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Non-absorbable disaccharides and antibacterials are the treatment of choice for hepatic encephalopathy
Hepatic encephalopathy (HE) encompasses a range of neuropsychiatric conditions, ranging from mild disturbances in cognitive function to coma and death. The non-absorbable disaccharides lactulose and lactitol are the treatments of choice. Second-line therapy includes the antibacterials neomycin and rifaximin. There is anecdotal evidence of the use of a number of alternative agents for treatment of HE. depletion of liver thiamine stores; all patients with chronic liver failure should, therefore, receive prompt, effective thiamine supplementation. This article summarizes a recent review of the available pharmacotherapy for HE by Phongsamran et al.
Non-absorbable disaccharides first-line therapy ...
The non-absorbable disaccharides lactulose and lactitol are generally used as first-line therapy (table I). Both agents undergo metabolism by bacteria in the colon to form acidic species. This creates a hostile environment for bacteria with urease activity that produce ammonia, and facilitates the conversion of absorbable ammonia to non-absorbable ammonium. The result is a reduction in ammonia levels in the colon and portal blood, and a 4-fold increase in faecal nitrogen excretion.
Common in patients with cirrhosis
Hepatic encephalopathy (HE), commonly occurring in patients with severe liver dysfunction, is a neuropsychiatric disorder characterized by disturbances in cognitive function, personality and behaviour, and a general depression of the CNS. HE may also be complicated by changes in neuromuscular activity, intellectual capacity, temporary neurological symptoms and abnormalities in EEG. The clinical manifestation of HE ranges from mild impairment of cognition and consciousness to coma. Although the pathogenesis of HE is unclear, gut-derived nitrogenous compounds, in particular ammonia, are thought to play a central role. HE has been shown to be precipitated by excess dietary protein, gastrointestinal (GI) bleeding, electrolyte imbalance (may be caused by the use of diuretics), infection and by the use of drugs affecting the CNS (e.g. benzodiazepines, other hypnosedatives and antiepileptics). Brain dysfunction in patients with end-stage liver disease is also associated with thiamine deficiency caused by the
y despite their modest efficacy
Lactulose and lactitol have consistently been shown to be more effective than placebo or no treatment in the treatment of HE (table II).[3-7] In a number of trials, lactulose was more effective than placebo or no treatment in patients with subclinical HE in trials of up to 3 months’ duration.[3-5,7] Efficacy was generally shown as improvements in psychometric tests and lowering of serum ammonia levels, with improved cognitive function and health-related quality of
Table I. Agents commonly used in the treatment of hepatic encephalopathy
Drug Formulation Typical dosages in clinical trials Adverse events Non-absorbable disaccharides Lactitol Highly soluble crystalline powder Disaccharide syrup 10 g every 6 h; 0.25 g/kg twice daily; 66.7 g/100 mL titrated to two bowel movements daily (equivalent of lactitol 30 g/d) Oral: 20 g/30 mL three or four times daily titrated to achieve 2–4 semi-soft stools daily Retention enema: 200 g/300 mL mixed into 700 mL of water or saline administered every 4 h 1–2 g every 6 h 600–1200 mg/d in divided doses Cramping, diarrhoea, flatulence; overdose may lead to severe diarrhoea, electrolyte imbalance, hypovolaemia Cramping, diarrhoea, flatulence; overdose may lead to severe diarrhoea, electrolyte imbalance, hypovolaemia
Antibacterials Neomycin Rifaximin Oral aminoglycoside antibacterial Oral synthetic antibacterial Nephrotoxicity, irreversible ototoxicity (particularly in patients with renal impairment) Headache, flatulence, abdominal pain, nausea, vomiting, constipation, urticarial skin reactions
1172-0360/11/0006-0017/$19.95 ª 2011 Adis Data Information BV. All rights reserved.
ammonia levels Mental status. (db) Massa et al. asterixis score. ammonia levels. (db) Festi et al. Moreover. stool pH. (db) Pedretti et al. PSE index. However. asterixis score. 6 placebo or no treatment in a meta-analysis of trials. EEG Ammonia levels. HRNB. ammonia levels. EEG. asterixis score. asterixis score. EEG. EEG. (ol) Miglio et al. non-absorbable disaccharides produced only modest improvements in HE symptoms compared with Drugs Ther Perspect 2011. HRNB. HE change Time to HE grade level change Neurological status. mood. ammonia levels. (ol) Lactulose vs lactitol Heredia et al. EEG. asterixis score Mental status. memory.  No. HRNB. (sb) Strauss et al. PSE index Psychometric tests. ammonia levels. PSE index Clinical examination. sb = single-blind. (db) Neomycin vs lactulose or placebo Rifaximin vs disaccharides 35 (21 d) 60 (2 wk each mo · 6 mo) 30 (21 d) Rifaximin » neomycin Rifaximin » neomycin Rifaximin ‡ neomycin co = crossover. PSE index Mental status. cancellation tasks. ammonia levels. ammonia levels. However. asterixis score. (db) Conn et al. The authors concluded that the evidence for treatment of HE with non-absorbable disaccharides was not sufficient to recommended these agents. db = double-blind. (db) Paik et al. cancellation tasks. Summary of clinical studies comparing the efficacy of non-absorbable disaccharides or antibacterials with other treatments in patients (pts) with hepatic encephalopathy (HE) Study (design) Dhiman et al. speech. HRNB = Halstead-Reitan Neuropsychological Test Battery. co) Morgan and Hawley (db) Morgan et al. psychometric tests. ammonia levels. HRNB. PSE = portal systemic encephalopathy. ammonia levels Psychometric tests. EEG. (ol) Leevy and Phillips (co) Mas et al. PSE index Mental status. of pts (duration) Assessment Overall efficacy Lactulose > no treatment Lactulose > placebo Lactulose > no treatment Lactulose + lactitol > placebo Lactulose > no treatment Lactulose » lactitol Lactulose » lactitol Lactulose » lactitol at study end Lactitol > lactulose at 24–72 h Lactulose » lactitol Neomycin » lactulose Neomycin » lactulose Neomycin » lactulose Neomycin » placebo Rifaximin > lactulose Rifaximin > lactulose Rifaximin » lactulose Rifaximin > lactulose Rifaximin » lactitol Rifaximin ‡ lactulose Rifaximin » lactulose Non-absorbable disaccharide vs placebo or no treatment 26 (3 mo) 14 (2 wk) 61 (14 mo) 15 (»3 d) 36 (2 mo) 25 (6 mo) 5 (6 mo) 25 (5 d) 9 (3 mo) 35 (»7 d) 29 (10 d) 173 (14 d) 39 (»7 d) 58 (15 d) 40 (first 2 wk of each mo · 3 mo) 21 (21 d) 145 (‡6 mo) 103 (5–10 d) 40 (15 d) 54 (7 d) Psychometric tests Psychometric tests. lactulose and lactitol enemas were more effective than tap water at improving clinical grading. asterixis score. 27.18 Table II. HRNB. In patients with acute HE. Vol. psychometric tests. PSE index Neurological signs of HE. EEG. (ol) Uribe et al. flapping tremor. behaviour. EEG. ammonia levels HE grade. gait. asterixis score. (ol) Horsmans et al. (ol) Rifaximin vs neomycin Festi et al. (co) Lanthier and Morgan (ol. number connection test. ammonia levels Psychometric tests. cancellation tasks. EEG. ammonia levels Asterixis score. HE index. when only well designed randomized trials were analyzed. EEG. writing Mental status. (db. HR-QOL = health-related quality of life. EEG. ammonia levels. ammonia levels. psychometric tests HE index severity. EEG. cerebral blood flow Psychometric tests. mortality Psychometric tests. HR-QOL Psychometric tests. No. HRNB. life shown in one study. psychometric tests Neurological signs of HE. ammonia levels. ol = openlabel. co) Orlandi et al. (db) Atterbury et al. mental status. at present . these agents had no significant effect on HE grade or mortality. mental status. PSE index (db) Prasad et al. asterixis score. (db) Watanabe et al. (db) Bucci and Palmieri (db) Fera et al. stool pH and mortality (table II). EEG. EEG Mental status. clinical grading. asterixis score.
lactitol appears to be better tolerated than lactulose. neomycin did not improve HE grade significantly more than placebo in patients with HE (table II). there is a lack of good quality evidence supporting its use in this indication.23.[8-11] In one study. except Pseudomonas aeruginosa. the efficacy of rifaximin was generally similar to lactulose. However. and nausea) than lactulose in three studies. However.. Moreover. y neomycin y The aminoglycoside neomycin (table I) is active against most Gram-negative aerobes. A systematic review of trials showed non-absorbable disaccharides to be inferior to antibacterials in improving HE symptoms and lowering blood ammonia levels. but there was no between-group difference in mortality. lactitol was associated with a faster response than lactulose. and GI symptoms. In three studies. Lactulose and lactitol appear to be equally effective at improving HE symptoms (table II). the long-term use of vancomycin for HE is limited by the potential for bacterial overgrowth and bacterial resistance. A case series in 11 patients suggested that metronidazole had similar efficacy to neomycin. Rifaximin generally seems to be as effective as lactulose and lactitol in the treatment of HE. with »98% of a dose recovered unchanged in the faeces. or for the prevention of variceal rebleeding associated with a high incidence of HE. rifaximin was associated with a significantly lower number and duration of hospitalizations and HE grade y secondary prophylaxis is important Lactulose with or without rifaximin appears to be effective for secondary prevention of HE in patients with previous episodes of HE following TIPS. largely due to a decreases in blood ammonia levels and EEG abnormalities. compared with lactulose. the overall global efficacy. diarrhoea. neomycin was often associated with adverse events.[16-22] In one of the larger studies. as it was associated with a lower incidence of adverse events (flatulence.9. importantly.. Antibacterials are understood to be effective at treating HE through the inhibition of ammonia production by bacteria in the GI tract. rifaximin was associated with a greater decrease in overall PSE index than lactitol.[8. but it was better tolerated (table II).. .[18. While it is potentially a safer option to metronidazole.22] Rifaximin appears to be at least as effective as neomycin in the treatment of HE and is associated with fewer adverse events (table III). as measured by improvements between 24 and 72 hours (table II). including that against aerobic and anaerobic Gram-positive and Gram-negative bacteria. and also possesses anti-staphylococcal activity. It has been used for the treatment of HE for over 40 years. although clinical trials comparing the agents are mostly small (table II). symptom improvement and total episode regression was similar for both groups. However.11] Antibacterials used as second-line therapy include .95 ª 2011 Adis Data Information BV.29] Significantly fewer patients receiving lactulose 30–60 mL/day experienced an episode of HE compared with placebo recipients (19. However. In a well designed clinical trial. No significant difference in the rate or severity of HE occurrence was seen between lactitol 60 mL/day. All rights reserved.24] However. y rifaximin y The synthetic antibacterial rifaximin (table I) has a broad spectrum of activity. In a second study that included over 100 patients. y metronidazole and vancomycin Metronidazole and vancomycin have undergone limited study in the treatment of HE. with no significant differences in neurological and biological parameters generally being seen in patients receiving either of the disaccharides in clinical studies in patients with cirrhosis. there are few well designed clinical trials available from which to draw firm conclusions. resulting in the achievement of high concentrations in the GI tract. three studies have shown no significant differences in efficacy between neomycin and lactulose (table II). and reductions from baseline in blood ammonia levels and adverse neurological signs. Transjugular intrahepatic portosystemic shunt (TIPS) is a procedure performed in patients with refractory ascites.[12-14] Although primary prophylaxis is ineffective following TIPS . While these events occurred early during the course of therapy..21.19 there is not enough evidence to advise against the use of non-absorbable disaccharides for the treatment of HE.[16-18. it was also associated with improved compliance. long-term use of this agent may cause neurotoxicity and is not recommended. rifaximin 1200 mg/day or no treatment when used as primary prophylaxis in 75 patients undergoing TIPS in a randomized controlled trial. such as increases in serum urea and creatinine levels.6% 1172-0360/11/0006-0019/$19. Furthermore. In smaller short-term studies. rifaximin and neomycin produced similar improvements in HE grade. rifaximin was generally associated with a more rapid response. they generally subsided during the course of therapy. However. It is poorly absorbed from the GI tract.[28.
neuropsychological tests and ammonia levels when used alone or in combination with lactulose in two RCTs[36. pts with zinc deficiency should receive supplemental zinc Sodium benzoate Sodium phenylbutyrate Zinc pts = patients.1% vs 45. double-blind study in 299 patients.001) and reduced risk of hospitalization (13. but did not reduce ammonia levels in a second study NMDA receptor antagonist approved for the treatment of Alzheimer’s disease dementia Overactivity of the NMDA receptor has been demonstrated in a rat model of encephalopathy Shown to improve clinical grading and other markers of encephalopathy in rats Memantine Ornithine aspartate Lowers serum ammonia levels by acting as a substrate for urea-genesis that converts ammonia to urea and glutamine Several controlled trials suggest that intravenous dosages of 18–30 g/d improved ammonia levels and symptoms in pts with mild to moderate HE Probiotics Appear to reduce serum ammonia levels by modulating intestinal bacteria and promoting colonization of non-ureaseproducing bacteria Produced improvements in symptoms.01) compared with placebo in a randomized. p < 0. Phongsamran PV. which is excreted via the kidneys and results in a net loss of ammonia ions Oral dosages of 5 g twice daily produced similar symptomatic improvements to lactulose in a RCT in pts with acute HE Effectiveness limited by risk of salt overload and unpleasant taste Promotes the excretion of glutamine. Cupo J. vs 46. restoring the appropriate balance has theoretical benefits A meta-analysis of 5 trials suggested that parenteral BCAA therapy improves mental recovery in pts with cirrhosis and acute HE A recent systematic review of 11 RCTs concluded that there was no convincing evidence for the use of oral BCAAs in pts with HE Benzodiazepine antagonists Branched-chain amino acids (BCAAs) Dopamine receptor Dopamine transmission may be affected by manganese accumulation in the basal ganglia of pts with cirrhosis agonists Little clinical data are currently available Elevated prolactin levels in pts receiving bromocriptine is a concern Levocarnitine May be protective against ammonia neurotoxicity according to animal data Reduced serum ammonia levels and improved mental status compared with placebo in pts with mild to moderate HE. However. Kim JW. Variety of alternative agents are under investigation A number of alternative and experimental agents for the treatment of hepatic encephalopathy have been identified (table III). Alternative and experimental agents for the treatment of hepatic encephalopathy (HE) Acarbose Inhibits a-glycosidase. diabetes mellitus and mild to moderate HE Hypothesized that ‘endogenous benzodiazepines’ exert an antidepressant effect by binding to GABA receptors A systematic review of 12 controlled trials showed that the benzodiazepine antagonist flumazenil produces symptomatic improvement in pts with HE vs placebo.001) in a randomized open-label trial in 125 cirrhotic patients.6% vs 22.20 Table III. 27. patients with HE or have only been seen to be effective in case reports or small uncontrolled studies. resulting in a net loss of ammonia Combination formulation with sodium benzoate (approved for the treatment of hyperammonaemia associated with urea cycle disorders) has been studied in pts with HE Glycerol phenylbutyrate is undergoing clinical trials in pts with cirrhosis and severe HE Zinc deficiency is common in pts with cirrhosis and HE. and is associated with overt HE Oral dosage of 600 mg/d produced conflicting results in studies While there is little evidence for its use in treating HE. which facilitates the reduction of proteolytic bacterial flora that produce benzodiazepine-like substances. Many of these agents have theoretical benefits in Drugs Ther Perspect 2011. No. 70 (9): 1131-48 by Adis editors and medical writers.8%.37] Interacts with glycine to form hippurate. most of whom were receiving concomitant lactulose.9%. but efficacy is often short lived Routine use not recommended As the ratio of aromatic amino acids to BCCAs is increased in pts with liver disease. 6 References 1. 70 (9): 1131-48 . large controlled studies are required to identify their place in therapy. The preparation of these articles was not supported by any external funding. While a number of these agents are available. mercaptans and ammonia Dosage of 150–300 mg/d reduced ammonia levels and produced symptomatic improvement in a RCT in pts with cirrhosis.6%. et al. p = 0. Disclosure This review was adapted from Drugs 2010. Vol. p = 0. RCTs = randomized controlled trials. rifaximin was associated with a significantly lower incidence of HE (22. Drugs 2010. Pharmacotherapy for hepatic encephalopathy.
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