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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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