Common side effects of NAD include an excessively sweet taste, flatulence, abdominal cramping, and electrolyte imbalance, particularly hypernatremia, which may further deteriorate mental status.
click for large version
click for large version
Als-Nielsen et al demonstrated in a systematic review that NAD were more effective than placebo in improving HE, but NAD had no significant benefit on mortality.1 However, the effect on HE no longer reached statistical significance when the analysis was confined to studies with the highest methodological quality. In a randomized, double-blind comparison, Morgan et al showed that lactitol was more tolerable than lactulose and produced fewer side effects.2 Lactitol is not currently available for use in the U.S.
Antibiotics: Certain oral antibiotics (e.g., neomycin, rifaximin, and metronidazole) reduce urease-producing intestinal bacteria, which results in decreased ammonia production and absorption through the gastrointestinal tract. Antibiotics generally are used in patients who do not tolerate NAD or who remain symptomatic despite NAD. The combined use of NAD and antibiotics is a subject of significant clinical relevance, though data are limited.
Neomycin is approved by the FDA for treatment of acute HE. It can be administered orally at a dose of 1,000 mg every six hours for up to six days. A randomized, controlled trial of neomycin versus placebo in 39 patients with acute HE demonstrated no significant difference in time to symptom improvement.3 Another study of 80 patients receiving neomycin and lactulose demonstrated no benefit against placebo, though some data suggest that the combination of lactulose and neomycin therapy might be more effective than either agent alone against placebo.4
Rifaximin was granted an orphan drug designation by the FDA for use in HE cases and has been compared with NAD. The recommended dose is 1,200 mg three times per day. It has minimal side effects and no reported drug interactions. A study of rifaximin versus lactitol administered for five to 10 days showed approximately 80% symptomatic improvement in both groups.5 Another trial demonstrated significantly greater improvement in blood ammonia concentrations, electroencephalographic (EEG) abnormalities, and mental status with rifaximin compared with lactulose.6 Studies comparing rifaximin and lactulose, either alone or in combination, have demonstrated that rifaximin is at least similar to lactulose, and in some cases superior in reversing encephalopathy, with better tolerability reported in the antibiotic group.7
Metronidazole is not approved by the FDA for the treatment of HE but has been evaluated. The recommended oral dose of metronidazole for chronic use is 250 mg twice per day. Prolonged administration of metronidazole can be associated with gastrointestinal disturbance and neurotoxicity. In a report of 11 HE patients with mild to moderate symptoms and seven chronically affected HE cirrhotic patients treated with metronidazole for one week, Morgan and colleagues showed metronidazole to be as effective as neomycin.8
Diet: Historically, patients with HE were placed on protein-restricted diets to reduce the production of intestinal ammonia. Recent evidence suggests that excessive restriction can raise serum ammonia levels as a result of reduced muscular ammonia metabolism. Furthermore, restricting protein intake worsens nutritional status and does not improve the outcome.9
In patients with established cirrhosis, the minimal daily dietary protein intake required to maintain nitrogen balance is 0.8 g/kg to 1.0 g/kg. At this time, a normoprotein diet for HE patients is considered the standard of care.
Other agents: L-ornithine L-aspartate (LOLA), a stable salt of ornithine and aspartic acid, provides crucial substrates for glutamine and urea synthesis—key pathways in deammonation. In patients with cirrhosis and HE, oral LOLA reduces serum ammonia and improves clinical manifestations of HE, including EEG abnormalities.10 LOLA, however, is not available in the U.S.