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Lactitol and lactulose for the treatment of subclinical hepatic encephalopathy in cirrhotic patients. A randomised, cross-over study
Abstract
Fourteen patients with cirrhosis and subclinical hepatic encephalopathy were randomised to treatment with lactitol or lactulose for a 2-month period during which they were monitored clinically, by electroencephalography and by manually administered and computer-based psychometric testing. Following a washout period of 4-6 weeks patients were crossed-over to treatment with the alternative sugar for a similar period of monitoring. None of the patients showed evidence of overt hepatic encephalopathy and only one showed slowing of the electroencephalogram mean cycle frequency at the onset of the trial. However, significant impairment was observed in the group as a whole in the performance of all three manually administered psychometric tests and in four of the ten computer-based test variables. No changes were observed in clinical status or in electroencephalogram mean cycle frequency during treatment with either lactitol or lactulose. However, psychometric performance improved consistently, and to the same degree, during treatment with both sugars. Patients required a mean of 26 g (range 8-36) of lactitol and 25 ml (10-60) of lactulose to achieve two semi-soft stools per day. The majority of patients complained of flatulence during treatment with both sugars but this tended to resolve with continued treatment. Diarrhoea developed in a small number of patients during both treatment periods but this was invariably dose-related. Patients were equally divided in their preference for the two sugars. Patients with subclinical hepatic encephalopathy benefit from treatment with lactitol and lactulose in terms of their psychometric performance. The feasibility and benefits of long-term treatment for this condition need to be elucidated.
... The second-generation NAD lactitol was introduced into clinical practice in the 1980s. (3)(4)(5)(6) The NADs are classified as osmotic laxatives but have also been classified as prebiotics, a generic term referring to agents that induce the growth or activity of commensal microorganisms. Although the pathogenesis of HE is incompletely understood, there is general agreement that the gut-derived neurotoxin ammonia plays a key role. ...
... (21,31,32,35,37,(43)(44)(45)51,55) Three RCTs used the Conn score, which is similar to the West Haven criteria. (4,28,50) Thirty-two RCTs employed NCT-A. (4)(5)(6)21,24,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)43,45,46,(48)(49)(50)(51)(52)(53)(54)(55) Twenty-five RCTs measured blood ammonia in plasma, venous, or arterial blood, (5,6,(21)(22)(23)(25)(26)(27)(28)(29)31,35,36,(38)(39)(40)(41)44,(46)(47)(48)(49)52,54,55) while 22 assessed the electroencephalogram mean cycle frequency. ...
... (4,28,50) Thirty-two RCTs employed NCT-A. (4)(5)(6)21,24,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)43,45,46,(48)(49)(50)(51)(52)(53)(54)(55) Twenty-five RCTs measured blood ammonia in plasma, venous, or arterial blood, (5,6,(21)(22)(23)(25)(26)(27)(28)(29)31,35,36,(38)(39)(40)(41)44,(46)(47)(48)(49)52,54,55) while 22 assessed the electroencephalogram mean cycle frequency. (4)(5)(6)(21)(22)(23)25,26,(28)(29)(30)32,36,(38)(39)(40)(41)(42)48,49,52,54) ...
Unlabelled:
Nonabsorbable disaccharides (NADs) have been used to treat hepatic encephalopathy (HE) since 1966. However, a Cochrane Review, published in 2004, found insufficient evidence to recommend their use in this context. This updated systematic review evaluates the effects of the NADs, lactulose and lactitol, for the treatment and prevention of HE in patients with cirrhosis. Thirty-eight randomized controlled trials, involving 1,828 patients, were identified through electronic and manual searches; 31 randomized controlled trials looked at the treatment of HE, while seven looked at its primary/secondary prevention. Random-effects meta-analyses showed that, compared to placebo/no intervention, NADs had a beneficial effect on HE (relative risk [RR] = 0.63, 95% confidence interval [CI] 0.53-0.74, number needed to treat [NNT] = 4) and serious liver-related adverse events such as liver failure, variceal bleeding, serious infections, spontaneous bacterial peritonitis, and hepatorenal syndrome (RR = 0.42, 95% CI 0.26-0.69, NNT = 50). Treatment was also associated with a reduction in mortality in patients with overt HE (RR = 0.36, 95% CI 0.14-0.94, NNT = 20), although not in patients with minimal HE. Meta-analyses of the prevention randomized controlled trials showed that NADs prevented the development of HE (RR = 0.47, 95% CI 0.33-0.68, NNT = 6), the risk of developing serious liver-related adverse events (RR = 0.48, 95% CI 0.33-0.70, NNT = 6), and reduced mortality (RR = 0.63, 95% CI 0.40-0.98, NNT = 20). Use of NADs was associated with nonserious gastrointestinal adverse events. There were no differences in the efficacy or safety of lactulose and lactitol.
Conclusions:
NADs have beneficial effects in the treatment and prevention of HE; their use, in this context, confers additional benefits including a reduction in serious liver-related morbidities and all-cause mortality. (Hepatology 2016;64:908-922).
... In patients with liver cirrhosis and portosystemic encephalopathy, this action of acarbose partially mimics the effect of lactulose or lactitol. [20] Acarbose has a favorable therapeutic profile for the long-term treatment of patients with type 2 diabetes and liver cirrhosis. ...
... Diabetes itself is associated with a 30% increase in colon cancer risk. [20] Holt et al. [22] suggest that the observed changes in bacterial flora, decreased stool pH and β-hydroxybutyrate seen with acarbose treatment are associated with antiproliferative effects in colonic epithelial cells that may potentially decrease the risk of carcinogenesis. Definite evidence of risk alteration has not yet been established; any inherent antiproliferative benefits of acarbose are unlikely to emerge for at least 10 years. ...
Alpha-glucosidase inhibitors are a class of drugs used in the treatment of type 2 diabetes mellitus, which act by inhibiting alpha-glucosidase enzyme, thereby delaying absorption of complex carbohydrates and lowering postprandial glucose peaks. Of the three alpha-glucosidase inhibitors that exist, acarbose was the first that was developed, and is the most prescribed. It delays absorption of monosaccharides after a meal. Its activity is reliable and persistent with long-term use, and there are no reports that indicate a possibility of acarbose failure. Voglibose, which was developed after acarbose, has similar pharmacology and comparable action, at a lower dose. Miglitol differs from the other alpha-glucosidase inhibitors in its pharmacology, where it is completely absorbed from the intestine, but also has postprandial glucose lowering effect. All alpha-glucosidase inhibitors have reported similar adverse events, generally gastrointestinal in nature. They are indicated for use in type 2 diabetes and have proven efficacy both in monotherapy and when taken with other oral anti-diabetic agents.
... Ammonia plays a key role in the pathogenesis of MHE (23)(24)(25)(26)(27) . Various treatment modalities have been tried for MHE, including dietary protein manipulation (29) , branched-chain amino acids (30,31) , lactu-lose (32)(33)(34)(35)(36)(37) , flumazenil (38) , L-ornithine Laspartate (39) , acetyl Lcarnitine (40) , and probiotics/synbiotics (41)(42)(43) . A majority of these attempts were aimed at reducing blood ammonia level, and most studies have shown improvement in psychometric measurements, ammonia levels, cerebral edema and HRQoL. ...
... Few studies used psychometric tests in assessment of response to treatment with lactulose (35) , because there are no data validating their use in a serial longitudinal manner, also age, education, and learning effects may adversely affect the results. Similarly, some studies used methods like brain stem auditory evoked potential and P300ERP to assess recovery from MHE (33,34,37) . Though these tests are more objective and do not show learning effects, they are expensive, difficult to perform and cannot be done at the bedside without trained personnel and standardization (36) . ...
... [15][16][17][18][19][20][21][22][23] Of these, five evaluated the effect of lactulose, 19-23 two of synbiotics 15,16 and two of probiotics 17, 18 on MHE. Eight potentially relevant trials were identified which used lactitol, however, they were excluded either because comparison was not with a placebo, but with an antibiotic 24,25 or different doses of lactitol, 26 or lactulose [27][28][29][30][31] or included patients with OHE. 31 Four controlled trials with lactulose were excluded because either they did not report the outcome of interest (number of patients that improved or worsened with treatment 32 but only mean change in the psychometric tests) or involved patients with OHE 33 or were not placebo controlled (compared with fructo-oligosaccharides 34 ) or was not an RCT. 35 Similarly, search with fibre yielded a study with acarbose 36 in low grade hepatic encephalopathy that was excluded from our review as it did not report the outcomes of interest. ...
... Eight potentially relevant trials were identified which used lactitol, however, they were excluded either because comparison was not with a placebo, but with an antibiotic 24,25 or different doses of lactitol, 26 or lactulose [27][28][29][30][31] or included patients with OHE. 31 Four controlled trials with lactulose were excluded because either they did not report the outcome of interest (number of patients that improved or worsened with treatment 32 but only mean change in the psychometric tests) or involved patients with OHE 33 or were not placebo controlled (compared with fructo-oligosaccharides 34 ) or was not an RCT. 35 Similarly, search with fibre yielded a study with acarbose 36 in low grade hepatic encephalopathy that was excluded from our review as it did not report the outcomes of interest. ...
Minimal hepatic encephalopathy (MHE) is characterised by subtle neurocognitive deficits without overt clinical manifestations. Although several trials have individually evaluated the role of prebiotics, probiotics and synbiotics, there is yet no consensus on the management of MHE.
To estimate the efficacy of prebiotics, probiotics and synbiotics in MHE in randomised controlled trials.
MEDLINE, EMBASE, CINAHL and the Cochrane Database of Systematic Reviews were searched for published studies in all languages. Inclusion and exclusion criteria were defined a priori. Pooled relative risk and heterogeneity were estimated as the measures of association.
Nine studies met our inclusion criteria. Use of prebiotics, probiotics and synbiotics significantly reduced the pooled relative risk (RR) of no improvement of MHE (RR 0.40, 95% CI 0.32-0.50; P<0.001). Upon subgroup analysis, five studies with lactulose showed significant reduction of risk of no improvement of MHE (RR 0.34, 95% CI 0.24-0.47; P<0.0001) with no inter-trial heterogeneity. In two trials each of probiotics and synbiotics, their use was associated with significant beneficial effects (RR 0.41, 95% CI 0.26-0.65; P<0.0001 and RR of 0.51, 95% CI 0.32-0.80; P=0.004 respectively). There were no major adverse events though probiotics and synbiotics were better tolerated than lactulose.
The use of prebiotics, probiotics and synbiotics was associated with significant improvement in minimal hepatic encephalopathy. Among individual agents, lactulose appears to have the most beneficial effect, followed closely by probiotics and synbiotics.
... Other studies came to the same conclusions regarding the efficacy of lactulose therapy [72]. Luo et al. found that lactulose therapy was superior to a placebo in all outcomes considered; in fact, it reduced the mean number of abnormal neuropsychological tests, time taken to complete the NCT-A (number connection test A), ammonium levels and risk of developing OHE, while improving quality of life [73]. ...
Minimal hepatic encephalopathy (MHE) is a frequent complication of hepatic encephalopathy (HE) and can affect up to 80% of patients with liver cirrhosis. It is characterized by the lack of obvious clinical signs and the presence of alterations detectable using psychometric or electrophysiological testing focused on attention, working memory, psychomotor speed and visuospatial ability. Ideally, each patient should be tested for this condition because, despite the absence of symptoms, it has severe repercussions on daily life activities. It may be responsible for an inability to drive, sleep disturbances, risk of falls and inability to work. Some studies have highlighted its prognostically unfavorable role on mortality and risk of “overt” HE (OHE). Finally, MHE severely affects the lives of patients and caregivers, altering their quality of life and their socioeconomic status. Several treatments have been proposed for MHE treatment, including non-absorbable disaccharides, poorly absorbable antibiotics, such as rifaximin, probiotics and branched-chain amino acids, with promising results. For this reason, early diagnosis and intervention with appropriate measures is essential, with the aim of improving both performance on psychometric tests, as well as clinical aspects related to this condition.
... Numerous studies have evaluated lactulose in the treatment of minimal HE, overt HE, and as a secondary prophylactic measure in patients with cirrhosis, confirming its efficacy and safety. 30---33 Clinical trials have shown that lactitol is better-tolerated and is just as efficacious as lactulose for the treatment of HE. 34,35 No significant difference has been found with respect to improving HE grade in the comparison of nonabsorbable antibiotics (rifaximin) versus nonabsorbable disaccharides (lactitol and/or lactulose). 23,25,27 Probiotics are mixtures of beneficial bacteria that are believed to aid in the treatment of HE by modulating the microbiome. ...
Understanding of the pathophysiology of hepatic encephalopathy has conditioned new treatment options. Ammonia detoxification in hepatic encephalopathy is regulated by two enzymes: glutaminase or glutamine synthetase. The first produces ammonia and the second detoxifies the ammonia, which is why treatments are aimed at glutaminase inhibition or glutamine synthetase activation. At present, we know that both enzymes are found not only in the liver, but also in the muscle, intestine, kidney, and brain. Therefore, current treatments can be directed at each enzyme at different sites. Awareness of those potential treatment sites makes different options of approach possible in the patient with hepatic encephalopathy, and each approach should be personalized.
... Múltiples estudios han evaluado la lactulosa con relación al tratamiento de la EH mínima, EH manifiesta y como medida de profilaxis secundaria en pacientes con cirrosis, confirmando su eficacia y seguridad [30][31][32][33] . En los ensayos clínicos se ha visto que el lactitol es mejor tolerado y ha demostrado ser igual de eficaz que la lactulosa para el tratamiento de la EH 34,35 . A la hora de comparar la utilización de antibióticos no absorbibles (rifaximina) versus disacáridos no absorbibles (lactitol y/o lactulosa) con miras a mejorar el grado de EH, se ha reportado que no existe diferencia significativa 23,25,27 . ...
Understanding of the pathophysiology of hepatic encephalopathy has conditioned new treatment options. Ammonia detoxification in hepatic encephalopathy is regulated by two enzymes: glutaminase or glutamine synthetase. The first produces ammonia and the second detoxifies the ammonia, which is why treatments are aimed at glutaminase inhibition or glutamine synthetase activation. At present, we know that both enzymes are found not only in the liver, but also in the muscle, intestine, kidney, and brain. Therefore, current treatments can be directed at each enzyme at different sites. Awareness of those potential treatment sites makes different options of approach possible in the patient with hepatic encephalopathy, and each approach should be personalized.
Copyright © 2019 Asociación Mexicana de Gastroenterología. Publicado por Masson Doyma México S.A. All rights reserved.
... At the end of two months, patients followed a washout period of 2-2.5 months and subsequently they started to follow the second treatment period, similar to before. It was, however, reported that there were no significant differences in clinical status, psychometric test performance and in electroencephalogram mean cycle frequency during treatment with either lactulose or lactitol, although there were overall improvements observed in the number connection test time, digit symbol score and digit copying score with the treatment of both lactulose and lactitol [172]. Similar types of result were reported by Heredia et al. [173]. ...
Lactose-derived prebiotics provide wide ranges of gastrointestinal comforts. In this review article, the probable biochemical mechanisms through which lactose-derived prebiotics offer positive gastrointestinal health are reported along with the up-to-date results of clinical investigations; this might be the first review article of its kind, to the best of our knowledge. Lactose-derived prebiotics have unique biological and functional values, and they are confirmed as ‘safe’ by the Food and Drug Administration federal agency. Medical practitioners frequently recommend them as therapeutics as a pure form or combined with dairy-based products (yoghurt, milk and infant formulas) or fruit juices. The biological activities of lactose-derived prebiotics are expressed in the presence of gut microflora, mainly probiotics (Lactobacillus spp. in the small intestine and Bifidobacterium spp. in the large intestine). Clinical investigations reveal that galacto-oligosaccharide reduces the risks of several types of diarrhea (traveler’s diarrhea, osmotic diarrhea and Clostridium difficile associated relapsing diarrhea). Lactulose and lactosucrose prevent inflammatory bowel diseases (Crohn’s disease and ulcerative colitis). Lactulose and lactitol reduce the risk of hepatic encephalopathy. Furthermore, lactulose, galacto-oligosaccharide and lactitol prevent constipation in individuals of all ages. It is expected that the present review article will receive great attention from medical practitioners and food technologists.
... With regards to HE, therapy was shown to be effective in treating patients with HE and preventing the development of HE. Nine randomized clinical trials compared lactulose with lactitol, finding similar efficacy in both, [28][29][30] with one trial noting patients on lactitol responded more quickly 31 and another noting better palatability. 32 A 2013 study by Sharma et al investigated the use of rifaximin in a double-blind, randomized controlled trial of 120 patients with OHE. ...
Hepatic encephalopathy (HE) is a complex disease requiring a multidisciplinary approach among specialists, primary care team, family, and caregivers. HE is currently a diagnosis of exclusion, requiring an extensive workup to exclude other possible etiologies, including mental status changes, metabolic, infectious, traumatic, and iatrogenic causes. The categorization of HE encompasses a continuum, varying from the clinically silent minimal HE (MHE), which is only detectable using psychometric tests, to overt HE, which is further divided into four grades of severity. While there has been an increased effort to create fast and reliable methods for the detection of MHE, screening is still underperformed due to the lack of standardization and efficient methods of diagnosis. The management of HE requires consultation from various disciplines, including hepatology, primary care physicians, neurology, psychiatry, dietician/nutritionist, social workers, and other medical and surgical subspecialties based on clinical presentation and clear communication among these disciplines to best manage patients with HE throughout their course. The first-line therapy for HE is lactulose with or without rifaximin. Following the initial episode of overt HE, secondary prophylaxis with lactulose and/or rifaximin is indicated with the goal to prevent recurrent episodes and improve quality of life. Recent studies have demonstrated the negative impact of MHE on quality of life and clinical outcomes. In light of all this, we emphasize the importance of screening and treating MHE in patients with liver cirrhosis, particularly through a multidisciplinary team approach.
... Therefore, lactulose was deemed to be effective in the primary prevention of overt hepatic encephalopathy. 25 Congruent with prior results, several other studies have reported an improvement in neuropsychometric tests with various doses and durations of lactulose and lactitol treatment [25][26][27][28][29][30] (Table 1). ...
Hepatic encephalopathy is a reversible progressive neuropsychiatric disorder that encompasses a wide clinical spectrum. Covert hepatic encephalopathy is defined as patients with minimal hepatic encephalopathy and Grade I encephalopathy by West-Haven Criteria. Terminology such as “sub-clinical”, “latent”, and “minimal” appear to trivialize the disease and have been replaced by the term covert. The lack of clinical signs means that covert hepatic encephalopathy is rarely recognized or treated outside of clinical trials with options for therapy based on patients with episodic hepatic encephalopathy. This review discusses the current available options for therapy in covert hepatic encephalopathy and focuses on non-absorbable disacharides (lactulose or lactitol), antibiotics (rifaximin), probiotics/synbiotics and l-ornithine-l-aspartate.
... In healthy non-constipated Japanese adults, the maximum permissive dose of lactitol that did not cause transitory diarrhoea was determined to be 0.36 g/kg body weight (Oku et al. 2005). A single dose of 8 g appears to be tolerated well by most subjects (Morgan et al. 1989), and in Western adults doses up to 40 g/day can be tolerated without side effects (Blanc et al. 1992). The relatively good tolerance for lactitol compared to the chemically similar lactulose may be due to a slower fermentation rate (Minekus et al. 1999). ...
Lactitol is a sweet-tasting sugar alcohol and may be used as a functional ingredient in a variety of food products to replace sucrose. Having similar technical and physico-chemical properties as sucrose, lactitol is included in foods for the reduction of caloric value and glycaemic response. Lactitol is also used in oral health products where it can help to reduce the risk of dental caries, and it has been suggested as an alternative in the treatment of hepatic encephalopathy. With regard to digestive health, the shortening of intestinal transit time following lactitol consumption has been reported consistently. In addition, lactitol may fulfil the scientific criteria required for prebiotic classification and can hence be described as an emerging prebiotic. The scientific evidence for the selective increase in lactobacilli and bifidobacteria following lactitol consumption looks promising. However, additional research using molecular techniques is needed to confirm lactitol's status as a prebiotic.
... Lactulose is widely used as a standard medicine to evaluate the effect of new drug for HE[30]. Besides, Lactitol is also well practiced for HE therapy with comparable effect to lactulose, but with better tolerance[31,32]. Although Neomycin is effective for HE patients, long-term usage is prohibited for its toxicity[33,34]. ...
In spite of the impressive progress in the investigation of hepatic encephalopathy (HE), the complex mechanisms underlying the onset and deterioration of HE are still not fully understood. Currently, none of the existing theories provide conclusive explanations on the symptoms that link liver dysfunction to nervous system disorders and clinical manifestations. This paper summarized the diagnostic and therapeutic approaches used for HE in modern medicine and traditional Chinese medicine and provided future perspective in HE therapies from the viewpoint of holistic and personalized Chinese medicine.
... This most likely relates to the relatively high fibre intake in this population. In this respect, it is also important to note that no side-effects were experienced, although this has been reported for lactitol (27) . While not specifically investigated, it was interesting that a number of subjects from the synbiotic group enquired whether and where the product could be purchased as it made them 'feel good'. ...
With increasing age, a number of physiological changes take place which are reflected in immune and bowel function. These changes may relate to the commonly assumed age-related changes in intestinal microbiota; most noticeably a reduction in bifidobacteria. The current study aimed at modifying the intestinal microbiota with a potential synbiotic on selected immune and microbiota markers. Healthy elderly subjects were randomised to consume during 2 weeks either a placebo (sucrose) or a combination of lactitol and Lactobacillus acidophilus NCFM twice daily in a double-blind parallel trial. After the intervention, stool frequency was higher in the synbiotic group than in the placebo group and a significant increase in faecal L. acidophilus NCFM levels was observed in the synbiotic group, after baseline correction. In contrast to the generally held opinion, the study subjects had faecal Bifidobacterium levels that were similar to those reported in healthy young adults. These levels were, nevertheless, significantly increased by the intervention. Levels of SCFA were not changed significantly. Of the measured immune markers, PGE2 levels were different between treatments and IgA levels changed over time. These changes were modest which may relate to the fact that the volunteers were healthy. Spermidine levels changed over time which may suggest an improved mucosal integrity and intestinal motility. The results suggest that consumption of lactitol combined with L. acidophilus NCFM twice daily may improve some markers of the intestinal microbiota composition and mucosal functions.
The EASL Clinical Practice Guidelines (CPGs) on the management of hepatic encephalopathy (HE) present evidence-based answers to a set of relevant questions (where possible, formulated in PICO [patient/population, intervention, comparison and outcomes] format) on the definition, diagnosis, differential diagnosis and treatment of HE. The document does not cover the pathophysiology of HE and does not cover all available treatment options. The methods through which it was developed and any information relevant to its interpretation are also provided.
The liver failure induced encephalopathy is commonly referred as hepatic encephalopathy (HE). For many
decades, scientists have tried to describe the symptoms of this disorder revealing a spectrum with different types
of HE. Studies on the mechanisms underlying the pathogenesis of HE have implicated several factors, mainly
neurotoxins, including ammonia, manganese, in addition to changes in various physiological factors, especially an
imbalance between true and false neurotransmitters, as well as the involvement of various pro-inflammatory
mediators. Such changes impact on the brain, which promote disorders in glia and neurons. This review focuses
on the most relevant basic pathophysiologic mechanisms associated with HE.
Keywords: Hepatic Encephalopathy, Pathophysiology, Liver Failure, Ammonia
Minimal hepatic encephalopathy (MHE) corresponds to the earliest stage of
hepatic encephalopathy (HE). MHE does not present clinically detectable
neurological-psychiatric abnormalities but is characterized by imperceptible
neurocognitive alterations detected during routine clinical examination via
neuropsychological or psychometrical tests. MHE may affect daily activities and
reduce job performance and quality of life. MHE can increase the risk of accidents
and may develop into overt encephalopathy, worsening the prognosis of patients
with liver cirrhosis. Despite a lack of consensus on the therapeutic indication,
interest in finding novel strategies for prevention or reversion has led to
numerous clinical trials; their results are the main objective of this review. Many
studies address the treatment of MHE, which is mainly based on the strategies
and previous management of overt HE. Current alternatives for the management
of MHE include measures to maintain nutritional status while avoiding
sarcopenia, and manipulation of intestinal microbiota with non-absorbable
disaccharides such as lactulose, antibiotics such as rifaximin, and administration
of different probiotics. This review analyzes the results of clinical studies that
evaluated the effects of different treatments for MHE.
Normal neuropsychiatric performance in cirrhosis has been traditionally defined by the absence of any degree of hepatic encephalopathy (HE) and/or the absence of psychometric or neurophysiological abnormalities, by comparison with reference data from the healthy population. It is our impression that as our understanding and management of end-stage liver disease continues to change, the concept of normal neuropsychiatric performance may also need updating. This review explores novel and possibly more pragmatic interpretations of neuropsychiatric “normality” by comparison with top personal performance, in terms of risk of overt HE/brain failure and in relation with events such as liver transplantation, decompensation, acute-on-chronic liver failure (ACLF) and Transjugular Intrahepatic Portal-systemic Shunt (TIPS) placement.
Hepatic encephalopathy (HE) is a challenging clinical complication of liver dysfunction with a wide spectrum of neuropsychiatric abnormalities that range from mild disturbances in cognitive function and consciousness to coma and death. The uncertainties on the pathogenesis of HE limit the development of specific pharmacological therapies but a key role is thought to be played by circulating gut-derived toxins of the nitrogenous compounds, most notably ammonia. Management of HE primarily involves avoidance of precipitating factors and administration of various ammonia-lowering therapies such as nonabsorbable disaccharides and select antimicrobial agents mostly rifaximin. The nonabsorbable disaccharides include lactulose and lactitol. Nonabsorbable disaccharides are considered the first-line therapy for treatment of acute HE, and improvement in symptoms occurs in 67–87%. Lactitol is comparable to lactulose in the treatment of HE with fewer side effects. Lactulose has also shown to be effective in primary and secondary prophylaxis of HE. Lactulose significantly improves cognitive function and health-related quality of life in patients with minimal hepatic encephalopathy. In a systematic review, the efficacy of nonabsorbable disaccharides was compared with either no intervention or placebo; the overall treatment effect was modest but statistically significant, with a relative risk of no improvement ranging from 0.62 to 0.92.82. There is insufficient evidence to support or refute the use of nonabsorbable disaccharides for HE.
Background:
Non-absorbable disaccharides (lactulose and lactitol) are recommended as first-line treatment for hepatic encephalopathy. The previous (second) version of this review included 10 randomised clinical trials (RCTs) evaluating non-absorbable disaccharides versus placebo/no intervention and eight RCTs evaluating lactulose versus lactitol for people with cirrhosis and hepatic encephalopathy. The review found no evidence to either support or refute the use of the non-absorbable disaccharides and no differences between lactulose versus lactitol.
Objectives:
To assess the beneficial and harmful effects of i) non-absorbable disaccharides versus placebo/no intervention and ii) lactulose versus lactitol in people with cirrhosis and hepatic encephalopathy.
Search methods:
We carried out electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 10), MEDLINE, EMBASE, and Science Citation Index Expanded to 19 October 2015; manual searches of meetings and conference proceedings; checks of bibliographies; and correspondence with investigators and pharmaceutical companies.
Selection criteria:
We included RCTs, irrespective of publication status, language, or blinding.
Data collection and analysis:
Two review authors, working independently, retrieved data from published reports and correspondence with investigators. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We presented the results of meta-analyses as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the quality of the evidence using 'Grading of Recommendations Assessment Development and Evaluation' (GRADE) and bias control using the Cochrane Hepato-Biliary Group domains. Our analyses included regression analyses of publication bias and other small study effects, Trial Sequential Analyses to detect type 1 and type 2 errors, and subgroup and sensitivity analyses.
Main results:
We included 38 RCTs with a total of 1828 participants. Eight RCTs had a low risk of bias in the assessment of mortality. All trials had a high risk of bias in the assessment of the remaining outcomes. Random-effects meta-analysis showed a beneficial effect of non-absorbable disaccharides versus placebo/no intervention on mortality when including all RCTs with extractable data (RR 0.59, 95% CI 0.40 to 0.87; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence) and in the eight RCTs with a low risk of bias (RR 0.63, 95% CI 0.41 to 0.97; 705 participants). The Trial Sequential Analysis with the relative risk reduction (RRR) reduced to 30% confirmed the findings when including all RCTs, but not when including only RCTs with a low risk of bias or when we reduced the RRR to 22%. Compared with placebo/no intervention, the non-absorbable disaccharides were associated with beneficial effects on hepatic encephalopathy (RR 0.58, 95% CI 0.50 to 0.69; 1415 participants; 22 RCTs; I(2) = 32%; moderate quality evidence). Additional analyses showed that non-absorbable disaccharides can help to reduce serious adverse events associated with the underlying liver disease including liver failure, hepatorenal syndrome, and variceal bleeding (RR 0.47, 95% CI 0.36 to 0.60; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence). We confirmed the results in Trial Sequential Analysis. Tests for subgroup differences showed no statistical differences between RCTs evaluating prevention, overt, or minimal hepatic encephalopathy. The evaluation of secondary outcomes showed a potential beneficial effect of the non-absorbable disaccharides on quality of life, but we were not able to include the data in an overall meta-analysis (very low quality evidence). Non-absorbable disaccharides were associated with non-serious (mainly gastrointestinal) adverse events (very low quality evidence). None of the RCTs comparing lactulose versus lactitol evaluated quality of life. The review found no differences between lactulose and lactitol for the remaining outcomes (very low quality evidence).
Authors' conclusions:
This review includes a large number of RCTs evaluating the prevention or treatment of hepatic encephalopathy. The analyses found evidence that non-absorbable disaccharides may be associated with a beneficial effect on clinically relevant outcomes compared with placebo/no intervention.
Background:
Non-absorbable disaccharides (lactulose and lactitol) are recommended as first-line treatment for hepatic encephalopathy. The previous (second) version of this review included 10 randomised clinical trials (RCTs) evaluating non-absorbable disaccharides versus placebo/no intervention and eight RCTs evaluating lactulose versus lactitol for people with cirrhosis and hepatic encephalopathy. The review found no evidence to either support or refute the use of the non-absorbable disaccharides and no differences between lactulose versus lactitol.
Objectives:
To assess the beneficial and harmful effects of i) non-absorbable disaccharides versus placebo/no intervention and ii) lactulose versus lactitol in people with cirrhosis and hepatic encephalopathy.
Search methods:
We carried out electronic searches of the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 10), MEDLINE, EMBASE, and Science Citation Index Expanded to 19 October 2015; manual searches of meetings and conference proceedings; checks of bibliographies; and correspondence with investigators and pharmaceutical companies.
Selection criteria:
We included RCTs, irrespective of publication status, language, or blinding.
Data collection and analysis:
Two review authors, working independently, retrieved data from published reports and correspondence with investigators. The primary outcomes were mortality, hepatic encephalopathy, and serious adverse events. We presented the results of meta-analyses as risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CI). We assessed the quality of the evidence using 'Grading of Recommendations Assessment Development and Evaluation' (GRADE) and bias control using the Cochrane Hepato-Biliary Group domains. Our analyses included regression analyses of publication bias and other small study effects, Trial Sequential Analyses to detect type 1 and type 2 errors, and subgroup and sensitivity analyses.
Main results:
We included 38 RCTs with a total of 1828 participants. Eight RCTs had a low risk of bias in the assessment of mortality. All trials had a high risk of bias in the assessment of the remaining outcomes. Random-effects meta-analysis showed a beneficial effect of non-absorbable disaccharides versus placebo/no intervention on mortality when including all RCTs with extractable data (RR 0.59, 95% CI 0.40 to 0.87; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence) and in the eight RCTs with a low risk of bias (RR 0.63, 95% CI 0.41 to 0.97; 705 participants). The Trial Sequential Analysis with the relative risk reduction (RRR) reduced to 30% confirmed the findings when including all RCTs, but not when including only RCTs with a low risk of bias or when we reduced the RRR to 22%. Compared with placebo/no intervention, the non-absorbable disaccharides were associated with beneficial effects on hepatic encephalopathy (RR 0.58, 95% CI 0.50 to 0.69; 1415 participants; 22 RCTs; I(2) = 32%; moderate quality evidence). Additional analyses showed that non-absorbable disaccharides can help to reduce serious adverse events associated with the underlying liver disease including liver failure, hepatorenal syndrome, and variceal bleeding (RR 0.47, 95% CI 0.36 to 0.60; 1487 participants; 24 RCTs; I(2) = 0%; moderate quality evidence). We confirmed the results in Trial Sequential Analysis. Tests for subgroup differences showed no statistical differences between RCTs evaluating prevention, overt, or minimal hepatic encephalopathy. The evaluation of secondary outcomes showed a potential beneficial effect of the non-absorbable disaccharides on quality of life, but we were not able to include the data in an overall meta-analysis (very low quality evidence). Non-absorbable disaccharides were associated with non-serious (mainly gastrointestinal) adverse events (very low quality evidence). None of the RCTs comparing lactulose versus lactitol evaluated quality of life. The review found no differences between lactulose and lactitol for the remaining outcomes (very low quality evidence).
Authors' conclusions:
This review includes a large number of RCTs evaluating the prevention or treatment of hepatic encephalopathy. The analyses found evidence that non-absorbable disaccharides may be associated with a beneficial effect on clinically relevant outcomes compared with placebo/no intervention.
Heute unterscheidet man mindestens 5 Erreger einer akuten Virushepatitis, die Viren A, B, C, D und E. Neben diesen primär hepatotropen Viren gibt es noch andere Virusinfektionen, die mit einer Hepatitis einhergehen können, wie z.B. Infektionen mit Epstein-Barr-Virus (EBV), Zytomegalievirus (CMV), Herpes-simplex-Virus, Coxsackie-Virus.
Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome characterized by global CNS dysfunction reSUlting in impaired consciousness and coma. The association of the syndrome with acute or chronic liver failure implicates a plethora of metabolic abnormalities and gut-derived toxins in its pathogenesis. Thus, it is difficult to ascribe the neurological and psychiatric manifestations of HE to the presence of a single agent or changes in a particular metabolic pathway. The manifestations of HE are determined by two principle components of the underlying liver disease: hepatocellular failure and systemic shunting of portal venous contents (BASILE et al. 1991 b). Significant portal venous shunting is often found in chronic liver disease. HE occurs most frequently in this setting, where it is a milder, more persistent and episodic variant of the syndrome. In contrast, fulminant hepatic failure (FHF) has no vascular component. HE associated with FHF shows an acute onset with delirium progressing to deep coma. While delirium and seizures are generally uncommon in HE, they may occur during the rapid evolution of HE due to FHF (PAPPAS 1986). Although some of the characteristics of HE associated with acute or chronic liver failure result from fundamental differences in the mechanism of pathogenesis, many findings regarding the pathogenesis and treatment of the syndrome are held in common. Finally, it is important to recognize that while many of the animal models of liver failure used in research emphasize one or the other component of liver failure, most clinical cases tend to have a mixture of both. Although a single, perfect animal model of this syndrome does not exist, the animal models in use have nonetheless provided valuahle insights into the pathogenesis of HE and allowed for the testing of new therapeutic modalities.
Fulminant hepatic failure may occur suddenly in the course of various liver diseases with viral hepatitis as the most common cause [17]:
Viral hepatitis (A, B, C, herpes simplex)
Drugs (paracetamol)
Alcohol abuse
Anesthetics (halothane)
Toxins (Amanita mushrooms, CCl4
Fatty liver of pregnancy
Others (Wilson’s disease, Budd-Chiari syndrome, lymphoma)
Die obere gastrointestinale Blutung äußert sich meist in Form der Leitsymptome Hämatemesis und/oder Meläna. Besonders starke Blutungen können auch zum peranalen Abgang roten Blutes (Hämatochezie) führen. Mehr als 80% aller Blutungsquellen sind im oberen Gastrointestinaltrakt lokalisiert. Pro Jahr werden etwa 100 Patienten/100000 Einwohner mit akuter Gastrointestinalblutung notfallmäßig hospitalisiert. Ätiologisch spielt die Einnahme nicht-steroidaler Antiphlogistika zunehmend eine Rolle. Auch Antikoagulanzien können zur Blutung führen. Bei peptischen Ulzera oder Angiodysplasien ist vor allem die Veranlagung des Patienten ursächlich relevant. Die Letalität bei gastrointestinaler Blutung ist mit 8–10% nach wie vor hoch und läßt sich nur durch eine Optimierung der diagnostisch-therapeutischen Entscheidungssequenz reduzieren.
Portal-systemic encephalopathy (PSE) is usually a complication of late and advanced liver disease. It may present either as insidious and slow deterioration in mental function or with variable waxing and waning severity. Alternatively acute exacerbations including frank coma may follow complications of cirrhosis or ill-advised therapy. Since several moderately effective methods of treatment are now available, it is important to look for PSE in every patient with advanced chronic liver disease, particularly if precipitating causes may be present. It should be ensured that such patients are adequately cared for. PSE may be diagnosed if a patient has chronic liver disease and a mental disturbance. Hyperammonemia may be regarded as confirmatory. Other causes of cerebral dysfunction, particularly metabolic encephalopathies (Table 1) and neurologic diseases, must be excluded in every case.
Oral antidiabetic drugs are becoming increasingly important as rates of type 2 diabetes, uncontrolled by dietary intervention alone, increase around the world. Therapeutic agents that target the early stages of type 2 diabetes, such as the α-glucosidase enzyme inhibitor acarbose, which reduces postprandial hyperglycaemia and hyperinsulinaemia, now have a more prominent role to play in diabetes management in view of increasing evidence that the postprandial state is an important contributing factor to the development of atherosclerosis.
This review provides an update on the role of acarbose in present-day diabetes care. Acarbose is a first-line treatment for newly diagnosed patients with type 2 diabetes, those who have high postprandial blood glucose and for patients where dietary treatment alone provides inadequate glycaemic control. Acarbose lowers blood glucose when administered as monotherapy and in combination with other oral antidiabetic drugs. It reliably reduces levels of glycated haemoglobin (HbA1c) and also increases insulin sensitivity; however, unlike insulin and the sulphonylureas, acarbose has not been associated with bodyweight gain.
The aim of this review is to present clinical data on the pharmacology and efficacy of acarbose in the treatment of patients with type 2 diabetes mellitus. It is not intended to present a comprehensive review of the treatment of diabetes mellitus in general.
Covert hepatic encephalopathy is a common problem in cirrhosis, affecting up to 80% of patients. It is defined as test-dependent brain dysfunction with clinical consequences in the setting of cirrhosis in patients who are not disoriented. Because it is not apparent clinically, and diagnostic testing has not been standardized, the issue has often been ignored in clinical practice. Yet, the clinical consequences are notable, including impaired quality of life, diminished work productivity, and poor driving skills.
Major complications of cirrhosis include the development of ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, variceal hemorrhage, hepatic encephalopathy, and hepatocellular carcinoma. Careful evaluation and management of ascites and varices with judicious use of prophylactic therapy can improve survival. Diagnosis of hepatic encephalopathy can lead to appropriate intervention without protein restriction. Patients should undergo hepatocellular carcinoma surveillance routinely every 6 months. The development of any decompensating event should prompt referral to a liver transplant center.
Background:
Hepatic encephalopathy (HE), which may be categorized as minimal or overt, is a serious and progressive neuropsychiatric condition that occurs in patients with liver disease or portosystemic shunting. Overt HE (OHE) presents as a wide spectrum of clinical signs and symptoms, ranging in severity from mild confusion to life-threatening coma. Minimal HE (MHE) is a more subtle form of the condition; it is characterized by deficits in cognitive function in patients with a normal clinical examination.
Objective:
The purpose was to review the effect of MHE on patients and caregivers, as well as its currently available diagnostic and treatment options.
Methods:
A MEDLINE search of published diagnostic assessments, clinical trials, and guidelines from 1985 to 2012 were reviewed and analyzed to assess the potential effect of MHE in the clinical practice setting.
Results:
Accumulating evidence suggests that MHE has a substantial negative effect on patient quality of life, particularly in activities that require attention, motor skills, and visuospatial ability. Because MHE lacks obvious clinical signs, specialized testing is required for diagnosis, although there is no consensus on the most appropriate assessment tools or treatment algorithms. Compounds derived from bacterial activities in the gut can cause neurochemical changes in the brain. These gut-derived toxins (eg, ammonia, benzodiazepine-like substances) are implicated in the pathophysiology of OHE. In patients with liver disease or portosystemic shunting, these toxins are inefficiently detoxified, accumulate in the blood, cross the blood-brain barrier, and result in abnormalities such as altered neurotransmission, astrocyte swelling, and impaired energy metabolism. Therefore, treatments have focused on toxin removal and the management of gut flora levels. Several studies have indicated that probiotics, nonabsorbable disaccharides, and nonsystemic antibiotics can all be effective in improving the symptoms of MHE. Furthermore, prophylaxis for MHE in patients with cirrhosis could serve to improve patient quality of life while preventing its transition to OHE.
Conclusions:
Although MHE detection and treatment is not currently the standard of care, several therapies have been reported to improve cognitive function and quality of life. Interest is increasing in the proactive diagnosis and management of MHE in the clinical practice setting. However, research is required to determine the conditions under which the putative benefits of prophylactic MHE therapy outweigh the costs.
AIM: The aim of the present study was to assess fecal organic acid excretion and gut flora changes in a group of patients with compensated liver cirrhosis without hepatic encephalopathy by comparing probiotic therapy with more common therapeutic approaches.
METHODS: Thirty patients with compensated Child B liver cirrhosis were allocated into one of three matched groups, which were randomly given one of three 3-week oral treatments: (i) lactitol 20 g t.i.d.; (ii) 400 mg rifaximin b.i.d.; or (iii) the synbiotic SCM-III (Microflorana-F, Named, Lesmo, Italy) 10 mL t.i.d. Stool samples were collected at both the time of entry into the study and at the end of the trial period for the assessment of intestinal bacterial flora and for the determination of fecal pH and of organic acid concentration.
RESULTS: All three tested compounds significantly increased the total anaerobic bacterial count to the same extent. The change was mainly due to a reduction in the Bacteriodes population and an expansion of the bifidobacteria population. However, only SCM-III significantly decreased the total count of Bacteroides and Clostridium. Lactitol and SCM-III decreased (to a similar extent) the fecal pH compared with healthy controls and with pretreatment values (P < 0.05). Both lactitol and SCM-III produced a significant increase in the fecal concentration of acetic acid and lactic acid. However, only SCM-III decreased the fecal concentration of toxic short-chain fatty acids.
CONCLUSIONS: In the present clinical study, we confirmed the findings from an in vitro study of enhanced-non-toxic organic acid recovery from stools during treatment with nonabsorbable disaccharides. In the present study, we found that lactitol did not produce any significant effect on Bacteroides and Clostridium, whereas the specific bacterial counts of such species significantly decreased only in the group treated with the synbiotic. These data suggest a potential role of synbiotics in the long term treatment of chronic liver disease.
Background and aim: In this study, the frequency of subclinical hepat- ic encephalopathy in cirrhotic patients was investigated. Methods: Seventy five cirrhotic patients and 75 healthy controls of the same age, sex and education level were included. In order to diagnose subclinical hepatic encephalopathy, the number connection test-A as a psychomet- ric test, and somatosensory evoked potential, visual evoked potential and Brain-stem auditory-evoked potential as electrophsiological tests were used. Electroencephalography and magnetic resonance imaging procedures were performed on each patient. Results: Abnormal results for number connection test-A, somatosensory evoked potential, brain- stem auditory-evoked potantial and visual evoked potential were 23%, 44%, 2.7% and 2.7% respectively. The frequency of abnormality as diagnosed by electroencepholography and magnetic resonance imaging were 5.3% and 32% respectively. The results indicated that subclinical hepatic encephalopathy was potentially present in some cirrhotic patients and that some of them might progress to overt hepatic coma. Conclusions: Periodic follow-up of these patients is necessary due to the negative effects that subclinical hepatic encephalopathy may have on physical tasks such as driving and manual work.
Sugar alcohols are used in food products for specific groups, such as diabetic and obese patients. The aim of this study was to determinate the effect of lactitol on glycemia, and lipid profile. Eighty male rats Sprague- Dawley, divided into four groups, received lactitol through oral catheter at doses of 0.3; 1.0; 5.0 g/kg/day and saline solution during 12 weeks. Before and after the treatment were measured fasting glycemia, triglycerides, total cholesterol, and cholesterol of high, low and very low density lipoproteins. After 12 weeks the highest dose of lactitol (5 g/Kg/día) significantly increased fasting glycemia (91.35±5.1 vs. 124.69±5.7 mg/dl; p
Management of hepatic encephalopathy (HE) primarily involves avoidance of precipitating factors and administration of various ammonia-lowering therapies such as nonabsorbable disaccharides and antimicrobial agents like rifaximin. The nonabsorbable disaccharides which include lactulose and lactitol are considered the first-line therapy for the treatment of HE and minimal hepatic encephalopathy (MHE). Lactulose significantly improves cognitive function and health-related quality of life in patients with MHE. Lactitol is comparable to lactulose in the treatment of HE with fewer side effects. Lactulose has also shown to be effective in primary and secondary prophylaxis of HE. Disaccharides were found to be comparable to rifaximin in recent systemic reviews in the treatment of HE however conclusion was based on inclusion of some poor quality trials. Combination therapy of disaccharides either with rifaximin, L-ornithine L-aspartate,probiotics for the treatment of HE needs further validation in large studies.
In the last decade, a significant amount of research has been devoted to the pathogenesis and treatment of hepatic encephalopathy (HE), Non-invasive neuroimaging techniques such as magnetic resonance imaging and spectroscopy have become important research tools. The search for a suitable animal model of HE associated with cirrhosis is still ongoing, Moreover, consensus terminology and diagnostic criteria for HE in humans are badly needed, Eur J Gastroenterol Hepatol 13:325-334 (C) 2001 Lippincott Williams & Wilkins.
In this preliminary study, we examined the effects of acarbose and placebo together with a standardized breakfast on blood glucose levels, on breath hydrogen excretion and on plasma insulin and glucagon levels, in addition, the effects on fasting blood levels of metabolites were studied following an evening meal with acarbose or placebo. Acarbose significantly reduced blood glucose levels in 10 patients with alcoholic cirrhosis following a meal containing 100 g of carbohydrate. There were no significant changes in plasma insulin after breakfast but glucagon levels were increased at 1 h after the meal. Breath hydrogen excretion did not change significantly. Acarbose given with a late evening snack reduced fasting β-hydroxybutyrate levels the next morning in these cirrhotic patients.
Aim: The aim of this study is to clarify the cerebral functions in patients with chronic hepatitis (CH) as well as those with liver cirrhosis (LC).
Methods: We studied 58 patients with CH (20 in fibrosis stage F1, 20 in F2, 18 in F3), 77 with LC (46 rated as Child–Pugh class A, 24 as B, 7 as C), and 20 healthy volunteers (HV). Computer-aided quantitative neuropsychiatric function test systems, including eight neuropsychiatric tests were performed.
Results: Subjects with results over the cut-off value for healthy subjects ranged from 11.1–28.6% in CH and 19.5–36.4% in LC. The percentages with abnormality in at least one test in CH and LC were 72.4% and 80.6%, respectively, which were significantly higher than that in the HV group (35.0%) (P = 0.003, P = 0.0003, respectively). Among CH subjects, those with three or more abnormal results in the F1, F2 and F3 subgroups were 15.0%, 20.0% and 38.9%, respectively. Among LC subjects, those with three or more abnormal results in the Child–Pugh class A, B and C subgroups comprised 30.4%, 50.0% and 57.1%, respectively. The rate in the CH F3 subgroup (P = 0.011) and in all three LC subgroups (P = 0.023, P = 0.001, P = 0.002, respectively) were significantly higher than that in the HV group.
Conclusion: The percentage of patients with neuropsychiatric function impairment was high in both LC and CH, especially in stage F3. Neuropsychiatric dysfunction may initiate in CH in a considerable number of patients.
Seventy-five cirrhotic patients with hyperammonemia in the past or at the time of the study were randomly divided into two groups (treated with lactulose or nontreated) in 14 hospitals in Japan. Thirty-six cirrhotic patients were diagnosed as having subclinical hepatic encephalopathy (SHE), and 39 were diagnosed as non-SHE. SHE was diagnosed when the results of all three of the quantitative psychometric tests used (number connection test, and symbol digit and block design tests of the Wechsler adult intelligence scale [revised]) were abnormal as compared with age-matched normal values. The mean number of abnormal psychometric test results and the prevalence of SHE were used for a quantitative evaluation of the efficacy of the lactulose treatment. Twenty-two of the SHE patients were treated with lactulose (45 mL/d) for 8 weeks, and the other 14 SHE patients did not receive lactulose. In the SHE patients administered lactulose, the results of the quantitative psychometric evaluation were significantly improved at 4 and 8 weeks after the beginning of the lactulose administration. The SHE had disappeared in 10 (50%) of the 20 treated patients at week 8, but it persisted in 11 (85%) of the untreated 13 patients. We concluded that lactulose treatment in cirrhotic patients with SHE is effective with respect to psychometric tests.
Hepatic encephalopathy is the commonest complication of cirrhosis. It comprises a spectrum of neuropsychiatric abnormalities ranging from subtle changes in cognition to clinically obvious changes in intellect, behaviour, motor function and consciousness. Hepatic encephalopathy has a detrimentally effect on health-related quality of life and on survival. Ammonia plays a key role in the pathogenesis of the syndrome via induction of astrocyte swelling and the development of low-grade cerebral oedema. Oxidative stress, disrupted glial–neuronal communication and neuronal dysfunction ensue. There is no diagnostic gold standard; a combination of clinical examination, psychometric testing and electroencephalography is recommended. Nevertheless, the condition is often undiagnosed and patients left untreated. Newer diagnostic approaches need further validation. Treatment is directed at reducing circulating ammonia, mainly through use of non-absorbable disaccharides/ non-absorbable antibiotics, and is generally effective. Newer treatment approaches, based on recent insights into the pathogenesis, need further appraisal.
The purpose of this study was to correlate the hyperintensity in the globus pallidus seen on T1-weighted magnetic resonance imaging (MRI) of the brain in chronic liver disease with changes in metabolite ratios measured from both proton and phosphorus-31 magnetic resonance spectroscopy (MRS) localised to the basal ganglia. T1-weighted spin echo (T1 WSE) images were obtained in 21 patients with biopsy-proven cirrhosis (nine Child's grade A, eight Child's grade B and four Child's grade C). Four subjects showed no evidence of neuropsychiatric impairment on clinical, psychometric and electrophysiological testing, four showed evidence of subclinical hepatic encephalopathy and 13 had overt hepatic encephalopathy. Signal intensities of the globus pallidus and adjacent brain parenchyma were measured and contrast calculated, which correlated with the severity of the underlying liver disease, when graded according to the Pugh's score (p1WSE MRI contrast measurements of the globus pallidus and the abnormalities in the metabolite ratios measured from either proton or phosphorus-31 MR spectra. Our results suggest that pallidal hyperintensity seen on T1WSE MR imaging of patients with chronic liver disease is not related to the functional abnormalities of the brain observed in hepatic encephalopathy.
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome associated with severe, acute and chronic liver failure. According
to the recommendations of a working party (Ferenci et al., 2002) held at the 4th World Congress of Gastroenterology in Vienna in 1998, 3 types of HE should be differentiated, on principle:
Neuronal and glial cell marker proteins were quantified in order to evaluate the possibility of increased proteolysis in the brain of rabbits with acute liver failure and acute hyperammonemia. Acute liver failure was induced by a two-stage devascularization procedure. Acute hyperammonemia was induced by a prolonged infusion of ammonium acetate, which simulates the plasma ammonia level in acute liver failure. Control animals received an infusion of sodium/potassium acetate. After development of severe encephalopathy, the animals were sacrificed (13.7 1.3 hours for rabbits with acute liver failure and 20.2 0.8 hours for rabbits with hyperammonemia) (x S.E.M./n=6) and their brains were dissected into cerebral cortex, hippocampus, cerebellum and brain stem. The total protein content and the concentrations of the neuronal cell marker proteins NSE (neuron specific enolase), NF68 and NF200 (68 kD and 200 kD neurofilament polypeptides) and the glial cell marker proteins GFAP (glial fibrillary acidic protein) and S-100 were determined. Total protein content was decreased in the brain stem in acute hyperammonemia only. The content of neuronal and glial cell markers was not affected in either of the two conditions. However, low molecular weight proteolytic fragments of the NF 68 kD polypeptide were observed in the hippocampus of three out of six animals in both experimental groups. No proteolytic degradation of GFAP was observed. The results show that, in experimental encephalopathy due to acute liver failure and acute hyperammonemia, no major changes occur in the marker proteins. The finding of proteolytic fragments of the NF68 polypeptide indicates that the neuronal population is affected prior to glial alterations. These findings are in agreement with the concept that acute hepatic encephalopathy is reversible and induces only slight structural changes.
Conventional T1-weighted spin echo (T1WSE) and T1-weighted magnetization transfer (MT) images were obtained in 26 patients with biopsy-proven cirrhosis (nine Child's grade A, 10 Child's grade B and seven Child's grade C). Four subjects showed no evidence of neuropsychiatric impairment on clinical, psychometric and electrophysiological testing, seven showed evidence of subclinical hepatic encephalopathy and 15 were classified as having overt hepatic encephalopathy. Signal intensities of basal ganglia nuclei (head of caudate, putamen, globus pallidus and thalamus) and adjacent brain parenchyma were measured and contrast calculated. On T1WSE imaging, contrast measurements of the globus pallidus were significantly greater in patients with neuropsychiatric dysfunction than in those who were unimpaired (p1WSE contrast measurements of the globus pallidus were increased with elevations in blood ammonia levels (p1WSE pallidal contrast measurements (p
Cirrhotics with minimal hepatic encephalopathy (MHE) have a poor health-related quality of life (HRQOL). Treatment of MHE is still evolving. The aim of this double-blind randomized pilot study was to assess the efficacy of rifaximin in improving neuropsychometric (NP) test performance and HRQOL in patients with MHE.
MHE was diagnosed if any two NP tests (number and figure connection tests, picture completion, digit symbol, and block design tests) were deranged beyond 2 s.d. of normal. HRQOL was assessed using the sickness impact profile (SIP) questionnaire.
A total of 486 patients with cirrhosis were screened and 284 were found eligible. Out of these 115 (40.9%) had MHE, of which 21 refused consent and 94 were randomized to receive placebo (n=45) and rifaximin (n=49; 1200 mg/day) for 8 weeks. At the end of treatment, significantly more number of patients in rifaximin group showed reversal of MHE (75.5% (37/49) vs. 20% (9/45) in placebo group; P<0.0001). Rifaximin group also showed significant reduction in mean number of abnormal NP tests (baseline, 2.35 (95% confidence interval (CI), 2.17-2.53); 2 weeks, 1.29 (95% CI, 1.02-1.56), P=0.002; 8 weeks, 0.81 (95% CI, 0.61-1.02), P=0.000), compared with placebo group (baseline, 2.31 (95% CI, 2.03-2.59); 2 weeks, 2.03 (95% CI, 1.74-2.31); 8 weeks, 1.97 (95% CI, 1.69-2.25), P>0.05). The mean total SIP score also improved significantly in rifaximin group (baseline, 11.67 (95% CI, 10.31-13.03); 8 weeks, 6.45 (95% CI, 5.59-7.30); P=0.000) compared with placebo group (baseline, 9.86 (95% CI, 8.66-11.06); 8 weeks, 8.51 (95% CI, 7.35-9.67); P=0.82). Improvement in HRQOL correlated with improvement in NP tests. Rifaximin was well tolerated.
Rifaximin significantly improves both cognitive functions and HRQOL in patients with MHE.
Lactitol is a disaccharide analogue of lactulose which is available as a pure crystalline powder. The efficacy of lactitol in the treatment of chronic hepatic encephalopathy was assessed in 9 cirrhotic patients in a randomised, double-blind, cross-over comparison with lactulose. The sugars were dispensed in solutions, identical in taste and appearance and with similar physico-chemical properties, which contained either 66.7 g/100 ml of lactitol or 66.7 ml (44.5 g)/100 ml of lactulose syrup. Patients were treated for periods of 3 months with each sugar, during which time they were monitored frequently by use of a number of clinical, psychometric and laboratory variables. The sugar solutions were dispensed in an initial dose of 0.75 ml/kg which was adjusted, as necessary, in order to produce two semi-soft stools per day. An adequate catharsis was achieved with a mean (+/- 1 SD) equivalent daily dose of 31.9 +/- 11.2 g of lactitol or 32.9 +/- 16.7 ml (21.9 +/- 11.1 g) of lactulose syrup. Both sugars were equally as effective in the treatment of this condition, even though events likely to cause decompensation arose in 5 patients during treatment with lactitol but in only 1 during treatment with lactulose. Side effects appeared to be more frequent during treatment with lactulose, despite the fact that the parent sugar was diluted in the trial solution; thus 5 patients experienced excessive flatulence and 8 experienced diarrhoea on lactulose compared with only 2 and 4 on lactitol, respectively. In all cases the excessive flatulence occurred independently of sugar dosage whereas the development of diarrhoea was dose-related.(ABSTRACT TRUNCATED AT 250 WORDS)
Eight stable cirrhotic patients with mild or subclinical portal-systemic encephalopathy (PSE) were studied after shunt surgery when they were off all antiencephalopathic therapy. Equal amounts of mixed proteins were alternated with animal or vegetable protein in a crossover protocol under metabolic conditions for five consecutive, one week periods. The different dietary periods were not associated with either a change in the neurological impairment score or the Trailmaking Tests, which showed a learning effect. The peak frequencies of the computer analysed EEG (CAEEG) were lower during the animal (6.58 +/- 0.42 Hz) than the vegetable (7.10 +/- 0.44 Hz) diet (p 0.01). Neither arterial ammonia levels nor plasma amino acid ratios changed with the diets, whereas urinary 3-methyl-histidine excretion increased during the animal diet. During the vegetable diet the apparent nitrogen balance tended to be more positive than during either the mixed or animal diets associated with decrease in the urinary nitrogen excretion. The peak frequency of the CAEEG is the most sensitive test to monitor methods of treatment in portal-systemic encephalopathy. A vegetable protein diet, rather than overall protein restriction, should be considered in the management of this disorder, particularly when the nutritional state is poor.
The authors thank Dr. M. Török, Medical School Hannover, Institute of Biometrics and Director Professor B. Schneider, Hannover, Federal Republic of Germany, for statistical assistance.
• Psychometric tests were administered to 36 alcoholic patients with cirrhosis without overt portal systemic encephalopathy and to 32 alcoholics without liver disease. Verbal ability was preserved in both groups. The cirrhotic patients scored worse than the alcoholics without liver disease on most of the tests of psychomotor performance. Based on the three most discriminative tests, 50% of the cirrhotic patients had one or more scores that were more abnormal than those of any member of the alcoholic group. Significant correlations were found between the severity of liver disease and most tests of performance in the cirrhotic group, due primarily to the influence of serum albumin as a component of the severity index. We conclude that psychomotor tests are sensitive tools for the detection of latent encephalopathy, and that nutritional status probably plays a role in determining test performance.
(Arch Intern Med 140:519-521, 1980)
The paper revies briefly the principles which should guide the development of automated psychological test systems. These are illustrated by reference to research and development studies undertaken with the Perceptual Maze Test. Building computer models of the way in which subjects might tackle problems can be a fruitful approach to research on human skills. The Perceptual Maze Test is particularly suited to the development of such simulation studies. The possible role of these tests in assessing treatment effects in neurology and psychiatry is discussed and an example of this type of application is presented.
Forty patients with chronic liver disease and portal hypertension but without clinical signs of portasystemic encephalopathy (15 patients with nonalcoholic cirrhosis, 15 patients with alcoholic cirrhosis, and 10 patients with minimal EEG changes) and a control group of 12 patients with chronic alcoholic pancreatitis were studied using an extensive psychometric program, which, in the same form, is used for expert reports on driving capacity. Of the cirrhotic patients, 60% were considered unfit to drive; in 25% driving capacity was questionable, 15% (only nonalcoholic cirrhotics) were considered fit to drive. In contrast 75% of the patients with alcoholic pancreatitis were considered fit to drive. Major defects were found only in three heavy alcoholics. Patients with alcoholic cirrhosis scored lower than patients with nonalcoholic cirrhosis. This was due, to differences in liver function rather than to the effect of alcohol consumption. Patients with minimal EEG changes were practically all considered unfit to drive.
A randomized double blind clinical comparison of neomycin and lactulose was performed in 33 cirrhotic patients with chronic portal-systemic encephalopathy (PSE) at seven cooperating hospitals. In order to maintain double blindness, sorbitol syrup was used as a control solution along with neomycin and was compared with lactulose syrup and placebo tablets in a double drug protocol. Twenty-nine patients were studied in a crossover investigation in which each received both therapeutic regimens preceded and followed by control periods. Four additional patients received one or the other agent, but did not receive both. Serial, semiquantitative assessments were made in all patients of mental status, asterixis, and the trailmaking test (TMT) and electroencephalograms (EEG) and arterial ammonia levels. Both neomycin-sorbitol and lactulose were effective in the majority of patients (83 and 90%, respectively). Each of these parameters (mental state, asterixis, TMT, EEG, and NH3) was improved significantly by neomycin-sorbitol and lactulose. The post-treatment levels for each of these measures were similar in the neomycin and lactulose-treated groups. Mean stool pH was reduced by neomycinsorbitol to 6.1 and by lactulose to 5.5. This difference was highly significant statistically. Bowel activity was similar in the two groups. Both drugs were free of toxicity. These investigations demonstrate that both lactulose and neomycin-sorbitol are effective in the treatment of chronic portal-systemic encephalopathy.
The former Kendrick Battery--the Synonym Learning Test (SLT) and the Digit Copying Test (DCT)--has been revised. The new version comprises the Object Learning Test (OLT) and the DCT. The discrepancy between Mill Hill and WAIS Verbasl IQs as a diagnostic sign has been eliminated. The Revised Battery has been shown to discriminate between elderly dementing and non-dementing subjects, and also between normal, depressed, and dementing elderly subjects. Utilizing test-retest data it has been found possible to discriminate absolutely between dementing and non-dementing subjects. The reliabilities and validities of the Battery have been ascertained by examining a broad spectrum of elderly subjects: normal, depressed, dementing and institutionalized.
Lactitol (beta-galactosido-sorbitol) is a nonabsorbable disaccharide available as a powder which, in open comparison, is as effective as lactulose in the treatment of chronic hepatic encephalopathy, but is better tolerated. Twenty-five cirrhotic patients experiencing 28 episodes of acute hepatic encephalopathy were randomized blindly to treatment with either lactitol (n = 15) or lactulose (n = 13). The sugars were dispensed in solutions identical in appearance, taste and pH and of similar osmolarity, which contained either 66.7 gm per 100 ml lactitol or 66.7 ml (44.5 gm) per 100 ml lactulose syrup. The initial dose of 0.75 ml per kg was adjusted to produce two semisoft stools per day. Patients were assessed every 12 hr for 5 days. There were no significant differences in sex ratio, age, body weight, clinical status, duration and extent of coma, etiology of liver disease or of hepatic encephalopathy between the two groups of patients on entry to the trial. An adequate catharsis was obtained with an equivalent mean (+/- 1 S.D.) daily dose of 26 +/- 5 gm lactitol or 31 +/- 7 ml (21 +/- 5 gm) lactulose syrup. During the trial, significant improvements occurred in clinical status and psychometric performance and in the electroencephalogram mean cycle frequencies in the majority of patients in both groups. At the end of the trial, 67% of the patients in the lactitol group and 69% of the lactulose group were clinically normal. However, patients treated with lactitol responded significantly more quickly than patients treated with lactulose.(ABSTRACT TRUNCATED AT 250 WORDS)
Thirty-seven patients, all with histologic evidence of cirrhosis and with a normal neurological examination and normal mental status were evaluated by psychometric testing for subclinical hepatic encephalopathy. They were all regarded as having well compensated cirrhosis, not requiring any treatment or dietary restrictions and they were working, and many of them driving. A group of 19 patients with a history of alcoholism, or medical disorders, but without clinical or biochemical evidence of cirrhosis, served as controls. They were matched by age, sex, education, and alcohol consumption. Investigations performed were an EEG, fasting arterial ammonia, liver biochemical tests and a series of verbal and performance psychometric tests. The EEG was abnormal in 3 (8.3%) of patients, the ammonia elevated in 17 (45.9%) of patients and 26 patients (70.3%) failed 2 or more psychometric tests, as compared to 2 (10.5%) of the control group. It is concluded that 2 out of 3 patients with stable, well compensated cirrhosis were suffering from subclinical hepatic encephalopathy and that impairment of performance rather than verbal skills occurred. The digital symbol test, trail test (number connection test) and block design tests readily identified the patients with subclinical hepatic encephalopathy. The implication of these observations in patients with cirrhosis, especially those working in mechanical or skilled occupations, needs consideration.
Lactulose is currently the drug of choice for the treatment of hepatic encephalopathy. It is, however, only available as a syrup which is contaminated with other sugars. Consequently patients may express aversion to its excessively sweet taste and many experience nausea because of its hyperosmolarity. Lactitol is a disaccharide analogue of lactulose which can be produced as a pure crystalline powder with a low relative sweetness. Theoretically it should have the same therapeutic effects as lactulose but fewer side effects. Five patients with chronic hepatic encephalopathy on maintenance lactulose were monitored clinically, psychometrically, and by measurement of venous blood ammonia, electroencephalogram mean cycle frequency, and cerebral blood flow during three months treatment with lactulose and a similar period on lactitol. Lactitol was at least as efficacious as lactulose but was more acceptable because its cathartic effect was more predictable, its formulation was more convenient and its less sweet taste preferred. Lactitol is the ideal successor to lactulose for treatment of this condition.
Thirty-two alcoholic cirrhotics without clinical evidence of encephalopathy were randomized to lactulose or sucrose treatment in order to evaluate the effects of chronic lactulose therapy on five psychomotor performance tests. Statistically significant improvement was seen in three of the five tests in the lactulose-treated group, while no significant improvement in any test was noted in the sucrose group. However, because of the limited extent of improvement in the lactulose treated group, problems with medication intolerance, and lack of improvement in complex psychosocial behavior, the impact of chronic lactulose therapy on mental function in cirrhotics without overt encephalopathy appears to be limited.
Psychometric tests were evaluated to reveal latent portal-systemic encephalopathy in well-compensated patients with non-alcoholic liver cirrhosis. Forty-five cirrhotics and 35 controls under the age of 60 years were submitted to the following tests: reitan's test (part A), spatial capacity test (hand test), and reaction times to sound and light. Forty-nine per cent of the cirrhotic patients showed impaired performance on at least one test. Reitan's test proved to be the most sensitive in revealing early cerebral damage (in 40 per cent of patients). The findings suggest that psychometric tests, particularly Reitan's test, can be useful in revealing and monitoring the encephalopathy even in well-compensated cirrhotics.
Forty patients with chronic liver disease and portal hypertension but without clinical signs of portasystemic encephalopathy (15 patients with nonalcoholic cirrhosis, 15 patients with alcoholic cirrhosis, and 10 patients with minimal EEG changes) and a control group of 12 patients with chronic alcohol pancreatitis were studied using an extensive psychometric program, which, in the same form, is used for expert reports on driving capacity. Of the cirrhotic patients, 60% were considered unfit to drive; in 25% driving capacity was questionable, 15% (only nonalcoholic cirrhotics) were considered fit to drive. In contrast 75% of the patients with alcoholic pancreatitis were considered fit to drive. Major defects were found only in three heavy alcoholics. Patients with alcoholic cirrhosis scored lower than patients with nonalcoholic cirrhosis. This was due to differences in liver function rather than to the effect of alcohol consumption. Patients with minimal EEG changes were practically all considered unfit to drive.
Psychomotor performance defects in cirrhotic patients without oven encephalopalhy
- S J Cilbersradr
- H Gilbersmdt
- L Sieve
- Buegei
- Collier
- C J Mcclain
Cilbersradr SJ. Gilbersmdt H. Sieve L. Buegei 6. Collier
RO Jr. McClain CJ. Psychomotor performance defects in
cirrhotic patients without oven encephalopalhy. Arch InternMed 1980: 14@ 519-521.
ecchio-B,a"co C. Cohnrti M Psychometric tests and 'knent portal systemic encephaloparhy
t.0guerci.a C. rJe, "ecchio-B,a"co C. Cohnrti M Psychometric tests and 'knent portal systemic encephaloparhy Br
J Ciin Przct 1984 3R: 3O-41 I.
Effect of d,e,ary protein mampulilduna in rubctinica,w,a,-systemic encepbulopathy
- De Bruijn
- K M Blendia
- L M Zilm
- D H Carlen
- P L Anderso
De Bruijn KM. Blendia LM. Zilm DH. Carlen PL. Anderso,, GH. Effect of d,e,ary protein mampulilduna in rubctinica,,w,a,-systemic encepbulopathy. Gut,983: 24: 53-M)
Branched chain amino aads in the treatment of latent study pattents under his care and Dr. G.-P. Ravelli of Zyma SA. Nyon for the supplies cf lactitol powder
- E H Egberu
- H Schomerirs
- W Hamster
- P Jurpens
Egberu EH. Schomerirs H. Hamster W. Jurpens P.
Branched chain amino aads in the treatment of latent
study pattents under his care and Dr. G.-P. Ravelli of
Zyma SA. Nyon for the supplies cf lactitol powder.
Lactitol versus lactulose in the treatment of chronic heparic eocephalaparhy
- M Y Morgan
- K E Hawley
- D Stambuk
I3 Morgan MY Hawley KE, Stambuk D. Lactitol versus lactulose in the treatment of chronic heparic eocephalaparhy. J
t-tepato, 19RI; 4: 2x-244.
Trail making and number-mn"ecti"n tssts in ttle assessment of mental state in portal systemic encephalopathy
- H O Corm
Corm HO. Trail making and number-mn"ecti"n tssts in ttle
assessment of mental state in portal systemic encephalopathy. Am I Dig Dis lm7; 22: 541-550.
Wcchsier Adult Intelligence Scale Manual
- D Wechrler
Wechrler D. Wcchsier Adult Intelligence Scale Manual.
New York: Psychological Corpormion.,955.
Automated osvcbological *es&g: some-principles and practice Int I M'a. Machine Stud
- A Elithorn
- S Morninetan
- A Starnou
Elithorn A. Morninetan S. Starnou A. Automated osvcbological *es&g: some-principles and practice Int I M'a. Machine Stud 1982: 17: 249-263.
Branched chain amino acids in the treatment of latent portosystemic encephalopathy. A double-bund placebocontrolled crossover study.
- Egberts EH
- Schomeras H
- Hamster W
- Jurgens P
Automated psychological testing: some principles and practice.
- Elithorn A
- Mornington S
- Starnou A