Diagnosis and Management of Hepatic Encephalopathy

Transcription

1 Diagnosis and Management of Hepatic Encephalopathy Fred Poordad, MD VP, Academic and Clinical Affairs The Texas Liver Institute Professor of Medicine University of Texas Health Science Center San Antonio, Texas Outline Diagnosis and Prognosis Therapeutic Options for Overt HE Long term adherence and safety 1

2 Hepatic Encephalopathy is an Independent Risk Factor for Mortality in Patients Awaiting Liver Transplantation 1.0 p< No HE Proportion survival HE Time since listing for liver transplantation (months) Fig. 1. Kaplan Meler survival estimate (months) of all patients until death according to the presence or absence of hepatic encephalopathy (HE) in patients listed for liver transplantation. [Figure 1.] Coenraad et al, EASL 2013 Abs. 147 Hepatic Encephalopathy Is A Clinical Diagnosis Clinical findings and history important Ammonia levels are unreliable Ammonia has poor correlation with diagnosis Measurement of ammonia not generally necessary Number connection test Other psychometric tests 2

3 Stages of Hepatic Encephalopathy Stage Mental state Neurologic signs 0 Minimal hepatic encephalopathy (MHE) 1 Mild confusion: limited attention Incoordination, tremor, span, irritability, inverted sleep impaired handwriting pattern 2 Drowsiness, personality changes, Asterixis, ataxia, dysarthria intermittent disorientation 3 Somnolent, gross disorientation, Hyperreflexia, muscle marked confusion, slurred speech rigidity, Babinski sign 4 Coma No response to pain, decerebrate posture A Genetic Variant in the Promoter of Phosphate Activated glutaminase (GLS) Gene Predicts the Risk of Developing Hepatic Encephalopathy Recently an association between a microsatellite in the promoter region of the phosphate activated glutaminase (GLS) gene and the risk of developing HE has been detected by Romero-Gomez et al. (Ann Int Med 2010) Genetic variants of the GLS microsatellite classified in homozygous minor, homozygous major and heterozygous alleles were carried by 32 (20%), 51 (32%) and 75 (48%) individuals, respectively In multivariate analysis homozygous carriers of the major GLS variant had a significantly higher risk than heterozygous patients to develop HE independent of age and presence of transjugular intrahepatic portosystemic shunt Mayer LB, et al EASL

4 Transient Elastography is a Useful Clinical Tool to Detect Minimal Hepatic Encephalopathy (mhe) in a Cohort of Compensated Cirrhotic Patients 29/86 patients (34%) had mhe on Psychometric Hepatic Encephalopathy Score (PHES) Liver stiffness measurement (LSM) in kpa was significantly higher in those with mhe than in those without mhe (median 38.6kPa v 17.3kPa; p=0.002) Based on the ROC curve a cut-off of 20.8kPa had a sensitivity of 79% and a specificity of 67% to detect mhe (AUROC = 0.785, p=0.001) Galvin Z, et al. EASL 2013 Recurrent HE Bajaj JS, et al. Aliment Pharmacol Ther 2010;31:

5 HE management Aliment Pharmacol Ther 2010;31: Overt HE Management options Nonabsorbable disaccharides Lactulose (Lactitol) Nonabsorbable antibiotics Rifaximin - Not licensed for treatment of acute HE Neomycin FDA approved for acute, not chronic HE Ototoxic and nephrotoxic Other Sodium Benzoate 5

6 Nonabsorbable disaccharides Liver Disease NH 3 CNS Urea Colonic flora (aerobic and anaerobic) NAD NH 4 + Non-absorbable disaccharides lower NH 3 by protonation and trapping as ammonium; inhibition of bacterial NH 3 production; purging of bacteria from colon. Gerber T, Schomerus H. Drugs. 2000;60: Dasarathy S. Indian J Gastroenterol. 2003;22(suppl 2):S50-S53. Overt HE Nonabsorbable disaccharides Nonabsorbable disaccharides vs placebo/no intervention Nonabsorbable disaccharides reduced risk of no improvement (relative risk: 0.62; 95% CI: 0.46 to 0.84) in poor quality trials only High quality trials found no beneficial effect of nonabsorbable disaccharides on risk of no improvement (0.92; 95% CI: 0.42 to 2.04) No significant effect on mortality (0.41; 95% CI: 0.02, 8.68) Als-Nielsen B, et al. BMJ. 2004;328:

7 Lactulose side effects Abdominal bloating Gas/Flatulence Nausea ± vomiting Diarrhea Dehydration Electrolyte imbalanced Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients Retrospective VAMC Study 137 cirrhotics Lactulose Rx following index HE episode 103 patients with recurrent HE (9 ± 1 months) 39 (38%) not adherent to lactulose 8 (8%) lactulose-associated dehydration In recurrent HE patients adherence 64% (p= ) Multivariate analysis predictors of recurrence Lactulose non-adherence (OR 3.26) MELD score (OR 1.14) Bajaj JS, et al. Aliment Pharmacol Ther 2010;31:

8 Hepatic encephalopathy Sodium benzoate Increases ammonia metabolism and renal elimination Dosage of 5g BID Limited clinical studies exist Also, caution raised by a study examining basal/post glutamine challenge ammonia levels in cirrhotic receiving sodium benzoate Not FDA or EU-approved for treatment of HE Am J Gastroenterol Dec;95(12): Nonabsorbable antibiotics Liver Disease Urea Colonic flora (aerobic and anaerobic) II NH 3 CNS Antibiotics Antibiotics gut-derived ammonia (NH 3 ) by decreasing the bacteria that produce it Other effects? Gerber T, Schomerus H. Drugs. 2000;60: Dasarathy S. Indian J Gastroenterol. 2003;22(suppl 2):S50-S53. 8

9 Overt HE Nonabsorbable antibiotics Neomycin Limited clinical studies Small bowel toxicity Ototoxicity Nephrotoxicity Not recommended Rifaximin vs Lactulose HEAD TO HEAD COMPARISON(S)? 9

10 Rifaximin in HE Dose-finding 1 Open-label 2-4 Comparative, randomized, controlled trials 5-16 Rifaximin vs neomycin 5-8 Rifaximin vs paromomycin 9-11 Rifaximin vs lactulose Rifaximin vs lactitol 16 Placebo-controlled trial Williams R, et al. Eur J Gastroenterol Hepatol. 2000;12: Sama C, et al. Curr Ther Res. 2004;65: Puxeddu A, et al. Curr Med Res Opin. 1995;13: Festi D, et al. Curr Ther Res. 1993;54: Miglio F, et al. Curr Med Res Opin. 1997;13: Pedretti G, et al. Ital J Gastroenterol. 1991;23: Di Piazza S, et al. Ital J Gastroenterol. 1991;23: Festi D, et al. Curr Ther Res. 1993;54: Parini P, et al. Curr Ther Res. 1992;52: De Marco F, et al. Curr Ther Res. 1984;36: Testa R, et al. Drugs Exp Clin Res. 1985;11: Fera G, et al. Eur J Clin Res. 1993;4: Bucci L, Palmieri GC. Curr Med Res Opin. 1993;13: Massa P, et al. Eur J Clin Res. 1993;4: Festi D, et al. Curr Ther Res. 1993;54: Mas A, et al. J Hepatol. 2003;38: Bass et al. N Engl J Med. 2010;362: Challenging nonabsorbable disaccharides AB = antibiotics; NADS = nonabsorbable disaccharides. a Low-quality studies excluded. b Conventional antibiotic. c Rifaximin. Als-Nielsen et al. BMJ. 2004;328:

11 Overt HE Treatment efficacy estimates Comparisons are NOT from head-to-head studies Efficacy estimates based on pooled data Generated primarily for pharmacoeconomic evaluation Huang E et al. Aliment Pharmacol Ther. 2007;26(8): Rifaximin for the maintenance of HE remission- RCT Study design Screening Observation period Rifaximin 550 mg b.i.d. Randomized 1:1 End of study Open-label study Day Placebo 168 Visit 1 Visits 2 14 Visit 15 Follow-up visit (day 182 or 14 days after early withdrawal) 6-month treatment period (concomitant lactulose permitted) Bass et al. N Engl J Med. 2010;362:

12 Efficacy and safety of rifaximin vs placebo Efficacy Rifaximin Placebo Hazard Ratio Significance No HE Breakthrough (%) < Delayed hospitalization (%) Bass et al. N Engl J Med. 2010;362: Drug-related adverse events Patients, n (%) Adverse event Rifaximin (n=140) Placebo (n=159) Nausea 4 (3) 12 (8) Diarrhea 5 (4) 11 (7) Muscle spasms 5 (4) 2 (1) Headache 2 (1) 5 (3) Abdominal distention 3 (2) 2 (1) Dizziness 3 (2) 2 (1) Bass et al. N Engl J Med. 2010;362:

13 Xifaxan 550 in HE: rate of adverse events RCT All Xifaxan 550 mg Adverse event,* % (rate ) Xifaxan 550 mg Placebo b.i.d. patients b.i.d. (n=159) (n=392) (n=140) Nausea 14 (0.4) 13 (0.5) 22 (0.2) Peripheral edema 15 (0.4) 8 (0.3) 21 (0.2) Urinary tract infection 6 (0.2) 9 (0.3) 20 (0.2) Ascites 11 (0.3) 9 (0.3) 17 (0.1) Anemia 8 (0.2) 4 (0.1) 16 (0.1) Abdominal pain 9 (0.2) 8 (0.3) 15 (0.1) Fatigue 12 (0.3) 11 (0.4) 14 (0.1) Vomiting 7 (0.2) 9 (0.3) 14 (0.1) Diarrhea 11 (0.3) 13 (0.5) 13 (0.1) Muscle spasms 9 (0.3) 7 (0.2) 13 (0.1) Dizziness 13 (0.4) 8 (0.3) 12 (0.1) Dyspnea 6 (0.2) 4 (0.2) 12 (0.1) b.i.d. = twice daily; HE = hepatic encephalopathy; RCT = randomized controlled trial. *Adverse events other than HE reported in >12% of patients in either RCT treatment group or all Xifaxan patients. Event rate was calculated as the number of events that occurred divided by patient exposure year). Consists of patients who took 1dose of rifaximin and for whom a safety assessment was conducted. Includes 140 patients from the RCT and 252 new rifaximin patients in the open-label extension trial. Mullen et al. Presented at: 46th Annual Meeting of the European Association for the Study of the Liver; April 2, 2011; Berlin, Germany. Treatment effect of rifaximin: reducing the long-term risk of overt HE recurrence (RCT + OLM) 1,2 CI = confidence interval; HE = hepatic encephalopathy; OLM = open-label maintenance; RCT = randomized controlled trial; XFN = Xifaxan. *Day 0 for these 82 patients coincides with randomization day into OLM and first dose of Xifaxan. These patients were previously randomized to placebo in the RCT. 1. Bass et al. N Engl J Med. 2010;362: Mullen et al. Presented at: 46th Annual Meeting of the European Association for the Study of the Liver; April 2, 2011; Berlin, Germany. 13

14 Complications of end stage liver disease: Overt hepatic encephalopathy After recovery from Overt HE episode Assess need to maintain remission lactulose or rifaximin Lactulose Historical standard of care with lower medication cost Rifaximin Good tolerability and safety profile Large RCT efficacy in maintaining remission Favorable direct comparison to lactulose alone Reduced hospitalisation(s)/costs Rifaximin structure and effects Semisynthetic antibiotic Related to rifamycin Antimicrobial spectrum (in vitro) includes Most Gram-positive and Gram-negative bacteria Both aerobes and anaerobes Scarpignato and Pelosini. Digestion. 2006;73(suppl 1):

15 Properties of rifaximin Nonsystemic 1 No known clinically relevant drug interactions 1,2 No effect on drugs metabolized by cytochrome P450 enzyme system 3,4 Adverse events comparable to placebo and representative of disease studied 1 Concentrated in GI tract 5 and primarily excreted in feces 6 Binds to the beta subunit of bacterial DNA-dependent RNA polymerase (inhibits bacterial RNA synthesis) 7,8 Very low biliary levels 9 No accumulation after multiple doses 3 1. Scarpignato and Pelosini. Digestion. 2006;73(suppl 1): Trapnell et al. Ann Pharmacother. 2007;41: Pentikis et al. Pharmacotherapy. 2007;27: Steffen et al. Am J Gastroenterol. 2003;98: Descombe et al. Int J Clin Pharm Res. 1994;14: Jiang et al. Antimicrob Agents Chemother. 2000;44: Umezawa et al. J Antibiot. 1968;21: Artsimovitch et al. Cell. 2005;122: Verardi and Verardi. Farmaco. 1990;45: Rifaximin treatment in HE CLDQ 1. All of the time 2. Most of the time 3. A good bit of the time 4. Some of the time 5. A little of the time 6. Hardly any of the time 7. None of the time CLDQ = Chronic Liver Disease Questionnaire; HE = hepatic encephalopathy. Sanyal et al. Aliment Pharmacol Ther

16 Summary Limited diagnostic and prognostic options for chronic HE Most historic therapies have multiple side effects and poor compliance Broad spectrum, non-absorbed antibiotic therapy has been shown to be safe long term, well tolerated and effective Future research for new therapeutic options will focus on enhancing survival in advanced liver disease 16