Fred Poordad, MD - American College of Gastroenterology

Fred Poordad, MD
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
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Fred Poordad, MD
Proportion survival
Hepatic Encephalopathy is an Independent Risk Factor
for Mortality in Patients Awaiting Liver Transplantation
1.0
p<0.001
0.8
No HE
0.6
HE
0.4
0.2
0.0
0.0
10.00
20.00
30.00
40.00
50.00
60.00
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
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Stages of Hepatic Encephalopathy
Stage
Mental state
Neurologic signs
0
Minimal hepatic encephalopathy (MHE)
1
Mild confusion: limited attention
span, irritability, inverted sleep
pattern
Incoordination, tremor,
impaired handwriting
2
Drowsiness, personality changes,
intermittent disorientation
Asterixis, ataxia, dysarthria
3
Somnolent, gross disorientation,
marked confusion, slurred speech
Hyperreflexia, muscle
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 2013
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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;31:1012-7.
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HE management
Aliment Pharmacol Ther 2010;31:537-47.
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
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Nonabsorbable disaccharides
Liver Disease
NH3
CNS
Colonic flora
(aerobic and
anaerobic)
Urea
NAD
NH4+
• Non-absorbable disaccharides lower NH3 by protonation and
trapping as ammonium; inhibition of bacterial NH3 production;
purging of bacteria from colon.
Gerber T, Schomerus H. Drugs. 2000;60:1353-1370. 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;328:1046.
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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=0.00001)
– Multivariate analysis predictors of recurrence
• Lactulose non-adherence (OR 3.26)
• MELD score (OR 1.14)
Bajaj JS, et al. Aliment Pharmacol Ther 2010;31:1012-7.
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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. 2000 Dec;95(12):3574-8.
Nonabsorbable antibiotics
Liver Disease
II
Urea
NH3
CNS
Colonic flora
(aerobic and
anaerobic)
Antibiotics
• Antibiotics  gut-derived ammonia (NH3) by decreasing
the bacteria that produce it
• Other effects?
Gerber T, Schomerus H. Drugs. 2000;60:1353-1370. Dasarathy S. Indian J Gastroenterol. 2003;22(suppl 2):S50-S53.
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Fred Poordad, MD
Overt HE
Nonabsorbable antibiotics
• Neomycin
–
–
–
–
Limited clinical studies
Small bowel toxicity
Ototoxicity
Nephrotoxicity
– Not recommended
Rifaximin vs Lactulose
HEAD TO HEAD COMPARISON(S)?
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Rifaximin in HE
• Dose-finding1
• Open-label2-4
• Comparative, randomized, controlled trials5-16
–
–
–
–
Rifaximin vs neomycin5-8
Rifaximin vs paromomycin9-11
Rifaximin vs lactulose12-15
Rifaximin vs lactitol16
• Placebo-controlled trial17
1. Williams R, et al. Eur J Gastroenterol Hepatol. 2000;12:203-208. 2. Sama C, et al. Curr Ther Res. 2004;65:413-422. 3. Puxeddu A, et al. Curr Med Res Opin.
1995;13:274-281. 4. Festi D, et al. Curr Ther Res. 1993;54:598-609. 5. Miglio F, et al. Curr Med Res Opin. 1997;13:593-601. 6. Pedretti G, et al. Ital J Gastroenterol.
1991;23:175-178. 7. Di Piazza S, et al. Ital J Gastroenterol. 1991;23:403-407. 8. Festi D, et al. Curr Ther Res. 1993;54:598-609. 9. Parini P, et al. Curr Ther Res.
1992;52:34-39. 10. De Marco F, et al. Curr Ther Res. 1984;36:668-674. 11. Testa R, et al. Drugs Exp Clin Res. 1985;11:387-392. 12. Fera G, et al. Eur J Clin Res.
1993;4:57-66. 13. Bucci L, Palmieri GC. Curr Med Res Opin. 1993;13:109-118. 14. Massa P, et al. Eur J Clin Res. 1993;4:7-18. 15. Festi D, et al. Curr Ther Res.
1993;54:598-609. 16. Mas A, et al. J Hepatol. 2003;38:51-58. 17. Bass et al. N Engl J Med. 2010;362:1071-1081.
Challenging nonabsorbable disaccharides
AB = antibiotics; NADS = nonabsorbable disaccharides.
a Low-quality studies excluded. b Conventional antibiotic.
c
Rifaximin.
Als-Nielsen et al. BMJ. 2004;328:1046-1051.
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Fred Poordad, MD
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):1147-1161.
Rifaximin for the maintenance of HE
remission- RCT
Study design
Rifaximin 550 mg b.i.d.
Observation
period
Screening
End of
study
Open-label
study
Randomized 1:1
Day -7
-3
Visit 1
0
Placebo
Visits 2 – 14
168
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;362:1071-1081.
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Efficacy and safety of rifaximin
vs placebo
Efficacy
Rifaximin
Placebo
Hazard Ratio
Significance
No HE Breakthrough (%)
77
53
0.42
<0.0001
Delayed hospitalization (%)
85
75
0.50
0.0129
Bass et al. N Engl J Med. 2010;362:1071-1081.
Drug-related adverse events
Adverse event
Nausea
Diarrhea
Muscle spasms
Headache
Abdominal distention
Dizziness
Patients, n (%)
Rifaximin (n=140)
Placebo (n=159)
4 (3)
12 (8)
5 (4)
11 (7)
5 (4)
2 (1)
2 (1)
5 (3)
3 (2)
2 (1)
3 (2)
2 (1)
Bass et al. N Engl J Med. 2010;362:1071-1081.
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Fred Poordad, MD
Xifaxan® 550 in HE: rate of adverse events
Adverse event,* % (rate†)
Nausea
RCT
Xifaxan 550 mg
b.i.d.
(n=140)
14 (0.4)
Placebo
(n=159)
All Xifaxan 550 mg
b.i.d. patients‡
(n=392)
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
Diarrhea
Muscle spasms
7 (0.2)
11 (0.3)
9 (0.3)
9 (0.3)
13 (0.5)
7 (0.2)
14 (0.1)
13 (0.1)
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;362:1071-1081. 2. Mullen et al. Presented at: 46th Annual Meeting of the European Association for the Study of the Liver; April 2, 2011;
Berlin, Germany.
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Fred Poordad, MD
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):13-27.
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Fred Poordad, MD
Properties of rifaximin
• Nonsystemic1
– 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 studied1
• Concentrated in GI tract5 and primarily excreted in feces6
• Binds to the beta subunit of bacterial DNA-dependent RNA
polymerase (inhibits bacterial RNA synthesis)7,8
• Very low biliary levels9
• No accumulation after multiple doses3
1. Scarpignato and Pelosini. Digestion. 2006;73(suppl 1):13-27. 2. Trapnell et al. Ann Pharmacother. 2007;41:222-228. 3. Pentikis et al. Pharmacotherapy. 2007;27:13611369. 4. Steffen et al. Am J Gastroenterol. 2003;98:1073-1078. 5. Descombe et al. Int J Clin Pharm Res. 1994;14:51-56. 6. Jiang et al. Antimicrob Agents Chemother.
2000;44:2205-2206. 7. Umezawa et al. J Antibiot. 1968;21:234-236. 8. Artsimovitch et al. Cell. 2005;122:351-363. 9. Verardi and Verardi. Farmaco. 1990;45:131-135.
Rifaximin treatment in HE
CLDQ
1.
2.
All of the time
Most of the time
3.
4.
5.
A good bit of the time
Some of the time
A little of the time
6.
7.
Hardly any of the time
None of the time
CLDQ = Chronic Liver Disease Questionnaire; HE = hepatic encephalopathy.
Sanyal et al. Aliment Pharmacol Ther. 2011.
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Fred Poordad, MD
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
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