My Patient With Hepatic Encephalopathy Continues to Be Mildly Confused Despite Taking Lactulose Twice Daily and Having Multiple Episodes of Diarrhea Daily. Should I Increase the Dose Further?
Generally, the answer to this question is “No.” Lactulose is an effective treatment for hepatic encephalopathy, but it is not innocuous and should not be used promiscuously. Lactulose dosage should be titrated to produce 2 to 4 loose stools per day. Increasing lactulose beyond this point does little to improve encephalopathy while greatly increasing adverse effects such as dehydration, electrolyte derangements, incontinence, perianal irritation, and skin breakdown. Indeed, the metabolic derangements caused by excessive diarrhea (hypernatremia or hyponatremia, hypokalemia, metabolic acidosis) may worsen symptoms of encephalopathy.
When hepatic encephalopathy is refractory to lactulose, one should consider the possibility that the symptoms may have an alternate cause. The differential diagnosis of persistent cognitive impairment in the patient with liver disease is extensive (Table 46-1). Minimal evaluation of the patient with refractory encephalopathy should include magnetic resonance imaging (MRI) of the brain, as well as blood tests for hypothyroidism, syphilis, vitamin B12 deficiency, and other correctable causes of dementia. Neurology consultation for more detailed evaluation may be appropriate. Electroencephalography in hepatic encephalopathy typically shows diffuse slowing; unexpected electroencephelogram (EEG) findings such as focal seizure activity may point to an alternative cause of the patient’s impairment. Lumbar puncture may be useful to exclude a variety of degenerative and chronic infectious processes.
If conditions other than hepatic encephalopathy have been excluded, one should look for exacerbating factors that can be corrected.1 Patients frequently are noncompliant with lactulose therapy and this can be addressed through counseling. If patients find the taste of liquid lactulose offensive, use of powdered lactulose may be preferred. Concurrent medications may contribute to encephalopathy in a variety of ways, for example, by direct sedative effects (benzodiazepines), by slowing colonic motility (narcotics), or by inducing dehydration or other metabolic derangements (diuretics); changing these may bring the problem under control. Acute deterioration of encephalopathy often is precipitated by gastrointestinal bleeding or acute infections such as spontaneous bacterial peritonitis.
Finally, if encephalopathy persists, one should consider alternative therapeutic interventions. The nonabsorbable antibiotic rifaximin administered orally appears to be as effective as lactulose for control of encephalopathy and has few side effects.2 Its principal drawback is its cost. Oral neomycin is less expensive and also effective but can occasionally cause acute renal failure in the cirrhotic patient. Severe restriction of dietary protein should be avoided because it leads to protein calorie malnutrition that increases the risk of infection and other complications. Indeed, malnutrition caused by inappropriate protein starvation may produce symptoms of lethargy and listlessness that can be mistaken for encephalopathy. Proteins of vegetable origin may be better tolerated than animal proteins. In the rare patient who cannot ingest 60 to 100 g of protein per day without becoming encephalopathic, one may consider providing specialized nutritional supplements such as Hepaticaid, which are enriched with branched chain amino acids, though these are expensive and of dubious efficacy.3 Occasionally a patient’s symptoms of encephalopathy may be attributable to a large portosystemic shunt, either spontaneous or therapeutic; closure of the shunt by surgical or radiological intervention may ameliorate the encephalopathy.
The definitive treatment of hepatic encephalopathy is liver transplantation. Early referral to a transplant center is encouraged. Unfortunately, hepatic encephalopathy, despite its profound effects on quality of life,4 does not currently constitute an indication for expedited transplantation,5 and encephalopathic patients whose liver function is otherwise well compensated may wait years for transplantation under the current system of deceased donor organ allocation. Living donor liver transplantation, which offers a means of circumventing the waiting list, may be an attractive alternative for such patients.
1. Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy—definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002;35:716-721.
2. Mas A, Rodes J, Sunyer L, et al. Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol. 2003;38:51-58.
3. ls-Nielsen B, Koretz RL, Kjaergard LL, Gluud C. Branched-chain amino acids for hepatic encephalopathy. Cochrane Database Syst Rev. 2003;No. 2:CD001939.
4. Prasad S, Dhiman RK, Duseja A, Chawla YK, Sharma A, Agarwal R. Lactulose improves cognitive functions and health-related quality of life in patients with cirrhosis who have minimal hepatic encephalopathy. Hepatology. 2007;45:549-559.
5. Ham J, Gish RG, Mullen K. Model for end-stage liver disease (MELD) exception for hepatic encephalopathy. Liver Transpl. 2006;12(suppl 3):S102-S104.