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Sarraf B, Skoien R, Hartel G, O'Beirne J, Clark PJ, Collins L, Leggett B, Powell EE, Valery PC. Rising hospital admissions for alcohol-related cirrhosis and the impact of sex and comorbidity - a data linkage study. Public Health 2024; 232:178-187. [PMID: 38795666 DOI: 10.1016/j.puhe.2024.04.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 04/15/2024] [Accepted: 04/21/2024] [Indexed: 05/28/2024]
Abstract
OBJECTIVES International studies have shown shifting demographic data and rising hospitalizations for alcohol-related cirrhosis (ARC), with a paucity of data from Australia. We examined hospitalizations, mortality and demographic data for people admitted with ARC over the last decade in Queensland, Australia. STUDY DESIGN Data linkage study. METHODS A retrospective analysis of adults hospitalized with ARC during 2008-2019 was performed using state-wide admissions data. International Classification of Diseases, 10th revision, codes identified admissions with the principal diagnosis of ARC based on validated algorithms. Comorbidity was assessed using the Charlson Comorbidity Index. RESULTS A total of 7152 individuals had 24,342 hospital admissions with ARC (16,388 were for ARC). There was a predominance of males (72.6%) and age ≥50 years (80.4%) at index admission. Females were admitted at a significantly younger age than men (59% of women and 43% of men were aged <60 years, P < 0.001). Comorbidities were common, with 45.1% of people having at least one comorbidity. More than half (54.6%) of the patients died over the study period (median follow-up time was 5.1 years; interquartile range 2.4-8.6). Women had significantly lower mortality, with 47.6% (95% confidence interval [CI] 45.0-50.2) probability of 5-year survival, compared with 40.1% (95% CI 38.5-41.6) in men. In multivariable analysis, this was attributable to significantly lower age and comorbidity burden in women. Significantly lower survival was seen in people with higher comorbidity burden. Overall, the number of admissions for ARC increased 2.2-fold from 869 admissions in 2008 to 1932 in 2019. CONCLUSIONS Hospital admissions for ARC have risen substantially in the last decade. Females were admitted at a younger age, with fewer comorbidities and had lower mortality compared with males. The association between greater comorbidity burden and higher mortality has important clinical implications, as comorbidity-directed interventions may reduce mortality.
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Affiliation(s)
- B Sarraf
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD, Australia; QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
| | - R Skoien
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
| | - G Hartel
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; School of Public Health, The University of Queensland, Brisbane, QLD, Australia; School of Nursing, Queensland University of Technology, Brisbane, QLD, Australia.
| | - J O'Beirne
- Department of Gastroenterology and Hepatology, Sunshine Coast University Hospital, Sunshine Coast, QLD, Australia.
| | - P J Clark
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD, Australia; Mater Hospital Brisbane, South Brisbane, QLD, Australia; Faculty of Medicine, The University of Queensland, QLD, Australia.
| | - L Collins
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia.
| | - B Leggett
- Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia; Faculty of Medicine, The University of Queensland, QLD, Australia.
| | - E E Powell
- Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, QLD, Australia; QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; Centre for Liver Disease Research, Translational Research Institute, Faculty of Medicine, The University of Queensland, QLD, Australia.
| | - P C Valery
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; Faculty of Medicine, The University of Queensland, QLD, Australia.
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Mohy-Ud-Din N, Lin FP, Rachakonda V, Al-Khafaji A, Biggins SW, Ganesh S, Bataller R, DiMartini A, Hughes C, Humar A, Malik SM. Expedited liver transplantation as first-line therapy for severe alcohol hepatitis: ELFSAH; deferring corticosteroids in the sickest subset of patients. Clin Transplant 2024; 38:e15340. [PMID: 39049597 DOI: 10.1111/ctr.15340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/03/2024] [Accepted: 05/10/2024] [Indexed: 07/27/2024]
Abstract
BACKGROUND & AIMS Severe alcohol-associated hepatitis (SAH) represents a lethal subset of alcohol-associated liver disease. Although corticosteroids are recommended by guidelines, their efficacy and safety remain questionable and so liver transplantation (LT) has been increasingly utilized. The timing and indication of corticosteroid use, specifically in patients being considered for LT requires further clarification. METHODS A retrospective analysis was conducted on 256 patients with SAH between 2018 and 2022 at a single US center. RESULTS Twenty of these patients underwent LT. Of the 256 patients, 38% had what we termed "catastrophic" SAH, defined as a MELD-Na ≥35 and/or discriminant function (DF) ≥100, which carried a mortality of 90% without LT. Compared with 100 matched controls, patients undergoing LT exhibited a one-year survival rate of 100% versus 35% (p < .0005). LT provided an absolute risk reduction of 65%, with a number needed to treat of 1.5. Steroid utilization in the entire cohort was 19% with 60% developing severe complications. Patients administered steroids were younger with lower MELD and DF scores. Only 10% of those prescribed steroids derived a favorable response. Sustained alcohol use post-LT was 20%. CONCLUSIONS We propose ELFSAH: Expedited LT as First Line Therapy for SAH; challenging the current paradigm with recommendations to defer steroids in patients with "catastrophic" SAH (defined as: MELD-Na ≥35 and/or DF ≥100). Patients should be seen urgently by hepatology, transplant surgery, psychiatry and social work. Patients without an absolute contraindication should be referred for LT as first-line therapy during their index admission.
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Affiliation(s)
- Nabeeha Mohy-Ud-Din
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Fei-Pi Lin
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Vikrant Rachakonda
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine Veteran's Association Northern California Healthcare System, Sacramento, California, USA
| | - Ali Al-Khafaji
- Department of Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Scott W Biggins
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Swaytha Ganesh
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | | | - Andrea DiMartini
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Christopher Hughes
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Abhinav Humar
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Shahid M Malik
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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Ayyala-Somayajula D, Dodge JL, Zhou K, Terrault NA, Yuan L. The impact of surging transplantation of alcohol-associated liver disease on transplantation for HCC and other indications. Hepatol Commun 2024; 8:e0455. [PMID: 38967588 PMCID: PMC11227353 DOI: 10.1097/hc9.0000000000000455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 04/01/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND Liver transplantation (LT) for alcohol-associated liver disease (ALD) is increasing and may impact LT outcomes for patients listed for HCC and other indications. METHODS Using US adults listed for primary LT (grouped as ALD, HCC, and other) from October 8, 2015, to December 31, 2021, we examined the impact of center-level ALD LT volume (ATxV) on waitlist outcomes in 2 eras: Era 1 (6-month wait for HCC) and Era 2 (MMaT-3). The tertile distribution of ATxV (low to high) was derived from the listed candidates as Tertile 1 (T1): <28.4%, Tertile 2 (T2): 28.4%-37.6%, and Tertile 3 (T3): >37.6% ALD LTs per year. Cumulative incidence of waitlist death and LT within 18 months from listing by LT indication were compared using the Gray test, stratified on eras and ATxV tertiles. Multivariable competing risk regression estimated the adjusted subhazard ratios (sHRs) for the risk of waitlist mortality and LT with interaction effects of ATxV by LT indication (interaction p). RESULTS Of 56,596 candidates listed, the cumulative waitlist mortality for those with HCC and other was higher and their LT probability was lower in high (T3) ATxV centers, compared to low (T1) ATxV centers in Era 2. However, compared to ALD (sHR: 0.92 [0.66-1.26]), the adjusted waitlist mortality for HCC (sHR: 1.15 [0.96-1.38], interaction p = 0.22) and other (sHR: 1.13 [0.87-1.46], interaction p = 0.16) were no different suggesting no differential impact of ATxV on the waitlist mortality. The adjusted LT probability for HCC (sHR: 0.89 [0.72-1.11], interaction p = 0.08) did not differ by AtxV while it was lower for other (sHR: 0.82 [0.67-1.01], interaction p = 0.02) compared to ALD (sHR: 1.04 [0.80-1.34]) suggesting a differential impact of ATxV on LT probability. CONCLUSIONS The high volume of LT for ALD does not impact waitlist mortality for HCC and others but affects LT probability for other in the MMAT-3 era warranting continued monitoring.
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Affiliation(s)
- Divya Ayyala-Somayajula
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Jennifer L. Dodge
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
- Department of Population and Public Health Sciences, University of Southern California, Los Angeles, California, USA
| | - Kali Zhou
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Norah A. Terrault
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Liyun Yuan
- Division of Gastrointestinal and Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
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Dasarathy S, Tu W, Bellar A, Welch N, Kettler C, Tang Q, Liangpunsakul S, Gawrieh S, Radaeva S, Mitchell M. Development and evaluation of objective trial performance metrics for multisite clinical studies: Experience from the AlcHep Network. Contemp Clin Trials 2024; 138:107437. [PMID: 38215876 PMCID: PMC11866342 DOI: 10.1016/j.cct.2024.107437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 11/05/2023] [Accepted: 01/08/2024] [Indexed: 01/14/2024]
Abstract
BACKGROUND Recruitment and retention are critical in clinical studies but there are limited objective metrics of trial performance. We tested if development of trial performance metrics will allow for objective evaluation of study quality. Performance metrics were developed using data from the observational cohort (OBS) and randomized clinical trial (RCT) arms of the prospective Alcoholic Hepatitis Network. METHODS Yield-rate (%YR; eligible/screened), recruitment index (RI; mean recruitment time/patient), completion index (CI; average number of days to complete the follow-up/patient), and protocol adherence index (AI; average number of deviations/subject recruited) were determined. RESULTS 2250 patients (1168 for OBS; 1082 for RCT) were screened across 8 sites. Recruitment in the RCT (57% target) was similar to that in the OBS (59% target). Of those screened, 743 (63.6%) subjects in the OBS and 147 (13.6%) subjects in the RCT were enrolled in the study. In OBS study, 253 (34.1%) subjects, and in the RCT, 68 (46.3%) subjects, completed the study or reached a censoring event. Across all sites (range), YR for OBS was 63.6% (41.3-98.3%) and for RCT was 13.6% (5.5-92.6%); RI for OBS was 1.66 (8.79-19.85) and for RCT was 4.05 (19.76-36.43); CI for OBS was 4.87 (22.6-118.3) and for RCT was 8.75 (27.27-161.5); and AR for OBS was 0.56 (0.08-1.04) and for RCT was 1.55 (0.39-3.21. Factors related to participants, research design, study team, and research sponsors contributed to lower performance metrics. CONCLUSIONS Objective measures of clinical trial performance allow for strategies to enhance study quality and development of site-specific improvement plans. TRIAL REGISTRATION NUMBER ClinicalTrials.gov NCT4072822 NCT03850899.
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Affiliation(s)
- Srinivasan Dasarathy
- Department of Gastroenterology & Hepatology and Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States of America.
| | - Wanzhu Tu
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Annette Bellar
- Department of Gastroenterology & Hepatology and Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States of America
| | - Nicole Welch
- Department of Gastroenterology & Hepatology and Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, United States of America
| | - Carla Kettler
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Qing Tang
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Suthat Liangpunsakul
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Samer Gawrieh
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Svetlana Radaeva
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, United States of America
| | - Mack Mitchell
- Department of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX, United States of America
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Sengupta S, Anand A, Lopez R, Weleff J, Wang PR, Bellar A, Attaway A, Welch N, Dasarathy S. Emergency services utilization by patients with alcohol-associated hepatitis: An analysis of national trends. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2024; 48:98-109. [PMID: 38193831 PMCID: PMC10783841 DOI: 10.1111/acer.15223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 10/10/2023] [Accepted: 11/03/2023] [Indexed: 01/10/2024]
Abstract
BACKGROUND Hospitalization and mortality in patients with alcohol-associated hepatitis (AH), a severe form of liver disease, continue to increase over time. Given the severity of the illness, most hospitalized patients with AH are admitted from the emergency department (ED). However, there are no data on ED utilization by patients with AH. Thus, the Nationwide Emergency Department Sample (NEDS) dataset was analyzed to determine the ED utilization for AH. METHODS Temporal trends (2016-2019) and outcomes of ED visits for AH were determined. Primary or secondary AH diagnoses were based on coding priority. Numbers of patients evaluated in the ED, severity of disease, complications of liver disease, and discharge disposition were analyzed. Crude and adjusted rates were examined, and temporal trends evaluated using logistic regression with orthogonal polynomial contrasts for each year. RESULTS There were 466,014,370 ED visits during 2016-2019, of which 448,984 (0.096%) were for AH, 85.0% of which required hospitalization. The rate of visits for AH (primary and secondary) between 2016 and 2019 increased from 85 to 106.8/100,000 ED visits. The rate of secondary AH increased more than the rate of primary AH (from 68.6 to 86.5 vs. from 16.4 to 20.3/100,000 ED visits). Patients aged 45-64 years had the highest rate of ED visits for AH, which decreased during the study period, while the rate of ED visits for AH increased in those aged 25-44 years (from 38.5% to 42.9%). The severity of disease (ascites, hepatic encephalopathy, and acute kidney injury) also increased over time. Medicaid and private insurance were the most common payors for patients seeking care in the ED for AH. CONCLUSIONS Temporal trends show an overall increase in ED utilization rates for AH, more patients requiring hospitalization, and an increase in the proportion of younger patients presenting to the ED with AH.
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Affiliation(s)
- Shreya Sengupta
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
| | - Akhil Anand
- Department of Psychiatry and Psychology, Cleveland Clinic, Cleveland, OH, USA
- Department of Psychiatry, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Rocio Lopez
- Center for Populations Health Research, Cleveland Clinic, Cleveland, OH, USA
| | - Jeremy Weleff
- Department of Psychiatry and Psychology, Cleveland Clinic, Cleveland, OH, USA
- Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT, 06511, USA
| | - Philip R Wang
- Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Annette Bellar
- Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
| | - Amy Attaway
- Pulmonary Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Nicole Welch
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
- Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
| | - Srinivasan Dasarathy
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
- Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
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Baweja S, Mittal A, Thangariyal S, Subudhi PD, Gautam S, Kaul R. Unveiling the effect of estrogen receptors in alcoholic liver disease: A novel outlook. LIVER RESEARCH 2023; 7:333-341. [PMID: 39958778 PMCID: PMC11791908 DOI: 10.1016/j.livres.2023.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 08/19/2023] [Accepted: 10/23/2023] [Indexed: 01/11/2025]
Abstract
Alcoholic liver disease (ALD) has a multifaceted development, progressing from alcoholic steatosis to alcoholic hepatitis and ultimately to alcoholic cirrhosis, irreversible liver damage that can even result in hepatocellular carcinoma. The prevalence of ALD is increasing globally, particularly among middle-aged adults. Gender-based studies have revealed that ALD affects more men; however, disease progression differs between men and women. Despite this, the molecular understanding of alcohol-induced liver injury among genders and its association with changes in sex hormone metabolism, particularly with estrogen and estrogen receptors (ERs) in ALD, remains poor. This review focuses on experimental and human studies describing alcohol and its association with estrogen metabolism and signaling via ERs. Chronic alcohol consumption affects the immune response, and whether estrogen has any contributory effect remains inadequately studied. This review also discusses various therapeutic approaches currently in use and future approaches that can affect the response or progression via estrogen signaling. The role of gender on alcohol consumption and its association with steroid hormones must be elucidated for a better understanding of the pathogenesis of ALD, the development of effective therapeutic approaches, and better disease management in both men and women, as ALD remains a major public health concern.
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Affiliation(s)
- Sukriti Baweja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ashmit Mittal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Swati Thangariyal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - P. Debishree Subudhi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shivani Gautam
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rashmi Kaul
- Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA
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Vannier AGL, Przybyszewski EM, Shay J, Patel SJ, Schaefer E, Goodman RP, Luther J. Psychotherapy for Alcohol Use Disorder Is Associated With Reduced Risk of Incident Alcohol-Associated Liver Disease. Clin Gastroenterol Hepatol 2023; 21:1571-1580.e7. [PMID: 35964893 PMCID: PMC9918606 DOI: 10.1016/j.cgh.2022.08.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Alcohol-associated liver disease (ALD) is a devastating complication of alcohol use disorder (AUD). Once it develops, ALD is exceedingly difficult to treat; it therefore is critical to identify ways to prevent ALD. By treating the causes of increased alcohol consumption, psychotherapy may offer prophylactic benefit against the development of ALD for patients with AUD. METHODS In this retrospective cohort study, we used International Classification of Diseases, 9th and 10th revision, codes to identify 9635 patients with AUD in the Mass General Brigham Biobank. The mean follow-up period from AUD diagnosis was 9.2 years. We used Cox regression models to generate hazard ratios (HR) for the development of ALD given the receipt or nonreceipt of psychotherapy, adjusting for a range of other contributors including the receipt of medication-assisted treatment. RESULTS In our cohort, 60.4% of patients were men, 83.5% of patients were white, the median age was 57.0 years, and 3544 patients (36.8%) received psychotherapy. ALD developed in 1135 patients (11.8%). In multivariable analysis, psychotherapy was associated with a reduced rate of ALD (HR, 0.59; 95% CI, 0.50-0.71; P < .001). This association held for both individual psychotherapy (HR, 0.70; 95% CI, 0.56-0.86; P < .001) and group psychotherapy (HR, 0.76; 95% CI, 0.61-0.94; P = .01). Among patients with cirrhosis, psychotherapy was associated with a lower rate of hepatic decompensation (HR, 0.68; 95% CI, 0.48-0.95; P = .03). CONCLUSIONS The receipt of psychotherapy in the setting of AUD is associated with reduced incidence and progression of ALD. Given the safety and potential benefit of psychotherapy, clinicians should consider using it to prevent the development of ALD.
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Affiliation(s)
- Augustin G L Vannier
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
| | | | - Jessica Shay
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Suraj J Patel
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts
| | - Esperance Schaefer
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Russell P Goodman
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Jay Luther
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts.
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8
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Frankeberger J, Coulter RWS, Mair C. A latent class analysis of alcohol-related problems among adults who drank in the past year. JOURNAL OF SUBSTANCE USE 2023; 29:753-758. [PMID: 39649387 PMCID: PMC11623289 DOI: 10.1080/14659891.2023.2203233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 04/12/2023] [Indexed: 12/10/2024]
Abstract
Background Research on alcohol-related problems often examines individual problem types in isolation or uses scales that provide a single cumulative severity score for alcohol-related harms. This study aims to assess the patterns of seventeen distinct alcohol-related problems and how they co-occur. Methods The East Bay Neighborhood Study surveyed a community sample of 864 adults who drank in the past year in Alameda County, California. Participants reported if they experienced each of seventeen alcohol-related problems in the last year. Latent class analysis assessed subgroups of problems. Logistic regression models examined associations between class membership, sociodemographics, and alcohol use. Results A two-class model best fit the data. The multiple problems class (18% of respondents) was characterized by experiencing problems of all types and almost all experiences of legal, violence, and risky sex-related problems. The none/few problems class (82%) was characterized by a low prevalence of all problem types, with only a small proportion experiencing hangovers. In adjusted models, only older age (AOR=0.90, 95% CI=0.88-0.92) had lower odds of multiple problems class membership. Conclusions Numerous alcohol-related problems co-occurred within a small subgroup of people who drank in the last year, while the majority experienced few problems. Results suggest that focusing on singular alcohol-related problems may overlook patterns of concurrent problems in high-risk groups.
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Affiliation(s)
- Jessica Frankeberger
- Department of Behavioral and Community Health Sciences, University of Pittsburgh School of Public Health, 130 De Soto Street, Pittsburgh, PA 15261, USA
- Center for Social Dynamics and Community Health, University of Pittsburgh School of Public Health, 130 De Soto Street, Pittsburgh, PA 15261, USA
| | - Robert W S Coulter
- Department of Behavioral and Community Health Sciences, University of Pittsburgh School of Public Health, 130 De Soto Street, Pittsburgh, PA 15261, USA
- Center for Social Dynamics and Community Health, University of Pittsburgh School of Public Health, 130 De Soto Street, Pittsburgh, PA 15261, USA
- Center for LGBT Health Research, University of Pittsburgh School of Public Health, 130 De Soto Street, Pittsburgh, PA 15261, USA
| | - Christina Mair
- Department of Behavioral and Community Health Sciences, University of Pittsburgh School of Public Health, 130 De Soto Street, Pittsburgh, PA 15261, USA
- Center for Social Dynamics and Community Health, University of Pittsburgh School of Public Health, 130 De Soto Street, Pittsburgh, PA 15261, USA
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Schulz P, Shabbir R, Ramakrishnan S, Asrani SK. Acute Alcohol-Associated Hepatitis in the COVID-19 Pandemic — a Structured Review. CURRENT TRANSPLANTATION REPORTS 2022; 9:227-239. [DOI: 10.1007/s40472-022-00387-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/23/2022] [Indexed: 11/22/2022]
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10
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Ayyala D, Bottyan T, Tien C, Pimienta M, Yoo J, Stager K, Gonzalez JL, Stolz A, Dodge JL, Terrault NA, Han H. Naltrexone for alcohol use disorder: Hepatic safety in patients with and without liver disease. Hepatol Commun 2022; 6:3433-3442. [PMID: 36281979 PMCID: PMC9701476 DOI: 10.1002/hep4.2080] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 07/28/2022] [Accepted: 08/10/2022] [Indexed: 01/21/2023] Open
Abstract
Naltrexone is an approved drug for management of alcohol use disorder (AUD), but data in patients with liver disease (LD) are limited. We aimed to evaluate the safety of naltrexone in those with LD. This is a retrospective cohort of adults with and without LD who were prescribed naltrexone for AUD from 2015 to 2019 in a safety-net setting. Naltrexone hepatic safety was determined by liver enzyme changes during and after compared to before naltrexone prescription as well as rates of subsequent hospitalization and death by Kaplan-Meier methods. Factors associated with hospitalization were examined by Cox regression. Of 160 patients prescribed naltrexone for AUD, 100 (63%) had LD and 47 (47%) of those with LD had cirrhosis (47% decompensated). The total cohort, LD, and cirrhosis groups had lower adjusted mean aspartate aminotransferase and alanine aminotransferase levels after versus before naltrexone prescription (p < 0.001). Two-year survival was 97.7% (95% confidence interval [CI], 84.6-99.7), 95.4% (95% CI, 82.8-98.8), 90.8% (95% CI, 73.5-97.0), and 81.3% (95% CI, 41.2-93.8) in those without LD, LD without cirrhosis, cirrhosis, and decompensated cirrhosis groups (p = 0.46), respectively. Alcohol-related 2-year hospitalization rates were 8.2% (95% CI, 2.7-24), 27.7% (95% CI, 16.6-44.0), 40.5% (95% CI, 24.8-61.6), and 41.7% (95% CI, 23.3-66.6) for the groups without LD, LD without cirrhosis, cirrhosis, and decompensated cirrhosis (p = 0.007), respectively. Independent predictors of subsequent hospitalization were LD, (hazard ratio [HR], 3.70; 95% CI, 1.19-11.51; p = 0.02), cirrhosis (HR, 5.16; 95% CI, 1.69-15.75), and shorter duration (≤30 days) of naltrexone prescription (HR, 2.50; 95% CI, 1.l2-5.20; p = 0.01). Conclusion: Naltrexone is safe to use in patients with underlying LD, including those with compensated cirrhosis. Although encouraging, more safety data are needed for those with decompensated cirrhosis.
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Affiliation(s)
- Divya Ayyala
- Division of Gastrointestinal and Liver DiseaseKeck School of Medicine, University of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Thomas Bottyan
- Department of PsychiatryStanford UniversityPalo AltoCaliforniaUSA
| | - Christine Tien
- Department of MedicineUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Michael Pimienta
- Department of MedicineUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Jennie Yoo
- Keck School of Medicine, University of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Kelli Stager
- Department of PsychiatryUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Jose Luis Gonzalez
- Department of MedicineUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Andrew Stolz
- Division of Gastrointestinal and Liver DiseaseKeck School of Medicine, University of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Jennifer L. Dodge
- Division of Gastrointestinal and Liver DiseaseKeck School of Medicine, University of Southern CaliforniaLos AngelesCaliforniaUSA,Department of Population and Public Health SciencesUniversity of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Norah A. Terrault
- Division of Gastrointestinal and Liver DiseaseKeck School of Medicine, University of Southern CaliforniaLos AngelesCaliforniaUSA
| | - Hyosun Han
- Division of Gastrointestinal and Liver DiseaseKeck School of Medicine, University of Southern CaliforniaLos AngelesCaliforniaUSA
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11
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Sedki M, Ahmed A, Goel A. Ethical and allocation issues in liver transplant candidates with alcohol related liver disease. Transl Gastroenterol Hepatol 2022; 7:26. [PMID: 35892052 PMCID: PMC9257533 DOI: 10.21037/tgh-2020-13] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 09/17/2020] [Indexed: 09/01/2024] Open
Abstract
In the past decade, alcohol-related liver disease (ALD) has become the leading indication for liver transplantation (LT) in the United States. Despite this major development, there still remains some controversy in a distinct subset of this patient population, those presenting with alcoholic hepatitis (AH). There is significant debate within the transplant community regarding acceptance criteria for patients with AH requiring LT, especially those with less than 6 months of sobriety. With that being said, LT in the setting of ALD and AH has shown an improvement in survival rates; additionally, many studies have reported that careful selection of patients with ALD has produced excellent post-transplant outcomes even if transplant occurred with less than 6 months of sobriety. In this review, we aim to discuss the ethical and allocation-associated issues that arise when considering ALD and/or AH for LT; furthermore, we delve into the history, controversies, current guidelines, and future directions of LT in this subgroup.
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Affiliation(s)
- Mai Sedki
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Aparna Goel
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
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12
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Lung Infection in Severe Alcohol-related Hepatitis: Not to be Underestimated. Am J Gastroenterol 2022; 117:1044-1045. [PMID: 35765906 DOI: 10.14309/ajg.0000000000001864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 06/07/2022] [Indexed: 12/11/2022]
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13
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Singal AK, Kwo P, Kwong A, Liangpunsakul S, Louvet A, Mandrekar P, McClain C, Mellinger J, Szabo G, Terrault N, Thursz M, Winder GS, Kim WR, Shah VH. Research methodologies to address clinical unmet needs and challenges in alcohol-associated liver disease. Hepatology 2022; 75:1026-1037. [PMID: 34496071 PMCID: PMC9235468 DOI: 10.1002/hep.32143] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 08/13/2021] [Indexed: 12/12/2022]
Abstract
Alcohol-associated liver disease (ALD) is emerging worldwide as the leading cause of liver-related morbidity, mortality, and indication for liver transplantation. The ALD Special Interest Group and the Clinical Research Committee at the digital American Association for the Study of Liver Diseases meeting in November 2020 held the scientific sessions to identify clinical unmet needs in ALD, and addressing these needs using clinical research methodologies. Of several research methodologies, the sessions were focused on (a) studying disease burden of ALD using large administrative databases, (b) developing biomarkers for noninvasive diagnosis of alcohol-associated hepatitis (AH) and estimation of disease prognosis, (c) identifying therapeutic targets for ALD and AH, (d) deriving accurate models to predict prognosis or posttransplant alcohol relapse as a basis for developing treatment algorithm and a uniform protocol on patient-selection criteria for liver transplantation, and (e) examining qualitative research methodologies in studying the barriers to implementation of multidisciplinary integrated care model by hepatology and addiction teams for the management of dual pathology of liver disease and of alcohol use disorder. Prospective multicenter studies are required to address many of these clinical unmet needs. Further, multidisciplinary care models are needed to improve long-term outcomes in patients with ALD.
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Affiliation(s)
- Ashwani K. Singal
- Department of Internal Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota, USA
- Division of Gastroenterology and Hepatology, Avera Transplant Institute, Sioux Falls, South Dakota, USA
| | - Paul Kwo
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California, USA
| | - Allison Kwong
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Indiana University, Indianapolis, Indiana, USA
| | | | - Pranoti Mandrekar
- Graduate School of Biomedical Sciences, UMass Medical School, Worcester, Massachusetts, USA
| | - Craig McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, Kentucky, USA
- Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Alcohol Research Center, University of Louisville School of Medicine, Louisville, Kentucky, USA
- Robley Rex Veterans Affairs Medical Center, Louisville, Kentucky, USA
| | - Jessica Mellinger
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan, USA
| | - Gyongyi Szabo
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Norah Terrault
- Division of Gastroenterology and Hepatology, University of Southern California, Los Angeles, California, USA
| | - Mark Thursz
- Division of Digestive Diseases, Imperial College London, London, UK
| | - Gerald S. Winder
- Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, USA
| | - W. Ray Kim
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California, USA
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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14
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Golabi P, Paik JM, Eberly K, de Avila L, Alqahtani SA, Younossi ZM. Causes of death in patients with Non-alcoholic Fatty Liver Disease (NAFLD), alcoholic liver disease and chronic viral Hepatitis B and C. Ann Hepatol 2022; 27:100556. [PMID: 34800721 DOI: 10.1016/j.aohep.2021.100556] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/23/2021] [Accepted: 07/05/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION AND OBJECTIVES Cause of mortality in patients with chronic liver diseases (CLDs) may differ based on underlying etiology of liver disease. Our aim was to assess different causes of death in patients with the most common types of CLD using a national database from the United States. MATERIALS AND METHODS Death data from 2008 and 2018 from the National Vital Statistics System (NVSS) by the National Center for Health Statistics (NCHS) were used. The rank of cause-of-death for each etiology of CLDs was assessed. Causes of death were classified by the ICD-10 codes. Liver-related deaths included liver cancer, cirrhosis and CLDs. RESULTS Among a total of 2,826,531 deaths in 2018, there were 85,807 (3.04%) with underlying CLD (mean age at death 63.0 years, 63.8% male, 70.8% white). Liver-related mortality was the leading cause of death for all types of CLD [45.8% in non-alcoholic fatty liver disease (NAFLD), 53.0% in chronic hepatitis C (CHC), 57.8% in chronic hepatitis B (CHB), 81.8% in alcoholic liver disease (ALD)]. This was followed by death from cardiac causes (NAFLD 10.3%, CHC 9.1%, CHB 4.6%, ALD 4.2%) and extrahepatic cancer (NAFLD 7.0%, CHC 11.9%, CHB 14.9%, ALD 2.1%). Although liver cancer was the leading cause of cancer death, lung, colorectal and pancreatic cancer were also common causes of cancer death. CONCLUSIONS Among deceased patients with CLD, underlying liver disease was the leading cause of death. Among solid cancers, liver cancer was the leading cause of cancer-related mortality.
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Affiliation(s)
- Pegah Golabi
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States
| | - James M Paik
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States
| | - Katherine Eberly
- Center for Liver Disease, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, VA, United States
| | - Leyla de Avila
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States
| | - Saleh A Alqahtani
- Division of Gastroenterology and Hepatology, Johns Hopkins University, Baltimore, MD, United States; Liver Transplant Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
| | - Zobair M Younossi
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, United States; Center for Liver Disease, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, VA, United States.
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15
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Di Ciaula A, Bonfrate L, Krawczyk M, Frühbeck G, Portincasa P. Synergistic and Detrimental Effects of Alcohol Intake on Progression of Liver Steatosis. Int J Mol Sci 2022; 23:ijms23052636. [PMID: 35269779 PMCID: PMC8910376 DOI: 10.3390/ijms23052636] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/24/2022] [Accepted: 02/25/2022] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the most common liver disorders worldwide and the major causes of non-viral liver cirrhosis in the general population. In NAFLD, metabolic abnormalities, obesity, and metabolic syndrome are the driving factors for liver damage with no or minimal alcohol consumption. ALD refers to liver damage caused by excess alcohol intake in individuals drinking more than 5 to 10 daily units for years. Although NAFLD and ALD are nosologically considered two distinct entities, they show a continuum and exert synergistic effects on the progression toward liver cirrhosis. The current view is that low alcohol use might also increase the risk of advanced clinical liver disease in NAFLD, whereas metabolic factors increase the risk of cirrhosis among alcohol risk drinkers. Therefore, special interest is now addressed to individuals with metabolic abnormalities who consume small amounts of alcohol or who binge drink, for the role of light-to-moderate alcohol use in fibrosis progression and clinical severity of the liver disease. Evidence shows that in the presence of NAFLD, there is no liver-safe limit of alcohol intake. We discuss the epidemiological and clinical features of NAFLD/ALD, aspects of alcohol metabolism, and mechanisms of damage concerning steatosis, fibrosis, cumulative effects, and deleterious consequences which include hepatocellular carcinoma.
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Affiliation(s)
- Agostino Di Ciaula
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School—Piazza Giulio Cesare 11, 70124 Bari, Italy; (A.D.C.); (L.B.)
| | - Leonilde Bonfrate
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School—Piazza Giulio Cesare 11, 70124 Bari, Italy; (A.D.C.); (L.B.)
| | - Marcin Krawczyk
- Department of Medicine II Saarland University Medical Center, Saarland University, 66424 Homburg, Germany;
- Laboratory of Metabolic Liver Diseases, Department of General, Transplant and Liver Surgery, Centre for Preclinical Research, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Gema Frühbeck
- Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, 31008 Pamplona, Spain;
- Metabolic Research Laboratory, Clínica Universidad de Navarra, 31008 Pamplona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), ISCIII, 31009 Pamplona, Spain
- Obesity and Adipobiology Group, Instituto de Investigación Sanitaria de Navarra (IdiSNA), 31009 Pamplona, Spain
| | - Piero Portincasa
- Clinica Medica “Augusto Murri”, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School—Piazza Giulio Cesare 11, 70124 Bari, Italy; (A.D.C.); (L.B.)
- Correspondence:
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16
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Cespiati A, Meroni M, Lombardi R, Oberti G, Dongiovanni P, Fracanzani AL. Impact of Sarcopenia and Myosteatosis in Non-Cirrhotic Stages of Liver Diseases: Similarities and Differences across Aetiologies and Possible Therapeutic Strategies. Biomedicines 2022; 10:biomedicines10010182. [PMID: 35052859 PMCID: PMC8773740 DOI: 10.3390/biomedicines10010182] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/13/2022] [Accepted: 01/14/2022] [Indexed: 12/15/2022] Open
Abstract
Sarcopenia is defined as a loss of muscle strength, mass and function and it is a predictor of mortality. Sarcopenia is not only a geriatric disease, but it is related to several chronic conditions, including liver diseases in both its early and advanced stages. Despite the increasing number of studies exploring the role of sarcopenia in the early stages of chronic liver disease (CLD), its prevalence and the relationship between these two clinical entities are still controversial. Myosteatosis is characterized by fat accumulation in the muscles and it is related to advanced liver disease, although its role in the early stages is still under researched. Therefore, in this narrative review, we firstly aimed to evaluate the prevalence and the pathogenetic mechanisms underlying sarcopenia and myosteatosis in the early stage of CLD across different aetiologies (mainly non-alcoholic fatty liver disease, alcohol-related liver disease and viral hepatitis). Secondly, due to the increasing prevalence of sarcopenia worldwide, we aimed to revise the current and the future therapeutic approaches for the management of sarcopenia in CLD.
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Affiliation(s)
- Annalisa Cespiati
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (A.C.); (M.M.); (G.O.); (P.D.); (A.L.F.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (A.C.); (M.M.); (G.O.); (P.D.); (A.L.F.)
| | - Rosa Lombardi
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (A.C.); (M.M.); (G.O.); (P.D.); (A.L.F.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
- Correspondence: ; Tel.: +39-02-5503-4192; Fax: +39-02-5503-3509
| | - Giovanna Oberti
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (A.C.); (M.M.); (G.O.); (P.D.); (A.L.F.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (A.C.); (M.M.); (G.O.); (P.D.); (A.L.F.)
| | - Anna Ludovica Fracanzani
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (A.C.); (M.M.); (G.O.); (P.D.); (A.L.F.)
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, 20122 Milan, Italy
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17
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Bloom PP, Fontana RJ. With Alcohol as the Fuel, COVID Is the Match: Liver Transplantation for Alcohol-Associated Liver Disease Is Increasing in the United States. Hepatology 2021; 74:2948-2951. [PMID: 34496063 DOI: 10.1002/hep.32141] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 08/31/2021] [Indexed: 12/17/2022]
Affiliation(s)
- Patricia P Bloom
- Division of Gastroenterology & Hepatology, University of Michigan Medical center, Ann Arbor, MI
| | - Robert J Fontana
- Division of Gastroenterology & Hepatology, University of Michigan Medical center, Ann Arbor, MI
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18
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Barnard A, Dave S. Editorial: trends in alcohol use and alcohol-related liver disease in the US population. Aliment Pharmacol Ther 2021; 54:511-512. [PMID: 34331814 DOI: 10.1111/apt.16491] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Abbey Barnard
- Division of Gastroenterology, Department of Medicine, University of California at San Diego, San Diego, CA, USA
| | - Shravan Dave
- Division of Gastroenterology, Department of Medicine, University of California at San Diego, San Diego, CA, USA
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19
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Makar M, Reja D, Chouthai A, Kabaria S, Patel AV. The impact of acute kidney injury on mortality and clinical outcomes in patients with alcoholic cirrhosis in the USA. Eur J Gastroenterol Hepatol 2021; 33:905-910. [PMID: 32976187 DOI: 10.1097/meg.0000000000001947] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Acute kidney injury (AKI) is associated with increased morbidity and mortality in patients with chronic liver disease. Although the impact of AKI on patients with liver disease has been established, its impact on alcoholic cirrhosis has not been studied. METHODS Our study utilized data from the National Inpatient Sample for the year 2016 for all patients with a diagnosis of alcoholic cirrhosis and AKI. Primary outcomes were mortality, length of stay (LOS) and hospitalization cost were compared. Secondary outcomes were complications of cirrhosis and its impact on mortality. Multivariate logistic regression analysis and propensity-score matching were used to compare the two groups. RESULTS A total of 29 906 patients were included and 6733 (22.5%) had AKI. Propensity-matched multivariate analysis demonstrates that AKI was associated with a significant increase risk of mortality [odds ratio (OR): 8.09; 95% confidence interval (CI), 6.68-9.79; P < 0.0001]. AKI prolonged the hospital stay by 3.68 days (95% CI, 3.42-3.93; P < 0.0001) and increased total hospital charges by $50 284 (95% CI, 45 829-54 739; P < 0.0001). AKI increased the risk of complications of cirrhosis, including hepatorenal syndrome (OR: 19.15; 95% CI, 16.1-22.76), ascites (OR: 2.27; 95% CI, 2.11-2.44), hepatic encephalopathy (OR: 2.54; 95% CI, 1.87-3.47) and portal hypertension (OR: 1.08; 95% CI, 1.01-1.16). CONCLUSION AKI in alcoholic cirrhosis significantly increases the risk of mortality, hospitalizations costs and LOS. Further studies are needed on addressing renal failure and treatment options for patients with alcoholic cirrhosis.
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Affiliation(s)
| | | | | | | | - Anish Vinit Patel
- Department of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
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20
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Davuluri G, Welch N, Sekar J, Gangadhariah M, Alchirazi KA, Mohan ML, Kumar A, Kant S, Thapaliya S, Stine M, McMullen MR, McCullough RL, Stark GR, Nagy LE, Prasad SVN, Dasarathy S. Activated Protein Phosphatase 2A Disrupts Nutrient Sensing Balance Between Mechanistic Target of Rapamycin Complex 1 and Adenosine Monophosphate-Activated Protein Kinase, Causing Sarcopenia in Alcohol-Associated Liver Disease. Hepatology 2021; 73:1892-1908. [PMID: 32799332 PMCID: PMC8847884 DOI: 10.1002/hep.31524] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 07/09/2020] [Accepted: 07/29/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND AIMS Despite the high clinical significance of sarcopenia in alcohol-associated cirrhosis, there are currently no effective therapies because the underlying mechanisms are poorly understood. We determined the mechanisms of ethanol-induced impaired phosphorylation of mechanistic target of rapamycin complex 1 (mTORC1) and adenosine monophosphate-activated protein kinase (AMPK) with consequent dysregulated skeletal muscle protein homeostasis (balance between protein synthesis and breakdown). APPROACH AND RESULTS Differentiated murine myotubes, gastrocnemius muscle from mice with loss and gain of function of regulatory genes following ethanol treatment, and skeletal muscle from patients with alcohol-associated cirrhosis were used. Ethanol increases skeletal muscle autophagy by dephosphorylating mTORC1, circumventing the classical kinase regulation by protein kinase B (Akt). Concurrently and paradoxically, ethanol exposure results in dephosphorylation and inhibition of AMPK, an activator of autophagy and inhibitor of mTORC1 signaling. However, AMPK remains inactive with ethanol exposure despite lower cellular and tissue adenosine triphosphate, indicating a "pseudofed" state. We identified protein phosphatase (PP) 2A as a key mediator of ethanol-induced signaling and functional perturbations using loss and gain of function studies. Ethanol impairs binding of endogenous inhibitor of PP2A to PP2A, resulting in methylation and targeting of PP2A to cause dephosphorylation of mTORC1 and AMPK. Activity of phosphoinositide 3-kinase-γ (PI3Kγ), a negative regulator of PP2A, was decreased in response to ethanol. Ethanol-induced molecular and phenotypic perturbations in wild-type mice were observed in PI3Kγ-/- mice even at baseline. Importantly, overexpressing kinase-active PI3Kγ but not the kinase-dead mutant reversed ethanol-induced molecular perturbations. CONCLUSIONS Our study describes the mechanistic underpinnings for ethanol-mediated dysregulation of protein homeostasis by PP2A that leads to sarcopenia with a potential for therapeutic approaches by targeting the PI3Kγ-PP2A axis.
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Affiliation(s)
- Gangarao Davuluri
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
| | - Nicole Welch
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH,Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH
| | - Jinendiran Sekar
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
| | | | | | - Maradumane L Mohan
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH
| | - Avinash Kumar
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
| | - Sashi Kant
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
| | - Samjhana Thapaliya
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
| | - McKenzie Stine
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
| | - Megan R McMullen
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
| | | | - George R. Stark
- Department of Cancer Biology, Cleveland Clinic, Cleveland, OH
| | - Laura E. Nagy
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
| | - Sathyamangla V Naga Prasad
- Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic, Cleveland, OH,Address correspondence to: Srinivasan Dasarathy MD, Gastroenterology and Hepatology, NE4 208 Lerner Research Institute, 9500 Euclid Avenue, Cleveland Clinic, Cleveland, OH 44195, , Tel: 2164442980, Fax 2164453889; Sathyamangla V Naga Prasad PhD, Cardiovascular and Metabolic Sciences, NB50, Lerner Research Institute, 9500 Euclid Avenue, Cleveland Clinic, Cleveland, OH 44195, , Tel: 2164443734, Fax: 2164458204
| | - Srinivasan Dasarathy
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH,Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH,Address correspondence to: Srinivasan Dasarathy MD, Gastroenterology and Hepatology, NE4 208 Lerner Research Institute, 9500 Euclid Avenue, Cleveland Clinic, Cleveland, OH 44195, , Tel: 2164442980, Fax 2164453889; Sathyamangla V Naga Prasad PhD, Cardiovascular and Metabolic Sciences, NB50, Lerner Research Institute, 9500 Euclid Avenue, Cleveland Clinic, Cleveland, OH 44195, , Tel: 2164443734, Fax: 2164458204
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Asrani SK, Mellinger J, Arab JP, Shah VS. Reducing the Global Burden of Alcohol-Associated Liver Disease: A Blueprint for Action. Hepatology 2021; 73:2039-2050. [PMID: 32986883 PMCID: PMC9361217 DOI: 10.1002/hep.31583] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/18/2020] [Accepted: 09/08/2020] [Indexed: 12/12/2022]
Abstract
Alcohol-associated liver disease (ALD) is a major driver of global liver related morbidity and mortality. There are 2.4 billion drinkers (950 million heavy drinkers) and the lifetime prevalence of any alcohol use disorder (AUD) is 5.1%-8.6%. In 2017, global prevalence of alcohol-associated compensated and decompensated cirrhosis was 23.6 million and 2.5 million, respectively. Combined, alcohol-associated cirrhosis and liver cancer account for 1% of all deaths worldwide with this burden expected to increase. Solutions for this growing epidemic must be multi-faceted and focused on both population and patient-level interventions. Reductions in ALD-related morbidity and mortality require solutions that focus on early identification and intervention, reducing alcohol consumption at the population level (taxation, reduced availability and restricted promotion), and solutions tailored to local socioeconomic realities (unrecorded alcohol consumption, focused youth education). Simple screening tools and algorithms can be applied at the population level to identify alcohol misuse, diagnose ALD using non-invasive serum and imaging markers, and risk-stratify higher-risk ALD/AUD patients. Novel methods of healthcare delivery and platforms are needed (telehealth, outreach, use of non-healthcare providers, partnerships between primary and specialty care/tertiary hospitals) to proactively mitigate the global burden of ALD. An integrated approach that combines medical and AUD treatment is needed at the individual level to have the highest impact. Future needs include (1) improving quality of ALD data and standardizing care, (2) supporting innovative healthcare delivery platforms that can treat both ALD and AUD, (3) stronger and concerted advocacy by professional hepatology organizations, and (4) advancing implementation of digital interventions.
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Affiliation(s)
- Sumeet K Asrani
- Baylor University Medical Center, Dallas, TX, United States,Corresponding Author and reprint requests Sumeet K Asrani MD MSc, Baylor University Medical Center, Dallas Texas, 2148208500
| | - Jessica Mellinger
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI
| | - Juan P Arab
- Depto. Gastroenterología y Hepatología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Chile
| | - Vijay S Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
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22
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Sang X, Wang B, Zhao P, Ding X, Ahmad KZ, Yu J, Ding X. Harnessing Artificial Intelligence to Expedite Identification of Therapeutic Phytochemical Combination for Alcoholic Hepatic Injury. ADVANCED THERAPEUTICS 2021. [DOI: 10.1002/adtp.202100042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Xiao Sang
- Shanghai Key Laboratory of Molecular Imaging Shanghai University of Medicine and Health Sciences Shanghai 201318 China
- Institute for Personalized Medicine School of Biomedical Engineering Shanghai Jiao Tong University Shanghai 200030 China
| | - Boqian Wang
- Institute for Personalized Medicine School of Biomedical Engineering Shanghai Jiao Tong University Shanghai 200030 China
| | - Peng Zhao
- Shanghai Key Laboratory of Molecular Imaging Shanghai University of Medicine and Health Sciences Shanghai 201318 China
- Institute for Personalized Medicine School of Biomedical Engineering Shanghai Jiao Tong University Shanghai 200030 China
| | - Xiaolong Ding
- Shanghai Key Laboratory of Molecular Imaging Shanghai University of Medicine and Health Sciences Shanghai 201318 China
- Institute for Personalized Medicine School of Biomedical Engineering Shanghai Jiao Tong University Shanghai 200030 China
| | - Khan Zara Ahmad
- Institute for Personalized Medicine School of Biomedical Engineering Shanghai Jiao Tong University Shanghai 200030 China
| | - Jianhua Yu
- Shanghai Key Laboratory of Molecular Imaging Shanghai University of Medicine and Health Sciences Shanghai 201318 China
- Institute for Personalized Medicine School of Biomedical Engineering Shanghai Jiao Tong University Shanghai 200030 China
| | - Xianting Ding
- Shanghai Key Laboratory of Molecular Imaging Shanghai University of Medicine and Health Sciences Shanghai 201318 China
- Institute for Personalized Medicine School of Biomedical Engineering Shanghai Jiao Tong University Shanghai 200030 China
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23
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Alshuwaykh O, Kwong A, Goel A, Cheung A, Dhanasekaran R, Ahmed A, Daugherty T, Dronamraju D, Kumari R, Kim WR, Nguyen MH, Esquivel CO, Concepcion W, Melcher M, Bonham A, Pham T, Gallo A, Kwo PY. Predictors of Outcomes of Patients Referred to a Transplant Center for Urgent Liver Transplantation Evaluation. Hepatol Commun 2021; 5:516-525. [PMID: 33681683 PMCID: PMC7917272 DOI: 10.1002/hep4.1644] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/24/2020] [Accepted: 10/20/2020] [Indexed: 12/18/2022] Open
Abstract
Liver transplantation (LT) is definitive treatment for end-stage liver disease. This study evaluated factors predicting successful evaluation in patients transferred for urgent inpatient LT evaluation. Eighty-two patients with cirrhosis were transferred for urgent LT evaluation from January 2016 to December 2018. Alcohol-associated liver disease was the common etiology of liver disease (42/82). Of these 82 patients, 35 (43%) were declined for LT, 27 (33%) were wait-listed for LT, 5 (6%) improved, and 15 (18%) died. Psychosocial factors were the most common reasons for being declined for LT (49%). Predictors for listing and receiving LT on multivariate analysis included Hispanic race (odds ratio [OR], 1.89; P = 0.003), Asian race (OR, 1.52; P = 0.02), non-Hispanic ethnicity (OR, 1.49; P = 0.04), hyponatremia (OR, 1.38; P = 0.04), serum albumin (OR, 1.13; P = 0.01), and Model for End-Stage Liver Disease (MELD)-Na (OR, 1.02; P = 0.003). Public insurance (i.e., Medicaid) was a predictor of not being listed for LT on multivariate analysis (OR, 0.77; P = 0.02). Excluding patients declined for psychosocial reasons, predictors of being declined for LT on multivariate analysis included Chronic Liver Failure Consortium (CLIF-C) score >51.5 (OR, 1.26; P = 0.03), acute-on-chronic liver failure (ACLF) grade 3 (OR, 1.41; P = 0.01), hepatorenal syndrome (HRS) (OR, 1.38; P = 0.01), and respiratory failure (OR, 1.51; P = 0.01). Predictors of 3-month mortality included CLIF-C score >51.5 (hazard ratio [HR], 2.52; P = 0.04) and intensive care unit (HR, 8.25; P < 0.001). Conclusion: MELD-Na, albumin, hyponatremia, ACLF grade 3, HRS, respiratory failure, public insurance, Hispanic race, Asian race, and non-Hispanic ethnicity predicted liver transplant outcome. Lack of psychosocial support was a major reason for being declined for LT. The CLIF-C score predicted being declined for LT and mortality.
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Affiliation(s)
- Omar Alshuwaykh
- Division of Gastroenterology and HepatologyStanford University Medical CenterStanfordCAUSA
| | - Allison Kwong
- Division of Gastroenterology and HepatologyStanford University Medical CenterStanfordCAUSA
| | - Aparna Goel
- Division of Gastroenterology and HepatologyStanford University Medical CenterStanfordCAUSA
| | - Amanda Cheung
- Division of Gastroenterology and HepatologyStanford University Medical CenterStanfordCAUSA
| | - Renumathy Dhanasekaran
- Division of Gastroenterology and HepatologyStanford University Medical CenterStanfordCAUSA
| | - Aijaz Ahmed
- Division of Gastroenterology and HepatologyStanford University Medical CenterStanfordCAUSA
| | - Tami Daugherty
- Division of Gastroenterology and HepatologyStanford University Medical CenterStanfordCAUSA
| | - Deepti Dronamraju
- Division of Gastroenterology and HepatologyStanford University Medical CenterStanfordCAUSA
| | - Radhika Kumari
- Division of Gastroenterology and HepatologyStanford University Medical CenterStanfordCAUSA
| | - W Ray Kim
- Division of Gastroenterology and HepatologyStanford University Medical CenterStanfordCAUSA
| | - Mindie H Nguyen
- Division of Gastroenterology and HepatologyStanford University Medical CenterStanfordCAUSA
| | - Carlos O Esquivel
- Division of Abdominal TransplantationStanford University Medical CenterStanfordCAUSA
| | - Waldo Concepcion
- Division of Abdominal TransplantationStanford University Medical CenterStanfordCAUSA
| | - Marc Melcher
- Division of Abdominal TransplantationStanford University Medical CenterStanfordCAUSA
| | - Andy Bonham
- Division of Abdominal TransplantationStanford University Medical CenterStanfordCAUSA
| | - Thomas Pham
- Division of Abdominal TransplantationStanford University Medical CenterStanfordCAUSA
| | - Amy Gallo
- Division of Abdominal TransplantationStanford University Medical CenterStanfordCAUSA
| | - Paul Yien Kwo
- Division of Gastroenterology and HepatologyStanford University Medical CenterStanfordCAUSA
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24
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Welch N, Attaway A, Bellar A, Alkhafaji H, Vural A, Dasarathy S. Compound Sarcopenia in Hospitalized Patients with Cirrhosis Worsens Outcomes with Increasing Age. Nutrients 2021; 13:nu13020659. [PMID: 33670535 PMCID: PMC7923160 DOI: 10.3390/nu13020659] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 02/10/2021] [Accepted: 02/13/2021] [Indexed: 02/07/2023] Open
Abstract
Background: There are limited data on outcomes of older patients with chronic diseases. Skeletal muscle loss of aging (primary sarcopenia) has been extensively studied but the impact of secondary sarcopenia of chronic disease is not as well evaluated. Older patients with chronic diseases have both primary and secondary sarcopenia that we term compound sarcopenia. We evaluated the clinical impact of compound sarcopenia in hospitalized patients with cirrhosis given the increasing number of patients and high prevalence of sarcopenia in these patients. Design: The Nationwide Inpatients Sample (NIS) database (years 2010–2014) was analyzed to study older patients with cirrhosis. Since there is no universal hospital diagnosis code for “muscle loss”, we used a comprehensive array of codes for “muscle loss phenotype” in the international classification of diseases-9 (ICD-9). A randomly selected 2% sample of hospitalized general medical population (GMP) and inpatients with cirrhosis were stratified into 3 age groups based on age-related changes in muscle mass. In-hospital mortality, length of stay (LoS), cost of hospitalization (CoH), comorbidities and discharge disposition were analyzed. Results. Of 517,605 hospitalizations for GMP and 106,835 hospitalizations for treatment of cirrhosis or a cirrhosis-related complication, 207,266 (40.4%) GMP and 29,018 (27.7%) patients with cirrhosis were >65 years old, respectively. Muscle loss phenotype in both GMP and inpatients with cirrhosis 51–65 years old and >65 years old was significantly (p < 0.001 for all) associated with higher mortality, LoS, and CoH compared to those ≤50 years old. Patients >65 years old with cirrhosis and muscle loss phenotype had higher mortality (adjusted OR: 1.06, 95% CI [1.04, 1.08] and CoH (adjusted odds ratio (OR): 1.10, 95% confidence interval (CI) [1.04, 1.08])) when compared to >65 years old GMP with muscle loss phenotype. Muscle loss in younger patients with cirrhosis (≤50 years old) was associated with worse outcomes compared to GMP >65 years old. Non-home discharges (nursing, skilled, long-term care) were more frequent with increasing age to a greater extent in patients with cirrhosis with muscle loss phenotype for each age stratum. Conclusion: Muscle loss is more frequent in older patients with cirrhosis than younger patients with cirrhosis and older GMP. Younger patients with cirrhosis had clinical outcomes similar to those of older GMP, suggesting an accelerated senescence in cirrhosis. Compound sarcopenia in older patients with cirrhosis is associated with higher inpatient mortality, increased LoS, and CoH compared to GMP with sarcopenia.
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Affiliation(s)
- Nicole Welch
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, USA;
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, USA; (A.B.); (H.A.); (A.V.)
| | - Amy Attaway
- Department of Pulmonary Medicine, Cleveland Clinic, Cleveland, OH 44195, USA;
| | - Annette Bellar
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, USA; (A.B.); (H.A.); (A.V.)
| | - Hayder Alkhafaji
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, USA; (A.B.); (H.A.); (A.V.)
| | - Adil Vural
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, USA; (A.B.); (H.A.); (A.V.)
| | - Srinivasan Dasarathy
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44195, USA;
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH 44195, USA; (A.B.); (H.A.); (A.V.)
- Correspondence:
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25
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Tibuakuu M, Jjingo C, Kirk GD, Thomas DL, Gray R, Ssempijja V, Nalugoda F, Serwadda D, Ocama P, Opio CK, Kleiner DE, Quinn TC, Reynolds SJ. Elevated liver stiffness without histological evidence of liver fibrosis in rural Ugandans. J Viral Hepat 2020; 27:1022-1031. [PMID: 32388879 PMCID: PMC8919060 DOI: 10.1111/jvh.13320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 02/20/2020] [Accepted: 04/12/2020] [Indexed: 12/09/2022]
Abstract
Liver fibrosis may be assessed noninvasively with transient electrography (TE). Data on the performance of TE for detecting liver fibrosis in sub-Saharan Africa are limited. We evaluated the diagnostic accuracy of TE by performing liver biopsies on persons with liver fibrosis indicated by TE. We enrolled HIV-infected and HIV-uninfected participants with TE scores consistent with at least minimal disease (liver stiffness measurement [LSM]≥7.1 kPa). Biopsies were performed and staged using the Ishak scoring system. A concordant result was defined using accepted thresholds for significant fibrosis by TE (LSM ≥ 9.3 kPa) and liver biopsy (Ishak score ≥ 2). We used modified Poisson regression methods to quantify the univariate and adjusted prevalence risk ratios (PRR) of the association between covariates and the concordance status of TE and liver biopsy in defining the presence of liver fibrosis. Of 131 participants with valid liver biopsy and TE data, only 5 participants (3.8%) had Ishak score ≥ 2 of whom 4 had LSM ≥ 9.3 kPa (sensitivity = 80%); of the 126 (96.2%) with Ishak score < 2, 76 had LSM < 9.3 kPa (specificity = 61%). In multivariable analysis, discordance was associated with female gender (adjPRR = 1.80, 95%CI 1.1-2.9; P = .019), herbal medicine use (adjPRR 1.64, 95% CI = 1.0-2.5; P = .022), exposure to lake or river water (adjPRR 2.05, 95% CI = 1.1-3.7; P = .016), and current smoking (adjPRR 1.72, 95%CI 1.0-2.9; P = .045). These data suggest that TE among rural Ugandans has low specificity for detection of histologically confirmed liver fibrosis. Caution should be exercised when using this tool to confirm significant liver fibrosis.
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Affiliation(s)
- Martin Tibuakuu
- Department of Medicine, St. Luke’s Hospital, Chesterfield, Missouri
| | - Caroline Jjingo
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | - Gregory Dale Kirk
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - David Lee Thomas
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Ronald Gray
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Rakai Health Sciences Program, Entebbe, Uganda
| | - Victor Ssempijja
- Clinical Research Directorate/Clinical Monitoring Research Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, Maryland
| | | | - David Serwadda
- Rakai Health Sciences Program, Entebbe, Uganda
- School of Public Health, Makerere University College of Health Sciences, Kampala, Uganda
| | - Ponsiano Ocama
- School of Medicine, Makerere University College of Health Sciences, Kampala, Uganda
| | | | | | - Thomas Charles Quinn
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Steven James Reynolds
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
- Rakai Health Sciences Program, Entebbe, Uganda
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26
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Russo MW, Fix OK, Koteish AA, Duggan K, Ditmyer M, Fuchs M, Chung RT, Reddy G. Modeling the Hepatology Workforce in the United States: A Predicted Critical Shortage. Hepatology 2020; 72:1444-1454. [PMID: 32898922 DOI: 10.1002/hep.31425] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 05/03/2020] [Accepted: 05/26/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Liver disease is prevalent in the United States, and as the population ages, an increasing number of patients are anticipated to present for care. The state of the current hepatology workforce and future demand for hepatology providers is not known. The aim of this study was to model future projections for hepatology workforce demand. APPROACH AND RESULTS A workforce study of hepatology providers in the United States was completed using primary and secondary data sources. An integrated workforce framework model was used that combined socioeconomic factors that drive economic demand, epidemiological factors that drive need, and utilization rates of health care services. Supply and demand projections were calculated for adult and pediatric hepatology professionals. Sensitivity analyses were conducted to cover the feasible range of these assumptions. An electronic survey of American Association for the Study of Liver Diseases (AASLD) members whose practice included 50% or more hepatology was conducted. In 2018, the adult and pediatric workforce included 7,296 and 824 hepatology providers, respectively, composed of hepatologists, gastroenterologists, and advanced practice providers whose practice was ≥50% hepatology. The modeling analysis projects that in 2023, 2028, and 2033, there will be shortages of 10%, 23%, and 35% adult hepatology providers, respectively, and 19%, 20%, and 16% pediatric hepatology providers, respectively. In sensitivity analyses, a shortage of hepatology providers is predicted even under optimistic assumptions. Among the respondents to the survey, the median age was higher among gastroenterologists and general hepatologists compared with transplant hepatologists. The most common category treated by transplant hepatologists was general hepatology. CONCLUSIONS There is an impending critical shortage of adult and pediatric hepatology providers. Strategies are needed to encourage clinicians to pursue hepatology, especially in areas outside of transplant centers.
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Affiliation(s)
- Mark W Russo
- Carolinas Medical Center, Atrium Health, Charlotte, NC, USA
| | - Oren K Fix
- Organ Transplant and Liver Center, Swedish Medical Center, Seattle, WA, USA
| | - Ayman A Koteish
- Advent Health, Orlando, FL, USA.,The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Katie Duggan
- American Association for the Study of Liver Diseases, Alexandria, VA, USA
| | | | - Michael Fuchs
- Central Virginia VA Health Care System, Virginia Commonwealth University, Richmond, VA, USA
| | - Raymond T Chung
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
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27
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Gender Disparities in Patients With Alcoholic Liver Disease Evaluated for Liver Transplantation. Transplantation 2020; 104:293-298. [PMID: 31283683 DOI: 10.1097/tp.0000000000002843] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND The morbidity and mortality from alcohol-related liver disease (ALD) is increasing in the United States. However, little is known about gender differences in evaluation and listing for liver transplantation (LT) in patients with ALD. METHODS This is a retrospective review of adult patients with ALD evaluated for LT at a single transplant center from January 1, 2010, to March 1, 2017. Univariate, multivariate, and time-series analyses were performed. RESULTS Among the 949 patients with ALD evaluated, mean age was 53 years, 84% were Caucasian, and 33% were women. The median model for end-stage liver disease score was similar between the genders. Women were less likely to be listed for LT (10% versus 19%; P < 0.05). The proportion of women not listed due to active substance use was significantly higher versus men (42% versus 35%; P < 0.05), while the frequency of medical contraindications was comparable between the genders. During a median follow-up of 416 days (range: 0-2784), listed women with ALD were less likely to undergo transplantation (42% versus 47%; P < 0.05). CONCLUSIONS Men with ALD were 95% more likely to be listed and 105% more likely to be transplanted compared to women with ALD. While men had more lifetime substance use and related consequences, women had more psychiatric comorbidities and were less likely to be listed due to active alcohol and opioid use. Early detection and effective treatment of psychiatric and substance use disorders in women with ALD may improve their transplant eligibility.
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28
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Causes and trends in liver disease and hepatocellular carcinoma among men and women who received liver transplants in the U.S., 2010-2019. PLoS One 2020; 15:e0239393. [PMID: 32946502 PMCID: PMC7500679 DOI: 10.1371/journal.pone.0239393] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 09/07/2020] [Indexed: 12/15/2022] Open
Abstract
Background and aims The national Organ Procurement and Transplant Network (OPTN) reported the major indication for liver transplants in 2018 was for other/unknown causes. This study was undertaken to examine all causes and trends in liver disease and hepatocellular carcinoma (HCC) among adults who received liver transplants in the past 10 years. Methods A national cohort study of all adults who received liver transplants from Jan 1, 2010 to Dec 31, 2019 recorded in the OPTN STAR database analyzed by etiology of liver disease and HCC, and gender. Results Adult liver transplants increased from 5,731 in 2010 to 8,345 in 2019 (45.6% increase). Between 2010 and 2014, liver disease and HCC associated with hepatitis C (HCV) was the major cause for liver transplantation. Proportion of liver transplants for HCV associated liver disease and HCC has since decreased to 18.7% in 2019 compared with 44.5% in 2010 [25.8%, (95% CI 24.3% to 27.3%), p<0.001], while liver transplants for liver disease and HCC associated with alcohol-associated liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) increased from 12.7% to 28.8% [16.1%, (95% CI 14.8% to 17.4%), p<0.001], and from 9.1% to 21.5% [12.4%, (95% CI 11.2% to 13.5%), p<0.001], respectively. When all causes of liver disease were examined, only 1.7% of liver transplants had unspecified causes. The five major causes of liver disease and HCC among men receiving liver transplants in 2019 were ALD (33.1%), HCV (21.9%), NAFLD (18.5%), cholestatic liver disease (5.7%) and hepatitis B (4.9%), while the major causes among women were NAFLD (26.8%), ALD (21.1%), HCV (13.1%), cholestatic liver disease (11.1%), and autoimmune liver disease (5.6%). Conclusions Our study found NAFLD in 2017 in women and ALD in 2019 in men have surpassed HCV as the leading causes of liver disease and HCC among adults receiving liver transplants.
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29
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Kardashian A, Patel AA, Aby ES, Cusumano VT, Soroudi C, Winters AC, Wu E, Beah P, Delshad S, Kim N, Yang L, May FP. Identifying Quality Gaps in Preventive Care for Outpatients With Cirrhosis Within a Large, Academic Health Care System. Hepatol Commun 2020; 4:1802-1811. [PMID: 33305151 PMCID: PMC7706302 DOI: 10.1002/hep4.1594] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 07/28/2020] [Accepted: 07/30/2020] [Indexed: 12/12/2022] Open
Abstract
We sought to identify specific gaps in preventive care provided to outpatients with cirrhosis and to determine factors associated with high quality of care (QOC), to guide quality improvement efforts. Outpatients with cirrhosis who received care at a large, academic tertiary health care system in the United States were included. Twelve quality indicators (QIs), including preventive care processes for ascites, esophageal varices, hepatic encephalopathy, hepatocellular carcinoma (HCC), and general cirrhosis care, were measured. QI pass rates were calculated as the proportion of patients eligible for a QI who received that QI during the study period. We performed logistic regression to determine predictors of high QOC (≥ 75% of eligible QIs) and receipt of HCC surveillance. Of the 439 patients, the median age was 63 years, 59% were male, and 19% were Hispanic. The median Model for End-Stage Liver Disease-Sodium score was 11, 64% were compensated, and 32% had hepatitis C virus. QI pass rates varied by individual QIs, but were overall low. For example, 24% received appropriate HCC surveillance, 32% received an index endoscopy for varices screening, and 21% received secondary prophylaxis for spontaneous bacterial peritonitis. In multivariable analyses, Asian race (odds ratio [OR]: 3.7, 95% confidence interval [CI]: 1.3-10.2) was associated with higher QOC, and both Asian race (OR: 3.3, 95% CI: 1.2-9.0) and decompensated status (OR: 2.1, 95% CI: 1.1-4.2) were associated with receipt of HCC surveillance. A greater number of specialty care visits was not associated with higher QOC. Conclusion: Receipt of outpatient preventive cirrhosis QIs was variable and overall low in a diverse cohort of patients with cirrhosis. Variation in care by race/ethnicity and illness trajectory should prompt further inquiry into identifying modifiable factors to standardize care delivery and to improve QOC.
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Affiliation(s)
- Ani Kardashian
- Vatche and Tamar Manoukian Division of Digestive Diseases Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA.,Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA
| | - Arpan A Patel
- Vatche and Tamar Manoukian Division of Digestive Diseases Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA.,Veterans Affairs Greater Los Angeles Healthcare System Los Angeles CA
| | - Elizabeth S Aby
- Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA
| | - Vivy T Cusumano
- Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA
| | - Camille Soroudi
- Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA
| | - Adam C Winters
- Vatche and Tamar Manoukian Division of Digestive Diseases Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA.,Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA
| | - Eric Wu
- Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA
| | - Peter Beah
- Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA
| | - Sean Delshad
- Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA
| | - Nathan Kim
- Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA
| | - Liu Yang
- Vatche and Tamar Manoukian Division of Digestive Diseases Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA
| | - Folasade P May
- Vatche and Tamar Manoukian Division of Digestive Diseases Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA.,Department of Medicine David Geffen School of Medicine at UCLA Los Angeles CA.,Veterans Affairs Greater Los Angeles Healthcare System Los Angeles CA.,Jonsson Comprehensive Cancer Center UCLA Los Angeles CA
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30
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Model to Predict Progression of Liver Disease in Heavy Drinkers Is Useful Today and Supports the Future of Deep Learning. Clin Gastroenterol Hepatol 2020; 18:2176-2178. [PMID: 32062043 DOI: 10.1016/j.cgh.2020.02.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 02/09/2020] [Indexed: 02/07/2023]
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31
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Aslam S, Buggs J, Melo S, Ermekbaeva A, Rogers E, Shaw R, Kumar A, Kemmer N. The Association Between Alcoholic Liver Disease and Alcohol Tax. Am Surg 2020; 87:92-96. [DOI: 10.1177/0003134820945223] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Background The incidence of alcoholic liver disease (ALD) has increased, causing it to become a primary indication for liver transplantation in the United States. We hypothesized an association between alcohol taxation and prevalence of ALD. Methods We conducted a retrospective study of united network for organ sharing (UNOS) waitlist additions for liver transplantation between January 2007 and December 2016. We also analyzed the average excise tax (2007-2016) for beer, wine, and spirits in listing states of liver transplant waitlist additions (LTWA). Results There were 104 805 adult UNOS LTWA with assigned diagnoses, an annual increase from 22% to 28%. There were 24 316 LTWA with ALD diagnosis. The mean value for beer tax was significantly lower for ALD patients than for non-ALD patients across all age groups ( P < .001). The analysis demonstrated significantly more ALD in waitlisted patients 35-54 years of age (30%), compared with 18-34 years (10%) and ≥55 years (20%), P < .001. The data confirmed significantly more ALD Medicaid patients in the 35-54 year age group (28%) compared with other age groups, P < .001. Discussion Our research demonstrated an association between lower beer tax and higher ALD prevalence across all age groups. We found a larger percentage of middle-aged (35-54 years) Medicaid patients listed with ALD. These findings raise the need for further investigation of a potential public health concern for an association between ALD and beer tax, especially for middle-aged patients of lower socioeconomic status.
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Affiliation(s)
- Sadaf Aslam
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Jacentha Buggs
- Department of Transplant Surgery, Tampa General Medical Group, Tampa, FL, USA
| | - Samantha Melo
- Indiana University School of Medicine, Indianapolis, IN, USA
| | | | - Ebonie Rogers
- Office of Clinical Research, Tampa General Hospital, Tampa, FL, USA
| | - Robert Shaw
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Ambuj Kumar
- Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Nyingi Kemmer
- Department of Transplant Hepatology, Tampa General Medical Group, Tampa, FL, USA
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Dasarathy S, Mitchell MC, Barton B, McClain CJ, Szabo G, Nagy LE, Radaeva S, McCullough AJ. Design and rationale of a multicenter defeat alcoholic steatohepatitis trial: (DASH) randomized clinical trial to treat alcohol-associated hepatitis. Contemp Clin Trials 2020; 96:106094. [PMID: 32739495 DOI: 10.1016/j.cct.2020.106094] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/26/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND/AIMS Despite high mortality of alcohol-associated hepatitis, there has been limited advancement in treatment strategies. Defeat Alcoholic Steatohepatitis (DASH) is a multicenter, randomized, double-blind controlled trial whose primary objective was to evaluate the safety and efficacy of a novel combination of 3 drugs targeting different perturbations in AH. METHODS Severe AH was diagnosed by liver biopsy or clinical and biochemical criteria and model for end stage liver disease (MELD) score ≥ 20 stratified by MELD scores (20-25 and ≥ 26) and randomized to a combination of an interleukin receptor 1 antagonist, Anakinra(100 mg daily for 14 days) to suppress acute inflammation, pentoxifylline (400 mg three times a day for 28 days) to prevent hepatorenal syndrome, and zinc sulfate (220 mg orally once daily for 6 months) or the standard of care therapy including methylprednisolone 32 mg orally once daily for 28 days. The primary efficacy outcome was the unadjusted log-rank test of the Kaplan-Meier survival estimates for the two treatment groups at 180 days. RESULTS Between July 2012 to March 2018, 500 subjects with severe AH were screened of which 104 subjects were enrolled with MELD score of 25.6 ± 3.2 (20.0-35.0) in the investigational arm and 25.8 ± 4.5 (20.0-40.0) in the standard of care arm. Causes of screen failures included not meeting eligibility criteria (n = 347), declining to participate (n = 39), and other reasons (n = 10). CONCLUSIONS Data from the DASH consortium studies will determine if a combination of drugs targeting multiple mechanisms of injury in the severe AH will improve clinical outcomes.
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Affiliation(s)
| | | | | | | | - Gyongyi Szabo
- Harvard Medical School & Beth Israel Deaconess Medical Center, USA
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Sterling SA, Palzes VA, Lu Y, Kline-Simon AH, Parthasarathy S, Ross T, Elson J, Weisner C, Maxim C, Chi FW. Associations Between Medical Conditions and Alcohol Consumption Levels in an Adult Primary Care Population. JAMA Netw Open 2020; 3:e204687. [PMID: 32401315 PMCID: PMC7221504 DOI: 10.1001/jamanetworkopen.2020.4687] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
IMPORTANCE Excessive alcohol consumption is associated with increased incidence of several medical conditions, but few nonveteran, population-based studies have assessed levels of alcohol use across medical conditions. OBJECTIVE To examine associations between medical conditions and alcohol consumption levels in a population-based sample of primary care patients using electronic health record data. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study used separate multinomial logistic regression models to estimate adjusted associations between 26 medical conditions and alcohol consumption levels in a sample of 2 720 231 adult primary care patients screened for unhealthy drinking between January 1, 2014, and December 31, 2017, then only among those reporting alcohol use. The study was conducted at Kaiser Permanente Northern California, a large, integrated health care delivery system that incorporated alcohol screening into its adult primary care workflow. Data were analyzed from June 29, 2018, to February 7, 2020. MAIN OUTCOMES AND MEASURES The main outcome was level of alcohol use, classified as no reported use, low-risk use, exceeding daily limits only, exceeding weekly limits only, or exceeding daily and weekly limits, per National Institute on Alcohol Abuse and Alcoholism guidelines. Other measures included sociodemographic, body mass index, smoking, inpatient and emergency department use, and a dichotomous indicator for the presence of 26 medical conditions in the year prior to the alcohol screening identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) and ICD-10-CM diagnosis codes. RESULTS Among the 2 720 231 included patients, 1 439 361 (52.9%) were female, 1 308 659 (48.1%) were white, and 883 276 (32.5%) were aged 18 to 34 years. Patients with any of the conditions (except injury or poisoning) had lower odds of drinking at low-risk and unhealthy levels relative to no reported use compared with those without the condition. Among 861 427 patients reporting alcohol use, patients with diabetes (odds ratio [OR], 1.11; 95% CI, 1.08-1.15), hypertension (OR, 1.11; 95% CI, 1.09-1.13), chronic obstructive pulmonary disease (COPD; OR, 1.16; 95% CI, 1.10-1.22), or injury or poisoning (OR, 1.06; 95% CI, 1.04-1.07) had higher odds of exceeding daily limits only; those with atrial fibrillation (OR, 1.12; 95% CI, 1.06-1.18), cancer (OR, 1.06; 95% CI, 1.03-1.10), COPD (OR, 1.15; 95% CI, 1.09-1.20), or hypertension (OR, 1.37; 95% CI, 1.34-1.40) had higher odds of exceeding weekly limits only; and those with COPD (OR, 1.15; 95% CI, 1.07-1.23), chronic liver disease (OR, 1.42; 95% CI, 1.32-1.53), or hypertension (OR, 1.48; 95% CI, 1.44-1.52) had higher odds of exceeding both daily and weekly limits. CONCLUSIONS AND RELEVANCE Findings suggest that patients with certain medical conditions are more likely to have elevated levels of alcohol use. Health systems and clinicians may want to consider approaches to help targeted patient subgroups limit unhealthy alcohol use and reduce health risks.
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Affiliation(s)
- Stacy A. Sterling
- Division of Research, Kaiser Permanente Northern California, Oakland
| | - Vanessa A. Palzes
- Division of Research, Kaiser Permanente Northern California, Oakland
| | - Yun Lu
- Division of Research, Kaiser Permanente Northern California, Oakland
| | | | | | - Thekla Ross
- Division of Research, Kaiser Permanente Northern California, Oakland
| | - Joseph Elson
- The Permanente Medical Group, San Francisco, California
| | - Constance Weisner
- Division of Research, Kaiser Permanente Northern California, Oakland
| | - Clara Maxim
- Division of Research, Kaiser Permanente Northern California, Oakland
| | - Felicia W. Chi
- Division of Research, Kaiser Permanente Northern California, Oakland
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Welch N, Dasarathy J, Runkana A, Penumatsa R, Bellar A, Reen J, Rotroff D, McCullough AJ, Dasarathy S. Continued muscle loss increases mortality in cirrhosis: Impact of aetiology of liver disease. Liver Int 2020; 40:1178-1188. [PMID: 31889396 PMCID: PMC7195232 DOI: 10.1111/liv.14358] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 12/19/2019] [Accepted: 12/26/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Sarcopenia or skeletal muscle loss adversely affects outcomes in cirrhosis. The impact of aetiology of liver disease on the severity or the rate of muscle loss is not known. METHODS Consecutive, well-characterized adult patients with cirrhosis due to viral hepatitis (VH), alcoholic liver disease (ALD) or non-alcoholic fatty liver disease (NAFLD) and non-diseased controls with at least two temporally distinct abdominal CT (computed tomography) scans were evaluated. Psoas, paraspinal and abdominal wall muscle areas at the L3 vertebra level were quantified on the CT scans. Standardized rate of change in muscle area was expressed as change in area/100 days. Univariate and multivariable analyses were performed to identify contributors to rate of muscle loss and survival. RESULTS Among 83 cirrhotics (NAFLD n = 26, ALD n = 39, VH n = 18), there were 20 (24.1%) deaths over 62.7 ± 41.3 months. The mean percentage change in psoas area was -0.03 ± 0.05/100d in controls and -3.52 ± 0.45/100d in cirrhosis (P < .001). The mean percentage change in psoas area was -1.72 ± 0.27/100d in NAFLD, -5.28 ± 0.86/100d in ALD and -2.29 ± 0.28/100d in VH. Among cirrhotics, patients with ALD had the lowest initial muscle area and most rapid rate of reduction in muscle area. Aetiology of liver disease, model for end-stage liver disease (MELD) and the rate of loss of muscle area were independent risk factors for survival. CONCLUSIONS Aetiology of liver disease is an independent risk factor for sarcopenia with the greatest rate of muscle loss noted in ALD. Survival in cirrhosis was dependent on initial muscle mass, rate of muscle loss and MELD score.
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Affiliation(s)
- Nicole Welch
- Departments of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio,Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio
| | | | - Ashok Runkana
- Department of Cardiology, West Virginia University Hospitals, Morgantown, West Virginia
| | - Revathi Penumatsa
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio
| | - Annette Bellar
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio
| | - Jaspreet Reen
- Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio
| | - Daniel Rotroff
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio
| | - Arthur J. McCullough
- Departments of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
| | - Srinivasan Dasarathy
- Departments of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio,Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, Ohio
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Skeletal muscle loss phenotype in cirrhosis: A nationwide analysis of hospitalized patients. Clin Nutr 2020; 39:3711-3720. [PMID: 32303380 DOI: 10.1016/j.clnu.2020.03.032] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Revised: 03/09/2020] [Accepted: 03/25/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS There are very limited data on the healthcare burden of muscle loss, the most frequent complication in hospitalized cirrhotics. We determined the healthcare impact of a muscle loss phenotype in hospitalized cirrhotics. METHODS The Nationwide Inpatient Sample (NIS) database (years 2010-2014) was analyzed. Search terms included cirrhosis and its complications, and an expanded definition of a muscle loss phenotype that included all conditions associated with muscle loss. In-hospital mortality, length of stay (LOS), post-discharge disposition, co-morbidities and cost during admission were analyzed. Univariate and multivariate analyses were performed to identify associations between a muscle loss phenotype and outcomes. Impact of muscle loss in cirrhotics was compared to that in a random sample (2%) of general medical inpatients. RESULTS A total of 162,694 hospitalizations for cirrhosis were reported, of which 18,261 (11.2%) included secondary diagnosis codes for a muscle loss phenotype. A diagnosis of muscle loss was associated with a significantly (p < 0.001 for all) higher mortality (19.3% vs 8.2%), LOS (14.2 ± 15.8 vs. 4.6 ± 6.9 days), and median hospital charge per admission ($21,400 vs. $8573) and a lower likelihood of discharge to home (30.1% vs. 60.2%). All evaluated outcomes were more severe in cirrhotics than general medical patients (n = 534,687). Multivariate regression analysis showed that a diagnosis of muscle loss independently increased mortality by 130%, LOS by 80% and direct cost of care by 119% (p < 0.001 for all). Alcohol use, female gender, malignancies and other organ dysfunction were independently associated with muscle loss. CONCLUSIONS Muscle loss contributed to higher mortality, LOS, and direct healthcare costs in hospitalized cirrhotics.
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Bellar A, Welch N, Dasarathy S. Exercise and physical activity in cirrhosis: opportunities or perils. J Appl Physiol (1985) 2020; 128:1547-1567. [PMID: 32240017 DOI: 10.1152/japplphysiol.00798.2019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Reduced exercise capacity and impaired physical performance are observed in nearly all patients with liver cirrhosis. Physical activity and exercise are physiological anabolic stimuli that can reverse dysregulated protein homeostasis or proteostasis and potentially increase muscle mass and contractile function in healthy subjects. Cirrhosis is a state of anabolic resistance, and unlike the beneficial responses to exercise reported in physiological states, there are few systematic studies evaluating the response to exercise in cirrhosis. Hyperammonemia is a mediator of the liver-muscle axis with net skeletal muscle ammonia uptake in cirrhosis causing signaling perturbations, mitochondrial dysfunction with decreased ATP content, modifications of contractile proteins, and impaired ribosomal function, all of which contribute to anabolic resistance in cirrhosis and have the potential to impair the beneficial responses to exercise. English language-publications in peer-reviewed journals that specifically evaluated the impact of exercise in cirrhosis were reviewed. Most studies evaluated responses to endurance exercise, and readouts included peak or maximum oxygen utilization, grip strength, and functional capacity. Endurance exercise for up to 12 wk is clinically tolerated in well-compensated cirrhosis. Data on the safety of resistance exercise are conflicting. Nutritional supplements enhance the benefits of exercise in healthy subjects but have not been evaluated in cirrhosis. Whether the beneficial physiological responses with endurance exercise and increase in muscle mass with resistance exercise that occur in healthy subjects also occur in cirrhotics is not known. Specific organ-system responses, changes in body composition, or improved long-term clinical outcomes with exercise in cirrhosis need evaluation.
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Affiliation(s)
- Annette Bellar
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio
| | - Nicole Welch
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Department of Gastroenterology, Hepatology Cleveland Clinic, Cleveland, Ohio
| | - Srinivasan Dasarathy
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.,Department of Gastroenterology, Hepatology Cleveland Clinic, Cleveland, Ohio
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Karsdal MA, Daniels SJ, Holm Nielsen S, Bager C, Rasmussen DGK, Loomba R, Surabattula R, Villesen IF, Luo Y, Shevell D, Gudmann NS, Nielsen MJ, George J, Christian R, Leeming DJ, Schuppan D. Collagen biology and non-invasive biomarkers of liver fibrosis. Liver Int 2020; 40:736-750. [PMID: 31997561 DOI: 10.1111/liv.14390] [Citation(s) in RCA: 127] [Impact Index Per Article: 25.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Revised: 12/19/2019] [Accepted: 01/18/2020] [Indexed: 12/12/2022]
Abstract
There is an unmet need for high-quality liquid biomarkers that can safely and reproducibly predict the stage of fibrosis and the outcomes of chronic liver disease (CLD). The requirement for such markers has intensified because of the high global prevalence of diseases such as non-alcoholic fatty liver disease (NAFLD). In particular, there is a need for diagnostic and prognostic tools, as well as predictive biomarkers that reflect the efficacy of interventions, as described by the BEST criteria (Biomarkers, EndpointS, and other Tools Resource). This review covers the various liver collagens, their functional role in tissue homeostasis and delineates the common nomenclature for biomarkers based on BEST criteria. It addresses the common confounders affecting serological biomarkers, and describes defined collagen epitope biomarkers that originate from the dynamic processes of extracellular matrix (ECM) remodelling during liver injury.
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Affiliation(s)
- Morten A Karsdal
- Nordic Bioscience, Fibrosis Biomarkers and Research, Herlev, Denmark
| | - Samuel J Daniels
- Nordic Bioscience, Fibrosis Biomarkers and Research, Herlev, Denmark
| | | | - Cecilie Bager
- Nordic Bioscience, Fibrosis Biomarkers and Research, Herlev, Denmark
| | | | - Rohit Loomba
- Division of Gastroenterology and Division of Epidemiology, NAFLD Research Center, University of California, San Diego, CA, USA
| | - Rambabu Surabattula
- Division of Gastroenterology and Division of Epidemiology, NAFLD Research Center, University of California, San Diego, CA, USA
| | - Ida Falk Villesen
- Nordic Bioscience, Fibrosis Biomarkers and Research, Herlev, Denmark.,University of Copenhagen, Copenhagen, Denmark
| | - Yi Luo
- Innovative Medicine, Bristol Myers-Squibb, Princeton, NJ, USA
| | - Diane Shevell
- Innovative Medicine, Bristol Myers-Squibb, Princeton, NJ, USA
| | - Natasja S Gudmann
- Nordic Bioscience, Fibrosis Biomarkers and Research, Herlev, Denmark
| | - Mette J Nielsen
- Nordic Bioscience, Fibrosis Biomarkers and Research, Herlev, Denmark
| | - Jacob George
- Storr Liver Centre, The Westmead Institute for Medical Research, University of Sydney and Westmead Hospital, Westmead, NSW, Australia
| | - Rose Christian
- Innovative Medicine, Bristol Myers-Squibb, Princeton, NJ, USA
| | - Diana J Leeming
- Nordic Bioscience, Fibrosis Biomarkers and Research, Herlev, Denmark
| | - Detlef Schuppan
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.,Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany
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Neuman MG, Seitz HK, French SW, Malnick S, Tsukamoto H, Cohen LB, Hoffman P, Tabakoff B, Fasullo M, Nagy LE, Tuma PL, Schnabl B, Mueller S, Groebner JL, Barbara FA, Yue J, Nikko A, Alejandro M, Brittany T, Edward V, Harrall K, Saba L, Mihai O. Alcoholic-Hepatitis, Links to Brain and Microbiome: Mechanisms, Clinical and Experimental Research. Biomedicines 2020; 8:E63. [PMID: 32197424 PMCID: PMC7148515 DOI: 10.3390/biomedicines8030063] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/02/2020] [Accepted: 03/09/2020] [Indexed: 02/07/2023] Open
Abstract
The following review article presents clinical and experimental features of alcohol-induced liver disease (ALD). Basic aspects of alcohol metabolism leading to the development of liver hepatotoxicity are discussed. ALD includes fatty liver, acute alcoholic hepatitis with or without liver failure, alcoholic steatohepatitis (ASH) leading to fibrosis and cirrhosis, and hepatocellular cancer (HCC). ALD is fully attributable to alcohol consumption. However, only 10-20% of heavy drinkers (persons consuming more than 40 g of ethanol/day) develop clinical ALD. Moreover, there is a link between behaviour and environmental factors that determine the amount of alcohol misuse and their liver disease. The range of clinical presentation varies from reversible alcoholic hepatic steatosis to cirrhosis, hepatic failure, and hepatocellular carcinoma. We aimed to (1) describe the clinico-pathology of ALD, (2) examine the role of immune responses in the development of alcoholic hepatitis (ASH), (3) propose diagnostic markers of ASH, (4) analyze the experimental models of ALD, (5) study the role of alcohol in changing the microbiota, and (6) articulate how findings in the liver and/or intestine influence the brain (and/or vice versa) on ASH; (7) identify pathways in alcohol-induced organ damage and (8) to target new innovative experimental concepts modeling the experimental approaches. The present review includes evidence recognizing the key toxic role of alcohol in ALD severity. Cytochrome p450 CYP2E1 activation may change the severity of ASH. The microbiota is a key element in immune responses, being an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. Alcohol consumption changes the intestinal microbiota and influences liver steatosis and liver inflammation. Knowing how to exploit the microbiome to modulate the immune system might lead to a new form of personalized medicine in ALF and ASH.
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Affiliation(s)
- Manuela G. Neuman
- In Vitro Drug Safety and Biotechnology, Toronto, ON M5G 1L5, Canada;
- Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L5, Canada
| | - Helmut Karl Seitz
- Department of Medicine, Centre of Alcohol Research, University of Heidelberg, Salem Medical Centre, 337374 Heidelberg, Germany; (H.K.S.); (S.M.)
| | - Samuel W. French
- Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA; (S.W.F.); (F.A.B.); (J.Y.); (A.N.); (M.A.); (T.B.); (V.E.)
| | - Stephen Malnick
- Department Internal Medicine C, Kaplan Medical Centre and Hebrew University of Jerusalem, Rehovot 76100, Israel;
| | - Heidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis, Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90089-5311, USA;
- Department of Veterans; Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA
| | - Lawrence B. Cohen
- Division of Gastroenterology, Sunnybrook Health Sciences Centre, Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON M4N 3M5, Canada;
| | - Paula Hoffman
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045-0511, USA; (P.H.); (B.T.); (K.H.); (L.S.)
| | - Boris Tabakoff
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045-0511, USA; (P.H.); (B.T.); (K.H.); (L.S.)
| | - Michael Fasullo
- College of Nanoscale Science and Engineering, SUNY Polytechnic Institute, Albany, NY 12205, USA;
| | - Laura E. Nagy
- Departments of Pathobiology and Gastroenterology, Center for Liver Disease Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA;
| | - Pamela L. Tuma
- Department of Biology, The Catholic University of America, Washington, DC 20064, USA; (P.L.T.); (J.L.G.)
| | - Bernd Schnabl
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA;
| | - Sebastian Mueller
- Department of Medicine, Centre of Alcohol Research, University of Heidelberg, Salem Medical Centre, 337374 Heidelberg, Germany; (H.K.S.); (S.M.)
| | - Jennifer L. Groebner
- Department of Biology, The Catholic University of America, Washington, DC 20064, USA; (P.L.T.); (J.L.G.)
| | - French A. Barbara
- Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA; (S.W.F.); (F.A.B.); (J.Y.); (A.N.); (M.A.); (T.B.); (V.E.)
| | - Jia Yue
- Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA; (S.W.F.); (F.A.B.); (J.Y.); (A.N.); (M.A.); (T.B.); (V.E.)
| | - Afifiyan Nikko
- Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA; (S.W.F.); (F.A.B.); (J.Y.); (A.N.); (M.A.); (T.B.); (V.E.)
| | - Mendoza Alejandro
- Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA; (S.W.F.); (F.A.B.); (J.Y.); (A.N.); (M.A.); (T.B.); (V.E.)
| | - Tillman Brittany
- Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA; (S.W.F.); (F.A.B.); (J.Y.); (A.N.); (M.A.); (T.B.); (V.E.)
| | - Vitocruz Edward
- Department of Pathology, Harbor-UCLA Medical Center and Los Angeles BioMedical Institute, Torrance, CA Harbor-UCLA Medical Center, Torrance, CA 90509, USA; (S.W.F.); (F.A.B.); (J.Y.); (A.N.); (M.A.); (T.B.); (V.E.)
| | - Kylie Harrall
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045-0511, USA; (P.H.); (B.T.); (K.H.); (L.S.)
| | - Laura Saba
- Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045-0511, USA; (P.H.); (B.T.); (K.H.); (L.S.)
| | - Opris Mihai
- In Vitro Drug Safety and Biotechnology, Toronto, ON M5G 1L5, Canada;
- Department Family Medicine Clinic CAR, 010164 Bucharest, Romania
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Crabb DW, Im GY, Szabo G, Mellinger JL, Lucey MR. Diagnosis and Treatment of Alcohol-Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases. Hepatology 2020; 71:306-333. [PMID: 31314133 DOI: 10.1002/hep.30866] [Citation(s) in RCA: 537] [Impact Index Per Article: 107.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 05/31/2019] [Indexed: 12/12/2022]
Affiliation(s)
- David W Crabb
- Indiana University School of Medicine, Indianapolis, IN
| | - Gene Y Im
- Icahn School of Medicine at Mount Sinai, New York, NY
| | - Gyongyi Szabo
- University of Massachusetts Medical School, Worcester, MA
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Winder GS, Fernandez AC, Klevering K, Mellinger JL. Confronting the Crisis of Comorbid Alcohol Use Disorder and Alcohol-Related Liver Disease With a Novel Multidisciplinary Clinic. PSYCHOSOMATICS 2019; 61:238-253. [PMID: 32033835 DOI: 10.1016/j.psym.2019.12.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 12/03/2019] [Accepted: 12/05/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Alcohol-related liver disease (ALD) is prevalent and deadly and increasingly affects younger people and women. No single discipline is adequately equipped to manage its biopsychosocial complexity. OBJECTIVES Depict the scope of the ALD problem, provide a narrative review of other integrated care models, share our experience forming and maintaining a multidisciplinary ALD clinic for over a year, and provide recommendations for replication elsewhere. METHODS Critical evaluation of clinic implementation and its first year of operation. RESULTS The clinical rationale for multidisciplinary ALD treatment is clear and supported by the literature. Such models are feasible although surprisingly rare and vulnerable to various surmountable challenges. CONCLUSIONS Successful ALD clinics must be built by teams with solid personal and professional relationships, supported by institutional leadership, and must use a new kind of multidisciplinary paradigm and training. Consultation-liaison psychiatry is uniquely positioned to lead future efforts in the care and study of ALD.
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Affiliation(s)
- Gerald Scott Winder
- Department of Psychiatry, University of Michigan, Ann Arbor, MI; Department of Surgery, University of Michigan, Ann Arbor, MI.
| | | | | | - Jessica L Mellinger
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI
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Godfrey EL, Malik TH, Lai JC, Mindikoglu AL, Galván NTN, Cotton RT, O'Mahony CA, Goss JA, Rana A. The decreasing predictive power of MELD in an era of changing etiology of liver disease. Am J Transplant 2019; 19:3299-3307. [PMID: 31394020 DOI: 10.1111/ajt.15559] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 06/24/2019] [Accepted: 07/19/2019] [Indexed: 01/25/2023]
Abstract
The field of liver transplantation has shifted considerably in the MELD era, including changing allocation, immunosuppression, and liver failure etiologies, as well as better supportive therapies. Our aim was to evaluate the predictive accuracy of the MELD score over time. The United Network for Organ Sharing provided de-identified data on 120 156 patients listed for liver transplant from 2002-2016. The ability of the MELD score to predict 90-day mortality was evaluated by a concordance (C-) statistic and corroborated with competing risk analysis. The MELD score's concordance with 90-day mortality has downtrended from 0.80 in 2003 to 0.70 in 2015. While lab MELD scores at listing and transplant climbed in that interval, score at waitlist death remained steady near 35. Listing age increased from 50 to 54 years. HCV-positive status at listing dropped from 33 to 17%. The concordance of MELD and mortality does not differ with age (>60 = 0.73, <60 = 0.74), but is lower in diseases that are increasing most rapidly-alcoholic liver disease and non-alcoholic fatty liver disease-and higher in those that are declining, particularly in HCV-positive patients (HCV positive = 0.77; negative = 0.73). While MELD still predicts mortality, its accuracy has decreased; changing etiology of disease may contribute.
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Affiliation(s)
- Elizabeth L Godfrey
- Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
| | - Tahir H Malik
- Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
| | - Jennifer C Lai
- Department of Medicine, University of California, San Francisco, San Francisco, California
| | - Ayse L Mindikoglu
- Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.,Margaret M. and Albert B. Alkek Department of Medicine, Section of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas
| | - N Thao N Galván
- Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
| | - Ronald T Cotton
- Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
| | - Christine A O'Mahony
- Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
| | - John A Goss
- Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
| | - Abbas Rana
- Division of Abdominal Transplantation, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas
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Abstract
Patients with portal hypertension will increasingly present for nontransplant surgery because of the increasing incidence of, and improving long-term survival for, chronic liver disease. Such patients have increased perioperative morbidity and mortality caused by the systemic pathophysiology of liver disease. Preoperative assessment should identify modifiable causes of liver injury and distinguish between compensated and decompensated cirrhosis. Risk stratification, which is crucial to preparing patients and their families for surgery, relies on scores such as Child-Turcotte-Pugh and Model for End-stage Liver Disease to translate disease severity into quantified outcomes predictions. Risk factors for postoperative complications should also be recognized.
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Affiliation(s)
- Melissa Wong
- Division of Transplant Surgery, Department of Surgery, Medical College of Wisconsin, Transplant Center, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
| | - Ronald W Busuttil
- Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California at Los Angeles, The Dumont-UCLA Transplant Center, 757 Westwood Blvd, Suite 8236, Los Angeles, CA 90095, USA.
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Giard JM, Dodge JL, Terrault N. Superior Wait-List Outcomes in Patients with Alcohol-Associated Liver Disease Compared With Other Indications for Liver Transplantation. Liver Transpl 2019; 25:1310-1320. [PMID: 31063642 PMCID: PMC8544021 DOI: 10.1002/lt.25485] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 04/17/2019] [Indexed: 01/18/2023]
Abstract
Alcohol-associated liver disease (ALD) is the most common indication for liver transplantation (LT) in the United States and Europe. A 6-month alcohol abstinence period has been required by many transplant programs prior to listing, which may influence wait-list (WL) outcomes. Therefore, we examined WL events in patients with ALD versus non-ALD with a special interest in whether these outcomes differed by sex. All US adults listed for LT from January 2002 to December 2016 were eligible except status 1 patients, Model for End-Stage Liver Disease exceptions, retransplants and those with acute alcoholic hepatitis. The outcomes of interest were cumulative WL death or being too sick and WL removal for improvement within 2 years of listing. Competing risk regression models were used to evaluate recipient factors associated with the outcomes. Among the 83,348 eligible WL patients, 23% had ALD. Unadjusted cumulative WL removal within 2 years was 19.0% for ALD versus 21.1% for non-ALD (P < 0.001). In fully adjusted models, ALD was associated with a significantly lower risk of WL removal for death or being too sick (subhazard ratio [SHR], 0.84; 95% confidence interval [CI], 0.81-0.87; P < 0.001) and a higher risk of removal for improvement (SHR, 2.91; 95% CI, 2.35-3.61; P < 0.001) versus non-ALD patients. After adjusting for potential confounders, women with ALD had a higher risk of removal for death or being too sick (SHR, 1.09; 95% CI, 1.00-1.08; P < 0.001) and a higher chance for improvement (SHR, 2.91; 95% CI, 2.35-3.61; P < 0.001) than men with ALD. In conclusion, WL candidates with ALD have more favorable WL outcomes than non-ALD patients with a 16% lower risk of removal for deterioration and 191% higher risk of removal for improvement. This result likely reflects the benefits of alcohol abstinence, but it suggests that listing criteria for ALD may be too restrictive, with patients who might derive benefit from LT not being listed.
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Affiliation(s)
- Jeanne-Marie Giard
- University of California San Francisco, San Francisco, CA, United States.,Université de Montréal, Montréal, Québec, Canada
| | - Jennifer L. Dodge
- University of California San Francisco, San Francisco, CA, United States
| | - Norah Terrault
- University of California San Francisco, San Francisco, CA, United States
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Bellos DA, Sharma D, McMullen MR, Wat J, Saikia P, de la Motte CA, Nagy LE. Specifically Sized Hyaluronan (35 kDa) Prevents Ethanol-Induced Disruption of Epithelial Tight Junctions Through a layilin-Dependent Mechanism in Caco-2 Cells. Alcohol Clin Exp Res 2019; 43:1848-1858. [PMID: 31237689 DOI: 10.1111/acer.14140] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 06/20/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Specific-sized species of the carbohydrate hyaluronan elicit a variety of cellular responses mediating tissue integrity and repair, as well as regulating inflammatory responses. Orally provided hyaluronan with an average molecular weight of 35 kDa (HA35) protects mice from short-term ethanol (EtOH)-induced liver injury. This protection was associated with maintenance of the colocalization of zonula occludens-1 (ZO-1) and occludin at tight junctions in the proximal colon. However, it is not known whether HA35 also protects other regions of the intestine or whether protection is due to a direct and/or indirect interaction of HA35 with the intestinal epithelium. METHODS Female C57BL/6J mice were fed an EtOH containing diet or pair-fed control diet (4 days) and treated with or without HA35 via daily gavage during the last 3 days of EtOH feeding. Intestinal morphology and tight junction integrity were assessed. Differentiated Caco-2 cells were transfected or not with scrambled siRNA or siRNA targeting layilin, a hyaluronan receptor. Caco-2 cells were treated with or without HA35 prior to challenge with EtOH. Localization of tight junction proteins, fluorescein isothiocyanate (FITC)-dextran permeability, and transepithelial electrical resistance (TEER) were evaluated. RESULTS While short-term EtOH did not result in any apparent changes in the gross morphology of the intestine, colocalization of ZO-1 and occludin at tight junctions was decreased in the proximal and distal colon. HA35 prevented these effects of EtOH. In differentiated Caco-2 cells, EtOH decreased the localization of ZO-1 and occludin at tight junctions and increased permeability of FITC-dextran. At higher concentrations, EtOH also decreased TEER. Pretreatment with HA35 prevented these changes. When the hyaluronan receptor layilin was knocked down in Caco-2 cells, HA35 no longer protected cells from EtOH-induced loss of tight junctions. CONCLUSIONS Taken together, these data indicate that HA35 interacts with layilin on intestinal epithelial cells and maintains intestinal tight junction integrity during short-term EtOH exposure.
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Affiliation(s)
- Damien A Bellos
- Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Dhara Sharma
- Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio
| | - Megan R McMullen
- Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio
| | - Jeanette Wat
- Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.,Department of Pathology, Case Western Reserve University, Cleveland, Ohio
| | - Paramananda Saikia
- Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Carol A de la Motte
- Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Laura E Nagy
- Department of Inflammation and Immunity, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio.,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio.,Department of Gastroenterology, Center for Liver Disease Research, Cleveland Clinic, Cleveland, Ohio
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Orman ES, Roberts A, Ghabril M, Nephew L, Desai A, Patidar K, Chalasani N. Trends in Characteristics, Mortality, and Other Outcomes of Patients With Newly Diagnosed Cirrhosis. JAMA Netw Open 2019; 2:e196412. [PMID: 31251379 PMCID: PMC6604080 DOI: 10.1001/jamanetworkopen.2019.6412] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
IMPORTANCE Changes in the characteristics of patients with cirrhosis are likely to affect future outcomes and are important to understand in planning for the care of this population. OBJECTIVE To identify changes in demographic and clinical characteristics and outcomes in patients with newly diagnosed cirrhosis. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study of patients with a new diagnosis of cirrhosis was conducted using the Indiana Network for Patient Care, a large statewide regional health information exchange, between 2004 and 2014. Patients with at least 1 year of continuous follow-up before the cirrhosis diagnosis were followed up through August 1, 2015. The analysis was conducted from December 2018 to January 2019. EXPOSURES Age, cause of cirrhosis, and year of diagnosis. MAIN OUTCOMES AND MEASURES Overall rates for mortality, liver transplant, hepatocellular carcinoma, and hepatic decompensation (composite of ascites, hepatic encephalopathy, or variceal bleeding). RESULTS A total of 9261 patients with newly diagnosed cirrhosis were identified (mean [SD] age, 57.9 [12.6] years; 5109 [55.2%] male). A 69% increase in new diagnoses occurred over the course of the study period (620 in 2004 vs 1045 in 2014). The proportion of those younger than 40 years increased by 0.20% per year (95% CI, 0.04% to 0.36%; P for trend = .02), and the proportion of those aged 65 years and older increased by 0.81% per year (95% CI, 0.51% to 1.11%; P for trend < .001). The proportion of patients with alcoholic cirrhosis increased by 0.80% per year (95% CI, 0.49% to 1.12%), and the proportion with nonalcoholic steatohepatitis increased by 0.59% per year (95% CI, 0.30% to 0.87%), whereas the proportion with viral hepatitis decreased by 1.36% per year (95% CI, -1.68% to -1.03%) (P < .001 for all). In patients younger than 40 years, 40 to 64 years, and 65 years and older, mortality rates were 6.4 (95% CI, 5.4 to 7.6), 9.9 (95% CI, 9.5 to 10.4), and 16.2 (95% CI, 15.2 to 17.2) per 100 person-years, respectively (P < .001). Mortality rates decreased during the study period (11.9 [95% CI, 10.7-13.1] per 100 person-years in 2004 vs 10.0 [95% CI, 8.1-12.2] per 100 person-years in 2014; annual adjusted hazard ratio, 0.87 [95% CI, 0.86 to 0.88]) and were lower in those with alcoholic cirrhosis compared with patients with viral hepatitis (adjusted hazard ratio, 0.89 [95% CI, 0.80 to 0.98]). Rates of hepatocellular carcinoma were low in patients younger than 40 years (0.5 [95% CI, 0.2 to 0.9] per 100 person-years). Liver transplant rates were low throughout the study period (0.3 [95% CI, 0.3-0.4] per 100 person-years). In patients with compensated cirrhosis, rates of hepatic decompensation were lower in patients younger than 40 years (adjusted subhazard ratio 0.78; 95% CI, 0.62 to 0.99) and in patients with nonalcoholic steatohepatitis (adjusted subhazard ratio, 0.51; 95% CI, 0.43 to 0.60). CONCLUSIONS AND RELEVANCE The population of patients with newly diagnosed cirrhosis in Indiana has experienced changes in the age distribution and cause of cirrhosis, with decreasing mortality rates. These findings support investment in the prevention and treatment of alcoholic liver disease and nonalcoholic steatohepatitis, particularly in younger and older patients. Additional study is needed to identify the reasons for decreasing mortality rates.
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Affiliation(s)
- Eric S. Orman
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis
| | - Anna Roberts
- Regenstrief Institute, Inc, Indianapolis, Indiana
| | - Marwan Ghabril
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis
| | - Lauren Nephew
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis
| | - Archita Desai
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis
| | - Kavish Patidar
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis
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Akinyemiju T, Abera S, Ahmed M, Alam N, Alemayohu MA, Allen C, Al-Raddadi R, Alvis-Guzman N, Amoako Y, Artaman A, Ayele TA, Barac A, Bensenor I, Berhane A, Bhutta Z, Castillo-Rivas J, Chitheer A, Choi JY, Cowie B, Dandona L, Dandona R, Dey S, Dicker D, Phuc H, Ekwueme DU, Zaki MES, Fischer F, Fürst T, Hancock J, Hay SI, Hotez P, Jee SH, Kasaeian A, Khader Y, Khang YH, Kumar A, Kutz M, Larson H, Lopez A, Lunevicius R, Malekzadeh R, McAlinden C, Meier T, Mendoza W, Mokdad A, Moradi-Lakeh M, Nagel G, Nguyen Q, Nguyen G, Ogbo F, Patton G, Pereira DM, Pourmalek F, Qorbani M, Radfar A, Roshandel G, Salomon JA, Sanabria J, Sartorius B, Satpathy M, Sawhney M, Sepanlou S, Shackelford K, Shore H, Sun J, Mengistu DT, Topór-Mądry R, Tran B, Ukwaja KN, Vlassov V, Vollset SE, Vos T, Wakayo T, Weiderpass E, Werdecker A, Yonemoto N, Younis M, Yu C, Zaidi Z, Zhu L, Murray CJL, Naghavi M, Fitzmaurice C. The Burden of Primary Liver Cancer and Underlying Etiologies From 1990 to 2015 at the Global, Regional, and National Level: Results From the Global Burden of Disease Study 2015. JAMA Oncol 2019; 3:1683-1691. [PMID: 28983565 PMCID: PMC5824275 DOI: 10.1001/jamaoncol.2017.3055] [Citation(s) in RCA: 1431] [Impact Index Per Article: 238.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Importance Objective Design, Settings, and Participants Main Outcomes and Measures Results Conclusions and Relevance Question Findings Meaning
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Affiliation(s)
| | - Tomi Akinyemiju
- School of Public Health, Birmingham, University of Alabama at Birmingham
| | - Semaw Abera
- Mekelle University, School of Public Health, College of Health Sciences, Mekelle, Tigray, Ethiopia,University of Hohenheim, Institute of Biological Chemistry and Nutrition, Stuttgart, Baden Württemberg, Germany
| | - Muktar Ahmed
- Jimma University Institute of Health, Department of Epidemiology, Jimma, Oromiya, Ethiopia
| | - Noore Alam
- Department of Health, Queensland Government, Herston, QLD, Australia,University of Queensland, School of Public Health, Herston, QLD, Australia
| | | | - Christine Allen
- University of Washington, Institute for Health Metrics and Evaluation, Seattle
| | | | - Nelson Alvis-Guzman
- Universidad de Cartagena, Grupo de Investigación en Economía de la Salud, Cartagena, Bolivar, Colombia
| | - Yaw Amoako
- Komfo Anokye Teaching Hospital, Department of Medicine, Bantama, Ghana
| | - Al Artaman
- University of Manitoba, Community Health Sciences, Winnipeg, Manitoba, Canada
| | | | - Aleksandra Barac
- Clinical Center of Serbia, Clinic for Infectious and Tropic Diseases, Belgrade, Serbia
| | - Isabela Bensenor
- Hospital Universitário, University of São Paulo Division of Internal Medicine, São Paulo, São Paulo, Brazil
| | - Adugnaw Berhane
- Debre Berhan University, College of Health Sciences, Debre Berhan, Amhara, Ethiopia
| | - Zulfiqar Bhutta
- Aga Khan University, Centre of Excellence in Women & Child, Karachi, Sindh, Pakistan,The Hospital for Sick Children, Centre for Global Child Health, Toronto, Ontario, Canada
| | - Jacqueline Castillo-Rivas
- Caja Costarricense de Seguro Social, Dirección Actuarial y Economica, San Jose, San Jose, Costa Rica
| | | | - Jee-Young Choi
- Seoul National University, College of Medicine Medical Library, Seoul, South Korea
| | - Benjamin Cowie
- Doherty Institute, WHO Collaborating Centre for Viral Hepatitis, Melbourne, Victoria, Australia
| | - Lalit Dandona
- University of Washington, Institute for Health Metrics and Evaluation, Seattle,Public Health Foundation of India, Research, Gurgaon, NCR, India
| | - Rakhi Dandona
- University of Washington, Institute for Health Metrics and Evaluation, Seattle,Public Health Foundation of India, Research, Gurgaon, NCR, India
| | - Subhojit Dey
- Indian Institute of Public Health-Delhi, Environmental and Occupational Health, Gurgaon, Haryana, India
| | - Daniel Dicker
- University of Washington, Institute for Health Metrics and Evaluation, Seattle
| | - Huyen Phuc
- Duy Tan University, Institute for Global Health Innovations, Da Nang, Vietnam
| | - Donatus U. Ekwueme
- Division of Cancer Prevention and Control, Centers for Disease Control and Prevention, Atlanta, Georgia
| | | | - Florian Fischer
- Bielefeld University, School of Public Health, Bielefeld, Germany
| | - Thomas Fürst
- Swiss Tropical and Public Health Institute, Epidemiology and Public Health, Basel, Switzerland,University of Basel, Switzerland,Imperial College London, School of Public Health, London, England
| | - Jamie Hancock
- University of Washington, Institute for Health Metrics and Evaluation, Seattle
| | - Simon I. Hay
- University of Washington, Institute for Health Metrics and Evaluation, Seattle
| | - Peter Hotez
- Baylor College of Medicine, National School of Tropical Medicine, Houston, Texas,Sabin Vaccine Institute & Texas Children's Hospital Center for Vaccine Development, Houston
| | - Sun Ha Jee
- Graduate School of Public Health, Yonsei University, Epidemiology and Health Promotion, Seoul, South Korea
| | - Amir Kasaeian
- Tehran University of Medical Sciences, Hematology-Oncology and Stem Cell Transplantation Research Center, Tehran, Tehran, Iran
| | - Yousef Khader
- Jordan University of Science and Technology, Public Health, Irbid, Irbid, Jordan
| | - Young-Ho Khang
- Seoul National University College of Medicine, Institute of Health Policy and Management, Seoul, Seoul Metropolitan City, South Korea
| | - Anil Kumar
- Public Health Foundation of India Research, Gurgaon (NCR), Haryana, India
| | - Michael Kutz
- University of Washington, Institute for Health Metrics and Evaluation, Seattle
| | - Heidi Larson
- Department Infectious Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, England
| | - Alan Lopez
- University of Washington, Institute for Health Metrics and Evaluation, Seattle,University of Melbourne, Melbourne School of Population and Global Health, Melbourne, VIC, Australia
| | - Raimundas Lunevicius
- Aintree University Hospital NHS Foundation Trust, General Surgery Department, Liverpool, England,School of Medicine, University of Liverpool, Liverpool, England
| | - Reza Malekzadeh
- Tehran University of Medical Sciences, Digestive Diseases Research Institute, Tehran, Tehran, Iran
| | - Colm McAlinden
- University Hospitals Bristol, Department of Medicine, Bristol, England
| | - Toni Meier
- Martin Luther University Halle-Wittenberg, Institute for Agricultural and Nutritional Sciences, Halle (Saale), Germany
| | | | - Ali Mokdad
- University of Washington, Institute for Health Metrics and Evaluation, Seattle
| | - Maziar Moradi-Lakeh
- Iran University of Medical Sciences, Gastrointestinal and Liver Disease Research Center, Tehran, Tehran, Iran,Iran University of Medical Sciences, Preventive Medicine and Public Health Research Center, Tehran, Tehran, Iran
| | - Gabriele Nagel
- Ulm University, Institute of Epidemiology and Medical Biometry, Ulm, Germany
| | - Quyen Nguyen
- Duy Tan University, Institute for Global Health Innovations, Da Nang, Vietnam
| | - Grant Nguyen
- University of Washington, Institute for Health Metrics and Evaluation, Seattle
| | - Felix Ogbo
- Western Sydney University, Centre for Health Research, School of Medicine, Penrith, NSW, Australia,Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia
| | - George Patton
- University of Melbourne, Paediatrics, Melbourne, Victoria, Australia
| | - David M. Pereira
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Farshad Pourmalek
- Department of Urology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Mostafa Qorbani
- Alborz University of Medical Sciences, Noncommunicable Diseases Research Center, Karaj, Alborz, Iran
| | - Amir Radfar
- A. T. Still University, College of Graduate Health Studies, Mesa, Arizona
| | - Gholamreza Roshandel
- Golestan University of Medical Sciences, Golestan Research Center of Gastroenterology and Hepatology, Gorgan, Iran
| | - Joshua A Salomon
- Harvard T.H. Chan School of Public Health, Department of Global Health and Population, Boston, Massachusetts
| | - Juan Sanabria
- Marshall University School of Medicine, Surgery, Huntington, West Virginia,Case Western Reserve University, Nutrition and Preventive Medicine, Ohio
| | - Benn Sartorius
- University of KwaZulu-Natal, Public Health Medicine, Durban, KwaZulu-Natal, South Africa
| | - Maheswar Satpathy
- Utkal University, Centre for Advanced Study in Psychology, Bhubaneswar, Odisha, India,AIIMS New Delhi, JPN Apex Trauma Centre, New Delhi, Delhi, India
| | - Monika Sawhney
- Marshall University Public Health, Huntington, West Virginia
| | - Sadaf Sepanlou
- Tehran University of Medical Sciences, Digestive Diseases Research Institute, Tehran, Tehran, Iran
| | - Katya Shackelford
- University of Washington, Institute for Health Metrics and Evaluation, Seattle
| | - Hirbo Shore
- Haramaya University School of Public Health, Harari, Harari, Ethiopia
| | - Jiandong Sun
- Queensland University of Technology, School of Public Health and Social Work, Brisbane, Queensland, Australia
| | | | - Roman Topór-Mądry
- Faculty of Health Sciences Jagiellonian University Medical College, Institute of Public Health, Kraków, Poland,Faculty of Health Sciences Wroclaw Medical University, Wroclaw, Poland
| | - Bach Tran
- Hanoi Medical University, Institute for Preventive Medicine and Public Health, Hanoi, Vietnam,Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland
| | | | - Vasiliy Vlassov
- Department of Health Care Administration and Economy, National Research University Higher School of Economics, Moscow, Russia
| | - Stein Emil Vollset
- Norwegian Institute of Public Health, Centre for Disease Burden, Bergen, Norway,University of Bergen, Department of Global Public Health and Primary Care, Bergen, Norway
| | - Theo Vos
- University of Washington, Institute for Health Metrics and Evaluation, Seattle
| | - Tolassa Wakayo
- Jimma University, Population and Family Health, Oromia, Ethiopia
| | - Elisabete Weiderpass
- Cancer Registry of Norway, Institute of Population Based Cancer Research, Oslo, Norway,University of Tromsø, The Arctic University of Norway, Department of Community Medicine, Faculty of Health Sciences, Tromsø, Norway,Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Andrea Werdecker
- Federal Institute for Population Research, Competence Center Mortality-Follow-Up of the National Cohort, Wiesbaden, Hesse, Germany
| | - Naohiro Yonemoto
- Kyoto University, School of Public Health Biostatistics, Sakyo, Kyoto, Japan
| | - Mustafa Younis
- Jackson State University, Health Policy & Management, Jackson, Mississippi,Harvard Asia Aging Center, Harvard Medical School, Boston, Massachuetts
| | - Chuanhua Yu
- Department of Epidemiology and Biostatistics, Wuhan University, Wuhan, Hubei Province, China
| | - Zoubida Zaidi
- Department of Epidemiology, University Hospital of Setif, Setif, Algeria,University Ferhat Abbas, Faculty of Medicine, Setif, Algeria
| | - Liguo Zhu
- Jiangsu Provincial Center for Disease Control and Prevention, Major Project Execution Office, Nanjing, Jiangsu, China
| | | | - Mohsen Naghavi
- University of Washington, Institute for Health Metrics and Evaluation, Seattle
| | - Christina Fitzmaurice
- University of Washington, Institute for Health Metrics and Evaluation, Seattle,Division of Hematology, Department of Medicine, University of Washington, Seattle
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Sanz-Garcia C, Poulsen KL, Bellos D, Wang H, McMullen MR, Li X, Chattopadhyay S, Sen G, Nagy LE. The non-transcriptional activity of IRF3 modulates hepatic immune cell populations in acute-on-chronic ethanol administration in mice. J Hepatol 2019; 70:974-984. [PMID: 30710579 PMCID: PMC6462245 DOI: 10.1016/j.jhep.2019.01.021] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 01/10/2019] [Accepted: 01/16/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Interferon regulatory factor 3 (IRF3) is a transcription factor mediating antiviral responses, yet recent evidence indicates that IRF3 also has critical non-transcriptional functions, including activating RIG-I-like receptors-induced IRF-3-mediated pathway of apoptosis (RIPA) and restricting activity of NF-κB. Using a novel murine model expressing only non-transcriptional IRF3 activity (Irf3S1/S1), we tested the hypothesis that non-transcriptional functions of IRF3 modulate innate immune responses in the Gao-binge (acute-on-chronic) model of alcohol-related liver disease. METHODS IRF3 and IRF3-mediated signals were analysed in liver samples from 5 patients transplanted for alcoholic hepatitis and 5 healthy controls. C57BL/6, Irf3-/- and Irf3S1/S1 mice were exposed to Gao-binge ethanol-induced liver injury. IRF3-mediated RIPA was investigated in cultured macrophages. RESULTS Phospho-IRF3 and IRF3-mediated signals were elevated in livers of patients with alcoholic hepatitis. In C57BL/6 mice, Gao-binge ethanol exposure activated IRF3 signaling and resulted in hepatocellular injury. Indicators of liver injury were differentially impacted by Irf3 genotype. Irf3-/-, but not Irf3S1/S1, mice were protected from steatosis, elevated alanine/aspartate aminotransferase levels and inflammatory cytokine expression. In contrast, neutrophil accumulation and endoplasmic reticulum stress were independent of genotype. Protection from Gao-binge injury in Irf3-/- mice was associated with an increased ratio of Ly6Clow (restorative) to Ly6Chigh (inflammatory) cells compared to C57BL/6 and Irf3S1/S1 mice. Reduced ratios of Ly6Clow/Ly6Chigh in C57BL/6 and Irf3S1/S1 mice were associated with increased apoptosis in the Ly6Clow population in response to Gao-binge. Activation of primary macrophage cultures with Poly (I:C) induced translocation of IRF3 to the mitochondria, where it associated with Bax and activated caspases 3 and 9, processes indicative of activation of the RIPA pathway. CONCLUSIONS Taken together, these data identify that the non-transcriptional function of IRF3 plays an important role in modulating the innate immune environment in response to Gao-binge ethanol exposure, via regulation of immune cell apoptosis. LAY SUMMARY Activation of the innate immune system contributes to inflammation in the progression of alcohol-related liver disease, as well as to the resolution of injury. Here we show that the protein IRF3 modulates the innate immune environment of the liver in a mouse model of alcoholic hepatitis. It does this by increasing the apoptotic cell death of immune cells that promote the resolution of injury.
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Affiliation(s)
- Carlos Sanz-Garcia
- Departments of Inflammation and Immunity, Case Western Reserve University, Cleveland, Ohio
| | - Kyle L. Poulsen
- Departments of Inflammation and Immunity, Case Western Reserve University, Cleveland, Ohio
| | - Damien Bellos
- Departments of Inflammation and Immunity, Case Western Reserve University, Cleveland, Ohio,,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Han Wang
- Departments of Inflammation and Immunity, Case Western Reserve University, Cleveland, Ohio
| | - Megan R. McMullen
- Departments of Inflammation and Immunity, Case Western Reserve University, Cleveland, Ohio
| | - Xiaoxia Li
- Departments of Inflammation and Immunity, Case Western Reserve University, Cleveland, Ohio,,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Saurabh Chattopadhyay
- Department of Medical Microbiology and Immunology, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio
| | - Ganes Sen
- Departments of Inflammation and Immunity, Case Western Reserve University, Cleveland, Ohio,,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
| | - Laura E. Nagy
- Departments of Inflammation and Immunity, Case Western Reserve University, Cleveland, Ohio,,Gastroenterology and Hepatology, Cleveland Clinic, Case Western Reserve University, Cleveland, Ohio,,Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio
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48
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Kant S, Davuluri G, Alchirazi KA, Welch N, Heit C, Kumar A, Gangadhariah M, Kim A, McMullen MR, Willard B, Luse DS, Nagy LE, Vasiliou V, Marini AM, Weiner ID, Dasarathy S. Ethanol sensitizes skeletal muscle to ammonia-induced molecular perturbations. J Biol Chem 2019; 294:7231-7244. [PMID: 30872403 DOI: 10.1074/jbc.ra118.005411] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 03/12/2019] [Indexed: 12/27/2022] Open
Abstract
Ethanol causes dysregulated muscle protein homeostasis while simultaneously causing hepatocyte injury. Because hepatocytes are the primary site for physiological disposal of ammonia, a cytotoxic cellular metabolite generated during a number of metabolic processes, we determined whether hyperammonemia aggravates ethanol-induced muscle loss. Differentiated murine C2C12 myotubes, skeletal muscle from pair-fed or ethanol-treated mice, and human patients with alcoholic cirrhosis and healthy controls were used to quantify protein synthesis, mammalian target of rapamycin complex 1 (mTORC1) signaling, and autophagy markers. Alcohol-metabolizing enzyme expression and activity in mouse muscle and myotubes and ureagenesis in hepatocytes were quantified. Expression and regulation of the ammonia transporters, RhBG and RhCG, were quantified by real-time PCR, immunoblots, reporter assays, biotin-tagged promoter pulldown with proteomics, and loss-of-function studies. Alcohol and aldehyde dehydrogenases were expressed and active in myotubes. Ethanol exposure impaired hepatocyte ureagenesis, induced muscle RhBG expression, and elevated muscle ammonia concentrations. Simultaneous ethanol and ammonia treatment impaired protein synthesis and mTORC1 signaling and increased autophagy with a consequent decreased myotube diameter to a greater extent than either treatment alone. Ethanol treatment and withdrawal followed by ammonia exposure resulted in greater impairment in muscle signaling and protein synthesis than ammonia treatment in ethanol-naive myotubes. Of the three transcription factors that were bound to the RhBG promoter in response to ethanol and ammonia, DR1/NC2 indirectly regulated transcription of RhBG during ethanol and ammonia treatment. Direct effects of ethanol were synergistic with increased ammonia uptake in causing dysregulated skeletal muscle proteostasis and signaling perturbations with a more severe sarcopenic phenotype.
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Affiliation(s)
- Sashi Kant
- From the Departments of Inflammation and Immunity
| | | | | | - Nicole Welch
- From the Departments of Inflammation and Immunity
| | - Claire Heit
- the Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045
| | | | | | - Adam Kim
- From the Departments of Inflammation and Immunity
| | | | - Belinda Willard
- Metabolomic and Proteomics Core, Cleveland Clinic, Cleveland, Ohio 44195
| | | | - Laura E Nagy
- From the Departments of Inflammation and Immunity
| | - Vasilis Vasiliou
- the Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut 06510
| | - Anna Maria Marini
- the Biology of Membrane Transport Laboratory, Department of Molecular Biology, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles CP300, 6041 Gosselies, Belgium
| | - I David Weiner
- the Division of Nephrology, Hypertension, and Renal Transplantation, Department of Medicine, School of Medicine, University of Florida, Gainesville, Florida 32610, and.,the Nephrology and Hypertension Section, North Florida/South Georgia Veterans Health System, Gainesville, Florida 32608
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49
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Abstract
Alcohol-associated cirrhosis (AC) contributes up to 50% of the overall cirrhosis burden in the United States. AC is typically a comorbid condition in association with alcohol-use disorder. AC is often coexistent with other conditions. Several noninvasive methods are available to assist in recognizing the presence of AC. The natural history of AC is governed by the patients continued drinking or abstinence. All treatment starts with abstinence. After decompensation, the progression to acute-on-chronic liver failure heralds death. When patients who have deteriorated are declined liver transplant, palliative care should be considered.
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50
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Godfrey EL, Stribling R, Rana A. Liver Transplantation for Alcoholic Liver Disease: An Update. Clin Liver Dis 2019; 23:127-139. [PMID: 30454827 DOI: 10.1016/j.cld.2018.09.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Alcoholic liver disease is a serious and increasing contributor to the global liver disease burden. Extensive selection criteria, including a minimum abstinence period, has previously been used to secure good outcomes but new research questions the effectiveness of abstinence periods and has recommended changes in integrated alcohol use treatment to effectively prevent relapse. Patients have unique health concerns, including posttransplantation risks of malignancy and metabolic complications, but overall very good long-term outcomes. Severe alcoholic hepatitis has been increasingly treated with early transplantation without a set sobriety period, with overall favorable outcomes, even with respect to recidivism.
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Affiliation(s)
- Elizabeth L Godfrey
- Department of Student Affairs, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
| | | | - Abbas Rana
- 6620 Main Street, Suite 1425, Houston, TX 77030, USA
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