G-CSF-In Patients With Severe Alcohol-Associated Hepatitis: A Real-World Experience.

BACKGROUND AND AIMS: Severe alcohol-associated hepatitis (SAH) is associated with high short-term mortality, and failure of response to corticosteroids is associated with a mortality of ~70%-80% within 6 months. Granulocyte colony-stimulating factor (G-CSF) has been studied in steroid non-responders; however, the data are limited. METHODS: This is a multicentre retrospective cohort study. The study period was from January 2016 to November 2023. SAH was defined as alcohol-associated hepatitis (ICD-10-CM codes) with serum bilirubin ≥ 5.0 mg/dL and INR ≥ 1.5. Other aetiologies of acute hepatitis and biliary obstruction were excluded. The primary outcome was 90-day median overall survival in SAH patients treated with G-CSF compared with standard medical therapy (SMT) or corticosteroids. Propensity score (1:1) matching was performed to control confounding variables. RESULTS: Among 20 132 patients with SAH, 10800 (53.65%) were treated with corticosteroids and 224 (1.11%) G-CSF. The G-CSF group was younger (45.5 vs. 48.4) White (79.91% vs. 72.40%); however, there was no age or gender difference between G-CSF and corticosteroid groups. Whites and patients with more comorbidities received G-CSF more frequently than SMT or corticosteroids. After propensity score matching, 90-day overall survival was better in patients who received G-CSF (88.31% vs. 62.36%, p < 0.01) compared with SMT or corticosteroids (88.31% vs. 74.39%, p < 0.01). Patients on G-CSF had better 6-month transplant-free survival compared with SMT (83.53% vs. 55.36%, p < 0.001) or corticosteroids (82.89% vs. 60.21%, p < 0.001). Gastrointestinal bleeding was less common in G-CSF group compared with corticosteroids (5.02% vs. 10.50%, p < 0.001). CONCLUSIONS: A small minority of patients with severe alcohol-associated hepatitis receive G-CSF. G-CSF improves 90-day overall survival in patients with severe alcohol-associated hepatitis and is non-inferior to corticosteroids.

Real-World Utilization of Corticosteroids in Severe Alcoholic Hepatitis: Eligibility, Response, and Outcomes.

Background and Objectives: Alcoholic hepatitis (AH) poses a medical challenge, causing moderately severe to life-threatening episodes with high short- and long-term mortality. This study aimed to explore real-world corticosteroid utilization in severe AH, response predictors, and patient outcomes. Materials and Methods: We conducted a retrospective study on patients admitted for severe AH, defined as a Maddrey Discriminant Function score equal to or above 32, at a tertiary care center. We reviewed patients' medical observation charts to identify corticosteroid prescriptions, reasons for ineligibility, and response rates. Responders were defined based on the Lille score, and predictors of non-response were identified. Short-term (one-month) and long-term (one-year) mortality rates were calculated according to treatment and response. Results: Out of 310 patients enrolled with severe AH, 59% received corticosteroids, achieving a response rate of 75.4%. The reasons for not administering corticosteroids were as follows: uncontrolled infections (27.6%), renal dysfunction (20.4%), gastrointestinal bleeding (18.9%), acute pancreatitis (7.1%), uncontrolled diabetes (3.1%), and other or unknown causes (22.8%). The overall 1-month mortality rate was 12.2%, higher in non-responders (35.3%) and patients who did not receive corticosteroids (13.4%) compared to responders (3.6%). The overall 1-year mortality rate was 62.5%, similar between patients who did not receive corticosteroids (78.7%) and non-responders (77.7%) and higher compared to responders (42.8%). Predictive factors for non-response included older age (OR = 1.05, 95%CI: 1.01-1.08), concomitant cirrhosis (OR= 2.11, 95% CI: 1.064-4.20), MELD scores exceeding 30 (OR = 2.42, 95% CI: 1.21-4.80), severe hypoalbuminemia (OR = 2.46, 95%CI: 1.12-5.37), and increased serum creatinine (OR = 1.5, 95% CI: 1.1-2.03). Among the prognostic scores, MELD 3.0 score exhibited superior efficacy for short-term (AUC = 0.734, 95% CI 0.656-0.811) and long-term mortality (AUC = 0.777, 95% CI: 0.724-0.830) compared to alternative scoring systems. Conclusions: Low eligibility rate and poor prognosis underscore the need for effective therapies. Our findings contribute to refining risk stratification and early prediction of non-response, aiding clinicians in identifying more beneficial therapies.

Enhanced diagnosis and prognosis of severe alcoholic hepatitis using novel metabolomic biomarkers.

AIM: Differentiating alcoholic hepatitis (AH) from acute decompensation of alcoholic cirrhosis (DC) is challenging, as the presentation and biochemistry are similar. We aimed to identify potential metabolomic biomarkers to differentiate between AH and DC, and to predict short-term mortality. METHODS: We included consecutive biopsy proven AH and DC patients, which were managed according to current guidelines and followed up until the end of the study. Untargeted metabolomics was assessed in all patients at baseline. Specific analyses were successively performed to identify potential biomarkers, which were further semi-quantitatively analysed against relevant clinical endpoints. RESULTS: Thirty-four patients with AH and 37 with DC were included. UHPLC-MS analysis identified 83 molecules potentially differentiating between AH and DC. C16-Sphinganine-1P (S1P) was the most increased, whereas Prostaglandin E2 (PGE2) was the most decreased. The PGE2/S1P ratio < 1.03 excellently discriminates between AH and DC: AUC 0.965 (p < 0.001), Se 90%, Sp 100%, PPV 0.91, NPV 1, and diagnostic accuracy 95%. This ratio is not influenced by the presence of infection (AUC 0.967 vs. 0.962), correlates with the Lille score at 7 days (r = -0.60; P = 0.022) and tends to be lower in corticosteroid non-responders as compared with patients who responded [0.85(±0.02) vs. 0.89(±0.05), P = 0.069]. Additionally, decreased ursodeoxycholic acid levels are correlated with MELD and Maddrey scores and predict mortality with a 77.27% accuracy (NPV = 100%). CONCLUSION: This study suggests the PGE2 (decreased)/S1P (increased) ratio as a biomarker to differentiate AH from DC. The study also finds that low levels of ursodeoxycholic acid could predict increased mortality in AH.

Granulocyte colony-stimulating factor plus pentoxifylline increases short-term survival in patients with severe alcoholic hepatitis: a network meta-analysis.

Background: Optimal treatments for severe alcoholic hepatitis (SAH) remain controversial. Previous network meta-analysis showed that corticosteroid (CS) combined with N-acetylcysteine (NAC) was superior in reducing short-term mortality of patients with SAH. Recently, granulocyte colony-stimulating factor (G-CSF) treatments for SAH yielded promising results.Objectives: To determine how currently available treatments affect the survival and complications of patients with SAH.Methods: The study was conducted following the guidelines of PRISMA. The data from PubMed, Embase, MEDLINE, Cochrane Library, and clinicaltrials.gov to October 2022 were searched, and patients with SAH with pharmacotherapy were included in our study. The primary outcome was short-term survival, and the other outcomes were medium- (3/6 months) or long-term (12 months) survival and complications after treatment. R software was used to establish network meta-analysis models and the result was expressed by the odd ratio (OR) value and 95% credible interval (Crls).Results: A total of 31 randomized controlled trials, including 19 treatment regimens, were enrolled in our study. As the primary outcome, G-CSF+ pentoxifylline (PTX) ranked first in one-month survival and showed significant superiority when compared with the placebo (OR 8.60, 95% Crls 1.92-45.10) and CS (OR 4.95, 95% Crls 1.11-25.53). Also, G-CSF+PTX ranked first in improving three-month survival and reducing the occurrence of infection. PTX+MTD ranked first in six-month survival, and G-CSF ranked first in twelve-month survival. CS+MTD ranked first in the occurrence of gastrointestinal bleeding and hepatorenal syndrome.Conclusions: The combination of G-CSF and PTX showed a significant benefit in improving the short-term survival of SAH patients.

Plasma-Signature-Model for End-Stage Liver Disease Score to Predict Survival in Severe Alcoholic Hepatitis.

BACKGROUND & AIMS: Severe alcoholic hepatitis (AH) is a highly lethal condition and it is still a challenge to predict the outcome. We previously identified and validated a composite score of hepatic 123-gene prognostic signature and the model for end-stage liver disease (MELD) score: gene signature-MELD. However, the need for liver biopsy limits its clinical application. Therefore, we aimed to identify a plasma protein-based surrogate of the gene signature and independently validate its prognostic capability. METHODS: All patients were diagnosed with severe AH at Cliniques universitaires de Bruxelles Hôpital Erasme (Brussels, Belgium), and the plasma samples were collected at admission before any treatment. The primary outcome was death or liver transplantation within 90 days. Using our computational pipeline, named translation of tissue expression to secretome (TexSEC), a hepatic-transcriptome-based prognostic signature was converted to a plasma-based secretome signature, which was optimized in 50 patients by comparing their hepatic molecular dysregulation status and combining it with the MELD score. The composite score was validated independently in 57 patients. RESULTS: The TexSEC and optimization process identified a 6-plasma-protein panel as a surrogate for the 123-gene signature. A composite score with the MELD score, the plasma-signature (ps)-MELD score, was created by using the coefficients of the gene signature-MELD equation. In the validation cohort, the high-risk ps-MELD (n = 23; 40%) was associated significantly with death or liver transplantation within 90 days (adjusted hazard ratio, 4.57; 95% CI, 2.15-9.30; P < .001). The ps-MELD score showed a stable, high prognostic association (time-dependent area under receiver operating characteristics curve, >0.80) and was well calibrated over time; it consistently outperformed existing clinical scores as indicated by various model performance indices. CONCLUSIONS: The high-risk ps-MELD score was associated with short-term survival in patients with severe AH.

Effect of rifaximin on infections, acute-on-chronic liver failure and mortality in alcoholic hepatitis: A pilot study (RIFA-AH).

BACKGROUND & AIMS: Alcoholic hepatitis (AH) is associated with a high incidence of infection and mortality. Rifaximin reduces bacterial overgrowth and translocation. We aimed to study whether the administration of rifaximin as an adjuvant treatment to corticosteroids decreases the number of bacterial infections at 90 days in patients with severe AH compared to a control cohort. METHODS: This was a multicentre, open, comparative pilot study of the addition of rifaximin (1200 mg/day/90 days) to the standard treatment for severe AH. The results were compared with a carefully matched historical cohort of patients treated with standard therapy and matching by age and model of end-stage liver disease (MELD). We evaluated bacterial infections, liver-related complications, mortality and liver function tests after 90 days. RESULTS: Twenty-one and 42 patients were included in the rifaximin and control groups respectively. No significant baseline differences were found between groups. The mean number of infections per patient was 0.29 and 0.62 in the rifaximin and control groups, respectively (p = .049), with a lower incidence of acute-on-chronic liver failure (ACLF) linked to infections within the treatment group. Liver-related complications were lower within the rifaximin group (0.43 vs. 1.26 complications/patient respectively) (p = .01). Mortality was lower in the treated versus the control groups (14.2% vs. 30.9, p = .15) without significant differences. No serious adverse events were associated with rifaximin treatment. CONCLUSIONS: Rifaximin is safe in severe AH with a significant reduction in clinical complications. A lower number of infections and a trend towards a lower ACLF and mortality favours its use in these patients.

Diagnostic criteria for acute-on-chronic liver failure and related disease conditions in Japan.

The Intractable Hepato-Biliary Disease Study Group of Japan, sponsored by the Ministry of Health, Labor and Wealth, proposed in 2018 that patients with cirrhosis and a Child-Pugh score of 5-9 should be diagnosed as having acute-on-chronic liver failure (ACLF) when a deterioration of liver function ("serum bilirubin level of 5.0 mg/dl or more" and "prothrombin time value of 40% or less of the standardized values and/or international normalization rates of 1.5 or more") caused by severe liver damage develops within 28 days after an acute insult, including alcohol abuse, bacterial infection, gastrointestinal bleeding, and the exacerbation of underlying liver diseases. Disease severity can be classified into 4 grades depending on the extent of the deterioration in organ functions, including liver, kidney, cerebral, blood coagulation, circulatory and respiratory functions. The Study Group has since performed an annual nationwide survey of patients with ACLF diagnosed according to the proposed diagnostic criteria as well as those with disease conditions related to ACLF. A total of 501 patients, including 183 patients diagnosed as having ACLF, seen between 2017 and 2019 were enrolled, and univariate and multivariate analyses revealed that the proposed diagnostic criteria were useful for identifying cirrhotic patients with an unfavorable outcome following an acute insult. Consequently, the Study Group determined that the proposed diagnostic criteria should be used in both clinical practice and clinical research as formal diagnostic criteria.

Natural Killer Cells Contribute to Pathogenesis of Severe Alcoholic Hepatitis by Inducing Lysis of Endothelial Progenitor Cells.

BACKGROUND: Endothelial progenitor cells (EPCs) help in neovascularization and endothelial repair during injury. Patients with cirrhosis show increased number and function of EPCs in circulation. METHODS: Since natural killer (NK) cells regulate EPCs, we investigated the relationship between the 2 in alcoholic cirrhosis (AC, n = 50) and severe alcoholic hepatitis (SAH, n = 18) patients and compared with nonalcoholic cirrhosis (n = 15) and healthy controls (HC, n = 30). Levels of systemic inflammatory cytokines were measured, and coculture assays were performed between EPCs and NK cells in contact-dependent and contact-independent manner. NK cell-mediated killing of EPCs was evaluated, and expression of receptors including fractalkine (FKN) on EPCs and its cognate receptor CX3CR1 on NK cells was studied by RT-PCR assays. RESULTS: Patients with SAH had higher regulated on activation, normal T cell expressed and secreted (RANTES) (p = 0.01), vascular endothelial growth factor (VEGF) (p = 0.04), IL-1ß (p = 0.04), and IL-6 (p = 0.00) growth factors and proinflammatory cytokines as compared to AC and HC. Distinct populations of CD31+ CD34+ EPCs with low and high expression of CD45 were significantly lower in SAH than HC (CD45low , p = 0.03; CD45hi , p = 0.04) and AC (CD45low , p = 0.05; CD45hi , p = 0.02). SAH patients, however, showed increased functional capacity of EPCs including colony formation and LDL uptake. NK cells were reduced in SAH compared with AC (p = 0.002), however with higher granzyme ability (p < 0.001 and p = 0.04, respectively). In SAH, EPC-NK cell interaction assays showed that NK cells lysed the EPCs in both contact-dependent and contact-independent assays. Expression of interaction receptor CX3CR1 was significantly higher on NK cells (p = 0.0005), while its cognate receptor, FKN, was increased on EPCs in SAH patients as compared to HC (p = 0.0055). CONCLUSION: We conclude that in SAH, NK cells induce killing of EPCs via CX3CR1/FKN axis that may be one of the key events contributing to disease severity and proinflammatory responses in SAH.

Update on liver transplantation-newer aspects

Liver transplantation (LT) remains the only therapeutic option offering gold standard treatment for end-stage liver disease (ESLD) and acute liver failure (ALF), as well as for certain early-stage liver tumors. Currently, the greatest challenge facing LT is the simple fact that there are not enough adequate livers for all the potential patients that could benefit from LT. Despite efforts to expand the donor pool to include living and deceased donors, organ shortage is still a major problem in many countries. To solve this problem, the use of marginal liver grafts has become an inevitable choice. Although the definition of marginal grafts or criteria for expanded donor selection has not been clarified yet, they are usually defined as grafts that may potentially cause primary nonfunction, impaired function, or late loss of function. These include steatotic livers, older donors, donors with positive viral serology, split livers, and donation after cardiac death (DCD). Therefore, to get the best outcome from these liver grafts, donor-recipient selection should be vigilant. Alcohol- related liver disease (ALD) is one of the most common indications for LT in Europe and North America. Traditionally, LT for alcoholic liver disease was kept limited for patients who have achieved 6 months of abstinence, in part due to social and ethical concerns regarding the use of a limited resource. However, the majority of patients with severe alcoholic hepatitis who fail medical therapy will not live long enough to meet this requirement. Besides, the initial results of early liver transplantation (ELT) without waiting for 6 months of abstinence period are satisfactory in severe alcoholic hepatitis (SAH). It will be important to take care of these patients from a newer perspective.

A Lille model for predicting the response of severe alcoholic hepatitis to corticosteroid treatment in Japanese patients.

AIM: Corticosteroids are the most widely used agents for the treatment of severe alcoholic hepatitis (SAH). The therapeutic effectiveness of corticosteroids is assessed by the Lille model, which has been validated well in patient cohorts in North America and Europe; however, its usefulness has not yet been confirmed independently in Japanese patients. The present study aimed to determine whether the Lille model could predict the prognosis of SAH in Japanese patients. METHODS: This was a retrospective cohort study including 32 SAH patients who were admitted to our institute from April 2011 to February 2018. According to the previously validated Lille model cut-off value, patients who received corticosteroids were classified as corticosteroid responders or non-responders (with responders obtaining a Lille score ≥ 0.45), followed by assessment for the 6-month prognosis. RESULTS: Out of 32 patients, 26 were treated with corticosteroids. The 28-day and 6-month mortality rates in the corticosteroid-treated group were 23.1% and 46.2%, respectively. The median Lille score was significantly higher in patients who died or underwent liver transplantation (0.647) than in those who survived without undergoing transplantation (0.226; P < 0.0182). The 6-month transplant-free survival rate of non-responders (Lille score ≥ 0.45) was significantly lower (27.3%; 95% confidence interval, 9.0-58.6%) than that of responders (Lille score < 0.45, 73.3%; 95% confidence interval, 46.7-90.0%; P = 0.0149, log-rank test). CONCLUSIONS: The Lille score could be useful for predicting the 6-month prognosis of Japanese SAH patients after corticosteroid therapy.

The prognostic value of acute-on-chronic liver failure during the course of severe alcoholic hepatitis.

BACKGROUND & AIMS: A better identification of factors predicting death is needed in alcoholic hepatitis (AH). Acute-on-chronic liver failure (ACLF) occurs during the course of liver disease and can be identified when AH is diagnosed (prevalent ACLF [pACLF]) or during follow-up (incidental ACLF [iACLF]). This study analyzed the impact of ACLF on outcomes in AH and the role of infection on the onset of ACLF and death. METHODS: Patients admitted from July 2006 to July 2015 suffering from biopsy-proven severe (s)AH with a Maddrey discriminant function (mDF) ≥32 were included. Infectious episodes, ACLF, and mortality were assessed during a 168-day follow-up period. Results were validated on an independent cohort. RESULTS: One hundred sixty-five patients were included. Mean mDF was 66.3 ±â€¯20.7 and mean model for end-stage liver disease score was 26.8 ±â€¯7.4. The 28-day cumulative incidence of death (CID) was 31% (95% CI 24-39%). Seventy-nine patients (47.9%) had pACLF. The 28-day CID without pACLF and with pACLF-1, pACLF-2, and pACLF-3 were 10.4% (95% CI 5.1-18.0), 30.8% (95% CI 14.3-49.0), 58.3% (95% CI 35.6-75.5), and 72.4% (95% CI 51.3-85.5), respectively, p <0.0001. Twenty-nine patients (17.5%) developed iACLF. The 28-day relative risk of death in patients developing iACLF was 41.87 (95% CI 5.2-335.1; p <0.001). A previous infection was the only independent risk factor for developing iACLF during the follow-up. Prevalence, incidence, and impact on prognosis of ACLF were confirmed in a validation cohort of 97 patients with probable sAH. CONCLUSIONS: ACLF is frequent during the course of sAH and is associated with high mortality. Infection strongly predicts the development of ACLF in this setting. LAY SUMMARY: In patients with chronic liver disease, an acute deterioration of liver function combined with single or multiple organ failures is known as acute-on-chronic liver failure. This study shows that acute-on-chronic liver failure is frequent during the course of severe alcoholic hepatitis. In severe alcoholic hepatitis, acute-on-chronic liver failure is associated with high mortality and frequently occurs after an infection.

Sepsis in alcohol-related liver disease.

Alcohol-related liver disease (ALD) remains the most important cause of death due to alcohol. Infections, particularly bacterial infections, are one of the most frequent and severe complications of advanced ALDs, such as alcoholic cirrhosis and severe alcoholic hepatitis (sAH). The specific mechanisms responsible for this altered host defence are yet to be deciphered. The aim of the present study is to review the current knowledge of infectious complications in ALD and its pathophysiological mechanisms, distinguishing the role of alcohol consumption and the contribution of different forms of ALD. To date, corticosteroids are the only treatment with proven efficacy in sAH, but their impact on the occurrence of infections remains controversial. The combination of an altered host defence and corticosteroid treatment in sAH has been suggested as a cause of opportunistic fungal and viral infections. A high level of suspicion with systematic screening and prompt, adequate treatment are warranted to improve outcomes in these patients. Prophylactic or preemptive strategies in this high-risk population might be a preferable option, because of the high short-term mortality rate despite adequate therapies. However, these strategies should be assessed in well-designed trials before clinical implementation.

SIRS at Admission Is a Predictor of AKI Development and Mortality in Hospitalized Patients with Severe Alcoholic Hepatitis.

BACKGROUND: Systemic inflammatory response syndrome (SIRS) is associated with an increased risk of hepatic encephalopathy, renal failure, and poor outcome in patients with cirrhosis; however, there is a paucity of studies on this entity for severe alcoholic hepatitis (SAH). AIM: To evaluate SIRS at baseline as a predictor of development of acute kidney injury (AKI) and mortality in patients with SAH. METHODS: Consecutive in-patients with SAH (discriminant function ≥ 32) without AKI at baseline were followed up for the development and progression of AKI (AKIN criteria). RESULTS: Of the 365 patients (mean age 45.5 ± 9.5, 356 males), SIRS at baseline was present in 236 (64.6%). AKI developed in 122 (33.4%), of which 50 (40.9%) had progression of AKI. SIRS was associated with bacterial infections in 96 (40.6%) and in 140 (59.3%) occurred in the absence of proven infection microbiologically. The presence of SIRS predicted both AKI development (p < 0.001, OR 2.9, 95% CI 1.7-4.8) and AKI progression (p = 0.002, OR 3.27, 95% CI 1.48-7.21). Resolution of AKI also had a significant inverse association with SIRS (p = 0.001). High MELD score (p = 0.002, HR 1.1, 95% CI 1.02-1.09), in-hospital progression of AKI (p = 0.04, HR 1.54, 95% CI 1.003-2.38), and SIRS (p = 0.004, HR 1.98, 95% CI 1.25-3.1) were significant predictors of 90-day mortality (model 1), while high MELD score (p < 0.001, HR 1.1, 95% CI 1.04-1.12) and bacterial infections (p = 0.001, HR 1.8, 95% CI 1.27-2.6) were independent predictors of mortality in the second multivariate model (model 2). CONCLUSION: SIRS at admission predicts both the development of AKI and 90-day mortality in patients with SAH. This could definitely have a therapeutic and prognostic implication.

Prognosis of treated severe alcoholic hepatitis in patients with gastrointestinal bleeding.

BACKGROUND & AIMS: All trials on severe alcoholic hepatitis (AH) have included patients with "pure" AH, i.e., without concomitant gastrointestinal bleeding (GIB). Severe AH is often suspected in cirrhotic patients with GIB. We aimed at (1) assessing the prevalence of AH in patients with GIB and Maddrey discriminant function (DF) ⩾32; (2) comparing the outcome in AH patients with or without GIB (AH-GIB+, AH-GIB-); and (3) assessing the performance of the Lille model for survival in AH-GIB+ patients. METHODS: We retrospectively included all patients with alcoholic cirrhosis admitted between January 2005 and March 2011 with the following: (1) jaundice <3 months; (2) DF ⩾32 at admission; (3) bilirubin level >50 µmol/L; and (4) active drinking. Exclusion criteria were advanced hepatocellular carcinoma, other etiology of cirrhosis, severe comorbidities and DF <32 after stabilization. In our centre, we systematically plan a liver biopsy for these patients. Patients with severe AH received prednisolone. RESULTS: We screened 161 patients (86 GIB+, 75 GIB-), and analyzed data for 58 and 47 patients in each group, respectively. The 2 groups did not differ in prevalence of AH (77.3% vs. 81%), demographic data, MELD/Child-Pugh score, or DF. The 2 groups were similar in 6-month probability of survival (73.9 ± 6.0% vs. 69.9 ± 7%, p=0.49). The probability of developing infection was lower for AH-GIB+ patients (24.1% vs. 44.7%, p=0.04). The AUC for the Lille model in predicting 6-month survival was 0.71 ± 0.06 for all patients and 0.74 ± 0.06 for AH-GIB+ patients (p>0.05). CONCLUSIONS: Prevalence of AH is 80% for patients with cirrhosis and GIB, recent jaundice and DF ⩾32. Infection was lower for AH-GIB+ patients, which suggests a beneficial role of antibiotic prophylaxis treatment. Survival among subjects with GIB was the same as among subjects without GIB.

Case of severe alcoholic hepatitis following acute pancreatitis.

This report describes the clinical course of a 41 year-old African woman who presented with an episode of acute alcoholic pancreatitis followed next by severe alcoholic hepatitis (SAH). Initially admitted for pancreatitis, the patient responded promptly to comprehensive treatment with strict abstinence from alcohol. However, remarkable elevations in white blood cell count to 44,000/µL and total bilirubin level to 12.4 mg/dL were observed 5-7 weeks later. Contrast-enhanced computed tomography revealed rapidly progressing hepatosplenomegaly. Histological analysis of a liver biopsy detected ballooned hepatocytes with Mallory-Denk bodies and significant neutrophilic infiltration in the hepatic parenchyma, which confirmed the diagnosis of SAH. The patient's hepatosplenomegaly and overall condition improved with supportive care alone. The reported case reveals the unexpected fact that SAH can develop after alcoholic acute pancreatitis.

Serum bile acids profiles are altered without change of the gut microbiota composition following a seven-day prednisolone therapy in severe alcoholic hepatitis.

Severe Alcoholic Hepatitis (sAH) is an acute form of liver injury caused by chronic and heavy alcohol drinking. A one-month corticosteroids course is the only sAH reference treatment, and its interactions with the Gut Microbiota (GM), which is a key contributor to liver injury, remain unknown. To evaluate the evolution of the GM in sAH patients, we retrospectively investigated the composition of the GM of 27 sAH patients at the Amiens University Hospital before (D0) and after (D7) a 7-day corticotherapy course using fecal metagenomics sequencing. We also quantified fecal Short-Chain Fatty Acids (SCFA) and fecal and serum Bile Acids (BA), as well as serum Lipopolysaccharide-Binding Protein (LBP). Overall, the community and taxonomical analyses did not reveal any GM evolution between D0 and D7, nor did the SCFA profiles analysis. However, in serum but not fecal samples, the ratio of glyco-conjugated to tauro-conjugated BA was significantly reduced at D7, independently of the response to treatment, while two BA were enriched in non-responder patients. LBP concentration significantly diminished between D0 and D7, which may indicate an improvement of the gut barrier. The stability of the GM of sAH is interesting in the perspective of new treatments based on GM modulation.

There is a gap in the understanding of the effects of corticosteroids on the gut microbiota of severe alcoholic hepatitis patients.In this study, the composition of the Gut Microbiota of sAH patients treated with prednisolone remains unchanged after 7 days of prednisolone treatment.Short-Chain Fatty Acid profiles are not impacted by the treatment, while Bile Acids profiles change in serum but not in stool samples.Responders and non-responders show different lipopolysaccharide-binding protein serum concentration evolution across time, as well as distinct Bile Acid profiles.

Impact of fecal microbiota transplantation in severe alcoholic hepatitis: A systematic review and meta-analysis.

Background and Aim: Severe alcoholic hepatitis (SAH) is a serious condition with few treatments. By modifying the gut-liver axis, fecal microbiota transplantation (FMT) was proposed as a treatment for SAH. The purpose of this meta-analysis was to evaluate the efficacy of FMT versus the standard of care (SOC) in improving SAH patient survival rates. Methods: A thorough search of electronic databases was conducted till September 2023. The survival rates of SAH patients undergoing FMT versus SOC were compared. Using Review Manager 5.4, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: The meta-analysis consisted of six studies with a total of 371 patients with SAH. Patients who received FMT had significantly higher survival rates at 1 and 3 months compared to those who received SOC, with pooled OR of 2.91 (95% CI: 1.56-5.42, P = 0.0008) and 3.07 (95% CI: 1.81-5.20, P < 0.0001), respectively. However, the survival advantage disappeared after 6 months (OR: 2.96, 95% CI: 0.99-8.85, P = 0.05) and 1 year of follow-up (OR: 1.81, 95% CI: 0.44-7.46, P = 0.41). Conclusion: This meta-analysis highlights the potential of FMT to significantly improve short-term survival rates in SAH patients. However, the survival benefit did not last 6-12 months. These findings call for additional research into the effectiveness of FMT over the long term, along with strategies for extending the survival benefit.

Fecal microbiota transplantation compared with prednisolone in severe alcoholic hepatitis patients: a randomized trial.

BACKGROUND: Severe alcoholic hepatitis (SAH) has high 90-day mortality. Prednisolone therapy has shown modest survival benefits over placebo at 28 but not 90 days. Fecal microbial transplantation (FMT) has shown promise in these patients. We compared the efficacy and safety of the two therapies in SAH patients. METHODS: Steroid eligible SAH patients were randomized in an open-label study to prednisolone (n = 60) 40 mg/day for 28 days (assessed at day-7 for continuation) or healthy donor FMT (n = 60) through naso-duodenal tube, daily for seven days. Primary outcome of study was day-90 survival. RESULTS: Patients in prednisolone and FMT arms were comparable at baseline (discriminant function score 65 ± 16.2 and 68 ± 14, MELD score 17.1 and 16.5, respectively). Of 120 patients, 112 [prednisolone-57; FMT-55] completed trial. As per intention-to-treat analysis, 90-day survival was achieved by 56.6% (34/60) patients in prednisolone and 75% (45/60) in FMT group (p = 0.044, FMT HR = 0.528, 95%CI 0.279-0.998). Secondary outcome of 28-day survival [78.33% (47/60) and 88.33% (53/60) (p = 0.243, FMT HR = 0.535, 95%CI 0.213-1.34)] with comparable severity scores over time between both arms. Infections accounted for 11 (19.3%) and 2 (3.6%) deaths in prednisolone and FMT groups, respectively (p = 0.01). Path-tracing showed a slow establishment of microbiota and alpha diversity (Shannon index) improvement by day-28 (p = 0.029). FMT resulted in 23 new taxa by day-28, reduction from baseline in pathogenic taxa [Campylobacter (19-fold, p = 0.035), anaerobes (Parcubacteria, Weisella and Leuconostocaceae)], and increase of Alphaproteobacteria [~ sevenfold, p = 0.047] and Thaumarcheota (known ammonia oxidizer, p = 0.06). Lachnospiraceae (p = 0.008), Prevotella and Viellonella communities in gut favored survival (p < 0.05). CONCLUSION: In severe alcoholic hepatitis, FMT is safe and improves 90-day survival and reduces infections by favorably modulating microbial communities. It can be a useful alternative to prednisolone therapy.

Alcoholic Hepatitis Mimicking Iron Overload Disorders With Hyperferritinemia and Severely Elevated Transferrin Saturation: A Case Report.

Iron overload disorders can present as non-specific symptoms and develop gradually but, if untreated, can be very fatal. The common causes include multiple blood transfusions for chronic anemia and increased iron absorption, including hereditary hemochromatosis (HH). HH is one of the common causes of iron overload disorders and usually presents with liver cirrhosis in a setting of significantly elevated ferritin and elevated transferrin saturation. Alcoholic hepatitis is a clinical syndrome of progressive inflammatory liver injury associated with long-term heavy intake of ethanol. However, in patients with alcohol abuse, excessive alcohol consumption can disrupt iron metabolism releasing large amounts of iron into circulation. This can cause severely elevated ferritin due to disruption of iron metabolism, simulating iron overload disorders such as HH, especially if the patient also has liver cirrhosis. Even though a high transferrin saturation of greater than 45% is recommended as a cutoff transferrin value as high sensitivity for detecting iron overload disorders, it has a low specificity and positive predictive value and often identifies people with other causes of acutely elevated ferritin levels such as alcohol liver disease and hepatitis. Recognizing this feature and timely management can spare the patient from unnecessary phlebotomies and prompt treatment for alcoholic hepatitis. We present an interesting case of severe alcoholic hepatitis mimicking HH with severely elevated ferritin levels and transferrin saturation with underlying liver cirrhosis.