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.

A randomized, placebo-controlled study of the NS5B inhibitor beclabuvir with peginterferon/ribavirin for HCV genotype 1.

Beclabuvir is a potent, non-nucleoside inhibitor of the HCV NS5B RNA polymerase, with nanomolar activity against HCV genotypes 1, 3, 4, 5 and 6 in vitro. This study evaluated the efficacy and safety of beclabuvir, in combination with peginterferon alfa-2a (pegIFN) and ribavirin (RBV), in HCV genotype 1. In this randomized (1:1:1), double-blinded, placebo-controlled, dose-ranging phase 2a study, 39 treatment-naive patients chronically infected with HCV genotype 1 were treated for 48 weeks with beclabuvir (75 mg or 150 mg) plus pegIFN (180 µg) and RBV (1000 mg/day [<75 kg] or 1200 mg/day [≥ 75 kg]) vs pegIFN/RBV alone. The primary efficacy endpoint of extended rapid virologic response (undetectable HCV RNA at treatment weeks 4 and 12) was achieved by 76.9% (10/13) of patients receiving beclabuvir 75 mg and 38.5% (5/13) receiving beclabuvir 150 mg vs 0% receiving pegIFN/RBV alone. Higher response rates were observed among patients receiving beclabuvir 75 mg for all secondary efficacy endpoints, including sustained virologic response at follow-up weeks 12 or 24. Three patients experienced virologic breakthrough on treatment, all in the beclabuvir 150-mg treatment group. Beclabuvir was well tolerated at both doses, with the most commonly observed adverse events (headache, fatigue, nausea, decreased appetite, irritability, depression and insomnia) consistent with those observed with pegIFN/RBV. In conclusion, beclabuvir was both effective and well tolerated when administered in combination with pegIFN/RBV for the treatment of chronic HCV GT 1, supporting the study of beclabuvir as part of an all-oral regimen for HCV GT1.

Liver transplantation in the United States, 1999-2008.

Changes in organ allocation policy in 2002 reduced the number of adult patients on the liver transplant waiting list, changed the characteristics of transplant recipients and increased the number of patients receiving simultaneous liver-kidney transplantation (SLK). The number of liver transplants peaked in 2006 and declined marginally in 2007 and 2008. During this period, there was an increase in donor age, the Donor Risk Index, the number of candidates receiving MELD exception scores and the number of recipients with hepatocellular carcinoma. In contrast, there was a decrease in retransplantation rates, and the number of patients receiving grafts from either a living donor or from donation after cardiac death. The proportion of patients with severe obesity, diabetes and renal insufficiency increased during this period. Despite increases in donor and recipient risk factors, there was a trend towards better 1-year graft and patient survival between 1998 and 2007. Of major concern, however, were considerable regional variations in waiting time and posttransplant survival. The current status of liver transplantation in the United States between 1999 and 2008 was analyzed using SRTR data. In addition to a general summary, we have included a more detailed analysis of liver transplantation for hepatitis C, retransplantation and SLK transplantation.

Effect modification in liver allografts with prolonged cold ischemic time.

Although prolonged cold ischemia time (PCIT) is generally associated with worse outcomes following liver transplantation, evidence suggests that some recipients and some donors might be more sensitive to PCIT than others. The purpose of this study was to identify factors that predict a higher risk of graft loss after a transplant with PCIT when compared with a similar transplant with average CIT (ACIT). 14 637 recipients reported to United Network for Organ Sharing (UNOS) in the model for end-stage liver disease (MELD) era were studied by interaction term analysis in proportional hazards models. Recipient diabetes, obesity and donor African American (AA) ethnicity were found to significantly amplify the adverse effects of PCIT. Graft loss was 1.85-fold higher in diabetic or obese PCIT recipients compared with diabetic or obese ACIT recipients, (vs. 1.17 for the same comparison in non-diabetic non-obese recipients). Similarly, graft loss was 1.80-fold higher in AA PCIT donors compared with AA ACIT donors, (vs. 1.31 for the same comparison in non-AA donors). Other factors may also exist, but current clinical practices might already mitigate the risks from those factors. As such, we recommend expanding clinical practice to include our findings, but not abandoning current judgment based on factors already perceived to amplify the adverse effects of PCIT.

Endoscopic retrograde cholangiopancreatography, but not esophagogastroduodenoscopy or colonoscopy, significantly increases portal venous pressure: direct portal pressure measurements through endoscopic ultrasound-guided cannulation.

BACKGROUND AND STUDY AIMS: Changes in portal pressure during endoscopy have not been previously evaluated. The aims of this study were to assess the effect of esophagogastroduodenoscopy (EGD), colonoscopy, and endoscopic retrograde cholangiopancreatography (ERCP) on portal vein, inferior vena cava (IVC), and systemic pressures. PATIENTS AND METHODS: Five acute experiments were performed on 50-kg pigs utilizing endoscopic ultrasound (EUS)-guided catheterization of the portal vein and IVC. Systemic, intra-abdominal, IVC, and portal vein pressures were monitored during colonoscopy, EGD, and ERCP with endoscopic sphincterotomy. After endoscopy the animals were sacrificed for necropsy. The main outcome measure was pressure change during each type of endoscopic procedure. RESULTS: There were no significant changes in heart rate or systemic pressure during all endoscopic procedures. Intra-abdominal pressure increased during colonoscopy ( P = 0.02) and ERCP ( P = 0.007). However, mean portal venous pressure was significantly elevated only after the injection of contrast into the common bile duct, reaching its peak value at the time of biliary sphincterotomy (39.0 +/- 15.2 mm Hg vs. 13.4 +/- 3.6 mm Hg at baseline, P = 0.006). Mean peak IVC pressure was also elevated during ERCP, but it did not reach statistical significance (24.0 +/- 10.7 mm Hg vs. 12.6 +/- 4.1 mm Hg at baseline, P = 0.06). CONCLUSION: EGD and colonoscopy did not cause significant changes in portal vein, IVC, or systemic pressures. ERCP with biliary sphincterotomy increased portal pressure with only limited effect on IVC and systemic pressures. These new data indicate a possible connection between ERCP with sphincterotomy and portal pressure, and may be clinically important for patients with liver disease and other causes of portal hypertension who undergo this procedure.

Endoscopic ultrasound and fine needle aspiration for the diagnosis of hepatocellular carcinoma.

Liver cancer is one of the most frequent solid cancers. The major risk factor associated with the development of hepatocellular carcinoma (HCC) is cirrhosis caused by hepatitis B, hepatitis C virus or chronic alcohol consumption. The overall prognosis of patients with HCC is very poor and this is mainly due to the advanced stages of cancer at presentation and also because of underlying cirrhosis. When HCC is diagnosed at early stages, prognosis is better with five-year disease free survival of around 50% with resection, or local ablative treatments such as radio-frequency ablation or percutaneous ethanol injection, and 70-80% with liver transplantation. Therefore, systematic screening of all the high-risk patients is the key to an early diagnosis of small HCC and the use of an appropriate treatment modality. The currently available tools for the screening, surveillance and diagnosis of HCC in the presence of cirrhosis remain sub-optimal. The advancements made in the past 10 years, however, have made HCC a potentially curable disease in a highly selected group of patients. This review will briefly discuss the current guidelines for surveillance and diagnosis of HCC in high-risk subjects and then review the potential role of endoscopic ultrasound and fine needle aspiration for the diagnosis of small HCC.

Endoscopic frontiers in the field of hepatology.

Hepatology is considered a cognitive specialty, but it will not be surprising if a subgroup of future hepatologists (''invasive hepatologists'') performed a variety of advanced endoscopic, laparoscopic, vascular or ablative procedures just like interventional gastroenterologists, interventional radiologists or minimally invasive surgeons. The increase in the prevalence of liver diseases including hepatocellular carcinoma, and effective treatment of end-stage liver disease with liver transplantation has expanded the subspecialty of hepatology into a major specialty. Therefore, it is only natural that some of the trainees in hepatology, familiar with invasive procedures just like their counterparts in gastroenterology, may become subspecialized in invasive aspects of this specialty, traditionally performed by interventional endoscopists, radiologists and surgeons. Moreover, there will be major developments in the management of the complications of liver disease. Endoscopic screening with esophageal capsule endoscopy and, to a lesser extent, ultrathin upper gastrointestinal endoscopy may replace conventional endoscopy. In addition to standard treatments for esophageal varices, removable esophageal stents with expansile pressure may be utilized in refractory variceal hemorrhage. Transjugular intrahepatic portosystemic shunts may be performed by hepatologists. Advances in argon plasma coagulation, cryotherapy and photodynamic therapy may result in novel treatment options for portal hypertensive gastropathy. Single-fiber cholangioscopy will allow for directed endoscopic screening for cholangiocarcinoma and primary sclerosing cholangitis in high-risk individuals. Minilaparoscopy will allow a macroscopic assessment of the liver surface as well as the ability to target specific regions for histopathology, and treatment including radiofrequency ablation of liver cancer. Endoscopic ultrasound (EUS) may provide the potential to directly measure portal vein pressure and this may have a future role in titration and optimization of pharmacological therapy of portal hypertension. EUS and fine needle aspiration may be used for staging hepatocellular and bile duct cancer. Finally, natural orifice transluminal surgery and endoscopic ultrasound-guided angiography may allow for targeted therapies traditionally outside the realm of the hepatologists.

Oral V2 receptor antagonist (RWJ-351647) in patients with cirrhosis and ascites: a randomized, double-blind, placebo-controlled, single ascending dose study.

BACKGROUND: RWJ-351647 is a selective V2 receptor antagonist that inhibits vasopressin-induced water reabsorption in the kidney. AIM: To investigate the safety and tolerability of RWJ-351647 compared with placebo after single oral dose administration to patients with cirrhosis and ascites, on a stable treatment with furosemide and spironolactone. METHODS: Single oral doses of 1, 2 and 5 mg of RWJ-351647 were administered to 24 patients with ascites on stable concomitant diuretic treatment. RESULTS: RWJ-351647 had a tmax of 1 to 1.1 h and mean half-life of 10.4-17.4 h. There was no affect on the pharmacokinetics of concomitant diuretics. Increases in cumulative urine volume and free water excretion, and a decrease in urine osmolality were noted in a dose-dependent manner reaching the statistical significance at the 5-mg dose. Four patients exhibited a decrease of > 2 kg in weight in the 24 h after dosing. RWJ-351647 was well tolerated, with no evidence of a dose-related increase in adverse events when compared with placebo. No changes in either serum chemistry or plasma AVP (arginine vasopressin) and renin levels were observed despite the observed aquaresis. CONCLUSION: RWJ-351647 is an effective aquaretic causing dose-dependent increases in urine output and free water clearance, when co-administered with conventional diuretics in patients with cirrhosis and ascites.

Phase II study of the efficacy and safety of cisplatin-epinephrine injectable gel administered to patients with unresectable hepatocellular carcinoma.

PURPOSE: To study the efficacy and safety of percutaneous cisplatin-epinephrine (CDDP-EPI) injectable gel in patients with localized unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Eligible patients had histologically proven HCC, no prior treatment except for surgery, and no more than three tumors (each measured < or = 7 cm, total tumor volume < or = 200 cm(3)). They were treated percutaneously under ultrasound or computed tomography (CT) guidance, with up to 10 mL of CDDP-EPI gel (1 mL contains 4 mg of CDDP and 0.1 mg of EPI) per treatment and four treatments in 6 weeks to a maximum of eight treatments. The primary end points were tumor response, defined by change of percentage of tumor necrosis according to CT criteria, and safety. Survival parameters were secondary end points. RESULTS: From June 1997 to April 2000, 58 patients (median age, 65 years) entered the study. All patients were assessable for safety, and 51 were assessable for efficacy. The median number of treatments was four (range, one to eight treatments). Objective response rate was 53% (27 of 51 patients), including 16 complete and 11 partial responses. Of the 27 responders, 14 (52%) subsequently developed progressive disease, but in most of them (93%), a new tumor arose at untreated liver sites. Median survival was 27 months (range, 18.4 to 35.7 months). The 1-, 2-, and 3-year survival rates were 79%, 56%, and 14% respectively. The procedure was well tolerated with only minor side effects. CONCLUSION: Percutaneous local ablation with CDDP-EPI injectable gel can induce significant tumor necrosis and local control for localized unresectable HCC, and the treatment is well tolerated.

Evaluation of nutritional status by using anthropometry in adults with alcoholic and nonalcoholic liver disease.

No systematic studies have examined the nutritional status of patients with alcoholic and nonalcoholic liver disease by using anthropometry. In this study the nutritional status of 132 patients with chronic liver disease was evaluated by using anthropometry, and results were compared with 56 control subjects and 46 patients with other diseases by using standards recommended by Frisancho. Nineteen percent of patients with liver disease were below the 5th percentile for arm fat area and 35% were below the 5th percentile for arm muscle area. Malnutrition was seen equally among patients with alcoholic and nonalcoholic liver disease. Nutritional status of patients with liver disease was similar to that of patients with carcinoma. Anthropometric measurements correlated significantly with measurements of albumin concentration but not with other liver-function tests or with the severity of liver disease as assessed by Child-Pugh score. These data suggest that malnutrition is common in patients with both alcoholic and nonalcoholic liver disease.

Human monocytic ehrlichiosis: an emerging pathogen in transplantation.

BACKGROUND: The spectrum of disease caused by Ehrlichia spp. ranges from asymptomatic to fatal. Awareness and early diagnosis of the infection is paramount because appropriate therapy leads to rapid defervescence and cure. If left untreated, particularly in immunosuppressed patients, ehrlichioses may result in multi-system organ failure and death. METHODS: We report the second case of human monocytic ehrlichiosis (HME) in a liver transplant recipient, and review the literature. RESULTS: The patient presented with fever and headache, had negative cultures, and despite broad-spectrum antimicrobial coverage appeared progressively septic. After eliciting a history of tick exposure we treated the patient empirically with doxycycline. The diagnosis of HME was confirmed by 1) polymerase chain reaction (PCR) for Ehrlichia chaffeensis, 2) acute and convalescent serum titers, and 3) in vitro cultivation of E chaffeensis from peripheral blood. CONCLUSION: Although human ehrlichioses are relatively uncommon, they are emerging as clinically significant arthropod-borne infections. Although epidemiological exposure is responsible for infection, immunosuppression makes patients more likely to succumb to disease. A high index of suspicion and early treatment results in a favorable outcome.

How valid are our reference standards of nutrition?

The validity of anthropometric measurements in the assessment of nutritional status depends on the use of appropriate standards. The most commonly used standards for triceps skinfold thickness and mid-arm muscle circumferences are based on Jelliffe's and Frisancho's tables. In this study we compared these two standards in a population of healthy subjects and patients with a variety of pathological disorders. The study showed that the correlation between these two standards was poor. When Frisancho's standards were used as "gold standards," the positive predictive value of Jelliffe's standards for triceps skinfold thickness was only 22% and for mid-arm muscle circumference only 53%; the false positive results for triceps skinfold thickness and mid-arm muscle circumference were 28% and 27%, respectively. This study emphasizes the need to develop appropriate standards for the studied population. Until such standards are available, workers assessing nutritional status in population studies would be advised to interpret their findings with caution, and, on the basis of this study, we recommend the use of Frisancho's standard in preference to Jelliffe's standards.

Biliary complications after liver transplantation: the role of endoscopy.

Biliary complications are important causes of early and late postoperative morbidity and mortality after liver transplantation and are seen in 10-20 % of the patients. The common biliary complications include bile leaks, stones or debris, and anastomotic strictures. Less common complications are hilar strictures, intrahepatic strictures, and papillary stenosis/dysfunction. The complications are similar in living-donor and cadaveric liver transplantations, except for a higher incidence of bile leaks among living-donor transplant recipients. The clinical presentation of post-liver transplant bile duct complications is often subtle, and noninvasive imaging studies may sometimes fail to detect mild but clinically significant stenoses or small leaks. Early recognition and prompt treatment of biliary complications following liver transplantation reduces the morbidity and improves long-term graft and patient survival. In this report, we discuss the role of endoscopy in the diagnosis, treatment options, and the outcome for patients with biliary complications following liver transplantation.

Salmonella and complications related to age--Sheffield experience.

Three instances of extra-intestinal infection in elderly patients and the recent outbreak at Stanley Royd Hospital promoted a retrospective review of all salmonella infections seen at the Regional Diseases Unit over a 30-month period with particular reference to management of those over the age of 65 years. The survey has confirmed a more protracted illness with higher mortality and morbidity in elderly people suggesting a need for routine antibiotic treatment in these patients.

Autonomic neuropathy and chronic liver disease.

Autonomic neuropathy has been reported in association with alcoholic cirrhosis but there is no information on its occurrence in non-alcoholic liver disease. We have examined autonomic function in 64 patients with biopsy-proven liver disease (22 with alcoholic liver disease and 42 with non-alcoholic liver disease) together with 29 age-matched controls. Forty-five per cent of patients with alcoholic liver disease and 43 per cent with non-alcoholic liver disease showed evidence of parasympathetic damage; 11 per cent of patients with alcoholic liver disease and 12 per cent with non-alcoholic liver disease had sympathetic damage. Forty-five per cent of patients with alcoholic liver disease and 22 per cent with non-alcoholic liver disease had peripheral neuropathy on clinical examination. Sixty-eight per cent of those with peripheral neuropathy also had autonomic neuropathy. This study confirms that autonomic neuropathy is common in alcoholic patients but the fact that it is found with comparable frequency in non-alcoholic liver disease suggests that the neurological defect may be secondary to the disturbed liver function. The implications of these observations with regard to prognosis of chronic liver disease are discussed.

Selenium in chronic liver disease.

In order to assess the role of selenium (Se) in chronic liver disease, we have measured serum, urinary and hepatic selenium in a range of liver diseases and correlated them with nutritional status and conventional liver biochemistry. Serum Se levels (microgram/l +/- S.D.) were significantly lower in both alcoholic (63.6 +/- 18.2, p less than 0.0001) and non-alcoholic liver disease (NALD) (60.6 +/- 13.6, p less than 0.0001) compared to healthy controls (87.8 +/- 21.2) and non-malignant 'disease controls' (80.3 +/- 19.1). Hepatic Se levels (microgram/g of dry weight) were also reduced in both ALD (0.568 +/- 0.647, p less than 0.005) and NALD (0.863 +/- 0.308, p less than 0.005) compared to controls (1.227 +/- 0.296), 24-h urinary Se excretion (microgram) in ALD (24.6 +/- 10.7) and NALD (29.0 +/- 14.3) was similar to controls (30.3 +/- 8.7). Serum Se showed a highly significant positive correlation with albumin (p less than 0.001) in both ALD and NALD. Serum levels were also significantly correlated with anthropometric measurements. Dietary assessment of patients with primary biliary cirrhosis and low serum Se levels did not show a reduced dietary intake. Our data show that Se levels are low in liver disease irrespective of aetiology and suggest that these low levels are more likely to be related to overall nutritional status than to dietary intake.