New treatments for hepatic encephalopathy

Educational Objectives

The goal of this program is to improve the diagnosis and treatment of hepatic encephalopathy (HE). After hearing and assimilating this program, the clinician will be better able to:

1. Identify and correct the precipitating factors in patients with hepatic encephalopathy (HE).

2. Consider rifaximin as an alternative to lactulose in the management of patients with HE.

Summary

Hepatic encephalopathy (HE): defined as disturbance in central nervous system function due to hepatic insuffi­ciency; can occur both in acute liver failure (ALF) and CLD; part of definition of ALF; component of Child-Tur­cotte-Pugh scoring (followed after liver transplantation to confirm functionality of graft); HE in setting of CLD usually reversible if precipitating factor identified

Categories of HE: type A  —  associated with ALF; type B  —caused by portosystemic shunt; type C  —  occurs in set­ting of cirrhosis; type C subcategorized as episodic (may be spontaneous [precipitating factor unrecognized] or re­current), persistent, and minimal (persistent mild HE can lead to subtle problems such as impaired quality of life [QOL] and decreased responsiveness; more overt persistent HE can present with parkinsonian-like symptoms [eg, flat affect])

Pathophysiology: proteins (nitrogen-containing compounds) that enter intestine broken down by bacteria; absorbed through gut and transported as ammonia through portal vein to liver; normal functioning liver converts ammonia to excretable form; in patients with hepatic insufficiency, ammonia accumulates in bloodstream, crosses blood-brain barrier, and causes alterations in cognitive function; in rare cases, encephalopathy caused by portosystemic shunt without associated liver disease (eg, in pediatric patients; patients who have received transjugular intrahepatic por­tosystemic shunt [TIPS]; patients with CLD and cirrhosis who have spontaneous splenorenal shunt)

Precipitating factors: include gastrointestinal (GI) bleeding, infection, electrolyte disturbances (eg, changes in so­dium and potassium levels [common in patients taking diuretics and those with dehydration]); constipation; medi­cations (especially benzodiazepines); dietary proteins (controversial; in general, intake of dietary protein not restricted, except in patients with extremely refractory HE); portosystemic shunt (TIPS often used in patients with symptomatic portal hypertension; HE follows placement of TIPS in »30% of cases; can usually be treated medi­cally)

Staging severity of disease: West Haven criteria  —  grade 1 (minimal changes [eg, trivial lack of awareness, short­ened attention span]); grade 2 (lethargy; disorientation to time or place; inappropriate behavior; difficulty with more complex cognitive functions); grade 3 (frank confusion; somnolence); grade 4 (coma); grade 3 trigger point at which patient may not be able to protect airway; much of criteria extremely subjective (can be difficult to distin­guish one grade from another); international consensus group recently proposed simplified staging system that dis­tinguishes only between covert (grade 1) and overt (grades ³2) HE; in patient with covert HE, mental status unimpaired, but some subtle findings present (diagnosis usually requires more extensive neuropsychiatric testing); symptoms of HE occur over spectrum (rather than in discrete stages)

Diagnosis: essentially one of exclusion; presence of asterixis on PE aids diagnosis; testing serum ammonia level has fallen out of favor as diagnostic tool (poor correlation with clinical progression of disease, except in patients who present with ALF [in whom ammonia level prognostic marker for outcome])

Treatment: mainstay supportive care; identify and correct precipitating factors; lactulose still first-line medical ther­apy; after initial episode of HE has been reversed, address long-term therapy to prevent recurrence; new-onset HE in patient with CLD suggests disease progression (consider evaluation for liver transplantation)

Lactulose: nonabsorbable disaccharide; in acute HE, should be administered frequently as cathartic; for mainte­nance, have patient take it at frequency that keeps bowels moving regularly; many side effects (particularly bloat­ing; if used too frequently, can cause significant free water loss and hypernatremia); robust clinical data on efficacy sparse

Alternatives to lactulose: antibiotics  —  neomycin (out of favor due to side effects [eg, ototoxicity, renal failure); metronidazole (eg, Flagyl, Metryl, Protostat); some risks associated with long-term use, particularly neurotoxic­ity]; rifaximin

Rifaximin: initially approved by Food and Drug Administration (FDA) for treatment of traveler’s diarrhea; advantages  —nonabsorbable antibiotic (can be used long-term without risk of inducing resistance); targets co­lonic bacteria directly; several studies have found drug at least as beneficial as lactulose; 2010 trial of rifaximin for HE  —  »300 patients with episodic HE randomized to rifaximin (550 mg bid) vs placebo, and followed for 6 mo; primary end point breakthrough HE; >90% of patients also on lactulose; breakthrough HE occurred in 22% of patients on rifaximin, vs 45% on placebo; time to first breakthrough episode, number of hospitalizations for re­current HE, and time to first HE-related hospitalization all significantly better in rifaximin group; no long-term adverse side effects noted; landmark trial (results led to FDA approval of rifaximin for prevention of recurrent HE)

Minimal HE (MHE): occurs in 50% to 80% of patients with cirrhosis; patients have normal findings on conventional neurologic examination, but have abnormal results on psychometric testing; can affect attention span and sleeping patterns; associated with higher rates of motor vehicle accidents and impaired QOL; psychometric testing time con­suming (may need to refer patient); however, several quick tests that can be completed in office available (eg, num­ber connection test, block design test, digit symbol test); treatment  —  recent studies have shown some benefit from treatment with lactulose, probiotics, and rifaximin

Questions and Answers

Clostridium difficile colitis and rifaximin: risk shown to be minimal

Mini Mental State Examination in patients with MHE: might be good tool for quick office assessment; speaker tends to ask patients with MHE questions about day-night sleep reversal and computational activities (eg, trouble balancing checkbook or paying bills, serial 7s)

Best management for patient with HIV and diarrhea who has HE: rifaximin safe; speaker adds that recent studies have found that rifaximin has some activity against C difficile

Cost of rifaximin: expensive, but most insurance companies reimburse cost since FDA approval

Treatment of HE with laxatives other than lactulose: speaker has prescribed polyethylene glycol 3350 (eg, Clear­lax, GlycoLax, MiraLax) off-label as alternative (better tolerated, but studies of efficacy in treatment of HE lack­ing)

f this program.

 

Readings

Suggested Reading

Aragon G, Younossi ZM: When and how to evaluate mildly elevated liver enzymes in apparently healthy patients. Cleve Clin J Med 2010 Mar;77(3):195-204; Bajaj JS et al: Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology  2011 Feb;140(2):478-487; Bai M et al: Predictors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in cirrhotic patients: a systematic review. J Gastroenterol Hepatol 2011 Jun;26(6):943-51; Donnan PT et al: Development of a decision sup­port tool for primary care management of patient with abnormal liver function tests without clinically apparent liver dis­ease: a record-linkage population cohort study and decision analysis (ALFIE). Health Technol Assess 2009 Apr;13(25):iii-iv, ix-xi, 1-134; Flamm SL: Rifaximin treatment for reduction of risk of overt hepatic encephalopathy recurrence. Therap Adv Gastroenterol 2011 May;4(3):199-206; Giannini EG, et al: Liver enzyme alteration: a guide for clinicians. CMAJ 2005 Feb 1;172(3):367-79; Klinken E, MacQuillan G: Lactulose a day keeps encephalopathy at bay. J Gastroenterol Hepatol 2011 Jun;26(6):939-40; Krier M, Ahmed A: The asymptomatic outpatient with ab­normal liver function tests. Clin Liver Dis 2009 May;13(2):167-77; McLernon DJ et al: Health outcomes following liver function testing in primary care: a retrospective cohort study. Fam Pract 2009 Aug;26(4):251-9l; Montgomery JY et al: Advances in the evaluation and management of minimal hepatic encephalopathy. Curr Gastroenterol Rep 2011 Feb;13(1):26-33; O'Brien CB: The hospitalized patient with abnormal liver function tests. Clin Liver Dis 2009 May;13(2):179-92; Prakash R, Mullen KD: Mechanisms, diagnosis and management of hepatic encephalopathy. Nat Rev Gastroenterol Hepatol 2010 Sep;7(9):515-25; Rochling FA: Evaluation of abnormal liver tests. Clin Corner­stone 2001;3(6):1-12; Romero-Gómez M: Pharmacotherapy of hepatic encephalopathy in cirrhosis. Expert Opin Pharmacother 2010 Jun;11(8):1317-27; Sanyal A et al: Randomised clinical trial: rifaximin improves health-related quality of life in cirrhotic patients with hepatic encephalopathy - a double-blind placebo-controlled study. Aliment Pharmacol Ther 2011 Oct;34(8):853-861; Shah AA et al: Analysis of elevated liver enzymes in an acute medical set­ting: jaundice may indicate increased survival in elderly patients with bacterial sepsis. Saudi J Gastroenterol 2010 Oct-Dec;16(4):260-3; Sidhu SS et al: Rifaximin improves psychometric performance and health-related quality of life in patients withminimal hepatic encephalopathy (the RIME Trial). Am J Gastroenterol 2011 Feb;106(2):307-16; Toris GT et al: Hepatic encephalopathy: an updated approach from pathogenesis to treatment. Med Sci Monit 2011 Feb;17(2):RA53-63; Zafirova Z, O'connor M: Hepatic encephalopathy: current management strategies and treat­ment, including management and monitoring of cerebral edema and intracranial hypertension in fulminant hepatic failure. Curr Opin Anaesthesiol 2010 Apr;23(2):121-7.

 

Disclosures

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Chang is a consultant for Gil­ead, Onyx Pharmaceuticals, and Vertex Pharmaceuticals. The planning committee reported nothing to disclose. 

Acknowledgements

Dr. Chang spoke at 7th Annual Challenges in Internal Medicine, held June 22-24, 2011, in New York, NY, and presented by Mount Sinai School of Medicine. For upcoming CME events presented by Mount Sinai School of Medicine, go to Mount Sinai’s website at www.mmsn.edu and click on “Continuing Medical Education.” The Audio-Digest Foundation thanks the speaker and the sponsor for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

IM584702

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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