RESUMO
OBJECTIVES: Chronic diarrhea caused by primary bile acid diarrhea (PBAD) is a common condition. We have previously shown PBAD is associated with low fasting serum levels of the ileal hormone, fibroblast growth factor 19 (FGF19). FGF19 is a negative regulator of hepatic bile acid synthesis and is stimulated by farnesoid X receptor agonists, which produce symptomatic improvement in PBAD. We aimed to assess possible causes for low serum FGF19 in patients with PBAD. METHODS: Patients with PBAD, defined by reduced (75)Se-labelled homocholic acid taurine (SeHCAT) retention, and idiopathic diarrhea controls had measurements of fasting lipids and fasting/post-prandial FGF19 serum profiles. Specific functional variants in candidate genes were investigated in exploratory studies. In further groups, basal and bile acid-stimulated transcript expression was determined in ileal biopsies and explant cultures by quantitative PCR. RESULTS: FGF19 profiles in PBAD patients included low fasting and meal-stimulated responses, which were both strongly correlated with SeHCAT. A subgroup of 30% of PBAD patients had fasting hypertriglyceridemia and higher FGF19. No clear significant differences were found for any genetic variant but there were borderline associations with FGFR4 and KLB. SeHCAT retention significantly correlated with the basal ileal transcript expression of FGF19 (rs=0.59, P=0.03) and apical sodium-dependent bile acid transporter (ASBT) (rs=0.49, P=0.04), and also with the degree of stimulation by chenodeoxycholic acid at 6 h for transcripts of FGF19 (median 184-fold, rs=0.50, P=0.02) and ileal bile acid binding protein (IBABP) (median 2.2-fold, rs=0.47, P=0.04). Median stimulation of FGF19 was lower in patients with SeHCAT retention <10% (P=0.01). CONCLUSIONS: These studies demonstrate a complex, multifactorial etiology of PBAD, including impairments in ileal FGF19 expression and responsiveness.
Assuntos
Ácidos e Sais Biliares/biossíntese , Diarreia , Fatores de Crescimento de Fibroblastos/sangue , Íleo , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Adulto , Índice de Massa Corporal , Diarreia/sangue , Diarreia/diagnóstico , Diarreia/etiologia , Feminino , Fatores de Crescimento de Fibroblastos/genética , Humanos , Íleo/metabolismo , Íleo/patologia , Proteínas Klotho , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Receptores Citoplasmáticos e Nucleares/genética , Radioisótopos de Selênio/farmacologia , Estatística como Assunto , Ácido Taurocólico/análogos & derivados , Ácido Taurocólico/farmacologia , Triglicerídeos/sangueRESUMO
Bile acid malabsorption occurs when there is impaired absorption of bile acids in the terminal ileum, so interrupting the normal enterohepatic circulation. The excess bile acids in the colon cause diarrhea, and treatment with bile acid sequestrants is beneficial. The condition can be diagnosed with difficulty by measuring fecal bile acids, or more easily by retention of selenohomocholyltaurine (SeHCAT), where this is available. Chronic diarrhea caused by primary bile acid diarrhea appears to be common, but is under-recognized where SeHCAT testing is not performed. Measuring excessive bile acid synthesis with 7α-hydroxy-4-cholesten-3-one may be an alternative means of diagnosis. It appears that there is no absorption defect in primary bile acid diarrhea but, instead, an overproduction of bile acids. Fibroblast growth factor 19 (FGF19) inhibits hepatic bile acid synthesis. Defective production of FGF19 from the ileum may be the cause of primary bile acid diarrhea.
Assuntos
Ácidos Cólicos/biossíntese , Diarreia/diagnóstico , Diarreia/etiologia , Síndromes de Malabsorção/complicações , Resinas de Troca Aniônica/uso terapêutico , Ácidos Cólicos/metabolismo , Diarreia/metabolismo , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Síndromes de Malabsorção/diagnóstico , Síndromes de Malabsorção/tratamento farmacológico , Transdução de Sinais , Ácido Taurocólico/análogos & derivadosRESUMO
Chronic diarrhoea is a common condition, resulting from a number of different disorders. Bile acid diarrhoea, occurring in about a third of these patients, is often undiagnosed. We hypothesised that a positive diagnosis of bile acid diarrhoea would reduce the need for subsequent investigations for alternative diagnoses. METHODS: Patients previously recruited to a study of chronic diarrhoea who had selenium homocholic acid taurine (SeHCAT) testing and subsequent follow-up at our institution were identified. In a retrospective analysis, the numbers of defined investigations undertaken from the first 3 months after SeHCAT in the following 5 years were compared. RESULTS: 90 patients were identified with primary bile acid diarrhoea (SeHCAT retention <15%, n=36) or idiopathic diarrhoea (SeHCAT retention >15%, n=54). Follow-up had been performed on 29 and 39 subjects, respectively, with no differences in previous investigations or the last contact date. In the follow-up period, the proportions of these patients who had undergone endoscopic procedures (gastroscopy, colonoscopy and sigmoidoscopy) were the same. However, there was a higher proportion of patients in the SeHCAT-negative group who had other investigations, including imaging, physiological tests and blood tests (p=0.037). The use of cross-sectional imaging was significantly higher in this group (p=0.015) with greater proportions having CT (0.44 vs 0.10) and MRI (0.26 vs 0.07). Ultrasound use and the number of blood tests were higher in the SeHCAT-negative group whereas the SeHCAT-positive group attended more clinic appointments (p=0.013). CONCLUSION: A positive diagnosis of bile acid diarrhoea, made by a SeHCAT test, resulted in reduced use of diagnostic investigations over the subsequent 5 years.
RESUMO
BACKGROUND: Bile acid diarrhoea (BAD) is a common cause of chronic diarrhoea with a population prevalence of primary BAD around 1%. Previous studies have identified associations with low levels of the ileal hormone fibroblast growth factor 19 (FGF19), obesity and hypertriglyceridaemia. The aim of this study was to identify further associations of BAD. METHODS: A cohort of patients with chronic diarrhoea who underwent 75selenohomocholic acid taurate (SeHCAT) testing for BAD was further analysed retrospectively. Additional clinical details available from the electronic patient record, including imaging, colonoscopy, chemistry and histopathology reports were used to calculate the prevalence of fatty liver disease, gallstones, colonic neoplasia and microscopic colitis, which was compared for BAD, the primary BAD subset and control patients with diarrhoea. FINDINGS: Of 578 patients, 303 (52%) had BAD, defined as a SeHCAT 7d retention value <15%, with 179 (31%) having primary BAD. 425 had an alanine aminotransferase (ALT) recorded, 184 had liver imaging and 176 had both. Overall, SeHCAT values were negatively associated with ALT (rs=-0.19, p<0.0001). Patients with BAD had an OR of 3.1 for an ALT >31 ng/mL with imaging showing fatty liver (p<0.001); similar figures occurred in the primary BAD group. FGF19 was not significantly related to fatty liver but low levels were predictive of ALT >40 IU/L. In 176 subjects with gallbladder imaging, 27% had gallstones, 7% had a prior cholecystectomy and 34% either of these. The median SeHCAT values were lower in those with gallstones (3.8%, p<0.0001), or gallstones/cholecystectomy (7.2%, p<0.001), compared with normal gallbladder imaging (14%). Overall, BAD had an OR of 2.0 for gallstones/cholecystectomy (p<0.05). BAD was not significantly associated with colonic adenoma/carcinoma or with microscopic colitis. INTERPRETATION: The diagnosis of BAD is associated with fatty liver disease and with gallstones. The reasons for these associations require further investigation into potential metabolic causes.
RESUMO
BACKGROUND: Bile acids [BA] are usually reabsorbed by the terminal ileum, but this process is frequently abnormal in Crohn's disease [CD]. BA malabsorption occurs, and excess colonic BA cause secretory diarrhea. Furthermore, the hormone fibroblast growth factor 19 [FGF19] is synthesized in the ileum in response to BA absorption and regulates BA synthesis. We hypothesized that reduced serum FGF19 levels will be associated with diarrheal symptoms and disease activity in both ileal resected[IR-CD] and non-resected CD [NR-CD] patients. METHODS: Fasting serum FGF19 levels were measured in 58 patients [23 IR-CD patients and 35NR-CD patients]. Disease activity was assessed using the Harvey Bradshaw Index and C-reactive protein [CRP]. Stool frequency, Bristol Stool Form Scale and length of previous ileal resection were recorded. FGF19 levels were also compared with healthy and diarrhea control patients. RESULTS: FGF19 levels were inversely correlated with ileal resection length in IR-CD patients[r = -0.54, p = 0.02]. In NR-CD patients, median FGF19 levels were significantly lower in patients with active disease compared with inactive disease [103 vs. 158 pg/ml, p = 0.04] and in those with symptoms of diarrhea compared with those without [86 vs. 145 pg/ml, p = 0.035]. FGF19 levels were inversely correlated with stool frequency, Bristol stool form and CRP in NR-CD patients with ileal disease. CONCLUSIONS: Reduced FGF19 levels are associated with ileal resection, diarrhea and disease activity. FGF19 may have utility as a biomarker for functioning ileum in CD. This study supports a potential role of FGF19 in guiding treatments for diarrhea in Crohn's disease.
Assuntos
Doença de Crohn/complicações , Fatores de Crescimento de Fibroblastos/fisiologia , Íleo/metabolismo , Adulto , Idoso , Biomarcadores/metabolismo , Biópsia , Doença de Crohn/metabolismo , Doença de Crohn/patologia , Diarreia/etiologia , Feminino , Humanos , Íleo/patologia , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
OBJECTIVES: Increased colonic bile acids can cause chronic diarrhea. Bile acid diarrhea (BAD) is treatable by sequestrants, and may be secondary to ileal disease or primary BAD. It is underdiagnosed, partly because the selenium-75-homocholic acid taurine (SeHCAT) retention test is not available in many countries, and is underutilized in others. Serum 7α-hydroxy-4-cholesten-3-one (C4), a measure of bile acid synthesis, is available for diagnosis in specialist centers. Recently, deficiency of the ileal hormone fibroblast growth factor 19 (FGF19) has been shown in BAD. Our aim is to evaluate the diagnostic value of FGF19 in a large and prospective group of patients with chronic diarrhea, previously investigated with C4. METHODS: Patients undergoing routine investigation provided fasting blood samples. C4 was determined by high-performance liquid chromatography, and used to stratify two groups: group 1 (n=119), consisting of patients with normal C4 (≤ 28 ng/ml), and group 2 (n=139), consisting of patients with high C4 (>28 ng/ml), including any of the possible causes of BAD. Serum FGF19 was measured in stored samples by enzyme-linked immunosorbent assay. RESULTS: FGF19 and C4 were significantly inversely related (r(s)=-0.64, P<0.001). Patients with raised C4 had significantly lower median FGF19 values. Both of these were more marked when secondary to ileal disease, in particular ileal resection, than in primary BAD. The sensitivity and specificity of FGF19 at 145 pg/ml for detecting a C4 level >28 ng/ml were 58% and 79%, respectively. For C4 >60 ng/ml, these were 74% and 72%; on receiver-operating characteristic analysis, the area under the curve was 0.80 (95% confidence interval 0.74-0.87). CONCLUSIONS: Serum FGF19 could be developed as a simple blood test to increase the diagnostic rates of BAD.
RESUMO
Bowel symptoms including diarrhoea can be produced when excess bile acids (BA) are present in the colon. This condition, known as bile acid or bile salt malabsorption, has been under recognized, as the best diagnostic method, the (75)Se-homocholic acid taurine (SeHCAT) test, is not available in many countries and is not fully utilized in others. Reduced SeHCAT retention establishes that this is a complication of many other gastrointestinal diseases. Repeated studies show SeHCAT tests are abnormal in about 30% of patients otherwise diagnosed as diarrhoea-predominant irritable bowel syndrome or functional diarrhoea, with an estimated population prevalence of around 1%. Recent work suggests that the condition previously called idiopathic bile acid malabsorption (BAM) is not in fact due to a defect in absorption, but results from an overproduction of BA because of defective feedback inhibition of hepatic bile acid synthesis, a function of the ileal hormone fibroblast growth factor 19 (FGF19). The approach to treatment currently depends on binding excess BA, to reduce their secretory actions, using colestyramine, colestipol and, most recently, colesevelam. Colesevelam has a number of potential advantages that merit further investigation in trials directed at patients with bile acid diarrhoea.