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Breaking News in Hepatic Encephalopathy CME

www.medscape.org/interview/hepatic-encephalopathy


Supported by an independent educational grant from Salix Pharmaceuticals, Inc.


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Target AudienceThis activity is intended for gastroenterologists, primary care physician, and emergency medicine physicians.

GoalsThe goal of this activity is to educate clinicians about emerging data presented at recent medical conferences on the diagnosis and management of hepatic encephalopathy (HE).

Learning ObjectivesUpon completion of this activity, participants will:

• Have increased knowledge regarding the recent data on HE presented at major medical conferences• Have greater competence related to applying principles for cost-effective management of HE based on real-world data

Credits AvailablePhysicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

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For Physicians

Medscape, LLC designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This article is a CME activity.To earn credit for this activity visit:


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Disclosures

Faculty

Jasmohan S. Bajaj, MD

Tenured ProfessorDepartment of Internal MedicineDivision of Gastroenterology, Hepatology, and NutritionVirginia Commonwealth University School of Medicine and McGuire VA Medical CenterRichmond, Virginia

Disclosure: Jasmohan S. Bajaj, MD, has disclosed the following relevant financial relationships: Served as an advisor or consultant for: Merz Pharmaceuticals; Norgine; Valeant Pharmaceuticals InternationalReceived grants for clinical research from: Grifols; Valeant Pharmaceuticals International

Editors

Roderick Smith, MS

Medical Education Director, Medscape, LLCDisclosure: Roderick Smith, MS, has disclosed no relevant financial relationships.

CME/Content Reviewer

Esther Nyarko, PharmD

Associate Clinical CME DirectorDisclosure: Esther Nyarko, PharmD, has disclosed no relevant financial relationships.

Nurse Planner

Amy Bernard, MS, BSN, RN-BC

Lead Nurse PlannerDisclosure: Amy Bernard, MS, BSN, RN-BC, has disclosed no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has disclosed no relevant financial relationships.

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Introduction

Hepatic encephalopathy (HE) describes a spectrum of neuropsychiatric abnormalities often seen in patients with chronic liver failure and cirrhosis.[1] Development of HE usually portends a poor prognosis, including increased risk for hospitalizations, mortality, and the need for liver transplantation.[2] The pathogenesis of HE is multifactorial, but is related to a buildup of ammonia in extrahepatic tissues, which is converted into metabolites that act as neurotoxins in the brain.[3,4] Clinical severity of HE is graded on a scale ranging from covert HE (minimal and Grade 1) through progressively more severe cognitive impairment and coma (overt HE; Grades 2-4).[5] Overt HE (OHE) affects up to 20% of patients with liver cirrhosis each year.[1] Up to 80% of patients with cirrhosis will experience some form of HE during their lifetime.[6]

The economic costs of HE are substantial and rising: from 2005 to 2009, costs of HE-associated hospitalizations rose from $4.68 billion to $7.25 billion.[2] Mean hospitalization costs (2012) for patients with HE have been reported to range between $25,634 and $58,625.[7]

Medscape spoke with Dr Jasmohan Bajaj to get his perspective on emerging data from recent conferences and publications on the diagnosis and management of HE.

Medscape: Several studies were presented at the 2019 meeting of the European Association of the Study of the Liver (EASL) that evaluated and compared diagnostic tests for minimal HE (MHE). Could you discuss a couple of them?

Jasmohan Bajaj, MD: Diagnosing HE in practice can be challenging due to the broad spectrum of clinical manifestations. MHE/CHE (minimal/covert HE), the mildest form of the disorder, is both underdiagnosed and clinically significant. Development of CHE in a patient with cirrhosis can herald a diminished quality of life, car accidents, falls, and progression to OHE.[5,8] It is therefore important for clinicians to be able to diagnose CHE quickly and accurately in the clinic.[3] Current HE guidelines recommend using at least 2 tests, if available, every 6 months to screen for MHE in the clinical setting or in clinical studies when more than 1 site is included.[5] However, it is important that local population norms be applied, and 1 test may be adequate if only 1 site is included.

At EASL, Gupta and colleagues presented findings from a study comparing 3 validated tests for MHE/CHE -- the psychometric hepatic encephalopathy score (PHES), sometimes called the “gold standard” test for HE, the EncephalApp Stroop test (Stroop), and the Critical Flicker Frequency (CFF) -- in 72 patients with cirrhosis.[8] Among the 3 tests, the Stroop test had the highest sensitivity (86%) compared to the CFF (71%) and the PHES (57%) for predicting progression to OHE in the following 6 months.[8] A second study presented at EASL by Taru and colleagues found the Stroop test to be superior to the CFF in diagnosing MHE in 85 patients with compensated liver cirrhosis.[9] These studies further validate the Stroop test for diagnosing MHE and predicting development of OHE.

An even simpler test for CHE is the Animal Naming Test (ANT), in which the patient is asked to name as many animals as possible in 1 minute.[10] A study published by an Italian group provided proof-of-concept for the utility of the ANT in diagnosing HE.[10] At EASL, Taneja and colleagues presented their findings from a comparison of the ANT with the PHES for the diagnosis of MHE and prediction of progression to OHE.[11] In this study, the ANT had a sensitivity of 89%, specificity of 96%, and a diagnostic accuracy for MHE of 93%. Out of 36 patients with an abnormal ANT, 14 developed OHE on follow up compared with 14 of 37 patients with an abnormal PHES.[11] This study validates the ANT as a simple and reliable test to predict OHE episodes in patients with cirrhosis.

Medscape: How does a clinician distinguish between HE and cognitive impairment due to other causes related to metabolic disorders?

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Dr Bajaj: This is an important question in the era of highly effective antiviral therapy for hepatitis C virus (HCV) infection. In the coming years we’re likely to see a shift away from HCV infection as a leading cause of cirrhosis and toward non-alcoholic fatty liver disease (NAFLD) with associated metabolic syndrome comorbidities. Patients with metabolic syndrome can have cognitive dysfunction from a variety of causes, such as diabetes mellitus, hypertension, and obstructive sleep apnea, which may be difficult to differentiate from HE.

Bar and colleagues presented data at EASL from 68 patients with NAFLD who were asked to report 5 HE-related complaints (confusion, sleep-wake disturbance, daytime somnolence, lack of concentration or energy) and who underwent laboratory tests, transient elastography, and HE testing (pen-and-paper tests, Stroop test, inhibitory control test, and CFF).[12] Two-third of patients in the study had at least 1 HE complaint, 33 (49%) had 2 complaints, and 19 (28%) had 3 or more complaints. From the abstract it was unclear whether or not all patients had cirrhosis. Potential MHE diagnosis was considered when at least 2 HE tests were abnormal. The researchers found that, in addition to stage of liver fibrosis, hypertension, duration of diabetes, and age were all associated with abnormal HE tests. Further, while having 3 or more HE complaints was not associated with severity of liver disease, it was associated with hypercholesterolemia and diabetic microvascular complications.[12]

This study raises important questions about the sensitivity vs specificity of tests used to diagnose or quantify the severity of HE in certain patients. It appears that, in a modest number of NAFLD patients, tests and symptoms that identify patients as cognitively impaired are sensitive, but not specific, for HE. Therefore, due to loss of specificity in patients with metabolic syndrome, screening tests for MHE or CHE should be used only in patients with documented cirrhosis.

Medscape: Hospital admissions and readmissions in patients with HE is one of the leading drivers of healthcare expenditures in advanced cirrhosis. There were a couple of abstracts at EASL and Digestive Disease Week (DDW) that looked at real-world data on causes of and prevention of readmission. Can you discuss these?

Dr Bajaj: Current guidelines recommend rifaximin, a semisynthetic antibiotic locally absorbed in the gut, as an adjunct to lactulose to maintain remission in patients who have experienced 1 or more episodes of OHE while on lactulose therapy.[5] These recommendations are primarily based on results from randomized studies showing that adding rifaximin to lactulose reduces OHE recurrences, hospitalizations, and related costs.[5,13] We now have “real-world” data on rifaximin for secondary prevention of OHE based on observational studies. Oey and colleagues in the Netherlands evaluated the efficacy of rifaximin plus lactulose on several key outcomes related to cirrhosis inpatient and outpatient care burden in 127 patients with cirrhosis.[14] They reported significant reductions in mean HE-related hospital admissions (.86 vs .41) and mean length of hospital stays (8.85 vs 3.79 bed days per admission) in the first 6 months after initiating rifaximin relative to the 6 months prior to starting rifaximin (P <.001 for both).[14]

My group presented data at EASL and DDW, now published, from a large multi-center cohort called North American Consortium for the Study of End-Stage Liver Disease (NACSELD).[15] The purpose of this study was to identify potential quality improvement targets for HE. We included 2810 patients with cirrhosis who were hospitalized for non-elective reasons from 14 centers in North America. We found that, with almost every parameter -- admissions due to medication-associated precipitants, development of aspiration pneumonia, lack of resumption of HE-medications, optimization of medications -- there is room for improvement. Looking at medications specifically, both HE-related medications and non-HE-related medications (eg, opioids, benzodiazepines, and other psychoactive drugs) were major precipitants for admission, either alone or with other factors. Non-adherence to lactulose (over/underuse) was determined to be a precipitating factor in 21% of patients, while underuse of rifaximin was a precipitant in 1%. Of the 790 patients who were discharged without HE therapy, 99 (12.5%) should have had therapy to prevent HE recurrence resumed at discharge but did not, which indicates an important quality improvement target.[15]

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Both studies reinforce the importance of following best practices in HE care, including starting medications as indicated and ensuring that patients are receiving medications as appropriate upon discharge from the hospital to prevent costly readmissions. This is typically a team effort involving clinicians, patients, and caregivers following specific protocols.

Medscape: Let’s switch gears a bit and look at developments in treatments for HE. A soluble solid dispersion (SDD) formulation of rifaximin is under study for the treatment of overt HE. Where does this stand?

Dr Bajaj: Rifaximin SSD is a novel formulation of rifaximin which, unlike the currently available bile-soluble form, is water-soluble, thereby increasing the availability of the drug in the gastrointestinal lumen while minimizing systemic exposure. Our group evaluated both the immediate release (IR) and sustained extended release (SER) formulations in several doses vs placebo in a randomized, double-blind phase 2 study.[16] This post-hoc analysis included a subset of 317 patients from the full study with less advanced cirrhosis (Conn score of 0) and no prior HE. We demonstrated a significant reduction in all-cause hospitalizations or morality with 40 mg IR SSD once daily vs placebo (19% vs 39%; P =.02).[16] The 40 mg IR SDD formulation is currently being investigated in a randomized, placebo-controlled phase 2 trial as inpatient therapy for overt HE.[17]

Medscape: Fecal transplantation has received a lot of attention of late as a treatment for certain bowel disorders. Could you describe the rationale for this therapy in HE and any recent data?

Dr Bajaj: Current therapies for HE are aimed at alleviating disturbances in the gut-liver-brain axis, intestinal barrier dysfunction, and gut microbial dysbiosis. Unfortunately, a subset of patients has recurrent or persistent episodes despite standard of care. Fecal microbial transplant (FMT) represents a novel and rational approach to correcting the aforementioned problems in HE patients who are not doing well on conventional therapies.[18] A safety study of FMT using donor stool delivered by enema found the treatment to be well tolerated with evidence of improved cognition in the FMT group.[18] We recently conducted a randomized, placebo-controlled, phase 1 trial of capsular FMT in 20 patients with cirrhosis and recurrent HE (at least 2 episodes in the prior year while on lactulose and rifaximin).[19] The FMT capsules were developed using stool from a rationally-derived donor.

While the study was not powered for efficacy endpoints, relative to placebo, FMT capsules favorably changed intestinal microbiota composition, enhanced the intestinal barrier, and improved Stroop test performance in patients who received them.[19] Serious adverse events were more frequent in the placebo group and were mainly related to progression of liver disease. Larger studies are needed to confirm these outcomes.

Medscape: Dr Bajaj, this has been a great discussion. We look forward to hearing more from you on new developments in HE in the future.

Dr Bajaj: My pleasure.

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Abbreviations

ANT = Animal Naming Test CFF = Critical Flicker Frequency CHE = covert hepatic encephalopathyDDW = Digestive Disease Week EASL = European Association of the Study of the Liver FMT = fecal microbial transplant HCV = hepatitis C virus HE = hepatic encephalopathy IR = immediate releaseMHE = minimal hepatic encephalopathyNACSELD = North American Consortium for the Study of End-Stage Liver DiseaseNAFLD = non-alcoholic fatty liver diseaseFDA = United States Food and Drug AdministrationHHV = human herpes virusHHV-6 = human herpes virus 6HSV = herpes simplex virusMALDI-TOF = matrix-assisted laser desorption/ionization time of flight PCR = polymerase chain reactionOHE = overt hepatic encephalopathy PHES = Psychometric hepatic encephalopathy score SDD = soluble solid dispersion SER = sustained extended release

Related Links

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Clinical Issues in Chronic Liver Disease: Hot Topics in HBV, HCV, and NASHhttps://www.medscape.org/viewarticle/909189

New Insights in Hepatorenal Syndrome: An Update for the Liver Specialisthttps://www.medscape.org/viewarticle/906190

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References

1. Ellul MA, Gholkar SA, Cross TJ. Hepatic encephalopathy due to liver cirrhosis. BMJ. 2015;351:h4187.

2. Stepanova M, Mishra A, Venkatesan C, et al. In-hospital mortality and economic burden associated with hepatic encephalopathy in

the United States from 2005 to 2009. Clin Gastroenterol Hepatol. 2012;10:1034-1041.

3. Wijdicks EFM. Hepatic encephalopathy. N Engl J Med. 2016;375:1660-1670.

4. Liere V, Sandhu G, DeMorrow S. Recent advances in hepatic encephalopathy. F1000Research. 2017;6:1637.

5. Vilstrup H, Amodio P, Bajaj J, et al. Hepatic encephalopathy in chronic liver disease: 2014 practice guideline by the American

Association for the Study of Liver Diseases and the European Association for the Study of the Liver. Hepatology. 2014;60:715-735.

6. Flamm SL. Considerations for the cost-effective management of hepatic encephalopathy. Am J Manag Care. 2018;24:S51-S61.

7. Irish W, Saynisch P, Mallow PJ, et al. Using the medicare claims database to understand the economic burden of liver disease: a case

study in hepatic encephalopathy. Value Health. 2015;18: Abstract A226.

8. Gupta R, Thomas J, Anderson G, et al. The stroop test is better at predicting the 6-month risk of developing overt hepatic

encephalopathy compared to the PHES and CFF tests. Presented at: 2019 EASL International Liver Congress; April 10-14, 2019;

Vienna, Austria. Abstract SAT-042.

9. Taru V, Ignat M, Indre M, et al. Minimal hepatic encephalopathy: proper diagnosis for a better quality of life. Presented at: 2019 EASL

International Liver Congress; April 10-14, 2019; Vienna, Austria. Abstract SAT-126.

10. Campagna F, Montagnese S, Ridola L, et al. The animal naming test: an easy tool for the assessment of hepatic encephalopathy.

Hepatology. 2017;66:198-208.

11. Taneja S, Agarwal A, Chopra M, et al. Animal naming test is simple and reliable for diagnosis of minimal hepatic encephalopathy and

prediction of development of overt hepatic encephalopathy in patients with cirrhosis. Presented at: 2019 EASL International Liver

Congress; April 10-14, 2019; Vienna, Austria. Abstract SAT-125.

12. Bar N, Deri S, Webb M, et al. Cognitive impairment or hepatic encephalopathy? A prospective cross-sectional study in patients with

non-alcoholic fatty liver disease. Presented at: 2019 EASL International Liver Congress; April 10-14, 2019; Vienna, Austria. Abstract

THU-316.

13. Neff G, Zachry III W. Systematic review of the economic burden of overt hepatic encephalopathy and pharmacoeconomic impact of

rifaximin. PharmacoEconomics. 2018;36:809-822.

14. Oey R, Buck LEM, Erler N, et al. The efficacy and safety of rifaximin-a: a 2-year observational study of overt hepatic encephalopathy.

Presented at: 2019 EASL International Liver Congress; April 10-14, 2019; Vienna, Austria. Abstract SAT-092.

15. Bajaj JS, O’Leary JG, Tandon P, et al. Targets to improve quality of care for patients with hepatic encephalopathy: data from a multi-

centre cohort. Ailment Pharmacol Ther. 2019;1-10.

16. Bajaj JS, Heimanson Z, Israel R, et al. Efficacy of rifaximin soluble solid dispersion in patients with early decompensated cirrhosis and

a Conn score of 0: A post hoc analysis of a randomized, double-blind, placebo-controlled trial. Presented at: 2019 EASL International

Liver Congress; April 10-14, 2019; Vienna, Austria. Abstract SAT-014.

17. ClinicalTrials.gov. Rifaximin soluble solid dispersion (SSD) tablets plus lactulose for the treatment of overt hepatic encephalopathy

(OHE). https://clinicaltrials.gov/ct2/show/NCT03515044. Accessed May 16, 2019.

18. Bajaj JS, Kassam Z, Fagan A, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a

randomized clinical trial. Hepatology. 2017;66:1727-1738.

19. Bajaj JS, Salzman NH, Acharya C, et al. Fecal microbial transplant capsules are safe in hepatic encephalopathy: a phase 1,

randomized, placebo-controlled trial. Hepatology. 2019. doi: 10.1002/hep.30690. [Epub ahead of print]..

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