Efficacy of Lactulose in Cirrhotic Patients with Subclinical Hepatic Encephalopathy

To investigate the role of lactulose in the treatment of cirrhotic patients with subclinical hepatic encephalopathy (SHE), 40 cirrhotic patients, 33 males and 7 females, were included in the study. The diagnosis of SHE was made by quantitative psychometric tests including the number connection test (NCT), figure connection test (FCT) parts A and B, and two performance subtests of Wechsler adult intelligence scale, ie, picture completion (PC) and block design (BD) tests. SHE was diagnosed in 26 (65%) of 40 patients. Of these 26 patients, 14 patients were randomized to treatment group (lactulose 30–60 ml/day for three months, SHE-L) and 12 patients to no treatment group (no lactulose, SHE-NL). Psychometric tests were repeated in all patients in both groups and in six patients with no SHE (group NSHE, N = 14) after three months. The mean scores and number of the abnormal psychometric tests at entry were significantly higher in patients in groups SHE-L and SHE-NL than in patients in group NSHE; however, there was no significant difference between SHE-L and SHE-NL. The mean number of the abnormal psychometric tests decreased in patients in group SHE-L after three months of treatment with lactulose (2.9 ± 0.9 vs 0.8 ± 1.2; P = 0.004); however, there was no change in patients in group SHE-NL after three months (3.7 ± 1.5 vs 3.5 ± 1.3; P = NS). While SHE improved in 8 of 10 patients in group SHE-L, none of the patients in group SHE-NL improved after three months of follow-up (P < 0.001). Two patients in group SHE-NL also developed overt encephalopathy during the study period. We conclude that lactulose treatment in cirrhotic patients with SHE is effective.     

Attention,Memory, and Cognitive Function in Hepatic Encephalopathy

Deficits in attention and arousal play a major role in the clinical presentation of hepatic encephalopathy. Attention deficits arealso the main components of minimal hepatic encephalopathy. The present paper summarizes some findings about attentional and memory dysfunction in hepatic encephalopathy, with reference to basic knowledgeabout normal attention and memory function and their cerebral representation.     

Attention Deficits in Minimal Hepatic Encephalopathy

Minimal hepatic encephalopathy (HE) is characterized by a decrease of psychomotor speed, and deficits in visual perception, visuo-spatial orientation, and visuo-constructive abilities. Attention deficits have also been proposed to be part of the syndrome. Several attempts were made in the past to elaborate suitable psychometric means for the assessment of minimal HE. However, there is still no gold standard for the diagnosis of minimal HE. We recently evaluated the so called PSE-Test for the assessment of minimal HE, a test battery which does not include a test predominantly aimed at the assessment of attention. We therefore presented a battery of attention tests in addition to the PSE-Test to a group of cirrhotics without clinical signs of HE compared to a healthy control group matched for age and education to determine whether the addition of special attention tests would increase the diagnostic sensitivity of the PSE-Test. It was shown that the patients with a pathological PSE-Test result differed significantly from controls in all attention tests applied, while the patients with normal PSE-Test results achieved attention test results similar to that of the controls. Thus, the PSE-Test results represent attention deficits as well as deficits in motor skills, visuo-spatial orientation, and visual construction.     

Predictors of Minimal Hepatic Encephalopathy in Patients with Cirrhosis

Background/Aim:

Minimal hepatic encephalopathy (MHE) impairs patient’s daily functioning of life. Predictors of MHE in cirrhotic patients have not been evaluated.

Patients and Methods:

A total of 200 cirrhotic patients (Child A, 74 [37%]; Child B, 72 [36%]; Child C, 54 [27%]) were evaluated by psychometry, P300 auditory event-related potential (P300ERP) and critical flicker frequency (CFF). MHE was diagnosed by abnormal psychometry (>2 S.D.) and P300ERP (>2.5 S.D.). Univariate and multivariate logistic regression analyses were performed to determine the predictors of MHE.

Results:

Eighty-two (41%) patients were diagnosed to have MHE – 26/74 (35%) in Child A, 26/72 (36%) in Child B and 30/54 (56%) in Child C. Ninety-seven (48.5%) patients had abnormal psychometric tests, and 96 (48%) had prolonged P300ERP (>358 ms). Sixteen (16.5%) patients with abnormal psychometry had P300ERP < 358 ms, and 15 (14.5%) patients with normal psychometry results had P300ERP > 358 ms. One hundred and three patients had CFF value < 39 Hz with specificity of 86.6% and sensitivity of 72.9% for MHE. Model for end-stage liver disease (MELD) (17.9 ± 5.7 vs. 13.4 ± 4.2, P = 0.005), Child-Turcotte-Pugh (CTP) score (8.4 ± 2.5 vs. 7.7 ± 2.2, P = 0.02), ammonia (104.8 ± 37.9 vs. 72.5 ± 45.2 µmol/L, P = 0.001) and CFF (37.0 ± 2.8 vs. 41.0 ± 3.4 Hz, P = 0.001) were significantly higher in MHE as compared to non-MHE patients. Ninety-one (45.5%) patients had MELD > 15.5, 115 (57.5%) had CTP score > 7.5, while 93 (46.5%) had venous ammonia > 84.5 µmol/L. On univariate analysis, MELD (8.52 [95% CI, 4.46-16.26; P = 0.001]), CFF (17.34 [95% CI, 8.16-36.85; P = 0.001]) and venous ammonia (7.80 [95% CI, 4.11-14.81; P = 0.003]) were associated with MHE; while CTP score (1.51 [95% CI, 0.85-2.69; P = 0.30]) was not significant. On multivariate analysis, MELD, CFF and venous ammonia were predictive of MHE.

Conclusion:

Prevalence of MHE in this study was 41%; and MELD > 15.5, CFF < 39 Hz and venous ammonia > 84.5 µmol/L were predictive of MHE.     

Minimal Hepatic Encephalopathy in Patients with Cirrhosis by Measuring Liver Stiffness and Hepatic Venous Pressure Gradient

Background/Aim:

Transient elastography (TE) of liver and hepatic venous pressure gradient (HVPG) allows accurate prediction of cirrhosis and its complications in patients with chronic liver disease. There is no study on prediction of minimal hepatic encephalopathy (MHE) using TE and HVPG in patients with cirrhosis.

Patients and Methods:

Consecutive cirrhotic patients who never had an episode of hepatic encephalopathy (HE) were enrolled. All patients were assessed by psychometry (number connection test (NCT-A and B), digit symbol test (DST), serial dot test (SDT), line tracing test (LTT)), critical flicker frequency test (CFF), TE by FibroScan and HVPG. MHE was diagnosed if there were two or more abnormal psychometry tests (± 2 SD controls).

Results:

150 patients with cirrhosis who underwent HVPG were screened; 91 patients (61%, age 44.0 ± 11.4 years, M:F:75:16, Child''s A:B:C 18:54:19) met the inclusion criteria. Fifty three (58%) patients had MHE (Child A (7/18, 39%), Child B (32/54, 59%) and Child C (14/19, 74%)). There was no significant difference between alanine aminotranferease (ALT), aspartate aminotransferase (AST) and total bilirubin level in patients with MHE versus non MHE. Patients with MHE had significantly lower CFF than non MHE patients (38.4 ± 3.0 vs. 40.2 ± 2.2 Hz, P = 0.002). TE and HVPG in patients with MHE did not significantly differ from patients with no MHE (30.9 ± 17.2 vs. 29.8 ± 18.2 KPas, P = 0.78; and 13.6 ± 2.7 vs. 13.6 ± 3.2 mmHg, P = 0.90, respectively).There was significant correlation of TE with Child''s score (0.25, P = 0.01), MELD (0.40, P = 0.001) and HVPG (0.72, P = 0.001) while no correlation with psychometric tests, CFF and MHE.

Conclusion:

TE by FibroScan and HVPG cannot predict minimal hepatic encephalopathy in patients with cirrhosis.     

Ammonia,the GABA Neurotransmitter System,and Hepatic Encephalopathy

There appears to be a consensus that hepatic encephalopathy (HE) is a metabolic encephalopathy with a multifactorial pathogenesis. One of the factors considered to be important in the pathogenesis of HE is ammonia. However, the mechanisms by which ammonia contributes to the manifestations of HE remain poorly defined. Ammonia could be more definitively implicated in the pathogenesis of HE if its effects can be shown to lead to an enhancement of inhibitory neurotransmission. In this context the effects of ammonia on the GABA (-aminobutyric acid) neurotransmitter system may be relevant. Ammonia, at the modestly increased concentrations that commonly occur in precoma HE (0.15 mM–0.75 mM), has been shown to increase GABA-induced chloride current in cultured neurons, probably by modifying the affinity of the GABA(A) receptor for GABA. Comparable ammonia concentrations also enhanced synergistically the binding of a GABA agonist and a benzodiazepine (BZ) agonist to the GABA(A) receptor complex, phenomena which would enhance the neuroinhibitory effects of these ligands. Also, GABA increased the potency of ammonia-induced enhancement of the binding of a BZ agonist to the GABA(A) receptor complex, and brain levels of BZ agonists are elevated in liver failure. In addition, ammonia has been shown to inhibit astrocytic uptake of GABA by 30%–50%, an effect which would increase the synaptic availability of GABA at GABA(A) receptors. Furthermore, increased ammonia concentrations upregulate the peripheral-type benzodiazepine receptor in the outer membrane of astroglial mitochondria, thereby enhancing astrocytic mitochondrial synthesis and release of neurosteroids. Some neurosteroids, for example tetrahydroprogesterone (THP) and tetrahydrodeoxycorticosterone (THDOC), are potent agonists of the GABA(A) receptor complex, on which there are specific binding sites for neurosteroids, that are distinct from those for BZs and barbiturates. Tetrahydroprogesterone and tetrahydrodeoxycorticosterone levels were found to be increased in a mouse model of acute liver failure, and, when THP or THDOC was injected into normal mice, sedation and Alzheimer type II astrocytic changes in the cortex, striatum, and hypothalmus were induced. Each of these direct or indirect effects of ammonia on the GABA neurotransmitter system has the potential of increasing inhibitory neurotransmission, and, hence, contributing to the manifestations of HE.     

Pathophysiology of Hepatic Encephalopathy: A New Look at Ammonia

Results of neuropathologic, spectroscopic, and neurochemical studies continue to confirm a major role for ammonia in the pathogenesis of the central nervous system complications of both acute and chronic liver failure. Damage to astrocytes characterized by cell swelling (acute liver failure) or Alzheimer Type II astrocytosis (chronic liver failure) can be readily reproduced by acute or chronic exposure of these cells in vitro to pathophysiologically relevant concentrations of ammonia. Furthermore, exposure of the brain or cultured astrocytes to ammonia results in similar alterations in expression of genes coding for key astrocytic proteins. Such proteins include the structural glial fibrillary acidic protein, glutamate transporters, and peripheral-type (mitochondrial) benzodiazepine receptors. Brain–blood ammonia concentration ratios (normally of the order of 2) are increased up to fourfold in liver failure and arterial blood ammonia concentrations are good predictors of cerebral herniation in patients with acute liver failure. Studies using ¹H magnetic resonance spectroscopy in patients with chronic liver failure reveal a positive correlation between the severity of neuropsychiatric symptoms and brain concentrations of the brain ammonia-detoxification product glutamine. Increased intracellular glutamine may be a contributory cause of brain edema in hyperammonemia. Positron emission tomography studies using ¹³HN₃ provide evidence of increased blood–brain ammonia transfer and brain ammonia utilization rates in patients with chronic liver failure. In addition to the use of nonabsorbable disaccharides and antibiotics to reduce gut ammonia production, new approaches to the treatment of hepatic encephalopathy by lowering of brain ammonia include the use of L-ornithine–L-aspartate and mild hypothermia.     

Quality of Life in Cirrhotics with Minimal Hepatic Encephalopathy

Minimal hepatic encephalopathy (HE) is a major cause of premature retirement in cirrhotics. The decision on the earning capability of a patient is usually based on clinical judgement, considering the patient's complaints and clinical findings such as nervousness and depression. In a comprehensive psychometric study we were able to show that cirrhotic patients, who are considered to be unable to earn their living, differ significantly from those who are working, in tests evaluating psychomotor function and in personality and subjective well-being scores representing nervousness, aggressiveness, depression. The latter scores are considered to represent the individual discrepancies between professional demands and cerebral performance. Since minimal HE affects psychomotor function but not verbal abilities this discrepancy exists predominantly in blue collar workers. In accordance with this 60% of blue collar (in contrast to 20% of white collar) workers of our patient group were considered unfit for work. Working ability is an essential element of quality of life in Western societies. Thus, an impairment of working capability is of major impact on quality of life in cirrhotics.     

Positron Emission Tomography in the Study of Hepatic Encephalopathy

Positron emission tomography (PET) is a powerful and versatile tool for the investigation of hepatic encephalopathy (HE). This nuclear medicine imaging technique produces quantitative images of the distribution of a radiopharmaceutical at one or more times after its administration. Thus, PET images can be used as data in mathematical models of physiologically important processes, including cerebral blood flow, an index of neural activity, or glucose and ammonia metabolism. Using PET, we have demonstrated abnormalities in all of these processes in patients, even though many had only minimal HE. In HE patients we have found increases in the cerebral ammonia metabolic rate, because of hyperammonemia and an increase in the permeability of the blood–brain barrier to ammonia and abnormal patterns of blood flow and glucose metabolism. In a recent collaborative study, alterations in the resting glucose metabolic rate were found to have significant correlations with a variety of neuropsychological tests used to detect mild HE including Trailmaking A and B, symbol-digit, and other tests. Activation techniques have not yet been applied to map sites affected by HE, but recent data using the paced serial auditory addition test and an auditory continuous performance task have proven to be sensitive indicators in minimally impaired patients. The full potential of PET to evaluate neurotransmitter function is as yet unrealized.     

Profile of Hepatic Encephalopathy in Children with Cirrhosis and Response to Lactulose

Background/Aim:

Hepatic encephalopathy (HE) is associated with a poor prognosis. There is paucity of data on the treatment of HE with lactulose in children with cirrhosis.

Patients and Methods:

Retrospective analysis of consecutive cirrhotic patients (<18 years) with HE was done. HE was defined according to West-Haven criteria. Response was defined as complete if patients recovered completely from HE, partial response was defined as improvement of encephalopathy by one or more grades from admission but not complete recovery, and defined as non response if patient did not show any improvement or deteriorated further even after 10 days of lactulose therapy.

Results:

A total of 300 patients were admitted with cirrhosis and HE (278 adults and 22 children). Of 22 patients, 16 (73%) patients had complete response to lactulose and six (27%) patients did not [three (13.5%) patients worsened (non response) and three (13.5%) did not recover fully even after 10 days of treatment (partial response)]. Comparing baseline characteristics of patients who had complete response (n=16) versus partial (n=3) and non response (n=3), there was significant difference in mean arterial pressure (78.1±10.7 vs 62.6±5.0 mmHg, P=0.003), serum sodium (131.3±3.2 vs 126.5±5.2, P=0.01) and serum creatinine (0.78±0.3 vs 1.1±0.3 mg/dl, P=0.02). We did not find any difference in baseline characteristics of these patients regarding CTP score (9.6±1.2 vs 10.6±1.2), MELD score (17.6±2.9 vs 17.1±3.4), severity of HE (2.5±0.6 vs 2.6±0.5) and etiology of precipitating factors (P=0.78).

Conclusions:

Lactulose therapy causes complete recovery from hepatic encephalopathy in 73% of pediatrics patients with cirrhosis.     

Cerebral Energy Metabolism in Hepatic Encephalopathy and Hyperammonemia

Hepatic encephalopathy (HE) is an important cause of morbidity and mortality in patients with severe liver disease. Although the molecular basis for the neurological disorder in HE remains elusive, elevated ammonia and its chief metabolite glutamine are believed to be important factors responsible for altered cerebral functions, including multiple neurotransmitter system(s) failure, altered bioenergetics, and more recently oxidative stress. Accumulated evidence suggests that direct interference of ammonia at several points in cerebral energy metabolism, including glycolysis, TCA cycle, and the electron transport chain, could lead to energy depletion. Additionally, recent studies from our laboratory have invoked the possibility that ammonia and glutamine may induce the mitochondrial permeability transition in astrocytes, a process capable of causing mitochondrial dysfunction. Altered mitochondrial metabolism appears to be an important mechanism responsible for the cerebral abnormalities associated with HE and other hyperammonemic states.     

Prediction of Hepatic Encephalopathy Development in Patients With Severe Acute Hepatitis

To identify factors predicting the development of hepatic encephalopathy, 164 patients with severe acute hepatitis (SAH), defined as acute hepatitis having a prolonged prothrombin time (PT) of < 40% activity but without hepatic encephalopathy, were prospectively observed at 57 major liver centers in Japan. From the data of 65 patients enrolled from 1997 to 1998, a prediction equation was developed by multiple logistic regression analysis and prospectively evaluated using the data of 99 patients since 1999. Of the 164 patients with SAH, 51 (31%) developed hepatic encephalopathy. From the etiologic viewpoint, the percentages of patients developing encephalopathy were highest in non–A-E hepatitis (41.9%). A predictive model, logit(p) = 0.084 × age (year)+ 0.129 × serum total bilirubin (TB, in mg/dL)–0.158× prothrombin time (%)–2.434, was developed. In conclusion, old age, prolonged PT, elevation of TB, and non–A-E hepatitis are potential risk factors for developing encephalopathy in SAH.     

Distinguishing Between Clinical and Minimal Hepatic Encephalopathy on the Basis of Specific Cognitive Impairment

It is well-known that liver cirrhosis is frequently accompanied by a wide range of neuropsychiatric abnormalities, including general and specific cognitive impairment. The aim of this study was to investigate which cognitive functions are selectively compromised in Hepatic Encephalopathy (HE) and to clarify the relationship between clinically overt or nonovert HE and the different forms and degrees of decay in cognitive deficits. Twenty-two patients without overt HE and 12 patients who showed overt HE at the first level of severity, along with matched control subjects, were compared in several cognitive domains. The results showed significant differences in some measures of attention between patients with minimal HE (mHE) and patients with overt HE. There were also notable differences in verbal short-term memory between patients with mHE and healthy subjects. Thus, we can hypothesize that there is a linear diminution in short-term memory and attentional performance starting from healthy patients, moving toward patients with mHE, and finally progressing toward patients with the first grade of overt HE. There are two types of diminution that we noted: between patients with mHE and the overt form, the decline in the attentional domain was more evident, while between healthy subjects and mHE patients, short-term memory showed a more evident decline.     

A Survey of Patterns of Practice and Perception of Minimal Hepatic Encephalopathy: A Nationwide Survey in India

Background/Aim:

Minimal hepatic encephalopathy (MHE) leads to overt hepatic encephalopathy (HE) and impairs quality of life in patients with cirrhosis. Awareness of MHE and its management among physicians is not known.

Patients and Methods:

We conducted a survey among 673 physicians in India from academic and nonacademic institutes to understand the clinical burden, perceived severity, management patterns, and the barriers to providing care for this condition.

Results:

Overall awareness of MHE in this survey was 75% (n = 504). Awareness of MHE was significantly higher in physicians working in teaching hospitals compared with those in nonteaching hospitals (79% vs 71%, P = 0.02). Similarly, gastroenterologists were more aware of MHE compared with nongastroenterologists (91% vs 66%, P = 0.001). Only 6.3% physicians screened all of their patients for MHE, whereas frequency of testing for MHE, either being nil or less than 10% of their patients was 64.7%. The most common test was paper and pencil test (86%) and the reason for nonscreening was nonavailability of time to test and also equipment or method (81%). A majority of physicians (88%) think that MHE affects quality of life. Physicians (61%) had an opinion that there should be some registry of MHE regardless of the cost and effort involved. Lactulose was used in 93% of cases, followed by rifaximin (82%) in the management of MHE.

Conclusion:

The overall awareness of MHE was 75% and it was significantly more in physicians of academic institutes. Despite awareness of its effect on quality of life, a majority of physicians did not test for MHE in their day-to-day practice.