Carvedilol Combined With Ivabradine Improves Left Ventricular Diastolic Dysfunction, Clinical Progression, and Survival in Cirrhosis.

BACKGROUND: Left ventricular diastolic dysfunction (LVDD) refers to impaired cardiac diastolic relaxation and may be improved by targeted heart rate reduction (THR). The authors evaluated whether a combination of carvedilol and ivabradine, an If channel blocker that reduces heart rate without affecting blood pressure, could improve LVDD and outcomes in cirrhosis. PATIENTS AND METHODS: THR was defined as heart rate reduction to 55 to 65 beats per minute. Of 260 patients with cirrhosis, 189 (72%) with LVDD were randomized to THR [group (Gr.)A; n=94; carvedilol±ivabradine)] or standard care (Gr.B; n=95; no ß-blockers) and followed for 12 months. RESULTS: In Gr.A, THR was achieved at 4 weeks in 88 (93%) patients (responders, R): 48 (61.5%) with carvedilol alone and 40 (86.9%) of 46 patients with additional ivabradine. In Gr.A, LVDD reversed in 16 (20.5%) and improved from grade 2 to 1 in 34 (35.4%)], whereas in Gr.B, it progressed from grade 1 to 2 in 10 (10.5%) patients. At 12 months, 21 (11.1%) patients died, 6 (14%) in Gr.A and 15 (18%) in Gr.B (P=0.240), but no mortality was seen in those who had persistent THR at 1 year (n=78; P=0.000). In multivariate analysis, model for end-stage liver disease [hazard ratio (HR), 1.52; 95% confidence interval (CI), 1.22-2.75; P=0.034] and E-wave transmitral/early diastolic mitral annular velocity (HR, 1.28; 95% CI, 1.23-2.42; P=0.048) predicted 1-year mortality. Nonresponders had an increased mortality risk (HR, 1.3; 95% CI, 1.2-1.8; P=0.046) independent of age, gender, and baseline model for end-stage liver disease. Levels of norepinephrine, N terminal brain natriuretic peptide, plasma renin activity, and aldosterone were reduced (P<0.01) in responders. More patients in Gr.B developed acute kidney injury (odds ratio, 4.2; 95% CI, 2.8-10.5; P=0.027) and encephalopathy (odds ratio, 6.6; 95% CI, 1.9-9.7; P=0.040). CONCLUSIONS: Ivabradine combined with carvedilol improves LVDD, achieves THR more often and reduces risk of encephalopathy, acute kidney injury with improved survival in patients with cirrhosis.

Modification Patterns of Urinary Albumin Correlates With Serum Albumin and Outcome in Severe Alcoholic Hepatitis.

BACKGROUND AND AIMS: Albumin modifications and deranged functions are well documented in serum of severe alcoholic hepatitis (SAH). We investigated whether urinary albumin (u-Alb) can serve as surrogate marker of circulatory albumin phenotype, functionality, and could predict outcome in SAH patients. PATIENTS AND METHODS: Baseline serum and urine samples from 100 SAH, 20 alcoholic cirrhosis, and 20 healthy controls were subjected to u-Alb, ischemia modified albumin (IMA), IMA to albumin ratio (IMAr), advanced oxidation protein products, advanced glycation end-products, albumin-binding capacity determination. In addition, SAH urinary samples were also analyzed at day 4 and day 7 to predict nonresponse to corticosteroid therapy. RESULTS: Urine and serum levels of IMA, advanced oxidation protein products and advanced glycation end-products were higher (P<0.05) in SAH versus alcoholic cirrhosis and healthy controls. IMAr was low in urine but high in serum of SAH (P<0.05). Albumin-binding capacity was lower (P<0.05) in both urinary and serum albumin of SAH. Urinary and serum albumin parameters showed direct correlation, whereas IMAr showed inverse correlation (cc>0.2, P<0.05). Baseline u-Alb level was significantly higher in SAH, and was correlated directly with corticosteroid treatment outcome and 12-month mortality in SAH. Baseline u-Alb showed an area under the receivers operating curve analysis of 0.7 and a hazard ratio of 1.23 for prediction of 12-month mortality in SAH. Baseline u-Alb level >9.0 mg/dL was associated with reduced 12-month survival in SAH (log rank <0.01). CONCLUSIONS: u-Alb modifications are reflective of serum albumin modifications. Further baseline u-Alb levels could be exploited to predict steroid response and mortality in SAH patients.

Molecular Ellipticity of Circulating Albumin-Bilirubin Complex Associates With Mortality in Patients With Severe Alcoholic Hepatitis.

BACKGROUND & AIMS: Hyperbilirubinemia and hypoalbuminemia are features of hepatic dysfunction that associate with disease severity. This is because hepatic insufficiency causes hypoalbuminemia, which indirectly increases the circulating levels of free bilirubin. Circular dichroism (CD) spectroscopy can be used to quantify the molecular ellipticity (ME) of the albumin-bilirubin complex, and might associate with the severity or outcome of severe alcoholic hepatitis (SAH). METHODS: We performed a cross-sectional study of 265 patients with SAH admitted in the Department of Hepatology, Institute of Liver and Biliary Sciences in New Delhi, India from January 2014 through January 2016. Blood samples were collected and patients were followed for 12 months or death. The molar ratios of bilirubin: albumin and albumin-bilirubin complexes were determined for a discovery cohort (30 patients who survived the study period and 60 patients who did not survive) and compared with those of 60 patients with alcoholic cirrhosis and 30 healthy individuals (controls). Optical activities of albumin-bilirubin complexes in blood samples were determined by CD spectroscopy and compared among groups. Findings were validated in a separate cohort of 150 patients with SAH from the same institute. We studied the correlation between ME and albumin binding capacity (ABiC). RESULTS: The molar ratio of bilirubin: albumin was higher in patients with SAH than with alcoholic cirrhosis or controls (P < .05). Patients with SAH had different CD spectra and higher ME than the other groups (P < .01); ME correlated with model for end-stage liver disease score (with and without Na) and discriminant function (r2 > .3; P < .01). ME values above a cut off of 1.84 mdeg predicted 3-month mortality in patients with SAH with an area under receiver operating characteristic curve of 0.87 (95% CI, 0.79-0.95), a 77% positive predictive value, and a 90% negative predictive value. The hazard ratio and concordance index of ME values for 3-month mortality in patients with SAH was 10% higher than the hazard ratio and concordance index of model for end-stage liver disease score. In patients with SAH, there was an inverse correlation between ME and ABiC (r2 > 0.7; P < .01). We observed a significant reduction in ABiC with increasing levels of bilirubin in vitro prepared albumin-bilirubin complex. CONCLUSION: In a cross-sectional study of patients with SAH, we associated ME of the albumin-bilirubin complex, measured by CD spectroscopy, with outcomes of patients with SAH. Increased loading of bilirubin on albumin could explain reduced albumin function. Bilirubin removal by albumin dialysis might benefit patients with SAH.

Changes in cardiac output and incidence of volume overload in cirrhotics receiving 20% albumin infusion.

BACKGROUND & AIMS: Patients with cirrhosis are prone to develop volume over load, have increased capillary permeability and latent or overt cardiomyopathy. Whether albumin infusion causes volume overload in cirrhotics has not been adequately studied. METHODS: Ninety nine consecutive cirrhotic patients receiving 1gm per kg albumin infusion were evaluated for development of volume overload. Clinical, echocardiographic and haemodynamic changes were closely monitored during and after albumin infusion. RESULTS: Thirty (30.30%) patients developed volume overload. Patients with higher BMI (P=.003), lower CTP (P=.01) and MELD (P=.034) were more often associated with the development of volume overload. Though baseline diastolic dysfunction was present in 82.8% of the patients, it did not influence the development of volume overload or changes in the cardiac output. The cardiac output increased significantly after albumin infusion (4.9±1.554 L/min to 5.86±1.85 L/min, P<.001) irrespective of the development of volume overload, or the presence of diastolic dysfunction or the Child's status. CONCLUSION: Nearly, one-third of cirrhotics receiving standard albumin infusion develop volume overload, specially, those with higher BMI and lower severity of liver disease. Cardiac output increases after albumin infusion, and, baseline diastolic dysfunction has little effect on the development of volume overload or changes in cardiac output.

Long Term HBsAg Responses to Peg-Interferon Alpha-2b in HBeAg Negative Chronic Hepatitis B Patients Developing Clinical Relapse after Stopping Long-Term Nucleos(t)ide Analogue Therapy.

Background and aims: A high proportion of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients develop clinical relapse after stopping long-term nucleotide analogues (NAs). The aim of this study was to assess the efficacy of pegylated interferon (PEG-IFN) alpha 2b in inducing hepatitis B surface antigen (HBsAg) loss in such patients. Methods: NAs were stopped in 118 HBeAg-negative CHB patients fulfilling the Asian Pacific Association for the Study of Liver (APASL) 2015 criteria for stopping NAs; they had received NAs for a median interquartile range (IQR) of 60 (48-84) months. Results: Overall, 82 of 118 (69.5%) patients developed clinical relapse after stopping NAs; 44 within 12 months (and treated with PEG-IFN alpha 2b 1.5 mcg/kg weekly subcutaneous injections for 48 weeks); and 38 after 12 months [and treated with tenofovir alafenamide fumarate (TAF) 25 mg daily] of follow-up. The decision to treat with either PEG-IFN or TAF was not a time-bound decision but was due to logistical problems.During the median IQR follow-up of 48 (43.5-52.5) months after the start of PEG-IFN, 14 of 44 (31.8%) patients developed clinical relapse after stopping PEG-IFN and were started on TAF. At the last follow-up visit, HBsAg was found to be negative in 7/44 (15.9%) of patients receiving PEG-IFN.Among 38 patients treated with TAF for clinical relapse, during the median IQR follow-up of 18 (12-30) months after start of TAF, no patient became HBsAg negative.36 patients did not develop clinical relapse during the follow-up, and after a median IQR follow-up of 60 (60-60) months after stopping NAs, HBsAg negative was found in 1/36 (2.8%) of patient at the last follow-up. Conclusions: Among patients with HBeAg-negative chronic hepatitis B who developed clinical relapse after stopping long-term NAs therapy and were subsequently treated with PEG-IFN alpha 2b, 15.9% achieved HBsAg loss on long-term follow-up.

Erectile Dysfunction in Cirrhosis: Its Prevalence and Risk Factors.

Background: Erectile dysfunction (ED) is common in men with cirrhosis. The aim of this study was to assess the prevalence of ED and the factors associated with ED in men with cirrhosis. Methods: 400 men with cirrhosis [Child-Turcotte-Pugh (CTP) class A, 44.0%; CTP class B, 41.0%; and CTP class C, 15.0%] having high Karnofsky performance score, and living in a stable monogamous relationship with a female partner were included in the study. International Index of Erectile Function (IIEF) questionnaire, and Short-Form (36) Health Survey (SF-36) were used to assess erectile function and the health-related quality of life (HRQOL), respectively. Results: ED was found in 289 (72.3%) patients. Patients with ED reported significantly lower SF-36 scores across all the eight domains of SF-36 (i.e., physical functioning score, role physical score, bodily pain score, general health perception score, vitality score, social functioning score, role emotional score, and mental health score); physical component summary score, and mental physical component summary score, compared with those without ED. On multivariate analysis, factors associated with ED were older age, longer duration of cirrhosis, CTP-C (vs. CTP-A), higher hepatic venous pressure gradient (HVPG), presence of generalized anxiety disorder (GAD), presence of major depression, and lower appendicular skeletal muscle index measured by dual-energy X-ray absorptiometry (DEXA ASMI). Conclusion: ED is common in men with cirrhosis, and men with ED have poor HRQOL compared with those without ED. Older age, longer duration of cirrhosis, CTP-C (vs. CTP-A), higher HVPG, presence of GAD, presence of major depression, and lower DEXA ASMI are associated with ED.

Differential blood transcriptome modules predict response to corticosteroid therapy in alcoholic hepatitis.

BACKGROUND & AIMS: In patients with severe alcoholic hepatitis (SAH), little is known about the profile of peripheral blood mononuclear cells (PBMCs) at baseline and during corticosteroid therapy, among those who can be treated successfully with steroids (steroid-responders [R] and those who cannot (steroid-non-responders [NR]); 2 groups with different outcomes. METHODS: We performed RNA-seq analysis in PBMCs from 32 patients with definite SAH, at baseline and after 7 days of corticosteroids. The data were sorted into R and NR (n = 16, each group) using the Lille model and 346 blood transcription modules (BTMs) were identified. BTMs are predefined modules of highly co-expressed PBMC genes, which can determine specific immune cell types and cellular functions. The activity of each BTM was taken as the mean value of its member genes. RESULTS: At baseline, 345 BTMs had higher activity (i.e. were upregulated) in NR relative to R. The 100 most upregulated BTMs in NR, included several modules related to lymphoid lineage (T, B, and natural killer [NK] cells), modules for cell division and mitochondrial respiratory electron transport chain (ETC, relating to energy production), but only a few modules of myeloid cells. Correlation studies of BTM activities found features of significantly greater activation/proliferation and differentiation for T and B cells in NR relative to R. After 7 days of corticosteroids, NR had no significant changes in BTM activities relative to baseline, whereas R had downregulation of BTMs related to innate and adaptive immunity. CONCLUSIONS: At baseline and during corticosteroid therapy, increased activity in the PBMCs of gene modules related to activation/proliferation and differentiation of T and B cells, NK cells, and mitochondrial ETC, is a hallmark of SAH patients who are steroid-non-responders. LAY SUMMARY: Patients with severe alcoholic hepatitis receive steroid therapy as the main line of treatment; however, this treatment is ineffective in some patients. This only becomes apparent after 7 days of steroid therapy. We have developed an approach where it can be estimated if a patient is going to respond or not to steroid therapy using the gene expression information of blood cells. This method will allow clinicians to assess the response of patients to steroids earlier, and will help them in adopting alternate strategies if the treatment is found to be ineffective in a particular patient.

Management Practices and Predictors of Outcome of Liver Abscess in Adults: A Series of 1630 Patients from a Liver Unit.

BACKGROUND: The management practices of liver abscess (LA) have evolved over time. The precise diagnosis of etiology and complications is pivotal for appropriate management. METHODS: Descriptive analyses of consecutive patients treated for LA using electronic medical records at a liver unit between years 2010 and 2020 and investigate relationships between clinical, imaging, laboratory and microbiological findings, treatment strategies and mortality. RESULTS: Of 1630 LA patients, the most common aetiologies were amoebic liver abscess (ALA; 81%) and pyogenic liver abscess (PLA; 10.3%, mainly related to biliary disease and/or obstruction). Abdominal pain (86%) and fever (85.3%) were the commonest presenting symptoms (median duration-10 days). Almost 10% had jaundice at presentation, 31.1% were diabetic, 35.5% had chronic alcohol use and 3.3% had liver cirrhosis. Nearly 54% LA were solitary, 77.7% localized to the right liver lobe (most commonly segment VII/VIII). Patients with large LA (>10 cm, 11.9%) had more frequent jaundice and abscess rupture (p-0.01). Compared with ALA, patients with PLA were older, more often had multiple and bilobar abscesses with local complications. Over four-fifth of the patients received percutaneous interventions (catheter drainage [PCD; 36.1%] alone and needle aspiration [PNA] plus PCD [34.1%] as most common). Fifty-eight patients underwent endoscopic retrograde cholangiography for intrabiliary abscess rupture (n = 36) or cholangitic abscess (n = 22). The median duration of hospital stay and PCD were 7 (4-10) days and 5 (4-8 days), respectively. The overall in-hospital mortality was 1.1%. Presence of septic encephalopathy (HR: 20.8; 95% CI: 1.9-220.7; p-0.012), liver cirrhosis (HR: 20.1; 95% CI: 2.7-146.9; p-0.003) and jaundice (HR: 7.6; 95% CI:1.7-33.1; p-0.006) were independent predictors of mortality. CONCLUSIONS: The commonest presentation was middle age male with right lobe solitary ALA. Patients with large, bilobar and/or pyogenic abscess had more complications. Nearly 70% patients require percutaneous interventions, which if given early improve treatment outcomes. Presence of jaundice, liver cirrhosis and septic encephalopathy were independent predictors of mortality.

Drug-induced liver injury: Asia Pacific Association of Study of Liver consensus guidelines.

Idiosyncratic drug-induced liver injury mimics acute and chronic liver disease. It is under recognized and underrecognised because of the lack of pathognomonic diagnostic serological markers. Its consequences may vary from being asymptomatic to self-limiting illness to severe liver injury leading to acute liver failure. Its incidence is likely to be more common in Asia than other parts of the world, mainly because of hepatotoxicity resulting from the treatment of tuberculosis disease and the ubiquitous use of traditional and complimentary medicines in Asian countries. This APASL consensus guidelines on DILI is a concise account of the various aspects including current evidence-based information on DILI with special emphasis on DILI due to antituberculosis agents and traditional and complementary medicine use in Asia.

Prevalence of and Factors Associated with Sleep-Wake Abnormalities in Patients with Cirrhosis.

BACKGROUND & AIMS: Sleep-wake abnormalities [poor nighttime sleep and excessive daytime sleepiness (EDS)] are common in patients with cirrhosis. The aim of this study was to assess the prevalence of sleep-wake abnormalities and clinical factors associated with these abnormalities in a group of patients with cirrhosis. METHODS: 1098 patients with cirrhosis [Child Turcotte Pugh (CTP) class A, 22.2%; CTP class B, 29.2% and CTP class C, 48.6%], with either no ascites or mild ascites controlled on diuretics, and no history of or current overt hepatic encephalopathy were included in the study. RESULTS: Poor nighttime sleep and EDS were found in 569 (51.8%) and 489 (44.5%) patients respectively. On multivariate analysis, factors associated with poor nighttime sleep were CTP class C (vs. class A), presence of minimal hepatic encephalopathy (MHE), intermediate or evening type of diurnal preference category (vs. morning type), high risk for obstructive sleep apnea (OSA), diuretic use, presence of major depression, and presence of generalized anxiety disorder (GAD). Factors associated with EDS on multivariate analysis were CTP class B and C (vs. class A), intermediate or evening type of diurnal preference category (vs. morning type), high risk for OSA, presence of major depression, and presence of GAD. CONCLUSIONS: Sleep-wake abnormalities are common in patients with cirrhosis. CTP status, diurnal preference chronotype, risk of OSA, major depression and GAD are associated with both poor nighttime sleep and EDS. MHE and diuretic use are associated with poor nighttime sleep, but not with EDS.

Left Ventricular Diastolic Dysfunction is Associated with Renal Dysfunction, Poor Survival and Low Health Related Quality of Life in Cirrhosis.

BACKGROUND: The presence of left ventricular diastolic dysfunction (LVDD) in patients with cirrhosis leads to a restriction of activities and a poor health related quality of life (HRQoL), which should be taken into consideration when treating them for liver and cardiac complications. AIMS: The prevalence, complications, predictors of HRQoL and survival in cirrhotic patients with LVDD were studied. METHODS: We report a prospective cohort study of 145 consecutive cirrhotic patients with LVDD who were evaluated for cardiac functional status at enrollment and followed up for hepatic complications, cardiac events, outcome and HRQoL using the Minnesota Living With Heart Failure Questionnaire (MLHFQ) over a period of 2 years. RESULTS: In total, 145 (mean age 61 years, 59% male) patients were included. Seventeen patients died with 10.5%, 22.5% and 40% mortality rates in patients with Grades 1, 2 and 3 LVDD respectively over 24 months. The parameters that were significant for predicting mortality on bivariate analysis were MELD, MELDNa, hepatic venous pressure gradient, MLHFQ, and left ventricular (LV) diastolic function (e' and E/e' ratio), but only MELD, MELDNa and E/e' remained significant on multivariate analysis. The E/e' ratio (8.7 ± 3.3 in survivors vs. 9.1 ± 2.3 in non-survivors) predicted outcome. On univariate analysis, the predictors of poor HRQoL were the Child-Pugh score ≥9.8 (OR 2.6; 95% confidence intervals (CI) 2.3-9.1, P = 0.041), MELD score ≥ 15.7 (OR 2.48; 95% CI 1.4-3.9, P = 0.029), refractory ascites (OR 1.9; 95% CI 1.1-6.1, P = 0.050), and E/e' ratio ≥7.6 (OR 1.9; 95% CI 1.8-7.1, P = 0.036) The presence of Class II/III (P = 0.046) symptoms of heart failure and MLHFQ≥ 45 (P = 0.042) were predictors of mortality at 24 months. CONCLUSION: The grade of LVDD correlates with liver function, clinical events, risk of renal dysfunction and HRQoL. Evaluation of novel therapies which target symptomatic improvement in LVDD, should be done with suitable outcome measures, including HRQoL assessment.

Senescent Hepatocytes in Decompensated Liver Show Reduced UPRMT and Its Key Player, CLPP, Attenuates Senescence In Vitro.

BACKGROUND AND AIMS: Non-dividing hepatocytes in end-stage liver disease indicates permanent growth arrest similar to senescence. Identifying senescence in vivo is often challenging and mechanisms inhibiting senescence are poorly understood. In lower organisms mitochondrial unfolded protein response (UPRMT) helps in increasing longevity; however, its role in senescence and liver disease is poorly understood. Aim of this study was to identify hepatocyte senescence and the role of UPRMT in cryptogenic cirrhosis. METHODS: Doxorubicin was used to induce senescence in non-neoplastic hepatocytes (PH5CH8) and hepatoma cells (HepG2 and Huh7). Senescence-associated markers and unfolded protein response was evaluated by fluorescence microscopy, immunoblotting and gene expression. Explants/biopsies from normal, fibrosis, compensated and decompensated cirrhosis without any known etiology were examined for presence of senescence and UPRMT by immunohistochemistry and gene expression. RESULTS: Accumulation of senescent hepatocytes in cryptogenic cirrhosis was associated with reduced proliferation, increased expression of γH2AX and p21, together with loss of LaminB1. Dysfunctional mitochondria and compromised UPRMT were key features of senescent hepatocytes both in vitro and also in decompensated cirrhosis. Intriguingly, compensated cirrhotic liver mounted strong UPRMT, with high levels of mitochondrial protease, CLPP. Overexpression of CLPP inhibited senescence in vitro, by reducing mitochondrial ROS and altering oxygen consumption. CONCLUSIONS: Our results implicate a role of hepatocyte senescence in cryptogenic cirrhosis together with a crucial role of UPRMT in preventing hepatocyte senescence. A compromised UPRMT may shift the fate of cirrhotic liver toward decompensation by exaggerating hepatocyte senescence. Restoring CLPP levels at least in cell culture appears as a promising strategy in mitohormesis, thereby, preventing senescence and possibly improving hepatocyte function.

Baseline urine metabolic phenotype in patients with severe alcoholic hepatitis and its association with outcome.

Severe alcoholic hepatitis (SAH) has a high mortality rate, and corticosteroid therapy is effective in 60% patients. This study aimed to investigate a baseline metabolic phenotype that could help stratify patients not likely to respond to steroid therapy and to have an unfavorable outcome. Baseline urine metabolome was studied in patients with SAH using ultra-high performance liquid chromatography and high-resolution mass spectrometry. Patients were categorized as responders (Rs, n = 52) and nonresponders (NRs, n = 8) at day 7 according to the Lille score. Multivariate projection analysis identified metabolites in the discovery cohort (n = 60) and assessed these in a validation cohort of 80 patients (60 Rs, 20 NRs). A total of 212 features were annotated by using metabolomic/biochemical/spectral databases for metabolite identification. After a stringent selection procedure, a total of nine urinary metabolites linked to mitochondrial functions significantly discriminated nonresponders, most importantly by increased acetyl-L-carnitine (12-fold), octanoylcarnitine (4-fold), decanoylcarnitine (4-fold), and alpha-ketoglutaric acid (2-fold) levels. Additionally, urinary acetyl-L-carnitine and 3-hydroxysebasic acid discriminated nonsurvivors (P < 0.01). These urinary metabolites significantly correlated to severity indices and mortality (r > 0.3; P < 0.01) and were associated with nonresponse (odds ratio >3.0; P < 0.001). In the validation cohort, baseline urinary acetyl-L-carnitine documented an area under the receiver operating curve of 0.96 (0.85-0.99) for nonresponse prediction and a hazard ratio of 3.5 (1.5-8.3) for the prediction of mortality in patients with SAH. Acetyl-L-carnitine at a level of >2,500 ng/mL reliably segregated survivors from nonsurvivors (P < 0.01, log-rank test) in our study cohort. Conclusion: Urinary metabolome signatures related to mitochondrial functions can predict pretherapy steroid response and disease outcome in patients with SAH. (Hepatology Communications 2018;2:628-643).

Pre-therapy liver transcriptome landscape in Indian and French patients with severe alcoholic hepatitis and steroid responsiveness.

Patients with severe alcoholic hepatitis (SAH) not responding to glucocorticoid therapy have higher mortality, though they do not differ in their baseline clinical characteristics and prognostic scores from those who respond to therapy. We hypothesized that the baseline hepatic gene expression differs between responders (R) and non-responders (NR). Baseline liver transcriptome was compared between R and NR in Indian (16 each) and French (5 NR, 3 R) patients with SAH. There were differentially expressed genes (DEGs) between NR and R, in Indian (1106 over-expressed, 96 under-expressed genes) and French patients (65 over-expressed, 142 under-expressed genes). Indian NR had features of hepatocyte senescence and French NR exhibited under-expression of genes involved in cell division, indicating a central defect in the capacity of hepatocytes for self-renewal in both populations. Markers of hepatic progenitor cell proliferation were either very few (Indian patients) or absent (French patients). No DEGs were enriched in inflammatory pathways and there were no differences in nuclear receptor subfamily 3 group C member 1 (NR3C1) transcript expression and splicing between NR and R. Our results reveal that baseline hepatic transcriptome is reflective of subsequent glucocorticoid non-response and indicate impaired regenerative potential of the liver as an underlying phenomenon in NR.