Is Cognitive Impairment Following

Overt Hepatic Encephalopathy

Completely Reversible?

• This 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.

Program Disclosure

Educational Objectives

• Evaluate data suggesting cognitive impairment

may persist following apparent recovery from an

overt hepatic encephalopathy episode

• Discuss the importance of primary and

secondary prophylactic therapy for preventing

hepatic encephalopathy

• Primary complications include:

– Ascites

– Jaundice

– Variceal hemorrhage

– Hepatic encephalopathy

• Other complications that can occur include:

– Spontaneous bacterial peritonitis

– Hepatic hydrothorax

– Hepatorenal syndrome

– Portopulmonary hypertension

– Hepatocellular carcinoma

– Portal vein thrombosis

Lefton HB et al. Med Clin N Am 2009;93:787-799.

Hepatic Encephalopathy is One of the

Primary Complications of Cirrhosis

TIPS = transjugular intrahepatic portosystemic shunt.

Poordad FF. Aliment Pharmacol Ther. 2006;25(Suppl 1):3-9.

Two Forms of HE are Recognized

• Covert hepatic encephalopathy (CHE) affects approximately 20% to 60% of patients with liver disease – Has been called subclinical encephalopathy or

minimal encephalopathy (MHE) in the past

– International Society for Hepatic Encephalopathy and Nitrogen Metabolism has recently endorsed using the term covert encephalopathy

• Overt hepatic encephalopathy (OHE) occurs in: – 30% to 45% of cirrhotic patients

– 10% to 50% of patients with TIPS

Hospital Discharges Due to

Cirrhosis Increased by 6% in 2010

6% growth

Year

*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 September 2012

8

HE = 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 September 2012.

Hospital Discharges Associated with HE

Increased by 21% in 2010

21% growth

Frederick RT. Clin Liver Dis 2012;16:147-158.

Cognitive Impairment Associated with OHE

May Not Be Reversible

• Traditional concept: Most OHE events are potentially

reversible

– Patients who regain consciousness and survive a severe HE

event typically seem to return to their baseline level of cognitive

functioning with supportive care, or with disaccharides, or with

rifaximin

– A subset of patients with OHE continue to suffer with symptoms

and are classified as chronic persistent HE that may not be

reversible with medical therapy

• Neuropathologic characteristics found in brains of

patients with HE at autopsy suggest that the concept of

complete reversibility requires more in-depth analysis

Prior overt HE*

(n=54)

‘Normal’ cirrhotic patients

(n=52)

P value

MELD score (median) 10 8 0.10

Number connection test-A (sec) 4532 278 0.001

Number connection test-B (sec) 13172 7541 0.0001

Digit symbol test (raw score) 4618 7213 0.0001

Block design test (raw score) 2611 3712 0.0001

ICT lures (# responded to out of 40) 139 54 0.0001

ICT targets (% correct response) 9110 983 0.0001

*Patients had first experienced OHE a mean of 12 5 months prior to study. Patients with neither covert HE nor prior OHE.

Bajaj JS et al. Gastroenterology 2010;138:2332-2340.

Psychometric Test Results In ‘Normal’

Cirrhotic Patients* vs. Prior OHE Patients

*Median 2 episodes, all on lactulose

Bajaj JS et al. J Hepatol 2012;56(Suppl 2):S242.

Prior OHE* (n=32) No OHE (n=131)

P value

NCT-A 65 44 0.02

NCT-B 146 102 0.01

DST 32 45 <0.0001

LTT time 130 100 0.02

LTT errors 49 31 0.1

SDT 86 74 0.2

BDT 13 34 <0.0001

Lures 16 15 0.6

Weighted lures 31 18 0.01

Targets 77% 92% 0.001

Persistence of Cognitive Impairment

after OHE

Patient Status First PHES

Evaluation*

Second PHES

Evaluation* P value

Normal cirrhotic patients (No previous

episode of OHE; no MHE; n=45) -0.751.6 -0.351.8 0.04

Cirrhotic patients without previous

episode of OHE but with MHE; n=34 -6.7 2 -5.73.2 0.016

Cirrhotic patients with at least 1

previous episode of OHE; n=27 -53.2 -4.33.2 NS

*PHES was considered altered if its value was -4. Second evaluation within 3 days after the first one.

Riggio O et al. Clin Gastroenterol Hepatol 2011;9:181-183.

Persistent Cognitive Impairment of Learning

Capacity After Resolution of OHE

(N=50)

Number of

hospitalizations for

OHE

Number of

episodes of

OHE

Duration from first

episode to testing

R P value R P value R P value

NCT-A (sec) 0.264 0.144 0.218 0.238 0.166 0.373

NCT-B (sec) 0.353 0.047 0.354 0.05 0.158 0.396

DST (raw score) -0.387 0.02 -0.461 0.009 -0.364 0.04

BDT (raw score) -0.108 0.631 -0.203 0.378 -0.282 0.292

ICT Lures (number) 0.502 0.002 0.591 0.001 0.483 0.007

ICT Targets (% correct) -0.433 0.009 -0.442 0.015 -0.2 0.135

Correlations Between OHE Episodes and Psychometric Tests

Bajaj JS et al. Gastroenterology 2010;138:2332-2340.

Cognitive Impairment May be Cumulative

Domains

PHES Results

OHE-PreLT

(n=25)

No OHE-PreLT

(n=14)

Controls

(n=20)

NCT-A (seconds) 34.08.3* 23.38.4 19.63.9

NCT-B (seconds) 98.430.5* 76.035.1 54.517.0

Digit symbol (points) 41.28.9*ǂ 50.49.8 54.68.4

Serial dotting (seconds) 61.325.2 59.320.1 54.818.1

Line tracing (seconds) 77.022.7 78.118.2 70.726.2

Line tracing (errors) 11.011.9 10.415.0 5.44.9

*p<0.001 vs. controls; p<0.01 vs. No HE-PreLT; ǂp<0.05 vs. No HE-PreLT.

Sotil EU et al. Liver Transpl 2009;15:184-192.

Impact of Preoperative OHE on Neurocognitive

Function after Liver Transplantation

• Neurocognitive abnormalities were more severe in liver transplant

recipients that had suffered from OHE prior to OLT

Can We Reduce Occurrences of HE In

Patients with Cirrhosis?

Drug Name Drug Class Indication

Lactulose Poorly absorbed disaccharide

• Decrease blood ammonia concentration

• Prevention and treatment of portal-

systemic encephalopathy

Rifaximin Non-aminoglycoside semi-

synthetic, nonsystemic antibiotic

Reduction in risk of OHE recurrence in

patients ≥ 18 years of age

Neomycin Aminoglycoside antibiotic Adjuvant therapy in hepatic coma

Metronidazole Synthetic antiprotozoal and

antibacterial agent Not approved for HE

Adapted from:

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommitt

ee/UCM201081.pdf.

Accessed 10/22/12, and http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022554lbl.pdf. Accessed 10/22/12.

Current Treatment Options for HE

Sharma BC et al. Gastroenterology. 2009;137:885-891.

Proposed Terminology for Prophylactic

Treatment of HE

• Treating patients with covert HE to prevent

development of a first episode is referred to as

primary prophylaxis of HE

• Preventing recurrence of HE in patients who had

a previous episode of HE is referred to as

secondary prophylaxis of HE

Hartmann IJ, et al. Am J Gastroenterol. 2000;95(8):2029-2034.

Consequences of Covert HE

• Those diagnosed with CHE are at increased risk

for progression to OHE: >50% develop overt HE

within 30 months

Primary Prophylaxis:

Prevention of a First Episode of HE

Sharma BC et al. J Hepatol 2012;56(Suppl 2):S238.

MHE at Baseline Develop OHE Died

32/60 36/60 6/55 15/50 5/55 10/50

Median follow-up 12 months

P=0.29

P=0.02

P=0.16

Primary Prophylaxis of Overt HE with

Lactulose in Cirrhotic Patients

Duration of Treatment

n=45 n=45 n=49 n=49

P<.0001

P<.0001

Sidhu S, et al. Am J Gastroenterol. 2011;106:307-316.

Rifaximin vs Placebo: Reversal of CHE

Secondary Prophylaxis:

Prevention of Recurrence of HE

*Values in parentheses indicate the cumulative number of subjects who developed HE.

Patients at risk*

Lactulose 61 60(1) 59(2) 58(3) 51(8) 45(9) 38(11) 28(12) 10(12) 7(12) 1(12)

Placebo 64 62(1) 59(4) 50(13) 37(24) 33(27) 28(27) 19(29) 13(30) 8(30) 4(30)

Sharma BC, et al. Gastroenterology. 2009:137:885-891.

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0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00

P=.001

Placebo (n=70)

Lactulose (n=70)

Probability of Developing HE in Patients Receiving

Prophylactic Lactulose vs Placebo

Bass NM, et al. N Engl J Med. 2010; 362(12):1071-1081.

Rifaximin Treatment in HE: Time to First

Breakthrough Episode (Primary End Point)

Pati

en

ts (

%)

Days since randomization

Hazard ratio with rifaximin, 0.42(95% CI, 0.28-0.64)

P<.001

(77.9%)

Rifaximin

Placebo

(54.1%)

100

80

60

40

20

0

0 28 56 84 112 140 168

2009 2010 2011

Eligible Patients Identified (n) 13,623 15,529 16,328

Patients with Inpatient Claims (%) 89.2% 87.8% 86.4%

Patients Receiving Ongoing Treatment (%) 39.7% 37.7% 36.1%

Neff GW, Frederick, RT. Abstract 1612. Poster presentation at The Liver Meeting 2012, Boston, MA,

November 12, 2012.

Most Patients are Not Receiving

Prophylactic Therapy to Prevent Recurrence

Is Cognitive Impairment Following Overt Hepatic

Encephalopathy Completely Reversible? Conclusions

• OHE occurs in 30% to 45% of cirrhotic patients

• Cognitive impairment after an OHE episode may be

persistent

• Impairment from recurrent OHE episodes may be

cumulative

• Treating patients with covert HE (primary prophylaxis)

can prevent development of a first episode of overt HE

• Treating patients following an overt HE episode

(secondary prophylaxis) can prevent recurrence

• Most patients, however, are not receiving prophylactic

therapy