Minimal Hepatic Encephalopathy

Background: Minimal hepatic Encephalopathy (MHE) is defined as HE without symptoms on clinical/neurological examination, but with deficits in some cognitive areas that can only be measured by neuropsychometric test- ing. However, numerous studies have shown that, although the neurological symptoms are slight, affected patients are markedly impaired in their quality of life and ability to work. Various treatment modalities that have been shown to reverse MHE include lactulose/lactitol, probiotics/synbiotics, L-carnitine but rifaximin has shown a general trend toward better efficacy and better to- lerability in patients with overt hepatic encephalopathy (OHE). Objective: Our objective is to assess the diagnostic role of minimental state examination (MMSE), electroencephalography (EEG) and visual evoked potential (VEP) in detection of MHE and to evaluate the efficacy of rifaximin in improving EEG and VEP in patients with MHE. Patients and Methods: Sixty cirrhotic patients were enrolled in the study depending on clinical evidence of stigmata of chronic liver disease, laboratory investigations including liver function tests, ultrasonographic features of liver cirrhosis and with no evidence of overt hepatic encephalopathy. Diagnois of MHE was made depending on mi- nimental state examination (MMSE) and neurophysiological tools including EEG and VEP. A control group of sixty healthy volunteers with age and sex matched were included. The patient group received Rifaximin 550 mg twice daily for 8 weeks then follow up EEG and VEP studies were done. Results: MHE was detected in 36.7%, 48.3%, 51.7% of our series based on MMSE, EEG and VEP respectively. Child Pouph A, B, C was found in 51.7%, 35%, 13.3% respectively. Rifaximin was well tolerated. At the end of treatment, How to cite this paper: Abdelfattah, A.M.,

In our study the mean score of all the tests were higher in the study group compared to the controls. This difference was statistically significant for all the tests [p value <0.05]. When compared between the cases and control groups the difference in the average score were higher for the DST and the NCT-B tests. These tests also had the highest sensitivity in detecting Minimal Hepatic Encephalopathy. They were also the least specific. It may well serve that these two tests can be used as screening tests and if positive, the child can be subjected to the entire battery of tests.

Hepatic encephalopathy (HE) is defined as an unspecific brain function disorder, due to either failure of (cirrhotic) liver function or to port osystemic shunting and thus by-passing the functional parenchyma. For an accurate diagnosis of HE, other brain diseases have to be prop- erly excluded. HE is characterized by cognitive, psychi- atric and/or motoric impairment [1] leading to changes in the circadian rhythm, atmospheric fluctuations, phased loss of concentration, increased forgetfulness, ir- ritability, and somnolence up to hepatic coma [2]. Sub- clinical neurological deficits are defined as minimal hepatic encephalopathy (MHE). The presence and de- gree of (M)HE can only measured by psychometric tests and clinically apparent deficits, graded by the West Haven criteria [1, 3]. Clinically apparent (i.e., overt) HE is estimated to be present in 30–45 % of patients with liver cirrhosis and leads to frequent hospitalization, im- pairment of health-related quality of life (HRQL) and ability to work [4]. Up to 80 % of cirrhotic patients present with MHE with cognitive dysfunction in special diagnostic testing [5, 6, 7]. In patients with MHE activ- ities of daily life are affected resulting, among other problems, in an increased risk for accidents when driv- ing and navigating [8]. The clinical manifestations of HE in each stage are potentially reversible by adequate therapeutic management. MHE is currently under-diag- nosed in patients with liver cirrhosis and carries a high po- tential for progression to overt HE. Current therapies are directed at the reduction of ammonia production from the gastrointestinal tract by administration of the non- absorbable disaccharide lactulose and the non-absorbable antibiotic rifaximin [9–18].

Minimal hepatic encephalopathy (MHE) produced mild motor and cognitive disorders and predisposes to suffer hepatic encephalopathy (HE), the most severe form of the disease. Currently, hyperammonemia (HA) and neuroinflammation are considered synergic factors involved in the pathogenesis of MHE and HE. The serine peptidase prolyl endopeptidase (PREP) cleaves short peptides (<30 amino acids) at the C-side of a proline residue. It has been proposes that PREP may play a role in the inflammatory response through peptide modulation. Objectives: In this paper we showed our results in relation to the expression of PREP in a model of MHE produces by induction of chronic moderate HA. Methods: Brain samples were collected from HA rats and PREP expression was determined by immunohistochemistry analysis and immunoblotting assessment in the neocortex, hippocampus, striatum and cerebellum. Results: The results indicated that HA produces PREP expression alterations in most of the areas analyzed. After 8 weeks of HA the expression of PREP was increased in the motor cortex, CA1 region of the hippocampus, the caudate putamen of the striatum and in the cerebellum. Conclusions; these results may indicate that prep increase may have a role in alterations seen in hyperammonemia without liver impairment.

MATERIALS AND METHODS: Our study included 65 patients with cirrhosis with covert hepatic encephalopathy (29 with minimal hepatic encephalopathy and 36 without hepatic encephalopathy). Participants underwent DTI, from which we generated mean diffusivity and fractional anisotropy maps. We used a Bayesian machine-learning technique, called Graphical-Model-based Multivariate Analysis, to determine WM regions that characterize group differences. To further test the clinical significance of these potential biomarkers, we performed Cox regression analysis to assess the potential of these WM regions in predicting survival.

Our study demonstrated the occurrence of Minimal Hepatic Encephalopathy (MHE) in patients with Cirrhosis irrespective of the etiology even in the presence of stable clinical condition . Both Critical Flicker Frequency (CFF) Test and Psychometric tests have been found out to be effective in detecting MHE . Psychometric tests have subjective variations due to their age factor , differences in education while CFF Test has no such limitations and more of objective in nature not requiring any educational qualification for undergoing and interpretation of the light stimulus and is reproducible .The detection of MHE in more numbers in our study may be due to higher number of patients with higher classes of Child Pugh classification .The presence of majority of the patients with Hepatitis B infection is due to our place of study being a tertiary care and a prestigious institute of Gastroenterology .

Hepatic encephalopathy includes a spectrum of transient and reversible neurological and psychiatric manifestations usually found in patients with chronic liver disease and portal hypertension. Its occurrence indicates a poor prognostic factor with a projected one year survival rate of 43%. It occurs in 50% to 70% of cirrhotic patients. The least severe form of hepatic encephalopathy, which is not recognized on clinical examination is Minimal hepatic encephalopathy (MHE). It impairs health related quality of life (HRQOL). It can be detected by using sensitive tests like number connection tests, line tracing tests and figure connection tests, EEG, visual, auditory and somatosensory evoked potentials. Ammonia levels are found to be elevated in patients with minimal hepatic encephalopathy and therefore can play a role in the causation of minimal hepatic encephalopathy. Minimal hepatic encephalopathy has a subtle but negative impact on a patient’s spatial and motor skills, the ability to perform complex tasks such as driving, and even quality of life. Some studies have reported that patients with MHE can progress and later on develop overt hepatic encephalopathy. Due to its negative impact on daily living, it has been suggested that the failure to diagnose this condition could be classified as a medical error.

This is to certify that the Dissertation entitled “EVALUATION OF THE PREVALENCE OF MINIMAL HEPATIC ENCEPHALOPATHY IN PATIENTS WITH COMPENSATED CIRRHOSIS” here with submitted by Dr. T.YOGANANDH, Post graduate in General Medicine, Coimbatore Medical College to the Tamilnadu Dr.M.G.R Medical University is a record of a bonafide research work carried out by him under my guidance and supervision from June 2008 to May 2009.

This is to certify that the dissertation entitled “PSYCHOMETRIC HEPATIC ENCEPHALOPATHY SCORE FOR THE DETECTION OF MINIMAL HEPATIC ENCEPHALOPATHY IN SOUTH INDIAN PATIENTS WITH LIVER CIRRHOSIS” is a bonafide original work done by Dr. G. KUMARAVEL, in partial fulfillment of the requirements for M.D. GENERAL MEDICINE BRANCH – I examination of the Tamilnadu Dr. M.G.R Medical University to be held in April 2015, under my guidance and supervision in 2014

During follow up OHE developed in 14 patients but MHE in this group was earlier diagnosed using psychometric tests in only 10 patients. Twelve of 14 patients with OHE had at least one abnormal result out of the seven tests. Multiple proportional hazard regression model showed a higher risk of OHE in patients with abnormal EEG (HR - 8.4, 95% CI 2.6 -27.3, p < 0.001). Other factors, including psychometric and standard and nonstandard tests, did not predict the OHE. Diagnosis of minimal hepatic encephalopathy needs further standardization. Among

The minimal hepatic encephalopathy is a condition, which raises many discussions and questions of its diagnosis and treatment. Several years ago it was called “subclinical”, “early” or “latent”. The current term was proposed in the 11th World Congress of Gastroenterology in Vienna in 1998. In the same Congress hepatic encephalopathy (HE) classification, West-Haven’s criteria, were published, but minimal hepatic encephalopathy was not mentioned (1). According to clinical symptoms overt HE was graded just into 4 grades – from 1 to 4, the grade 0 was added later. Although cirrhotic patients with encephalopathy grade 0 do not have any clinical signs of HE, further studies revealed presence of cognitive disturbances, MHE, in part of them (2–4).

Hepatic encephalopathy is a potentially reversible, metabolically caused disturbance of central nervous system function that occurs in patients with acute or chronic liver disease. MHE is defined as HE without symptoms on clinical/neurological examination, but with deficits in some cognitive areas that can only be measured by neu- ropsychometric testing [1]. MHE has a high frequency among patients with liver cirrhosis (22% - 74%) and also occurs in patients with non cirrhotic liver disease such as portal vein thrombosis [2] or portosystemic shunt [3]. The true frequency of patients with MHE is unknown, firstly because the diagnostic criteria in use around the world are not entirely uniform, and secondly because MHE often remains undiagnosed due to the lack of evident symptoms [4]. However, numerous studies have shown that, although the neurological symptoms are slight, af- fected patients are markedly impaired in their quality of life and ability to work [5]. Various tools have been evaluated for the diagnosis of MHE including neuropsychological tests, neurophysiological tests as auditory brain stem response, p300 event, regional cerebral blood flow changes [6], magnetic resonance imaging and spectroscopy [7]. Several hypotheses attempt to explain the etiopathophysiology of HE. Metabolic products from the intestine are normally metabolized in the liver. However, in people with significant liver disease, im- paired hepatic detoxification leads to systemic accumulation of by-products of gut metabolism, specifically ammonia [8]. Zinc is integrally involved in the metabolism of ammonia. Zinc deficiency markedly decreases the activity of the urea cycle enzyme, ornithine transcarbamylase, and zinc supplementation corrects this [9]. Simi- larly, zinc deficiency has been reported to impair activity of muscle glutamine synthetase, which causes hyper- ammonemia [10]. Glutamine synthetase activity has also been reported to be decreased in patients with hepatic encephalopathy [11].

Lastly, in our study, we reported a multivariate analysis for different risk factors for the development of MHE as the predicted risk factors for the development of MHE were age and smoking where with increasing age, the odd ratio and hazard increase 1.572 in older age than in younger age, and in smoking, the odd ratio and hazard increase 8.070 in than non-smoking. This comes in agreement with Gad et al. [21] who reported smoking as a significant risk factor for MHE. These results were not the same as Seo et al. [19] who reported that education years, Child–Pugh score (consists of five clinical features: total bilirubin, serum albumin, prothrombin time, ascites, and hepatic encephalopathy and is used to assess the prognosis of chronic liver disease and cirrho- sis), and venous ammonia level were independently associated with MHE on multivariate analysis.

6. Chen HJ, Wang Y, Zhu XQ, Li PC, Teng GJ. Classification of cirrhotic patients with or without minimal hepatic encephalopathy and healthy subjects using resting-state attention-related network analysis. PLoS One., 2017; 9: e89684. doi:10.1371/journal.pone.0089684

Minimal hepatic-encephalopathy was the neurocognition disorder where individual has an mal-performance in various psychometric tests. This usually occurs in cirrhotic individuals how ever it can be observed in initial stages of fibrotic process as well as portosystemic shunting. This entity, recognized during 1970s, were originally called as sub-clinical HE which was relied on the performance of individuals in trail-making as well as various cognitive test [32,35]. A study was conducted by Hamster et al to understand the several neuro- cognitive domains altered in this condition. [36]. He conducted greater than three hindered various test of psychometry to estimate cognition domain which is varying from premorbid-intelligence levels and verbal-abilities to visuomotor- function and its coordinatents.

Abstract: Alterations in the levels of intestinal microbiota, endo- toxemia, and inflammation are novel areas of interest in the pathogenesis of hepatic encephalopathy (HE). Probiotics and symbiotics are a promising treatment option for HE due to possible beneficial effects in modulating gut microflora and might be better tolerated and more cost-effective than the traditional treatment with lactulose, rifaximin or L -ornithine- L -aspartate. A systematic search of the electronic databases PubMed, ISI Web of Science, EMBASE, and Cochrane Library was conducted for randomized controlled clinical trials in adult patients with cirrhosis, evaluating the effect of probiotics and symbiotics in changes on intestinal microflora, reduction of endotoxemia, inflammation, and ammo- nia, reversal of minimal hepatic encephalopathy (MHE), pre- vention of overt hepatic encephalopathy (OHE), and improvement of quality of life. Nineteen trials met the inclusion criteria. Pro- biotics and symbiotics increased beneficial microflora and decreased pathogenic bacteria and endotoxemia compared with placebo/no treatment, but no effect was observed on inflammation. Probiotics significantly reversed MHE [risk ratio, 1.53; 95% con- fidence interval (CI): 1.14, 2.05; P = 0.005] and reduced OHE development (risk ratio, 0.62; 95% CI: 0.48, 0.80; P = 0.0002) compared with placebo/no treatment. Symbiotics significantly decreased ammonia levels compared with placebo (15.24; 95% CI: 26.01, 4.47; P = 0.006). Probiotics did not show any additional benefit on reversal of MHE and prevention of OHE development when compared with lactulose, rifaximin, and L -ornithine- L -

Material and Methods: A cross-sectional study was conducted. Cirrhotic outpatients were included. Exclusion criteria: overt hepatic encephalopathy, illiteracy, active alcohol consumption, psychotropic drug use and therapy with lactulose. The presence of minimal hepatic encephalopathy was defined as a value ≤ -4 on the Psychometric Hepatic Encephalopathy Score, calculated according to the Portuguese norms. Variables analyzed: etiology and severity of liver disease and venous blood ammonia concentration. p values < 0.05 were considered significant.

further categorized into episodic, persistent, and minimal HE (MHE). Episodic HE involves episodes of delirium with rapid onset and fluctuation in severity. Persistent HE and MHE describe the gradient in clinical status described by overt HE (OHE). OHE is stratified into four grades by the West Haven Criteria for Semiquantitative Grading of Mental State. Grade 1 OHE is characterized by trivial lack of awareness, euphoria or anxiety, shortened attention span, and impaired performance of addition. Grade 2 OHE is characterized by lethargy or apathy, minimal disorientation, subtle personality change and inappropriate behavior, and impaired ability to subtract. Grade 3 OHE is characterized by confusion, gross disorientation, and somnolence to semi-stupor, but respon- siveness to verbal stimuli. Grade 4 OHE is characterized by coma. While OHE is clinically apparent, MHE encompasses cognitive impairment only discernible through additional dedicated neuropsychiatric testing.

Thus, cirrhotic patients graded 0 or 1 no clinical encephalopathy had no cerebral oxygenation depression, Grades 2 and 3 had mean oxygen uptakes of 2.9 cc and 2.0 cc per 100 g brain per [r]

Rifaximin has potential beneficial effects in both overt HE and to prevent recurrent episodes of HE. Additional evidence is needed to determine the effects of rifaximin in clinical practice. In particular, the evidence supporting the use of rifaximin for minimal HE is weak. Knowledge about long- term maintenance treatment is scarce. The current cost of the drug may very well influence both the duration of treatment and adherence to medication.