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Before progressing, I wanted to emphasise this is not necessarily the same type of malabsorption caused by exocrine pancreatic insufficiency (EPI) which can potentially lead to something known as steatorrhea (amongst other things) but it can produce the same effect. Steatorrhea is different from bile acid issues and is more related to fatty acids. But it’s another piece of the diarrhea jigsaw.
Bile Acid Malabsorption (BAM) and Bile Acid Diarrhea (BAD)
Post-surgical diarrhea is probably something to expect in the early days and after time, adjustments can be made to cater for these side effects. With NETs, particularly where there has been small intestine surgery, there can be a number of reasons which are totally unrelated to carcinoid syndrome. It’s not just about having a shorter bowel, it’s also about some of the side effects of the missing piece of bowel (see diagram below). I’m referring to something called bile acid malabsorption (BAM), also known as bile acid diarrhea (BAD) and these two terms mean exactly the same thing. The latter is a fitting acronym. The issue can also be exacerbated by the removal of the gallbladder (Cholecystectomy), a common occurrence in NET patients scheduled for long-term use of somatostatin analogues.
What is bile acid malabsorption?
Bile contains bile acids which are used for two main purposes. Firstly, in the breakdown and absorption of fats and vitamins from food as it passes through the gut and, secondly, to aid with the removal of waste products. Bile acids are made in the liver, stored in the gallbladder and released into the small intestine when food is eaten. Virtually all (~95%) of the bile acids are then re-absorbed in the final section of the small intestine (ileum) and returned to the liver. This cycle repeats itself and is called the enterohepatic circulation. When this cycle is disturbed, this is termed bile acid malabsorption. Bile acid malabsorption is said to affect up to 1 in 100 people in the UK. See the diagram below to see a normal bile function.
What happens when the bile system is impaired?
Those who have had small intestine surgery are at risk for this condition because the terminal ileum plays an important part in the bile system. There are also suggestions it can be exacerbated by small intestine bacteria overload (SIBO) – this is an area lacking scientific objectivity but may be an added complication of abdominal surgery.
If that wasn’t bad enough, if you’ve also had your gallbladder removed, that is potentially going to add to the effect. Without the gallbladder which under normal circumstances would release bile in reaction to eating, the liver instead sends a steady trickle of bile into the small intestine all the time. This can often overwhelm the small intestine’s now decreased capability to absorb it back into the body for recycling (i.e. via the liver). Instead, more than normal passes into the large intestine (colon), irritating the lining and stimulating salt and water secretion resulting in diarrhea. This type of diarrhea is usually frequent during the day and sometimes at night. It may be pale, greasy and hard to flush away (similar to steatorrhea induced by exocrine pancreatic insufficiency (EPI)). BAD may be unusually coloured (e.g. often green (ish) or orange (ish)). Those with BAM may also have general abdominal issues such as bloating, cramping abdominal pain and excessive wind.
Actually, during my research, I did find that this issue is not limited to NET patients who have had surgery, it’s much wider being also related to Crohn’s disease, IBS and other gastrointestinal issues. A couple of UK sites listed 3 types:
- Type 1: Bile acid malabsorption, secondary to ileal resection, or ileal inflammation, e.g. Crohn’s disease, ileal resections.
- Type 2: Idiopathic/primary bile acid malabsorption. i.e. when no definitive cause can be found (as in Type 1 and 3).
- Type 3: Secondary to various gastrointestinal diseases, e.g. Cholecystectomy, small intestinal bacterial overgrowth, post-radiation, coeliac disease, chronic pancreatitis.
The NET Effect
With Neuroendocrine Cancer patients, the mention of “diarrhea“ is a topical subject. There’s the usual claim that it’s caused by carcinoid syndrome and for some that will be true, particularly people who have tumours associated with that syndrome, that is, those who have mostly a midgut primary; and that is, those who mostly have elevated levels of serotonin (via 5HIAA testing). When you look at epidemiology data, it becomes clear the numbers associated with carcinoid syndrome are much lower than what might be perceived when analysing many comments in any patient group – most epidemiological data suggests around 10% of the total number of NET cases.
There are a number of reasons for this confusion including the belief that any type of Neuroendocrine Cancer can get carcinoid syndrome when in fact this is way off-beam. There are several other types of NET and other NET syndromes that also have diarrhea as a listed symptom (read more here). I often wonder if this is partly due to our impaired awareness initiatives at the international and national level that drives people to believe this. I’m also slightly suspicious that patients are being told the ‘easy answer’ in appointments with physicians. The use of the outdated and misnomer term “carcinoid” does not help either. There are many reasons why a Neuroendocrine Cancer patient can get diarrhea and it’s not all about serotonin and (so-called) carcinoid syndrome.
The differential diagnosis of diarrhea in a NET patient is potentially an extensive list of possibilities but in this article, I wanted to focus on the area of bile system impairment which leads to a form of malabsorption causing diarrhea and/or steatorrhea. This is a piece of the diarrhea jigsaw but is an under-reported or at least an under-discussed problem within the community.
So, I guess I’m focusing on tumours where there has been some sort of small bowel resection and/or gallbladder removal (although other resections may be involved or contributing). I remember one question in a patient group along these lines “my recent surgery and administration of somatostatin analogues have not improved my carcinoid syndrome; I still have diarrhea” ……. cue a long and difficult explanation. They’re difficult answers mainly because of two things, firstly it’s a complex scenario, and secondly because it isn’t an exact science. But I’ll try to at least give you some food for thought if you think this might apply to you. At the very least I hope to give you some tools in order to have a fairly sensible conversation with your doctors and nurses (and dietitians where applicable).
Does the length of small intestine resection make a difference?
Short answer – yes. The length of the small intestine removed may produce both problems (diarrhea and steatorrhea). e.g. Large ileal resections (>100 cm) can lead to luminal bile salt deficiency resulting in fat malabsorption and colonic secretion caused by hydroxy fatty acids. Shorter ileal resections (< 100 cm) may cause diarrhea as a result of stimulation of colonic secretion by unabsorbed bile salts. By binding intestinal bile salts, oral cholestyramine (4 g four times a day) may control this type of diarrhea. The fat malabsorption caused by longer ileal resections may react to pancreatic enzyme replacement therapy (PERT) e.g. creon, nutrizym etc. It is also thought that somatostatin analogues could potentially exacerbate fat malabsorption as they are known to inhibit digestive enzymes. Although technically fat malabsorption caused by pancreatic enzyme insufficiency is related to fatty acids rather than bile acids.
Patients with mild to moderate bile acid malabsorption present with watery diarrhea and generally respond very well to treatment with bile acid binders such as cholestyramine. Patients with more severe bile acid malabsorption have both diarrhea and steatorrhea.
Testing for BAM
The gold standard test is said to be something called the 75Se-homocholic acid taurine (75SeHCAT). The SeHCAT test, performed at a Nuclear Medicine Department, is simple, fast, and well-tolerated and requires two scans one week apart. But its use seems to be confined to Europe. It is said to be expensive; the threshold sensitivity is vague/not agreed in guidelines. There are two tests available in the USA for evaluating BAM — the serum 7αC4 test and the fecal bile acid test.
Treatment for BAM
Bile acid diarrhea is said to resolve quickly after taking bile acid sequestrants (BAS). Some adjustment with dose may be required to find the right balance. Always best to let your prescribing doctor know about your other medications and supplements as, like any treatment, there can be side effects and contraindications. The main medications include:
- Colestyramine and colestipol – these medications only come in powder form. Unfortunately, some people may find them unpalatable and if the dose is too high, it can cause constipation, so it is important to adjust the dose according to symptoms.
- Colesevelam – this is a newer medication and comes in tablet form. Some patients find it easier to take than colestyramine. Due to current cost and drug licensing colesevelam may not be widely available.
Monitoring. Monitoring fat-soluble vitamins (ADEK) may be required along with a lipid panel including triglycerides.
Diet. a key piece of dietary advice may be to keep to a strict low-fat and a dietitian may help with that.
Authors note: Perhaps with the limited access to this test and the cost and sensitivity/selectivity issues, sometimes, doctors may prescribe treatment (see above) instead of testing as the response to medication (does make the real diagnosis difficult though). Might be something to suggest to your doctor/dietitian on a trial basis to assess efficacy for your individual situation.
- Bile acid malabsorption – Guts UK (gutscharity.org.uk)
- What is BAM? – University Hospitals Coventry & Warwickshire (uhcw.nhs.uk)
- Identifying diarrhea caused by bile acid malabsorption – Mayo Clinic
- Review article: bile acid diarrhoea – pathogenesis, diagnosis and management
- Chapter 9 – Gastrointestinal Complications in the Postoperative Period
- Why Gallbladder Removal Surgery Can Cause Diarrhea – and How to Treat It | Eat + Run | US News
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