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Empirical trial or diagnostic tests for bile acid diarrhea? That is the question!

To the editor, We read with great interest the paper by Costa et al entitled “Prevalence and clinical features of bile acid diarrhea in patients with chronic diarrhea.” Bile acid malabsorption (BAM) and bile acid diarrhea (BAD) are not rare findings, but they are somewhat overlooked diagnoses. Indeed, 25%-30% of patients complaining of functional diarrhea or diarrheapredominant irritable bowel syndrome could have BAM, and a lack or delay of diagnosis is highly costly for both patients and the healthcare system, leading to pointless or expensive prescription of tests and drugs. So, in our opinion, the study by Costa et al has the great merit of highlighting the need to evaluate the prevalence of BAD in patients with chronic diarrhea and discussing the way to reach an effective diagnosis. Indeed, different methods, serological, fecal and scintigraphic, have been suggested; however, at present they are rarely carried out or are totally unavailable in many countries and regions. Therefore, it is not surprising, as the authors' report, that empirical testing with cholestyramine, a bile acid sequestrant (BAS), is used in everyday clinical practice to diagnose BAM. In fact, it is less expensive and is immediately available everywhere. Unfortunately, the use of BAS is not supported by quantitative data, because there is no consensus about the right dosage (4 to 36 g/d as reported in the literatures) and the adequate duration (10 days? 4 weeks?) of such a trial. Finding the adequate dosage is not simple, especially for patients taking many drugs, for example elderly patients, because cholestyramine, and generally all BAS, may lead to the malabsorption of fat and liposoluble vitamins (vitamins A, D and K), increasing the risk of osteoporosis and coagulation abnormalities, and they can interact with different types of drugs, thus decreasing their efficacy. So, the risk of both overtreatment and undertreatment are not negligible. Moreover, it is also important to establish clearly the degree of symptom improvement that is considered sufficient in order to determine a positive empirical test as well as the time period that is considered to be adequate after cholestyramine is discontinued. Furthermore, evaluating only the clinical response to BAS could lead to false positive results due to a placebo effect, which is not uncommon when treating patients with functional digestive disorders. Or the false positivity could also be the result of a lack of specificity of cholestyramine; indeed it may inactivate some etiological agents of diarrhea such as the Clostridium difficile toxin and could be effective also in patients without BAM. This could lead to an inappropriate, prolonged and sometimes lifelong prescription of a drug that is not very easy to manage. On the other hand, false negative results for poor compliance to the drug are not to be neglected. Indeed, cholestyramine is very unpalatable. Therefore, even if it is effective, some patients autonomously decide to stop taking it or, at least, decrease its dosage after only a few weeks from starting the therapy. Unfortunately, in most countries, for example Italy, cholestyramine is the only BAS available; while colesevelam, which is more expensive but more palatable, because it is marketed in tablets, is not available. For these reasons different guidelines have reported that there is insufficient evidence to recommend the use of an empirical trial with BAS, rather than making a positive diagnosis using the determination of serum 7α-hydroxy-4-cholesten-3-one (C4) or fibroblastic growth factor (FGF)-19 levels, or the selenium homocholic acid taurine (SeHCAT) test. Even if the specificity and sensitivity of these tests need to be improved and the normal values of C4 and FGF-19 are not yet universally agreed, a recent systematic review showed an association between the severity of BAM, as evaluated by the SeHCAT test, and the response to cholestyramine. Moreover, a quantitative BAM evaluation could make doctors confident in increasing the dosage of a drug not devoid of adverse events and, on the other hand, a confirmed, instrumental diagnosis could encourage patients to start and to stay on unpalatable therapy like BAS, motivating them to adhere more strictly to the treatment. Unfortunately, in most countries BAM diagnostic tests are usually available only at tertiary referral centers due to their costs or to the relatively poor awareness of gastroenterologists regarding the importance of this disturbance. Therefore, a blind empirical test often remains the first diagnostic choice suggested to most patients. It is hoped that gastroenterologists, nuclear medicine physicians and laboratory doctors can work closely together to detect normal and shared values of serological tests and compare them with the SeHCAT test, which is currently the gold standard for a BAM diagnosis. In this way the diagnostic tests could become increasingly widespread and made accessible to all patients suspected of BAM or with diarrheic symptoms who need the clearest diagnosis possible.