% of patients. BAM was also frequent after treatment for conditions not previously associated with BAM, such as anal and colorectal cancer, and was present in > 75% of
Introduction The increasingly sophisticated options available for the treatment of cancer have led to a significant increase in the number of survivors, but this has been accompanied by a hidden burden. During treatment with chemotherapy and radiotherapy, up to 90% of patients will develop acute gastrointestinal (GI) symptoms, which may interfere with delivery of cancer treatment and affect quality of life [1]. There has been very limited research investigating the cause of these symptoms. Acute symptoms often settle after completion of treatment, but approximately 25% of patients go on to expeCorrespondence to: Dr Jervoise Andreyev, Department of Medicine, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK. E-mail: [email protected]
730
patients referred after pancreatic surgery. It was also unexpectedly frequent in patients who were treated for malignancy outside the GI tract, such as breast cancer and haematological malignancy. Conclusion BAM/BAD are very common and underappreciated causes of GI symptoms after cancer treatment. Health professionals should have a low threshold in suspecting this condition, as diagnosis and treatment can significantly improve quality of life. Keywords SeHCAT, bile acid malabsorption, diarrhoea, cancer, chemotherapy, radiotherapy What does this paper add to the literature? The study identifies, for the first time, that a wide spectrum of cancers are associated with BAM/BAD. Smallbowel dysfunction is frequently present after treatment for rectal and anal cancer. BAD is frequent in patients treated for upper-GI-tract cancer. Patients with intermittent or continuous loose stool during and after cancer treatment should be routinely assessed for the presence of BAM/BAD.
rience chronic disturbances that reduce quality of life. GI symptoms are one of the most common consequences of cancer treatment and have the greatest impact on daily activity [1]. Despite this, most patients with GI symptoms are never referred to a GI specialist, and, even if they are, the doctor may be unfamiliar with the spectrum of problems that can develop or how to manage these problems optimally and as a result prescribe ineffective, or dangerous, treatment [1]. It is gradually being understood that many patients can be treated effectively if they are appropriately investigated. A fundamental finding is that the cause is multifactorial in two-thirds of patients. If each cause is treated appropriately then this can give significant symptom relief [2]. Possibly causes
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 730–734
F. Phillips et al.
for chronic GI dysfunction in this setting are the development of bile acid malabsorption (BAM) or bile acid diarrhoea (BAD). Malabsorption occurs when there is dysfunction of absorptive mechanisms in the terminal ileum – for example after right hemicolectomy or when the terminal ileum is diseased (e.g. in those with Crohn’s disease or radiation enteropathy). However, in a landmark paper, Walters et al. [3] showed that in patients with so called idiopathic bile acid malabsorption, the mechanism for diarrhoea is that of ineffective feedback so that while absorption capacity is normal or enhanced, it is overwhelmed by excessive bile production by the liver a condition which should be called BAD. It is now recognized that 1% of the population in the western world are misdiagnosed as having diarrhoea-predominant irritable bowel syndrome, when in fact they have BAD [4]. BAM/BAD as the cause of chronic symptoms after treatment for cancer is less well established. Studies, often containing small numbers of patients, have suggested that BAM/BAD may occur in 1–80% of patients with chronic diarrhoea [5–12]. However, most of these studies have concentrated on patients with gynaecological cancer treated with radiotherapy and, because of their small size, definitive conclusions cannot be drawn. The present study aimed to investigate the prevalence of BAM/BAD in a large consecutive cohort of patients referred to a specialist GI clinic for the management of symptoms developing after treatment for cancer (Fig. 1).
Method This retrospective study was reviewed and approved by the Royal Marsden Hospital Committee for Clinical Research and did not require informed consent from patients. Patients attending the specialist gastroenterology clinic for the late effects of cancer therapy were managed using a peer-reviewed investigational and treatment algorithm [13]. They underwent a set of investigations dictated by that algorithm to identify the cause(s) for their symptoms. As part of the initial consultation, all patients were routinely asked to describe the consistency of their stool with reference to the Bristol Stool Chart [14]. Those reporting type 6 (fluffy or mushy) or type 7 (liquid) stool were routinely offered a (75Se) Selenium homocholic acid taurocholate (SeHCAT) scan. The severity of BAM was graded according to the SeHCAT retention values at 7 days, as follows: 10–15% for mild BAM; 5–10% for moderate BAM; and 0–5% for severe BAM. A list of consecutive patients attending for a SeHCAT scan was obtained.
Bile acid malabsorption/diarrhoea after cancer therapy
As this was a retrospective, observational study, comparative statistics were felt not to be appropriate. As the mechanism leading to an abnormal SeHCAT scan is not known in many of the patients, both the terms bile acid diarrhoea and malabsorption have both been used.
Results Between October 2009 and August 2013, 506 consecutive patients were referred for a SeHCAT scan; 276 [54.5%; median age 66 (range: 20–86) years] were men and 230 [45.5%; median age 61 (range: 22–91) years] were women. Two-thirds of these patients had been treated with pelvic radiotherapy and one-quarter had received other treatments, including GI surgery and/or chemotherapy with or without biological agents. Up to 5% were seen either before the cancer treatment starts or without having cancer. Of the 506 patients who had undergone a SeHCAT scan, 171 (34%) had had urological cancer, 128 (25%) gynaecological cancer, 100 (20%) lower-GI-tract cancer, 58 (12%) upper-GI-tract cancer (oesophagogastric in 43 and pancreatic in 15), 35 (7%) haematological malignancy (10 with multiple myeloma and 25 with leukaemia) and 14 (3%) breast cancer. The results are shown in Fig. 1. Overall, 215 (42.5%) of the 506 patients had a new diagnosis of BAM or BAD. This was mild in 25.6%, moderate in 29.3% and severe in 45.1%.
Discussion This large consecutive series of patients who presented with a multiple GI symptoms to a specialist gastroenterological clinic focussing on treating GI and nutritional consequences of cancer therapies, suggests that if patients are selected [for a SeHCAT scan on the basis of intermittent or continuous type 6 or 7 Bristol type stool that bile acid malabsorption or bile acid diarrhoea will be found in almost half [15]. In the 11 European countries, and Canada and Australia, where SeHCAT is licensed for use, BAM/BAD can be diagnosed with high sensitivity and specificity with very reliable reproducibility [16,17]. Patients generally respond to treatment with bile-acid-binding drugs [18] and manipulating dietary fat intake [19], with a subsequent improvement in quality of life. The 128 patients with gynaecological cancer in the present study is double that reported in 1977 when the possibility of BAM was first raised. It also appears that many patients with a pelvic tumour treated with chemotherapy and radiotherapy, such as those with anal, vulval or cervical cancer, had higher rates of BAM than those having radiotherapy alone, for example for prostate can-
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 730–734
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F. Phillips et al.
Bile acid malabsorption/diarrhoea after cancer therapy
Gynaecological cancer 50%
70%
Lower GI cancer 42%
50%
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
No BAM Mild BAM Moderate BAM Severe BAM
Cervical (n = 64)
No BAM Mild BAM Moderate BAM Severe BAM
Anal (n = 36)
Rectum (n = 43)
Colon (n = 21)
Upper GI cancer
Urological cancer
35%
50%
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
No BAM Mild BAM Moderate BAM Severe BAM
Prostate (n = 161)
71%
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
Endometrial Vaginal & (n = 52) vulval (n = 12)
22%
42%
73%
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
No BAM Mild BAM Moderate BAM Severe BAM
Oesophagogastric (n = 43)
Bladder (n = 10)
Pancreatic (n = 15)
Haematological & breast cancer 44%
70%
43%
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
No BAM Mild BAM Moderate BAM Severe BAM
Haem (n = 25)
Myeloma (n = 10)
Breast (n = 14)
Figure 1 Frequency and severity of bile acid malabsorption (BAM) in 506 patients undergoing a (75Se) Selenium homocholic acid taurocholate (SeHCAT) scan: 171 with urological cancer, 128 with gynaecological cancer, 100 with colorectal cancer, 58 with upper GI cancer and 49 with haematological and breast cancer (White, no BAM; red, mild BAM; yellow, moderate BAM; green, severe BAM. Haem, haematological malignancy).
cer or for endometrial cancer. It is likely that this is the result of the sensitization of the terminal ileal mucosa by the chemotherapy to the effect of radiation. We have previously shown that the terminal ileum is sensitive to relatively low doses of irradiation [12], so in an era when intensity modulated radiotherapy to tumours in the pelvis is used more widely especially in combination with chemotherapy it is likely that BAM will be seen increasingly frequently. A right hemicolectomy was invariably associated with severe or moderate BAM in this group, a previously documented association, but one that may not be widely appreciated [20]. The sever-
732
ity of malabsorption depends on the extent of terminal ileum resected, although even very short resections can lead to severe BAM [21]. Upper-GI-tract surgery, especially a Whipple’s procedure, was associated with a positive SeHCAT result in 89% of patients, but the mechanism responsible for this is not clear. BAM/BAD occurs after upper-GI-tract surgery associated with vagotomy [22], but the mechanism for new-onset BAM/BAD after pancreatic surgery is likely to be associated with alteration in bile production in the liver or possibly rapid transit of bile acids, leading to reduced time for absorption or interference from
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 730–734
F. Phillips et al.
nonhydrolyzed triglycerides, which also impairs absorption [23]. The finding that BAM/BAD was very frequent after Whipple’s procedure is in keeping with fact that BAM/BAD is known to be associated with chronic pancreatitis and pancreatic disease in cystic fibrosis [23,24]. The mechanism responsible for BAM in patients with haematological malignancy and breast cancer is probably damage of the terminal ileum following chemotherapy or radiotherapy, reducing bile uptake. This has not been previously recognized. Some of the BAM/BAD seen in the present study may be secondary to other disease processes. Small intestinal bacterial overgrowth (SIBO) may contribute to late-onset diarrhoea, and may arise from damage of the bowel mucosa or altered motility. SIBO is also known to be a cause of BAM, as bacteria deconjugate bile acids and thereby alter their absorbability. We systematically assess our patients for SIBO and have not seen any resolution of BAM in patients successfully treated for SIBO, which indicates that BAM and SIBO are different conditions. The rate of intestinal transit is important in some patients as inducing diarrhoea with laxatives causes a mild BAM that is unresponsive to cholestyramine [25]. It has also been reported that giving loperamide to patients with diarrhoea increases SeHCAT retention [7]. In conclusion, the present study confirms that BAM or BAD is a common cause of loose stools or diarrhoea in patients following treatment for many different cancers. Testing for BAM, preferably using a SeHCAT scan, should therefore be the first line of investigation for all cancer patients with type 6 or 7 stool, as the yield of a positive test is high. Other investigations may also be required as many patients have more than one cause of their symptoms. Most patients diagnosed with new-onset BAM, and particularly those with severe BAM, report significant benefit of using a combination of dietary fat manipulation and/or bile acid-sequestering agents [13].
Acknowledgements We acknowledge support from the National Institute for Health Research to the Royal Marsden Biomedical Research Centre. Ann Muls is funded by Macmillan Cancer Support.
Conflicts of interest This study was unfunded. HJNA has acted as a paid consultant for GE, manufacturers of SeHCAT and for Sanofi Aventis/Genzyme, manufacturers of colesevelam,
Bile acid malabsorption/diarrhoea after cancer therapy
a bile acid sequestrant. FP has received travel support from GE.
References 1 Andreyev HJ, Davidson SE, Gillespie C, Allum WH, Swarbrick E. Practice guidance on the management of acute and chronic gastrointestinal problems arising as a result of treatment for cancer. Gut 2012; 61: 179–92. 2 Andreyev HJN, Benton BE, Lalji A et al. Algorithm-based management of patients with gastrointestinal symptoms in patients after pelvic radiation treatment (ORBIT): a randomised controlled trial. Lancet 2013; 382: 2084–92. 3 Walters JR, Tasleem AM, Omer OS, Brydon WG, Dew T, le Roux CW. A new mechanism for bile acid diarrhea: defective feedback inhibition of bile acid biosynthesis. Clin Gastroenterol Hepatol 2009; 7: 1189–94. 4 Wedlake L, A’Hern R, Russell D, Thomas K, Walters JR, Andreyev HJ. Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2009; 30: 707–17. 5 Sullivan M. Dependence of radiation diarrhoea on the presence of bile in the intestine. Nature 1962; 195: 1217–8. 6 Stryker JA, Demers LM. The effect of pelvic irradiation on the absorption of bile acids. Int J Radiat Oncol Biol Phys 1979; 5: 935–9. 7 Yeoh E, Lui D, Lee N. The mechanism of diarrhoea resulting from pelvic and abdominal radiotherapy; a prospective study using selenium-75 labelled conjugated bile acid and cobalt-58 labelled cyanocobalamin. Br J Radiol 1984; 57: 1131–6. 8 Arlow F, Dekovich A, Priest R, Beher W. Bile acids in radiation-induced diarrhea. South Med J 1987; 80: 1259– 61. 9 Fernandez-Ba~ nares F, Villa S, Esteve M et al. Acute effects of abdominopelvic irradiation on the orocecal transit time: its relation to clinical symptoms, and bile salt and lactose malabsorption. Am J Gastroenterol 1991; 86: 1771–7. 10 Danielsson A, Nyhlin H, Persson H, Stendahl U, Stenling R, Suhr O. Chronic diarrhoea after radiotherapy for gynaecological cancer: occurrence and aetiology. Gut 1991; 32: 1180–7. 11 al-Hadrani A, Lavelle-Jones M, Kennedy N, Neill G, Sutton D, Cuschieri A. Bile acid malabsorption in patients with post-vagotomy diarrhoea. Ann Chir Gynaecol 1992; 81: 351–3. 12 Harris V, Benton BE, Sohaib A, Dearnaley D, Andreyev HJN. Bile acid malabsorption after pelvic and prostate intensity modulated radiation therapy: an uncommon but treatable condition. Int J Radiat Biol Phys 2012; 84: e601–e606. 13 Andreyev HJN, Muls AC, Norton C et al. The practical management of the gastrointestinal symptoms of pelvic radiation disease. Frontline Gastroenterol 2015; 6: 53–72.
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14 Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 1997; 32: 920–4. 15 Muls AC. Gastrointestinal symptoms after cancer treatment and the wider context. Acta Oncol 2014; 53: 297–306. 16 Bajor A, Kilander A, Sj€ ovall H, Rudling M, Ung KA. The bile acid turnover rate assessed with the (75)SeHCAT test is stable in chronic diarrhoea but slightly decreased in healthy subjects after a long period of time. Dig Dis Sci 2008; 53: 2935–40. 17 Eusufzai S, Axelson M, Angelin B, Einarsson K. Serum 7alpha-hydroxy-4-cholesten-3-one concentrations in the evaluation of bile acid malabsorption in patients with diarrhoea: correlation to SeHCAT test. Gut 1993; 1993: 698–701. 18 Wedlake L, Thomas K, Lalji A, Anagnostopoulos C, Andreyev HJN. Effectiveness and tolerability of colesevelam hydrochloride for bile-acid malabsorption in patients with cancer: a retrospective chart review and patient questionnaire. Clin Ther 2009; 31: 2549–58. 19 Bosaeus I, Andersson H, Nystrom C. Effect of a low-fat diet on bile salt excretion and diarrhoea in the gastrointestinal radiation syndrome. Acta Radiol Oncol Radiat Phys Biol 1979; 18: 460–4.
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20 Jewkes AJ, Windsor CW, Ward RS, Timmins AE. Relationship between bile acid malabsorption using the 75Se homocholic acid taurine scanning method and diarrhoea following right hemicolectomy. Br J Surg 1989; 76: 707–8. 21 Kurien M, Evans KE, Leeds JS, Hopper AD, Harris A, Sanders DS. Bile acid malabsorption: an under-investigated differential diagnosis in patients presenting with diarrhea predominant irritable bowel syndrome type symptoms. Scand J Gastroenterol 2011; 46: 818–22. 22 Smith MJ, Cherian P, Raju GS, Dawson BF, Mahon S, Bardhan KD. Bile acid malabsorption in persistent diarrhoea. J R Coll Physicians Lond 2000; 34: 448–51. 23 Weber AM, Roy CC, Morin CL, Lasalle R. Malabsorption of bile acids in children with cystic fibrosis. N Engl J Med 1973; 289: 1001–5. 24 Nakamura T, Kikuchi H, Takebe K et al. Correlation between bile acid malabsorption and pancreatic exocrine dysfunction in patients with chronic pancreatitis. Pancreas 1994; 9: 580–4. 25 Schiller LR, Hogan RB, Morawski SG et al. Studies of the prevalence and significance of radiolabeled bile acid malabsorption in a group of patients with idiopathic chronic diarrhea. Gastroenterology 1987; 92: 151–60.
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 730–734
Original article
Are bile acid malabsorption and bile acid diarrhoea important causes of loose stool complicating cancer therapy? F. Phillips, A. C. G. Muls, A. Lalji and H. J. N. Andreyev The GI unit, The Department of Medicine, The Royal Marsden Hospital, London, UK Received 8 October 2014; accepted 22 December 2014; Accepted Article online 28 February 2015
Abstract Aim Gastrointestinal (GI) symptoms during and after cancer therapy can significantly affect quality of life and interfere with treatment. This study assessed whether bile acid malabsorption (BAM) or bile acid diarrhoea (BAD) are important causes of diarrhoea associated with cancer treatment. Method A retrospective analysis was carried out of consecutive patients assessed for BAM using (75Se) Selenium homocholic acid taurocholate (SeHCAT) scanning, after reporting any episodes of loose stool, attending a gastroenterology clinic in a cancer centre. Results Between 2009 and 2013, 506 consecutive patients (54.5% male; age range: 20–91 years), were scanned. BAM/BAD was diagnosed in 215 (42.5%). It was mild in 25.6%, moderate in 29.3% and severe in 45.1%. Pelvic chemoradiation had induced BAM in > 50% of patients. BAM was also frequent after treatment for conditions not previously associated with BAM, such as anal and colorectal cancer, and was present in > 75% of
Introduction The increasingly sophisticated options available for the treatment of cancer have led to a significant increase in the number of survivors, but this has been accompanied by a hidden burden. During treatment with chemotherapy and radiotherapy, up to 90% of patients will develop acute gastrointestinal (GI) symptoms, which may interfere with delivery of cancer treatment and affect quality of life [1]. There has been very limited research investigating the cause of these symptoms. Acute symptoms often settle after completion of treatment, but approximately 25% of patients go on to expeCorrespondence to: Dr Jervoise Andreyev, Department of Medicine, Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK. E-mail: [email protected]
730
patients referred after pancreatic surgery. It was also unexpectedly frequent in patients who were treated for malignancy outside the GI tract, such as breast cancer and haematological malignancy. Conclusion BAM/BAD are very common and underappreciated causes of GI symptoms after cancer treatment. Health professionals should have a low threshold in suspecting this condition, as diagnosis and treatment can significantly improve quality of life. Keywords SeHCAT, bile acid malabsorption, diarrhoea, cancer, chemotherapy, radiotherapy What does this paper add to the literature? The study identifies, for the first time, that a wide spectrum of cancers are associated with BAM/BAD. Smallbowel dysfunction is frequently present after treatment for rectal and anal cancer. BAD is frequent in patients treated for upper-GI-tract cancer. Patients with intermittent or continuous loose stool during and after cancer treatment should be routinely assessed for the presence of BAM/BAD.
rience chronic disturbances that reduce quality of life. GI symptoms are one of the most common consequences of cancer treatment and have the greatest impact on daily activity [1]. Despite this, most patients with GI symptoms are never referred to a GI specialist, and, even if they are, the doctor may be unfamiliar with the spectrum of problems that can develop or how to manage these problems optimally and as a result prescribe ineffective, or dangerous, treatment [1]. It is gradually being understood that many patients can be treated effectively if they are appropriately investigated. A fundamental finding is that the cause is multifactorial in two-thirds of patients. If each cause is treated appropriately then this can give significant symptom relief [2]. Possibly causes
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 730–734
F. Phillips et al.
for chronic GI dysfunction in this setting are the development of bile acid malabsorption (BAM) or bile acid diarrhoea (BAD). Malabsorption occurs when there is dysfunction of absorptive mechanisms in the terminal ileum – for example after right hemicolectomy or when the terminal ileum is diseased (e.g. in those with Crohn’s disease or radiation enteropathy). However, in a landmark paper, Walters et al. [3] showed that in patients with so called idiopathic bile acid malabsorption, the mechanism for diarrhoea is that of ineffective feedback so that while absorption capacity is normal or enhanced, it is overwhelmed by excessive bile production by the liver a condition which should be called BAD. It is now recognized that 1% of the population in the western world are misdiagnosed as having diarrhoea-predominant irritable bowel syndrome, when in fact they have BAD [4]. BAM/BAD as the cause of chronic symptoms after treatment for cancer is less well established. Studies, often containing small numbers of patients, have suggested that BAM/BAD may occur in 1–80% of patients with chronic diarrhoea [5–12]. However, most of these studies have concentrated on patients with gynaecological cancer treated with radiotherapy and, because of their small size, definitive conclusions cannot be drawn. The present study aimed to investigate the prevalence of BAM/BAD in a large consecutive cohort of patients referred to a specialist GI clinic for the management of symptoms developing after treatment for cancer (Fig. 1).
Method This retrospective study was reviewed and approved by the Royal Marsden Hospital Committee for Clinical Research and did not require informed consent from patients. Patients attending the specialist gastroenterology clinic for the late effects of cancer therapy were managed using a peer-reviewed investigational and treatment algorithm [13]. They underwent a set of investigations dictated by that algorithm to identify the cause(s) for their symptoms. As part of the initial consultation, all patients were routinely asked to describe the consistency of their stool with reference to the Bristol Stool Chart [14]. Those reporting type 6 (fluffy or mushy) or type 7 (liquid) stool were routinely offered a (75Se) Selenium homocholic acid taurocholate (SeHCAT) scan. The severity of BAM was graded according to the SeHCAT retention values at 7 days, as follows: 10–15% for mild BAM; 5–10% for moderate BAM; and 0–5% for severe BAM. A list of consecutive patients attending for a SeHCAT scan was obtained.
Bile acid malabsorption/diarrhoea after cancer therapy
As this was a retrospective, observational study, comparative statistics were felt not to be appropriate. As the mechanism leading to an abnormal SeHCAT scan is not known in many of the patients, both the terms bile acid diarrhoea and malabsorption have both been used.
Results Between October 2009 and August 2013, 506 consecutive patients were referred for a SeHCAT scan; 276 [54.5%; median age 66 (range: 20–86) years] were men and 230 [45.5%; median age 61 (range: 22–91) years] were women. Two-thirds of these patients had been treated with pelvic radiotherapy and one-quarter had received other treatments, including GI surgery and/or chemotherapy with or without biological agents. Up to 5% were seen either before the cancer treatment starts or without having cancer. Of the 506 patients who had undergone a SeHCAT scan, 171 (34%) had had urological cancer, 128 (25%) gynaecological cancer, 100 (20%) lower-GI-tract cancer, 58 (12%) upper-GI-tract cancer (oesophagogastric in 43 and pancreatic in 15), 35 (7%) haematological malignancy (10 with multiple myeloma and 25 with leukaemia) and 14 (3%) breast cancer. The results are shown in Fig. 1. Overall, 215 (42.5%) of the 506 patients had a new diagnosis of BAM or BAD. This was mild in 25.6%, moderate in 29.3% and severe in 45.1%.
Discussion This large consecutive series of patients who presented with a multiple GI symptoms to a specialist gastroenterological clinic focussing on treating GI and nutritional consequences of cancer therapies, suggests that if patients are selected [for a SeHCAT scan on the basis of intermittent or continuous type 6 or 7 Bristol type stool that bile acid malabsorption or bile acid diarrhoea will be found in almost half [15]. In the 11 European countries, and Canada and Australia, where SeHCAT is licensed for use, BAM/BAD can be diagnosed with high sensitivity and specificity with very reliable reproducibility [16,17]. Patients generally respond to treatment with bile-acid-binding drugs [18] and manipulating dietary fat intake [19], with a subsequent improvement in quality of life. The 128 patients with gynaecological cancer in the present study is double that reported in 1977 when the possibility of BAM was first raised. It also appears that many patients with a pelvic tumour treated with chemotherapy and radiotherapy, such as those with anal, vulval or cervical cancer, had higher rates of BAM than those having radiotherapy alone, for example for prostate can-
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 730–734
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Bile acid malabsorption/diarrhoea after cancer therapy
Gynaecological cancer 50%
70%
Lower GI cancer 42%
50%
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
No BAM Mild BAM Moderate BAM Severe BAM
Cervical (n = 64)
No BAM Mild BAM Moderate BAM Severe BAM
Anal (n = 36)
Rectum (n = 43)
Colon (n = 21)
Upper GI cancer
Urological cancer
35%
50%
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
No BAM Mild BAM Moderate BAM Severe BAM
Prostate (n = 161)
71%
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
Endometrial Vaginal & (n = 52) vulval (n = 12)
22%
42%
73%
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
No BAM Mild BAM Moderate BAM Severe BAM
Oesophagogastric (n = 43)
Bladder (n = 10)
Pancreatic (n = 15)
Haematological & breast cancer 44%
70%
43%
100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
No BAM Mild BAM Moderate BAM Severe BAM
Haem (n = 25)
Myeloma (n = 10)
Breast (n = 14)
Figure 1 Frequency and severity of bile acid malabsorption (BAM) in 506 patients undergoing a (75Se) Selenium homocholic acid taurocholate (SeHCAT) scan: 171 with urological cancer, 128 with gynaecological cancer, 100 with colorectal cancer, 58 with upper GI cancer and 49 with haematological and breast cancer (White, no BAM; red, mild BAM; yellow, moderate BAM; green, severe BAM. Haem, haematological malignancy).
cer or for endometrial cancer. It is likely that this is the result of the sensitization of the terminal ileal mucosa by the chemotherapy to the effect of radiation. We have previously shown that the terminal ileum is sensitive to relatively low doses of irradiation [12], so in an era when intensity modulated radiotherapy to tumours in the pelvis is used more widely especially in combination with chemotherapy it is likely that BAM will be seen increasingly frequently. A right hemicolectomy was invariably associated with severe or moderate BAM in this group, a previously documented association, but one that may not be widely appreciated [20]. The sever-
732
ity of malabsorption depends on the extent of terminal ileum resected, although even very short resections can lead to severe BAM [21]. Upper-GI-tract surgery, especially a Whipple’s procedure, was associated with a positive SeHCAT result in 89% of patients, but the mechanism responsible for this is not clear. BAM/BAD occurs after upper-GI-tract surgery associated with vagotomy [22], but the mechanism for new-onset BAM/BAD after pancreatic surgery is likely to be associated with alteration in bile production in the liver or possibly rapid transit of bile acids, leading to reduced time for absorption or interference from
Colorectal Disease ª 2015 The Association of Coloproctology of Great Britain and Ireland. 17, 730–734
F. Phillips et al.
nonhydrolyzed triglycerides, which also impairs absorption [23]. The finding that BAM/BAD was very frequent after Whipple’s procedure is in keeping with fact that BAM/BAD is known to be associated with chronic pancreatitis and pancreatic disease in cystic fibrosis [23,24]. The mechanism responsible for BAM in patients with haematological malignancy and breast cancer is probably damage of the terminal ileum following chemotherapy or radiotherapy, reducing bile uptake. This has not been previously recognized. Some of the BAM/BAD seen in the present study may be secondary to other disease processes. Small intestinal bacterial overgrowth (SIBO) may contribute to late-onset diarrhoea, and may arise from damage of the bowel mucosa or altered motility. SIBO is also known to be a cause of BAM, as bacteria deconjugate bile acids and thereby alter their absorbability. We systematically assess our patients for SIBO and have not seen any resolution of BAM in patients successfully treated for SIBO, which indicates that BAM and SIBO are different conditions. The rate of intestinal transit is important in some patients as inducing diarrhoea with laxatives causes a mild BAM that is unresponsive to cholestyramine [25]. It has also been reported that giving loperamide to patients with diarrhoea increases SeHCAT retention [7]. In conclusion, the present study confirms that BAM or BAD is a common cause of loose stools or diarrhoea in patients following treatment for many different cancers. Testing for BAM, preferably using a SeHCAT scan, should therefore be the first line of investigation for all cancer patients with type 6 or 7 stool, as the yield of a positive test is high. Other investigations may also be required as many patients have more than one cause of their symptoms. Most patients diagnosed with new-onset BAM, and particularly those with severe BAM, report significant benefit of using a combination of dietary fat manipulation and/or bile acid-sequestering agents [13].
Acknowledgements We acknowledge support from the National Institute for Health Research to the Royal Marsden Biomedical Research Centre. Ann Muls is funded by Macmillan Cancer Support.
Conflicts of interest This study was unfunded. HJNA has acted as a paid consultant for GE, manufacturers of SeHCAT and for Sanofi Aventis/Genzyme, manufacturers of colesevelam,
Bile acid malabsorption/diarrhoea after cancer therapy
a bile acid sequestrant. FP has received travel support from GE.
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