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Robert Gish, MDMedical Director of the Hepatitis B Foundation San Diego, CAProgram DisclosureThis activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the sponsorship of Purdue University College of Pharmacy and the Chronic Liver Disease Foundation. Purdue University School of Pharmacy is accredited by the ACCME to provide continuing medical education for physicians.This program is supported by an educational grant from Salix Pharmaceuticals.Educational ObjectivesReview current recommendations for the treatment of overt hepatic encephalopathyAssess the benefits of primary prophylactic therapy for cirrhotic patients with covert hepatic encephalopathy and of secondary prophylactic therapy for patients who have recovered from an overt hepatic encephalopathy episodeEvaluate data that suggest cognitive impairment following an episode of overt hepatic encephalopathy may not be completely reversible and that impairment from recurrent episodes of hepatic encephalopathy may be cumulative

82%Following recovery from an overt hepatic encephalopathy (OHE) episode, the percentage survival rate at one year for those who receive no secondary prophylactic therapy is: Following recovery from an OHE episode, experts in the field recommend administration of secondary prophylactic therapy for:

1 month3 months6 monthsAn indefinite period of timeor until liver transplantThe most common precipitating factor for OHE found in a review of 109 patients with 200 hospital admissions for OHE was:

InfectionOpioids and benzodiazepinesLactulose noncomplianceConstipationA patient with cirrhosis who exhibits no signs or symptoms of encephalopathy, but who fails the psychometric hepatic encephalopathy score (PHES) battery of tests would be diagnosed as having:

Covert hepatic encephalopathyWest Haven Grade I overt hepatic encephalopathyWest Haven Grade II overt hepatic encephalopathyAltered mental status due to a cause other than hepatic encephalopathyFollowing recovery from an OHE episode, cognitive impairment:

Is completely reversibleImproves, but only if patient receives a liver transplantMay persistIs usually not a post-OHE sequelaCirrhosisWhat is Cirrhosis?

Trichrome stainFrom http://digestive.niddk.nih.gov/ddiseases/pubs/cirrhosis/. Accessed January 2014.Trichrome stain micrograph from http://en.wikipedia.org/wiki/Cirrhosis. Accessed January 2014.Cirrhosis is a condition in which the liver slowly deteriorates and malfunctions due to chronic injuryFibrosis can lead to increased portal pressures and manifestations of portal hypertensionHepatic veins are absentLiver cell clusters are surrounded by fibrous tissueDefinition of CirrhosisDiffuse fibrosis following hepatocyte destruction and nodular regenerationMultiple causesAsymptomatic (compensated)Symptomatic (decompensated)portal hypertensionhepatic failure

Clinical PresentationAnorexiaWeight lossGeneralized weaknessEasy fatigabilityNauseaVomitingDiarrhea

Spider angiomatasPalmar erythemaGynecomastiaTesticular atrophyAmenorrheaParotid and lacrimal gland hypertrophyDupuytrens contracturesClubbingJaundice

Asymptomatic>Symptomatic ContinuumNatural History of CirrhosisStageDefinition1-year mortalityMedian Survival1Compensated without varices1%>12 years2Compensated with varices3%3Decompensated with ascites without variceal hemorrhage20%~2 years

4Decompensated with/out ascites with variceal hemorrhage57%History --or

Patient presents with signs and symptoms of chronic liver disease or has risk factors for chronic liver disease Physical --or ExaminationPatient has hallmark findings consistent with chronic liver diseaseLaboratory --or StudiesPatient has incidental liver panel abnormalities (e.g., ALT and/or AST) or positive screen for serologic markers of liver disease

Radiographic StudiesPatient has incidental findings suggestive of liver disease on routine studies (e.g., abdominal ultrasonagraphy, CT, MRI)Physical examination findings consistent with liver disease or high suspicion for chronic liver diseaseConfirm history via signs and symptoms of chronic liver disease and positive risk factors Confirm history via signs and symptoms of chronic liver disease and positive risk factors and screen for hallmark physical examination findings(cont)Adapted from Heidelbaugh JJ, Bruderly M. Am Fam Physician 2006;74:756-762.Diagnosis of Cirrhosis and Chronic Liver FailureObtain liver panel* (if not already obtained), CBC with platelets, INR, AFP, AST/ALT ratio, AFP, APRI score, and targeted serologic studies to determine etiology of cirrhosis, highlighting risk factors and family history for liver diseaseObtain abdominal ultrasonography with Doppler with Spleen Size and PV size(if not already preformed) to evaluate for morphologic abnormalities consistentwith cirrhosis and to assess for potential complications (e.g.,ascites, varices, portal hypertension, portal vein thrombosis).Refer for possible liver biopsy if diagnosis of cirrhosis is uncertain,as well as possible determination of etiology via histology if notreadily determinable through serologic testing and if potentialbenefit outweighs risk of procedure*Tests typically include ALT, AST, alkaline phosphatase, and -glutamyltransferase, total, direct and indirect serum bilirubin, and serum albumin.Adapted from Heidelbaugh JJ, Bruderly M. Am Fam Physician 2006;74:756-762.Diagnosis of Cirrhosis and Chronic Liver Failure (cont)

Fibroscan 502 TouchTransient Elastography example: (Fibroscan)Non invasive liver stiffness measurement Received 510(k) clearance from FDA on April 5, 2013Manufactured by Echosens (Paris)Distributed in the United States by Sandhill Scientific, Inc.Courtesy of Echosens. Available at http://www.echosens.com/. Accessed January 2014.Transient Elastography (Fibroscan)Works by measuring sheer wave velocityNon-invasiveHigh concordance with biopsyFibroscan eliminates the need for biopsy in some patientsAfdhal NH. Gastroenterol Hepatol (N Y) 2012;8:605-607. Works by measuring sheer wave velocity; 50-MHz wave passed into liver from a small transducer on the end of an ultrasound probe; Transducer measures the velocity of the shear wave (in meters per second) as the wave passes through the liver; Shear wave velocity can be converted into liver stiffness, which is expressed in kilopascals;Procedure provides better reproducibility and accuracy with 10 valid stiffness measurements at the same measurement point;Test takes 5 7 minutes to perform;Results of the test are instantaneous

17Transient Elastography (Fibroscan)Technical limitations of transient elastographyTesting cannot be performed in all patients Either the test cannot be performed or the results are unreliable in patients who: Have ascitesAre morbidly obeseHave large amounts of chest wall fat

Afdhal NH. Gastroenterol Hepatol (N Y) 2012;8:605-607. Other Methods for ElastographySupersonicARFIMagnetic resonancePrevalence of Cirrhosis1. Schuppan D, Afdhal NH. Lancet 2008;371(9615):838-851.2. Available at http://pubs.niaaa.nih.gov/publications/surveillance83/Cirr05.htm. Accessed January 2014.3. Khungar V, Poordad F. Clin Liver Dis 2012;16:73-89.The prevalence of cirrhosis, both worldwide and in the US, is unknown1Cirrhosis is an outcome of a variety of causes; underlying cause is commonly used for surveillance purposes2Compensated cirrhosis often goes undetected for prolonged periods of time1Experts estimate that up to 5.5 million people in the United States have cirrhosis3Annual Prevalence Rates Between 1996 and 2006 Among HCV-Infected VeteransProgressive Increase in Incidence of HCV-Related Cirrhosis and HCC in USEl-Serag HB. Gastroenterology 2012;142:12641273.

Liver-Related Mortality in the US is Underestimated Liver related mortality in the United states is underestimated by the National Center for Health Statistics (NCHS), in part, as a result of incomplete inclusion of liver-related deathsUse of an updated definition of liver mortality increased the estimated death rate by >2 fold from 11.7 to 25.7 deaths/100,000Asrani, SK et al. Gastroenterology 2013;145:375-382.Year10 % increase*ICD-9-CM diagnosis codes 571.2. 571.5, 571.6; all listed diagnoses. HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD. http://hcupnet.ahrq.gov. Accessed January 2014US Hospital Discharges Due to CirrhosisAre IncreasingHospital Readmissions Among Patients with Decompensated Cirrhosis are CommonRetrospective study of 402 patients from an academic transplant centerFollow-up time censored at death, elective admissions such as transplant or post-procedure observation, or the date of last clinic note; median follow-up was 203 daysPopulation included cirrhotic patients hospitalized for ascites, spontaneous bacterial peritonitis, renal failure, hepatic encephalopathy, or variceal hemorrhageMedian time to first readmission was 67 daysMedian number of readmissions was 2 (range 0-40); overall rate was 3 hospitalizations/person-yearsVolk ML et al. Am J Gastroenterol 2012;107:247-252. % of PatientsHepatic EncephalopathyPrimary complications of cirrhosis include:AscitesJaundiceVariceal hemorrhageHepatic encephalopathyOther complications that can occur include:Hepatocellular carcinomaSpontaneous bacterial peritonitisHepatic hydrothoraxHepatorenal syndromePortopulmonary hypertensionPortal vein thrombosis Hepatopulmonary syndromeNutritional wastingOsteoporosisHepatic Encephalopathy is One of the Primary Complications of CirrhosisLefton HB et al. Med Clin N Am 2009;93:787-799.Hepatic encephalopathy reflects a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction after exclusion of other known brain disease.Hepatic EncephalopathyConsensus recommendation of Working Party on Hepatic Encephalopathy, World Congress of Gastroenterology Ferenci P et al. Hepatology 2002;35:716-721.Total Number of Discharges8% growthYearUS Hospital Discharges Associated with Hepatic Encephalopathy* Are IncreasingHE = hepatic encephalopathy; ICD = International Classification of Diseases. *Data calculated using ICD-9-CM codes 291.2 (alcoholic dementia, not elsewhere classified), 348.30 (encephalopathy, not otherwise specified), and 572.2 (hepatic coma). Includes all listed discharge diagnoses. HCUPnet, Healthcare Cost and Utilization Project. Agency for Healthcare Research and Quality, Rockville, MD. http://hcupnet.ahrq.gov. Accessed January 2014.

InflammationICPNH3Proinflammatory CytokinesNitric Oxide & Oxidative Stress

Glutamate& NH3GlutamineIncreased brain water,deterioration in neuropsychologicalfunction & hepatic encephalopathyCerebralBlood FlowAstrocyteSwellingAstrocyteAdapted from Mullen KD et al. Semin Liver Dis. 2007;27(Suppl 2):32-47. Hepatic Encephalopathy: PathophysiologyTwo Forms of Hepatic Encephalopthy (HE) are RecognizedCovert hepatic encephalopathy (CHE) affects approximately 20% to 60% of patients with liver diseaseHas been called subclinical encephalopathy or minimal encephalopathy (MHE) in the past

Overt hepatic encephalopathy (OHE) occurs in:30% to 45% of cirrhotic patients10% to 50% of patients with TIPS

TIPS = transjugular intrahepatic portosystemic shunt.Mullen KD, et al. Semin Liver Dis. 2007;27(Suppl 2):32-47.Mullen KD, Prakash RK. Clin Liver Dis 2012;16:91-93, Poordad FF. Aliment Pharmacol Ther. 2006;25(Suppl 1):3-9.Characterization of HE StagesNormalCovert HEIIIIIIIVOvert HE StagesCategorization is often arbitrary and varies between ratersSimple ClinicalDiagnosisWorsening cognitive dysfunction comaBajaj JS, et al. Hepatology. 2009;50:2014-2021.Drug NameDrug ClassMechanism of ActionLactulosePoorly absorbed disaccharide Decreases blood ammonia concentration - Promotes elimination of NH3 - Fermentation by bacteria acidify colon and prevent absorption - Reduces urease-producing bacteriaRifaximinNon-aminoglycoside semi-synthetic, nonsystemic antibiotic Decreases blood ammonia concentration - Broad spectrum antibiotic; results in a change in bowel flora - May cause downregulation of intestinal glutaminase activityNeomycinDO NOT USEAminoglycoside antibiotic Decreases blood ammonia concentration - Use limited because of nephrotoxicity and ototoxicity

FDA Approved Treatment Options for Hepatic EncephalopathyAdapted from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM201081.pdf and http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022554lbl.pdf. Accessed January 2014.Drug NameMechanism of ActionLactulose Decreases blood ammonia concentration - Promotes elimination of NH3 - Fermentation by bacteria acidify colon and prevent absorption - Reduces urease-producing bacteria Rifaximin Decreases blood ammonia concentration - Broad spectrum antibiotic; results in a change in bowel flora - May cause downregulation of intestinal glutaminase activityNeomycin Decreases blood ammonia concentration - Inhibits intestinal glutaminase - Use limited because of nephrotoxicity and ototoxicityFDA Approved Treatment Options for Hepatic EncephalopathyAdapted from Khungar V, Poordad F. Clin Liver Dis 2012;16:301320.Non-FDA Approved Treatment Options for Hepatic EncephalopathyDrug NameDrug ClassMechanism of ActionMetronidazoleSynthetic antiprotozoal/ antibacterial agentModulates fecal flora; reduces generation of ammoniaLactobacillus, bifidobacteriumProbioticsModulate fecal flora; reduce generation of ammoniaValine, leucine, isoleucineBranched chain amino acids (BCAA)Correct plasma ratio of BCAAs to aromatic amino acids; may reduce catabolism and muscle breakdown and prevent synthesis of false neurotransmittersSodium benzoate and/or sodiumphenlyacetateNitrogen binding agentsPromotes renal excretionZincTrace mineralMay increase efficiency of urea cycleKhungar V, Poordad F. Clin Liver Dis 2012;16:301320.Al Sibae MR, McGuire BM. Ther Clin Risk Manag 2009;5:617-626.Acute Overt Hepatic EncephalopathyDiagnosis of OHEClinical recognition of the distinctive neurologic features of HEKnowledge that underlying cirrhosis is presentExclusion of all other etiologies of neurologic and/or metabolic abnormalitiesIdentification of precipitating factorsGrading systems to evaluate mental status Portal-systemic encephalopathy score (PSE score; West Haven Criteria) to evaluate overall severityAdapted from:Mullen KD. Semin Liver Dis. 2007;27(suppl 2):3-9.Lawrence KR, Klee JA. Pharmacotherapy. 2008;28(8):1019-1032. ComplicationSurvival at 1 yearSurvival at 3 yearsVarices (non-bleeding) w/o ascites1 97%NAAscites varices1,2 80%50%Bleeding Varices Ascites143%NAHepatic Encephalopathy342%23%Comparative Outcome Probabilities for Various Complications of CirrhosisProjected survival rates 1 year after diagnosis of overt HE are comparable to survival rates of cirrhotic patients with bleeding varicesNA=Not Available

1. Adapted from DAmico G et al. J Hepatol 2006;44:217-231. 2. Arroyo V, Colmenero J. J Hepatol. 2003;38:S69-S89. 3. Adapted from Bustamante et al. J Hepatol. 1999;30:890-895. 100806040200Survival, %012243648Months42% survival at 1 year23% survival at 3 yearsOvert HE is Associated with aPoor Prognosis