BACKGROUND AND AIMSAlcoholic hepatitis (AH) is the most florid manifestation of alcoholic liver disease. In this study, we examined the clinical characteristics and risk factors associated with ...mortality in hospitalized AH patients in the United States using the 2007 Nationwide inpatient sample of the Healthcare Cost and Utilization Project.
METHODSPatients who were hospitalized with the primary diagnosis of AH in the United States in 2007 were identified using International Classification of Diseases-9 code. We further characterized these subjects based on associated symptoms (such as ascites, hepatic encephalopathy, and coagulopathy), complications during hospitalization (such as sepsis, pneumonia, spontaneous bacterial peritonitis, and acute renal failure), and categories pertaining to hospital characteristics, such as teaching status. The predictors of mortality were calculated using logistic regression analyses.
RESULTSThere were 8,043,415 in-patient admissions, of which 56,809 (0.71%) were hospitalized with the primary diagnosis of AH. The mean age was 53.2 years, and 27% were female. The average length of stay was 6.5±7.7 days and 3,881 subjects (6.8%) died during hospitalization. Medicare and Medicaid were the main primary expected payer sources (51.8%) with the average total charges during hospital stay of $37,769. In the multivariate analyses, older age, presence of sepsis, spontaneous bacterial peritonitis, pneumonia, urinary tract infection, acute renal failure, hepatic encephalopathy, and coagulopathy were independently associated with in-patient mortality.
CONCLUSIONSIn-hospital mortality rate for AH remains high, especially in those with infectious complications, hepatic encephalopathy, coagulopathy, and acute renal failure. Our analysis documented significant healthcare cost and utilization among hospitalized AH patients.
Alcoholic liver diseases comprise a spectrum of clinical disorders and changes in liver tissue that can be detected by pathology analysis. These range from steatosis to more severe signs and symptoms ...of liver disease associated with inflammation, such as those observed in patients with alcoholic hepatitis or cirrhosis. Although the relationship between alcohol consumption and liver disease is well established, severe alcohol-related morbidities develop in only a minority of people who consume alcohol in excess. Inter-individual differences in susceptibility to the toxic effects of alcohol have been studied extensively—they include pattern of alcohol consumption, sex, environmental factors (such as diet), and genetic factors, which vary widely among different parts of the world. Alcoholic liver disease is becoming more common in many parts of Asia, but is decreasing in Western Europe. Treatment approaches, including availability of medications, models of care, and approach to transplantation, differ among regions.
It is generally recommended that patients with nonalcoholic fatty liver disease (NAFLD) not consume alcohol. However, because these patients are at increased cardiovascular risk, and light to ...moderate alcohol consumption may have hepatic benefits in people with or at risk for NAFLD, this recommendation may be ill-advised. We reviewed the literature on alcohol consumption and NAFLD and conclude that (i) heavy consumption has many harmful effects, including those on the liver, and should be discouraged whether a person has NAFLD or not; (ii) it is unknown whether cardiovascular and metabolic benefits of light to moderate consumption observed in the general population extend to those with NAFLD; (iii) epidemiological and cohort studies suggesting that light to moderate drinking may have hepatic benefits are largely cross-sectional and used surrogate end points; and (iv) until further data from rigorous prospective studies become available, people with NAFLD should avoid alcohol of any type or amount.
To examine the association between macronutrient dietary patterns and alcohol consumption using the Third National Health and Nutritional Examination Survey III.
A total of 9877 subjects (5144 males) ...constituted the study cohort. Dietary interviews were conducted with all examinees by a trained dietary interviewer in a mobile examination center (MEC). Subjects reported all foods and beverages consumed except plain drinking water for the previous 24-h time period. Physical examination and history of alcohol consumption were obtained. Pearson correlation coefficients were used to evaluate the association of the levels of alcohol consumption and the percentage of energy derived from macronutrients. Univariate and multivariate regression analyses were performed accounting for the study sampling weight to further explore the relationships between alcohol consumption and calories derived from each macronutrient.
Subjects who drank were younger than non-drinker controls in both genders (P < 0.01). Alcohol intake was inversely associated with body mass index and body weight in women. Of all macronutrients, carbohydrate intake was the first to decrease with increasing alcohol consumption. In the multivariate analyses, the level of alcohol consumption was found to be an independent predictor associated with lower intake of other macronutrients.
Our results show that there is an alteration in the daily dietary pattern with increasing alcohol consumption and that energy derived from alcoholic beverages substitutes that from other macronutrients such as carbohydrate, protein, and fat.
MicroRNAs are small non-coding RNAs that range in length from 18 to 24 nucleotides. As one of the most extensively studied microRNAs, microRNA-21 (miR-21) is highly expressed in many mammalian cell ...types. It regulates multiple biological functions such as proliferation, differentiation, migration, and apoptosis. In this review, we summarized the mechanism of miR-21 in the pathogenesis of various liver diseases. While it is clear that miR-21 plays an important role in different types of liver diseases, its use as a diagnostic marker for specific liver disease or its therapeutic implication are not ready for prime time due to significant variability and heterogeneity in the expression of miR-21 in different types of liver diseases depending on the studies. Additional studies to further define miR-21 functions and its mechanism in association with each type of chronic liver diseases are needed before we can translate the bedside observations into clinical settings.
Alcoholic hepatitis(AH)is an acute hepatic inflammation associated with significant morbidity and mortality.Current evidence suggests that the pathogenesis is the end result of the complex interplay ...between ethanol metabolism,inflammation and innate immunity.Several clinical scoring systems have been derived to predict the clinical outcomes of patients with AH;such as Child-Turcotte-Pugh score,the Maddrey discriminant function,the Lille Model,the model for end stage liver disease scores,and the Glasgow alcoholic hepatitis score.At present,Corticosteroids or pentoxifylline are the current pharmacologic treatment options;though the outcomes from the therapies are poor.Liver trans-plantation as the treatment of alcoholic hepatitis remains controversial,and in an era of organ shortage current guidelines do not recommend transplantation as the treatment option.Because of the limitations in the therapeutic options,it is no doubt that there is a critical need for the newer and more effective pharmacological agents to treat AH.
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•ALDH2 deficiency is associated with an increased risk of HCC from cirrhosis in those who drink alcohol.•Chronic CCl4+EtOH treatment induces greater hepatic mitochondrial DNA damage ...in Aldh2-deficient mice than WT mice.•Oxidized mitochondrial DNA is delivered to HCC cells via hepatocyte-derived extracellular vesicles.•Oxidized mitochondrial DNA and acetaldehyde synergistically promote ROS production and multiple oncogenic pathways.
Excessive alcohol consumption is one of the major causes of hepatocellular carcinoma (HCC). Approximately 30–40% of the Asian population are deficient for aldehyde dehydrogenase 2 (ALDH2), a key enzyme that detoxifies the ethanol metabolite acetaldehyde. However, how ALDH2 deficiency affects alcohol-related HCC remains unclear.
ALDH2 polymorphisms were studied in 646 patients with viral hepatitis B (HBV) infection, who did or did not drink alcohol. A new model of HCC induced by chronic carbon tetrachloride (CCl4) and alcohol administration was developed and studied in 3 lines of Aldh2-deficient mice: including Aldh2 global knockout (KO) mice, Aldh2*1/*2 knock-in mutant mice, and liver-specific Aldh2 KO mice.
We demonstrated that ALDH2 deficiency was not associated with liver disease progression but was associated with an increased risk of HCC development in cirrhotic patients with HBV who consumed excessive alcohol. The mechanisms underlying HCC development associated with cirrhosis and alcohol consumption were studied in Aldh2-deficient mice. We found that all 3 lines of Aldh2-deficient mice were more susceptible to CCl4 plus alcohol-associated liver fibrosis and HCC development. Furthermore, our results from in vivo and in vitro mechanistic studies revealed that after CCl4 plus ethanol exposure, Aldh2-deficient hepatocytes produced a large amount of harmful oxidized mitochondrial DNA via extracellular vesicles, which were then transferred into neighboring HCC cells and together with acetaldehyde activated multiple oncogenic pathways (JNK, STAT3, BCL-2, and TAZ), thereby promoting HCC.
ALDH2 deficiency is associated with an increased risk of alcohol-related HCC development from fibrosis in patients and in mice. Mechanistic studies reveal a novel mechanism that Aldh2-deficient hepatocytes promote alcohol-associated HCC by transferring harmful oxidized mitochondrial DNA-enriched extracellular vesicles into HCC and subsequently activating multiple oncogenic pathways in HCC.
Alcoholics with an ALDH2 polymorphism have an increased risk of digestive tract cancer development, however, the link between ALDH2 deficiency and hepatocellular carcinoma (HCC) development has not been well established. In this study, we show that ALDH2 deficiency exacerbates alcohol-associated HCC development both in patients and mouse models. Mechanistic studies revealed that after chronic alcohol exposure, Aldh2-deficient hepatocytes produce a large amount of harmful oxidized mitochondrial DNA via extracellular vesicles, which can be delivered into neighboring HCC cells and subsequently activate multiple oncogenic pathways, promoting HCC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Sestrin proteins have been implicated in multiple biological processes including resistance to oxidative and genotoxic stresses, protection against aging-related pathologies, and promotion of ...metabolic homeostasis; however, the underlying mechanisms are incompletely understood. Some evidence suggests that sestrins may inhibit mTORC1 (mechanistic target of rapamycin complex 1) through inhibition of RagA/B GTPases or activation of AMPK; however, whether sestrins are also involved in mTORC2 regulation and function is unclear. To investigate the functions and mechanisms of Sestrin 3 (Sesn3), we generated Sesn3 liver-specific transgenic and knockout mice. Our data show that Sesn3 liver-specific knockout mice exhibit insulin resistance and glucose intolerance, and Sesn3 transgenic mice were protected against insulin resistance induced by a high-fat diet. Using AMPK liver-specific knockout mice, we demonstrate that the Sesn3 insulin-sensitizing effect is largely independent of AMPK. Biochemical analysis reveals that Sesn3 interacts with and activates mTORC2 and subsequently stimulates Akt phosphorylation at Ser473. These findings suggest that Sesn3 can activate Akt via mTORC2 to regulate hepatic insulin sensitivity and glucose metabolism.
Once ingested, most of the alcohol is metabolized in the liver by alcohol dehydrogenase to acetaldehyde. Two additional pathways of acetaldehyde generation are by microsomal ethanol oxidizing system ...(cytochrome P450 2E1) and catalase
Acetaldehyde can form adducts which can interfere with cellular function, leading to alcohol-induced liver injury. The variants of alcohol metabolizing genes encode enzymes with varied kinetic properties and result in the different rate of alcohol elimination and acetaldehyde generation. Allelic variants of these genes with higher enzymatic activity are believed to be able to modify susceptibility to alcohol-induced liver injury; however, the human studies on the association of these variants and alcohol-associated liver disease are inconclusive. In addition to acetaldehyde, the shift in the redox state during alcohol elimination may also link to other pathways resulting in activation of downstream signaling leading to liver injury.
MATα1 catalyzes the synthesis of S-adenosylmethionine, the principal biological methyl donor. Lower MATα1 activity and mitochondrial dysfunction occur in alcohol-associated liver disease. Besides ...cytosol and nucleus, MATα1 also targets the mitochondria of hepatocytes to regulate their function. Here, we show that mitochondrial MATα1 is selectively depleted in alcohol-associated liver disease through a mechanism that involves the isomerase PIN1 and the kinase CK2. Alcohol activates CK2, which phosphorylates MATα1 at Ser114 facilitating interaction with PIN1, thereby inhibiting its mitochondrial localization. Blocking PIN1-MATα1 interaction increased mitochondrial MATα1 levels and protected against alcohol-induced mitochondrial dysfunction and fat accumulation. Normally, MATα1 interacts with mitochondrial proteins involved in TCA cycle, oxidative phosphorylation, and fatty acid β-oxidation. Preserving mitochondrial MATα1 content correlates with higher methylation and expression of mitochondrial proteins. Our study demonstrates a role of CK2 and PIN1 in reducing mitochondrial MATα1 content leading to mitochondrial dysfunction in alcohol-associated liver disease.
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