Publications by authors named "Ahmad H Ali"

24 Publications

  • Page 1 of 1

Clinically Actionable Findings Derived From Predictive Genomic Testing Offered in a Medical Practice Setting.

Mayo Clin Proc 2021 06 21;96(6):1407-1417. Epub 2020 Oct 21.

Center for Individualized Medicine, Mayo Clinic, Rochester, MN; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN. Electronic address:

Objective: To assess the presence of clinically actionable results and other genetic findings in an otherwise healthy population of adults seen in a medical practice setting and offered "predictive" genomic testing.

Patients And Methods: In 2014, a predictive genomics clinic for generally healthy adults was launched through the Mayo Clinic Executive Health Program. Self-identified interested patients met with a genomic nurse and genetic counselor for pretest advice and education. Two genome sequencing platforms and one gene panel-based health screen were offered. Posttest genetic counseling was available for patients who elected testing. From March 1, 2014, through June 1, 2019, 1281 patients were seen and 301 (23.5%) chose testing. Uptake rates increased to 36.3% [70 of 193]) in 2019 from 11.8% [2 of 17] in 2014. Clinically actionable results and genetic findings were analyzed using descriptive statistics.

Results: Clinically actionable results were detected in 11.6% of patients (35 of 301), and of those, 51.7% (15 of 29) with a cancer or cardiovascular result = did not have a personal or family history concerning for a hereditary disorder. The most common actionable results were in the BCHE, BRCA2, CHEK2, LDLR, MUTYH, and MYH7 genes. A carrier of at least one recessive condition was found in 53.8% of patients (162 of 301). At least one variant associated with multifactorial disease was found in 44.5% (134 of 301) (eg, 25 patients were heterozygous for the F5 factor V Leiden variant associated with thrombophilia risk).

Conclusion: Our predictive screening revealed that 11.6% of individuals will test positive for a clinically actionable, likely pathogenic/pathogenic variant. This finding suggests that wider knowledge and adoption of predictive genomic services could be beneficial in medical practice, although additional studies are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mayocp.2020.08.051DOI Listing
June 2021

Evaluation of circulating cell-free DNA in cholestatic liver disease using liver-specific methylation markers.

BMC Gastroenterol 2021 Apr 1;21(1):149. Epub 2021 Apr 1.

Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

Background: Quantification of circulating organ-specific cell-free DNA (cfDNA) provides a sensitive measure of ongoing cell death that could benefit evaluation of the cholestatic liver diseases primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), which lack reliable non-invasive biomarkers. Our goal in this pilot study was to determine whether liver-specific cfDNA levels are increased in PBC and PSC patients relative to controls and in advanced versus early disease, to evaluate their potential as novel disease biomarkers.

Methods: Peripheral blood derived bisulfite-treated DNA was PCR amplified from patients with PBC (n = 48), PSC (n = 48) and controls (n = 96) to evaluate methylation status at 16 CpG sites reported to be specifically unmethylated in liver tissue near the genes IGF2R, ITIH4 and VTN. Amplicons were used to prepare paired end libraries which were sequenced on a MiSeq sequencer. Trimmed reads were aligned and used to determine unmethylation ratios and to calculate concentration of liver-specific cfDNA. Comparisons between groups were performed using the two-tailed Mann-Whitney Test and relationships between variables were evaluated using Pearson's Correlation.

Results: Levels of liver-specific cfDNA, as measured at the 3 genetic loci, were increased in PBC and PSC patients relative to controls and in late-stage relative to early-stage patients. As well, cfDNA levels were correlated with levels of alkaline phosphatase, a commonly used biochemical test to evaluate disease severity in liver disease, in patients, but not in controls.

Conclusions: cfDNA offers promise as a non-invasive liquid-biopsy to evaluate liver-specific cell-death in patients with cholestatic liver diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12876-021-01741-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017778PMC
April 2021

Bile Acid Profiles in Primary Sclerosing Cholangitis and Their Ability to Predict Hepatic Decompensation.

Hepatology 2020 Nov 23. Epub 2020 Nov 23.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN.

Background And Aims: Altered bile acid (BA) homeostasis is an intrinsic facet of cholestatic liver diseases, but clinical usefulness of plasma BA assessment in primary sclerosing cholangitis (PSC) remains understudied. We performed BA profiling in a large retrospective cohort of patients with PSC and matched healthy controls, hypothesizing that plasma BA profiles vary among patients and have clinical utility.

Approach And Results: Plasma BA profiling was performed in the Clinical Biochemical Genetics Laboratory at Mayo Clinic using a mass spectrometry based assay. Cox proportional hazard (univariate) and gradient boosting machines (multivariable) models were used to evaluate whether BA variables predict 5-year risk of hepatic decompensation (HD; defined as ascites, variceal hemorrhage, or encephalopathy). There were 400 patients with PSC and 302 controls in the derivation cohort (Mayo Clinic) and 108 patients with PSC in the validation cohort (Norwegian PSC Research Center). Patients with PSC had increased BA levels, conjugated fraction, and primary-to-secondary BA ratios relative to controls. Ursodeoxycholic acid (UDCA) increased total plasma BA level while lowering cholic acid and chenodeoxycholic acid concentrations. Patients without inflammatory bowel disease (IBD) had primary-to-secondary BA ratios between those of controls and patients with ulcerative colitis. HD risk was associated with increased concentration and conjugated fraction of many BA, whereas higher G:T conjugation ratios were protective. The machine-learning model, PSC-BA profile score (concordance statistic [C-statistic], 0.95), predicted HD better than individual measures, including alkaline phosphatase, and performed well in validation (C-statistic, 0.86).

Conclusions: Patients with PSC demonstrated alterations of plasma BA consistent with known mechanisms of cholestasis, UDCA treatment, and IBD. Notably, BA profiles predicted future HD, establishing the clinical potential of BA profiling, which may be suited for use in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.31652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141059PMC
November 2020

Single-cell mass cytometry on peripheral blood identifies immune cell subsets associated with primary biliary cholangitis.

Sci Rep 2020 07 28;10(1):12584. Epub 2020 Jul 28.

Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.

The relationship between primary biliary cholangitis (PBC), a chronic cholestatic autoimmune liver disease, and the peripheral immune system remains to be fully understood. Herein, we performed the first mass cytometry (CyTOF)-based, immunophenotyping analysis of the peripheral immune system in PBC at single-cell resolution. CyTOF was performed on peripheral blood mononuclear cells (PBMCs) from PBC patients (n = 33) and age-/sex-matched healthy controls (n = 33) to obtain immune cell abundance and marker expression profiles. Hierarchical clustering methods were applied to identify immune cell types and subsets significantly associated with PBC. Subsets of gamma-delta T cells (CD3TCRgd), CD8 T cells (CD3CD8CD161PD1), and memory B cells (CD3CD19CD20CD24CD27) were found to have lower abundance in PBC than in control. In contrast, higher abundance of subsets of monocytes and naïve B cells were observed in PBC compared to control. Furthermore, several naïve B cell (CD3CD19CD20CD24CD27) subsets were significantly higher in PBC patients with cirrhosis (indicative of late-stage disease) than in those without cirrhosis. Alternatively, subsets of memory B cells were lower in abundance in cirrhotic relative to non-cirrhotic PBC patients. Future immunophenotyping investigations could lead to better understanding of PBC pathogenesis and progression, and also to the discovery of novel biomarkers and treatment strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-69358-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387528PMC
July 2020

Associations Between Drug Exposure and Outcomes in Patients With Primary Sclerosing Cholangitis and Inflammatory Bowel Disease.

Clin Gastroenterol Hepatol 2020 05 5;18(5):1244-1245. Epub 2019 Oct 5.

Division of Gastroenterology, Olive View-UCLA Medical Center, Sylmar, California.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cgh.2019.09.044DOI Listing
May 2020

Pilot evaluation of PD-1 inhibition in metastatic cancer patients with a history of liver transplantation: the Mayo Clinic experience.

J Gastrointest Oncol 2018 Dec;9(6):1054-1062

Division of Hematology & Oncology, Department of Medicine, Mayo Clinic, Scottsdale, AZ, USA.

Background: Patients with solid organ transplants (SOTs) have been excluded from programmed death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitor clinical trials due to concern for allograft rejection. The use of immune checkpoint inhibitor therapy remains controversial in transplant patients.

Methods: A retrospective pilot evaluation was conducted to assess the safety and efficacy of PD-1 inhibitors in patients with liver transplantation (LT). The primary endpoint was the rate of allograft rejection. Secondary endpoints included overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Translational objectives included evaluation of tumor PD-L1, tumor infiltrating lymphocytes (TILs) and allograft PD-L1 expression.

Results: Seven metastatic cancer patients with a history of LT who received PD-1 inhibitor therapy were included [hepatocellular carcinoma (HCC), n=5; melanoma, n=2]. Rejection was observed in 2 of 7 patients. When rejection occurs it appears to be an early event with a median time to rejection of 24 days in our cohort. One patient achieved a complete response (CR), 3 patients had progressive disease (PD) and 3 patients discontinued therapy prior to restaging assessments. Two of five patients with available tissue had PD-L1 expression in the allograft and both developed rejection. One of five evaluable patients had abundant TILs. Two of five evaluable patients had PD-L1 tumor staining. The single patient with both abundant TILs and PD-L1 staining obtained a response. The median OS and PFS were 1.1 (0.3-21.1) and 1.8 (0.7-21.1) months, respectively.

Conclusions: In this pilot evaluation both preliminary efficacy (1 of 4) and allograft rejection (2 of 7) were exhibited in evaluable patients. Larger, prospective trials are needed to elucidate optimal patient selection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21037/jgo.2018.07.05DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286929PMC
December 2018

Primary Sclerosing Cholangitis, Part 2: Cancer Risk, Prevention, and Surveillance.

Gastroenterol Hepatol (N Y) 2018 Jul;14(7):427-432

Dr Tabibian is an associate professor at the Geffen School of Medicine at UCLA in Los Angeles, California and director of endoscopy and resident research director in the Department of Medicine at Olive View-UCLA Medical Center in Sylmar, California.

Primary sclerosing cholangitis (PSC) is a chronic, fibroinflammatory, progressive cholangiopathy. In a clinically significant proportion of patients, the disease course of PSC is punctuated by carcinogenesis, namely cholangiocarcinoma, gallbladder carcinoma, hepatocellular carcinoma, and/or colorectal carcinoma. Indeed, malignancy is arguably the most consequential sequela and the cause of nearly 50% of deaths in patients with PSC. This statistic is multifactorial, relating partly to the premalignant nature of PSC, challenges in diagnosis due to obscuration of cancer by the inflammation and fibrosis inherent to PSC, and the unpredictability of which type of cancer will develop in PSC and when. Here, in the second of a 2-part series, we review cancer risk, prevention, and surveillance in patients with PSC. We also discuss potential cancer surveillance strategies in PSC and, where evidence is limited, make pragmatic recommendations based on current data and expert opinion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111497PMC
July 2018

Primary Sclerosing Cholangitis, Part 1: Epidemiology, Etiopathogenesis, Clinical Features, and Treatment.

Gastroenterol Hepatol (N Y) 2018 May;14(5):293-304

Dr Tabibian is an associate professor in the Geffen School of Medicine at UCLA in Los Angeles, California and director of endoscopy in the Department of Medicine at Olive View-UCLA Medical Center in Sylmar, California. Dr Ali is a research fellow in the Division of Gastroenterology and Hepatology at Mayo Clinic in Phoenix, Arizona. Dr Lindor is a professor of medicine in the Division of Gastroenterology and Hepatology at Mayo Clinic and senior advisor to the provost at Arizona State University in Phoenix, Arizona.

Primary sclerosing cholangitis (PSC) is a chronic, idiopathic cholangiopathy that can progress to cirrhosis, end-stage liver disease, hepatobiliary cancer, and/or colorectal cancer. The course of PSC is often complicated by portal hypertension, symptoms of cholestasis, and recurrent bacterial cholangitis, among other conditions, with a consequent decrease in survival (median, approximately 20 years) and quality of life. The etiopathogenesis of PSC remains poorly understood, and, as such, pharmacotherapy has yet to be definitively established. Despite its rarity, PSC is the fifth leading indication for liver transplantation (LT) in the United States. Although the only intervention known to extend survival of patients with PSC, LT is costly and invasive, and recurrent PSC affects approximately 30% of LT recipients. Over the past several years, owing in part to progress in the understanding of PSC, novel pharmacotherapeutics have been developed, some of which are currently in the PSC clinical trial pipeline. Here, in the first of a 2-part series, we provide a review and update of the epidemiology, etiopathogenesis, clinical features, and treatment of PSC. The second part of the series will focus on cancer risk, prevention, and surveillance of PSC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034608PMC
May 2018

The Effect of Perioperative Cimetidine Administration on Time to Colorectal Cancer Recurrence.

Am J Ther 2018 Jul/Aug;25(4):e405-e411

Department of Internal Medicine, Texas Tech University Health Sciences Center, Amarillo, TX.

Background: Studies have reported that the perioperative use of cimetidine, a histamine type 2 receptor antagonist, in addition to chemotherapy in patients with lymph node-positive colorectal cancer (CRC) improves the survival.

Study Question: To determine if time to CRC recurrence could be prolonged with cimetidine.

Study Design: Cimetidine was prescribed to American Joint on Cancer Committee (AJCC) stage III CRC patients perioperatively. Tumor recurrence was defined as the time (in days) between tumor resection and CRC recurrence. Medical charts of patients diagnosed with CRC between 1996 and 2006 were reviewed. Inclusion criteria were patients with (a) AJCC stage III CRC, (b) who had undergone surgical resection of the tumor, and (c) who received chemotherapy (5-fluorouracil).

Measures And Outcomes: AJCC stage III CRC patients who did and did not receive cimetidine as part of the treatment regimen were compared with respect to their clinical outcomes using univariate analysis and Kaplan-Meier modeling.

Results: Between 1996 and 2006, 38 patients met our inclusion criteria. Twenty-six percent (10/38) received perioperative cimetidine (mean daily dose, 750 mg; mean duration, 369 days; mean total cumulative cimetidine dose, 274,070 mg/d) in addition to chemotherapy. Time to recurrence and cancer deaths were prolonged in the chemotherapy plus cimetidine group compared with the group that received chemotherapy alone (mean ± SD: 1078 ± 290 vs. 446 ± 62; P = 0.03). In addition, we found a significant positive relationship between the duration of cimetidine therapy (days) and survival duration (correlation coefficient = 0.94, P = 0.02) and time until cancer recurrence (correlation coefficient = 0.99, P = 0.04). Moreover, there was a significant positive relationship between the total cumulative cimetidine dose and survival duration (correlation coefficient = 0.92, P = 0.03).

Conclusions: Prolonged duration of cimetidine may be superior to shorter courses in prolonging recurrence of CRC and thus survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MJT.0000000000000547DOI Listing
October 2018

The Microbiome and Primary Sclerosing Cholangitis.

Semin Liver Dis 2016 09 20;36(4):340-348. Epub 2016 Dec 20.

Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, Arizona.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease with detrimental sequela. In many patients, PSC progresses to end-stage liver disease and hepatobiliary cancer. There is no medical therapy that is proven to halt or reverse the progression of PSC. Approximately 70 to 80% of PSC patients have inflammatory bowel disease, usually ulcerative colitis. The etiology of PSC is poorly understood. Several lines of evidence suggest that the intestinal microbiota plays an important role in the etiopathogenesis of PSC. Stemming from this theory, several antibiotics have been tried in PSC, some of which had shown promising results. Fecal microbiota transplantation is a novel therapy, and is currently being investigated as a potential therapeutic strategy in PSC along with probiotics. In this article, the authors discuss the current knowledge of the intestinal microbiota in PSC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0036-1594007DOI Listing
September 2016

Update on pharmacotherapies for cholestatic liver disease.

Hepatol Commun 2017 02 21;1(1):7-17. Epub 2016 Dec 21.

Division of Gastroenterology and Hepatology Mayo Clinic Scottsdale AZ.

Cholestatic liver diseases are conditions with impaired bile formation and/or flow due to genetic, immunologic, environmental, or other causes. Unless successfully treated, this can lead to chronic liver injury and end-stage liver disease. Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) embody the most prominent adult cholestatic liver diseases with regard to incidence, morbidity, and mortality. A considerable proportion of patients with PBC and PSC experience progressive liver disease and ultimately liver-related death due to a paucity of effective pharmacotherapy; however, novel pharmacologic developments offer substantial promise in this regard. Here, we provide a brief review and update on current and emerging pharmacotherapies for PBC and PSC. (Hepatology Communications 2017;1:7-17).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep4.1013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747033PMC
February 2017

Novel treatments in primary sclerosing cholangitis.

Clin Liver Dis (Hoboken) 2016 Nov 30;8(5):132-135. Epub 2016 Nov 30.

Division of Gastroenterology and Hepatology Mayo Clinic Phoenix AZ.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cld.588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6490214PMC
November 2016

Obeticholic acid for the treatment of primary biliary cholangitis.

Expert Opin Pharmacother 2016 Sep 9;17(13):1809-15. Epub 2016 Aug 9.

a Division of Gastroenterology and Hepatology , Mayo Clinic , Phoenix , AZ , USA.

Introduction: Primary biliary cholangitis (PBC) is an autoimmune disease of the liver characterized by destruction and inflammation of the intrahepatic bile ducts. The disease affects mainly women. The disease is often discovered through abnormal alkaline phosphatase (ALP) activity, and is confirmed when anti-mitochondrial antibodies (AMA) are present. The etiology of PBC is poorly understood. Cigarette smoking, immune dysregulation, nail polish, urinary tract infections, and low socioeconomic status have been implicated but none have been confirmed. Genome wide association studies (GWAS) have disclosed strong associations between certain human leukocyte antigen (HLA) alleles and PBC. PBC can progress to cirrhosis and end-stage liver disease. Hepatocellular carcinoma (HCC) develops in up to 3.5% of PBC patients. Ursodeoxycholic acid (UDCA) is the only medication approved for the treatment of PBC. The use of UDCA in PBC delays histological progression and extends the transplant-free survival. 40% of PBC patients do not respond adequately to UDCA, and these patients are at high risk for serious complications. Therefore, there is a critical need for more effective therapies for this problematic disease. Multiple other agents have either been or are currently being studied as therapeutic options in UDCA non-responder PBC patients. Six-ethyl chenodeoxycholic acid (6-ECDCA), a potent farnesoid X receptor (FXR) agonist, has shown anti-cholestatic activity in rodent models of cholestasis. Obeticholic acid (OCA, 6-ECDCA, or INT-747), a first-in-class FXR agonist, has been examined in PBC patients with inadequate response to UDCA, and shown promising results. Particularly, initial clinical trials have demonstrated that the use of OCA (in addition to UDCA) in PBC patients with inadequate response to UDCA led to significant reduction of serum alkaline phosphatase (ALP, an important prognostic marker in PBC). More recently, the results of a randomized clinical trial of OCA monotherapy in PBC reported significant reduction of ALP in the treatment group compared to placebo.

Areas Covered: This review covers the preclinical and clinical studies of OCA in PBC. In addition, other alternative therapies that are currently being examined in PBC patients will also be discussed in this review. A literature search was carried out using the PubMed database.

Expert Opinion: If approved by the U.S. FDA, OCA will likely be an important alternative add-on therapy in PBC patients who have inadequate response to UDCA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/14656566.2016.1218471DOI Listing
September 2016

A Randomized, Placebo-Controlled Clinical Trial of Efficacy and Safety: Modafinil in the Treatment of Fatigue in Patients With Primary Biliary Cirrhosis.

Am J Ther 2017 Mar/Apr;24(2):e167-e176

1Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN; 2Division of Gastroenterology and Hepatology, Case Western Reserve University, Louis Stokes Cleveland VA Medical Center and Case Medical Center, Cleveland, OH; 3Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ; and 4College of Health Solutions, Arizona State University, Phoenix, AZ.

Background And Aims: Fatigue is a common symptom of primary biliary cirrhosis (PBC), and is associated with an impaired quality of life.

Study Question: No studies have assessed the use of modafinil in fatigue related to PBC in a controlled manner.

Study Design, Measures, And Outcomes: A randomized, double-blind, placebo-controlled study was conducted to determine the safety and efficacy of modafinil for the treatment of fatigue in PBC. Forty patients were randomized to modafinil (n = 20) or placebo (n = 20) for 12 weeks. A verbal report of fatigue for at least 6 months was required for enrollment. Modafinil was administered at 100 mg by mouth once daily; a change by 50 mg every 2 weeks (maximum: 200 mg once daily) was allowed, depending on the subject's response to treatment. The primary outcome was defined as a ≥50% improvement in fatigue severity [quantified by the Fisk Fatigue Impact Scale (FFIS)] after 12 weeks of treatment, compared with baseline values.

Results: Thirty-three PBC patients completed the study. After 12 weeks of therapy, only 5 patients had a ≥50% reduction in FFIS scores: 3 patients (17.6%) in the modafinil arm and 2 (12.5%) in the placebo arm (P = 1.00). Change in median FFIS score was not statistically different between patients in the 2 treatment groups (P = 0.36). Modafinil was associated with minimal adverse events (headaches, diarrhea, and rash).

Conclusions: In patients with PBC who have fatigue, treatment with modafinil for 12 weeks was safe and fairly well tolerated; however, it did not result in beneficial effects on fatigue compared with patients treated with placebo (CONSORT Table 1). ClinicalTrials.gov identifier NCT00943176.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MJT.0000000000000387DOI Listing
March 2017

Emerging drugs for the treatment of Primary Biliary Cholangitis.

Expert Opin Emerg Drugs 2016 ;21(1):39-56

Introduction: Primary biliary cholangitis (PBC) is an autoimmune chronic disease of the liver that can progress to cirrhosis and hepatocellular carcinoma. It affects approximately 1 in 4,000 with a 10:1 female to male ratio. The diagnosis of PBC can be made based on serum antimitochondrial antibodies (AMA) in a patient with abnormally high serum alkaline phosphatase after ruling out other causes of cholestasis and biliary obstruction. Genome-wide association studies have revealed several human leukocyte antigen (HLA) and non-HLA risk loci in PBC, and complex environmental-host immunogenetic interactions are believed to underlie the etiopathogenesis of the disease. Fatigue and pruritus are the most common and often problematic symptoms; although often mild, these can be severe and life-alternating in a subset of patients. Ursodeoxycholic acid (UDCA) is the only drug approved by the United States Food and Drug Administration for the treatment of PBC. Clinical trials have shown that UDCA significantly improves transplant-free survival. However, nearly 40% of PBC patients do not respond adequately to PBC and are at higher risk for serious complications when compared to PBC patients with complete response to UDCA.

Areas Covered: Here we provide a detailed discussion regarding novel therapeutic agents and potential areas for further investigation in PBC-related research.

Expert Opinion: Results of ongoing clinical trials and emerging treatment paradigms for PBC will likely further improve medical management of this disorder in the near future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1517/14728214.2016.1150999DOI Listing
October 2016

The management of autoimmunity in patients with cholestatic liver diseases.

Expert Rev Gastroenterol Hepatol 2016 2;10(1):73-91. Epub 2015 Nov 2.

a 1 Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA.

Cholestatic liver diseases are rare diseases that often lead to cirrhosis and its consequent complications. In addition to liver-related morbidity, patients with cholestatic liver diseases often suffer from autoimmune diseases that affect several organs and tissues. The robust and efficient data collection and collaboration between hepatologists and rheumatologists have led to significant advancements in understanding the relationship between the cholestatic liver diseases and associated autoimmune diseases. In this paper, we discuss the cholestatic liver diseases (primary biliary cirrhosis, primary sclerosing cholangitis and immunoglobulin G4 associated cholangitis) and associated autoimmune diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1586/17474124.2016.1095088DOI Listing
September 2016

Primary biliary cirrhosis.

Lancet 2015 Oct 11;386(10003):1565-75. Epub 2015 Sep 11.

Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA; Arizona State University, College of Health Solutions, Phoenix, AZ, USA. Electronic address:

Primary biliary cirrhosis is a chronic cholestatic liver disease characterised by destruction of small intrahepatic bile ducts, leading to fibrosis and potential cirrhosis through resulting complications. The serological hallmark of primary biliary cirrhosis is the antimitochondrial antibody, a highly disease-specific antibody identified in about 95% of patients with primary biliary cirrhosis. These patients usually have fatigue and pruritus, both of which occur independently of disease severity. The typical course of primary biliary cirrhosis has changed substantially with the introduöction of ursodeoxycholic acid (UDCA). Several randomised placebo-controlled studies have shown that UDCA improves transplant-free survival in primary biliary cirrhosis. However, about 40% of patients do not have a biochemical response to UDCA and would benefit from new therapies. Liver transplantation is a life-saving surgery with excellent outcomes for those with decompensated cirrhosis. Meanwhile, research on nuclear receptor hormones has led to the development of exciting new potential treatments. This Seminar will review the current understanding of the epidemiology, pathogenesis, and natural history of primary biliary cirrhosis, discuss management of the disease and its sequelae, and introduce research on new therapeutic options.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S0140-6736(15)00154-3DOI Listing
October 2015

Recent advances in the development of farnesoid X receptor agonists.

Ann Transl Med 2015 Jan;3(1)

Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.

Farnesoid X receptors (FXRs) are nuclear hormone receptors expressed in high amounts in body tissues that participate in bilirubin metabolism including the liver, intestines, and kidneys. Bile acids (BAs) are the natural ligands of the FXRs. FXRs regulate the expression of the gene encoding for cholesterol 7 alpha-hydroxylase, which is the rate-limiting enzyme in BA synthesis. In addition, FXRs play a critical role in carbohydrate and lipid metabolism and regulation of insulin sensitivity. FXRs also modulate live growth and regeneration during liver injury. Preclinical studies have shown that FXR activation protects against cholestasis-induced liver injury. Moreover, FXR activation protects against fatty liver injury in animal models of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and improved hyperlipidemia, glucose intolerance, and insulin sensitivity. Obeticholic acid (OCA), a 6α-ethyl derivative of the natural human BA chenodeoxycholic acid (CDCA) is the first-in-class selective FXR agonist that is ~100-fold more potent than CDCA. Preliminary human clinical trials have shown that OCA is safe and effective. In a phase II clinical trial, administration of OCA was well-tolerated, increased insulin sensitivity and reduced markers of liver inflammation and fibrosis in patients with type II diabetes mellitus and NAFLD. In two clinical trials of OCA in patients with primary biliary cirrhosis (PBC), a progressive cholestatic liver disease, OCA significantly reduced serum alkaline phosphatase (ALP) levels, an important disease marker that correlates well with clinical outcomes of patients with PBC. Together, these studies suggest that FXR agonists could potentially be used as therapeutic tools in patients suffering from nonalcoholic fatty and cholestatic liver diseases. Larger and Longer-term studies are currently ongoing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3978/j.issn.2305-5839.2014.12.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293481PMC
January 2015

Current research on the treatment of primary sclerosing cholangitis.

Intractable Rare Dis Res 2015 Feb;4(1):1-6

Division of Gastroenterology and Hepatology, Mayo Clinic, Arizona, USA; ; Arizona State University, College of Health Solutions, Phoenix, Arizona, USA.

Primary sclerosing cholangitis (PSC) is a progressive disease of the liver characterized by inflammation and destruction of the intra- and/or extra-hepatic bile ducts, leading to fibrosis and ultimately liver failure, cirrhosis and an increased risk of malignancy. The etiology of PSC is unclear. It is often associated with the inflammatory bowel diseases (IBD), particularly Ulcerative Colitis (UC); up to 75% of PSC patients have UC. PSC is more prevalent in men than in women. Ursodeoxycholic acid (UDCA) has been extensively studied in PSC in randomized clinical trials but failed to show a positive impact on the natural course of the disease. Currently, there is no effective medical therapy for PSC, and the majority of patients will eventually require liver transplantation. PSC is one of the leading indications for liver transplantation. In this paper, we review the current research on the potential therapeutic agents for the treatment of PSC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5582/irdr.2014.01018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322589PMC
February 2015

Diagnosis and management of primary biliary cirrhosis.

Expert Rev Clin Immunol 2014 Dec 10;10(12):1667-78. Epub 2014 Nov 10.

Division of Gastroenterology and Hepatology, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease characterized histologically by destruction of intrahepatic bile ducts and serologically by the presence of antimitochondrial antibodies. The incidence and prevalence of PBC are increasing. Fatigue and pruritus are common symptoms in PBC, although the proportion of asymptomatic PBC is increasing due to the widespread use of screening biochemical tests and antimitochondrial antibody assays. PBC may eventually lead to cirrhosis and its consequent complications. In the 1980s, PBC was the leading indication for liver transplantation. Ursodeoxycholic acid is the only US FDA-approved therapeutic agent for PBC. Clinical trials have shown that the use of ursodeoxycholic acid in PBC results in reduction of liver biochemistries, a delay in histological progression, a delay in the development of varices and improvement in survival without liver transplantation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1586/1744666X.2014.979792DOI Listing
December 2014

Pyogenic liver abscess and the emergence of Klebsiella as an etiology: a retrospective study.

Int J Gen Med 2013 23;7:37-42. Epub 2013 Dec 23.

Department of Internal Medicine, Texas Tech University Health Sciences Center, Amarillo, TX, USA.

Objectives: Pyogenic liver abscess (PLA) is a significant, though uncommon, cause of morbidity in the United States. Recently, Klebsiella has emerged as an important cause of PLA. We analyzed the clinical course, microbiology, and treatment outcomes of patients discharged with PLA. In addition, we sought to examine the incidence of and risk factors for Klebsiella liver abscess (KLA).

Methods: We reviewed the charts of patients who discharged with PLA from two teaching hospitals in West Texas between January 1, 2007 and December 31, 2011.

Results: We identified 49 cases of PLA. Abscess cultures were positive in 23 (48%) patients. The mean age of the cohort was 56 years (range: 20-83 years). Sixty percent were male. The most frequent conditions associated with PLA were intra-abdominal infections (ten cases; 20%), diabetes mellitus (nine cases; 18%) and malignancy (nine cases; 18%). Klebsiella was the most commonly isolated species from the abscess cultures (seven cases; 30% of all positive abscess cultures). We used univariate and logistic regression analyses to identify the risk factors for KLA. Controlling for age, only malignancy was identified in our cohort as a risk factor for a Klebsiella liver abscess. The overall mortality was 2%.

Conclusion: Klebsiella is emerging as an important cause of liver abscesses. Malignancy may be an important risk factor for Klebsiella liver abscess.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/IJGM.S54448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3873814PMC
December 2013

Nasopharyngeal perforation by a new electromagnetically visualised enteral feeding tube.

BMJ Case Rep 2013 May 23;2013. Epub 2013 May 23.

Section of Critical Care Medicine, Department of Internal Medicine, Texas Tech University Health Sciences Center, Amarillo, Texas, USA.

Enteral nutrition is the preferred route of feeding in critically ill patients. It has multiple advantages over parenteral nutrition and potentially improves patients' outcome. Enteral nutrition is delivered via gastric or postpyloric (small intestine) feeding tubes. The latter option used to be a more challenging choice to achieve unless the feeding tube is placed endoscopically or by interventional radiology. Multiple technical advances have facilitated postpyloric feeding, including a new electromagnetically visualised jejunal feeding tube system (CORTRAK Enteral Access System). We are presenting a case of a 50-year-old woman who suffered a nasopharyngeal perforation caused by this novel technology. The complication was recognised promptly and managed successfully with conservative measures. This case illustrates the importance of recognising patients at high risk for feeding tube placement complications, meticulous placement technique and appropriate follow-up once the tube has been inserted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bcr-2013-009807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669988PMC
May 2013

Varices in early histological stage primary biliary cirrhosis.

J Clin Gastroenterol 2011 Aug;45(7):e66-71

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA.

Background/goals: Esophageal varices (EV) in early histological stages of primary biliary cirrhosis (PBC) have been recognized but not well defined. We sought to determine the prevalence, clinical characteristics, and predictors of EV in early-stage PBC, as well as to evaluate the effectiveness of recent guidelines regarding EV screening in PBC patients.

Study: We retrospectively reviewed the charts of 325 PBC patients who had undergone complete evaluation before enrollment into 2 large clinical trials at the Mayo Clinic.

Results: Nineteen percent (62/325) of our patient population had EV on esophagogastroduodenoscopy; 6% (8/127) of early-stage PBC patients had EV. Ninety five percent of our PBC patients with varices met at least one of the following conditions: male sex, low albumin (<3.5 g/dL), elevated bilirubin level (≥1.2 mg/dL), and/or prolonged prothrombin time (≥12.9 s). The sensitivity and specificity of these variables in combination to predict the presence of varices were 95% and 55%, respectively. Serum bilirubin ≥1.2 mg/dL and albumin <3.5 were independent predictors of varices with hazard values of 5.4 and 3.5 respectively.

Conclusions: EV can occur in a minority of early-stage PBC patients. Various models may be used to identify PBC patients who are candidates for screening esophagogastroduodenoscopy for EV. Based on adequate performance and its simplicity, we propose that male sex, low albumin, elevated bilirubin, and/or prolonged prothrombin time be used as a model to noninvasively predict EV. Further validation is required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MCG.0b013e3181f18c4eDOI Listing
August 2011