Carol Rees Parrish, R.D., M.S., Series Editor Hepatic .
NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #95Carol Rees Parrish, R.D., M.S., Series EditorHepatic Encephalopathy:Are NH4 Levels and ProteinRestriction Obsolete?Peter CaruanaNeeral ShahMeasurement of plasma ammonia and restriction of dietary protein were once standard practice in the management of hepatic encephalopathy. Recent evidence, however,suggests that ammonia levels have little value in the diagnosis of hepatic encephalopathy. Furthermore, protein restriction may have adverse consequences in cirrhoticpatients prone to malnutrition. With a review of the current literature, the followingarticle addresses these controversial issues and discusses current recommendations forthe diagnosis and treatment of hepatic encephalopathy.INTRODUCTIONepatic encephalopathy is a major complication ofacute and chronic liver disease. This neuropsychiatric syndrome presents clinically with abnormalities in mental status and neuromotor function.Symptoms exist on a spectrum ranging from subtledeficits in attentiveness to severe confusion and evencoma. The pathogenesis of this disease is not fullyunderstood, but the accumulation of gut-derived neurotoxins in the setting of hepatic insufficiency remainsHPeter Caruana, University of Virginia School ofMedicine, Charlottesville, VA. Neeral Shah, M.D.,Assistant Professor, Division of Gastroenterology andHepatology, University of Virginia, Charlottesville, VA.6PRACTICAL GASTROENTEROLOGY MAY 2011central to current investigations. Over 5.5 million people in the United States have been diagnosed with cirrhosis.1 Of this population, 30–45% of patients developovert hepatic encephalopathy during the course of theirdisease.2 This debilitating condition can negativelyimpact quality of life for patients and their families.1Furthermore, admissions for hepatic encephalopathycommonly result in prolonged hospital stays and acostly burden on our health care system.2Hepatic encephalopathy is usually classified intothree groups differentiated by the absence or presenceof liver disease: encephalopathy due to acute liver failure (Type A), portosystemic shunting without associated liver disease (Type B), and cirrhosis with portalhypertension (Type C).3 Further subdivisions distin-
Hepatic EncephalopathyNUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #95guish episodic and persistent hepatic encephalopathyfrom the clinical entity known as minimal hepaticencephalopathy.A boom of research has recently occurred in thearea of minimal hepatic encephalopathy. This condition is highly prevalent among patients with cirrhosis,affecting up to 80% of this population.4 Unlike overthepatic encephalopathy, patients with minimal hepaticencephalopathy may lack obvious clinical symptoms.Often, the subtle symptoms of minimal hepaticencephalopathy can only be diagnosed through specialized neuropsychiatric testing.3 This condition isbest described as a disorder of executive functioning.Patients have deficits in vigilance, response inhibition,working memory, and orientation.5 Minimal hepaticencephalopathy has been shown to decrease quality oflife and interfere with daily functioning such as theability to safely operate an automobile.4PATHOPHYSIOLOGYThe specific mechanisms underlying the pathogenesisof hepatic encephalopathy are still under investigation.Episodes are usually precipitated by factors thatincrease inflammation or ammonia production.6 Thereis agreement that ammonia is a key toxin involved inthe disease process. Current research is aimed at characterizing the effects of inflammation, oxidative stressand other factors working in synergy with ammonia toTable 1.Precipitants of Hepatic Encephalopathy Gastrointestinal bleedingInfectionDehydration secondary to diuretic useDiarrheaVomitingHyponatremiaShunting procedures (transjugular intrahepaticportosystemic shunts—TIPS)ConstipationBenzodiazepine useNarcotic useNoncompliance with lactulose therapyproduce astrocyte swelling as a common pathwaytowards cerebral dysfunction.7There are many possible precipitants of hepaticencephalopathy including gastrointestinal bleeding,infection, and dehydration secondary to diuretic use,diarrhea, or vomiting. Other causes include hyponatremia, shunting procedures (transjugular intrahepaticportosystemic shunts—TIPS), constipation, etc. (seeTable 1). Each of these precipitants has the potential toincrease ammonia production/absorption, increaseinflammation, or reduce cognitive reserve.6 Renal failure can also contribute to increased ammonia levelsdue to a relative decrease in renal excretion.5The Role of AmmoniaIn humans, the colon is a major site of ammonia production. Ammonia is a by-product of intestinal bacterial metabolism of protein and other nitrogenouscompounds. Intestinal enterocytes also contribute toammonia production through the utilization of glutamine.8 In healthy individuals, ammonia is converted tourea in the liver, which is then excreted by the kidneys.In patients with liver failure or portosystemic shunting,ammonia bypasses liver metabolism and accumulatesin systemic circulation. This ammonia then undergoesmetabolism at extrahepatic sites such as skeletal muscle and brain tissue. In the central nervous system,astrocytes are the glial cells that provide nutrients,maintain extracellular ion balance, and express theenzyme glutamine synthetase which converts ammonia to glutamine.7 Exposure of astrocytes to toxic levels of ammonia and subsequent accumulation ofglutamine causes changes that may explain the neuronal dysfunction seen in hepatic encephalopathy.Astrocytes exposed to ammonia for prolongedperiods can undergo a morphologic change toAlzheimer’s type 2 astrocytes characterized by largenuclei, prominent nucleoli, and marginated chromatin.5 Prolonged exposure to ammonia can alsocause a shift in the balance of neurotransmission toresult in overall inhibition of post-synaptic potentials.This neuroinhibitory state is characteristic of thehepatic encephalopathy seen in patients with chronicliver disease. Accumulated glutamine acts as anosmolyte within astrocytes, causing cellular swellingPRACTICAL GASTROENTEROLOGY MAY 20117
Hepatic EncephalopathyNUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #95Table 2.Symptoms Associated with Hepatic EncephalopathyCognitive findings include: Altered consciousness Shortened attention span Disorientation Memory impairment Affective/emotional disturbancesMotor findings can include: Asterixis Hyperreflexia Rigidityand low-grade cerebral edema disturbing the cerebraloscillatory networks.7 Glutamine also increases theoxidative stress within astrocytes causing protein andRNA modifications which impact synaptic plasticityand glioneuronal communication.9 Studies suggest thecombined effects of astrocyte swelling and oxidativestress cause the decline in brain function seen inhepatic encephalopathy. Researchers are currently trying to define how other factors such as inflammation,infection, hyponatremia, and sedative/narcotic usemay work synergistically with ammonia to promoteastrocyte changes and symptom progression.DIAGNOSISOvert hepatic encephalopathy is a clinical diagnosisbased on the presence of impaired mental status andneuromotor functioning. The West Haven Criteria is aclinical scale used to assess patients’ cognitive, behavioral, and motor function. Patients are assigned a gradebased on the presence of specific symptoms and theirseverity (see Table 2).9,10 The constellation of symptoms seen in hepatic encephalopathy is not specific tothis disease; therefore, the diagnosis is usually established on the basis of exclusion. Laboratory and imaging studies can be helpful in ruling out alternativediagnoses and identifying precipitating causes.3 Thediagnosis and grading of hepatic encephalopathy ischallenging given the fluctuant course of symptoms,lack of objective clinical markers, and subjectiveassessment by physicians. Currently, researchers are8PRACTICAL GASTROENTEROLOGY MAY 2011investigating the speed of involuntary eye movements(saccadic eye movements) as an objective marker forhepatic encephalopathy.11Utility of Ammonia LevelsThe determination of plasma ammonia (NH4) levels isoften performed in the clinical setting to support thediagnosis of hepatic encephalopathy. However, thispractice has been scrutinized over the past decade withpoor correlation between NH4 levels and hepaticencephalopathy.12 Many conditions unrelated to liverdisease can result in elevated NH4 levels. Compared tocontrols, plasma NH4 levels are generally higher inpatients with liver disease; however, the use of plasmaNH4 levels as a diagnostic marker for hepaticencephalopathy presents many challenges. Poor phlebotomy technique can artificially elevate NH4 measurements.13 It is also unclear if NH4 measurementsfrom peripheral circulation truly reflect NH4 concentrations at the blood-brain barrier.14 Most convincingare the recent studies that have shown little or no correlation between NH4 concentration and severity ofhepatic encephalopathy.Ong et al. compared four different measurementsof NH4 concentration (arterial and venous total, arterial and venous partial pressure) in 121 patients withcirrhosis and grade 0–4 hepatic encephalopathy.14Even though this study showed a moderate correlationbetween all four measurements and grade of hepaticencephalopathy, there was significant overlap in NH4levels between patients with and without hepaticencephalopathy. The researchers concluded that singleNH4 levels have little clinical utility in the diagnosis ofhepatic encephalopathy.In a smaller study of 20 patients with chronic liverfailure, Kundra et al. found no statistically significantcorrelation in the patients with elevated NH4 levelsand the presence of hepatic encephalopathy.15Researchers concluded that NH4 levels were not usefulin making the diagnosis of hepatic encephalopathy.In another study, Nicalao et al. measured NH4 levelsin 27 cirrhotics recovering from hepatic encephalopathy.12 Ammonia levels were either unchanged orincreased in 17 patients after complete clinical resolution(continued on page 13)
Hepatic EncephalopathyNUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #95(continued from page 8)of their hepatic encephalopathy episode. This studyhighlighted the minimal utility of sequential NH4 levelsin the management of hepatic encephalopathy.Plasma NH4 levels are neither required to makethe diagnosis of hepatic encephalopathy, nor helpful inmonitoring the effectiveness of NH4-lowering therapies. Therefore, the routine determination of NH4 levels in patients with suspected encephalopathy is notindicated. Current standard of care dictates thatpatients diagnosed with hepatic encephalopathy aretreated with ammonia-lowering therapies regardless ofplasma NH4 levels and monitored clinically forimprovement in mental function.TREATMENTThe approach to patients with suspected hepaticencephalopathy involves identifying and treating precipitating causes, ruling out alternative diagnoses, andinitiating ammonia-lowering therapy. The two majortherapies used to reduce circulating NH4 are nonabsorbable disaccharides and oral antibiotics. Boththerapies are directed at the gut, and reduce intestinalproduction and absorption of NH4.4 Lactulose, the primary non-absorbable disaccharide used in the UnitedStates, is fermented by colonic bacteria, resulting inthe production of organic acids. These organic acidslower colonic pH, favoring the survival of acid resistant, non-urease producing bacteria. Therefore, urea,NH3, is converted to ammonium, NH4, (the lessabsorbable form) and trapped in the colon preventingabsorption and systemic effects. Lactulose also has alaxative effect, further promoting the elimination ofurea through the evacuation of colonic contents.16Lactulose possesses a large side effect profile,which presents many challenges to its success in thesepatients. Many patients find its taste unpalatable, andsignificant gastrointestinal symptoms are common.Nausea, vomiting, and severe diarrhea are commonside effects and can lead to dehydration and noncompliance.4 In 2004, a systematic review of randomizedtrials found insufficient evidence to support or refutethe use of non-absorbable disaccharides for the treatment of hepatic encephalopathy.17 However, a studypublished in 2009 by Sharma et al. found lactulose tobe superior to placebo in the secondary prophylaxis ofhepatic encephalopathy in the outpatient setting. Mostclinicians still consider lactulose as their primary agentto prevent hepatic encephalopathy.16 During periods ofseverely altered consciousness which prohibits oralintake, lactulose enemas can be used to treatencephalopathy. Often, enema administration is difficult and can be associated with decreased efficacyfrom oral administration due to large variation in dwelltimes and medication exposure. Nutrition editors note:given the level of malnutrition often seen in thesepatients, placing a nasogastric feeding tube (orogastricif mechanically ventilated) would allow both feedingand more efficacious delivery of lactulose until mentalstatus clears or patient able to eat adequately. Further,enemas should also be considered a viable option ifpatients do not have bowel movements and begin toexperience severe bloating and distention. As weimprove our understanding of hepatic encephalopathy,the development of other agents with fewer sideeffects may change our current algorithm for treatmentand prevention in the future.Other agents for the treatment of hepaticencephalopathy include several oral antibiotics. Thesemedications work by reducing the number of ammoniaproducing bacteria present in the gut. Neomycin andmetronidazole have been used successfully for this purpose. However, the concerns of nephrotoxicty and ototoxicity with neomycin and peripheral neuropathy withmetronidazole have justifiably limited the use of theseagents.5 Rifaximin, a gut-selective antibiotic with lowsystemic bioavailability, was recently approved for usein chronic hepatic encephalopathy. A study publishedby Bass et al. in 2010 showed that rifaximin plus lactulose is more effective than lactulose alone in thesecondary prophylaxis of hepatic encephalopathy.1Recent studies have examined the role of rifaximin inthe treatment of minimal hepatic encephalopathy.18,19Sidhu et al. evaluated the efficacy of rifaximin inimproving neuropsychometric test (NP) performanceand health-related quality of life (HRQOL) in patientswith minimal hepatic encephalopathy.19 This trialdemonstrated that rifaximin significantly improved NPperformance and HRQOL after 8 weeks compared toplacebo. Researchers concluded that rifaximin is asafe and effective treatment for minimal hepaticencephalopathy (MHE), and suggested that all patientsPRACTICAL GASTROENTEROLOGY MAY 201113
Hepatic EncephalopathyNUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #95Table 3.Factors Associated with Malnutrition in Cirrhotic PatientsDecreased Intake Anorexia Early satiety Ascites Altered mental status/encephalopathy Frequent hospitalizationsDecreased Absorption Inadequate bile flow Bacterial overgrowth Pancreatic insufficiencyMetabolic alterations Increased or decreased metabolic rate Increased protein requirements Glucose intolerance/insulin resistance Rapid postprandial gluconeogenesis Reduced glycogen stores Elevated leptin Elevated TNF-α Decreased insulin-like growth factor-1Iatrogenic Factors Excessive dietary restrictions Intolerance of hospital food Frequent Paracentesis Diuresis (micronutrient losses) Lactulose therapywith cirrhosis be screened for minimal hepaticencephalopathy. In a related study, Bajaj et al. assessedthe efficacy of rifaximin in improving driving simulator performance in patients with MHE.18 Theresearchers found that patients receiving rifaximingroup showed significant improvement in total drivingerrors after 8 weeks compared to placebo.Rifaximin lacks the side effect profile of neomycinand metronidazole and is well tolerated. Insurancecoverage and cost have been limiting factors in its use,but with its recent FDA approval this may mitigatethose issues for patients and increase its accessibility.With any long-term antibiotic therapy there is alwaysa potential for developing drug resistance orClostridium difficile infection. If more patients are14PRACTICAL GASTROENTEROLOGY MAY 2011placed on antibiotics for hepatic encephalopathy in thecoming years, these adverse events may become moreapparent.Utility of Protein RestrictionMalnutrition is well documented in cirrhotic patients,with higher rates found in patients with liver diseasesecondary to excessive alcohol consumption.20 Theneed for increased caloric needs is often evident andwidely agreed upon. However, proper levels of proteinreplacement in cirrhotic patients is controversial.Dietary protein restriction has been suggested in thetreatment of hepatic encephalopathy as a means toreduce the nitrogenous load entering the gut, therebyreducing NH4 production and absorption. Conversely,accelerated protein catabolism in liver diseasepatients may require higher levels of protein loads formaintenance.10 Cirrhotic patients require on average0.8–1.3 g protein/kg/day to maintain their nitrogenbalance as compared to 0.6 g protein/kg/day in healthypatients.21Cordoba et al. performed a randomized controlledtrial in 20 cirrhotic patients with hepatic encephalopathy comparing protein-restricted diets to normal protein diets.22 There was no difference in the course ofthe disease between the two groups; however, higherprotein breakdown was documented in the proteinrestricted group. Researchers concluded that there areno benefits to restricting protein intake. Rather, significant adverse nutritional consequences may resultwhen protein is limited. In cirrhotic patients, poornutritional status is a major risk factor for mortality.6Malnutrition in these patients is multifactorial (seeTable 3). When protein requirements are not achieveddue to limitations with restricted diets, increased skeletal muscle breakdown releases nitrogen-containingamino acids that contribute to NH4 production, prolonging the course of encephalopathy. For these reasons, protein restriction is no longer recommended forthe treatment of hepatic encephalopathy and possiblycould be harmful. Patients should be started on a normal protein diet and treated with the proper medicaltherapies for encephalopathy episodes.(continued on page 17)
Hepatic EncephalopathyNUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #95(continued from page 14)Table 4.Comparison of Standard Enteral Products with Hepatic FormulasCalories/mLProteing/1000 Kcal% Fat(%MCT)% Fat1000 Kcal*1.173528 (0) 51.981.540 g(26 BCAA)12 (70) 44.501.54538 (30) 6.78Jevity 1.5(Ross)1.54329 (19) 4.40Osmolite 1.5(Ross)1.54229 (20) 4.47Nutren 1.5(Nestle)1.54040 (50) 6.00ProductHepatic FormulasHepatic-Aid II(Hormel Healthlabs)NutriHep(Nestle)Standard FormulasIsosource 1.5(Nestle)*Cost information obtained from company toll-free # (March 2011); does not include tax and shipping. Nestle Nutrition: (888) 240-2713; www.nestlenutritionstore.com Abbott Nutrition: (800) 258-7677; www.abbottnutrition.com www.4webmed.com: (877) 493-2633*Used with permission from the University of Virginia Health System Nutrition Support Traineeship Syllabus23Branched Chain Amino Acids (BCAA)CONCLUSIONThe possibility of dietary modifications with branchedchain amino acids (BCAA) to avoid complications ofencephalopathy are often considered. However, trialsof specialized BCAA formulas are limited by the smallnumber of patients enrolled, the lack of adequate feeding in the “control” group, or the failure to providestandard “anti-encephalopathic” agents (such as lactulose) during the study. Branched chain amino acid formulas should be rarely used due to their expense andquestionable efficacy, and reserved only for thosepatients who appear intolerant of adequate proteinfrom standard formulas and after all other efforts havefa
6 PRACTICAL GASTROENTEROLOGY † MAY 2011 Hepatic Encephalopathy: Are NH 4 Levels and Protein . cialized neuropsychiatric testing.3 This condition is . nia to glutamine.7 Exposure of astrocytes to toxic lev-els of ammonia and subsequent accumulation of
Revenge of the Cyst –Part II NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #55 Joe Krenitsky, MS, RD, Nutrition Support Specialist; Diklar Makola, MD, MPH, PhD, Gastroen-terology Fellow; Carol Rees Parrish MS, RD, Nutrition Support Specialist all at Digestive Health Center of Excellence, University of Virginia Health System, Charlottesville, VA.
Parrish Village News. page 2 Parrish Village News Official publication of the Parrish Civic Association, a non profit coporation. P. O. Box 257 Parrish, FL 34219
WEST COAST HOTEL CO. v. PARRISH. 379 Syllabus. WEST COAST ttOTEL CO. v. PARRISH ET AL. APPEAL FROM THE SUPREME COURT OF WASHINGTON. No. 293. Argued December 16, 17, 1936.-Decided March 29, 1937. 1. Deprivatio
WEST COAST HOTEL CO. v. PARRISH. 379 Syllabus. WEST COAST ttOTEL CO. v. PARRISH ET AL. APPEAL FROM THE SUPREME COURT OF WASHINGTON. No. 293. Argued December 16, 17, 1936.-Decided March 29, 1937. 1. Deprivation of liberty to contract is forbidden by the Constitution if without due process of law; but restraint or regulation of this .
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Carol’s mother, Emilia, dies when Carol is just 8 years old. Young Carol takes the Blessed Virgin Mary as his mother. Carol enters a secret seminary in 1942, and is ordained a priest in 1946. Carol Wojtyla is elected Pope in 1978, and takes the name John Paul II. Pope John Paul II travels to more countries and canonizes more saints than
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