The MELD Score Is Superior to the Maddrey Discriminant Function Score to Predict Short-Term Mortality in Alcohol-Associated Hepatitis: A Global Study.

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.

Acute Kidney Injury in Cirrhosis: Baseline Serum Creatinine Predicts Patient Outcomes.

OBJECTIVES: The International Ascites Club (IAC) recently defined Stage 1 acute kidney injury (AKI) for cirrhosis as an acute increase in serum creatinine (SCr) by ≥0.3 mg/dl or by ≥50% in <48 h from a stable value within 3 months. The baseline SCr may influence AKI risk and patient outcomes. The objective of this study is to determine in cirrhosis whether the baseline SCr has any effect on the in-hospital AKI course and patient survival. METHODS: North American Consortium for the Study of End-Stage Liver Disease is a consortium of tertiary-care hepatology centers prospectively enroling non-elective cirrhotic inpatients. Patients with different baseline SCr levels (≤0.5, 0.51-1.0, 1.01-1.5, >1.5 mg/dl) were evaluated for the development of AKI, and compared for AKI outcomes and 30-day survival. RESULTS: 653 hospitalized cirrhotics (56.7±10years, 64% men, 30% with infection) were included. The incidence of AKI was 47% of enrolled patients. Patients with higher baseline SCr were more likely to develop AKI, with significantly higher delta and peak SCr (P<0.001) than the other groups, more likely to have a progressive AKI course (P<0.0001), associated with a significantly reduced 30-day survival (P<0.0001). Multivariate logistic regression showed that the delta SCr during an AKI episode to be the strongest factor impacting AKI outcomes and survival (P<0.001), with a delta SCr of 0.70 mg/dl having a 68% sensitivity and 80% specificity for predicting 30-day mortality. CONCLUSIONS: Admitted cirrhotic patients with higher baseline SCr are at higher risk for in-hospital development of AKI, and more likely to have AKI progression with reduced survival. Therefore, such patients should be closely monitored and treated promptly for their AKI.

Secondary and tertiary structure modeling reveals effects of novel mutations in polycystic liver disease genes PRKCSH and SEC63.

Polycystic liver disease (PCLD) is characterized by intralobular bile duct cysts in the liver. It is caused by mutations in PRKCSH, encoding hepatocystin, and SEC63, encoding Sec63p. The main goals of this study were to screen for novel mutations and to analyze mutations for effects on protein structure and function. We screened 464 subjects including 76 probands by direct sequencing or conformation-sensitive capillary electrophoresis. We analyzed the effects of all known and novel mutations using a combination of splice site recognition, evolutionary conservation, secondary and tertiary structure predictions, PolyPhen, and pMut and sift. We identified a total of 26 novel mutations in PRKCSH (n = 14) and SEC63 (n = 12), including four splice site mutations, eight insertions/ deletions, six non-sense mutations, and eight missense mutations. Out of 48 PCLD mutations, 13 were predicted to affect splicing. Most mutations were located in highly conserved regions and homology modeling for two domains of Sec63p showed severe effects of the residue substitutions. In conclusion, we identified 26 novel mutations associated with PCLD and we provide in silico analysis in order to delineate the role of these mutations.

Predictors of early re-bleeding and mortality after acute variceal haemorrhage in patients with cirrhosis.

BACKGROUND AND AIMS: Risk factors for mortality and re-bleeding following acute variceal haemorrhage (AVH) are incompletely understood. The aim of this study was to determine risk factors for 6-week mortality, and re-bleeding within 5 days in patients with cirrhosis and AVH. METHODS: Kaplan-Meier and Cox proportional hazards regression analyses were used to determine risk factors among 256 patients with AVH entered into a randomised, prospective trial. RESULTS: Thirty-five patients (14%) died within 6 weeks of AVH; 14 deaths (40%) occurred within 5 days. Only the Model for End-stage Liver Disease (MELD) score and units of packed red blood cells (PRBCs) transfused in the first 24 h were associated with 6-week mortality univariately (HR 1.11, p < 0.001; HR 1.22, p < 0.001) and bivariately (HR MELD = 1.10, p < 0.001; HR per unit of PRBCs transfused = 1.15, p = 0.005). Re-bleeding within 5 days occurred in 37 patients (15%); MELD score (p = 0.01) and a clot on a varix (p = 0.05) predicted re-bleeding. Patients with a MELD score > or = 18; both MELD score > or = 18 and > or = 4 units of PRBCs transfused; both MELD score > or = 18 and active bleeding at index endoscopy; and variceal re-bleeding had increased risk of death 6 weeks post-AVH (HR = 7.4, p < 0.001; 11.3, p < 0.001; 9.9, p < 0.001; 10.2, p < 0.001 respectively). CONCLUSIONS: Patients with AVH and MELD score > or = 18, requiring > or = 4 units of PRBCs within the first 24 h or with active bleeding at endoscopy are at increased risk of dying within 6 weeks. MELD score > or = 18 is also a strong predictor of variceal re-bleeding within the first 5 days.

Systematic review with meta-analysis: the association between hepatitis E seroprevalence and haemodialysis.

BACKGROUND: Hepatitis E virus (HEV) infection appears to be more common than previously thought. HEV seroprevalence in patients on maintenance haemodialysis (HD) is unclear with a range from 0% to 44%. In addition, risk factors of transmission of HEV in patients on haemodialysis are unknown. AIM: To perform a systematic review and meta-analysis of HEV seroprevalence in HD patients compared with controls. METHODS: A systematic search of several databases identified all observational studies with comparative arms. Two reviewers extracted data and assessed the methodological quality. A random-effects model was used for pooled odds ratio (OR) and 95% confidence interval (CI) of positive anti-HEV IgG in both groups. Heterogeneity and publication bias were assessed with appropriate tests. RESULTS: We identified 31 studies from 17 countries between 1994 and 2016. Sixteen studies were judged to have adequate quality and 15 to have moderate limitations. HEV infection was more prevalent in patients on haemodialysis compared with controls (OR 2.47, 95% CI 1.79-3.40, I2 = 75.2%, P < .01). We conducted several subgroup analyses without difference in results. Egger regression test did not suggest publication bias (P = .83). Specific risk factors of HEV transmission in patients on haemodialysis were not clearly identified. CONCLUSIONS: Hepatitis E virus infection is more prevalent in patients on haemodialysis compared with non-haemodialysis control groups. Further studies are needed to determine risk factors of acquisition, impact on health, and risk for chronic HEV especially among those patients going to receive organ transplantation.

Reduction of postprandial plasma glucose by Bengal gram dal (Cicer arietinum) and rajmah (Phaseolus vulgaris).

Postprandial plasma glucose levels were measured in six healthy subjects at 0, 15, 30, 45, 60, 90, and 120 min after taking 50 g of carbohydrate in the form of wheat, rice, bengal gram dal (channa dal), and rajmah (red kidney beans) and compared with the plasma glucose values obtained after taking 50 g dextrose. Bangal gram dal and rajmah, when compared with dextrose, were found to be more effective in reducing postprandial plasma glucose levels than wheat and rice. Moreover, the mean peak rise in plasma glucose was decreased by 82.1% with bengal gram dal, 67% with rajmah, while wheat and rice showed reduction only by 25 and 16%, respectively, when compared with dextrose. This study suggests a reappraisal of the diet for diabetics.

Hepatic hydrothorax: pathogenesis, diagnosis, and management.

Hepatic hydrothorax is defined as a pleural effusion in a patient with cirrhosis of the liver and no cardiopulmonary disease. The estimated prevalence of this often debilitating complication in patients with liver cirrhosis is 4% to 10%. Its pathophysiology involves movement of ascitic fluid from the peritoneal cavity into the pleural space through diaphragmatic defects. As a result patients are at increased risk of respiratory infection. Initial management consists of sodium restriction, diuretics, and thoracentesis. A transjugular intrahepatic portosystemic shunt may be required. Because most patients with hepatic hydrothorax have end-stage liver disease, a liver transplant should be considered if these options fail.

Regional and systemic hemodynamic disturbances in cirrhosis.

In cirrhosis of the liver there is an imbalance between factors mediating vasodilatation such as nitric oxide and factors mediating vasoconstriction such as endothelins. These imbalances result in portal hypertension, hepatorenal syndrome, portopulmonary hypertension, hepatopulmonary syndrome, as well as alterations in cerebral blood flow.

Clinical approach to the patient with abnormal liver test results.

Abnormal results of standard biochemical liver tests occur frequently; however, the prevalence of clinically significant liver disease is only about 1% in all patients screened. Thus, development of a rational and cost-effective approach to these patients is important. Liver diseases are generally classified as hepatocellular, cholestatic, and infiltrative. Cholestatic liver disease is further categorized as intrahepatic and extrahepatic. Hepatocellular disease is characterized by transaminase increases greater than 5 times the upper limit of normal, with alkaline phosphatase levels usually increased less than 2 to 3 times the upper limit of normal. Cholestatic disease is characterized by an increase in the alkaline phosphatase level that is 3 to 5 times greater than the upper limit of normal, with only a mild increase of transaminases. The exception to this is cholestasis with cholangitis when the transaminases can be more substantially increased. In infiltrative diseases of the liver such as lymphoma or granulomatous hepatitis, the alkaline phosphatase level is increased disproportionately to that of the bilirubin. Specific etiologic diagnoses cannot usually be based on routine biochemical liver test results, and thus more specialized serum tests are necessary. A liver biopsy is often needed for a precise diagnosis in patients with long-term increases in liver test results. Ultrasonography is the best initial imaging technique for the liver, and if biliary dilatation is noted, endoscopic retrograde cholangiopancreatography is recommended.

Managing the complications of cirrhosis.

The 3 major and potentially fatal complications of cirrhosis of the liver result from portal hypertension and include variceal bleeding, ascites, and encephalopathy. The cause of other complications, eg, thyroid dysfunction and hepatopulmonary syndrome, is uncertain. Several recent advances have occurred in the treatment of varices. However, treatment of ascites is still primarily confined to achieving a negative sodium balance, and therapy for encephalopathy centers on the use of lactulose. Although effective therapy may be available for most complications of cirrhosis, a major complication indicates a poor long-term prognosis. Liver transplantation is the only effective long-term treatment of complications due to cirrhosis.

Spontaneous bacterial peritonitis: an update.

OBJECTIVE: To describe spontaneous bacterial peritonitis (SBP) in the context of currently accepted criteria for diagnosis, treatment, and prevention. DESIGN: A review of SBP and its associated etiopathogenic factors is presented. MATERIAL AND METHODS: Numerous studies on mechanisms of disease, diagnosis, treatment, and prevention are discussed. Diagnostic and therapeutic algorithms are presented. RESULTS: Peritonitis in patients with ascites in the absence of secondary causes, such as peforation of a viscus, occurs primarily in patients with end-stage liver disease. Enteric organisms, mainly gram-negative bacilli, probably translocate to regional lymph nodes to produce bacteremia and seeding of ascitic fluid. Signs and symptoms of peritonitis are usually subtle. The ascitic fluid polymorphonuclear leukocyte count is the best determinant for early diagnosis and treatment of SBP. Third-generation cephalosporins such as cefotaxime are considered the drugs of choice for treatment, whereas quinolones such as norfloxacin are used to decrease recurrence. CONCLUSION: Despite increased awareness, early diagnosis, and prompt and effective antimicrobial therapy, SBP recurs frequently and is associated with a high mortality rate. Patients with SBP should be assessed for candidacy for liver transplantation.

Ascites and hepatorenal syndrome: pathophysiology and management.

Ascites, a late manifestation of cirrhosis of the liver, causes increased morbidity and mortality. The renin-angiotensin-aldosterone system, the sympathetic nervous system, and arginine vasopressin are responsible for sodium and water retention in patients with cirrhosis. Fluid localizes to the peritoneal cavity mainly as a result of portal hypertension. Recent developments in the understanding of the pathophysiologic mechanisms of ascites include the role of inadequate renal prostaglandin production in the development of the hepatorenal syndrome and the possible role of nitric oxide in the pathogenesis of the renal complications of cirrhosis. The aim of medical therapy is to achieve a negative sodium balance and, consequently, fluid loss. Large-volume paracentesis is safe and effective in the management of tense ascites, but use of diuretic agents should be continued to prevent reaccumulation of ascites. Liver transplantation, transjugular intrahepatic portosystemic shunts, or LeVeen shunts should be considered in selected patients with persistent ascites. In patients with diuretic-resistant or diuretic-refractory ascites, a thorough assessment must be performed to exclude potentially reversible causes. The hepatorenal syndrome has an associated grave prognosis, especially in patients who are not candidates for liver transplantation.

Pathophysiology and treatment of variceal hemorrhage.

Portal hypertension results from increases in portal flow and portal vascular resistance. Factors increasing portal blood flow are predominantly humoral. Resistance to portal flow has a fixed component due to distortion of the vasculature by cirrhotic nodules and a variable component that is related to vasoactive substances. Varices result from an increase in portal pressure. Factors predicting the risk of variceal bleeding include continued alcohol use, poor liver function, large varices, and red wale markings on varices at endoscopy. Octreotide is probably the drug of choice for pharmacologic management of bleeding esophageal varices. Propranolol has an established role in the prevention of variceal hemorrhage, and variceal band ligation may be the preferred endoscopic technique. Transjugular intrahepatic portosystemic shunts have emerged as an important treatment for patients in whom pharmacologic and endoscopic therapies have failed and are an effective bridge to liver transplantation.

Differentiation of typhoid fever from fulminant hepatic failure in patients presenting with jaundice and encephalopathy.

OBJECTIVE: To determine the clinical and laboratory features that allow the early diagnosis of typhoid fever in patients who present with jaundice and encephalopathy. PATIENTS AND METHODS: This 12-month prospective study, conducted in Bangalore, India, between 1990 and 1991, evaluated the clinical and laboratory features of all patients (N=47) who presented with encephalopathy within 8 weeks of onset of jaundice. Ciprofloxacin and dexamethasone were used to treat 11 patients diagnosed on blood culture as having typhoid fever. The other 36 patients were presumed to have fulminant hepatic failure with a viral cause and were treated with supportive measures (bioartificial liver support and transplantation were not available). RESULTS: In patients with jaundice and encephalopathy, a liver span of greater than 9 cm on physical examination, thrombocytopenia, elevated alkaline phosphatase level, aspartate aminotransferase level greater than alanine aminotransferase level, and only mild prolongation of the prothrombin time suggested a diagnosis of typhoid fever. All 11 patients diagnosed as having typhoid fever had an excellent response to treatment with ciprofloxacin and dexamethasone with no mortality and with normalization of the liver test results in 2 weeks. On the other hand, 30 of the 36 patients with nontyphoid fulminant hepatic failure died. CONCLUSIONS: In patients presenting with jaundice and encephalopathy, physical examination and simple laboratory tests can help make an early diagnosis of typhoid fever. We believe that patients with a presumptive diagnosis of typhoid fever should be treated with ciprofloxacin and dexamethasone, even before the results of blood cultures are available.

Budd-Chiari syndrome: early intervention with angioplasty and thrombolytic therapy.

We present a complex case of the Budd-Chiari syndrome due to thrombosis of the hepatic veins in the presence of stenosis of the left hepatic vein and membranous obstruction of the inferior vena cava. The acute thrombosis occurred after laparoscopic surgical removal of the gallbladder. Because we strongly suspected the Budd-Chiari syndrome, hepatic venography was performed. The hepatic venous outflow obstruction was relieved by angioplasty and thrombolytic therapy with use of local infusions of urokinase into the clot. We propose that angiography be performed in patients in whom the Budd-Chiari syndrome is suspected and that angioplasty and thrombolytic therapy be initiated early.

Thoracic duct-cutaneous fistula in a patient with cirrhosis of the liver: successful treatment with a transjugular intrahepatic portosystemic shunt.

Patients with cirrhosis of the liver have increased hepatic and gastrointestinal lymph flow that may contribute to the formation of ascites and pleural effusions. Increased lymph flow, which is due to postsinusoidal portal hypertension, causes a high rate of flow through the thoracic duct. Because of the high flow rates, disrupted lymphatic vessels in patients with cirrhosis of the liver may fail to close, a situation that results in chylous ascites, pleural effusions, or chylous fistulas. Chylous fistulas deplete proteins, fluid, and lymphocytes and thus lead to volume depletion and coagulopathy. Herein we describe an unusual case in which a high-output traumatic thoracic duct-cutaneous fistula developed in a patient with cirrhosis and led to volume depletion and coagulopathy. Correction of the portal hypertension with placement of a transjugular intrahepatic portosystemic shunt led to closure of the fistula and normalization of accompanying metabolic abnormalities.

Development of hepatic veno-occlusive disease after Mylotarg infusion for relapsed acute myeloid leukemia.

Mylotarg (gemtuzumab zogamicin) is a conjugated monoclonal antibody that has recently become available for use in patients with relapsing or refractory acute myeloid leukemia. Reversible hepatotoxicity is common after administration. We describe the first report of hepatic veno-occlusive disease (HVOD) developing after Mylotarg infusion in a patient who underwent hematopoietic stem cell transplantation 8 months earlier. Certain antineoplastic agents have been implicated as a cause of HVOD, but the disease is most commonly seen within 30 days after hematopoietic stem cell transplantation. The possible association between Mylotarg infusion and HVOD is discussed.

Charcoal hemofiltration for hepatic veno-occlusive disease after hematopoietic stem cell transplantation.

Hepatic veno-occlusive disease (HVOD) after hematopoietic stem cell transplantation (HSCT) results in considerable morbidity and mortality. No therapy has been shown to be uniformly effective. Several studies have highlighted the pivotal role of endothelial injury and the hemostatic system in the pathogenesis of HVOD. Charcoal hemofiltration has been shown to be effective for adsorbing circulating bilirubin and other protein-bound toxins and for supporting patients in hepatic failure. We describe two adult patients with severe, biopsy-proven HVOD (peak bilirubin levels, more than 50 mg/dl in both cases) after HSCT who were successfully treated with charcoal hemofiltration after other treatments failed (including defibrotide in one patient). Both patients were heavily treated before they underwent either autologous (melphalan and total body irradiation conditioning) or allogeneic (cyclophosphamide and total body irradiation conditioning) HSCT. Additional studies are warranted to confirm this preliminary observation and investigate the mechanism of action.