Jun 042013
 

Relative adrenal insufficiency in decompensated cirrhosis. relationship to short-term risk of severe sepsis, hepatorenal syndrome and death.

Hepatology. 2013 May 31;

Authors: Acevedo J, Fernández J, Prado V, Silva A, Castro M, Pavesi M, Roca D, Jimenez W, Ginès P, Arroyo V

Abstract
BACKGROUND: The prevalence of relative adrenal insufficiency (RAI) in critically ill cirrhotic patients with severe sepsis is over 60% and associated features include poor liver function, renal failure, refractory shock and high mortality. RAI may also develop in non-critically ill cirrhotic patients but its relationship to clinical course has not yet been assessed. The current study was performed in 143 non-critically ill cirrhotic patients admitted for acute decompensation. METHODS: Within 24h after hospitalization adrenal function, plasma renin activity, plasma noradrenaline and vasopressin concentration, and serum levels of nitric oxide, IL-6 and TNF-α were determined. RAI was defined as a serum total cortisol increase <9 μg/dL after 250 μg of intravenous corticotropin from basal values <35 μg/dL. Patients were followed-up during 3 months. RESULTS: RAI was detected in 26% of patients (n=37). At baseline, patients with RAI presented lower mean arterial pressure (76±12 vs. 83±14 mmHg, p=0.009) and serum sodium (131±7 vs. 135±5 mEq/L, p=0.007) and higher BUN (32±24 vs. 24±15 mg/dl, p=0.06), plasma renin activity (7.1±9.9 vs. 3.4±5.6 ng/mL*h, p=0.03) and noradrenaline concentration (544±334 vs. 402±316 pg/ml, p=0.02). During follow-up patients with RAI presented a higher probability of infection (41% vs. 21%, p=0.008), severe sepsis (27% vs. 9%, p=0.003), type-1 HRS (16% vs. 3%, p=0.002) and death (22% vs. 7%, p=0.01). CONCLUSIONS: RAI is frequent in non-critically ill patients with acute decompensation of cirrhosis. As compared with those with normal adrenal function, patients with RAI present greater impairment of circulatory and renal function, higher probability of severe sepsis and type-1 HRS and higher short-term mortality. (HEPATOLOGY 2013.).

PMID: 23728792 [PubMed - as supplied by publisher]

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May 262013
 
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Diastolic dysfunction is a predictor of poor outcomes in patients with cirrhosis, portal hypertension and a normal creatinine.

Hepatology. 2013 May 23;

Authors: Ruíz-Del-Árbol L, Achécar L, Serradilla R, Rodríguez-Gandía MA, Rivero M, Garrido E, Natcher JJ

Abstract
We investigated the left ventricular diastolic dysfunction (LVDD) and its relationship with circulatory function and prognosis in cirrhosis with portal hypertension and normal creatinine. Conventional and Tissue Doppler (TDI) echocardiography, systemic and hepatic hemodynamics and the activity of endogenous vasoactive systems (AEVS) were measured prospectively in 80 patients. Plasma renin activity (PRA)(> 4 ng/mL/h) is used as a surrogate of effective arterial blood volume. Patients were followed-up for 12 months. Thirty-seven patients had LVDD (19 grade-1, 18 grade-2). Left ventricular hypertrophy, left atrial volume, AEVS and natriuretic peptides levels were significantly greater in patients with LVDD than without LVDD. Patients with grade-2 LVDD compared with grade-1 LVDD and without LVDD had significantly lower mean arterial pressure and higher Model for End-Stage Liver Disease (MELD) score, E/e' ratio, cardiopulmonary pressures, PRA and natriuretic peptides levels. Systolic and cardiac chronotropic function were significantly lower in patients with grade-2 LVDD than without LVDD. LVDD was more frequent in patients with ascites and increased PRA than patients without ascites or with ascites but normal PRA. Fourteen patients with LVDD developed hepatorenal syndrome (HRS) Type-1 on follow-up. Survival was different according to degree of LVDD (without LVDD, 95%; grade-1 LVDD, 79%; grade-2 LVDD, 39%; P < 0.001). Independent predictive factors of mortality were MELD score and E/e' ratio. Conclusion: LVDD occurs simultaneously with other changes in cardiac structure and function and is associated to an impairment of effective arterial blood volume. LVDD is a sensitive marker of advanced cirrhosis, type-1 HRS development and mortality. (HEPATOLOGY 2013.).

PMID: 23703953 [PubMed - as supplied by publisher]

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May 262013
 
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Anticoagulation in cirrhosis: Ready …. Set…. Wait!

Hepatology. 2013 May 23;

Authors: Seijo S, Garcia-Pagan JC

Abstract
BACKGROUND & AIMS: We performed a randomized controlled trial to evaluate the safety and efficacy of enoxaparin, a low-molecular-weight heparin, in preventing portal vein thrombosis (PVT) in patients with advanced cirrhosis. METHODS: In a nonblinded, single-center study, 70 outpatients with cirrhosis (Child-Pugh classes B7-C10) with demonstrated patent portal veins and without hepatocellular carcinoma were assigned randomly to groups that were given enoxaparin (4000 IU/day, subcutaneously for 48 weeks; n=34( or no treatment (controls, n=36). Ultrasonography (every 3 months) and computed tomography (every 6 months) were performed to check the portal vein axis. The primary outcome was prevention of PVT. Radiologists and hepatologists that assessed outcomes were blinded to group assignments. Analysis was by intention to treat. RESULTS: At 48 weeks, none of the patients in the enoxaparin group had developed PVT, compared with 6 of 36 (16.6%) controls (P=0.025). At 96 weeks, no patient developed PVT in the enoxaparin group, compared with 10 of 36 (27.7%) controls (P=0.001). At the end of the follow-up period, 8.8% of patients in the enoxaparin group and 27.7% of controls developed PVT (P=0.048). The actuarial probability of PVT was lower in the enoxaparin group (P=0.006). Liver decompensation was less frequent among patients given enoxaparin (11.7%) than controls (59.4%) (P=0.0001); overall values were 38.2% vs 83.0%, respectively (P=0.0001). The actuarial probability of liver decompensation was lower in the enoxaparin group (P=0.0001). Eight patients in the enoxaparin group and 13 controls died. The actuarial probability of survival was higher in the enoxaparin group (P=0.020). No relevant side effects or hemorrhagic events were reported. CONCLUSIONS: In a small randomized controlled trial, a 12-month course of enoxaparin was safe and effective in preventing PVT in patients with cirrhosis and a Child-Pugh score of 7-10. Enoxaparin appeared to delay the occurrence of hepatic decompensation and to improve survival. (HEPATOLOGY 2013.).

PMID: 23703896 [PubMed - as supplied by publisher]

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May 262013
 
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Non-transfusional approach to increase platelet count in patients with cirrhosis and thrombocytopenia.

Hepatology. 2013 May 23;

Authors: Tripodi A, Primignani M

Abstract
BACKGROUND: Eltrombopag is an oral thrombopoietin-receptor agonist. This study evaluated the efficacy of eltrombopag for increasing platelet counts and reducing the need for platelet transfusions in patients with thrombocytopenia and chronic liver disease who are undergoing an elective invasive procedure. METHODS: We randomly assigned 292 patients with chronic liver disease of diverse causes and platelet counts of less than 50,000 per cubic millimeter to receive eltrombopag, at a dose of 75 mg daily, or placebo for 14 days before a planned elective invasive procedure that was performed within 5 days after the last dose. The primary end point was the avoidance oxf a platelet transfusion before, during, and up to 7 days after the procedure. A key secondary end point was the occurrence of bleeding (World Health Organization [WHO] grade 2 or higher) during this period. RESULTS: A platelet transfusion was avoided in 104 of 145 patients who received eltrombopag (72%) and in 28 of 147 who received placebo (19%) (P<0.001). No significant difference between the eltrombopag and placebo groups was observed in bleeding episodes of WHO grade 2 or higher, which were reported in 17% and 23% of patients, respectively. Thrombotic events of the portal venous system were observed in 6 patients who received eltrombopag, as compared with 1 who received placebo, resulting in the early termination of the study. The incidence and severity of other adverse events were similar in the eltrombopag and placebo groups. CONCLUSIONS: Eltrombopag reduced the need for platelet transfusions in patients with chronic liver disease who were undergoing elective invasive procedures, but it was associated with an increased incidence of portal-vein thrombosis, as compared with placebo. (HEPATOLOGY 2013.).

PMID: 23703879 [PubMed - as supplied by publisher]

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Dec 222012
 

High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury.

Hepatology. 2012 Dec 19;

Authors: Chen M, Borlak J, Tong W

Abstract

Drug induced liver injury (DILI) is a leading cause of drug failure in clinical trials and a major reason for drug withdrawals from the market. While there is evidence for doses of ? 100mg/day to be associated with increased risk for hepatotoxicity, many drugs are safe at such doses. There is unmet need to predict more reliably risk for DILI and lipophilicity might be a contributing factor. We analyzed the combined factors of daily dose and lipophilicity for 164 FDA-approved oral medications and observed high risk for hepatotoxicity (odds ratio: 14.05, P < 0.001) for drugs given at daily doses ? 100mg and logP ? 3. This defined the "rule-of-two". Similar results were obtained for an independent set of 179 oral medications with 85% of the "rule-of-two" positives being associated with hepatotoxicity (odds ratio: 3.89, P < 0.01). Using the WHO Anatomical Therapeutic Chemical classification system, the "rule-of-two" performed best in predicting DILI in seven therapeutic categories. Among 15 "rule-of-two" positives, 14 were withdrawn hepatotoxic drugs and one was OTC medication labeled for liver injury. We additionally examined drug pairs that have similar chemical structures and act on the same molecular target but differ in their potential for DILI. Again, the "rule-of-two" predicted reliable hepatotoxicity. Finally, the "rule-of-two" was applied to clinical case studies to identify hepatotoxic drugs in complex co-medication regimes to further demonstrate its utility. Conclusion: Apart from dose, lipophilicity contributes significantly to risk for hepatotoxicity. Applying the "rule-of-two" is an appropriate means to estimate risk for DILI as compared to dose alone. (HEPATOLOGY 2012.).

PMID: 23258593 [PubMed - as supplied by publisher]

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Aug 142012
 
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Hepatic encephalopathy is associated with decreased cerebral oxygen metabolism and blood flow, not increased ammonia uptake.

Hepatology. 2012 Aug 10;

Authors: Dam G, Keiding S, Munk OL, Ott P, Vilstrup H, Bak LK, Waagepetersen HS, Schousboe A, Sørensen M

Abstract

Studies have shown decreased cerebral oxygen metabolism (CMRO(2) ) and blood flow (CBF) in cirrhotic patients with hepatic encephalopathy (HE). It remains unclear, however, whether these disturbances are associated with HE or with cirrhosis itself and how they may relate to arterial blood ammonia concentration and cerebral metabolic rate of blood ammonia (CMRA). We addressed these questions in a paired study design by investigating cirrhotic patients during and after recovery from an acute episode of HE type C. CMRO(2) , CBF, and CMRA were measured by dynamic PET/CT. Ten cirrhotic patients were studied during an acute episode of HE; nine were reexamined after recovery. Nine cirrhotic patients with no history of HE served as controls. Mean CMRO(2) increased from 0.73 ?mol oxygen/mL brain tissue/min during HE to 0.91 ?mol oxygen/mL brain tissue/min after recovery (paired t-test; P < 0.05). Mean CBF increased from 0.28 mL blood/mL brain tissue/min during HE to 0.38 mL blood/mL brain tissue/min after recovery (P < 0.05). After recovery from HE, CMRO(2) and CBF were not significantly different from values in the control patients. Arterial blood ammonia concentration decreased 20% after recovery (P < 0.05) and CMRA was unchanged (P > 0.30); both values were higher than in the control patients (both P < 0.05). CONCLUSIONS: The low values of CMRO(2) and CBF observed during HE increased after recovery from HE and were thus associated with HE rather than the liver disease as such. The changes in CMRO(2) and CBF could not be linked to blood ammonia concentration or CMRA. (HEPATOLOGY 2012.).

PMID: 22886493 [PubMed - as supplied by publisher]

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