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Accredited by:

Disease Burden

Hospital Discharges Associated with

Cirrhosis are Increasing

403,664 411,029 436,901 444,882

459,496

498,181

0

100000

200000

300000

400000

500000

600000

2004` 2005 2006 2007 2008 2009

Pati

en

t D

isch

arg

es w

ith

Cir

rho

sis

*

8.4%

*ICD-9-CM codes 571.2, 571.5, and 571.6, all listed diagnoses

Healthcare Cost and Utilization Project, US Department of Health and Human Services.

Available at http://hcupnet.ahrq.gov/HCUPnet.jsp. Accessed 04/24/12.

Complications of Cirrhosis:

Focus on 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.

Increased Hospital Discharges Associated with

HE Parallel Those of Cirrhosis

403,664 411,029 436,901 444,882

459,496

498,181

182,843 196,521 215,767

239,425

323,564 345,887

0

100000

200000

300000

400000

500000

600000

2004` 2005 2006 2007 2008 2009

Pati

en

t D

isch

arg

es

Cirrhosis* HE

*ICD-9-CM codes 571.2,571.5, and 571.6, all listed diagnoses ICD-9-CM codes 291.2, 348.30, and 472.2, all listed diagnoses

Healthcare Cost and Utilization Project, US Department of Health and Human Services.

Available at http://hcupnet.ahrq.gov/HCUPnet.jsp. Accessed 04/24/12.

Prevalence of HE:

Two Forms are Recognized

• Covert hepatic encephalopathy (CHE) affects

approximately 20% to 60% of patients with liver disease2

– Has been called subclinical encephalopathy or minimal

encephalopathy (MHE) in the past3

– International Society for Hepatic Encephalopathy and Nitrogen

Metabolism has recently endorsed using the term covert

encephalopathy3

• Overt hepatic encephalopathy (OHE) occurs in:

– 30% to 45% of cirrhotic patients2

– 10% to 50% of patients with TIPS2

TIPS = transjugular intrahepatic portosystemic shunt. 1Mullen KD, et al. Semin Liver Dis. 2007;27(Suppl 2):32-47. 2Poordad FF. Aliment Pharmacol Ther. 2006;25(Suppl 1):3-9. 3Mullen KD, Prakash RK. Clin Liver Dis 2012;16:91-93,

Characterization of HE Stages

Normal Covert HE I II III IV

Overt HE Stages

Categorization is often arbitrary and

varies between raters

Simple Clinical

Diagnosis

Worsening cognitive dysfunction

coma

Bajaj JS, et al. Hepatology. 2009;50:2014-2021.

Diagnosis of Covert HE

• Patients with covert HE have no clinical signs and

symptoms of overt HE

– The diagnosis of covert HE is only possible through specialized

psychometric and neurological measures

– No consensus on diagnostic criteria or diagnostic tests has

been established

Bajaj JS et al. Hepatology 2009;50:2014-2021.

Mullen KD. Aliment Pharmacol Ther 2006;25(suppl 1):11-16.

Diagnostic Methods for

Detecting Covert HE

Methods Advantages Limitations

Formal neuropsychological assessment

• Established and well-recognized clinical significance

• Expensive • Time-consuming

Short neuropsychological batteries

• Easy to administer in office setting

• Inexpensive • Rapid results • High sensitivity for

discerning MHE from other encephalopathies

• Test often copyrighted • Limited access

Computerized tests (CFF, ICT, reaction times, etc.)

• Easy to apply • Limited data on diagnostic significance

• Require standardization

Neurophysiologic tests (EEG, spectral EEG, P300)

• Allows for objective repeat testing

• Equipment • Limited data on

diagnostic significance

CFF = critical flicker frequency; ICT = inhibitory control test; P300 = auditory event-related evoked potential.

Adapted from: Mullen KD, et al. Semin Liver Dis. 2007;27(Suppl 2):32-47.

Diagnosis of Overt HE

• Clinical recognition of the distinctive neurologic

features of HE

• Knowledge that underlying cirrhosis is present

• Exclusion of all other etiologies of neurologic and/or

metabolic abnormalities

• Identification of precipitating factors

• Severity can be measured using West Haven Criteria

Adapted from Mullen KD. Semin Liver Dis. 2007;27(suppl 2):3-9.

West Haven Criteria for Grading

Mental State in Patients With Cirrhosis

Grade Features

0 No abnormalities detected

I Trivial lack of awareness

Euphoria or anxiety

Shortened attention span

Impairment of addition or subtraction

II Lethargy or apathy

Disorientation for time

Obvious personality change

Inappropriate behavior

III Somnolence to semi-stupor

Responsive to stimuli

Confused

Gross disorientation

Bizarre behavior

IV Coma, unable to test mental state

Bajaj JS, et al. Aliment Pharmacol Ther. 2011;33:739-747.

Hepatic Encephalopathy: Pathophysiology

• HE pathogenesis appears to be multifactorial and

involves:

– An increase in nitrogenous substances in the systemic

circulation, derived from production in the gut

– Cerebral edema, due to uptake of ammonia into astrocytes

where it is combined with intracellular glutamate

– Oxidative stress

– Inflammatory mediators

Adapted from Mullen KD et al. Semin Liver Dis. 2007;27(suppl 2):32-47.

Consequences of Covert HE

• Increased progression to OHE: >50% develop overt HE

within 30 months1

• Significantly diminishes quality of life2

• Significantly diminishes working and earning capacity in

“blue-collar workers”2

• Impairs driving on structured driving tests3,4

• Increases risk of traffic accidents and violations5

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

2. Groeneweg M, et al. Hepatology. 1998;28(1):45-49.

3. Wein C, et al. Hepatology. 2004;39(3):739-745.

4. Watanabe A, et al. Metab Brain Dis. 1995;10(3):239-248.

5. Bajaj JS, et al. Am J Gastroenterol. 2007;102(9):1903-1909.

Probability of OHE in Patients

With and Without MHE

MHE positive

MHE negative

Develo

pm

en

t o

f clin

ical

HE

110

100

90

80

70

60

50

40

30

20

10

0

0 10 20 30 40

Months

P < .001

(21)

(25)

(20)

(11)

(91) (88)

(84)

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

Overt HE is Associated with a Poor Prognosis

• <50% survival at 1 year after diagnosis of HE; <25%

survival at 3 years

100

80

60

40

20

0

Su

rviv

al, %

0 12 24 36 48

Months

42% survival

at 1 year 23% survival

at 3 years

Bustamante et al. J Hepatol. 1999;30:890-895.

ICU and One Year Mortality of Patients with

Severe HE

Isolated HE*

(n=45)

Other HE

Patients

(n=26)

p

Glasgow Coma Scale at Admission 8.20.6 6.74.4 0.10

Child-Pugh Score 111.6 111.8 0.06

ICU Mortality 4 (8.9%) 21 (80.7%) <0.001

1-Year Mortality 12 (30%) 24 (92%) <0.001

*Patients with HE, but no acute renal failure or vasopressor use during

ICU stay. HE patients with acute renal failure and/or vasopressor use during

ICU stay.

Fichet J et al. J Crit Care 2009;24:364-370.

Multivariate Analysis for ICU and 1-Year

Mortality of Patients with Severe HE

Variables

ICU Mortality 1-Year Mortality

Odds

ratio

95%

CI

p Odds

ratio

95%

CI

p

Vasopressor Use 7.67 1.40-41 0.02 11.30 1.20-90 0.03

Acute Renal Failure or

Hepatorenal Syndrome

7.32 1.50-35 0.01 5.32 1.10-

32

0.04

Severity of Acute Illness

(SAPSII)*

1.03 0.98-

1.07

0.17 1.07 0.97-

1.04

0.70

• Vasopressor use and acute renal failure were the main independent

predictors of ICU death and 1-year mortality

*SAPSII, Simplified Acute Physiology Score Fichet J et al. J Crit Care 2009;24:364-370.

Comparative Outcome Probabilities for Various

Complications of Cirrhosis

19

Complication Survival at

1 year Survival at 3

years

Varices (non-bleeding) w/o ascites1 97% NA

Ascites ± varices1,2 80% 50%

Bleeding Varices ± Ascites1 43% NA

Hepatic Encephalopathy3 42% 23%

• Projected survival rates 1 year after diagnosis of overt HE are

comparable to survival rates of cirrhotic patients with bleeding varices

NA=Not Available

1. Adapted from D’Amico 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.

Minimal HE Affects Quality of Life

in Cirrhotic Patients

Mean

SIP

Score*

Reference

Population

(n=594)

Cirrhosis

With MHE

(n=48)

Cirrhosis

W/O MHE

(n=131)

SIP Scales

0

5

10

15

20

25

30

*Sickness Impact Profile (SIP) used to determine influence of chronic disease on patients’ daily functioning;

scores range from 0 (best score) to 100 (worst score).

Groeneweg M, et al. Hepatology. 1998;28:45-49.

HE Affects Health-Related Quality of Life

According to Presence and Degree

Physical

Functioning

Physical

Role

Bodily

Pain

General

Health

Vitality

Social

Functioning

Emotional

Role

Mental

Health

US Norms

No HE (n=35)

MHE (n=36)

OHE (n=89)

0

20

40

60

80

100

Physical

Summary Mental

Summar

y

Sco

re

Short Form-36 Questionnaire Results

Arguedas M et al. Dig Dis Sci 2003;48:1622-1626.

Burden of Cirrhosis and HE: Impact of

Cirrhosis-Related Expenses on Daily Life

56%

46%

15% 11% 10%

7% 7%

0

20

40

60

80

%

Impact Within Past 3 Years

• 104 patients (70% male, median MELD 12,

44% HCV, 49% veterans)

• 44% had previous HE (all were on lactulose

while 23% had severe previous HE and

were on both rifaximin and lactulose)

Bajaj JS, et al. Am J Gastroenterol 2011;106:1646-1653.

Burden of Cirrhosis and HE: Impact of Cirrhosis-

Related Medical Expenses on Adherence

36%

26%

12% 10%

5%

0

10

20

30

40

50

%

N=104

Bajaj JS, et al. Am J Gastroenterol 2011;106:1646-1653.

Impact Within Past Year

Lost

insurance

Missed

appointments

Did not

take meds

Took less

than

prescribed

meds

Missed

procedures

Burden of Cirrhosis and HE:

Impact on Ability to Work

Bajaj JS, et al. Am J Gastroenterol 2011;106:1646-1653.

No Previous

HE (n=58)

Previous

HE (n=46)

P value

Age (years) 58.6 57.1 0.272

MELD score 10.7 15.5 0.00001

Currently working 81% 12.5% 0.001

Need to decrease hours 39% 71% 0.017

Worse off regarding job 47% 74% 0.009

Worse off financially 61% 85% 0.019

Median longest period free of work 21 days 365 days 0.035

Debt from cirrhosis 36% 54% 0.06

Utilization and Outcome of Critical Care

in Patients With Cirrhosis

• Reviewed 2006 Nationwide Inpatient Sample (NIS) of the Health Care Utilization Project to identify hospitalization records with cirrhosis and/or portal hypertensive complications

• 65,072 discharge records met the inclusion criteria,

which projected to 317,300 cirrhosis hospitalizations

(95% CI, 300;100-334,400)

• Characteristics of patients requiring critical care

‒ Mean age: 55.5 years

‒ Male: 63%

‒ Ascites: 49%

‒ Encephalopathy: 41%

‒ Variceal bleeding: 14%

‒ Hepatorenal syndrome: 12%

Kim W, et al. Hepatology. 2010;52(Suppl S1):910A-911A.

Utilization and Outcome of Critical Care

in Patients With Cirrhosis

Factor In-Hospital Death Total Charges

Odds Ratio P % Increase P

ICU care 13.9 <.01 280% <.01

Encephalopathy 2.0 <.01 28% <.01

Hepatorenal syndrome 6.1 <.01 45% <.01

Ascites 1.1 <.01 23% <.01

Variceal hemorrhage 0.8 <.01 36% <.01

HCC 1.5 <.01 9% .08

Increased risk of death and hospital charges associated with complications

Kim W, et al. Hepatology. 2010;52(Suppl S1):910A-911A.

Current Treatment Options for HE

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

Vancomycin Aminoglycoside

antibiotic Not approved for HE

Adapted from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugs

Advisory Committee/UCM203247.pdf. Accessed 02/17/11;

http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022554lbl.pdf. Accessed 02/17/11.

Accredited by:

Treatment

OHE Treatment Goals

• Acute episode of HE

– Treatment of precipitating factors

– Improvement in mental status

– Evaluation for liver transplant

• Out-patient management after an episode of HE

– Prevention of recurrent episodes of HE

– Improvement of daily functioning

– Evaluation for liver transplant

Bajaj JS. Aliment Pharmacol Ther. 2010;31:537-547.

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

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

Secondary Prophylaxis of OHE:

Lactulose vs Placebo

• Open-label randomized controlled trial

• Consecutive cirrhotic patients who recovered from HE

randomized to receive lactulose (n=70) or placebo (n=70)

• Primary end point was development of OHE

• Median follow-up of 14 months (range 1-20 months)

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

Probability of Developing HE in Patients

Receiving Prophylactic Lactulose vs Placebo

*Values in parentheses indicate the cumulative number of subjects who

developed HE.

1.0

0.8

0.6

0.4

0.2

0.0 Pro

ba

bilit

y o

f h

ep

ati

c e

nce

ph

alo

path

y

Follow-up in months

0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00 20.00

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)

P=.001

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

Side Effects in Patients Receiving Prophylactic

Lactulose vs Placebo

Lactulose

(n=61)

Placebo

(n=64)

Diarrhea 14 (23%) ---

Abdominal bloating 6 (10%) ---

Distaste to lactulose 8 (13%) ---

Constipation --- 10 (16%)

• All patients could tolerate and remained compliant to lactulose therapy

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

Secondary Prophylaxis of HE:

Rifaximin vs Placebo

Rifaximin 550 mg BID

for 6 mo (n=140) Placebo

for 6 mo (n=159)

Discontinued n=52 (37%)

Breakthrough HE: n=28

Adverse event: n=8

Death: n=6

Patient request: n=6

Exclusion criteria: n=1

Other: n=3

Discontinued n=93 (58%)

Breakthrough HE: n=69

Patient request: n=9

Adverse event: n=7

Death: n=3

Exclusion criteria: n=3

Other: n=2

Completed Study

n=88

Completed

Study

n=66

Randomization 1:1

N=299

(Randomized

Controlled Trial)

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

Rifaximin Treatment in HE: Lactulose

Use at Baseline and During Study

Rifaximin

(n=140)

Placebo

(n=159)

Lactulose use at baseline — n (%)* 128 (91.4) 145 (91.2)

Lactulose use during study — n (%)* 128 (91.4) 145 (91.2)

*During the study, 3 patients who had been receiving lactulose discontinued the therapy and another

3 patients started lactulose (1 in the rifaximin group and 2 in the placebo group).

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

Rifaximin Treatment in HE: Time to First

Breakthrough Episode (Primary End Point)

100

80

60

40

20

0

Pati

en

ts (

%)

Days since randomization

0 28 56 84 112 140 168

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

P<.001

(77.9%)

Rifaximin

Placebo

(54.1%)

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

Rifaximin Treatment in HE: Time to First

HE-Related Hospitalization (Secondary End Point)

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

100

80

60

40

20

0

Days since randomization

0 28 56 84 112 140 168

Hazard ratio with rifaximin, 0.50(95% CI, 0.29-0.87)

P=.01

(86.4%)

Rifaximin

Placebo

(77.4%)

Pati

en

ts (

%)

Rifaximin and HE:

Side Effects Similar to Placebo

Adverse Events Reported in ≥10% of Patients in

Either Study Group

Event, n (%) Rifaximin

(n=140)

Placebo

(n=159)

Any event

Nausea

Diarrhea

Fatigue

Peripheral edema

Ascites

Dizziness

Headache

112 (80.0)

20 (14.3)

15 (10.7)

17 (12.1)

21 (15.0)

16 (11.4)

18 (12.9)

14 (10.0)

127 (79.9)

21 (13.2)

21 (13.2)

18 (11.3)

13 (8.2)

15 (9.4)

13 (8.2)

17 (10.7)

• The incidences of adverse events did not differ significantly between the two

study groups (P>.05 for all comparisons)

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

RCT N=299

Rifaximin 550 mg b.i.d.

n=140

Placebo

n=159

Continuing Rifaximin 550 mg b.i.d.

n=70

New patients n=170

Switched from placebo to Rifaximin 550 mg

b.i.d. n=82

All Patients OLM

N=322

Randomized Controlled Trial

(6 months)

Open Label Maintenance

Concomitant lactulose use was permitted throughout the RCT and OLM trial

Mullen KD et al. J Hepatol 2011;54(Suppl 1):S49.

Rifaximin Long Term Efficacy and Safety:

Patient Disposition

Infection Rates Remain Stable During

Long-Term Rifaximin Treatment

Infection Incidence, n (rate*)

RCT Placebo n=159; PEY=46

RCT Rifaximin n=140; PEY=50

All Rifaximin

n=392; PEY=510

Any infection 49 (1.32) 46 (1.12) 214 (0.72)

Cellulitis 3 (0.066) 3 (0.060) 34 (0.071)

C.difficile infection 0 2 (0.040) 6 (0.012)

Peritonitis 6 (0.131) 3 (0.060) 22 (0.044)

Pneumonia 1 (0.022) 4 (0.080) 42 (0.084)

Sepsis/Septic shock

5 (0.109) 2 (0.040) 31 (0.062)

Urinary tract/ kidney

14 (0.320) 9 (0.187) 83 (0.193)

*Rate = number of subjects/person exposure years (PEY) All rifaximin = rifaximin treated patients from both randomized controlled trial (RCT)

and open label maintenance trial

Sanyal A et al. J Hepatol 2012;56(Suppl 2):S255-S256.

Complications Seen During Long-Term

Administration of Rifaximin

Rifaximin (n=23) Controls (n=46) P value

Variceal bleeding (%) 35.0 59.5 P=.011

Hepatic encephalopathy (%) 31.5 47.0 P=.034

Spontaneous bacterial

peritonitis (%) 5.5 46.0 P=.027

Hepatorenal syndrome (%) 4.5 51.0 P=.037

Death 7 / 23 (30.4%) 24 / 46 (52.2%) --

5-year cumulative probability

of survival (%) 61 13.5 P=.012

• Patients were followed for up to 5 years, death, or

liver transplantation

Vlachogiannakos J, et al. Hepatology. 2010:52(Suppl S1):328A-329A.

Primary Prophylactic Therapy:

MHE Treatment Goals

• Goals of primary prophylactic therapy

– Delay progression to overt HE

– Improve quality of life

– Maintain employment status

– Preserve driving privilege

Prakash R, Mullen KD. Nat Rev Gastroenterol Hepatol. 2010;7:515-525.

Lactulose for Primary Prophylaxis of Overt HE in

Cirrhotic Patients: Results

53%

11% 9%

60%

30%

20%

0

10

20

30

40

50

60

70

MHE at

Baseline

Developed

OHE

Died

% of

Patients

32/

60

36/

60

6/

55

15/

50 5/55

10/

50

Lactulose

No Lactulose

Median follow-up 12 months

P=0.29

P=0.02

P=0.16

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

Lactulose Improves Health-related QoL

in Patients With MHE

0

5

10

15

20

25

Score

3 months 0 months

Prasad S, et al. Hepatology. 2007;45:549-559.

Rifaximin vs Placebo:

Reversal of MHE

Placebo (n=45)

Rifaximin (n=49)

Patients Showing Reversal of MHE

(%)

Duration of Treatment

P<.0001

P<.0001

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

Rifaximin Improves Health-related QoL

in Patients With MHE

0

5

10

15

20

Total P

sych

Total P

hysic

al

Sleep

/Res

t

Work

Hom

e M

gmt

Rec

/Pas

times

Eatin

g

Total S

IP

Mean SIP

Score

8 Weeks (n=37)

Baseline (n=42)

P=.007 P=.050

P=.002

P=.00

P=.000

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

Rifaximin Improves Driving Simulator

Performance: Methods

• Minimal HE patients were diagnosed using a cognitive

battery of 5 tests

– All who were current car drivers without overt HE were included

in an 8-week trial

• Trial involved at baseline

– Driving and navigation simulation

– Quality of life and Sickness Impact Profile

– Ammonia

– MELD score

• Patients were randomized to rifaximin 550 mg or

placebo BID

• All tests repeated on the 8-week visit

Bajaj JS, et al. Gastroenterology 2011;140:478-487.

Rifaximin Improves Driving Simulator

Performance: Results

Rifaximin

(n=21)

Placebo

(n=21) P value

Improved cognitive tests 91% 61% .02

Reduced total driving errors 76% 33% .013

Reduced speeding tickets 81% 33% .005

Reduced illegal turns 62% 19% .012

Reduced collisions 43% 33% .751

Bajaj JS, et al. Gastroenterology 2011;140:478-487.

Reversibility of HE

• Traditional concept: Most OHE events are potentially

reversible

– Only those patients who succumb to the precipitating event

(i.e., bleeding, infection) are not 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

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

Psychometric Test Results Before and After

Development of First Episode of OHE

Patients tested before and after first episode of OHE (n=15)

Pre-OHE Post-OHE p-value

MELD score (median) 9 10 0.10

Number connection test-A (sec) 4012 4835 0.33

Number connection test-B (sec) 9822 14298 0.11

Digit symbol test (points) 5114 4715 0.21

Block design test (points) 2913 3320 0.39

ICT targets (% correct) 939 9311 0.96

ICT lures (# responded to) 128 1810 0.03

ICT lures (first half: runs I-III) 85 95 0.12

ICT lures (second half: runs IV-VI) 44* 85 0.012

*p=0.00001 in the first half compared with the second half indicating successful learning

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

Persistence of Cognitive

Impairment after OHE: Results

Prior OHE No OHE 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

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

N=163

Persistence of Cognitive

Impairment after OHE: Results

No OHE Prior OHE

1st Half 2nd Half 1st Half 2nd Half

Lures 7.9 5.5 6.7 8* 8.4 5.5 7.7 5.3

Weighted lures 11 8 8 7* 18 13 15 14

Targets (%) 94.7 17.4 97.0 16.9* 75.7 29.4 75.7 29.1

• Patients without prior OHE improved significantly on ICT

from 1st to 2nd half, but those with prior OHE could not

improve their performance indicating poor learning

capability and persistent cognitive dysfunction

*P<0.0001 on paired t-test

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

Impact of Preoperative OHE on Neurocognitive

Function after Liver Transplantation

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.

• Neurocognitive abnormalities were more severe in liver

transplant recipients that had suffered from OHE prior to OLT

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

Conclusions

• The incidence of cirrhosis is increasing and the

incidence of hepatic encephalopathy parallels the

increase in cirrhosis

• HE has a negative impact on a cirrhotic patient’s quality

of life

• Patients diagnosed with covert HE have a high

probability of experiencing an overt HE episode

– Primary prophylactic treatment of covert HE patients with either

lactulose or rifaximin is effective in preventing overt HE

Conclusions (cont)

• Overt HE is associated with a poor prognosis

– Survival is <50% at one year, similar to survival of patients with

bleeding varices

– Secondary prophylactic treatment following an overt HE episode

with either lactulose or rifaximin is effective in preventing a

recurrent episode of overt HE

• Recent evidence suggests that cognitive impairment

associated with overt HE may not be completely

reversible

Post Test

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