Complication Of Advanced Liver Disease Research Articles

Stress management: How the unfolded protein response impacts fatty liver disease

Induction of the unfolded protein response (UPR) is recognized as central to fatty liver disease (FLD) pathophysiology. This pathway may be a potential therapeutic target for FLD, as well as other diseases. However, fundamental questions as to how UPR contributes to FLD remain unanswered. Conflicting data suggest that this pathway can both protect against and augment this disease. Here, we review the relationship between protein secretion, endoplasmic reticulum function (ER), and UPR activation. The UPR serves to maintain secretory pathway homeostasis by enhancing the protein folding environment in the ER, and we review data investigating the role for individual UPR players in fatty liver (steatosis). We explore a novel concept in the field that all cases of UPR activation do not equal "ER stress". Rather, different types of UPRs that can either protect against or cause FLD are discussed. Refining our current understanding of this complex pathway is particularly important, as drugs that affect the protein folding environment in the ER and affect UPR activation are being successful in clinical trials for FLD.

At the End of the Beginning

At the End of the Beginning

The Management of Hospitalized Patients with Cirrhosis: The Mount Sinai Experience and a Guide for Hospitalists

Cirrhosis and chronic liver disease carry appreciable morbidity and mortality. Cirrhotic patients frequently require hospitalization and their care is both extremely complex and labor-intensive. We seek to provide a review for gastroenterologists, hepatologists, internists, and hospitalists on the approach to care in patients hospitalized for complications related to end-stage liver disease. The Mount Sinai Medical Center's inpatient liver service has developed an integrated team approach for cirrhotic patients and throughout the years has educated fellows-in-training and medical house staff on both the treatment principles and "pearls" in managing the hospitalized cirrhotic patient. We reviewed the literature and provide recommendations on the management of complications of end-stage liver disease. Additionally, we provide a review of the protocols used at our institution in the care for cirrhotic patients. Major complications of advanced liver disease include infection, ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, portal hypertension, variceal hemorrhage, hepatorenal syndrome, and hepatocellular carcinoma. Management of these complications involves selecting the appropriate diagnostic studies and prompt administration of therapy. There are many complications of cirrhosis. Management of these complications can be complex and are targeted at stabilizing the patient's clinical condition. Liver transplantation remains the only definitive treatment.

Detection of ascitic fluid infections in patients with liver cirrhosis and ascites

Background and study aims Ascitic fluid infections (AFIs) are the frequent complications of advanced liver disease. Bacterial translocation is considered a key step in the pathogenesis of gut-derived bacterial infections; mainly spontaneous bacterial peritonitis (SBP) in cirrhotic patients. Bacterial DNA (bactDNA) in ascitic fluid and serum has been suggested as a surrogate marker for bacterial translocation. We attempted at the isolation and identification of bacteria in ascitic fluid in cirrhotic patients and the assessment of polymerase chain reaction (PCR) in ascitic fluid and serum. Patients and methods Fifty cirrhotic patients having ascites with no signs of infection were included. Ascitic fluid cultures were obtained from patients. Ascitic fluid and serum were subjected to DNA extraction and PCR for the universal amplification of a region of the 16S ribosomal RNA (16S rRNA) gene to detect bactDNA. Results Bacteria were isolated from 9 (18%) of the ascitic fluid samples, and were mainly Gram-positive bacteria. BactDNA was detected simultaneously in the ascitic fluid and serum of 17 (34%) patients and in the ascitic fluid of only 2 patients. In a single patient with positive ascitic fluid culture no bactDNA was detected in ascitic fluid or serum. By considering AFIs as a positive ascitic fluid culture and/or the presence of bactDNA in the ascitic fluid and/or serum, ascitic fluid culture could detect 9 out of 20 patients with AFIs (45%), PCR of ascitic fluid could detect 19 out of 20 (95%) while PCR of serum could detect 17 out of 20 (85%). In 10 patients with culture negative non-neutrocytic ascites (CNNNA) bactDNA could be detected in serum and ascitic fluid. Conclusion AFI can be caused by Gram positive as well as Gram negative organisms. A substantial percentage of cases with CNNNA show bactDNA in serum and ascitic fluid. PCR of ascitic fluid should, therefore, be used in the diagnostic workup of suspected cases of ascitic fluid infections.

Terlipressin therapy for reversal of type 1 hepatorenal syndrome: A meta‐analysis of randomized controlled trials

Hepatorenal syndrome (HRS) is a serious complication of advanced liver disease and carries a poor prognosis. Recent trials have indicated that terlipressin may be effective in reversing HRS. Our aim was to evaluate the efficacy of terlipressin therapy in reversing type 1 HRS defined as a serum creatinine <1.5 mg/dL during treatment. Randomized controlled trials in which patients with type 1 HRS received at least 3 days of terlipressin therapy and albumin in the intervention arm were included after a systematic search of the published English reports. Studies with other vasoconstrictor therapies in the control group were excluded. A total of 223 patients with HRS type 1 in four different trials, were included in the final analysis. Alcohol-related cirrhosis was the most common underlying etiology. The risk ratio for reversal in type 1 HRS with terlipressin therapy was 3.66 (95% confidence interval 2.15-6.23). Recurrence of HRS was low (8%). Serious side-effects requiring discontinuation of therapy were seen only in 6.8% of patients on terlipressin therapy. There was a trend towards improved transplant-free survival at 90 days in the terlipressin group (relative risk 1.86 95% confidence interval 1.0-3.4, P = 0.05). Terlipressin is effective in reversing HRS type 1. Recurrence of HRS is rare with at least 14 days of therapy. Serious side-effects requiring discontinuation of therapy are less common. There appears to be a survival benefit in patients with HRS treated with terlipressin.

Quality of life in cirrhosis is related to potentially treatable factors

Improvement of prognosis and availability of diverse therapeutic options for complications of advanced liver disease highlight the importance of health-related quality of life (HRQOL) in cirrhosis. The aim of this study was to identify factors that influence HRQOL and may be potentially treatable in patients with cirrhosis. HRQOL was measured in 212 outpatients with cirrhosis using a generic questionnaire (Medical Outcomes Study Form, SF-36) and a liver-specific questionnaire (Chronic Liver Disease Questionnaire, CLDQ). All patients underwent a systematic clinical and neuropsychological assessment. Independent factors associated with poor HRQOL were identified by multiple linear regression. HRQOL scores exhibited by patients were: global CLDQ: 4.8+/-1.2; Physical Component Score of SF-36: 38.5+/-10.7; Mental Component Score of SF-36: 45.3+/-14.3. The independent variables for global CLDQ were female sex, nonalcoholic etiology, current ascites, and a decrease in albumin (R = 0.22). For Physical Component Score of SF-36, the independent variables were prior hepatic encephalopathy, current ascites, and a decrease in hemoglobin (R = 0.22). For Mental Component Score of SF-36, the independent variables were nonalcoholic etiology, the Grooved Pegboard test, and a decrease in hemoglobin (R = 0.14). Several clinical variables, potentially treatable, may alter particular aspects of HRQOL. Correction of ascites, hypoalbuminemia, minimal hepatic encephalopathy, and anemia may cause a positive impact on HRQOL of patients with cirrhosis.

Oral Antibiotic Prophylaxis Reduces Spontaneous Bacterial Peritonitis Occurrence and Improves Short-Term Survival in Cirrhosis: A Meta-Analysis

Spontaneous bacterial peritonitis (SBP) is a serious complication of advanced liver disease resulting in high mortality rates. Although studies that assessed the use of oral antibiotics in advanced liver disease demonstrated a clear benefit in reducing the risk of recurrent peritonitis, it is unclear whether mortality rates are similarly affected by this practice. The goal of this study was to determine whether oral antibiotic therapy provides a survival benefit for patients with advanced cirrhosis and ascites. Through subgroup analysis, we also evaluated the effect of prophylactic oral antibiotic therapy on the prevention of SBP and the incidence of all infections (including SBP) when compared with non-treated or placebo controls. We conducted a comprehensive search of the Cochrane Database of Systematic Reviews, MEDLINE (1966 to May 2008), bibliographies of retrieved trials, and reports presented at major scientific meetings. Eligible studies included prospective, randomized controlled trials comparing high-risk cirrhotic patients receiving oral antibiotic prophylaxis for SBP with groups receiving placebo or no intervention. Dichotomous outcomes were reported as relative risk (RR) with 95% confidence intervals (CIs). Eight studies with a total of 647 patients were identified and included in this analysis. The combined analysis showed an overall mortality benefit (RR=0.65; 95% CI, 0.48-0.88) for treatment groups. The overall mortality rate was 16% (52/324) for treated patients and 25% (81/323) for the control group. Groups treated with prophylactic antibiotics also demonstrated a lower incidence of all infections (including SBP) of 6.2% as compared with the control groups with a rate of 22.2% (RR=0.32; P<0.00001; 95% CI, 0.20-0.51). Subgroup analysis showed a survival benefit at 3 months (RR=0.28; P=0.005; 95% CI, 0.12-0.68). Antibiotic prophylaxis improved short-term survival in treated patients when compared with untreated control groups and reduced the overall risk of infections, including SBP, during follow-up. In summary, antibiotic prophylaxis should be considered for high-risk cirrhotic patients with ascites.

Emerging drugs for complications of end-stage liver disease

Background: The prevalence of end-stage liver disease is rising rapidly and constitutes a major healthcare burden currently. Many cases are diagnosed at a later stage when liver transplantation is the only effective treatment option. There is thus an urgent need for novel treatments to reverse the earlier stages of cirrhosis as well as to treat the many associated life-threatening complications. Objectives: To review the current drugs available for treating the complications of advanced liver disease. To address novel treatment strategies that are in development, with particular reference to the rapidly developing area of antifibrotic therapy. To assess how the obstacles that have so far impeded the development of effective new drugs for end-stage liver disease may be overcome in the future. Methods: The literature was reviewed to define current therapies and therapies in clinical trials. We used the current models of the molecular basis of liver fibrogenesis to determine potential new therapeutic targets for antifibrotic therapy. Conclusions: Insights into the pathogenesis of liver injury and fibrosis have opened up new avenues for therapy and there are now candidates and targets with real potential for the development of a new generation of antifibrotic therapies.

Review article: the burden of hepatic encephalopathy

Hepatic encephalopathy, a challenging complication of advanced liver disease, occurs in approximately 30-45% of patients with cirrhosis and 10-50% of patients with transjugular intrahepatic portosystemic shunt, while minimal hepatic encephalopathy affects approximately 20-60% of patients with liver disease. Although the total direct and indirect costs of hepatic encephalopathy have not been formally quantified, data from the Healthcare Cost and Utilization Project suggest that hepatic encephalopathy-related hospitalizations are associated with substantial costs. In 2003, there were over 40 000 patients hospitalized in the United States for a primary diagnosis of hepatic encephalopathy, resulting in total charges of approximately $932 million. Furthermore, trends over the past 10 years suggest that the burden of hepatic encephalopathy is increasing, as indicated by increases in hospital admissions and higher charges per stay. Because of inconsistencies in coding for hepatic encephalopathy, the prevalence and cost data from this data source are believed to significantly underestimate the true burden of hepatic encephalopathy. In addition, expenditures for physician fees and out-patient care, as well as indirect costs attributable to lost work days and decreased productivity, have not been quantified. Thus, there is need for future studies to more accurately define the burden of hepatic encephalopathy, including minimal hepatic encephalopathy.

A Case of Portopulmonary Hypertension Associated with Primary Biliary Cirrhosis

Portopulmonary hypertension (PPHTN) is a clinically and pathophysiologically distinct complication of advanced liver disease. PPHTN is characterized by the development of pulmonary arterial hypertension in association with advanced hepatic disease-related portal hypertension. A characteristic feature of PPHTN is an obstruction to the pulmonary artery flow caused by vasoconstriction, the proliferation of the endothelium and smooth muscle components of the vascular wall, as well as in situ thrombosis. This disorder is commonly underdiagnosed but the clinical implications are significant because it has substantial effects on survival and requires special treatment. We report a case of portopulmonary hypertension in a 53-year-old woman with primary biliary cirrhosis who presented with exertional dyspnea. (Tuberc Respir Dis 2007; 62: 421-426)

Maintenance Interferon Therapy for Patients with Chronic Hepatitis C Infections

Fifty to sixty percent of patients infected with hepatitis C virus (HCV) have treatment success with pegylated interferon plus ribavirin. Low-dose interferon without ribavirin is currently being evaluated as maintenance therapy for suppressing viral replication and retarding liver-fibrosis progression to prevent complications of advanced liver disease and to lengthen survival. In this randomized trial, investigators assessed the ability of interferon alfa-2a to lengthen complication-free survival in HCV-positive patients with compensated cirrhosis. From …

Current management of the hepatorenal syndrome

Hepatorenal syndrome (HRS) is a serious complication of advanced liver disease. Historically, the development of HRS was considered a pre-terminal event due to a lack of efficacious therapy. Although liver transplantation remains the optimum therapy for HRS, many patients may be unsuitable for liver grafting. In addition, organ shortage may necessitate the institution of alternative pharmacological therapies to bridge patients to transplantation or to maintain renal function. This article reviews the definitions of Types-1 and -2 HRS, and addresses strategies for the prevention of the syndrome. It will also discuss management approaches to the cirrhotic patient with renal failure, specifically, assessment of novel vasoconstrictor therapies, such as vasopressin analogues, alpha-adrenoreceptor agonists, and the use of transjugular intra-hepatic shunts either alone or in combination with other therapeutic agents.

Management of polycystic liver disease

The adult forms of polycystic liver disease are characterized by autosomal dominant inheritance and numerous hepatic cysts, with or without renal involvement. Mutations in two distinct genes predispose to renal and liver cysts (PKD1 and PKD2), and mutations in two different genes yield isolated liver cysts (PRKCSH and SEC63). Mutations at certain loci of PKD1 may predispose to more severe renal cystic disease or cerebral aneurysms. Risk factors for severe hepatic cystic disease include aging, female sex, pregnancy, use of exogenous female steroid hormones, degree of renal cystic disease, or severity of renal dysfunction (in patients with mutations in PKD1 or PKD2). Although liver failure or complications of advanced liver disease is rare, some patients develop massive hepatic cystic disease and become clinically symptomatic. There is no effective medical therapy. Treatment options include cyst aspiration and sclerosis, open or laparoscopic cyst fenestration, hepatic resection, and liver transplantation.

Mechanisms of Disease: mechanisms of hepatic fibrosis and therapeutic implications

Hepatic fibrosis, or scarring of the liver, is emerging as a treatable complication of advanced liver disease, following significant progress in understanding its underlying mechanisms. Efforts have focused on the hepatic stellate cell, as these cells can undergo 'activation' into proliferative and fibrogenic myofibroblast-like cells during liver injury. Stimuli driving stellate cell activation include hepatocellular necrosis due to oxidant stress, apoptosis, and soluble growth factors. Specific lymphocyte subsets can also stimulate fibrogenesis. A cascade of signaling and transcriptional events in stellate cells underlies the fibrogenic response to liver injury, with each step in the cascade being a potential target for antifibrotic therapy. Disease-specific fibrogenic mechanisms have also been uncovered: in hepatitis C, this may include direct stimulation of stellate cell activation by viral infection; in nonalcoholic steatohepatitis, elevated levels of leptin and increased leptin signaling by stellate cells increase fibrogenesis. Determinants of fibrosis progression include both environmental and genetic factors, with ongoing efforts to define specific polymorphisms correlating with fibrosis progression rates. Human studies now indicate that fibrosis and even cirrhosis could be reversible, especially if the underlying disease is eradicated. A key challenge is to establish noninvasive means of assessing fibrosis stage and progression using either serum tests and/or imaging. In addition, endpoints of antifibrotic clinical trials need to be established so that reliable evidence of benefit can be identified. We are on the cusp of a new era in which antifibrotic therapies could become important in treating chronic fibrosing liver disease.

Polycystic disease of the liver.

Autosomal dominant polycystic disease is genetically heterogeneous with mutations in two distinct genes predisposing to the combination of renal and liver cysts (AD-PKD1 and AD-PKD2) and mutations in a third gene yielding isolated liver cysts (the polycystic liver disease gene). Transcription and translation of the PKD1 gene produces polycystin-1, an integral membrane protein that may serve as an extracellular receptor. Mutations occur throughout the PKD1 gene, but more severe disease is associated with N-terminal mutations. The PKD2 gene product, polycystin-2, is an integral membrane protein with molecular characteristics of a calcium-permeant cation channel. Mutations occur throughout the PKD2 gene, and severity of disease may vary with site of mutation in PKD2 and the functional consequence on the resultant polycystin-2 protein. Polycystic liver disease is genetically linked to protein kinase C substrate 80K-H (PRKCSH). The PRKCSH gene encodes hepatocystin, a protein that moderates glycosylation and fibroblast growth factor receptor signaling. More prominent in women, hepatic cysts emerge after the onset of puberty and dramatically increase in number and size through the child-bearing years of early and middle adult life. Although liver failure or complications of advanced liver disease are rare, some patients develop massive hepatic cystic disease and become clinically symptomatic. There is no effective medical therapy. Interventional and surgical options include cyst aspiration and sclerosis, open or laparoscopic cyst fenestration, hepatic resection, and liver transplantation.

Progressive Portopulmonary Hypertension After Liver Transplantation Treated With Epoprostenol

Portopulmonary hypertension (PPHTN) is an uncommon complication of advanced liver disease. Epoprostenol has been effective in the treatment of PPHTN and has been used as a bridge to orthotopic liver transplantation (OLT). The role of OLT in the reversal of PPHTN is unclear. We report a case of severe PPHTN (mean pulmonary artery pressure of 45 mm Hg) that progressed after OLT. Acute dosing with epoprostenol improved the pulmonary vascular resistance by 55% and the cardiac index by 134%. Hemodynamic and symptomatic improvements were maintained after 18 months of long-term treatment with epoprostenol. This is the first reported case of a successful favorable outcome after treatment for progressive PPHTN after OLT. Our case report complements previous reports by highlighting the potential effective use of epoprostenol as a definitive treatment for PPHTN.

Indications for referral and assessment in adultliver transplantation: a clinical guideline

This document, on the indications and referral of patients for liver transplantation, was commissioned by the British Society of Gastroenterology (BSG) as part of a wider initiative to develop guidelines...

Liver transplantation from living related donors

OBJECTIVES: To present the experience with the first 12 living related liver transplants performed at Hospital Sírio-Libanês in São Paulo. METHODS: The donors were the fathers (6) and the mothers (6) with age ranging from 30 to 48 years. All candidates for donation were submitted to a full informed consent form, clinical and radiological evaluation and had blood withdrawn for autotransfusion. Recipient age ranged from 7 months to 10 years whereas recipient weight varied from 6.3 to 34 kg. Six patients were considered as high risk due to complications of advanced liver disease and were submitted to urgent transplantation. RESULTS: Mean donor hospital stay was 10 days with no mortality. Technical complications were observed in 4 recipients. Seven patients presented at least one episode of bacterial, viral or fungal infection. One or more biopsy proven rejection episodes were disclosed in 7 patients. Overall recipient survival was 67%, being 83% for elective cases and 50% for urgent cases. Long term follow up ranged from 8 to 25 months. Seven out of 8 survivors present excellent quality of life and normal liver function. The other patient is currently under reduced immunosuppression due to Epstein-Barr virus infection.CONCLUSIONS: These results demonstrate the safety and viability of living related liver transplantation which, in face of the current donor scarcity, should be considered as a valid option for the treatment of children with end stage liver disease.

An economic analysis of norfloxacin prophylaxis against spontaneous bacterial peritonitis

Background/Aims/Methods: Spontaneous bacterial peritonitis (SBP) is a frequent complication of advanced liver disease and in high-risk patients, it is associated with a mean (per episode) mortality of 29% and a mean 1-year mortality of 82%. The 1-year recurrence rate of SBP can be as high as 30–70%. Selective intestinal decontamination with antibiotic prophylaxis has been shown to significantly reduce the incidence of recurrent SBP. The aim of this study was to perform an economic analysis of norfloxacin prophylaxis to prevent SBP recurrence. Results: This analysis showed that nofloxacin prophylaxis in high-risk patients with cirrhosis resulted in USD 4632 savings per patient per year by avoiding SBP and its associated expense. A sensitivity analysis showed that the norfloxacin prophylaxis remained cost-saving, even if it resulted in only a modest reduction in the SBP recurrence rate. Conclusions: Selective gut decontamination with norfloxacin is not only efficacious in preventing SBP, but can also be cost-saving by avoiding the resource utilization associated with its treatment.

Cerebral abnormalities in patients with cirrhosis detected by proton magnetic resonance spectroscopy and magnetic resonance imaging

Hepatic encephalopathy is a common problem in cirrhosis. The pathogenesis of this complication of advanced liver disease still remains unclear. Magnetic resonance spectroscopy was used to assess prospectively cerebral metabolism in 51 patients with histologically proven cirrhosis (Child-Pugh classes A, B, and C, 18, 18, and 15, respectively) and 36 healthy volunteers. According to the results of psychometric tests, overt hepatic encephalopathy, subclinical encephalopathy, and no encephalopathy were found in 14, 21, and 16 patients, respectively. Myoinositol/creatine ratios in gray (.36 +/- .17) and white (.35 +/- .22) matter voxel were reduced significantly (P < .0001) in cirrhotic patients compared with healthy volunteers (gray matter, .51 +/- .11; white matter, .64 +/- .16). In addition, patients showed a significant reduction (P = .024) in white matter choline/creatine ratio (.77 +/- .27) compared with controls (.92 +/- .25), and glutamine/glutamate level was elevated in cirrhotic patients compared with controls (gray matter, P < .0001; white matter, P = .036). Changes in cerebral myoinositol and glutamine/glutamate levels correlated significantly with the severity of hepatic encephalopathy (P < .0001). However, these metabolic alterations were also detected in patients without hepatic encephalopathy (normal psychometric test results). N-acetyl aspartate/creatine ratios did not differ between patients and controls. Magnetic resonance imaging detected bright basal ganglia in 37 patients, which correlated significantly with portal-systemic shunting and elevation of glutamine/glutamate, but not with the degree of hepatic encephalopathy. In conclusion, magnetic resonance imaging and spectroscopy showed that alterations of cerebral metabolism are common in patients with cirrhosis, even without evidence of clinical or subclinical hepatic encephalopathy.(Hepatology 1997 Jan;25(1):48-54)