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INTRODUCTION: Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction. METHODS: Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days. RESULTS: In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9-55.0 years). The median MELD score was 23.5 (interquartile range 20.5-27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC. DISCUSSION: These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality.

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Anaemia is defined by the presence of haemoglobin (Hb) levels < 13 g/dL in men and 12 g/dL in women. Up to 39% of cancer patients present it at the time of diagnosis and up to 40% have iron deficiency. Anaemia causes fatigue, functional deterioration and a reduction in the quality of life; it has also been associated with a poorer response to anti-tumour treatment and lower survival. Basic diagnostic tests for anaemia are simple and should be a routine part of clinical practice. These guidelines review the available evidence on the use of different therapies for treating anaemia: erythropoiesis-stimulating agents, iron supplements, and transfusion of blood products (AU)

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Anaemia is defined by the presence of haemoglobin (Hb) levels < 13 g/dL in men and 12 g/dL in women. Up to 39% of cancer patients present it at the time of diagnosis and up to 40% have iron deficiency. Anaemia causes fatigue, functional deterioration and a reduction in the quality of life; it has also been associated with a poorer response to anti-tumour treatment and lower survival. Basic diagnostic tests for anaemia are simple and should be a routine part of clinical practice. These guidelines review the available evidence on the use of different therapies for treating anaemia: erythropoiesis-stimulating agents, iron supplements, and transfusion of blood products.

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Secreted protein, acidic and rich in cysteine (SPARC) is involved in many biological process including liver fibrogenesis, but its role in acute liver damage is unknown. To examine the role of SPARC in acute liver injury, we used SPARC knock-out (SPARC(-/-)) mice. Two models of acute liver damage were used: concanavalin A (Con A) and the agonistic anti-CD95 antibody Jo2. SPARC expression levels were analyzed in liver samples from patients with acute-on-chronic alcoholic hepatitis (AH). SPARC expression is increased on acute-on-chronic AH patients. Knockdown of SPARC decreased hepatic damage in the two models of liver injury. SPARC(-/-) mice showed a marked reduction in Con A-induced necroinflammation. Infiltration by CD4+ T cells, expression of tumor necrosis factor-α and interleukin-6 and apoptosis were attenuated in SPARC(-/-) mice. Sinusoidal endothelial cell monolayer was preserved and was less activated in Con A-treated SPARC(-/-) mice. SPARC knockdown reduced Con A-induced autophagy of cultured human microvascular endothelial cells (HMEC-1). Hepatic transcriptome analysis revealed several gene networks that may have a role in the attenuated liver damaged found in Con A-treated SPARC(-/-) mice. SPARC has a significant role in the development of Con A-induced severe liver injury. These results suggest that SPARC could represent a therapeutic target in acute liver injury.

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BACKGROUND/AIMS: High-conductance Ca(2+)-activated K(+) (BK(Ca)) channels modulate the effects of vasoactive factors in contractile cells. It is unknown whether hepatic stellate cells (HSCs) contain BK(Ca) channels and what their role in the regulation of HSCs contractility is. METHODS: The presence of BK(Ca) channels in HSCs was assessed by the patch-clamp technique. The functional role of BK(Ca) channels was investigated by measuring intracellular calcium concentration ([Ca(2+)](i)) and cell contraction in individual cells after stimulation with endothelin-1 in the presence or absence of specific modulators of BK(Ca) channels. RESULTS: BK(Ca) channels were detected by patch-clamp in most of the activated HSCs studied. Incubation of cells with iberiotoxin, a BK(Ca) channel blocker, increased both the sustained phase of [Ca(2+)](i) elicited by endothelin-1 and the number of cells undergoing contraction, while the use of NS1619, a BK(Ca) channel opener, induced opposite effects. Stimulation of HSCs with S-nitroso-N-acetyl-penicillamine (SNAP), a nitric oxide (NO)-donor, increased the opening of BK(Ca) channels and reduced the effects of endothelin-1. Conversely, iberiotoxin abolished the inhibitory effect of SNAP on endothelin-induced [Ca(2+)](i) increase and cell contraction. CONCLUSIONS: Activated human HSCs contain BK(Ca) channels that modulate the contractile effect of endothelin-1 and mediate the inhibitory action of NO.

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Following chronic liver injury of any etiology, there is progressive fibrosis. To date, removing the causative agent is the only effective therapy to stop or even reverse liver fibrosis. Therefore, the development of effective antifibrotic therapies represents a challenge for modern hepatology. In the past decade, dramatic advances have been made in the understanding of the cellular and molecular mechanisms underlying liver fibrogenesis. The identification of activated hepatic stellate cells (HSCs) as the major fibrogenic cell type in the injured liver, as well as the recognition of key cytokines involved in this process, have facilitated the design of promising new antifibrotic therapies. These therapies are aimed at inhibiting the accumulation of activated HSCs at the sites of liver injury and preventing the deposition of extracellular matrix. Although many of these approaches are effective in experimental models of liver fibrosis, their efficacy and safety in humans are still unknown. This review describes the current therapeutic approaches for liver fibrosis and discusses different features of activated HSCs as a target to design new treatments to inhibit scar formation in chronic liver diseases.

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BACKGROUND/AIMS: Hepatic stellate cells (HSCs) are perisinusoidal pericytes which have receptors for vasoactive factors, such as endothelin-1, which can regulate cell contractility in an autocrine manner. It is unknown whether human HSCs have receptors for and are able to synthesize the vasodilator peptide adrenomedullin (ADM), a peptide produced by most contractile cells. METHODS AND RESULTS: Stimulation of HSCs with ADM resulted in a dose-dependent raise in cAMP concentration (radioimmunoassay) and markedly blunted the endothelin-induced increase in [Ca2+]i and cell contraction, as assessed in cells loaded with fura-2 using a morphometric method. The existence of the receptor CRLR for ADM and their associated proteins RAMP-1 and RAMP-2 was demonstrated by reverse transcriptase-polymerase chain reaction (RT-PCR). Moreover, activated human HSCs spontaneously secreted ADM in the culture medium in a time-dependent manner. ADM secretion was markedly enhanced by tumour necrosis factor-alpha and interleukin-1beta. Specific mRNA for ADM (RT-PCR and Northern blot) was detected in HSCs and increased after incubation of cells with cytokines. CONCLUSIONS: Human HSCs have functional receptors for ADM, the stimulation of which blunts the contractile effect of endothelin-1. Cultured human HSCs secrete ADM in baseline conditions. This secretion is markedly increased by cytokines. These results suggest that ADM can regulate HSCs' contractility in an autocrine manner.

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Following chronic liver injury, hepatic stellate cells (HSCs) transdifferentiate into myofibroblast-like cells, which develop contractile properties and contribute to increased resistance to blood flow. We investigated whether this phenotypic activation includes changes in the expression of L-type voltage-operated Ca2+ channels (VOCC), which mediate Ca2+ influx and regulate cell contraction in vascular cell types. Rat HSCs were studied in the quiescent phenotype and after their activation in vitro (cultured on plastic for 14 days) and in vivo (isolated from rats with CCl(4)-induced cirrhosis). Patch-clamp studies showed Ca2+ currents through L-type VOCC in HSCs activated both in vitro and in vivo, whereas no currents were detected in quiescent HSCs. Moreover, binding studies with (3)H-isradipine, a specific L-type VOCC antagonist, showed a large number of binding sites in activated HSCs, while no specific binding was found in quiescent HSCs. Finally, messenger RNA (mRNA) encoding L-type VOCC was not detected in quiescent HSCs as assessed by reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis, whereas it was present in activated HSCs. Stimulation of L-type VOCC with KCl resulted in a marked increase in [Ca2+](i) followed by cell contraction in HSCs activated both in vitro and in vivo, whereas no effects were observed in quiescent HSCs. We conclude that the activation of HSCs is associated with up-regulation of L-type VOCC that mediate Ca2+ influx and cell contraction. These results may be relevant to the pathogenesis of portal hypertension.

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BACKGROUND: Malnutrition seen in chronic alcoholics is partly due to reduced energy intake. Leptin is a peptide hormone implicated in the regulation of appetite and expenditure of energy. The prevalence and significance of abnormal circulating leptin levels in alcoholics, as well as the relationship of these levels with nutritional status, liver disease, and ethanol consumption, remain uncertain. METHODS: Serum leptin levels were measured in 60 active asymptomatic alcoholics, 20 active alcoholics with cirrhosis of the liver, 20 abstinent alcoholics, and 60 controls. Nutritional status and ethanol consumption also were assessed. RESULTS: In the control group, circulating leptin levels (mean 4.7+/-0.3 microg/liter) correlated with body fat stores. Despite showing a lower fat area of the arm, active alcoholics had significantly higher leptin levels than the controls (p < 0.001), regardless of the presence of cirrhosis. By contrast, none of the abstinent alcoholics showed hyperleptinemia. In the multivariate regression analysis, the fat area of the arm (p < 0.001), the lifetime ethanol consumption (p = 0.007), and the number of cigarettes smoked per day (p = 0.02) were found to be independent factors that influenced leptin levels in active alcoholics. After we adjusted for age, fat area of the arm, and tobacco consumption, a significant correlation was observed between lifetime consumption of ethanol and serum leptin concentrations (r = 0.36, p < 0.001). CONCLUSIONS: Circulating leptin levels are increased in a dose-dependent manner in chronic alcoholism, regardless of nutritional status or the presence of compensated liver disease.

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BACKGROUND/AIMS: Parameters evaluating renal function and systemic hemodynamics are of prognostic significance in cirrhosis with ascites but are rarely used in the evaluation of survival of these patients. The aim of the current study was to develop a prognostic model to estimate survival of patients with cirrhosis and ascites. METHODS: 216 Cirrhotic patients admitted to hospital for the treatment of ascites were evaluated. Thirty-two demographic, clinical and laboratory variables, including parameters assessing liver and renal function and systemic hemodynamics, were analyzed as predictive factors of survival by using a Cox regression model. RESULTS: Four variables had independent prognostic value: renal water excretion, as assessed by measuring diuresis after water load, mean arterial pressure, Child-Pugh class, and serum creatinine. According to these features a prognostic index was calculated that allows to estimate survival in patients with cirrhosis and ascites. The model accurately predicted survival in an independent series of 84 patients with cirrhosis and ascites. CONCLUSION: A prognostic model that uses four easily available variables and predicts prognosis in cirrhotic patients with ascites has been developed. This model may be useful in the evaluation of patients with ascites for liver transplantation.

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