Degree Of Hepatic Encephalopathy Research Articles

OC-034 The diagnosis of hepatic encephalopathy: test performance of novel paradigms: Abstract OC-034

Introduction The diagnosis of hepatic encephalopathy remains problematic, mainly because the current validated methods for assessing this syndrome, the PHES battery and spectral analysis of the EEG, are not universally available. Current interest has, therefore, focused on more novel computer-based systems, the most recent being the Inhibitory Control test (ICT), which, it is claimed, is able using a threshold of five incorrect lure responses, to diagnose hepatic encephalopathy with a sensitivity of 88% and a specificity of 77% (Bajaj et al , 2008). Experience with two other novel techniques viz: (i) the Sternberg paradigm (Sternberg, 1966), which is a computer-based, digit recognising task of memory scanning, and (ii) assessment of the ability to execute Smooth Pursuit Eye Movements (SPEM) (Montagnese et al , 2005) indicates that they have diagnostic potential. The aim of this study was to assess the performance of the ICT, Sternberg paradigm and SPEM for the diagnosis of hepatic encephalopathy, in patients with cirrhosis, both used singly and in combination. Methods The patient population comprised 53 individuals (36 men, 17 women) of mean (range) age 57 (34–80) years, with biopsy-proven cirrhosis classified, using the West Haven criteria for mental state, the PHES test battery, and spectral analysis of the EEG, as either neuropsychiatrically unimpaired (n=34), or as having minimal (n=10) or overt (n=9) hepatic encephalopathy. The control population comprised 33 healthy volunteers (16 men, 17 women) of mean age 39 (21–70) years. The Sternberg and the ICT were performed using software programs supplied by the providers; SPEM assessments were performed using an infrared, video-based eye-tracking system. All the assessments were carried out under standard conditions, in a quiet, darkened room. Test thresholds, sensitivities and specificities were identified using ROC analysis. Binary logistic regression was used for a multivariate analysis of the test combinations. Results Both healthy volunteers and patients found the ICT difficult to perform and its diagnostic performance was inferior to that of the other two techniques (Abstract 034). The best diagnostic performance was observed with the Sternberg/SPEM combination. Conclusion The Sternberg test, used alone or in combination with SPEM, has excellent performance characteristics for the diagnosis of any degree of hepatic encephalopathy. The diagnostic performance of the ICT was disappointing.

Predictors of bacteraemia and mortality in patients with acute liver failure

To determine what physiological and biochemical factors predict development of bacteraemia and mortality in patients with acute liver failure (ALF). Retrospective analysis of 206 ALF patients admitted to a specialist liver intensive therapy unit (LITU) from January 2003 to July 2005 (data collected prospectively). A total of 206 patients were defined with ALF: 72 (35%) suffered bacteraemia (BAClf) and 134 (65%) did not (NBAClf). Gram positive organisms were observed in 44% of isolates, gram negatives in 52% and fungaemia in 4%. Median time to first bacteraemia was 10 (7-16) days. On admission, BAClf patients had higher SIRS scores and degrees of hepatic encephalopathy (HE). During their LITU course, BAClf patients had significantly increased requirements for renal replacement therapy (RRT), mechanical ventilation, and longer median LITU stay. Multivariate analysis (logistical regression) demonstrated significant predictors of bacteraemia on admission were HE grade >2 (Odds Ratio 1.6) and SIRS score >1 (OR 2.7). In all patients, independent predictors of mortality (logistical) were age (OR 1.41), maximum HE grade pre-intubation (1.76), Lactate (1.14) and Acute Physiology and Chronic Health Evaluation II score (APACHEII) (1.09), but not bacteraemia. Transplantation was protective (OR 0.20). In this study, severity of hepatic encephalopathy and SIRS score >1 were predictive of bacteraemia. APACHEII was independently predictive of mortality in all ALF patients but not bacteraemia.

Liver failure as initial presentation of autoimmune hepatitis: Clinical characteristics, predictors of response to steroid therapy, and outcomes #

In a recent study, we had reported the impact of ethnicity on the natural history of autoimmune hepatitis (AIH).1 We did a further subgroup analysis of those with initial presentation with liver failure (LF), defined as either international normalized ratio (INR) ≥ 2 and or any degree of hepatic encephalopathy. Twenty patients (20/101, 19.8%) presented with LF, and they were more likely to be black (70% versus 7.4%, P = 0.001), require referral for liver transplantation (LT) (70% versus 24.6%, P < 0.0001), and have a higher mortality (45% versus 4.9%, P < 0.0001), compared to those without LF. Of the 14 (70%) patients with LF who were treated medically with steroids, seven (50%) responded (Table 1). Responders had a Model for End-Stage Liver Disease (MELD) score at admission ≤ 28 and were more likely to have cirrhosis (71.1% versus 28.5%); they showed a stable trend in serum bilirubin (mg/dL) (15.2 ± 13.2 versus 14.1 ± 14.1) and INR (1.8 ± 0.4 versus 1.8 ± 0.5) after a mean of 3.7 ± 0.6 days of steroid therapy. In contrast, nonresponders showed a worsening of serum bilirubin (22.5 ± 4.2 versus 23.1 ± 5.6) and INR (3.0 ± 1.5 versus 3.6 ± 2.1). All responders survived without need for a LT, whereas all nonresponders had a fatal outcome (of whom one died after LT). Six patients (30%) with LF were not treated medically, of whom five had submassive necrosis on liver biopsy. Five of these six patients underwent transplantation and all but one survived. One could not undergo transplantation due to development of fatal cholangitis. In conclusion, about 20% of patients with AIH have LF at initial presentation. A lower MELD score at admission (≤ 28), more severe hepatic fibrosis, and an early (within 4 days of steroid therapy) improvement or stabilization in serum bilirubin and INR identify those who are likely to respond to steroid therapy, and thus survive without LT. Our observations need further corroboration, but if confirmed, such a stratification strategy could optimize care of patients with AIH who present with LF. Sumita Verma*, Anurag Maheshwari , Paul Thuluvath , * Gastroenterology/Hepatology, Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton, UK, Gastroenterology and Hepatology, Johns Hopkins University Hospitals, Baltimore, MD, Mercy Medical Center, Institute for Digestive Health and Liver Diseases, Baltimore, MD.

Decreased heart rate variability in patients with cirrhosis relates to the presence and degree of hepatic encephalopathy

Heart rate variability (HRV) is reduced in several clinical settings associated with either systemic inflammation or neuropsychiatric impairment. The possibility that the changes in HRV observed in patients with neuropsychiatric impairment might relate to the overproduction of inflammatory cytokines does not seem to have been considered in the studies undertaken to date. HRV is decreased in patients with liver cirrhosis but its relationship to the impairment of neuropsychiatric performance, commonly observed in these patients, is unknown. The aim of this study was to investigate the relationship between HRV, hepatic encephalopathy, and production of inflammatory cytokines in patients with cirrhosis. Eighty patients with cirrhosis [53 men, 27 women; mean (+/-1SD) age 54 +/- 10 yr], classified as neuropsychiatrically unimpaired or as having minimal or overt hepatic encephalopathy, and 11 healthy subjects were studied. HRV was assessed by applying Poincaré plot analysis to the R-R interval series on a 5-min ECG. Inflammatory cytokines (TNF-alpha, IL-6, IL-10, and IL-12) were measured in a subgroup of patients. Long-term R-R variability was significantly decreased in the patients with cirrhosis, in parallel with the degree of neuropsychiatric impairment (P < 0.01) and independently of the degree of hepatic dysfunction (P = 0.011). The relative risk of death increased by 7.7% for every 1-ms drop in this variable. Plasma levels of IL-6 significantly correlated with indexes of both HRV and neuropsychiatric performance. The changes observed in HRV and in neuropsychiatric status in patients with cirrhosis are significantly correlated, most likely reflecting a common pathogenic mechanism mediated by inflammatory cytokines.

The management of hepatic encephalopathy and cerebral oedema in acute liver failure

Acute liver failure is a term that first became established in the 1960s to describe a rare clinical syndrome that is characterized by severe hepatocyte injury, jaundice and hepatic encephalopathy, usually in the absence of pre-existing chronic liver disease. Acute liver failure has a variety of aetiologies. It is associated with high mortality and morbidity. While acute liver failure is a disease of multi-organ failure, all patients with acute liver failure will have some degree of hepatic encephalopathy, which, when advanced, is associated with a high incidence of cerebral oedema and intracranial hypertension. When these symptoms are combined with other failing bodily systems, this group of patients are extremely challenging to manage. This article presents an overview of hepatic encephalopathy and the management of cerebral oedema in this group of patients, examining current medical and nursing strategies.

Multidimensional assessment of neuro-psychiatric symptoms in patients with low-grade hepatic encephalopathy: A clinical rating scale

To evaluate the feasibility of a new clinical rating scale for a standardized assessment of cirrhosis-associated neuro-psychiatric symptoms. Forty patients with liver cirrhosis (LC, with or without low-grade hepatic encephalopathy) were invest-igated using a clinical neuro-psychiatric rating scale based on a comprehensive list of neurological, psychomotor, cognitive, affective, behavioral symptoms, and symptoms of disturbed bioregulation. The analysis revealed that the majority of cirrhotic patients showed, besides characteristic neurological symptoms of hepatic encephalopathy, various psychomotor, affective and bioregulatory symptoms (disturbed sleep and sexual dysfunction). Patients were impaired in the following subscales: sleep and biorhythm disorder (75.0% of patients), Parkinsonoid symptoms (25.0%), affective symptoms (17.5%), and psychomotor retardation (12.5%). The increase of total neuro-psychiatric clinical score was significantly associated with the degree of hepatic enceph-alopathy. This study suggests that a substantial number of patients with LC and low-grade hepatic encephalopathy manifest various clinical neuro-psychiatric symptoms. The use of a rating scale, which explores clinical dimensions of hepatic encephalopathy, would improve the management of patients with LC.

Liver transplantation for fulminant and subfulminant hepatic failure

Aims The aim of this study was to assess the long-term course and outcome after liver transplantation (LTX) for fulminant/subfulminant hepatic failure (FSHF) to determine which factors relate to outcome. Patients and methods Between April 1990 and October 2002, 30 adult patients with FSHF underwent LTX. King's College criteria were used to decide which patients needed LTX. Pretransplantation parameters (age, sex, degree of hepatic encephalopathy, etiology, and time between onset of symptoms and LTX) were examined as risk factors for LTX outcome. Results Mean age at LTX was 40.4 ± 13.9 years and 46.7% were men. The most frequent causes of FSHF were virus B in 23.3%, autoimmune hepatitis in 23.3%, and cryptogenic in 20%. Fifty percent of the patients with a survival longer than 15 days suffered episodes of acute rejection; chronic rejection occurred in 25%. One- and five-year patient and allograft survival rates for FSHF were 56.3% and 54.7%, respectively. Autoimmune hepatitis was the only factor associated with better posttransplantation outcome, although there were no differences in posttransplant course. Patient survival rates increased during the study period. During the first 5 years (1990–1995) the survival rates were 53.3% (1-year and 5-year), whereas they were 60% at 1 and 5 years in the second interval (1996–2002). Conclusions The mortality rate of FSHF is high during the first year post-LTX. LTX for FSHF of autoimmune etiology showed better outcomes with increasing patient survival rates during the study period.

Improvement in central nervous system functions during treatment of liver failure with albumin dialysis MARS--a review of clinical, biochemical, and electrophysiological data.

The Molecular Adsorbent Recirculating System (MARS) is a nonbiological liver support method based on the principles of dialysis, filtration, and adsorption. It allows the safe and efficient removal of both albumin-bound and water-soluble toxic metabolites, including ammonia, aromatic amino acids, tryptophan, and related phenolic and indolic products, as well as benzodiazepines. A well-documented effect of the treatment is the improvement of the hemodynamic situation of decompensated chronic patients. Systemic vascular resistance, mean arterial pressure, cerebral blood flow, and cerebral oxygen consumption increased significantly. The degree of hepatic encephalopathy decreased significantly. Increased intracranial pressure could be normalized in both chronic and fulminant liver failure. In three randomized clinical trials significant improvement of survival could be demonstrated. In a model of murine neuronal networks cultured on multi-microelectrode array plates and incubated with plasma from liver failure patients, a normalization of the spike and burst pattern could be observed, if plasma samples from MARS-treated patients before and after treatment were compared. In conclusion, MARS significantly improves central nervous system functions. It can serve as a model for the further investigation of the role of protein-bound substances in hepatic encephalopathy and cerebral hemodynamics.

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)

Effects of cisapride on blood ammonia and prolactin in patients with cirrhosis

Cisapride is a prokinetic agent used to treat gastrointestinal motility disorders. This drug restores, normalizes, and facilitates smooth muscle function from the esophagus to the colon without antidopaminergic effects. To evaluate the effects of cisapride on prolactin, blood ammonia, stool frequency, and degree of hepatic encephalopathy, 10 patients with cirrhosis and 10 healthy controls were treated with the drug for 10 days. Cisapride increased stool frequency and did not modify prolactin and blood ammonia levels. The drug was well tolerated. Cisapride's favorable effects on dyspepsia and gastrointestinal motility can improve the treatment of patients with chronic liver disease.

Brain mapping analysis in patients with hepatic encephalopathy

Topographical analysis of cerebral electrical activity was performed in 44 patients with hepatic encephalopathy. These patients were classified in 5 groups according to clinical criteria. Eight healthy subjects were used as a control group. All were studied in an awake, eyes closed, condition and some [Control Group (CG), Group 0 (G0), Group 1 (G1) and Group 2 (G2)] also in an awake, eyes open, condition. The awake, eyes closed, maps showed marked differences in the power spectral density (PSD) of the different bands, when comparing normal subjects with patients with several degrees of hepatic encephalopathy. These differences were related to the degree of clinical involvement, mainly in the alpha and delta PSD bands. The combination of a decreased alpha PSD, increased delta PSD, and decreased mean dominant frequency (MDF) allowed a clear discrimination between the different clinical groups. The differences observed between awake, eyes closed, and awake, eyes open, conditions were especially helpful to discriminate between CG subjects and G0, G1 and G2 patients.

Cerebral blood flow and liver function in patients with encephalopathy due to acute and chronic liver diseases.

The purpose of the present investigation was to study changes in cerebral blood flow (CBF) in hepatic encephalopathy, to ascertain whether this was related to the changes in liver function and whether these changes gave any prognostic information. CBF, determined by the intravenous xenon-133 method, and liver functions, assessed by the prothrombin index, bilirubin concentration, and the galactose elimination capacity, were studied in patients with acute fulminant liver failure and in patients with encephalopathy due to chronic liver diseases--that is, cirrhosis of various etiologies. The CBF range in healthy young subjects (age, 23-42 years) was 44-61 ml/100 g/min; in patients with grade I + II encephalopathy (mean +/- SEM) it was 32.8 +/- 3.6 ml/100 g/min in acute (n = 4; age, 28 +/- 8 years) and 37.0 +/- 3.3 ml/100 g/min in chronic liver patients (n = 10; age, 51 +/- 2 years). In grade III + IV encephalopathy it was 28.7 +/- 3.8 ml/100 g/min in acute (n = 8; age, 28 +/- 3 years) and 32.9 +/- 3.7 ml/100 g/min in chronic patients (n = 12; age, 49 +/- 3 years). CBF did not correlate with the liver function and was of no prognostic value. The liver function was markedly reduced in all the patients, without any differences between patients with acute or chronic liver diseases or the different degrees of hepatic encephalopathy. In conclusion, a marked reduction of the CBF was seen in hepatic encephalopathy, irrespective of the etiology of the disease.

Psychosomatic aspects of liver transplantation.

Forty patients received orthotopic liver transplants at Massachusetts General Hospital between May 21, 1983 and July 21, 1987 (mean follow-up: 64 weeks, range: 2-186 weeks). Twenty-seven patients (68%) were living as of July 21. Among survivors, 15 (56%) returned to full activity; and 7 (26%) were partially rehabilitated. Five patients were rehospitalized or recently transplanted. Successful outcome occurred most often among those who came to transplant early in the course of illness. All adults experienced preoperative anxiety and 17 (50%) of adults had some degree of hepatic encephalopathy. Following operation, 8 adults (24%) were referred for treatment of depressive disorder typically associated with deterioration of hepatic status, infectious complication or recurrence of cancer. Medical noncompliance required psychiatric intervention in 3 cases. Other psychiatric events an increasingly successful intervention of major scope and affords meaningful survival to many patients whose liver disease allow less than a year of life. Psychiatric consultation is an essential support to the transplant program.

A 25-year experience with total portosystemic shunts and reappraisal of colon exclusion.

The results of 43 total shunt procedures for bleeding esophageal varices performed consecutively at two community hospitals from 1956 to 1981 are reviewed. Of 15 patients with immediate preoperative bilirubins greater than 2.0 mg/dl, 11 died following shunt surgery. Of 28 other shunted patients with immediate preoperative bilirubins of less than 2.0 mg/dl, there was only one in-hospital death, thus substantiating the contention that the last preoperative serum bilirubin value is the best predictor of operative mortality. Of ten patients with appreciable ascites verified at the time of operation, there were only two survivors, and both of these had preoperative bilirubins of less than 2.0 mg/dl. Twenty-nine of the 31 patients who left the hospital were still living at least one year after operation. All 23 patients operated on prior to 1977 were available for 5-year follow-up, and there were 14 survivors (60%). Thirteen of the 31 patients (42%) manifested some degree of hepatic encephalopathy, as interpreted by necessity for protein restriction and either Neomycin or Lactulose. Incapacitating post-shunt hepatic encephalopathy developed in one patient who required recurrent hospitalizations for episodic coma. This patient underwent a total abdominal colectomy and ileorectal anastomosis, with elimination of all episodes of encephalopathy for the subsequent 4 1/2 years. The previous 16 cases in the literature of surgical treatment of post-shunt encephalopathy are reviewed, and the efficacy of such colon exclusion is reassessed.

Plasma and cerebrospinal fluid amino acid patterns in hepatic encephalopathy.

Plasma and cerebrospinal fluid amino acid levels wee measured in 12 cirrhotic patients in grade 0 hepatic encephalopathy and 17 in grade 3-4 hepatic encephalopathy. In 5 of these patients amino acid determinations were performed during the evolution of the encephalopathy. No correlation was found between the degree of hepatic encephalopathy and the plasma amino acid imbalance. In the CSF of cirrhotic patients without encephalopathy, a significant increase was found in nearly all amino acids, including those known to not easily cross the blood-brain barrier; this suggests the presence of a nonspecific modification of the blood-brain barrier permeability. In patients with severe hepatic encephalopathy, the further increase only in cerebrospinal fluid aromatic amino acids and methionine levels suggests the presence of a selective stimulation of the neutral amino acid transport system across the blood-brain barrier. Finally, the good correlation between glutamine and the sum of neutral amino acids found in the cerebrospinal fluid only in the presence of encephalopathy supports the hypothesis that brain glutamine may stimulate neutral amino acid transport across the blood-brain barrier.

THE MESOCAVAL “H” GRAFT EXPERIENCE WITH 22 CASES

During the past 32 months, 22 consecutive unselected patients who had bled from oesophageal varices have undergone mesocaval "H" graft operations. There have been nine deaths, three in the early and six in the late postoperative periods. Two deaths were the result of bleeding complicating severe primary fibrinolysis and three were due to disseminated sepsis, one originating from an infected shunt. Continued alcohol intake may have contributed to five of the late deaths. Ten of the 19 patients who left hospital developed some degree of hepatic encephalopathy easily controlled by diet and medical therapy. However, in one case the development of grade IV coma necessitated ligation of the shunt to reverse the coma. Patency of the shunt was demonstrated in all but one patient. Recurrence of bleeding occurred only in this patient and the one in whom the shunt was ligated. Although the operation had a comparatively low operative mortality, the long-term mobidity and mortality were no better than those of the more conventional portacaval anastomosis.