Leslie J. Donato

Effect of colesevelam on faecal bile acids and bowel functions in diarrhoea‐predominant irritable bowel syndrome

About one‐third of patients with IBS‐diarrhoea (irritable bowel syndrome‐D) have evidence of increased bile acid synthesis or excretion.

Effect of increased bile acid synthesis or fecal excretion in irritable bowel syndrome-diarrhea

OBJECTIVES:Approximately 25% of patients with irritable bowel syndrome-diarrhea (IBS-D) have increased total fecal bile acids (BA) and serum C4 (surrogate for BA synthesis). BA synthesis-related genes (KLB and FGFR4) are associated with colonic transit (CT) in IBS-D. Our aims were: (i) to compare phenotype and pathophysiology in IBS-D patients with increased or normal fecal excretion or synthesis of BA; and (ii) to explore association of variations in two candidate bile-acid synthesis genes (KLB and FGFR4) in these two subgroups of IBS-D.METHODS:A total of 64 IBS-D patients underwent on one occasion: fasting serum C4 and FGF19, total fecal fat and BA excretion, CT, intestinal and colonic permeability, and candidate genotyping (rs17618244 (KLB), rs351855 (FGFR4)). Colonic sensation and tone were measured in 47 of the IBS-D patients. IBS-D subgroups were identified by fecal BA >2,337 mM per 48 h or by serum C4 >47.1 ng/ml.RESULTS:IBS-D patients with fecal BA >2,337 mM per 48 h (19/54) had significantly greater body mass index, fecal fat, percent chenodeoxycholic acid (CDCA) in feces, and intestinal permeability, and borderline increased CT (P=0.13). Those IBS-D patients with serum C4 >47.1 ng/ml (13/54) had increased total fecal BA excretion and borderline increased colonic permeability. Variants in genes involved in feedback regulation of BA synthesis (KLB, P=0.06 and FGFR4, P=0.09) were potentially associated with the subgroup with elevated serum C4.CONCLUSIONS:IBS-D with increased BA excretion or synthesis is associated with significant pathophysiological changes relative to patients with normal BA profile. BA diarrhea is identified more effectively with total fecal BA than with serum C4.

Validating biomarkers of treatable mechanisms in irritable bowel syndrome.

A valid biomarker is ‘an indicator of normal biologic or pathogenic processes, or pharmacological responses to a therapeutic intervention’. There is no validated biomarker for irritable bowel syndrome (IBS). The aim of the study was to assess ability of three quantitative traits to identify treatable processes to discriminate between IBS‐diarrhea (IBS‐D) patients, IBS‐constipation (IBS‐C) patients and healthy volunteers (HV).

Effects of Rifaximin on Transit, Permeability, Fecal Microbiome, and Organic Acid Excretion in Irritable Bowel Syndrome

Objectives:Rifaximin relieves irritable bowel syndrome (IBS) symptoms, bloating, abdominal pain, and loose or watery stools. Our objective was to investigate digestive functions in rifaximin-treated IBS patients.Methods:In a randomized, double-blind, placebo-controlled, parallel-group study, we compared the effects of rifaximin, 550 mg t.i.d., and placebo for 14 days in nonconstipated IBS and no evidence of small intestinal bacterial overgrowth (SIBO). All subjects completed baseline and on-treatment evaluation of colonic transit by scintigraphy, mucosal permeability by lactulose–mannitol excretion, and fecal microbiome, bile acids, and short chain fatty acids measured on random stool sample. Overall comparison of primary response measures between treatment groups was assessed using intention-to-treat analysis of covariance (ANCOVA, with baseline value as covariate).Results:There were no significant effects of treatment on bowel symptoms, small bowel or colonic permeability, or colonic transit at 24 h. Rifaximin was associated with acceleration of ascending colon emptying (14.9±2.6 h placebo; 6.9±0.9 h rifaximin; P=0.033) and overall colonic transit at 48 h (geometric center 4.0±0.3 h placebo; 4.7±0.2 h rifaximin; P=0.046); however, rifaximin did not significantly alter total fecal bile acids per g of stool or proportion of individual bile acids or acetate, propionate, or butyrate in stool. Microbiome studies showed strong associations within subjects, modest associations with time across subjects, and a small but significant association of microbial richness with treatment arm (rifaximin vs. treatment).Conclusions:In nonconstipated IBS without documented SIBO, rifaximin treatment is associated with acceleration of colonic transit and changes in microbial richness; the mechanism for reported symptomatic benefit requires further investigation.

A 71-year-old woman with multiple myeloma status after stem cell transplantation.

A 71-year-old woman with a 9-year history of monoclonal gammopathy of undetermined significance presented with anemia [hemoglobin, 11.6 g/dL (116 g/L); reference interval (RI),3 12–15.5 g/dL (120–155 g/L)], an increased serum calcium concentration [10.2 mg/dL (2.55 mmol/L); RI, 8.9–10.1 mg/dL (2.22–2.52 mmol/L)], and a 4800-mg/dL (48-g/L) monoclonal protein band (M-spike) after serum protein electrophoresis (SPEP). Immunofixation electrophoresis (IFE) revealed a monoclonal IgA κ protein. Her IgA concentration was markedly increased to 4720 mg/dL [47.2 g/L; RI, 61–356 mg/dL (0.61–3.56 g/L)], and the serum immunoglobulin free light chain (FLC) κ/λ ratio was 7 (RI, 0.26–1.65). A bone marrow biopsy confirmed 40% involvement by monoclonal κ-restricted plasma cells with a plasma cell labeling index of 0.4% (intermediate). A bone survey revealed diffuse osteopenia, multiple small lytic lesions throughout the skeleton, and a lesion consistent with a plasmacytoma at T7. A diagnosis of multiple myeloma (MM) (Durie–Salmon stage IIIA, international stage 2) was confirmed. The patient was initially treated medically and then underwent successful autologous stem cell transplantation. The patient was asymptomatic, with negative results in serum and urine protein electrophoresis and IFE evaluations for 1.5 years. A follow-up SPEP evaluation 2 years after the patient received her transplant revealed an M-spike of 3920 mg/dL (39.2 g/L) and an IgA concentration of 3810 mg/dL (38.1 g/L). A bone marrow biopsy showed 60%–70% involvement by monoclonal plasma cells. The results of a urine IFE test were negative. The patient was treated with a regimen of 25 mg Revlimid daily on days 1–21 and 20 mg dexamethasone weekly. The patients M-spike decreased to 1100 mg/dL (11 g/L) by 1 month after treatment, and her IgA concentration was reduced to 1260 mg/dL (12.6 g/L). Two months into treatment, the patient had detectable monoclonal protein but no measurable M-spike, and her IgA concentration was 402 mg/dL …

Reference and Interpretive Ranges for α1-Antitrypsin Quantitation by Phenotype in Adult and Pediatric Populations

Laboratory evaluation of α(1)-antitrypsin (A1AT) deficiency involves measurement of circulating A1AT protein (quantitation) and characterization of A1AT genetic polymorphisms (phenotyping or genotyping). This study compared adult and pediatric A1AT reference ranges in patients with nondeficiency alleles and examined A1AT concentrations in multiple other phenotypes. A1AT phenotype and quantitation were retrospectively collected on adult (n = 21,444) and pediatric (n = 2,469) samples that were submitted for laboratory evaluation of A1AT deficiency. The 95% reference ranges for normal adult and pediatric populations with the M/M phenotype were determined to be 100 to 273 mg/dL (18.4-50.2 μmol/L) and 93 to 251 mg/dL (17.1-46.2 μmol/L), respectively (P < .0001). Decreased concentrations of A1AT correlated with heterozygosity and homozygosity for the S and Z alleles in both the adult and pediatric groups. Other rare alleles, such as I, were also associated with decreased concentrations of A1AT, particularly in the context of a Z allele, and may warrant monitoring for symptoms of deficiency.

Genetic variation in GPBAR1 predisposes to quantitative changes in colonic transit and bile acid excretion

The pathobiology of irritable bowel syndrome (IBS) is multifaceted. We aimed to identify candidate genes predisposing to quantitative traits in IBS. In 30 healthy volunteers, 30 IBS-constipation, and 64 IBS-diarrhea patients, we measured bowel symptoms, bile acid (BA) synthesis (serum 7α-hydroxy-4-cholesten-3-one and FGF19), fecal BA and fat, colonic transit (CT by scintigraphy), and intestinal permeability (IP by 2-sugar excretion). We assessed associations of candidate genes controlling BA metabolism (KLB rs17618244 and FGFR4 rs351855), BA receptor (GPBAR1 rs11554825), serotonin (5-HT) reuptake (SLC6A4 through rs4795541 which encodes for the 44-bp insert in 5HTTLPR), or immune activation (TNFSF15 rs4263839) with three primary quantitative traits of interest: colonic transit, BA synthesis, and fecal BA excretion. There were significant associations between fecal BA and CT at 48 h (r = 0.43; P < 0.001) and IP (r = 0.23; P = 0.015). GPBAR1 genotype was associated with CT48 (P = 0.003) and total fecal BA [P = 0.030, false detection rate (FDR) P = 0.033]. Faster CT48 observed with both CC and TT GPBAR1 genotypes was due to significant interaction with G allele of KLB, which increases BA synthesis and excretion. Other univariate associations (P < 0.05, without FDR correction) observed between GPBAR1 and symptom phenotype and gas sensation ratings support the role of GPBAR1 receptor. Associations between SLC6A4 and stool consistency, ease of passage, postprandial colonic tone, and total fecal BA excretion provide data in support of future hypothesis-testing studies. Genetic control of GPBAR1 receptor predisposing to pathobiological mechanisms in IBS provides evidence from humans in support of the importance of GPBAR1 to colonic motor and secretory functions demonstrated in animal studies.

Bile Acid Deficiency in a Subgroup of Patients With Irritable Bowel Syndrome With Constipation Based on Biomarkers in Serum and Fecal Samples

Background & Aims Short‐term administration of delayed‐release chenodeoxycholic acid to patients with irritable bowel syndrome with constipation (IBS‐C) accelerates colonic transit and reduces symptoms. A preliminary study has shown that patients with IBS‐C have reduced levels of bile acids (BAs) in feces and reduced synthesis of BA. We compared the levels of primary and secondary BAs in fecal samples collected over a 48‐hour period from patients with IBS‐C on a diet that contained 100 g fat per day, and compared them with levels in samples from healthy volunteers (controls). We also examined the relationship between overall colonic transit and biomarkers of BAs in patients with IBS‐C. Methods We performed a retrospective study of 45 patients with IBS‐C and 184 controls. For controls, we estimated the 10th percentile of fasting serum levels of 7&agr;‐hydroxy‐4‐cholesten‐3‐one (C4, n = 184) and 48‐hour fecal BAs (n = 46), and the 90th percentile of the fasting serum level of fibroblast growth factor 19 (FGF19, n = 50). Colonic transit was measured in patients using a validated scintigraphic method. Data from patients with IBS‐C were analyzed using Spearman correlations to determine the relationships among levels of C4, FGF19, fecal BAs, and colonic transit. Results Among the patients with IBS‐C, 2 of 45 had low serum levels of C4, 4 of 43 had increased serum levels of FGF19, and 6 of 39 had low levels of BAs in feces collected over 48 hours. Patients with IBS‐C had a significant increase in the proportions of fecal lithocholic acid compared with controls (P = .04), and a decrease in deoxycholic acid compared with controls (P = .03). In patients with IBS‐C, there were inverse relationships between serum levels of C4 and FGF19 and correlations among levels of 48‐hour fecal BAs, colonic transit, and serum C4 and FGF19. Conclusions Approximately 15% of patients with IBS‐C have reduced total BAs and level of deoxycholic acid in fecal samples collected over 48 hours on a 100 g fat diet. In these patients, lower levels of excretion of BAs into feces correlated with slower colonic transit.

How novel molecular diagnostic technologies and biomarkers are revolutionizing genetic testing and patient care.

Technological applications and novel biomarkers in the field of molecular diagnostics have never been evolving at a more rapid pace. These novel applications have the promise to change the face of clinical care as we move into the era of personalized medicine. While some of these technologies and biomarkers have been adopted by some clinical laboratories, most laboratories face a steep learning curve in bringing these dramatically new and different molecular diagnostic applications on board. Furthermore, interpreting the vast amounts and new types of data produced by these novel applications brings forth challenges for laboratorians and clinicians alike. In this article, we discuss how some of these emerging novel molecular diagnostic technologies and analytes, such as next-generation sequencing, chromosomal microarray, microRNAs and circulating fetal nucleic acids are revolutionizing patient care and personalized medicine.

Implementation of Clinical Decision Support Rules to Reduce Repeat Measurement of Serum Ionized Calcium, Serum Magnesium, and N-Terminal Pro-B-Type Natriuretic Peptide in Intensive Care Unit Inpatients

BACKGROUND We assessed the impact of clinical decision support (CDS) rules within the electronic health record for ionized calcium (iCa), serum magnesium (Mg), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in intensive care unit (ICU) inpatients at a large academic center. METHODS A repeat order for measurement of iCa or Mg placed within 24 (iCa) or 48 (Mg) h of a previously nonactionable result, or additional orders for NT-proBNP beyond 1 within a single hospitalization, triggered a CDS pop-up alert showing the prior result and offering the opportunity to cancel the order or to place the order after entering an indication for repeat testing. The number of tests performed for each of these analytes and incidence of adverse clinical outcomes potentially associated with hypocalcemia or hypomagnesemia were compared between the 90-day period before CDS implementation and two 90-day periods immediately following. RESULTS iCa test volumes decreased by 48%, Mg by 39%, and NT-proBNP by 28% in the 90-day period immediately following implementation and remained decreased by 54%, 49%, and 22%, respectively, during the following 90-day period (all P values <0.0002). Adverse clinical outcomes potentially associated with hypocalcemia or hypomagnesemia did not increase (all P-values >0.17). CONCLUSIONS Implementation of CDS dramatically decreased repeat testing of iCa, Mg, and NT-proBNP without adversely impacting clinical outcomes in the ICU. Expansion of the rules from the ICU units to include the entire hospitalized patient population and expansion to additional analytes is expected to lead to further reductions in testing.