Javier Michelena

A Histologic Scoring System for Prognosis of Patients With Alcoholic Hepatitis

BACKGROUND & AIMS There is no histologic classification system to determine prognoses of patients with alcoholic hepatitis (AH). We identified histologic features associated with disease severity and created a histologic scoring system to predict short-term (90-day) mortality. METHODS We analyzed data from 121 patients admitted to the Liver Unit (Hospital Clinic, Barcelona, Spain) from January 2000 to January 2008 with features of AH and developed a histologic scoring system to determine the risk of death using logistic regression. The system was tested and updated in a test set of 96 patients from 5 academic centers in the United States and Europe, and a semiquantitative scoring system called the Alcoholic Hepatitis Histologic Score (AHHS) was developed. The system was validated in an independent set of 109 patients. Interobserver agreement was evaluated by weighted κ statistical analysis. RESULTS The degree of fibrosis, degree of neutrophil infiltration, type of bilirubinostasis, and presence of megamitochondria were independently associated with 90-day mortality. We used these 4 parameters to develop the AHHS to identify patients with a low (0-3 points), moderate (4-5 points), or high (6-9 points) risk of death within 90 days (3%, 19%, and 51%, respectively; P < .0001). The AHHS estimated 90-day mortality in the training and test sets with an area under the receiver operating characteristic value of 0.77 (95% confidence interval, 0.71-0.83). Interrater agreement values were 0.65 for fibrosis, 0.86 for bilirubinostasis, 0.60 for neutrophil infiltration, and 0.46 for megamitochondria. Interestingly, the type of bilirubinostasis predicted the development of bacterial infections. CONCLUSIONS We identified histologic features associated with the severity of AH and developed a patient classification system that might be used in clinical decision making.

Systemic inflammatory response and serum lipopolysaccharide levels predict multiple organ failure and death in alcoholic hepatitis.

Alcoholic hepatitis (AH) frequently progresses to multiple organ failure (MOF) and death. However, the driving factors are largely unknown. At admission, patients with AH often show criteria of systemic inflammatory response syndrome (SIRS) even in the absence of an infection. We hypothesize that the presence of SIRS may predispose to MOF and death. To test this hypothesis, we studied a cohort including 162 patients with biopsy‐proven AH. The presence of SIRS and infections was assessed in all patients, and multivariate analyses identified variables independently associated with MOF and 90‐day mortality. At admission, 32 (19.8%) patients were diagnosed with a bacterial infection, while 75 (46.3%) fulfilled SIRS criteria; 58 patients (35.8%) developed MOF during hospitalization. Short‐term mortality was significantly higher among patients who developed MOF (62.1% versus 3.8%, P < 0.001). The presence of SIRS was a major predictor of MOF (odds ratio = 2.69, P = 0.025) and strongly correlated with mortality. Importantly, the course of patients with SIRS with and without infection was similar in terms of MOF development and short‐term mortality. Finally, we sought to identify serum markers that differentiate SIRS with and without infection. We studied serum levels of high‐sensitivity C‐reactive protein, procalcitonin, and lipopolysaccharide at admission. All of them predicted mortality. Procalcitonin, but not high‐sensitivity C‐reactive protein, serum levels identified those patients with SIRS and infection. Lipopolysaccharide serum levels predicted MOF and the response to prednisolone. Conclusion: In the presence or absence of infections, SIRS is a major determinant of MOF and mortality in AH, and the mechanisms involved in the development of SIRS should be investigated; procalcitonin serum levels can help to identify patients with infection, and lipopolysaccharide levels may help to predict mortality and the response to steroids. (Hepatology 2015;62:762–772)

Acute Kidney Injury Is an Early Predictor of Mortality for Patients With Alcoholic Hepatitis

BACKGROUND & AIMS Alcoholic hepatitis (AH) is a severe condition with high mortality. To improve therapeutic strategies, it is important to identify factors that affect survival times. The age, bilirubin, international normalized ratio, and creatinine scoring system (also known as the ABIC scoring system) was developed previously to determine the prognosis of patients with AH. We studied effects of acute kidney injury (AKI) on survival of patients with AH. METHODS We retrospectively analyzed data from 103 patients with biopsy-proven AH. AKI was defined as an abrupt reduction (within 48 h) in kidney function that resulted in an absolute increase of at least 0.3 mg/dL (or a 50% increase) in serum levels of creatinine from baseline (the AKI network [AKIN] criteria). RESULTS Twenty-nine patients (28%) developed AKI during hospitalization, with a median time to diagnosis of 3 days. Overall 90-day mortality was 23%, which was significantly higher among patients with AKI than those without (65% vs 7%; P < .0001). The age, bilirubin, international normalized ratio, and creatinine score (P < .0001) and development of AKI (P < .0001) were the most accurate independent predictors of 90-day mortality. The presence of systemic inflammatory response syndrome (P < .0001), serum bilirubin (P = .01), and international normalized ratio at admission (P = .03) were the most accurate predictors of AKI. Importantly, the AKIN criteria were more accurate than traditional criteria for renal failure (serum creatinine >1.5 mg/dL) in predicting 90-day mortality (area under the receiver operating characteristic, 0.83 vs 0.70, respectively; P = .02). CONCLUSIONS Development of AKI reduces survival of patients with AH, in the short term. The AKIN criteria are useful and more accurate than traditional criteria in predicting mortality. Strategies to prevent AKI therefore should be considered in the management of patients with AH.

Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis

We identified, in the transcriptome analysis of patients with alcoholic hepatitis (AH), osteopontin (OPN) as one of the most up‐regulated genes. Here, we used a translational approach to investigate its pathogenic role. OPN hepatic gene expression was quantified in patients with AH and other liver diseases. OPN protein expression and processing were assessed by immmunohistochemistry, western blotting and enzyme‐linked immunosorbent assay. OPN gene polymorphisms were evaluated in patients with alcoholic liver disease. The role of OPN was evaluated in OPN−/− mice with alcohol‐induced liver injury. OPN biological actions were studied in human hepatic stellate cells (HSCs) and in precision‐cut liver slices. Hepatic expression and serum levels of OPN were markedly increased in AH, compared to normal livers and other types of chronic liver diseases, and correlated with short‐term survival. Serum levels of OPN also correlated with hepatic expression and disease severity. OPN was mainly expressed in areas with inflammation and fibrosis. Two proteases that process OPN (thrombin and matrix metalloproteinase 7) and cleaved OPN were increased in livers with AH. Patients with AH had a tendency of a lower frequency of the CC genotype of the +1239C single‐nucleotide polymorphism of the OPN gene, compared to patients with alcohol abuse without liver disease. Importantly, OPN−/− mice were protected against alcohol‐induced liver injury and showed decreased expression of inflammatory cytokines. Finally, OPN was induced by lipopolysaccharide and stimulated inflammatory actions in HSCs. Conclusion: Human and experimental data suggest a role for OPN in the pathogenesis of AH. Further studies should evaluate OPN as a potential therapeutic target. (Hepatology 2013;58:1742–1756)

The Amount of Alcohol Consumption Negatively Impacts Short-Term Mortality in Mexican Patients With Alcoholic Hepatitis

OBJECTIVES:Mexicans have an increased rate of alcohol abuse and alcoholic liver disease. Factors influencing the severity of alcoholic hepatitis (AH) in Mexicans are unknown. The aims of the present study were to identify the prognostic factors of short-term mortality in Mexican patients with AH and to validate the existing prognostic models.METHODS:One hundred seventy-five consecutive patients with AH were recruited from four hospital centers in Mexico. Demographic, clinical, and biochemical parameters were obtained at admission. Univariate and multivariate logistic regression analyses were used for the identification of prognostic factors. The accuracy of different models was evaluated by their area under the receiver operating characteristic (AUROC) curve and comparative risk analysis was performed using the Kaplan–Meier method.RESULTS:Age, serum creatinine, serum bilirubin, leukocyte count, and alcohol consumption >120 g/day were independently associated with short-term mortality. The impact of alcohol consumption was significant among patients with severe AH (48 vs. 72% risk of death, P=0.03). The AUROC (95% confidence interval) curves for the different scores were Maddreys discriminant function 0.79 (0.72–0.86); model for end-stage liver disease (MELD) 0.83 (0.75–0.89); Glasgow AH score 0.77 (0.70–0.84); and age–bilirubin–international normalized ratio–creatinine (ABIC) score 0.82 (0.75–0.88). The ABIC score allowed an accurate stratification into three different risk subgroups with 13%, 50%, and 81% mortality rate at 90 days (P<0.001).CONCLUSIONS:The amount of alcohol consumption has a negative impact on short-term mortality among Mexicans with AH. The ABIC score is useful and comparable with MELD score for the prognostic stratification of these patients.

Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: Prediction and impact on long-term survival

Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease. Most studies have focused on short‐term prognosis, whereas factors associated with long‐term survival are largely unknown. The aims of our study were to (1) determine the impact of complete abstinence from alcohol on long‐term survival and (2) identify prognostic factors at admission capable of predicting abstinence during long‐term follow‐up in patients with AH. One hundred forty‐two patients with biopsy‐proven AH that survived the first episode were included. Demographic, psychiatric, and biochemical variables at admission and drinking status during follow‐up were obtained. Cox regression, logistic regression, and classification and regression trees (CART) analyses were used for statistical analysis. Overall mortality was 38% with a median follow‐up of 55 months. During follow‐up, complete abstinence was reported in 39% and was associated with better long‐term survival (hazard ratio, 0.53; P = 0.03). After adjustment for baseline prognostic scoring systems (Model for End‐Stage Liver Disease and age, bilirubin, international normalized ratio, creatinine scores), complete abstinence was independently associated with survival (P < 0.05). Age and lack of past alcoholism treatments were independently associated with complete abstinence (P < 0.001 and P = 0.02, respectively) during follow‐up. CART analysis generated a simple and practical algorithm based on the combination of past alcoholism treatments and age. Using CART analysis, we stratified 2 subgroups of patients with high (65%) and low (26%‐29%) rates of complete abstinence after an episode of AH. Conclusion: Complete abstinence after an episode of AH positively impacts long‐term survival. The combination of 2 variables easily obtained at admission might be useful to predict long‐term abstinence after an episode of AH. Strategies aimed at promoting alcohol abstinence in these patients are necessary. (Hepatology 2017;66:1842–1853)

Enfermedad hepática inducida por el alcohol

Alcohol induced liver disease Alcoholic liver disease comprises different clinical diseases from pure fatty liver to cirrhosis. The pathogenesis is complex, including the direct toxic effects of alcohol and genetic and environmental factors. Alcoholic hepatitis, frequently associated to cirrhosis, is the most characteristic disease and its clinical presentation ranges from asymptomatic cases to severe forms with a high shortterm mortality. Alcohol abstinence is the most important prognostic factor and, consequently, the most effective treatment. In severe alcoholic hepatitis, apart from supportive measures and the improvement of nutritional status, corticosteroids are the only treatment recommended in the clinical guidelines. However, only a proportion of patients benefit from corticosteroids and, on the other hand, this treatment has important adverse effects, especially severe infections. Thus, it is necessary to look for new therapies based on a better knowledge of the pathogenesis. In patients with cirrhosis, liver transplantation is the only possible treatment in those who remain abstinent. Palabras Clave: - Hepatitis alcoholica - Esteatosis - Cirrosis - Abstinencia - Corticosteroides - Trasplante hepatico

Overexpression of angiopoietin-2 in rats and patients with liver fibrosis. Therapeutic consequences of its inhibition

Studies in experimental models of cirrhosis showed that anti‐angiogenic treatments may be effective for the treatment of liver fibrosis. In this context, angiopoietins are potential therapeutic targets as they are involved in the maintenance and stabilization of newly formed blood vessels. In addition, angiopoietin‐2 is expressed in fibrotic livers and its inhibition in tumours results in vessel stability. Therefore, our study was aimed to assess the therapeutic utility of inhibiting angiopoietin‐2.

Nutrition in Alcoholic Steatohepatitis

Alcoholic steatohepatitis (ASH) is characterized by hepatocellular necrosis, ballooning degeneration, inflammatory reaction with polymorphonuclear leukocyte infiltration and fibrosis [1]. The severity of ASH ranges from asymptomatic cases to severe forms identified by the presence of encephalopathy or a discriminant function greater than 32. More recently, other severity scores such as the ABIC (age, bilirubin, INR and creatinine) identified patients with mild, moderate and severe ASH. The risk of death within 2 months after diagnosis is 40–50 % in patients with severe ASH [2]. Corticosteroids are the recommended treatment in patients with severe ASH, but a significant percentage of patients do not respond to steroid treatment or have severe complications, especially bacterial infections [3]. Therefore, the search for alternative therapeutic options is mandatory.

Alcohol consumption as a cofactor for other liver diseases

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