Predictive value of dobutamine stress echocardiography for coronary artery disease detection in liver transplant candidates.

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.

Neuropsychological characterization and detection of subclinical hepatic encephalopathy.

OBJECTIVE: To elucidate the nature of the neuropsychological deficits associated with subclinical hepatic encephalopathy. DESIGN: Prospective study comparing the performance of patients with liver disease and carefully matched normal controls on a short but comprehensive neuropsychological test battery. SETTING: A university medical center. PARTICIPANTS: Twenty patients with cirrhosis (10 alcoholic and 10 nonalcoholic) and 20 controls carefully matched on the basis of age, sex, education, and alcohol history. RESULTS: The cirrhotic patients exhibited relatively selective deficits in complex attentional and fine motor skills, with preservation of general intellectual ability, memory, language and visuospatial perception. CONCLUSIONS: This pattern of neuropsychological deficits suggests a subcortical pathophysiology, possibly reflecting involvement of the basal ganglia. These neuropsychological findings are consistent with recent neuroradiological, electrophysiological, and neurophysiological research implicating basal ganglia involvement in cirrhosis.

Protein C deficiency in splanchnic venous thrombosis.

Deficiencies of protein C activity and antigen were observed in eight consecutive patients with splanchnic venous thrombosis. There was a significant reduction in the ratio of protein C to factor X. Six of the eight patients had a decrease in antithrombin III, but free protein S antigen was within normal limits in all but two subjects. It is proposed that a thrombogenic stimulus such as stasis, altered hormonal milieu, or failure of hepatic clearance of activated coagulants results in consumption of protein C and antithrombin III, predisposing to splanchnic venous occlusion. This further impairs hepatic function, prevents restitution of protein C and antithrombin levels, and promotes continuing venous thrombosis. Thus, a vicious cycle of thrombosis and hepatic damage is perpetuated.

Hyperammonemia complicating mesenteric vein thrombosis.

Hyperammonemic coma developed in a 69-year-old woman with prolonged symptoms of abdominal pain, dysphagia, and fever. At laparotomy for an acute condition within the abdomen, mesenteric vein thrombosis was found and partial intestinal resection was performed. Following surgery, the patient regained consciousness and blood ammonia levels became normal. Hyperammonemia and coma complicating mesenteric vein thrombosis have not yet been described. Venous shunts are suggested as being responsible for this rare complication.

Primary sclerosing cholangitis in the presence of a lupus anticoagulant.

Lupus anticoagulant, an immunoglobulin that prolongs the partial thromboplastin time, has been associated with thrombotic events, including deep venous thrombosis, pulmonary emboli, and Budd-Chiari syndrome. In this report, primary sclerosing cholangitis was diagnosed in a man with a 10-year history of multiple thrombotic events related to a circulating lupus anticoagulant. Progressive jaundice and pruritus developed, and sclerosing cholangitis was confirmed by direct cholangiography. Sclerosing cholangitis is the second hepatobiliary disease reported in association with a lupus anticoagulant.

alpha 1-antitrypsin deficiency-associated panniculitis: resolution with intravenous alpha 1-antitrypsin administration and liver transplantation.

Panniculitis is a rare complication of alpha 1-antitrypsin (A1AT) deficiency that is characterized by acute inflammatory infiltrate and fat necrosis. Different treatment strategies are used to provide symptomatic relief. Here we describe two patients with homozygous A1AT deficiency who developed panniculitis and were successfully treated with A1AT replacement. The patient who received a liver transplant experienced complete resolution of the skin lesions. The patient who received A1AT intravenously showed complete response, but the skin lesions recurred when the levels of A1AT fell below 50 mg/100 ml. Panniculitis secondary to A1AT deficiency can be successfully treated with liver transplantation or intravenous infusion of A1AT.

Current status of liver support systems.

The search for a support system for liver failure has been intensified. Methods currently being tested include those based on artificial support, on biological approaches (including extracorporeal liver perfusion and transplanted hepatocytes) as well as hybrid devices that combine artificial aspects with biological systems. Each of these three areas is undergoing fast technological and conceptual development. Controlled clinical trials are also under way.

Role of the liver in the disposition of intravenous nitroglycerin in the rat.

Previous studies have indicated that the liver is the main site of nitroglycerin (NTG) elimination when the drug is systematically infused. To examine this hypothesis, we measured the apparent systemic clearance (Cls) of nitroglycerin in anesthesized rats receiving a constant intravenous infusion at a dose of 100 micrograms per kg per min. Animals were divided into shunt and sham groups; the former had undergone a portal vein ligation 10 days prior to the study, while the latter was subjected to a sham operation. On the study day, half of the animals of each group also received probenecid at 200 mg/kg, i.v., a drug previously reported to inhibit organic nitrate ester reductase (ONER) activity in rat liver. Arterial NTG samples were obtained at 41, 43 and 45 min of infusion in all four experimental groups; Cls was 439 +/- 32 ml per kg per min (mean +/- S.E.) in sham, 460 +/- 44 in sham and probenecid, 477 +/- 39 in shunt, and 461 +/- 34 in shunt and probenecid animals. During NTG infusion, hepatic blood flow (measured with a constant infusion of indocyanine green) was decreased markedly in shunted rats as was liver/body weight, indicating hepatic atrophy. The specific activity of hepatic ONER was similar in all four groups. In spite of marked differences in hepatic blood flow and hepatic mass, the Cls was similar in all four groups. The liver does not appear to be a major site for the elimination of systemic nitroglycerin as hitherto assumed.

Pharmacological vs. mechanical reduction in portal pressure: a comparative study.

Previous studies have shown that decreasing blood flow in the superior mesenteric artery (SMA) by the infusion of intra-arterial vasopressin into or partial mechanical obstruction of the SMA by a balloon catheter (partial balloon obstruction) causes similar alterations in splanchnic hemodynamics, but divergent changes in systemic hemodynamics. The effects of these two methods of reducing SMA blood flow were compared in each of six anesthetized normal dogs. Vasopressin and partial balloon obstruction induce similar reductions in portal pressure (-54 +/- 12% vs. -46 +/- 11%), wedge hepatic vein pressure (-54 +/- 13% vs. -53 +/- 18%), and portal venous flow (-34 +/- 7% vs. -37 +/- 7%). Significantly different effects between intra-arterial vasopressin and partial balloon obstruction were observed, however, in cardiac output (a decrease of -24 +/- 5% vs. an increase of +12 +/- 4%) (P less than 0.001), heart rate (-8 +/- 3% vs. 0) (P less than 0.05), and systemic vascular resistance (+36 +/- 8% vs. -2 +/- 2%) (P less than 0.005), respectively. These results indicate that the two procedures are equally effective in reducing portal venous pressure and blood flow. Partial balloon obstruction, however, does not induce the potentially deleterious systemic hemodynamic effects seen with vasopressin infusion. In fact, some of the changes observed with partial balloon obstruction, especially the increase in cardiac output, are considered to be beneficial. In an additional five dogs, partial balloon obstruction was maintained for 5 hours. Throughout, the reduction in portal venous pressure (hepatic venous wedge minus hepatic venous free pressure) was maintained at less than half of the baseline levels (4.75 +/- 0.43 vs. 2.25 +/- 0.32 mm Hg), and the mean arterial pressure at baseline values. All of the dogs survived and were well at 1 week after the prolonged partial obstruction. No abnormalities were observed in the anatomical or histological studies of the small intestine. This study suggests that partial balloon obstruction of the SMA has theoretical therapeutic advantages over intra-arterial vasopressin for reducing portal venous pressure.

Portacaval anastomosis disrupts circadian locomotor activity and pineal melatonin rhythms in rats.

To determine whether hepatic encephalopathy may be associated with a disruption of circadian function, the circadian rhythms of locomotor activity and pineal melatonin content were examined in an animal model of complete portal-systemic shunting, rats with a portacaval anastomosis (PCA). The locomotor activity rhythm of all sham-operated animals entrained normally to a light/dark cycle and exhibited a normal free-running period during exposure to constant light. In contrast, PCA led to a dampening of the locomotor activity rhythm in all animals and the abolishment of a circadian periodicity in the activity rhythm of approximately 50% of rats during exposure to either a light/dark cycle or constant light. While normal diurnal variations of pineal melatonin content were seen in sham-operated rats, the amplitude of this variation appeared to be decreased in PCA animals. The similar effects of PCA on both a behavioral and an endocrine circadian rhythm, known to be regulated by a common neural pacemaker, coupled with studies indicating that a variety of other circadian rhythms may be disrupted in both animals and humans with hepatic dysfunction, suggests that this circadian disturbance originates within the pacemaker or on one of its afferent/efferent pathways.

Intensive care management of patients with acute liver failure with emphasis on systemic hemodynamic instability and cerebral edema: a critical appraisal of pathophysiology.

Acute liver failure (ALF) is a devastating disease leading to multiorgan dysfunction. The most dramatic impact of ALF is on the brain, as hepatic encephalopathy and intracranial hypertension (IH) develop. IH is associated with systemic hemodynamic instability, alterations in the regulation of cerebral blood flow and the development of cerebral edema. This review focuses on the pathophysiology of IH with special emphasis on cerebral blood flow and the development of cerebral edema. Based on these considerations, both traditional and new treatments for the management of IH in the future are discussed.

[Changes in the 24-hour rhythm of plasma melatonin in patients with liver cirrhosis--relation to sleep architecture]. / Veränderung des 24-Stunden-Rhythmus von Plasma-Melatonin bei Patienten mit Leberzirrhose--Beziehung zur Schlafarchitektur.

OBJECTIVE: To assess the 24 hr plasma melatonin profile as a marker of the output rhythm from the circadian clock and to study sleep diaries as reflection of subjective sleep quality in patients with liver cirrhosis. DESIGN: Prospective cohort study. PATIENTS: A total of 14 subjects, 7 non-alcoholic cirrhotics and 7 age-, sex-, and educationally-matched controls. Exclusion criteria were factors that could affect melatonin levels (intercontinental travel, shift work, therapy with betablockers or corticosteroids). MEASUREMENTS: Plasma melatonin was measured every 30 min for 24 hr by radioimmuno assay and sleep recordings by polysomnography. Neuropsychological testing included visual reaction time. Trailmaking test A and B and the Digit Symbol Test. Sleep diaries were kept for the week prior to admission. RESULTS: Time of onset of melatonin rise was displaced from 19:50 +/- 26 min in the controls to 21:30 +/- 13 min (p = 0.013) in patients with liver cirrhosis. The time of peak melatonin levels was consistently and significantly delayed from 00:36 +/- 33 min in controls to 5:36 +/- 29 min (p < 0.001) in patients. Cirrhotic subjects showed markedly elevated melatonin levels during daytime, when melatonin is normally absent. Polysomnographic tracings showed no differences in patients and controls, but sleep diaries indicated more frequent nocturnal awakenings (p = 0.05) and daytime naps. CONCLUSIONS: A marked alteration of plasma melatonin rhythm is found in cirrhotic patients with subclinical hepatic encephalopathy. This disruption may reflect changes in the output of the circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus. It is possible that some of the metabolic disturbances that lead to hepatic encephalopathy may also alter the function of the biological "clock".

[Portal hypertension hemodynamics]. / Evaluacion hemodinamica en la hipertension portal.

The syndrome of portal hypertension represents the end point of a number of factors which causes obstruction to portal bood flow. In this paper we review the pathogenic factors associated with portal hypertension and make comments on the new invasive and non invasive techniques used to study portal hemodynamics. Special emphasis is placed on endoscopic and ultrasonographic methods (Doppler. It is now posible to obtain direct variceal pressure determinations by modifying endoscopic assessment and with new ultrasound devices we are able to obtain information by noninvasive techniques of portal patency and portal flow.

Randomised clinical trial: the safety and efficacy of long-acting octreotide in patients with portal hypertension.

BACKGROUND: It remains unclear whether a long-acting preparation of octreotide (Sandostatin LAR) can be safely used for portal hypertension in patients with compensated cirrhosis. AIM: To determine the safety and efficacy of LAR among patients with Child Pugh Class A or B cirrhosis and small oesophageal varices. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

The treatment of hepatic encephalopathy.

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.

Diagnosis and treatment of hepatic encephalopathy.

Hepatic encephalopathy arises from the combination of hepatocellular dysfunction and portal-systemic shunting. Encephalopathy is more prominent in advanced stages of liver cirrhosis and signals the presence of fulminant hepatic failure in patients with acute liver injury. As important as the extent of shunting is the presence of large spontaneous collaterals. Ammonia continues to be a leading toxin influencing brain function. Endogenous benzodiazepines and cytokines may contribute to one of ammonia's key effects in the brain: astrocyte swelling. The diagnosis of hepatic encephalopathy is a diagnosis of exclusion; the search for a precipitating factor should be started immediately in all cases of encephalopathy. The treatment of hepatic encephalopathy has three aims: decrease the nitrogenous load from the gut, improve the extra-intestinal elimination of ammonia and counteract central abnormalities of neurotransmission. The mainstay of treatment is directed at the colon. Newer approaches targeting the brain, such as flumazenil, have become available.