Decompensated Alcoholic Liver Disease Research Articles

Lipid and renal profile in assessing the severity of alcoholic liver disease.

Lipid and Renal dysfunction in Alcoholic liver disease (ALD) patients occurs either due to multi-organ involvement or secondary to alcoholism. This study was conducted to evaluate the role of lipid and renal parameters in assessing the severity of progression of ALD. Sixty cases of ALD (two groups based on compensated and decompensated features) and thirty healthy controls for comparison were included. Lipid profile (Total Cholesterol, LDL, HDL and Triglycerides) and renal parameters (serum urea, creatinine and uric acid), total and direct bilirubin, total protein and albumin were measured using automated chemistry analyzer. There was a significant decrease in Total cholesterol ,LDL and HDL levels and increased triglycerides when compared to controls (mean of 128.4 ± 59 vs 155 ± 27.2, 77 ± 44.3 vs 97.4 ± 27.2, 28.3 ± 18 vs 39.5 ± 14.1 and 115.8 ± 70.4 vs 91 ± 38 mg/dL respectively). Lipid profile showed a linear decrease while progressing from compensated to decompensated ALD. Renal parameters revealed a statistically significant decrease in serum urea ,increased creatinine and uric acid levels when compared to controls (17.57±2.96 vs23.73±4.94, 1.12±0.55 vs0.88±0.16,6.60±1.32 vs 4.68±1.40 mg/dL respectively).Total cholesterol and HDL showed a linear decrease when ALD progresses. Serum uric acid showed an early increase in compensated stage of ALD. This study inferred that Total cholesterol, TGL, HDL and uric acid can be used for assessing the severity of progression of ALD.

IL-1 receptor like 1 protects against alcoholic liver injury by limiting NF-κB activation in hepatic macrophages

Alcohol consumption increases intestinal permeability and causes damage to hepatocytes, leading to the release of pathogen- and damage-associated molecular pattern molecules (PAMPs and DAMPs), stimulating hepatic macrophages and activating NF-κB. The resultant inflammation exacerbates alcoholic liver disease (ALD). However, much less is known about the mechanisms attenuating inflammation and preventing disease progression in most heavy drinkers. Interleukin (IL)-33 is a DAMP (alarmin) released from dead cells that acts through its receptor, IL-1 receptor like 1 (ST2). ST2 signaling has been reported to either stimulate or inhibit NF-κB activation. The role of IL-33/ST2 in ALD has not been studied. Serum levels of IL-33 and its decoy receptor, soluble ST2 (sST2) were measured in ALD patients. Alcohol-induced liver injury, inflammation and hepatic macrophage activation were compared between wild-type, IL-33-/- and ST2-/- mice in several models. Elevation of serum IL-33 and sST2 were only observed in patients with severe decompensated ALD. Consistently, in mice with mild ALD without significant cell death and IL-33 release, IL-33 deletion did not affect alcohol-induced liver damage. However, ST2-deletion exacerbated ALD, through enhancing NF-κB activation in liver macrophages. In contrast, when extracellular IL-33 was markedly elevated, liver injury and inflammation were attenuated in both IL-33-/- and ST2-/- mice compared to wild-type mice. Our data revealed a dichotomous role of IL-33/ST2 signaling during ALD development. At early and mild stages, ST2 restrains the inflammatory activation of hepatic macrophages, through inhibiting NF-κB, and plays a protective function in an IL-33-independent fashion. During severe liver injury, significant cell death and marked IL-33 release occur, which triggers IL-33/ST2 signaling and exacerbates tissue damage. In mild ALD, ST2 negatively regulates the inflammatory activation of hepatic macrophages, thereby protecting against alcohol-induced liver damage, whereas in the case of severe liver injury, the release of extracellular IL-33 may exacerbate tissue inflammation by triggering the canonical IL-33/ST2L signaling in hepatic macrophages.

Histological parameters and alcohol abstinence determine long-term prognosis in patients with alcoholic liver disease

Few data exist on predictors of long-term prognosis in patients with alcoholic liver disease (ALD). Most studies have only assessed short-term prognosis in patients with advanced ALD. We aimed to assess the prognostic impact of clinical, biochemical and histological parameters on long-term prognosis in patients with early/compensated and decompensated ALD. Consecutive patients (n=192) with biopsy-proven liver disease due to alcohol abuse were analyzed retrospectively. Prognostic factors were evaluated in patients with early/compensated ALD (n=60) and in patients with decompensated ALD (clinical decompensation and/or bilirubin >3mg/dl at entry) (n=132). Factors that predict long-term survival were identified using Cox regression models. Liver-related mortality at 5years was 13% in early/compensated and 43% in decompensated ALD. In early/compensated ALD patients, long-term prognosis was determined by fibrosis stage, but not by clinical or biochemical variables. Severe fibrosis (F3/4) was present in 52% and had a major impact on 10-year mortality (F3/4: 45% vs. F0-2: 0%, p<0.001). In contrast, in decompensated patients, a combination of clinical features (sex), biochemical markers of liver failure (bilirubin, international normalized ratio [INR]), and histological features (pericellular fibrosis) predicted long-term survival. During follow-up, abstinence from alcohol was an important predictor of survival in both early/compensated and decompensated ALD. Fibrosis stage is the main predictor of long-term survival in patients with early/compensated ALD, while clinical, biochemical and histological parameters predict survival in patients with decompensated disease. Promoting abstinence may improve survival in patients with both early and advanced ALD. In this study, we evaluated long-term outcome in 192 patients with alcoholic liver disease who underwent liver biopsy: 60 patients with early disease (no symptoms) and 132 patients with advanced disease (jaundice, complications of cirrhosis). Importantly, half of the patients with 'early' disease already had severe fibrosis or cirrhosis on liver histology and dismal outcome (45% mortality at 10years). Abstinence from alcohol improved the prognosis in both early and advanced stages of the disease.

Metronidazole-Induced Encephalopathy in Alcoholic Liver Disease: A Diagnostic and Therapeutic Challenge

BackgroundAcute encephalopathy in a patient with alcoholic liver disease (ALD) is a commonly encountered emergency situation occurring most frequently due to liver failure precipitated by varying etiologies. Acute reversible cerebellar ataxia with confusion secondary to prolonged metronidazole use has been reported rarely as a cause of encephalopathy in patients with ALD. Case ReportWe describe a decompensated ALD patient with recurrent pyogenic cholangitis associated with hepatolithiasis who presented to the emergency department with sudden-onset cerebellar ataxia with dysarthria and mental confusion after prolonged use of metronidazole. Magnetic resonance imaging (MRI) of the brain was suggestive of bilateral dentate nuclei hyper intensities on T2 and fluid-attenuated inversion recovery sections seen classically in metronidazole-induced encephalopathy (MIE). Decompensated liver cirrhosis resulted in decreased hepatic clearance and increased cerebrospinal fluid concentration of metronidazole leading to toxicity at a relatively low total cumulative dose of 22 g. Both the clinical symptoms and MRI brain changes were reversed at 7 days and 6 weeks, respectively, after discontinuation of metronidazole. Why Should an Emergency Physician Be Aware of This?A patient with ALD presenting with encephalopathy creates a diagnostic dilemma for the emergency physician regarding whether to continue metronidazole and treat for hepatic encephalopathy or to suspect for MIE and withhold the drug. Failure to timely discontinue metronidazole may worsen the associated hepatic encephalopathy in these patients. Liver cirrhosis patients have higher mean concentration of metronidazole and its metabolite in the blood, making it necessary to keep the cumulative dose of metronidazole to < 20 g in them.

PTU-085 Decompensated Alcoholic Liver Disease (ALD): High Long-Term Mortality Despite Initial Survival

IntroductionWhilst early management and outcome of decompensated ALD has been extensively studied, there are few published data on long-term outcome. We have previously (McFarlane, Gut 2006; 55:A2 and 55:A36) reported...

PTU-100 Decompensated Alcoholic Liver Disease (ALD) is Associated with Starting Heavy Drinking at an Older Age: a Case-Control Study

IntroductionThe relationship between development of ALD (which affects only 10–15% of heavy drinkers) and rate, duration and age of onset of alcohol consumption is incompletely understood. We have previously reported...

121 HIGH LIVER EXPRESSION OF SPINK-1 IS ASSOCIATED WITH PROGENITOR CELL AND HEPATOCYTE PROLIFERATION AND DETERMINES MELD SCORE IMPROVEMENT IN DECOMPENSATED ALCOHOLIC LIVER DISEASE

Background and aims: The prognostic significance of liver progenitor cell (LPC) and macrophage expansion in the regeneration of decompensated alcoholic liver disease (ALD) remain ill defined. In a well-characterized population of patients with acutely decompensated ALD (Hepatology 2011, A62), we analysed macrophage infiltration, proliferative LPC and differential expression of hepatic genes at baseline in relation to outcome at 3 months follow up. Methods: Fifty-eight patients (MELD 20) were included. Liver biopsy at inclusion was used for (1) immunohistological analysis of proliferative LPC (MIB1+/CK7+), proliferative hepatocytes (MIB1+/CK7- parenchymal cells), morphometric analysis of macrophage infiltration (CD68) and LPC expansion (CK7), and (2) transcriptome profiling using Affymetrix GeneChip Human arrays. Serum levels of HGF were determined by immunoassay. A ≥ 3 points decrease in MELD at 3 months as compared to baseline defined the improvers. Fifteen abstinent cirrhotics served as controls. CD68 and SPINK3 mRNA expression was determined in various mice models of liver injury. Results: At baseline, patients with decompensated ALD presented a significant expansion of CD68+ macrophages and CK7+ cells compared to abstinent cirrhotics. Patients who will improve (n=34) were characterized at baseline by a higher number of CK7+/MIB1+ cells (1.9 ± 1.5 versus 0.9 ± 0.9 cells/field, p<0.01), MIB1+ hepatocytes (4.1 ± 3.6 versus 1.8 ± 1.4 cells/field, p<0.01), an increased expansion of liver macrophages (4.4% versus 3.3% of surface area, p<0.05) and a higher level of serum HGF (p<0.05), compared to those who will not (n=24). Transcriptome analysis revealed that the first pathways upregulated in improvers were related to cell cycle and a 7-fold increase of liver serine peptidase inhibitor Kazal type I (SPINK1) compared with non-improvers (p=0.005). SPINK1 liver expression positively correlated with CD68 (r=0.46) and cyclinE1 (r=0.6). In mice, a 20-fold increase in liver SPINK3 expression, the homolog of human SPINK1, was evidenced following partial hepatectomy, concurrent with hepatocyte proliferation. Conclusions: Baseline markers of liver macrophages and liver cell proliferation predict the clinical outcome in decompensated ALD. This study reveals an unexpected implication of SPINK1, an acute phase reactant, in liver regeneration and human ALD.

Autologous Bone Marrow Mononuclear Cell Transplantation in Patients with Decompensated Alcoholic Liver Disease: A Randomized Controlled Trial

ObjectiveImpaired liver regeneration is associated with a poor outcome in patients with decompensated alcoholic liver disease (ALD). We assessed whether autologous bone marrow mononuclear cell transplantation (BMMCT) improved liver function in decompensated ALD.Design58 patients (mean age 54 yrs; mean MELD score 19, all with cirrhosis, 81% with alcoholic steatohepatitis at baseline liver biopsy) were randomized early after hospital admission to standard medical therapy (SMT) alone (n = 30), including steroids in patients with a Maddrey’s score ≥32, or combined with G-CSF injections and autologous BMMCT into the hepatic artery (n = 28). Bone marrow cells were harvested, isolated and reinfused the same day. The primary endpoint was a ≥3 points decrease in the MELD score at 3 months, corresponding to a clinically relevant improvement in liver function. Liver biopsy was repeated at week 4 to assess changes in Ki67+/CK7+ hepatic progenitor cells (HPC) compartment.ResultsBoth study groups were comparable at baseline. After 3 months, 2 and 4 patients died in the BMMCT and SMT groups, respectively. Adverse events were equally distributed between groups. Moderate alcohol relapse occurred in 31% of patients. The MELD score improved in parallel in both groups during follow-up with 18 patients (64%) from the BMMCT group and 18 patients (53%) from the SMT group reaching the primary endpoint (p = 0.43 (OR 1.6, CI 0.49–5.4) in an intention to treat analysis. Comparing liver biopsy at 4 weeks to baseline, steatosis improved (p<0.001), and proliferating HPC tended to decrease in both groups (−35 and −33%, respectively).ConclusionAutologous BMMCT, compared to SMT is a safe procedure but did not result in an expanded HPC compartment or improved liver function. These data suggest either insufficient regenerative stimulation after BMMCT or resistance to liver regenerative drive in patients with decompensated alcoholic cirrhosis.Trial RegistrationControlled-Trials.com ISRCTN83972743.

Decompensated alcoholic liver disease and birth weight

IntroductionOnly a minority of heavy drinkers develop serious alcoholic liver disease (ALD). Low birth weight has been associated with a several adult-onset diseases such as ischemic heart disease, hypertension and...

Spectrum of Liver Histology in Presumed Decompensated Alcoholic Liver Disease

In presumed decompensated alcoholic liver disease (ALD; liver decompensation, heavy alcohol intake, and negative results of noninvasive screening for other causes), liver biopsy is often performed to assess severity of liver injury and to rule out other liver diseases. The aim of the study is to describe the spectrum of liver histology in such patients. We reviewed all patients with presumed decompensated ALD seen between 1998 and 2004, in whom liver tissue was available for histology (N = 110). A total of 104 of the 110 patients had at least one of the histological features suggestive of ALD: fat, Mallory's hyalin, neutrophilic infiltrate, and hepatocyte ballooning. These features were more prevalent in tissue obtained within a month after presentation with decompensation than in that obtained before decompensation or more than 1 month after. These features were also associated with more severe liver dysfunction. Histology revealed a major additional diagnosis (Budd-Chiari syndrome) in only one case. In 41 patients biopsied within a month of first presentation with decompensation, Child score and Maddrey discriminant function (DF), but none of the histological features, were predictive of survival by Cox multivariate analysis. Of the 26 of these 41 patients with a Maddrey DF >32, 22 (85%) had alcoholic hepatitis. In patients with presumed decompensated ALD, other liver diseases are uncommon. Routine liver biopsy is of limited added value but biopsy should be considered in those in whom the noninvasive workup, or failure to recover despite abstinence, raises the possibility of other liver diseases.

MARS dialysis in decompensated alcoholic liver disease: A single-center experience

Acute decompensation of chronically stable alcoholic liver disease (ALD) is the most common cause of terminal liver failure in developed countries. Molecular adsorbent recirculation system (MARS) is increasingly used as artificial liver support to facilitate spontaneous organ recovery. However, the experience to date and the evidence to justify this therapeutic strategy in acutely decompensated ALD are still insufficient. We report our clinical experience with MARS in 14 patients with acutely decompensated ALD (6 male subjects; median age [interquartile range], 51 [47-56] years; Child-Pugh score, 12 [10-13]; Acute Physiology and Chronic Health Evaluation (APACHE) II score, 20 [18-24]) and severely impaired liver function whose disease was unresponsive to conventional supportive care. At least 3 sessions were applied in any patient (48 sessions in total). Under MARS treatment, the following levels decreased: bilirubin (544 [489-604] to 242 [178-348] micromol/L; P<0.001), creatinine (212 [112-385] to 91 [66-210] micromol/L; P=0.002), cholestatic parameter gamma-glutamyl transpeptidase (5.9 [1.8-13.1] to 4.6 [1.8-8.3] micromol/L) (P<0.001), blood urea nitrogen (56 [32-91] to 34 [21-68] mmol/L; P=0.044), and platelet count (176 [85-241] to 84 [31-145] Gpt/L; P=0.004). In contrast, MARS failed to improve daily urine output (P=0.846), ammonia levels (P=0.340), or thromboplastin time (P=0.775). Only 3 patients survived the hospital stay (mortality 78.6%). Although MARS improved laboratory parameters of hepatic detoxification and renal function in patients with acutely decompensated ALD, the patients' mortality remained unsatisfactorily high. Our experience does not support the indiscriminative use of MARS in acutely decompensated ALD without further controlled studies.

Liver disease in alcohol abusers: clinical perspective

Alcoholic liver disease remains one of the most common causes of chronic liver disease in the world. The severity of liver damage related to alcohol varies among different individuals and even within any given individual at different times. Certain symptoms, signs, and abnormal findings on laboratory tests help clinicians distinguish among the various stages of alcohol-induced liver damage and, thus, have some prognostic significance. However, because all stages of this disease can persist for decades without causing overt evidence of serious liver damage, liver biopsy is the only test that can reliably distinguish among the various stages of alcohol-induced liver damage in many patients. The therapy of alcohol-induced liver disease varies according to the severity of histologic liver damage and clinically overt portal hypertension and hepatic dysfunction. Abstinence from alcohol consumption improves the clinical outcome of all stages of alcoholic liver disease. However, only two agents have proved to lessen early mortality in patients who require hospitalization for acutely decompensated alcoholic liver disease. It is not known whether either of these agents or other treatments prevent the development of alcohol-induced cirrhosis or improve the survival of patients who have already developed cirrhosis.

Effect of Head-Out Water Immersion on Hepatorenal Syndrome

A 47-year-old patient with severe decompensated alcoholic liver disease developed a progressive deterioration of her renal function (serum creatinine 4.0 mg/dL) with a renal failure index (RFI: UNa/U/PCr) consistently less than 1.0. In the absence of other causes of renal failure, these values supported the diagnosis of hepatorenal syndrome (HRS). A five-hour head-out water immersion (HWI) in a sitting position was carried out to increase the patient's "effective" blood volume (EBV) in an attempt to reverse the HRS. Hemodynamic monitoring (Swan-Ganz) was performed during the entire HWI procedure. Cardiac index increased by 64% during HWI (2.57 to 4.22 L/min/m2). Stroke volume index doubled (32.9 to 65.0 mL/m2) and systemic vascular resistance decreased by 48% (1426 to 754 dyne sec/cm). Increases in right atrium (RA) pressure (7.5 to 17.5 mm Hg) and pulmonary wedge (PW) capillary pressure (7.5 to 16.3 mm Hg) also occurred. Hemoglobin, hematocrit, and plasma protein concentrations decreased by 18% during HWI. Only a modest improvement in creatinine, urea, inulin, and para-aminohippurate (PAH) clearances was observed during HWI, and the RFI remained below 1.0. Plasma levels of antidiuretic hormone (ADH), aldosterone, and renin activity decreased during HWI. The patient's renal function progressively deteriorated over the next 15 days, but tubular function, as assessed by an RFI less than 1.0, was still intact seven days after our study. Our results indicate that a considerable increase in effective blood volume does not restore renal function in HRS.