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References

1. Gilbar PJ, Ridge AM: Inappropriate labelling of patients asopioid allergic. J Oncol Pharm Pract 2004;10:177–182.

2. Fisher MM. Harle DG. Baldo BA: Anaphylactoid reactions tonarcotic analgesics. Clin Rev Allergy 1991;9:309–318.

3. Hermens JM: Comparison of histamine release in human skinmast cells induced by morphine, fentanyl, and oxymorphone.Anesthesiology 1985;62:124–129.

4. Kroigaard M, Garvey LH, Menne T, Husum B: Allergic reac-tions in anaesthesia: Are suspected causes confirmed on sub-sequent testing? Br J Anaesth 2005;95:468–41.

5. Tcheurekdjian H, Gundling K: Continuous hydromrphone

infusion for opioid intolerance J Allergy Clin Immunol2006;118:282–284.

6. Joint Council of Allergy Asthma and Immunology: Practiceparameters for drug hypersensitivity. Ann Allergy AsthmaImmunol 1999;83:S665–700.

Address reprint requests to:Hunter E. Woodall, M.D.

Anmed Health Family Medicine Residency2000 East Greenville Street, Suite 3600

Anderson, SC 29621

E-mail: hunter.woodall@anmedhealth.org

DOI: 10.1089/jpm.2008.2816

Hepatic Encephalopathy in End-Stage Liver Disease #188

Julie Wilson Childers, M.D. and Robert M. Arnold, M.D.

Background

HEPATIC ENCEPHALOPATHY (HE) is a neuropsychiatric syn-drome with a fluctuating course associated with end-

stage liver disease (ESLD). HE symptoms, which are gradedfrom 0 to IV, range from subtle personality or sleep distur-bances to confusion and coma. Severe HE (grade III or IV)is manifested by gross disorientation, bizarre behavior, stu-por, or coma.1 Without transplantation, severe HE signifiesa poor prognosis (58% 1 year and 77% 3 year mortality inone case series).2 In addition, 15% of patients awaiting livertransplantation die before receiving an organ.3

Etiology

The cause of HE is uncertain, but may be related to the ac-cumulation of neurotoxic substances normally metabolizedby the liver; these include ammonia and endogenous ben-zodiazepine-like substances that activate GABA-receptors tocause neurotoxicity.

Evaluation

HE is a diagnosis of exclusion, and in one study 80% ofcases were associated with an identifiable secondary causesuch as gastrointestinal bleeding, infection (including spon-taneous bacterial peritonitis), renal failure, alcohol with-drawal, excessive dietary protein, volume depletion, ordrugs (particularly benzodiazepines).4 Serum ammonia lev-els are usually elevated in patients with HE, although theutility of following these has not been established.

Therapy

Therapy begins with correction of the underlying causesif this is consistent with the goals of care. Specific therapy ofHE is aimed at limiting production of and increasing excre-tion of intestinally derived toxins, particularly ammonia.

• Nonabsorbable disaccharides such as lactulose and lacti-tol are the mainstay of treatment though there is a lack ofcontrolled evidence supporting their use.5 These agentsnot only cause increased transit time through the gut andless absorption of toxins, but also promote bacterial fer-mentation, leading to a hostile environment for ammonia-producing bacteria. The daily dose of lactulose should betitrated to result in two to four soft stools daily. For mostpatients the daily dose is between 30 and 60 grams. Sideeffects include gastrointestinal cramping, diarrhea, andflatulence.

• Nonabsorbable antibiotics such as neomycin and vanco-mycin were the first treatments for HE. They lower am-monia by combating urea-producing bacteria in the gut.Neomycin likely produces more rapid improvement thanlactulose but its use is limited by its nephrotoxic and oto-toxic effects.5 Rifaximin is a nonabsorbable derivative ofrifampin which received orphan drug status from theFodd and Drug Administration in 2005 for treatment ofHE. Rifaximin, given at 400 mg orally three times a day,is as effective as neomycin or lactitol and better toleratedthan other nonabsorbable antibiotics.6 Rifaximin costs$4.00 per pill (average wholesale price). Because of thisand its lack of clear superiority to disaccharides, rifaximinis considered a second-line agent for patients who cannottolerate or who are not responding to disaccharide ther-apy.

• Other therapies have limited efficacy in treating HE andplay no clear role in its management. These includebranched chain amino acids,7 the benzodiazepine antago-nist flumazenil,8,9 and limitation of dietary protein.10

Advance Care Planning

The patient’s values, goals of care, and treatment optionsshould be discussed in the context of HE’s poor prognosis.

A health care proxy should be established before cognitiveimpairment prevents this.

Supportive Care

The patient and family must be educated to recognizeHE’s symptoms and understand its fluctuating course,avoiding precipitating factors when possible. Patients whoare confused should be reoriented and measures should betaken to prevent falls, skin breakdown, and aspiration. In-travenous fluids, nasogastric feeding, and airway protectionare sometimes appropriate. Dose-adjusted acetaminophen(� 2 g/d) is the first line analgesic. Opioids can worsen HEbut are sometimes necessary to adequately treat pain; theiruse should be closely monitored and balanced with the pa-tient’s degree of suffering and goals of care.11 Dying patientsshould receive attentive comfort care. In addition to pain,dyspnea, restlessness, and edema and secretion managementare common challenges in dying ESLD patients.

References

1. Blei AT, Cordoba J: Practice guidelines: Hepatic encephalo-pathy. Am J Gastroenterology 2001;96:1968–1976.

2. Bustamante J, Rimola A, Ventura PJ, Navasa M, Cirera I,Reggiardo V, Rodés J:. Prognostic significance of hepatic en-cephalopathy in patients with cirrhosis. J Hepatol 1999;30:890–895.

3. Russo MW, LaPointe-Rudow D, Kinkhabwaa M, Emond J,Brown RS: Impact of adult living donor liver transplanta-tion on waiting time survival in candidates listed for livertransplantation. Am J Transplant 2004;4:427–431.

4. Fessel JM, Conn HO: An analysis of the causes and preven-tion of hepatic coma. Gastroenterology 1972;62:191.

5. Als-Nielsen B, Gluud LL, Gluud C: Non-absorbable disac-charides for hepatic encephalopathy. Cochrane DatabaseSyst Rev 2004;(2):CD003044.

6. Mas A, Rodes J, Sunyer L, Rodrigo L, Planas R, Vargas V,Castells L, Rodríguez-Martínez D, Fernández-Rodríguez C,Coll I, Pardo A; Spanish Association for the Study of theLiver Hepatic Encephalopathy Cooperative Group: Com-parison of rifaximin and lactitol in the treatment of acute he-patic encephalopathy: Results of a randomized, double-blinded, double-dummy, controlled clinical trial. J Hepatol2003;38:51–58.

7. Als-Nielsen B, Koretz RL, Kjaergard LL, Gluud C: Branched-chain amino acids for hepatic encephalopathy. CochraneDatabase Syst Rev 2003;(2):CD001939.

8. Barbaro G, Di Lorenzo G, Soldini M, Giancaspro G, BellomoG, Belloni G, Grisorio B, Annese M, Bacca D, Francavilla R,Barbarini G: Flumazenil for hepatic encephalopathy gradeIII and IVa in patients with cirrhosis: An Italian multicenterdouble-blind, placebo-controlled, cross-over study. Hepa-tology 1998;28:374–378.

9. Als-Nielsen B, Gluud LL, Gluud C: Benzodiazepine recep-tor antagonists for acute and chronic hepatic encephalo-pathy. Cochrane Database Syst Rev 2004;(2):CD002798.

10. Cordoba J, Lopez-Hellin J, Planas M, Sabín P, Sanpedro F,Castro F, Esteban R, Guardia J: Normal protein diet for episodic hepatic encephalopathy. J Hepatol. 2004;41:38–43.

11. Larson AM, Curtis JR: Integrating palliative care for livertransplant candidates: “Too well for transplant, too sick forlife.” JAMA 2006;295:2168–2176.

Address reprint requests to:Robert M. Arnold, M.D.

UPMC-Montefiore HospitalUniversity of Pittsburgh

200 Lothrop Street, Suite 933 WestPittsburgh, PA 15213

E-mail: rabob@pitt.edu

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