Diferencias por sexo y nivel de renta en la mortalidad y morbilidad directamente relacionadas con el alcohol en Navarra / Differences by sex and income level in mortality and morbidity directly related to alcohol consumption in Navarre

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Transplant Outcomes in Older Patients With Nonalcoholic Steatohepatitis Compared to Alcohol-related Liver Disease and Hepatitis C.

BACKGROUND: Patients with nonalcoholic steatohepatitis (NASH) are waitlisted at older ages than individuals with other liver diseases, but the effect of age on liver transplantation (LT) outcomes in this population and whether it differs from other etiologies is not known. We aimed to evaluate the impact of age on LT outcomes in NASH. METHODS: The United Network for Organ Sharing database was used to identify adults with NASH, hepatitis C virus (HCV) infection, and alcohol-related liver disease (ALD) listed for LT during 2004-2017. Patients were split into age groups (18-49, 50-54, 55-59, 60-64, 65-69, ≥70), and their outcomes were compared. RESULTS: From 2004 to 2017, 14 197 adults with NASH were waitlisted, and the proportion ≥65 increased from 15.8% to 28.9%. NASH patients ages 65-69 had an increased risk of waitlist and posttransplant mortality compared to younger groups, whereas the outcomes in ages 60-64 and 55-59 were similar. The outcomes of individuals with NASH were similar to patients of the same age group with ALD or HCV. Functional status and dialysis were predictors of posttransplant mortality in individuals ≥65 with NASH, and cardiovascular disease was the leading cause of death. CONCLUSIONS: Older NASH patients (≥65) have an increased risk of waitlist and posttransplant mortality compared to younger individuals, although outcomes were similar to patients with ALD or HCV of corresponding age. These individuals should be carefully evaluated prior to LT, considering their functional status, renal function, and cardiovascular risk. Further studies are needed to optimize outcomes in this growing population of transplant candidates.

Causes of Mortality in Non-Alcoholic Fatty Liver Disease (NAFLD) and Alcohol Related Fatty Liver Disease (AFLD).

Non-alcoholic fatty liver disease (NAFLD) and alcohol related fatty liver disease (AFLD) both represent a spectrum of liver disease severity from hepatic steatosis to fibrosis and cirrhosis. Both NAFLD and AFLD are common diseases in the general population. NAFLD affects ~25% of the adult global population whilst AFLD has become the commonest indication for liver transplantation in the United States. It is often not possible to distinguish between NAFLD and AFLD on examination of liver histology, consequently, differentiation between NAFLD and AFLD is heavily reliant on a history of alcohol consumption. Age, smoking, alcohol consumption and sex appear to influence the risk of mortality in NAFLD or AFLD. In NAFLD and AFLD, the key causes of increased liver-related mortality are advanced liver fibrosis and cirrhosis leading to complications such as hepatocellular carcinoma and decompensated cirrhosis. NAFLD and AFLD are also associated with an increased risk of all-cause mortality including an increased risk of extra-hepatic malignancy. Non-invasive biomarkers of liver disease severity in NAFLD and AFLD perform poorly to predict mortality. However, alanine aminotransferase, gamma-glutamyl transpeptidase, FIB-4 and the NAFLD Fibrosis Score are independently associated with increased mortality in NAFLD. Both NAFLD and AFLD are associated with extra-hepatic risk factors and complications such as metabolic syndrome encompassing obesity, hypertension, type 2 diabetes mellitus, and chronic kidney disease. AFLD is associated with hypertension and cardiovascular disease as well as other organ damage. This narrative review discusses the associations, risk factors and diagnostic biomarkers linking NAFLD and AFLD with increased mortality.

Long-term outcomes in patients with decompensated alcohol-related liver disease, steatohepatitis and Maddrey's discriminant function <32.

BACKGROUND & AIMS: Patients with alcoholic hepatitis and a modified Maddrey's discriminant function (mDF) <32 have a low risk of short-term mortality. However, few data exist concerning long-term outcomes. The aims of this study were to evaluate 5-year survival rates and to identify predictive factors for long-term prognosis in this patient population. METHODS: We studied patients from 2 centers who were admitted for hepatic decompensation (ascites, hepatic encephalopathy, or jaundice) and who had histological findings of steatohepatitis and an mDF <32. Clinical and biological parameters were recorded at the time of liver biopsy and alcohol consumption was recorded during follow-up. We performed Cox proportional hazard survival analysis to identify factors associated with 5-year survival. RESULTS: One hundred and twenty-one patients were included (male: 64%, mean age: 51.5 ± 10.3 years, presence of cirrhosis: 84%). The median model for end-stage liver disease and mDF scores were 14 (IQR 11.7-16.1) and 19 (IQR 11.1-24), respectively. During follow-up, 30% of the patients remained abstinent. Survival rates at 1, 6, 12, 24, and 60 months were 96.7 ± 1.6%, 90.1 ± 2.7%, 80.8 ± 3.6%, 69.9 ± 4.3%, and 50.7 ± 4.9%, respectively. The majority of deaths (80%) were liver related. In multivariable analysis, encephalopathy at baseline and alcohol abstinence were predictive of 5-year survival. The 5-year survival rates of patients without and with encephalopathy at baseline were 60.5 ± 5.8% and 29.7 ± 8.0%, respectively, and the 5-year survival rates of abstinent and non-abstinent patients were 74.0 ± 8.0% and 40.9 ± 5.8%, respectively. CONCLUSIONS: The mortality rate of patients with alcoholic hepatitis and an mDF <32 is around 50% at 5 years. Hepatic encephalopathy at baseline and lack of alcohol abstinence impair long-term prognosis. New treatment strategies, including measures to ensure abstinence, are required. LAY SUMMARY: Patients with alcoholic hepatitis that is of intermediate severity have a low risk of short-term mortality but not much is known regarding long-term outcomes for these patients. This study clearly indicates that patients with intermediate disease characteristics have poor long-term outcomes. The presence of hepatic encephalopathy at the time of diagnosis and the absence of alcohol abstinence during follow-up are factors that predict poor long-term mortality.

Changing trends in the disease burden of primary liver cancer caused by specific etiologies in China.

BACKGROUND: Liver cancer is a commonly diagnosed malignancy in China. The etiologies of liver cancer are widely known, although studies on temporal trends in liver cancer caused by specific etiologies are rare. METHODS: Data on the incidence and mortality of liver cancer were retrieved from the Global Burden of Diseases Study 2017. The estimated annual percentage change (EAPC) was used to quantify temporal trends in the age-standardized incidence rate (ASIR) and the age-standardized mortality rate (ASMR) of liver cancer from 1990 to 2017. RESULTS: Nationwide, the number of incident cases of liver cancer increased from 258 000 in 1990 to 515 900 in 2017. The ASIR decreased from 27.16 per 100 000 to 26.04 per 100 000 during this period, with an EAPC of -0.64 (95% confidence interval [CI] -0.84, -0.44). The number of deaths increased from 245 300 in 1990 to 418 200 in 2017, and the ASMR decreased from 26.72 to 21.30 (EAPC = -1.16, 95% CI -1.35, -0.97). The most pronounced decreases in the ASIR and ASMR were observed in liver cancer due to hepatitis B and in people aged 15-49 years. CONCLUSIONS: Since the extensive efforts for prevention of hepatitis B virus infection, the incidence of liver cancer due to hepatitis B has significantly decreased. However, liver cancer due to hepatitis C, NASH, and other causes remains a major public health concern. Additional preventive strategies tailored to liver cancer are needed to further reduce its disease burden in China.

Natural history of histologically proven alcohol-related liver disease: A systematic review.

BACKGROUND & AIMS: To date, studies into the natural history of alcohol-related liver disease (ALD) have lacked long-term follow-up, large numbers of participants, or both. We performed a systematic review to summarise studies that describe the natural history of histologically proven ALD. METHODS: PubMed and Medline were searched for relevant studies according to pre-specified criteria. Data were extracted to describe the prevalence of ALD, histological progression of disease and mortality. Single-proportion meta-analysis was used to combine data from studies regarding rates of progression or mortality. RESULTS: Thirty-seven studies were included, reporting data from 7,528 participants. Amongst cohorts of hazardous drinkers, on average 15% had normal histological appearance, 27% had hepatic steatosis, 24% had steatohepatitis and 26% had cirrhosis. The annualised rates of progression of pre-cirrhotic disease to cirrhosis were 1% (0-8%) for patients with normal histology, 3% (2-4%) for hepatic steatosis, 10% (6-17%) for steatohepatitis and 8% (3-19%) for fibrosis. Annualised mortality was 6% (4-7%) in patients with steatosis and 8% (5-13%) in cirrhosis. In patients with steatohepatitis on biopsy a marked difference was seen between inpatient cohorts (annual mortality 15%, 8-26%) and mixed cohorts of inpatients and outpatients (annual mortality 5%, 2-10%). Only in steatosis did non-liver-related mortality exceed liver-specific causes of mortality (5% per year vs. 1% per year). CONCLUSIONS: These data confirm the observation that alcohol-related hepatic steatohepatitis requiring admission to hospital is the most dangerous subtype of ALD. Alcohol-related steatosis is not a benign condition as it is associated with significant risk of mortality. LAY SUMMARY: Knowledge of the natural history of a disease allows clinicians and patients to understand the risks that are associated with a medical condition. In this study we systematically gathered all the published data regarding the natural history of alcohol-related liver disease in people who had a liver biopsy. We used this data to define the prevalence of the disease, the annual risk of progression to cirrhosis and the annual risk of death at each stage of the disease.

Alcoholic and Nonalcoholic Fatty Liver Disease and Liver-Related Mortality: A Cohort Study.

OBJECTIVES: We compared liver-related mortality by fibrosis severity between 2 types of fatty liver disease (FLD), nonalcoholic FLD (NAFLD) and alcoholic FLD (AFLD), in a large cohort of nonobese and obese individuals. METHODS: A cohort study was performed with 437,828 Korean adults who were followed up for up to 14 years. Steatosis was diagnosed based on ultrasonography; fibrosis severity was determined by the fibrosis 4 (FIB-4) score. Vital status and liver-related deaths were ascertained through linkage to national death records. RESULTS: The prevalence of NAFLD and AFLD was 20.9% and 4.0%, respectively. During 3,145,541.1 person-years of follow-up, 109 liver-related deaths were identified (incidence rate of 3.5 per 10 person-years). When changes in fatty liver status, FIB-4 scores, and confounders during follow-up were updated as time-varying covariates, compared with the reference (absence of both excessive alcohol use and FLD), the multivariable-adjusted hazard ratios with 95% confidence intervals for liver-related mortality among those with low, intermediate, and high FIB-4 scores were 0.43 (0.19-0.94), 2.74 (1.23-6.06), and 84.66 (39.05-183.54), respectively, among patients with NAFLD, whereas among patients with AFLD, the corresponding hazard ratios (95% confidence intervals) were 0.67 (0.20-2.25), 5.44 (2.19-13.49), and 59.73 (27.99-127.46), respectively. The associations were more evident in nonobese individuals than in obese individuals (P for interaction = 0.004). DISCUSSION: In this large cohort of young and middle-aged individuals, NAFLD and AFLD with intermediate to high fibrosis scores were associated with an increased risk of liver-related mortality in a dose-dependent manner, especially among nonobese individuals.

Metabolic factors affecting hepatocellular carcinoma in steatohepatitis.

BACKGROUND & AIMS: With the rising prevalence of alcoholism, obesity and metabolic syndrome, steatohepatitis will become the leading cause of end-stage liver disease and hepatocellular carcinoma in the United States by 2025. Patients with non-alcoholic steatohepatitis and alcoholic liver disease have similar clinical and histopathological presentations, whether these similarities persist in non-alcoholic steatohepatitis and alcoholic liver disease patients with hepatocellular carcinoma remains unknown. METHODS: A retrospective analysis of the clinical features of adult patients from a large transplant center who underwent liver transplantation for steatohepatitis due to non-alcoholic steatohepatitis and alcoholic causes (alcoholic liver disease) between 1/1/02 and 1/1/12 was performed. Clinical features, explant histopathology, and clinical outcomes were compared. RESULTS: Hepatocellular carcinoma was present in 80 of 317 patients, who underwent liver transplantation for steatohepatitis with equivalent distribution in non-alcoholic steatohepatitis and alcoholic liver disease patients (24% vs 26%; P = 0.8). On multivariate analysis, significant predictors of hepatocellular carcinoma included age, ethnicity (Hispanic), and diabetes, but not BMI, hypertension or smoking. A lower risk of hepatocellular carcinoma was associated with a clinical history of hyperlipidemia. Clinical parameters were similar between patients with alcoholic liver disease - hepatocellular carcinoma and non-alcoholic steatohepatitis-hepatocellular carcinoma, except sex and presence of metabolic syndrome. non-alcoholic steatohepatitis-hepatocellular carcinoma livers retained histopathological features of non-alcoholic steatohepatitis such as ballooning and Mallory bodies, while alcoholic liver disease-hepatocellular carcinoma livers did not. There were no significant differences in hepatocellular carcinoma recurrence rates or post-transplant overall survival. CONCLUSIONS: We report the largest single-center study evaluating clinical, histopathological and outcome measures of patients undergoing liver transplantation for steatohepatitis. Older patients, diabetics, and Hispanics may warrant more frequent cancer screening due to increased risk of hepatocellular carcinoma.

The sex specific effect of alcohol consumption on circulating levels of CTRP3.

The goal of this project was to establish the effect of alcohol consumption on the circulating levels of the adipose tissue derived protein C1q TNF Related Protein 3 (CTRP3). Adipose tissue secretes several adipokines, such as adiponectin and leptin, which exert a multitude of biological effects important for human health. However, adipose tissue is extremely sensitive to alcohol consumption, leading not only to disrupted fat storage, but also to disruptions in adipokine production. Changes to adipokine secretion could have widespread biological effects and potentially contribute to alcohol-induced ailments, such as alcoholic fatty liver disease (ALD). CTRP3 has been previously demonstrated to attenuate fatty liver disease, and suppression of CTRP3 with alcohol consumption could contribute to development of and progression to alcoholic fatty liver disease. To examine the effect of ethanol consumption on circulating adipokine levels, male and female mice were fed an ethanol containing diet (Lieber-DeCarli 5% (v/v) ethanol diet) for 10-days followed by a single gavage of 5 g/kg ethanol (the NIAAA model), or for 6-weeks with no binge added (chronic model). In female mice, adiponectin levels increased ~2-fold in both models of ethanol feeding, but in male mice increased adiponectin levels were only observed after chronic ethanol feeding. On the other hand, in female mice, circulating CTRP3 levels decreased by ~75% and ~50% in the NIAAA and chronic model, respectively, with no changes observed in the male mice in either feeding model. Leptin levels were unchanged with ethanol feeding regardless of model or sex of mice. Lastly, chronic ethanol feeding led to a significant increase in mortality (~50%) in female mice, with no difference in relative ethanol consumption. These findings indicate that ethanol consumption can dysregulate adipokine secretion, but that the effects vary by sex of animal, method of ethanol consumption, and adipokine examined. These findings also indicate that female mice are more sensitive to the chronic effects of ethanol than male mice. Notably, this is the first study to document the effects of ethanol consumption on the circulating levels of CTRP3. Understanding the impact of excessive alcohol consumption on adipokine production and secretion could identify novel mechanisms of alcohol-induced human disease. However, the mechanism responsible for the increased sensitivity remains elusive.

Presence of alcoholic steatohepatitis, but no selective histological feature, indicates an increased risk of cirrhosis and premature death.

OBJECTIVE: The prognostic impact of early stages of histologically confirmed alcoholic liver disease is uncertain. Our aim was to determine the risk of cirrhosis and premature death, and identify prognostic markers, in patients with biopsy-proven alcoholic steatohepatitis - and to compare prognosis in patients with alcoholic pure fatty liver and the general population. MATERIAL AND METHODS: Patients with biopsy-proven alcoholic fatty liver disease diagnosed during 1976-1987 were identified. Data were collected from medical records, the Danish National Patient Registry and the Registry of Causes of Death. All biopsies were re-examined and morphological findings assessed. A reference cohort matched for age and gender was created. Cox proportional hazard models adjusted for age and gender were used to analyse differences in mortality and cirrhosis development, as well as the prognostic impact of histological and biochemical parameters. RESULTS: Two hundred and twenty-five patients with fatty liver and 111 with steatohepatitis were followed for median 13 and 9.7 years, respectively. There was a significantly higher risk of developing cirrhosis amongst patients with steatohepatitis compared to both patients with fatty liver (p < 0.001) and the reference cohort (p < 0.001). Mortality was significantly higher in patients with steatohepatitis compared to patients with fatty liver (p = 0.046) and the general population (p < 0.001). No histological or biochemical parameters with prognostic significance for mortality were identified. CONCLUSION: Presence of steatohepatitis indicates an increased risk of cirrhosis and premature death. However, none of the histological parameters defining steatohepatitis can independently identify patients at risk for premature death.

Contribution of Alcoholic and Nonalcoholic Fatty Liver Disease to the Burden of Liver-Related Morbidity and Mortality.

Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. NAFLD is associated with obesity and metabolic syndrome whereas ALD is associated with excessive alcohol consumption. Both diseases can progress to cirrhosis, hepatocellular carcinoma, and liver-related death. A higher proportion of patients with NAFLD die from cardiovascular disorders than patients with ALD, whereas a higher proportion of patients with ALD die from liver disease. NAFLD and ALD each are associated with significant morbidity, impairment to health-related quality of life, and economic costs to society.

Epidemiology of alcoholic liver disease in Denmark 2006-2011: a population-based study.

AIMS: To describe incidence, prevalence, hospitalization rates and survival for alcoholic liver disease (ALD) in Denmark 2006-2011. METHODS: Using nationwide healthcare registries we identified all Danish residents with a hospital diagnosis of ALD and computed standardized incidence, prevalence, and hospitalization rates in 2006-2011, age- and birth cohort-specific incidence for the 1930-1974 birth cohorts, and 1- and 5-year survival. RESULTS: In 2006-2011, the overall standardized ALD incidence decreased from 343 to 311 per 1,000,000 population per year. ALD incidence increased among women aged 65 years or older, but decreased in younger persons and men. Persons born in 1950-1959 had higher age-specific incidence than earlier and later birth cohorts. The prevalence (0.2% of the Danish adult population) and hospitalization rate were constant. The 1- and 5-year survival were 43 and 70%, respectively. CONCLUSION: In Denmark, persons born in 1950-1959 have had the highest age-specific incidence. The overall ALD incidence has been decreasing (along with per capita consumption). Despite increases in affordability during the study period, Denmark did not experience the increase in ALD seen, for example, in the UK. It is possible that this is due to the greater impact of government recommendations on safer drinking in Denmark than the UK.

Long-term follow-up and liver-related death rate in patients with non-alcoholic and alcoholic related fatty liver disease.

BACKGROUND: Few studies have compared the prognosis and liver-related mortality in patients with NAFLD (nonalcoholic fatty liver disease) and AFLD (alcoholic fatty liver disease). We aimed to investigate the etiology and liver-related mortality of patients with liver biopsy verified fatty liver disease in a population based setting. METHODS: In this retrospective study, all patients who underwent a liver biopsy 1984-2009 at the National University Hospital of Iceland were identified through a computerized pathological database with the code for fatty liver. Only patients with NAFLD and AFLD were included and medical records reviewed. The patients were linked to the Hospital Discharge Register, the Causes of Death Registry and Centre for Addiction Medicine. RESULTS: A total of 151 had NAFLD and 94 AFLD with median survival of 24 years and 20 years, respectively (p = NS). A total of 10/151 (7%) patients developed cirrhosis in the NAFLD group and 19/94 (20%) in AFLD group (p = 0.03). The most common cause of death in the NAFLD group was cardiovascular disease (48%). Liver disease was the most common cause of death in the AFLD group (36%), whereas liver-related death occurred in 7% of the NAFLD group. The mean liver-related death rate among the general population during the study period was 0.1% of all deaths. There was a significantly worse survival for patients in the AFLD group compared to the NAFLD group after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.16, p = 0.009). The survival for patients with moderate to severe fibrosis was significantly worse than for patients with mild fibrosis after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.09, p = 0.01). CONCLUSIONS: Patients with fatty liver disease showed a markedly higher risk of developing liver-related death compared to the general population. The AFLD group had higher liver-related mortality and had a worse survival than the NAFLD group. Patients with more severe fibrosis at baseline showed a worse survival than patients with none or mild fibrosis at baseline.

Hiperglucemia, cetoacidosis y lesión de Armanni-Ebstein: un caso ilustrativo / Hyperglycemia, ketoacidosis and Armanni-Ebstein lesion: an illustrative case

La cetoacidosis es una alteración metabólica que puede conducir a la muerte de forma rápida e inesperada y, por tanto, ser objeto de una autopsia judicial. Histológicamente se caracteriza por el hallazgo de vacuolas subnucleares en los túbulos proximales renales, la denominada lesión de Armanni-Ebstein (AE). Aunque suele ser de etiología diabética también puede tener otro origen, fundamentalmente alcohólico. Presentamos el caso de una mujer de 45 años con una historia de abuso de alcohol, se encuentra fallecida en su domicilio. Se observó hialinosis arteriolar, lesión AE en riñones y esteatosis en hígado; el estudio químico-toxicológico demostró cuerpos cetónicos en sangre y el análisis bioquímico del humor vítreo niveles de glucosa elevados. Se discute el origen más probable de cetoacidosis y la necesidad de un abordaje multidisciplinar en la investigación de las muertes súbitas inesperadas (AU)

The ketoacidosis is a metabolic disorder that may lead to unexpected sudden death and therefore be issued for a forensic autopsy. Its histopathology is characterized by subnuclear vacuoles in the renal proximal tubules, namely the Armanni-Ebstein (AE) lesion. It is usually caused by diabetes, although other origins are possible, mainly alcoholic abuse. We hereby show the case of a 45-year-old woman with a history of alcohol consumption found dead at her home. An arteriolar hyalinosis, AE lesion in kidneys and steatosis in the liver were found; results revealed ketonic bodies in blood and a high glucose value in vitreous humour. The most probable cause of ketoacidosis is discussed and also the need for a multidisciplinary approach in unexpected sudden deaths investigations (AU)

Steroids or pentoxifylline for alcoholic hepatitis (STOPAH): study protocol for a randomised controlled trial.

BACKGROUND: Alcoholic hepatitis is the most florid presentation of alcohol-related liver disease. In its severe form, defined by a Maddrey's discriminant function (DF) ≥32, the 28-day mortality rate is approximately 35%. A number of potential treatments have been subjected to clinical trials, of which two, corticosteroids and pentoxifylline, may have therapeutic benefit. The role of corticosteroids is controversial as trial results have been inconsistent, whereas the role of pentoxifylline requires confirmation as only one previous placebo-controlled trial has been published. METHODS/DESIGN: STOPAH is a multicentre, double-blind, factorial (2 × 2) trial in which patients are randomised to one of four groups:1. Group A: placebo / placebo2. Group B: placebo / prednisolone3. Group C: pentoxifylline / placebo4. Group D: pentoxifylline / prednisoloneThe trial aims to randomise 1,200 patients with severe alcoholic hepatitis, in order to provide sufficient power to determine whether either of the two interventions is effective. The primary endpoint of the study is mortality at 28 days, with secondary endpoints being mortality at 90 days and 1 year. DISCUSSION: STOPAH aims to be a definitive study to resolve controversy around the existing treatments for alcoholic hepatitis. Eligibility criteria are based on clinical parameters rather than liver biopsy, which are aligned with standard clinical practice in most hospitals. The use of a factorial design will allow two treatments to be evaluated in parallel, with efficient use of patient numbers to achieve high statistical power. TRIAL REGISTRATION: EudraCT reference number: 2009-013897-42 ISRCTN reference number: ISRCTN88782125.

Update on the management of alcoholic steatohepatitis.

Among heavy drinkers with liver disease, the development of severe alcoholic hepatitis (AH) is a serious complication. Prognosis is grave and associated with a high mortality due to liver failure, hepatorenal syndrome or intractable sepsis. Clinically, AH presents as a syndrome of progressive inflammatory liver injury in patients with recent or ongoing heavy alcohol consumption. Although approximately 20% of alcoholics undergoing liver biopsy reveal histological features of AH, only a minority progress to severe AH with markedly elevated serum liver enzymes, jaundice and impaired liver function. To establish the diagnosis of AH, histology is recommended but not mandatory. Prognostic scores include the Maddrey's discriminant function, the model of end-stage liver disease, the Glasgow Alcoholic Hepatitis score, and the ABIC score. While the former scores identify patients at risk of death or the need for corticosteroids, the response to corticosteroid therapy can be assessed using the Lille model. Treatments include abstinence and enteral nutrition, while pharmacotherapy using corticosteroids either with or without N-acetylcysteine may be indicated for patients with severe AH. Pentoxifylline was found to reduce the risk of hepatorenal syndrome, but data on mortality are limited. Although considered a contraindication in most transplant centers, recent evidence indicates that carefully selected patients with AH could be good candidates for liver transplantation with a prognosis comparable to other indications.

Successful transplantation of reduced-sized rat alcoholic fatty livers made possible by mobilization of host stem cells.

Livers from Lewis rats fed with 7% alcohol for 5 weeks were used for transplantation. Reduced sized (50%) livers or whole livers were transplanted into normal DA recipients, which, in this strain combination, survive indefinitely when the donor has not been fed alcohol. However, none of the rats survived a whole fatty liver transplant while six of seven recipients of reduced sized alcoholic liver grafts survived long term. SDF-1 and HGF were significantly increased in reduced size liver grafts compared to whole liver grafts. Lineage-negative Thy-1+CXCR4+CD133+ stem cells were significantly increased in the peripheral blood and in allografts after reduced size fatty liver transplantation. In contrast, there were meager increases in cells reactive with anti Thy-1, CXCR4 and CD133 in peripheral blood and allografts in whole alcoholic liver recipients. The provision of plerixafor, a stem cell mobilizer, salvaged 5 of 10 whole fatty liver grafts. Conversely, blocking SDF-1 activity with neutralizing antibodies diminished stem cell recruitment and four of five reduced sized fatty liver recipients died. Thus chemokine insufficiency was associated with transplant failure of whole grafts, which was overcome by the increased regenerative requirements promoted by the small grafts and mediated by SDF-1 resulting in stem cell influx.

Cirrhosis and mortality risks of biopsy-verified alcoholic pure steatosis and steatohepatitis: a nationwide registry-based study.

BACKGROUND: Alcoholic fatty liver disease comprises alcoholic pure steatosis and alcoholic steatohepatitis. These diseases are prevalent, but their prognostic outcome is uncertain, particularly regarding the impact of hepatic inflammation. The paucity of data based on liver biopsy diagnoses contributes to this uncertainty. AIM: To examine the cirrhosis and mortality risks of Danish men and women with biopsy-verified alcoholic pure steatosis or steatohepatitis. METHODS: In this registry-based historical cohort study we combined liver biopsy diagnoses with hospital discharge diagnoses from nationwide healthcare registries to identify all Danish citizens with alcoholic pure steatosis (N = 136) or alcoholic steatohepatitis (N = 58) during 1997-2008. We enrolled a reference cohort of 100 gender- and age-matched persons from the general population for each patient and compared cirrhosis and mortality risks through 2010. RESULTS: The 5-year cirrhosis risks were 6.9% (95% CI: 3.4-12.2%) for patients with alcoholic pure steatosis and 16.0% (95% CI: 7.8-26.8%) for patients with alcoholic steatohepatitis, their 5-year mortality risks were 16.7% (95% CI: 11.3-24.2%) and 25.1% (95% CI: 15.7-38.9%), respectively. Patients with steatohepatitis had a higher liver-related mortality than patients with pure steatosis. In the reference cohort, the 5-year cirrhosis and mortality risks were 0.3% and 4.3%, respectively. CONCLUSIONS: Patients with alcoholic fatty liver disease had markedly increased cirrhosis and mortality risks compared with a matched reference cohort. The cirrhosis risk was more than twice as high for the patients with steatohepatitis than for those with pure steatosis; and was higher for women than for men.

Early liver biopsy, intraparenchymal cholestasis, and prognosis in patients with alcoholic steatohepatitis.

BACKGROUND: Alcoholic steatohepatitis (ASH) is a serious complication of alcoholic liver disease. The diagnosis of ASH requires the association of steatosis, evidence of hepatocellular injury with ballooning degeneration, and polynuclear neutrophil infiltration on liver biopsy. Whether these lesions, in addition to other histological features observed in liver tissue specimens, have prognostic significance is unclear. METHODS: We studied 163 patients (age 55 yrs [35-78], male/female 102/61) with recent, heavy (> 80 gr/day) alcohol intake, histologically-proven ASH (97% with underlying cirrhosis, Maddrey's score 39 [13-200], no sepsis), who had a liver biopsy performed 3 days [0-10] after hospital admission for clinical decompensation. A semi-quantitative evaluation of steatosis, hepatocellular damage, neutrophilic infiltration, periportal ductular reaction, intraparenchymal cholestasis, and iron deposits was performed by two pathologists. All patients with a Maddrey's score ≥ 32 received steroids. The outcome at 3 months was determined. Statistical analysis was performed using the Wilcoxon and Fisher's exact tests, Kaplan-Meier method, and the Cox proportional hazard model. RESULTS: 43 patients died after 31 days [5-85] following biopsy. The 3-month survival rate was 74%. Mean kappa value for histological assessment by the two pathologists was excellent (0.92). Univariate analysis identified age, the Maddrey's score, the Pugh's score, the MELD score and parenchymal cholestasis, but not other histological features, as factors associated with 3-month mortality. At multivariate analysis, age (p = 0.029, OR 2.83 [1.11-7.2], intraparenchymal cholestasis (p = 0.001, OR 3.9 [1.96-7.8], and the Maddrey's score (p = 0.027, OR 3.93 [1.17-13.23] were independent predictors of outcome. Intraparenchymal cholestasis was more frequent in non survivors compared to survivors (70% versus 25%, p < 0.001). Serum bilirubin was higher in patients with severe compared to those with no or mild intraparenchymal cholestasis (238 [27-636] versus 69 [22-640] umol/l, p < 0.001). CONCLUSIONS: In this large cohort of patients with histologically documented ASH early after admission and no sepsis, liver biopsy identified marked intraparenchymal cholestasis as an independent predictor of poor short term outcome together with age and the Maddrey's score. It may be hypothesized that incorporation of this particular variable into existing disease severity scores for ASH would improve their performance.