In Patients With Severe Alcoholic Hepatitis, Prednisolone Increases Susceptibility to Infection and Infection-Related Mortality, and Is Associated With High Circulating Levels of Bacterial DNA

Vergis, Nikhil; Atkinson, Stephen R.; Knapp, Suzanne; Maurice, James; Allison, Michael; Austin, Andrew; Forrest, Ewan; Masson, Steven; McCune, Anne; Patch, David; Richardson, Paul; Gleeson, Dermot; Ryder, Stephen; Wright, Mark; Thursz, Mark

doi:10.1053/j.gastro.2016.12.019

Cited by 159 publications

(185 citation statements)

References 24 publications

(38 reference statements)

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“…Infections are common in severe AH with 12%‐26% prevalence at the time of admission, with up to half infected at some point while receiving corticosteroids . Infection‐related biomarkers like pretreatment serum lipopolysaccharide, bacterial DNA, high‐sensitivity C‐reactive protein, and procalcitonin are associated with the risk of infection and 90‐day mortality . Furthermore, as mentioned previously, the presence of SIRS at admission, with or without infection, predicts multiorgan failure (especially AKI) and early death .…”

Section: Diagnosis and Treatment Of Alcohol‐associated Liver Diseasesmentioning

confidence: 85%

“…If infection is present, appropriate antibiotics should be started immediately. Although there have been reports of frequent fungal infections resulting in high mortality, particularly Aspergillus species, in corticosteroid‐treated patients with AH in France and Belgium, this has not been reported elsewhere in Europe or the United States . Despite these concerns, the presence of infection alone has not been shown to be a driver of short‐term mortality .…”

Section: Diagnosis and Treatment Of Alcohol‐associated Liver Diseasesmentioning

confidence: 99%

See 1 more Smart Citation

Diagnosis and Treatment of Alcohol‐Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases

et al. 2020

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Section: Diagnosis and Treatment Of Alcohol‐associated Liver Diseasesmentioning

confidence: 85%

Section: Diagnosis and Treatment Of Alcohol‐associated Liver Diseasesmentioning

confidence: 99%

Diagnosis and Treatment of Alcohol‐Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases

et al. 2020

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“…Recent studies have indicated that AH results in systemic inflammation that affects multiple organ systems. 39–41 Tissue damage from systemic inflammation associated with AH is another possible and likely source of K18 release. While measurements of LDH and AST, which are widely expressed, did not correlate with M30 or M65, it remains a possibility that cell death in non-hepatic tissues are potential additional sources of M30 and M65 release.…”

Section: Discussionmentioning

confidence: 99%

Cell Death and Prognosis of Mortality in Alcoholic Hepatitis Patients Using Plasma Keratin-18

et al. 2017

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Alcoholic liver disease encompasses the progressive stages of liver dysfunction that culminates in alcoholic cirrhosis (AC) and in severe cases alcoholic hepatitis (AH). Currently, prognostic scores have limited specificity and sensitivity. Plasma keratin-18 (K18) levels are elevated during liver disease and may be biomarkers of outcome. The objective of this study was to determine if total K18 (M65) or caspase-cleaved K18 (M30) levels were different between AC and AH patients. M65 and M30 levels were measured in plasma of consented healthy controls, and patients with AC and AH. Cell death was assessed by TUNEL staining and caspase activity. M65 and M30 values were significantly higher in AC patients compared to healthy controls and further increased in AH patients. The M65 values and the M30/M65 ratios of non-surviving AH patients were significantly elevated above their surviving counterparts and healthy controls. Statistical analysis indicated that M30/M65 ratios outperformed current indices for accurately distinguishing the prognosis of AH patient. These scores occurred with minimal increase in plasma cell death markers such as ALT and AST. Serum caspase activity, TUNEL staining, and M30 immunohistochemistry in biopsies indicated serum and tissue values may not correlate well with overall cell death. In conclusion, both M65 and M30 differentiate AH from AC patients and M65 values and the M30/M65 ratio are capable of predicting early-stage mortality; however, they may not accurately reflect pure hepatocyte cell death in these populations as they do not strongly correlate with traditional cell death markers.

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“…Although most of the studies investigating the gut–liver axis focus on bacteria and bacterial products, little is known about another integral component of the gut microbiota, the commensal fungi in the gut (also called mycobiota). Invasive fungal infections, primarily with Candida albicans and Aspergillus , occur in patients with alcoholic hepatitis and are associated with a high mortality …”

mentioning

confidence: 99%

Intestinal Fungal Dysbiosis and Systemic Immune Response to Fungi in Patients With Alcoholic Hepatitis

et al. 2019

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Chronic alcohol consumption causes increased intestinal permeability and changes in the intestinal microbiota composition, which contribute to the development and progression of alcohol‐related liver disease. In this setting, little is known about commensal fungi in the gut. We studied the intestinal mycobiota in a cohort of patients with alcoholic hepatitis, patients with alcohol use disorder, and nonalcoholic controls using fungal‐specific internal transcribed spacer amplicon sequencing of fecal samples. We further measured serum anti–Saccharomyces cerevisiae antibodies (ASCA) as a systemic immune response to fungal products or fungi. Candida was the most abundant genus in the fecal mycobiota of the two alcohol groups, whereas genus Penicillium dominated the mycobiome of nonalcoholic controls. We observed a lower diversity in the alcohol groups compared with controls. Antibiotic or steroid treatment was not associated with a lower diversity. Patients with alcoholic hepatitis had significantly higher ASCA levels compared to patients with alcohol use disorder and to nonalcoholic controls. Within the alcoholic hepatitis cohort, patients with levels of at least 34 IU/mL had a significantly lower 90‐day survival (59%) compared with those with ASCA levels less than 34 IU/mL (80%) with an adjusted hazard ratio of 3.13 (95% CI, 1.11‐8.82; P = 0.031). Conclusion: Patients with alcohol‐associated liver disease have a lower fungal diversity with an overgrowth of Candida compared with controls. Higher serum ASCA was associated with increased mortality in patients with alcoholic hepatitis. Intestinal fungi may serve as a therapeutic target to improve survival, and ASCA may be useful to predict the outcome in patients with alcoholic hepatitis.

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In Patients With Severe Alcoholic Hepatitis, Prednisolone Increases Susceptibility to Infection and Infection-Related Mortality, and Is Associated With High Circulating Levels of Bacterial DNA

Cited by 159 publications

References 24 publications

Diagnosis and Treatment of Alcohol‐Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases

Diagnosis and Treatment of Alcohol‐Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases

Cell Death and Prognosis of Mortality in Alcoholic Hepatitis Patients Using Plasma Keratin-18

Intestinal Fungal Dysbiosis and Systemic Immune Response to Fungi in Patients With Alcoholic Hepatitis

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