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Prediagnostic alterations in circulating bile acid profiles in the development of hepatocellular carcinoma.
Stepien, M, Lopez-Nogueroles, M, Lahoz, A, Kühn, T, Perlemuter, G, Voican, C, Ciocan, D, Boutron-Ruault, MC, Jansen, E, Viallon, V, et al
International journal of cancer. 2022;(8):1255-1268
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Abstract
Bile acids (BAs) play different roles in cancer development. Some are carcinogenic and BA signaling is also involved in various metabolic, inflammatory and immune-related processes. The liver is the primary site of BA synthesis. Liver dysfunction and microbiome compositional changes, such as during hepatocellular carcinoma (HCC) development, may modulate BA metabolism increasing concentration of carcinogenic BAs. Observations from prospective cohorts are sparse. We conducted a study (233 HCC case-control pairs) nested within a large observational prospective cohort with blood samples taken at recruitment when healthy with follow-up over time for later cancer development. A targeted metabolomics method was used to quantify 17 BAs (primary/secondary/tertiary; conjugated/unconjugated) in prediagnostic plasma. Odd ratios (OR) for HCC risk associations were calculated by multivariable conditional logistic regression models. Positive HCC risk associations were observed for the molar sum of all BAs (ORdoubling = 2.30, 95% confidence intervals [CI]: 1.76-3.00), and choline- and taurine-conjugated BAs. Relative concentrations of BAs showed positive HCC risk associations for glycoholic acid and most taurine-conjugated BAs. We observe an association between increased HCC risk and higher levels of major circulating BAs, from several years prior to tumor diagnosis and after multivariable adjustment for confounders and liver functionality. Increase in BA concentration is accompanied by a shift in BA profile toward higher proportions of taurine-conjugated BAs, indicating early alterations of BA metabolism with HCC development. Future studies are needed to assess BA profiles for improved stratification of patients at high HCC risk and to determine whether supplementation with certain BAs may ameliorate liver dysfunction.
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Faecal bile acids and colonic bile acid membrane receptor correlate with symptom severity of diarrhoea-predominant irritable bowel syndrome: A pilot study.
Wei, W, Wang, H, Zhang, Y, Zhang, Y, Niu, B, Chen, S, Zhang, W, Yao, S
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2021;(9):1120-1127
Abstract
AIMS: To compare both the faecal bile acids (BAs) and the levels of two bile acid receptors, Takeda G protein-coupled receptor 5 (TGR5) and vitamin D receptor (VDR), in the colonic mucosa between patients with irritable bowel syndrome with predominant diarrhea (IBS-D) and healthy controls, and explore the correlations among clinical characteristics, bile acid receptors expression, and BAs. METHODS The severity of abdominal pain and diarrhoea was assessed in IBS-D patients using validated questionnaires, faecal BAs were measured by ultraperformance liquid chromatography coupled to tandem mass spectrometry, and rectosigmoid biopsies were taken for the analyses of TGR5 and VDR expression using immunohistochemistry. RESULTS The level of TGR5 immunoreactivity in rectosigmoid mucosal biopsies was significantly higher in IBS-D patients than in controls, while the VDR immunoreactivity displayed no significant difference between patients and controls. The patients with more severe or more frequent abdominal pain had significantly higher TGR5 level. Faecal primary BAs were significantly increased in IBS-D patients and were positively correlated with the severity of diarrhoea. The level of TGR5 was positively associated with primary BAs and negatively associated with secondary BAs among all participants providing both mucosal and stool samples. CONCLUSIONS Colonic mucosal TGR5 protein expression and faecal bile acids were correlated with the symptom severity of IBS-D patients.
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Total bile acid-to-cholesterol ratio as a novel noninvasive marker for significant liver fibrosis and cirrhosis in patients with non-cholestatic chronic hepatitis B virus infection.
Yan, LT, Wang, LL, Yao, J, Yang, YT, Mao, XR, Yue, W, Mao, YW, Zhou, W, Chen, QF, Chen, Y, et al
Medicine. 2020;(8):e19248
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Abstract
Although serum bile acids and total cholesterol (TC) are closely related to liver cirrhosis, the potential diagnostic value of total bile acid-to-cholesterol ratio (TBA/TC) for liver fibrosis is unclear. The present study aimed to evaluate the value of TBA/TC in the diagnosis of cirrhosis and the relationship between TBA/TC and significant liver fibrosis in chronic hepatitis B virus (HBV) infected patients without cholestasis.667 patients with alkaline phosphatase (ALP) ≤ 1.5 upper limit of normal (ULN) and gamma-glutamyl transferase (GGT) ≤ 3 ULN were rigorously included in this cross-sectional study. Liver biopsy was performed in 32 patients and METAVIR scoring system was used to evaluate liver fibrosis stage. Liver ultrasound elastography was performed in 138 patients, significant fibrosis was defined as fibrosis ≥ F2. Multiple logistic regression as well as receiver operating characteristic (ROC) curves analyses were performed.Compared to patients with non-cirrhosis, TBA and TBA/TC were significantly higher in cirrhosis while TC was significantly lower (all P < .001). In multivariate analysis, TBA/TC was also independently associated with cirrhosis [odds ratio (OR) = 1.102, 95% confidence interval (CI): 1.085-1.166]. The area under the curve (AUC) of TBA/TC (0.87) was almost equivalent to the aspartate aminotransferase to platelet ratio index (APRI, AUC = 0.84) and fibrosis 4 score (FIB-4, AUC = 0.80), and the optimal cut-off value for TBA/TC to diagnose cirrhosis was 2.70. Among the patients performed liver biopsy, TBA/TC were significantly higher both in significant fibrosis and cirrhosis as well as significantly correlated with fibrosis stage (all P < .001). Furthermore, In patients performed liver ultrasound elastography, TBA/TC was also independently associated with significant fibrosis (OR = 1.040, 95% CI: 1.001-1.078).Assessment of TBA/TC could serve as an additional marker of significant liver fibrosis and cirrhosis in non-cholestatic chronic HBV infection.
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Gallbladder Dyskinesia Is Associated With an Impaired Postprandial Fibroblast Growth Factor 19 Response in Critically Ill Patients.
Koelfat, KVK, Plummer, MP, Schaap, FG, Lenicek, M, Jansen, PLM, Deane, AM, Olde Damink, SWM
Hepatology (Baltimore, Md.). 2019;(1):308-318
Abstract
Critical illness is associated with a disturbed regulation of gastrointestinal hormones resulting in functional and metabolic anomalies. Fibroblast growth factor 19 (FGF19) is an ileum-derived metabolic hormone induced by bile salts upon gallbladder emptying after enteral nutrient stimulation. Our aim was to study the nutrient-stimulated FGF19 response in 24 patients admitted to the intensive care unit (ICU) compared with 12 healthy controls. All subjects received intraduodenal high-lipid nutrient infusion for 120 minutes. Blood was collected every 30 minutes until 1 hour after infusion, and gallbladder emptying was studied by ultrasound. Serum levels of bile salts and FGF19 were assessed. ICU patients had significantly higher fasting bile salt serum levels compared with controls, whereas FGF19 serum levels were similar. In both groups, nutrient infusion elicited substantial bile salt elevations (P < 0.001), peaking at 90 minutes, albeit with a significantly lower peak in the ICU patients (P = 0.029). In controls, FGF19 was significantly elevated relative to baseline from 120 minutes onward (P < 0.001). In ICU patients, the FGF19 response was blunted, as reflected by significantly lower FGF19 elevations at 120, 150, and 180 minutes (P < 0.05) and significantly lower area under the curve (AUC) values compared with controls (P < 0.001). Gallbladder dysmotility was associated with the impaired FGF19 response in critical illness. The gallbladder ejection fraction correlated positively with FGF19 AUC values (ρ = +0.34, P = 0.045). In 10 of 24 ICU patients, gallbladder emptying was disturbed. These patients had significantly lower FGF19 AUC values (P < 0.001). Gallbladder emptying and the FGF19 response were respectively disturbed or absent in patients receiving norepinephrine. Conclusion: The nutrient-stimulated FGF19 response is impaired in ICU patients, which is mechanistically linked to gallbladder dysmotility in critical illness. This may contribute to disturbed liver metabolism in these patients and has potential as a nutritional biomarker.
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Clinical and histopathologic features of sodium taurocholate cotransporting polypeptide deficiency in pediatric patients.
Dong, C, Zhang, BP, Wang, H, Xu, H, Zhang, C, Cai, ZS, Wang, DW, Shu, SN, Huang, ZH, Luo, XP
Medicine. 2019;(39):e17305
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Abstract
Until now, the recognition of sodium taurocholate cotransporting polypeptide (NTCP) deficiency has been mainly based on sporadic case reports. It was previously believed to be mildly symptomatic and resulting in mild liver dysfunction. However, to our knowledge, there have been no reports about the histopathologic and ultrastructural pathologic characteristics of the disease. The aim of the study was to analyze the clinical, histopathologic and ultrastructural pathologic characteristics of NTCP deficiency in 13 pediatric patients.From August 2012 to October 2018, this retrospective study conducted in the Department of Pediatrics of Tongji Hospital, China analyzed the data of 13 NTCP deficient patients with an SLC10A1 gene mutation. Except for NTCP deficiency, no other liver diseases were present in the patients, which was determined by both a genetic testing panel for jaundice and by reviewing medical records. The laboratory results, imaging, histopathologic, and ultrastructural pathologic information were recorded for analysis.The serum level of total bile acid was high in all 13 patients. All patients had adequate growth and development. Eight of the patients (8/13) presented with visible jaundice and 12 (12/13) were found to have hyperbilirubinemia. A needle liver biopsy was performed in 11 cases, which revealed slightly chronic inflammation in all 11 patients. One of the patients (1/13) was found to be suffering from gallstones.The data showed that although NTCP deficiency was often asymptomatic, some of the patients showed obvious clinical expressions, such as jaundice. Among the 13 pediatric patients with NTCP deficiency, both the biochemical and histopathologic features were similar to those of mild hepatocellular jaundice. In addition, it was determined that the clinical features in the patient with gallstones may have been caused by NTCP deficiency.
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Acute caloric restriction counteracts hepatic bile acid and cholesterol deficiency in morbid obesity.
Straniero, S, Rosqvist, F, Edholm, D, Ahlström, H, Kullberg, J, Sundbom, M, Risérus, U, Rudling, M
Journal of internal medicine. 2017;(5):507-517
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Abstract
BACKGROUND Bile acid (BA) synthesis is regulated by BA signalling in the liver and by fibroblast growth factor 19 (FGF19), synthesized and released from the intestine. In morbid obesity, faecal excretion and hepatic synthesis of BAs and cholesterol are strongly induced and caloric restriction reduces their faecal excretion considerably. We hypothesized that the high intestinal food mass in morbidly obese subjects promotes faecal excretion of BAs and cholesterol, thereby creating a shortage of both BAs and cholesterol in the liver. METHODS Ten morbidly obese women (BMI 42 ± 2.6 kg m-2 ) were monitored on days 0, 3, 7, 14 and 28 after beginning a low-calorie diet (800-1100 kcal day-1 ). Serum was collected and liver size and fat content determined. Synthesis of BAs and cholesterol was evaluated from serum markers, and the serum levels of lipoproteins, BAs, proprotein convertase subtilisin/kexin type 9 (PCSK9), insulin, glucose and FGF19 were monitored. Fifty-four nonobese women (BMI <25 kg m-2 ) served as controls. RESULTS At baseline, synthesis of both BAs and cholesterol and serum levels of BAs and PCSK9 were elevated in the obese group compared to controls. Already after 3 days on a low-calorie diet, BA and cholesterol synthesis and serum BA and PCSK9 levels normalized, whereas LDL cholesterol increased. FGF19 and triglyceride levels were unchanged, and liver volume was reduced by 10%. CONCLUSIONS The results suggest that hepatic BAs and cholesterol are deficient in morbid obesity. Caloric restriction rapidly counteracts these deficiencies, normalizing BA and cholesterol synthesis and circulating PCSK9 levels, indicating that overproduction of cholesterol in enlarged peripheral tissues cannot explain this phenotype. We propose that excessive food intake promotes faecal loss of BAs and cholesterol contributing to their hepatic deficiencies.
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Influence of Partial External Biliary Diversion on the Lipid Profile in Children With Progressive Familial Intrahepatic Cholestasis.
Jankowska, I, Czubkowski, P, Wierzbicka, A, Pawłowska, J, Kaliciński, P, Socha, P
Journal of pediatric gastroenterology and nutrition. 2016;(6):598-602
Abstract
OBJECTIVES The concentration of bile acids is highly increased in progressive familial intrahepatic cholestasis (PFIC). Bile acids are the end products of cholesterol metabolism, and aid in the absorption of fat-soluble vitamins and dietary fat. The aim of our study was to investigate lipid metabolism in patients with PFIC with focus on the effect of partial external biliary diversion (PEBD). METHODS In 26 patients with PFIC, who underwent PEBD surgery at the median age of 2.2 years (range: 0.4-16.6), we analyzed the concentrations of lipids and apolipoproteins both before and 6 months after PEBD. Patients were split into 2 groups according to the outcome of surgery (either "good" or "poor"), and were analyzed separately. A "good" result following surgery was defined as complete relief from pruritus, and normalization of total bilirubin (<1.0 mg/dL) and bile acid concentration in serum (<12 μmol/L). RESULTS We found abnormal lipid concentrations at baseline in all 26 patients: cholesterol was increased (>190 mg/dL) in 13 patients, phospholipids were increased (>250 mg/dL) in 5 patients, and triglyceride concentration was increased (>150 mg/dL) in 13 patients. After PEBD, the concentrations of plasma cholesterol, triglycerides, and phospholipids decreased significantly, whereas, ApoA-I and high-density lipoprotein cholesterol concentrations increased and the concentrations of apolipoprotein B, low-density lipoprotein cholesterol, and very low-density lipoprotein cholesterol significantly decreased. PEBD had neither an effect on ApoE concentration nor on lecithin-cholesterol acyl transferase activity. In the group with a "poor" outcome report following PEBD, total serum cholesterol concentration decreased significantly, and no effect on the concentrations of triglycerides and phospholipids were observed. CONCLUSIONS Patients with PFIC present with a high risk of lipid disturbances. PEBD has a beneficial effect on lipid profile in the majority of cases.
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Are bile acid malabsorption and bile acid diarrhoea important causes of loose stool complicating cancer therapy?
Phillips, F, Muls, AC, Lalji, A, Andreyev, HJ
Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland. 2015;(8):730-4
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 ((75) Se) 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 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 under-appreciated 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.