[Show abstract][Hide abstract] ABSTRACT: It remains unclear whether a long-acting preparation of octreotide (Sandostatin LAR) can be safely used for portal hypertension in patients with compensated cirrhosis.
To determine the safety and efficacy of LAR among patients with Child Pugh Class A or B cirrhosis and small oesophageal varices.
A randomised, double-blind, placebo-controlled study was conducted in 39 patients with cirrhosis and small oesophageal varices. Safety was based on frequency and severity of adverse events. Efficacy was determined by hepatic vein pressure gradient (HVPG) measured at baseline and day 84 following administration of LAR 10 mg (n = 15), 30 mg (n = 10) or saline (n = 14). Fasting and postprandial portal blood flow (PBF), superior mesenteric artery pulsatility index (SMA-PI), glucagon and octreotide levels were measured. An intention-to-treat analysis was performed.
Four patients in the LAR 30 group (40%) withdrew from the study due to serious adverse events. No patient in the LAR 10 or control group had serious adverse events. There was no statistically significant decrease between HVPG at day 84 and baseline with LAR 30 mg (11.8 ± 2.3 mmHg vs. 14.1 ± 3.2), LAR 10 mg (15.3 ± 4.8 mmHg vs. 15.1 ± 3.8), or saline (13.3 ± 3.8 mmHg vs. 15.1 ± 4.3) (P = 0.26). Neither PBF, SMA-PI nor plasma glucagon levels were significantly decreased from baseline (P = 0.56).
The absence of significant haemodynamic benefit, as well as the high frequency of severe adverse events associated with use of LAR, do not support the use of this agent in the treatment of portal hypertension.
[Show abstract][Hide abstract] ABSTRACT: Administration of terlipressin plus albumin is effective in reversing type 1 HRS as compared to albumin alone. However, only about 1/3 of patients respond to treatment, therefore, predictors of response and survival would help identify the patients most likely to benefit from treatment.
We analyzed our controlled trial of terlipressin vs. placebo (Gastroenterology 2008;134:1360) to define factors predictive of a response and to correlate hemodynamic changes to changes in renal function.
Single variant analysis showed treatment with terlipressin, MELD score, and baseline serum creatinine to be predictive of HRS reversal. Alcoholic hepatitis, baseline serum creatinine, and MELD score were predictive of survival. When treatment was not considered as a variable, only baseline serum creatinine predicted HRS reversal. Baseline serum creatinine, presence of alcoholic hepatitis, and Child-Pugh score were also predictive of survival on multivariate analysis. The rise in mean arterial pressure (MAP) following terlipressin administration was not predictive of HRS reversal. However, in those who achieved HRS reversal from terlipressin, there was a significant rise in MAP from beginning to end of treatment.
The most consistent predictor of response to terlipressin and of survival is the baseline serum creatinine. Patients most likely to benefit from terlipressin have earlier onset renal failure (i.e. serum creatinine <5.0mg/dl). A sustained rise in MAP is required for HRS reversal. As MAP is a surrogate marker for the hyperdynamic circulation, it is only with improvement in the hyperdynamic circulation that HRS reversal is observed.
Journal of Hepatology 12/2010; 55(2):315-21. DOI:10.1016/j.jhep.2010.11.020 · 10.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives of the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Commission were to identify well-characterized animal models of hepatic encephalopathy (HE) and to highlight areas of animal modelling of the disorder that are in need of development. Features essential to HE modelling were identified. The best-characterized animal models of HE in acute liver failure, the so-called Type A HE, were found to be the hepatic devascularized rat and the rat with thioacetamide-induced toxic liver injury. In case of chronic liver failure, surgical models in the rat involving end-to-side portacaval anastomosis or bile duct ligation were considered to best model minimal/mild (Type B) HE. Unfortunately, at this time, there are no satisfactory animal models of Type C HE resulting from end-stage alcoholic liver disease or viral hepatitis, the most common aetiologies encountered in patients. The commission highlighted the urgent need for such models and of improved models of HE in chronic liver failure in general as well as a need for models of post-transplant neuropsychiatric disorders. Studies of HE pathophysiology at the cellular and molecular level continue to benefit from in vitro and or ex vivo models involving brain slices or exposure of cultured cells (principally cultured astrocytes) to toxins such as ammonia, manganese and pro-inflammatory cytokines. More attention could be paid in the future to in vitro models involving the neurovascular unit, microglia and neuronal co-cultures in relation to HE pathogenesis.
Liver international: official journal of the International Association for the Study of the Liver 08/2009; 29(6):783-8. DOI:10.1111/j.1478-3231.2009.02034.x · 4.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The grading of hepatic encephalopathy (HE) is based on a combination of indicators that reflect the state of consciousness, intellectual function, changes in behavior, and neuromuscular alterations seen in patients with liver failure.
We modified the traditional West Haven criteria (WHC) to provide an objective assessment of the cognitive parameters to complement the subjective clinical ratings for the performance of extracorporeal albumin dialysis (ECAD) using a molecular adsorption recirculating system in patients with cirrhosis and severe (grade III / IV) encephalopathy. The HE Scoring Algorithm (HESA) combined clinical indicators with those derived from simple neuropsychological tests,the latter more often used in milder grades of HE (I / II). The performance of each indicator was compared across grades and sites.
Results of HESA were also compared with the Glasgow Coma Scale. A total of 597 evaluations were performed in patients randomized to ECAD plus standard medical therapy or the latter only. Most parameters exhibited significant separation between grades; the most effective indicators were lack of verbal, eye, and motor response (grade IV), somnolence and disorientation to place (grade III), and lethargy and disorientation to time (grade II). Two clinical and four neuropsychological indicators were useful to classify patients as grade I. The Glasgow Coma Scale differed among the four stages of the WHC, but the differences between grades I and II were small and not clinically useful.
HESA extends the traditional WHC for grading HE. In the absence of a "gold" standard, the most useful indicators noted in this trial should be further validated.
The American Journal of Gastroenterology 06/2009; 104(6):1392-400. DOI:10.1038/ajg.2009.160 · 9.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Hyperamylasemia (HA) is often reported in patients with acute liver failure (ALF). Direct toxic effects of acetaminophen on the pancreas have been postulated, but the occurrence of HA in other etiologies raises the question of whether multiorgan failure is part of the pathogenesis of HA in this setting. Our main aim was to describe and analyze the incidence, clinical characteristics, and outcomes of HA in ALF of different etiologies.
Patients enrolled in the Acute Liver Failure Study Group registry with an admission amylase value available were included. For the purpose of this analysis, HA was defined as > or =3x upper limits of normal. Patients were classified as having acetaminophen (APAP)- or non-APAP-induced ALF, and by amylase group: normal (<115), mildly elevated (115-345), or HA (>345). Significant variables identified by univariate analysis were added to a multiple linear regression model. The primary outcome was overall survival.
In total, 622 eligible patients were identified in the database, including 287 (46%) with APAP-induced ALF; 76 (12%) patients met the criteria for HA. Among patients with HA, 7 (9%) had documented clinical pancreatitis. The incidence of HA was similar among APAP (13%) and non-APAP (12%) patients. Although HA was associated with renal failure and greater Model for End-stage Liver Disease scores for both groups, HA was not an independent predictor of mortality in multivariate analysis.
Although not an independent predictor of mortality, HA in ALF was present in all etiologies and was associated with diminished overall survival. HA appeared to be related to renal dysfunction in both groups and multiorgan failure in non-APAP ALF.
The American Journal of Gastroenterology 02/2009; 104(3):592-7. DOI:10.1038/ajg.2008.84 · 9.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the current Model for End-Stage Liver Disease allocation system, patients are at risk of suffering repeated episodes of hepatic encephalopathy (HE) while waiting for an orthotopic liver transplantation (OLT); the posttransplantation impact of these episodes has not been well explored. We evaluated the cognitive function and quality of life in a group of OLT recipients (n = 25) who had suffered from overt HE prior to their procedure (HE-PreLT group) and compared their performance to that of a similar group of patients (n = 14) without overt HE (No HE-PreLT group) as well as to controls. Patients were selected from a cohort of 280 patients who underwent OLT during this period; the presence of clinical confounders excluded many of the remaining subjects. Demographic and clinical characteristics were balanced among groups. At an average of 18 months after OLT, we administered 2 neuropsychological batteries [Psychometric Hepatic Encephalopathy Score (PHES) test battery and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)]; a pyschophysiological test (critical flicker frequency); and the SF-36 quality of life score. The HE-PreLT group scored below controls in 5 of 6 cognitive domains tested by RBANS, 3 of 6 PHES subtests, as well as the critical flicker frequency test. The No HE-PreLT group scored below the controls in 1 of the 6 cognitive domains tested by RBANS. The more severe neurocognitive abnormalities seen in the HE-PreLT group did not appear to affect quality of life, as lower values than normative data were only found in 1 of the 8 SF-36 scales. In conclusion, neurocognitive abnormalities were more severe in liver transplant recipients that had suffered from overt HE prior to OLT. Prospective studies of neurocognitive function pre-OLT and post-OLT are needed to fully determine the impact of such abnormalities.
[Show abstract][Hide abstract] ABSTRACT: Disseminated herpes simplex virus (HSV) infection may lead to acute liver failure (ALF) and the need for emergency liver transplantation (LT). The primary aim of this study was to determine the utility of HSV serological testing and HSV DNA testing by polymerase chain reaction (PCR) in the diagnosis and management of indeterminate, pregnancy-related, and known HSV-related ALF. Stored sera obtained on study day 1 or 2 from patients enrolled in the United States ALF Study Group with indeterminate (n = 51), pregnancy-related (n = 12), and HSV-related (n = 4) ALF were screened for HSV DNA by PCR and serology. While 7 of the indeterminate and pregnant patients had positive anti-HSV immunoglobulin M, none had detectable HSV DNA. The 4 known HSV cases all had high-titer HSV DNA on presentation (range: 3.5 to 36 x 10(8) copies/mL). Two HSV patients underwent LT but developed posttransplant extrahepatic HSV infection despite suppression of HSV DNA with acyclovir treatment, and one of them eventually died. The 2 other fulminant HSV patients died within 48 hours of presentation. In conclusion, serum HSV DNA indicative of occult HSV infection was not detected in 51 indeterminate and 12 pregnancy-related ALF patients. The 4 patients with known HSV-related ALF all had high HSV DNA levels at presentation, and despite the rapid use of antiviral therapy and emergency LT, substantial morbidity and mortality were encountered, highlighting the poor prognosis with severe disseminated HSV infection.
[Show abstract][Hide abstract] ABSTRACT: For acute liver failure (ALF), living donor liver transplantation (LDLT) may reduce waiting time and provide better timing compared to deceased donor liver transplantation (DDLT). However, there are concerns that a partial graft would result in reduced survival of critically ill LDLT recipients and that the rapid evolution of ALF would lead to selection of inappropriate donors. We report outcomes for ALF patients (and their donors) evaluated for LDLT between 1998 and April 2007 from the Adult-to-Adult Living Donor Liver Transplantation Cohort. Of the 1201 potential LDLT recipients, 14 had ALF, only 6 of whom had an identified cause. The median time from listing to first donor evaluation was 1.5 days, and the median time from evaluation to transplantation was 1 day. One patient recovered without liver transplant, 3 of 10 LDLT recipients died, and 1 of 3 DDLT recipients died. Five of the 10 living donors had a total of 7 posttransplant complications. In conclusion, LDLT is rarely performed for ALF, but in selected patients it may be associated with acceptable recipient mortality and donor morbidity.
[Show abstract][Hide abstract] ABSTRACT: Hepatic encephalopathy (HE) is a neuropsychiatric disorder that results from impaired liver function. In humans, hepatic encephalopathy
occurs in two major forms: (1) Associated with acute or fulminant hepatic failure, a clinical syndrome resulting from severe inflammatory and/or necrotic liver disease of rapid onset. The neurological disorder
progresses from altered mental status to coma, generally within hours or days. Death frequently results from increased intracranial
pressure caused by massive brain edema. (2) Portal-systemic encephalopathy (PSE), the most common form of hepatic encephalopathy that accompanies liver cirrhosis. Cirrhosis frequently results from
chronic alcohol abuse (at least in Western hemisphere countries) but may also be caused by viral infections, biliary obstruction,
drugs, or various toxins. Portal hypertension arises as a result of the cirrhotic process; the high portal pressure stimulates
the opening of embryonic venous channels or simply reverses the direction of flow in the existing ones. These shunts permit
toxins of intestinal origin to bypass the liver into the systemic circulation; hence the term “portal-systemic encephalopathy.”
Animal Models of Neurological Disease, II, 06/2008: pages 183-222;
[Show abstract][Hide abstract] ABSTRACT: Hepatorenal syndrome (HRS) type 1 is a progressive functional renal failure in subjects with advanced liver disease. The aim of this study was to evaluate the efficacy and safety of terlipressin, a systemic arterial vasoconstrictor, for cirrhosis type 1 HRS.
A prospective, randomized, double-blind, placebo-controlled clinical trial of terlipressin was performed. Subjects with type 1 HRS were randomized to terlipressin (1 mg intravenously every 6 hours) or placebo plus albumin in both groups. The dose was doubled on day 4 if the serum creatinine (SCr) level did not decrease by 30% of baseline. Treatment was continued to day 14 unless treatment success, death, dialysis, or transplantation occurred. Treatment success was defined by a decrease in SCr level to </=1.5 mg/dL for at least 48 hours by day 14 without dialysis, death, or relapse of HRS type 1.
Fifty-six subjects were randomized to each arm. Treatment success with terlipressin was double that with placebo (25% vs 12.5%, P = .093). SCr level improved from baseline to day 14 on terlipressin (-0.7 mg/dL) as compared with placebo (0 mg/dL), P < .009. Terlipressin was superior to placebo for HRS reversal (34% vs 13%, P = .008), defined by decrease in SCr level </=1.5 mg/dL. Overall and transplantation-free survival was similar between study groups; HRS reversal significantly improved survival at day 180. One nonfatal myocardial infarction occurred with terlipressin, but the total adverse event rate was similar to placebo.
Terlipressin is an effective treatment to improve renal function in HRS type 1.
[Show abstract][Hide abstract] ABSTRACT: Patients with obstructive coronary artery disease (CAD) undergoing orthotopic liver transplantation (OLT) are at increased risk of poor outcomes. The accuracy of dobutamine stress echocardiography (DSE) to detect obstructive CAD is not well established in this population. We retrospectively identified patients with end-stage liver disease who underwent both DSE and coronary angiography as part of risk stratification prior to OLT. One hundred and five patients had both DSE and angiography, of whom 14 had known CAD and 27 failed to reach target heart rate during DSE. Among the remaining 64 patients (45 men; average age 61 +/- 8 years) DSE had a low sensitivity (13%), high specificity (85%), low positive predictive value (PPV) (22%) and intermediate negative predictive value (NPV) (75%) for obstructive CAD. DSE as a screening test for obstructive CAD in OLT candidates has a poor sensitivity. The frequent chronotropic incompetence and low sensitivity in patients who achieve target heart rate, even in those with multiple cardiovascular disease risk factors, suggest that alternative or additional methods of risk stratification are necessary.
American Journal of Transplantation 06/2008; 8(7):1523-8. DOI:10.1111/j.1600-6143.2008.02276.x · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute liver failure (ALF), the abrupt loss of liver function in a patient without previous liver disease, remains a highly mortal condition. Patients with ALF often succumb to their liver injury after the development of cerebral edema, resulting in intracranial hypertension and brain herniation. While the management of cerebral edema in ALF always includes the administration of osmotically active agents, osmotherapy often reduces intracranial pressure (ICP) insufficiently, such that herniation may be delayed but not prevented. Therapeutic hypothermia, the intentional reduction of body core temperature, has been increasingly used to treat cerebral edema in patients with traumatic and hypoxic brain injury. Data in animal models of ALF also suggest that hypothermia is effective in the prevention and treatment of cerebral edema, and case reports in humans have suggested that hypothermia is an effective bridge to orthotopic liver transplantation. A randomized, controlled trial comparing the management of ALF patients under normothermic and hypothermic conditions is a logical extension of these preliminary observations. Herein, we consider the many difficulties which will be encountered in the design of such a trial in patients with ALF at high risk of developing cerebral edema.
Neurocritical Care 05/2008; 9(1):90-6. DOI:10.1007/s12028-008-9090-y · 2.60 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Acute liver failure (ALF) is a syndrome of rapidly deteriorating liver function that manifests as coagulopathy and encephalopathy in a previously healthy individual. This article analyzes the repercussions of ALF on the brain through a discussion of special features of this syndrome, important for the interpretation of neurologic findings. Of particular interest within the context of ALF are hepatic encephalopathy and the pathogenesis of brain edema in acute liver failure as well as its clinical and therapeutic aspects.
Critical Care Clinics 02/2008; 24(1):99-114, ix. DOI:10.1016/j.ccc.2007.11.001 · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reversible cardiomyopathy has been reported in patients after liver transplantation. However, there are few data on the incidence, risk factors, and prognosis of this condition. Liver transplantation recipients who underwent preoperative right- and left-sided cardiac catheterization as well as preoperative transthoracic echocardiography from 2001 to 2005 were identified. Eighty-six patients met the outlined criteria and were included in the study. The incidence of severe heart failure (HF) after transplantation in this population was 6 of 86 (approximately 7%). Patients who developed HF were slightly older (mean age 61.2 +/- 8.9 vs 55.4 +/- 9.2 years, p = 0.08) but had similar preoperative ejection fractions (60 +/- 5% vs 57 +/- 8%, p = 0.22) and comparable systemic arterial blood pressure (116 +/- 22/62 +/- 11 vs 127 +/- 9/66 +/- 9, p >0.1). In addition, the severity of liver disease as measured by the model for end-stage liver disease score was not different between the 2 groups (23.9 +/- 9.7 vs 26 +/- 10.7, p = 0.5). There was also no significant difference in the preoperative cardiac index (3.8 +/- 1 vs 3.6 +/- 1.5 L/min/m2, p = 0.9) or pulmonary artery wedge pressure (13.6 +/- 5.8 vs 15.3 +/- 2.8 mm Hg, p = 0.42). The incidence of alcohol use as the presumed cause of liver failure was equivalent in the 2 groups (33% vs 25%, p = 0.65). The patients who developed HF did have significantly higher preoperative mean pulmonary arterial systolic pressures (43 +/- 10 vs 30 +/- 9 mm Hg, p = 0.02) and right ventricular systolic pressures (44 +/- 13 vs 34 +/- 8 mm Hg, p = 0.05). In conclusion, severe systolic HF may occur after liver transplantation in patients without traditional risk factors for HF. This study suggests that those patients with preoperative elevated right-sided cardiac pressures, as well as older patients, may be at excess risk for developing HF after transplantation.
The American Journal of Cardiology 01/2008; 101(2):242-4. DOI:10.1016/j.amjcard.2007.08.056 · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Current recommendations for the treatment of hepatic encephalopathy are based, to a large extent, on open or uncontrolled trials, undertaken in very small numbers of patients. In consequence, there is ongoing discussion as to whether the classical approach to the treatment of this condition, which aims at reducing ammonia production and absorption using either non-absorbable disaccharides and/or antibiotics, should be revisited, modified or even abandoned. Pros and cons of present therapeutic strategies and possible future developments were discussed at the fourth International Hannover Conference on Hepatic Encephalopathy held in Dresden in June 2006. The content of this discussion is summarized.