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Hepatic Encephalopathy

Kevin D Mullen

MetroHealth Medical Center

Cleveland Ohio USA

Disclosures

I have nothing to disclose.

Hepatic Encephalopathy

Kevin D Mullen MD, FRCPI, FAASLD

Digestive Diseases

West Virginia University

Morgantown

West Virginia

USA

The BrainMy second favorite organ

Woody Allen

“ Sleeper ”

Hepatic Encephalopathy

A constellation of neuropsychiatric abnormalities observed in patients with significant liver dysfunction not attributable to known anatomical or metabolic abnormalities.

Ranges from subtle minimal changes detectable only by psychometric tests to full blown coma.

Reversible in most circumstances

1998 WCOG Working Group on HE:

Clinical ClassificationType HE Associated With Category Subcategory

cute liver

failure

Acute liver failure

ypassPortal-systemic Bypass and no intrinsic hepatocellular disease

Episodic

Persistent

Minimal

PrecipitatedSpontaneousRecurrent

MildSevereTreatment-dependent

irrhosisCirrhosis and portalhypertension or portosystemic shunts

Adapted from Ferenci P et al. Hepatology. 2002;35:716-721. & from Mullen KD. Aliment Pharmacol Ther. 2006:25(suppl 1) ;11-16.

A

B

COvert

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Proposed Clinical Classification

Type HE Associated With Category Subcategory

cute liver

failure

Acute liver failure

ypassPortal-systemic Bypass and no intrinsic hepatocellular disease

Episodic

Persistent

Covert

PrecipitatedSpontaneousRecurrent

MildSevereTreatment-dependent

irrhosisCirrhosis and portalhypertension or portosystemic shunts

A

B

COvert

Significant Liver Dysfunction

A --- Acute liver injury

B --- Portosystemic Bypass

C --- Cirrhosis or advanced hepatic fibrosis

Type A associated with severe cerebral edema

Types B & C recently shown to also have cerebral edema albeit subtle

Evidence for Brain Edema

CT and MRI and ICP measurement

Magnetic Transfer ratio in Subtle Edema

Decreased Myo-inositol by NMR spect

In Vitro models- PTBR upregulation

NH3 infusion in PCS rat model Rovira, A. et al. Neurology 2002;59:335-341

Figure 3. Serial transverse T2-weighted fast-FLAIR images (9900 ms/110 ms/2500 ms/1 = repetition time/echo time/inversion time/number of acquisitions) at the level of the

centrum semiovale in a patient with liver cirrhosis before (A), at 1 month (B), and at 12 months (C) after successful liver transplantation

Showcross D & Jalan R Cell Mol Life Sci 2005.

The pathophysiologic basis of hepatic encephalopathy: central role for ammonia and inflammation.

Pathogenesis of HE

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Olde Damink et al Hepatology 2002

Venous – arterial differences of Ammonia and Glutamine

(μm

ol/l)

Intestinal ammonia production from the degradation of glutamineby Phosphate Activated Glutaminase.

Ammonia () and breath hydrogen concentration ( ) following an oral glutamine and lactitol load

Riggio O et al. Am J of Gastroenterol 1999.

• Hyperammonemia after P-C shunt similar in germ-free and non germ-free rats.

• In pts. with TIPS large amount of ammonia are derived by GLN degradation.

• The increase of ammonia after GLN challenge supports the small-intestine origin of hyperammonoemia.

• Glutaminase is increased in cirrhotic patients

Glutaminase Activity

Overall Concept

Astrocyte changes lead to upregulation of genes for PTBR, Aquaporin etc

Disruption of Neuronal/Astrocyte signals

Ammonia, Cytokines, Manganese,Neurosteroids key toxins

Control of ammonia levels key

Why so little progress ?

If the human brain was so simple that we could understand it we would be so simple that we couldn’t.

Emerson Pugh “ Kevin I’m sorry you cannot work on protein

metabolism in liver disease. Find Dan’s notebook’s and see if you can start up the Hepatic Encephalopathy project again.

E Anthony Jones. July 1984

West Haven CriteriaGrade Symptoms

0 (minimal) • No detectable changes in behavior or personality1

1

• Euphoria or anxiety2

• Impaired performance of addition2

• Shortened attention span2

• Trivial lack of awareness2

2

• Minimal disorientation to time or place2

• Inappropriate behavior2

• Impaired performance of subtraction2

• Lethargy or apathy2

• Subtle personality change2

3

• Confusion2

• Gross disorientation2

• Somnolence to semistupor (may respond to verbal stimuli)2

4 • Coma ( no response to verbal or noxious stimuli)2HE = hepatic encephalopathy.1. Mullen et al. Semin Liver Dis. 2007;27(suppl 2):32-48. 2. Ferenci et al. Hepatology. 2002;35:716-721.

West Haven CriteriaGrade Symptoms

Covert Abnormal Psychometric Test performance Normal Orientation

Overt Moderate

Minimal disorientation to time or place2

Asterixis Inappropriate behavior2

Impaired performance of subtraction2

Lethargy or apathy2

Subtle personality change2

Overt Severe

Confusion2

Asterixis Gross disorientation2

Somnolence to semistupor (may respond to verbal stimuli)2

Overt Coma

Coma (no response to verbal or noxious stimuli)2HE = hepatic encephalopathy.

1. Mullen et al. Semin Liver Dis. 2007;27(suppl 2):32-48. 2. Ferenci et al. Hepatology. 2002;35:716-721.

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SONIC

Covert HE

Psychometric Test Battery

Spectrum of neuro‐cognitive impairment in cirrhosis (SONIC)

Worsening cognitive function

Minimal Hepatic Encephalopathy

Replaces term subclinical

Normal neurological examination

Currently defined by subnormal performance in

Number connection tests A and B

Line drawing x 2

Serial dotting

Digit symbol

Weissenborn et al . J Hepatol 2001

Burden of Minimal HE A mild neurocognitive disorder present in

patients with cirrhosis

Cognitive deficits in attention, speed of information processing, and motor abilities

Impairs social interactions, physical and work activities

Predicts the development of overt HE

Economic burden has not been assessed

Impairs ability to safely drive a car

Groeneweg M, et al. Hepatology. 1998;28:45-49.Wein C, et al. Hepatology. 2004;39:739-745.Romero-Gomez M, et al. Am J Gastroenterol. 2001;96:2718-2723.Hartmann IJ, et al. Am J Gastroenterol. 2000;95:2029-2034.

Study Title: Computerized Psychometric Testing for the Diagnosis of Minimal HE

110 cirrhosis subjects and 78 controls have so far been enrolled in this ongoing study

A high correlation was observed between CNSVS and PHES (r=0.59, p=0.001)

Domains within the CNSVS testing system which demonstrated maximum correlation with the diagnosis of MHE were reaction time (r=0.71), executive functioning (r =0.60) and complex attention (r= 0.48)

CNSVS appears to fulfill the criteria as a reliable, sensitive and convenient alternative psychometric test for the diagnosis of MHE

Probability of Hepatic Encephalopathy in Patients With and Without Minimal Hepatic Encephalopathy

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

Months

SHE positive

SHE negative

0 10 20 30 40

(25)(21)

(91)(88)

(84)

(20)

(11)

100

90

80

70

60

50

40

30

20

10

0

De

velo

pm

en

t o

f c

lin

ica

l HE

P<0.001

Quality of Life in Cirrhotic Patients With and Without Minimal HE

MeanSIP

Scorea

Controls(n=594)

CirrhosisWith MHE(n=48)

CirrhosisW/O MHE(n=131)

SIP Scales

aSickness 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(1):45-49.

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LactuloseNo Lactulose

Lactulose Improves HRQOL in MHE

HRQOL=health-related quality of life; SIP=Sickness Impact Profile.*Significant (P<.0001 to P=.049).Prasad S et al. Hepatology. 2007;45:549-559.

Me

an

SIP

Sc

ore

Me

an

SIP

Sc

ore

Baseline (n=30)3 Months (n=20)

Baseline (n=31)3 Months (n=25)

*

* *

* *

Driving History Characteristics of Cirrhotics and Controls

TV and/or MVAs within 1 yr

TV within 1 yr

MVA within 1 yr

TV and/or MVAs within 5 yr

TV within 5 yr

MVA within 5 yr

Cirrhoticsa (n=109)

Controls (n=98)

% of Patients

TV, traffic violations; MVA, motor vehicle accidents.a27 MHE-, 42 MHE+, 42 not tested.Bajaj JS et al. Am J Gastroenterol. 2007;102(9):1903-1909.

Driving Simulation: Navigation and Divided Attention Impairment in MHE

Patients

Bajaj JS et al. Hepatology. 2008;47(2):596-604.

Patients with MHE had significantly highera. collisionsb. illegal turns on a navigation task andc. misses on divided attention

compared with controls and cirrhotics without MHE

MHE+ (n=33) MHE- (n=14) Controls (n=48)

Ille

ga

l Tu

rns

P=.007 4

3

2

1

0

Problems with HE treatment

Precipitating factors

Concomitant disease

Poor evidence for lactulose efficacy

Gross over dosing of lactulose

Failure to refer for liver transplantation

Ileus, renal failure and bowel obstruction

Precipitants of HE

Conn HO. In: Maddrey WC, ed. Atlas of the Liver. Vol 1. 2nd ed. Philadelphia, PA: Current Medicine LLC; 2000.

Precipitating Factors

Dehydration neglected

Sepsis often inapparent

Lot of unprescribed drugs taken

90% of trials do not mention

Blood in gut easy to identify

Renal failure, electrolyte changes ok

Some factors can precipitate non-HE CNS problems.

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Concurrent Disease

In theory other processes make Dx of HE impossible

Examples are Hypothyroidism, subdural hematoma, shock, meningoencephalitis, Hypoxia, drugs, etc

Real issue is Hep C associated brain dysfunction

Concurrent causes of encephalopathy

Systemic sepsis

CNS sepsis

Seizures

Post Ictal confusion

Drug misadventures

Hypoglycemia

Hyperglycemia

Hypothyroidism

CNS bleed

CNS thrombosis

Management of Hepatic Encephalopathy

Identify and treat Precipitating Factors

Rule out other causes of encephalopathy

Supportive care of the unconscious patient

Commence specific additional measures

Supportive Care of HE patient

Adequate Hydration and Electrolyte management

Nutritional support

Avoidance of aspiration

Adequate urine output

Skin care and avoidance of pressure sores

Commencement of Empirical Tx

Delivery of lactulose into upper GI tract

? Lactulose enemas if bowel obstruction or ileus

Gastric or Colonic lavage

Antibiotic Tx after cultures done

Avoidance of dehydration

Provocative Proposition

Significant number of severe HE episodes in non-septic Cirrhotics caused by dehydration from lactulose.

Lactulose difficult to titrate Lactulose wrongly given credit for waking HE

patients. Precipitant correction is key. Hydration on admission often key to recovery

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Non-Absorbable Sugar Vs Placebo Rifaximin Treatment in HENEJM March 25, 2010

Rifaximin Is Poorly Soluble in Water But Is Soluble in Bile

Bile in physiologic concentrations increases

rifaximin bioavailability by 70-120 fold

Rifaximin 550 mg

This results in high small bowel antibiotic activity and less activity in the colon

Rifaximin Reduced Risk of Breakthrough HE Episode by 58% vs

Placebo

From Bass N,Mullen KD et al. N Engl J Med. 2010;362:1071-1081. With permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

Rifaximin 550 mg b.i.d. (n=140)

Placebo (n=159)

Pat

ien

ts w

ith

ou

t H

E

bre

akth

rou

gh

, %

Days post-randomization

P<0.001

HR = 0.42 (95% CI, 0.28-0.64)

Rifaximin Reduced the Risk of HE-Related Hospitalization by 50% vs

Placebo

b.i.d. = twice daily; CI = confidence interval; HE = hepatic encephalopathy; HR = hazard ratio.From Bass N, Mullen KD et al. N Engl J Med. 2010;362:1071-1081. With permission. Copyright © 2010 Massachusetts Medical Society. All rights reserved.

Pat

ien

ts w

ith

no

HE

-rel

ated

ho

spit

aliz

atio

n,

%

Days post-randomization

Placebo (n=159)

P=0.01

Rifaximin 550 mg b.i.d. (n=140)

HR = 0.50 (95% CI, 0.29-0.87)

Points Re Treatments

Metronidazole

Often effective(Morgan) Tolerance not bad Accumulates in CLD Toxicity 10% reaches colon Not practical long term

Neomycin

Tolerance good Too much absorbed Toxicity How effective at lower

doses Only placebo trial

indicates no effect

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Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy.

Strauss E. Hepato-Gastroenter. 1992

Neomycin

Placebo P=

N° of Pts. 20 19

Age (yrs) 50 48

Child-P a/b/c 0/3/17 0/2/17 NS

Grade of HE I

II

III

8 (40%)

3 (15%)

9 (45%)

8 (42%)

6 (32%)

5 (26%)

NS

Precipitating GI Bleeding

Factors Infections

Hydro-Electro Imbala.

4 (20%)

9 (45%)

7 (35%)

3 (16%)

7 (37%)

9 (47%)

NS

Success of treatment 18 (90%) 17 (89.5%) NS

Time to Grade 0 (hours) 39 ± 23 49 ± 22 NS

Example of Challenging Case

Recurrent bouts of severe HE

Biopsy Proven Cirrhosis from Alcohol

Albumin 3.3 g/dl PT - N

Has COPD so not OLT candidate

Endoscopy - No Varices

MELD 10

Management Difficulties

Poor response to Lactulose

Blood ammonia levels 100-150 M

Rarely out of hospital for a week

Nutritional status worsening

Important Points Re Case

Still good synthetic function

No visible varices

HE with low MELD score

This suggests major shunting

The Problem…

•This suggests major shunting

•Confirmed on CT scan

•Shunt CLOSED - HE gone

Clinical CaseA.G., 67 years, Splenectomy and left nephrectomy for

car accident 25 years ago.10 years ago diagnosis of HCV pos. liver cirrhosisJanuary 2006 ascites; April 2006 first appearance of hepatic encephalopathy

At the end of may the patient was hospitalized because of persistent alteration in mental state, time disorientation, flapping tremor despite protein restriction and lactulose therapy.

At entry : Child-Pugh Class C, Score 10.

Mental status grade IIVenous ammonia: 163, arterial ammonia: 238 microg/dl TMT-A: 125 sec; Z-score: 3.2TMT-B: 260 sec; Z-score : 3.1

The abscess was drained. Gram neg. bacteria (E. Coli) were cultured

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No treatment 25 25 19 17 lactitol 25 24 21 16Rifaximin 25 24 18 17

0,25

0,50

0,75

1,00

0 10 20 30Time (days)

Patien

ts f

ree

of H

E

p = 0.97

Actuarial rate of patients free of hepatic encephalopathy in the three groups of patients. Observation re Hepatic

EncephalopathyPeople who know little about HE think there

is little to know

People who know a lot about HE know there is little known