Publications by authors named "David M Chascsa"

8 Publications

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APECED-Associated Hepatitis: Clinical, Biochemical, Histological and Treatment Data From a Large, Predominantly American Cohort.

Hepatology 2021 Mar;73(3):1088-1104

Translational, Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.

Background And Aims: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), caused by autoimmune regulator (AIRE) mutations, manifests with chronic mucocutaneous candidiasis (CMC) and multisystem autoimmunity, most often hypoparathyroidism (HP) and adrenal insufficiency (AI). European cohorts previously reported a ~10% prevalence of APECED-associated hepatitis (APAH) with presentations ranging from asymptomatic laboratory derangements to fatal fulminant hepatic failure. Herein, we characterized APAH in a large APECED cohort from the Americas.

Approach And Results: Forty-five consecutive patients with APECED were evaluated (2013-2015) at the National Institutes of Health (NIH; NCT01386437). Hepatology consultation assessed hepatic and autoimmune biomarkers and liver ultrasound in all patients. Liver biopsies evaluated autoimmune features and fibrosis. The 16S ribosomal RNA (rRNA) sequencing was performed in 35 patients' stools (12 with and 23 without APAH). Among 43 evaluable patients, 18 (42%) had APAH; in 33.3% of those with APAH, APAH occurred before developing classic APECED diagnostic criteria. At APAH diagnosis, the median age was 7.8 years, and patients manifested with aminotransferase elevation and/or hyperbilirubinemia. All patients with APAH were in clinical remission during their NIH evaluation while receiving immunomodulatory treatment. We found no difference in age, sex, or prevalence of CMC, AI, or HP between patients with or without APAH. Autoantibody positivity against aromatic L-amino acid decarboxylase, cytochrome P450 family 1 subfamily A member 2, histidine decarboxylase (HDC), bactericidal/permeability-increasing fold-containing B1, tryptophan hydroxlase, and 21-hydroxylase (21-OH), and the homozygous c.967_979del13 AIRE mutation were associated with APAH development. Classical serological biomarkers of autoimmune hepatitis (AIH) were only sporadically positive. AIH-like lymphoplasmacytic inflammation with mild fibrosis was the predominant histological feature. Stool microbiome analysis found Slackia and Acidaminococcus in greater abundance in patients with APAH.

Conclusions: APAH is more common than previously described, may present early before classic APECED manifestations, and most often manifests with milder, treatment-responsive disease. Several APECED-associated autoantibodies, but not standard AIH-associated biomarkers, correlate with APAH.
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http://dx.doi.org/10.1002/hep.31421DOI Listing
March 2021

Update on Emerging Treatment Options for Primary Biliary Cholangitis.

Hepat Med 2020 25;12:69-77. Epub 2020 May 25.

Department of Gastroenterology & Hepatology, Mayo Clinic, Phoenix, AZ, USA.

Primary biliary cholangitis (PBC) is a rare autoimmune cholestatic liver disease that may progress to fibrosis or cirrhosis. Treatment options are currently limited. Ursodeoxycholic acid (UDCA) remains first-line therapy and has been proven to normalize serum biochemistries, halt histologic disease progression, and lead to patient survival comparable to the general population. Obeticholic acid (OCA) was recently approved as adjunct therapy in PBC patients with inadequate response or intolerance to UDCA. However, OCA has been associated with worsening pruritus in clinical studies which may limit its use in this patient population. Several studies are currently underway to address the lack of treatment options for PBC. Of these, fibrates, which have been used in Japan for over a decade, have produced promising results. Furthermore, as currently approved therapies for PBC do not address the potentially debilitating clinical symptoms of PBC such as pruritus and fatigue, supplemental therapy is often required for symptom control.
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http://dx.doi.org/10.2147/HMER.S205431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259454PMC
May 2020

Cancer risk, screening and surveillance in primary sclerosing cholangitis.

Minerva Gastroenterol Dietol 2019 Sep 19;65(3):214-228. Epub 2019 Jun 19.

Office of University Provost, Arizona State University, Phoenix, AZ, USA.

Primary sclerosing cholangitis (PSC) is a rare chronic inflammatory condition mainly of the large bile ducts, affecting predominantly young men, and is associated with the presence of inflammatory bowel disease. There is no known cure for PSC, which progresses to cirrhosis or death over 10-20 years. Hepatobiliary malignancy, especially cholangiocarcinoma, is a feared complication associated with poor overall survival. Screening and surveillance appear to improve overall outcomes. To capture as many relevant studies, broad search criteria were employed within the PubMed database. Given the high prevalence of IBD and its own associations with the development of malignancy two separate search strategies were employed. Results were filtered by English language. The first search identified the risks, epidemiological factors and surveillance strategies for patients with PSC at risk for developing malignancy. MeSH terms included: cholangitis, sclerosing, digestive system neoplasms, liver neoplasms, biliary tract neoplasms, cholangiocarcinoma, gallbladder neoplasms, colonic neoplasms, rectal neoplasms, or pancreatic neoplasms, risk factors, risk, surveillance, epidemiology and screen. The second included inflammatory bowel diseases, Crohn's, or colitis, and assessed for additional malignancies such as lymphoma and skin neoplasms. A total of 288 results returned with 21 duplicates; 267 remaining abstracts were assessed for relevance for inclusion by the authors. Patients with PSC show significantly higher than average risk for the development of hepatobiliary and colonic malignancies including cholangiocarcinoma, gallbladder carcinoma and colorectal carcinoma. Yearly ultrasound surveillance followed with more definitive cross-sectional imaging is prudent to arrive in a timely diagnosis of carcinoma, reducing morbidity and mortality.
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http://dx.doi.org/10.23736/S1121-421X.19.02586-8DOI Listing
September 2019

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

Antimitochondrial Antibody-Negative Primary Biliary Cholangitis: Is It Really the Same Disease?

Clin Liver Dis 2018 08;22(3):589-601

Division of Gastroenterology and Hepatology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA; Office of the Provost, Arizona State University, 550 North 3rd Street, Phoenix, AZ 85004, USA. Electronic address:

Antimitochondrial antibody (AMA)-negative primary biliary cholangitis (PBC) is a term reserved for patients with clinical and histopathological findings consistent with PBC but without positive AMA. There does not seem to be a natural progression from AMA negativity to positivity. Antinuclear and antismooth muscle antibodies are frequently found in the absence of histologic autoimmune hepatitis features. The disease course may be more severe than AMA-positive. Response to standard therapy for PBC and autoimmune hepatitis varies. Nevertheless, there is insufficient evidence to suggest AMA-negative PBC is different enough to warrant classification as a separate disease from AMA-positive PBC.
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http://dx.doi.org/10.1016/j.cld.2018.03.009DOI Listing
August 2018

Patient and Caregiver Attitudes and Practices of Exercise in Candidates Listed for Liver Transplantation.

Dig Dis Sci 2018 12 3;63(12):3290-3296. Epub 2018 Sep 3.

Division of Gastroenterology and Hepatology, Mayo Clinic in Arizona, 5777 E. Mayo Blvd, Phoenix, AZ, 85054, USA.

Background: Impaired physical capacity increases peri-liver transplant complications. Patient perceptions regarding exercise prior to transplantation are not known.

Aims: This study aimed to assess patient and caregiver activity levels, perceptions of willingness to exercise, and of provider advice.

Methods: Consecutive patients listed for liver transplant and caregivers presenting for routine outpatient visits were evaluated over a 3-month interval. Anonymous surveys adapted to patients and caregivers addressed the importance and safety of exercise, type and duration of exercise performed, barriers, willingness to wear a monitoring device, and perceived provider recommendations. Responses were logged on a Likert scale from 1 to 5.

Results: Three hundred and sixty-eight responses were received. Most participants perceived exercise as important. Patients exercised three times per week for 30 min. Eighty percent endorsed walking (median response: 2-agree; IQR 1-2). Most did not jog, swim, cycle, or strength train. Fatigue, reported by 70%, was the major barrier (2, IQR 1-3). Over 90% of caregivers endorsed exercise as important (1-strongly agree, IQR 1-2) and encouraged exercise (median response 2, IQR 1-2). Over 60% of patients (median response 2, IQR 1-3) and caregivers (median response 2, IQR 2-3) felt providers encouraged exercise.

Conclusions: Patients and caregivers are willing to exercise to optimize physical fitness prior to liver transplantation.
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http://dx.doi.org/10.1007/s10620-018-5271-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532051PMC
December 2018

Managing PBC: Expanding the Provider Comfort Zone.

Dig Dis Sci 2018 10;63(10):2487-2488

Mayo Clinic, Arizona, USA.

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http://dx.doi.org/10.1007/s10620-018-5162-9DOI Listing
October 2018

The gastroenterologist's guide to management of the post-liver transplant patient.

Am J Gastroenterol 2018 06 11;113(6):819-828. Epub 2018 May 11.

Department of Gastroenterology and Hepatology Mayo Clinic, Phoenix, AZ, USA. Transplant Center, Mayo Clinic, Phoenix, AZ, USA.

The management of the post-liver transplant patient is complex and involves a large interdisciplinary team. After referral to a transplant center, evaluation and listing, and eventual transplantation, the patient is cared for closely by the transplant center. Once deemed ready for discharge, the patient returns to the primary care provider for ongoing management of the various issues that increase in incidence post transplant such as osteoporosis, cardiovascular, and renal diseases, as well as metabolic syndrome. The role of the gastroenterologist is not well defined, but certainly, he or she may be called upon for the initial evaluation and ongoing management of gastrointestinal as well as hepatobiliary issues. This includes but is not limited to the investigation of abnormal liver tests, non-specific gastrointestinal complaints such as nausea, vomiting, or diarrhea, biliary complications, and even recurrent hepatic disease. Having familiarity with post-transplant immunosuppressive agents, drug interactions, and potential infectious and malignancy-related complications of transplant is essential, as the primary gastroenterologist may be expected in some situations to field the initial work-up, if patient access to the transplant center is limited. The aim of this review is to summarize the gastroenterologist's role in the management of the post-liver transplant patient.
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http://dx.doi.org/10.1038/s41395-018-0049-0DOI Listing
June 2018