Malnutrition and diabetes mellitus are related to hepatic encephalopathy in patients with liver cirrhosis.

BACKGROUND/AIMS: Studies on animal models of hepatic encephalopathy (HE) suggest that poor nutritional status may facilitate the development of HE. Insulin resistance and diabetes mellitus have recently been reported to affect cognition in patients with hepatitis C cirrhosis awaiting liver transplantation. Our aim was to investigate the effects of malnutrition and diabetes mellitus on HE in unselected patients with liver cirrhosis. METHODS: A total of 128 consecutive cirrhotic patients were prospectively evaluated for the presence of HE according to the West-Haven criteria as well as by means of two psychometric tests and fasting plasma ammonium ion concentrations. Nutritional status was assessed by anthropometry and estimation of recent weight change. Fasting plasma glucose was measured, and in a subgroup of 84 patients fasting serum insulin and insulin resistance were also determined. RESULTS: Fifty-one (40%) cirrhotics were malnourished, 33 (26%) had diabetes and 42 (34%) had HE. Patients with vs. without malnutrition had more frequently HE (46 vs. 27%; P=0.031) but did not differ in age, aetiology or severity of liver cirrhosis (P>0.1). Multivariate analysis showed that the time needed to perform number connection test A was independently correlated to age, the Child-Pugh score, diabetes and malnutrition (P<0.05 for all). Plasma ammonium ion levels were related to insulin resistance (r=0.42, P<0.001) and muscle mass (r=0.28, P=0.003). CONCLUSION: Malnutrition and diabetes mellitus seem to be related to HE in patients with liver cirrhosis. Nutritional status and insulin resistance might be implicated in the pathogenesis of HE.     

Role of artificial liver support in hepatic encephalopathy

Hepatic encephalopathy (HE) refers to the reversible neuropsychiatric disorders observed in acute liver failure and as a complication of cirrhosis and/or portal hypertension. This review aims to describe the pathophysiology of HE, the rationale for the use of artificial liver support in the treatment of HE, the different concepts of artificial liver support and the results obtained. Ammonia has been considered central to its pathogenesis but recently an important role for its interaction with inflammatory responses and auto-regulation of cerebral hemodynamics has been suggested. Artificial liver support might be able to decrease ammonia and modulate inflammatory mediators and cerebral hemodynamics. Bioartificial liver support systems use hepatocytes in an extracorporeal device connected to the patient’s circulation. Artificial liver support is intended to remove protein-bound toxins and water-soluble toxins without providing synthetic function. Both systems improve clinical and biochemical parameters and can be applied safely to patients. Clinical studies have shown that artificial liver support, especially albumin dialysis, is able to improve HE in acute and acute-on-chronic liver failure. Further studies are required to better understand the mechanism, however, artificial liver support can be added to the therapeutic bundle in treating HE.     

Beneficial effect of vegetable protein diet supplemented with psyllium plantago in patients with hepatic encephalopathy and diabetes mellitus

A controlled crossover study was performed in 8 diabetic patients with chronic portal-systemic encephalopathy. After a basal period the patients were treated during periods A and B. During period A, a meat protein diet (0.8 g/kg body wt, approximately 1800 kcal/day) was consumed and neomycin plus laxatives were given. During period B patients received vegetable protein (0.8 g/kg body wt, 1800 kcal/day). This diet was supplemented with psyllium fiber to reach 35 g of fiber per day. Four patients were randomly assigned to receive the treatments in the order A-B and the other 4 patients in the order B-A. At the end of the first experimental period, fasting glucose levels were 204 +/- 86 mg% in the meat protein diet group and 127 +/- 8 mg% in the vegetable protein diet group (p less than 0.014). The patients were receiving 2.5 +/- 0.2 g/day and 2.1 +/- 0.5 g/day of tolbutamide at the end of the meat protein diet and vegetable protein diet, respectively. In all cases, fasting glucose levels decreased at the end of the vegetable diet period regardless of the previous treatment. An improvement of greater than or equal to 25 mg% of fasting glucose levels was observed in 7 of the 8 patients after the vegetable protein diet and in no case after the meat protein diet (p less than 0.0078). The parameters of encephalopathy were comparable at the end of both the meat protein diet and the vegetable protein diet. A significant increase in the number of bowel movements was noticed after the vegetable diet plus fiber (p less than 0.01). We propose the use of vegetable diet plus fiber to facilitate the treatment of patients with both diabetes and hepatic encephalopathy.     

肝源性糖尿病的糖代谢特征研究

２７例慢性肝病，据其是否合并糖尿病分为两组，并以２２例急性肝炎和４１例原发性糖尿病作对照。测定ＯＧＴＴ空腹及餐后２小时血糖、胰岛素及Ｃ肽浓度，并求出诸比值。结果表明ＩＲＩ（２ｈ／０°）和Ｃ／Ｉ（２ｈ）是肝源性糖尿病两项颇具特征性的实验室指标。     

Role of antibiotics in the management of hepatic encephalopathy

This article explores the rationale for use of antibiotics in the treatment of hepatic encephalopathy, discusses the role of antibiotics relative to other therapeutic approaches, and considers the reasons that limit the use of the antibiotics most commonly prescribed for the management of hepatic encephalopathy in the United States. Although the scientific rationale for the use of antibiotics in hepatic encephalopathy is well founded, the clinical evidence for their benefits is rather limited. There is no doubt that many antibiotics cause a decrease in intraluminal production of ammonia. However, the commonly prescribed antibiotics are also associated with a variety of adverse effects. None of the antibiotics typically used for hepatic encephalopathy is adequately tolerated in the target patient population. The clinical evidence to date does not support the first-line use of currently available antibiotics in the treatment of hepatic encephalopathy. To improve upon current antibiotic offerings for hepatic encephalopathy, an antibiotic should provide broad-spectrum coverage against both aerobic and anaerobic bacteria, effectively control neuropsychiatric signs and symptoms, and be extremely well tolerated in the target population. An antibiotic fulfilling these criteria would constitute an advance in therapy for hepatic encephalopathy.     

Role of ammonia and inflammation in minimal hepatic encephalopathy

Background: Minimal hepatic encephalopathy (MHE) is common in cirrhosis but its pathophysiologic basis remains undefined. We evaluated whether the presence of MHE was associated with severity of liver disease, ammonia levels or the presence of inflammation and assessed factors determining neuropsychological deterioration accompanying induction of hyperammonemia. Methods: Eighty four cirrhotics were studied. A neuropsychological test battery was performed and blood taken for ammonia, WCC, CRP, nitrate/nitrite, IL-6 and amino acids, before and after, induction of hyperammonemia by administration of a solution mimicking the amino acid composition of haemoglobin (60) or placebo (24). Results: The presence and severity of MHE were independent of severity of liver disease and ammonia concentration but markers of inflammation were significantly higher in those with MHE compared with those without. Induction of hyperammonemia produced deterioration in one or more neuropsychological tests by ≥1 SD in 73.3%. This was independent of the magnitude of change in plasma ammonia and severity of liver disease but was significantly greater in those with more marked inflammation. Conclusion: Our data show that inflammation is an important determinant of the presence and severity of MHE. The change in neuropsychological function following induced hyperammonemia is greater in those with more severe inflammation.     

Role of endothelin-1 in diabetes mellitus

Endothelin-1 is mainly synthesized by the vascular endothelial cells and acts on the vascular smooth muscle. Because of its vasoconstrictor and mitogenic effects it plays a role in the development of vascular diseases. In diabetes mellitus atherosclerosis is accelerated. The authors summarize the available data of the role of endothelin-1 in Type 1 and Type 2 diabetes mellitus and the development of diabetic complication. © 1998 John Wiley & Sons, Ltd.     

Diabetes mellitus is associated with hepatic encephalopathy in patients with HCV cirrhosis

OBJECTIVES: An increased ammonia level of gut bacterial origin is an important mediator in the pathogenesis of hepatic encephalopathy (HE), and constipation is a frequent precipitant of hepatic coma. Because diabetes mellitus (DM) may be associated with delayed gastrointestinal transit, we speculated that its presence in patients with HCV-related cirrhosis would predispose to and exacerbate HE. METHODS: Sixty-five patients (50 men, 15 women) with HCV-related cirrhosis attending a liver transplantation clinic were assessed for severity of liver disease and presence of DM in a cross-sectional study. A modified Child-Pugh score that excluded HE was calculated. Frequency and severity of HE (absent, mild, and severe) in diabetic and nondiabetic patients were assessed. Clinical severity of cirrhosis and results of neuropsychometric testing in diabetic and nondiabetic patients with mild and severe HE were compared. RESULTS: Fifty-four patients (83%) had HE (33 mild, 21 severe). Twenty patients (31%) had DM. HE was present in 19 (95%) patients with diabetes and 35 (78%) patients without diabetes (p = 0.087). Severity of HE was greater in diabetic (35% mild, 60% severe) than in nondiabetic patients (58% mild, 20% severe) (p = 0.007). In both the mild and severe HE categories, severity of liver disease in diabetic patients was otherwise milder than in the nondiabetic patients. CONCLUSIONS: Diabetic patients with HCV cirrhosis have more severe HE. Diabetic patients have severe HE at earlier stages of biochemical decompensation and portal hypertension compared with nondiabetic patients.     

门冬氨酸鸟氨酸治疗显性和轻微型肝性脑病

检索2000年至2010年期间在国内外发表的有关门冬氨酸鸟氨酸治疗显性肝性脑病（HE）和轻微型肝性脑病（MHE）的文献,并进行分析综述。结果显示,门冬氨酸鸟氨酸的治疗机制是直接降低血氨,疗效可靠,无明显不良反应,其对显性HE的疗效已得到公认,对MHE的疗效也在国内外研究中得到初步证实。     

Subclinical hepatic encephalopathy predicts the development of overt hepatic encephalopathy

OBJECTIVES: In patients with compensated liver cirrhosis the clinical repercussions of detecting subclinical hepatic encephalopathy (SHE) are unclear. We present a long-term follow-up study in cirrhotic patients to examine the relationship between SHE and subsequent episodes of overt hepatic encephalopathy. METHODS: A total of 63 cirrhotic patients were studied by Number Connection Test and auditory evoked potentials. We determined glutamine, ammonia, zinc, glutamate, urea, and ratio of branched chain amino acids to aromatic amino acids, and Child-Pugh classification. RESULTS: Of 63 patients, 34 (53%) exhibited SHE. Nineteen out of 63 (30%) developed overt hepatic encephalopathy during follow-up. Hepatic encephalopathy in follow-up was related to alcoholic etiology, ammonia, glutamine, zinc, ratio of branched chain amino acids to aromatic amino acids, liver function, presence of esophageal varices, and detection of SHE (84% of patients who exhibited hepatic encephalopathy in follow-up showed SHE). In Cox-regression, glutamine levels, SHE, esophageal varices, and Child-Pugh class were the independent variables related to hepatic encephalopathy in follow-up. CONCLUSIONS: SHE (defined on the basis of number connection test or auditory evoked potentials alteration) could predict a subsequent episode of overt hepatic encephalopathy. Lower glutamine levels, presence of esophageal varices, and liver dysfunction were also related to the development of overt hepatic encephalopathy.     

Pericentral hepatic fibrosis and intracellular hyalin in diabetes mellitus

Five patients with maturity-onset diabetes mellitus and hepatomegaly were studied. This group in cluded moderately obese females in whom hepatomegaly and abnormal liver studies were associated with a marked elevation in the erythrocyte sedimentation rate. Liver biopsies from all 5 showed fatty steatosis and pericentral fibrosis. In 3 of the 5, fibrous bridging between central veins and portal tracts was present. Collagen surrounded swollen hepatocytes, some of which contained intracellular hyalin indistinguishable from Mallory's hyalin. Polymorphonuclear neutrophils and regenerating nodules were not present. None of the patients had a history of alcohol use, and in 2 followed closely for 2 yr, alcohol was never detected in random blood samples. The recognition of this morphologic lesion may help to clarify the significance of this finding as an intermediate lesion between fatty steatosis and cirrhosis in diabetics.     

乳果糖治疗肝性脑病和亚临床肝性脑病149例临床观察

目的 进一步评估乳果糖对肝硬化肝性脑病和亚临床肝性脑病的疗效。方法 观察乳果糖治疗前后患者的精神状态、扑翼状震颤、脑电图、静脉血氨浓度和数字连接试验的改善情况。结果 乳果糖对肝性脑病组的脑病表现总有效率达96.5％,治疗前后静脉血氨浓度和数字连接试验的改善均有非常显著性差异(P<0.01);亚临床肝性脑病组治疗前后血氨有非常显著性差异(P<0.01),数字连接试验有显著性差异(P<0.05)。在乳果糖治疗观察期间,无一例亚临床肝性脑病患者发展为肝性脑病。结论 乳果糖适合于肝硬化肝性脑病和亚临床肝性脑病患者长期服用,可作为预防和治疗肝性脑病的常规用药。     

Minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE), formerly known as subclinical hepatic encephalopathy, is the mild cognitive impairment commonly seen in patients who have cirrhosis. Current understanding suggests that MHE forms part of the spectrum of hepatic encephalopathy, although this remains to be proven. Although traditionally viewed as having negligible clinical significance, MHE has a significant impact on quality of life. MHE often goes undiagnosed because in many patients there is no evidence of clinically overt signs of impaired cognition. In addition, the diagnostic criteria for MHE have not been standardized, which means that the exact characteristics of MHE remain in question. This Review focuses on the pathogenesis and neuropsychological findings (incorporating neuroimaging) of MHE, as well as the effect of MHE on quality of life and survival, and developments in treatment.     

Minimal hepatic encephalopathy

The term minimal hepatic encephalopathy (MHE) refers to the subtle changes in cognitive function, electrophysiological parameters, cerebral neurochemical/neurotransmitter homeostasis, cerebral blood flow, metabolism, and fluid homeostasis that can be observed in patients with cirrhosis who have no clinical evidence of hepatic encephalopathy; the prevalence is as high as 84% in patients with hepatic cirrhosis. Physician does generally not perceive cirrhosis complications, and neuropsychological tests and another especial measurement like evoked potentials and image studies like positron emission tomography can only make diagnosis. Diagnosis of minimal hepatic encephalopathy may have prognostic and therapeutic implications in cirrhotic patients. The present review pretends to explore the clinic, therapeutic, diagnosis and prognostic aspects of this complication.     

Minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) is the mildest form of spectrum of hepatic encephalopathy (HE). Patients with MHE have no recognizable clinical symptoms of HE but have mild cognitive and psychomotor deficits. The prevalence of MHE is high in patients with cirrhosis of liver and varies between 30% and 84%; it is higher in patients with poor liver function. The diagnostic criteria for MHE have not been standardized but rest on careful patient history and physical examination, normal mental status examination, demonstration of abnormalities in cognition and/or neurophysiological function, and exclusion of concomitant neurological disorders. MHE is associated with impaired health-related quality of life, predicts the development of overt HE and is associated with poor survival. Hence, screening all patients with cirrhosis for MHE using psychometric tests, and treatment of those patients diagnosed to have MHE has been recommended. Ammonia plays a key role in the pathogenesis of MHE, which is thought to be similar to that of overt HE. Thus, ammonia-lowering agents such as lactulose and probiotics have been tried. These agents have been shown to improve cognitive and psychometric deficits, and have good safety profile. Future studies will better define the role of other drugs, such as rifaximin, acetyl L-carnitine and L-ornithine L-aspartate.     

Role of zinc supplementation in type II diabetes mellitus

Zinc is required for normal immune function and taste acuity and enhances the in vitro effectiveness of insulin. Impaired immune function and taste have been reported in diabetic subjects, and decreased serum zinc levels and hyperzincuria occur in some diabetic subjects and animals. Subjects with type II diabetes were examined to determine whether the similar effects of zinc depletion and diabetes are causally related. Low serum zinc levels were found in 16 of 180 subjects (9 percent). There was no correlation between serum zinc and glycosylated hemoglobin levels. Natural killer cell activity did not differ between diabetic subjects (n = 28) and control subjects (n = 38) and did not correlate with serum zinc levels. T lymphocyte response to phytohemagglutinin was lower in diabetic subjects than in control subjects (70 +/- 10 versus 103 +/- 7 X 10(3) counts per minute) but was not lowest in those with the lowest zinc levels. Taste thresholds for hydrochloric acid, sucrose, sodium chloride, and urea were elevated in diabetic subjects (n = 28) versus control subjects (n = 10), but thresholds did not correlate with glycosylated hemoglobin or serum zinc levels. Zinc supplementation in nine diabetic subjects had no effect on the glycosylated hemoglobin level, natural killer cell activity, or taste thresholds, but it did increase mitogen activity in those with the lowest initial phytohemagglutinin responses. It is concluded that zinc deficiency occurs in a subset of subjects with type II diabetes but is not related to diabetes control and does not explain decreased taste acuity. Zinc deficiency may play a role in abnormal immune function in type II diabetes mellitus.     

Minimal hepatic encephalopathy

Minimal hepatic encephalopathy (MHE) is the earliest form of hepatic encephalopathy and can affect up to 80% of cirrhotic patients. By definition, it has no obvious clinical manifestation and is characterized by neurocognitive impairment in attention, vigilance and integrative function. Although often not considered to be clinically relevant and, therefore, not diagnosed or treated, MHE has been shown to affect daily functioning, quality of life, driving and overall mortality. The diagnosis of MHE has traditionally been achieved through neuropsychological examination, psychometric tests or the newer critical flicker frequency test. A new smartphone application (EncephalApp Stroop Test) may serve to function as a screening tool for patients requiring further testing. In addition to physician reporting and driving restrictions, medical treatment for MHE includes non-absorbable disaccharides (eg, lactulose), probiotics or rifaximin. Liver transplantation may not result in reversal of the cognitive deficits associated with MHE.