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.

Hepatitis C virus in Mexican Americans: a population-based study reveals relatively high prevalence and negative association with diabetes.

This study aimed to estimate the prevalence and risk factors for hepatitis C virus (HCV) infection in Mexican Americans living in South Texas. We tested plasma for the presence of HCV antibody from the Cameron County Hispanic Cohort (CCHC), a randomized, population-based cohort in an economically disadvantaged Mexican American community on the United States/Mexico border with high rates of chronic disease. A weighted prevalence of HCV antibody of 2·3% [n = 1131, 95% confidence interval (CI) 1·2-3·4] was found. Participants with diabetes had low rates of HCV antibody (0·4%, 95% CI 0·0-0·9) and logistic regression revealed a statistically significant negative association between HCV and diabetes (OR 0·20, 95% CI 0·05-0·77) after adjusting for sociodemographic and clinical factors. This conflicts with reported positive associations of diabetes and HCV infection. No classic risk factors were identified, but important differences between genders emerged in analysis. This population-based study of HCV in Mexican Americans suggests that national studies do not adequately describe the epidemiology of HCV in this border community and that unique risk factors may be involved.

MELD exceptions for portopulmonary hypertension: current policy and future implementation.

Since 2006, waitlist candidates with portopulmonary hypertension (POPH) have been eligible for standardized Model for End-Stage Liver Disease (MELD) exception points. However, there are no data evaluating the current POPH exception policy and its implementation. We used Organ Procurement and Transplantation Network (OPTN) data to compare outcomes of patients with approved POPH MELD exceptions from 2006 to 2012 to all nonexception waitlist candidates during this period. Since 2006, 155 waitlist candidates had approved POPH MELD exceptions, with only 73 (47.1%) meeting the formal OPTN exception criteria. Furthermore, over one-third of those with approved POPH exceptions either did not fulfill hemodynamic criteria consistent with POPH or had missing data, with 80% of such patients receiving a transplant based on receiving exception points. In multivariable multistate survival models, waitlist candidates with POPH MELD exceptions had an increased risk of death compared to nonexception waitlist candidates, regardless of whether they did (hazard ratio [HR]: 2.46, 95% confidence interval [CI]: 1.73-3.52; n = 100) or did not (HR: 1.60, 95% CI: 1.04-2.47; n = 55) have hemodynamic criteria consistent with POPH. These data highlight the need for OPTN/UNOS to reconsider not only the policy for POPH MELD exceptions, but also the process by which such points are awarded.

Persisting role of healthcare settings in hepatitis C transmission in Pakistan: cause for concern.

Transmission of hepatitis C (HCV) in Pakistan is a continuing public health problem; 15 years ago it was linked to the practice of reusing therapeutic instruments in healthcare settings. We sought to examine current risk factors for HCV transmission in a hospital population in Karachi, Pakistan. We enrolled 300 laboratory-confirmed HCV-positive participants and 300 laboratory confirmed HCV-negative participants from clinics at Indus Hospital. Independent and significant risk factors for both men and women were: receiving o12 injections in the past year, blood transfusions, having had dental work performed, and delivery in hospital or transfusion for women. Interestingly, being of Mohajir origin or born in Sindh province were protective.Encouragingly, a strong protective effect was observed for those that reported bringing their own needle for injections (59%). The widespread reuse of therapeutic needles in healthcare settings in Karachi remains a major driver of the HCV epidemic.

Hypercoagulation and thrombophilia in liver disease.

A complex balance exists between endogenous procoagulants and the anticoagulant system in liver disease patients. Hypercoagulable events occur in cirrhosis patients despite the well-known bleeding diathesis of liver disease. These events may be clinically evident, such as in portal vein thrombosis or pulmonary embolism, but these conditions may also be a silent contributor to certain disease states, such as portopulmonary hypertension or parenchymal extinction with liver atrophy as well as thrombosis of extracorporeal circuits in dialysis or liver assist devices. Moreover, liver disease-related hypercoagulability may contribute to vascular disease in the increasingly common condition of non-alcoholic fatty liver disease. Despite the incidence of these problems, there are few widely accessible and practical laboratory tests to evaluate the risk of a hypercoagulable event in cirrhosis patients. Furthermore, there is little research on the use of commonly accepted anticoagulants in patients with liver disease. This article is a result of an international symposium on coagulation disorders in liver disease and addresses several areas of specific interest in hypercoagulation in liver disease. Critical areas lacking clinical information are highlighted and future areas of research interest are defined with an aim to foster clinical research in this field.

Hepatopulmonary syndrome and venous emboli causing intracerebral hemorrhages after liver transplantation: a case report.

Increasing experience has fostered the acceptance of liver transplantation as a treatment for patients with hepatopulmonary syndrome. Morbidity and mortality is most commonly attributed to progressive arterial hypoxemia postoperatively. A cerebral hemorrhage has been reported in one patient with hepatopulmonary syndrome after transplantation. However, a postmortem examination of the brain was not performed and the pathogenesis or type of cerebral hemorrhage was undefined. We report on a patient with severe hepatopulmonary syndrome who developed multiple intracranial hemorrhages after transplantation. The intracerebral hemorrhages were most consistent with an embolic etiology on postmortem examination. We postulate that venous embolization, caused by the manipulation of a Swan Ganz catheter in a thrombosed central vein, resulted in pulmonary emboli that passed through dilated intrapulmonary vessels into the cerebral microcirculation. Special attention to central venous catheters and avoidance of manipulation may be warranted in subjects with severe hepatopulmonary syndrome after liver transplantation.

The hepatopulmonary syndrome.

The hepatopulmonary syndrome occurs in subjects with chronic liver disease and/or portal hypertension who develop intrapulmonary vasodilation resulting in arterial deoxygenation. Clinical and basic science studies investigating the pathophysiology of HPS are presented. A diagnostic algorithm is provided using contrast echocardiography, the lung perfusion scan, and pulmonary angiography. Medical therapy and experience with liver transplantation are reviewed.

Hepatic venous pressure gradient measurements to assess response to primary prophylaxis in patients with cirrhosis: a decision analytical study.

BACKGROUND: The measurement of the hepatic venous pressure gradient may identify a suboptimal response to beta-blockers in patients with varices at risk for bleeding. However, the cost-effectiveness of routine hepatic venous pressure gradient measurements to guide primary prophylaxis has not been examined. METHODS: We used decision analysis to evaluate two hepatic venous pressure gradient measurement strategies relative to standard beta-blocker therapy in a hypothetical cohort of patients with high-risk varices: (i) hepatic venous pressure gradient measurement 4 weeks after the initiation of beta-blocker therapy; and (ii) hepatic venous pressure gradient measurement prior to and 4 weeks after the initiation of beta-blocker therapy. The total expected costs, variceal bleeding episodes and deaths were calculated over a 1-year time horizon. RESULTS: Beta-blocker therapy was associated with total costs of $1464, seven variceal bleeding episodes, one variceal bleeding episode-related death and 15 deaths. One hepatic venous pressure gradient measurement was associated with total costs of $5015, four variceal bleeding episodes, one variceal bleeding episode-related death and 15 deaths. Two hepatic venous pressure gradient measurements were associated with total costs of $8657, four episodes of variceal bleeding, one variceal bleeding episode-related death and 15 deaths. Compared with beta-blocker therapy alone, the incremental costs per variceal bleeding episode prevented and death averted were, respectively, $108 185 and $355 100 (one hepatic venous pressure gradient measurement) and $202 796 and $719 300 (two hepatic venous pressure gradient measurements). The results were sensitive to the time horizon of the analysis, the probability of bleeding whilst on beta-blockers and the cost of hepatic venous pressure gradient measurement. CONCLUSION: Hepatic venous pressure gradient measurement to guide primary prophylaxis is an expensive strategy for reducing variceal bleeding or death, especially in patients with limited life expectancy, such as those with advanced, decompensated cirrhosis.

Effects of exogenous insulin, glucagon, and somatostatin on islet hormone secretion in the perfused chicken pancreas.

The effects of exogenous insulin were examined in the isolated perfused chicken pancreas with the duodenum excluded. At low background glucose (50 mg/dl), exogenous insulin infused at a concentration of 20,000 microU/ml elicited clear stimulation of somatostatin secretion while simultaneously inhibiting glucagon release. When the background glucose concentration was elevated to 750 mg/dl, exogenous insulin, had no effect on either somatostatin or glucagon release. When graded doses of exogenous insulin were infused into the chicken pancreas at low background glucose, low concentrations (200 microU/ml) had little effect on somatostatin or glucagon release, but higher concentrations (2000 and 20,000 microU/ml) had clear effects on both somatostatin and glucagon secretion. Glucagon infused at 100 ng/ml stimulated both insulin and somatostatin release. When somatostatin was infused at 25 ng/ml, clear inhibition of glucagon was seen with insulin inhibited to a lesser extent. This study supports the notion of a negative feedback relation between B and D-cells of the pancreatic islets and suggests a paracrine mediation.

Prevention in liver disease.

Prevention has become an important component of medical therapy for a variety of diseases. Preventive strategies in liver disease are relatively underdeveloped and have focused mainly on specific complications of chronic liver disease and vaccination for viral hepatitis. Although public health initiatives designed to prevent certain forms of liver disease are in place, they seem to be underutilized and their utility has not been evaluated. The development of a comprehensive approach using public health initiatives in conjunction with strategies by health care providers is important because of the potential for decreasing the human and health care costs associated with hepatic dysfunction. This article reviews the available literature regarding prevention for health care providers, includes a summary of ongoing public health initiatives, and suggests an approach to prevention in liver disease. It is intended to raise awareness and encourage implementation of preventive strategies in hepatology.

Hepatopulmonary syndrome.

Hepatopulmonary syndrome is caused by intrapulmonary vasodilation that leads to abnormal arterial gas exchange in the setting of liver disease or portal hypertension. It is seen in up to 15% of cirrhotics and is an increasingly common indication for liver transplantation. Testing for the presence of oxygenation abnormalities and intrapulmonary vasodilation is needed to make the diagnosis. Excess production of nitric oxide in the lung contributes to pulmonary vasodilation and may be triggered by the release of mediators from the damaged liver. No medical therapies are established as effective, and liver transplantation is the only documented curative treatment.

Treatment of hepatopulmonary syndrome with Allium sativum L. (garlic): a pilot trial.

No medical therapy exists for subjects with hepatopulmonary syndrome (HPS). A patient with HPS was reported to have improvement in arterial oxygenation while self-administering garlic. Our goal was to determine whether a standardized garlic powder improves arterial oxygenation and dyspnea in subjects with HPS. A prospective, open label uncontrolled pilot study in 15 subjects with HPS were administered garlic powder capsules daily for a minimum of 6 months. Arterial blood gases were determined every 4-8 weeks, in the same position on room air, and a subjective dyspnea transition index was reported. Six of 15 subjects (40%, confidence interval: 0.15-65) had at least a 10 mmHg increase in the P(O2) or decrease in the alveolar-arterial gradient. The mean pre- and postarterial difference in these patients were: P(O2) (14+/-4 mmHg) and alveolar-arterial gradient (18+/-5 mmHg). All 6 subjects who responded to garlic had less dyspnea on exertion. Garlic improved arterial oxygenation in younger subjects (mean 40 versus 56 years old; p = 0.021) or those with lower macroaggregated albumin shunt fractions (mean 21 versus 44%, p = 0.058). Garlic may improve arterial oxygenation and symptoms in patients with hepatopulmonary syndrome and warrants further investigation.

Hepatic toxicity of vitamin A and synthetic retinoids.

Vitamin A and synthetic retinoids have recently been used increasingly in a variety of health related concerns. Hepatic toxicity is an uncommon but serious side-effect of several Vitamin A derivatives which may lead to cirrhosis. This review will focus on the clinical and pathologic findings of hepatic involvement in chronic hypervitaminosis A and on the evidence concerning the potential hepatotoxicity of currently available synthetic retinoids.

Scenario number one: hepatopulmonary syndrome.

HPS is an increasingly recognized clinical entity resulting from intrapulmonary vasodilatation in patients with liver disease and/or portal hypertension. The pathogenesis of alterations in the pulmonary vascular bed in affected patients is poorly understood and the subject of ongoing investigation. The differential diagnosis of pulmonary symptoms and gas-exchange abnormalities in patients with liver disease being evaluated for transplantation is broad and should be focused on differentiating pulmonary causes that significantly increase the risk for transplantation from HPS where transplantation has emerged as a useful treatment. Specific contraindications to transplantation in patients with HPS have not been identified, though unique postoperative complications have been observed and may be treatable during the frequently prolonged resolution of intrapulmonary vasodilatation. The development of a database of information on patients with HPS undergoing transplantation will provide insight into potential contraindications, prognostic features, and postoperative complications unique to these patients.

Altered expression and localization of the tight junction protein ZO-1 after common bile duct ligation.

Hepatocyte tight junctions form the intercellular barrier between bile and blood. Cholestasis due to common bile duct ligation (CBDL) results in structural changes in the tight junction (TJ) and an overt paracellular leak, although the molecular basis for these alterations is undefined. Using the epithelial isoform of the TJ protein ZO-1 (ZO-1 alpha +) as a marker for molecular changes in hepatocyte TJs, we investigated the effects of CBDL on ZO-1 alpha + immunofluorescence (IF) localization and on ZO-1 alpha + mRNA and protein expression over 2 wk of CBDL. ZO-1 alpha + IF staining was altered after 2 days of CBDL and appeared to accumulate in pericanalicular regions after 7 and 9 days. Quantitative immunoblotting and ribonuclease protection revealed a marked increase in hepatic ZO-1 alpha + protein expression and ZO-1 alpha + mRNA levels, respectively. In contrast to changes in ZO-1 alpha + IF, which occurred throughout the lobule, and changes in mRNA and protein expression, which were maximal after 9 days of ligation, the maximal hepatocyte proliferation occurred within 2 days after CBDL and was confined to periportal regions. CBDL results in altered hepatic localization and increased expression of the TJ protein ZO-1 alpha + and appears to represent a specific response by hepatocytes to pathological junction injury independent of cell proliferation.

Multistep mechanism of polarized Ca2+ wave patterns in hepatocytes.

The spatial organization of cytosolic Ca2+ (Ca2+i) signals is thought to be important for regulation of cell function. In epithelial cells, the involvement of inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ release in evoking Ca2+i signals is appreciated, but the location of IP3-sensitive Ca2+ stores and the role of Ca(2+)-induced Ca2+ release (CICR) for Ca2+ signaling are less defined. Here, we demonstrate that IP3 receptors are localized to the apical region in hepatocytes. We also show that hormone-induced Ca2+i waves propagate across the cell at a rate that depends on mobilization of Ca2+ stores that are sensitive to caffeine, ryanodine, and dantrolene, and that these agents, at concentrations that inhibit CICR, decrease the magnitude of Ca2+i signals. Furthermore, Ca2+i wave speed is not reduced in Ca(2+)-free medium. These findings suggest that Ca2+i signals in epithelial cells begin as apical-to-basal Ca2+i waves that result from sequential release of Ca2+, first from IP3-sensitive stores in the apex and then from Ca(2+)-sensitive stores distributed across the remainder of the cell.

Oral thymic extract for chronic hepatitis C in patients previously treated with interferon. A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Hepatitis C is an important cause of chronic liver disease. It is claimed that Complete Thymic Formula, an over-the-counter herbal dietary supplement, is beneficial for patients with hepatitis C. OBJECTIVE: To evaluate the efficacy and safety of Complete Thymic Formula. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Tertiary referral center. PATIENTS: 38 patients with hepatitis C who did not respond to or were intolerant of interferon therapy. INTERVENTION: Complete Thymic Formula for 3 to 6 months or placebo for 3 months. MEASUREMENTS: Serial measurements of hepatitis C virus (HCV) RNA titers. RESULTS: No differences were noted at 3 months between the placebo group (n = 13) and the treatment group (n = 19) in mean HCV RNA titers (4.06 +/- 1.52 x 10(6) copies/mL compared with 3.48 +/- 1.92 x 10(6) copies/mL; P > 0.2). The 19 patients who completed 6 months of treatment with Complete Thymic Formula remained positive for HCV, and their mean HCV RNA titers were similar at 6 months and at baseline (2.78 +/- 1.96 x 10(6) copies/mL compared with 3.12 +/- 1.94 x 10(6) copies/mL; P > 0.2). CONCLUSIONS: Complete Thymic Formula did not benefit patients who had previously received interferon therapy. Patients should be advised about use of this over-the-counter compound.

Endothelin-1 in the rat bile duct ligation model of hepatopulmonary syndrome: correlation with pulmonary dysfunction.

BACKGROUND/AIMS: Models of hepatopulmonary syndrome require both hepatic injury and portal hypertension to develop pulmonary microvascular and gas exchange abnormalities. Recently, increased endothelin-1 levels associated with vasodilatation, have been observed in cirrhosis. We investigated endothelin-1 production in common bile duct ligated animals with hepatopulmonary syndrome in comparison to partial portal vein ligated animals that do not develop hepatopulmonary syndrome. METHODS: Organ and plasma endothelin-1 were measured in sham, bile duct ligated and portal vein ligated rats, and Northern analysis and immunohistochemistry were performed in liver. Plasma endothelin-1 levels were correlated with pulmonary endothelial nitric oxide synthase levels and alveolar-arterial oxygen gradients. RESULTS: Hepatic and plasma endothelin-1 increased only after bile duct ligation, and were accompanied by increased hepatic endothelin-1 mRNA and increased endothelin-1 protein in biliary epithelium. Plasma endothelin-1 levels correlated directly with both pulmonary endothelial nitric oxide synthase levels and alveolar-arterial gradients. CONCLUSIONS: Enhanced hepatic production and increased plasma levels of endothelin-1 occur after bile duct ligation, but not after portal vein ligation, and correlate with associated molecular and gas exchange alterations in the lung. Endothelin-1 may contribute to the pathogenesis of hepatopulmonary syndrome.

Muscle cramps in patients with cirrhosis.

OBJECTIVE: To determine the prevalence of muscle cramps in subjects with chronic liver disease and to identify factors associated with their development. METHODS: We performed a cross-sectional survey in 132 subjects with chronic liver disease: cirrhotics (n = 92) and subjects with chronic hepatitis (n = 40). In addition, to control for diuretic use, patients with congestive heart failure (n = 40) were included as a comparison group. RESULTS: The prevalence of chronic muscle cramps was significantly greater in cirrhotics compared with patients with chronic hepatitis [48/92 (52%) vs 3/40 (7.5%), respectively, p < 0.0001] and compared with subjects with congestive heart failure [8/40 (20%), p < 0.001]. Factors, including age, gender, alcoholic liver disease, electrolytes, and diuretic use were similar among cirrhotics with and without cramps. Significantly higher total bilirubin and lower albumin levels were noted in cirrhotics with and without cramps, respectively; however, there was no significant difference in Child's A or B classification. CONCLUSIONS: There is an increased prevalence of chronic muscle cramps in subjects with cirrhosis that appears to be independent of the etiology of cirrhosis, diuretic consumption, serum electrolyte alterations, or differences in Child's classification. These results suggest that cramps in these patients are related specifically to the development of cirrhosis, and worsening liver function may be a risk factor for the development of cramps.