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Core Curriculum Handout

Presenter: Mamie Dong
Preceprot: Sam Ho
December 29, 2009

Hepatic Encephalopathy

I. Introduction: HE is a term used to describe a spectrum of neuropsychiatric abnormalities
occurring in patients with significant liver disease and/or portosystemic shunting of blood.

II. Definition and Nomenclature
A. The first consensus panel to standardize terminology occurred in 1998 (11
th
World
Congress of Gastroenterology, report published in 2002
2
)

Type Nomenclature Subcategory Subdivision
A Encephalopathy associated with
Acute liver failure

B Encephalopathy associated with
portal-systemic Bypass and no
intrinsic liver disease

C Encephalopathy associated with
Cirrhosis and portal hypertension
or portal-systemic shunts
Episodic HE Precipitated
Spontaneous*
Recurrent**
Persistent HE Mild (Grade 1)
Severe (Grade 2-4)
Treatment-dependent
Minimal HE
* No trigger identified ** 2 or more episodes in 1 year
Lasting > 4 weeks No clinically discernable symptoms
Older terms, such as portal-systemic encephalopathy (PSE) and subclinical encephalopathy are
no longer endorsed.

III. Pathophysiology General Points
A. Nearly all investigators agree that the toxins causing HE arise from the gut, but
what exactly those toxins are and how they cause HE are still an area of debate
B. Patients with total diversion of portal blood around the liver but with normal liver
histology (such as PV thrombus) rarely have overt HE, even after massive variceal
bleeding. This is still an area of research/debate and is not well understood.
C. The sensitized brain Gut toxins not only play a role in inducing HE, but may
sensitize the brain to other insults. This potentially explains why patients with normal
ammonia levels can have classic HE responsive to lactulose.
D. HE is not just a reversible metabolic encephalopathy. Brain atrophy and
Parkinsonian signs are also elements of this syndrome.

IV. Pathophysiology Hypotheses

A. The Original Ammonia Hypothesis Ammonia is directly neurotoxic
Described in the 1950s when HE was reported in patients taking
ammonia exchange resins for treatment of ascites
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Supportive evidence
Recent studies in the last decade have found a reliable correlation
(r=0.6 or higher) between ammonia levels and severity of HE.
Previously described lack of correlation is thought to be due to
suboptimal lab technique.
Patients with hereditary urea cycle enzyme defects and
hyperammonemia develop encephalopathy
Most treatments thought to be effective in HE are best explained
by an ability to reduce the generation of ammonia and its
absorption from the gut
Contradictory evidence
Unlike in HE, patients with pure hyperammonemia (without liver
disease) frequently have seizures
Controlled trials administering ammonia to cirrhotic patients failed
to induce HE

B. The Unifying Ammonia Hypothesis Ammonia influx to the brain triggers
astrocyte swelling and cerebral edema
Originally suggested by Haussinger et al in 2006, now accepted by most
HE investigators
The only mechanism for handling excessive ammonia in the brain is
catalysis by glutamate synthetase within astrocytes. Accumulation of
osmotically active glutamine causes astrocyte swelling, which then leads
to a host of downstream events.
In chronic liver disease, cerebral edema tends to be low grade due to
compensating efflux of myoinositol.

C. Synergistic Neurotoxin Hypothesis Mercaptans, a byproduct of methionine
metabolism, in conjunction with other gut-derived toxins, causes HE
HE has been reportedly induced in animal models and human cirrhotics
given oral methionine
Fetor hepaticus, commonly present in patients with or likely to develop
HE, has been conclusively proven to be derived from mercaptans

D. False Neurotransmitter Hypothesis False or weak neurotransmitters, byproducts
of liver failure, lead to failure of neurotransmission
Direct injection of octopamine into rat CNS failed to produce any effect
Some data suggests that this may play a role in the hyperdynamic
circulation seen in advanced liver disease

E. Plasma Amino Acid Imbalance Hypothesis Elevated brain levels of tyrosine and
phenylalanine in the brain, caused by decreased blood levels of branched chain amino
acids, causes HE
Ammonia also influences glutamine transport across the blood-brain
barrier
Many nutritional supplements were developed (with low levels of tyrosine
and phenylalanine and enriched in branched-chain amino acids), but
despite normalization of amino acid ratios, clearcut improvement in HE
was difficult to prove
3

F. GABA / Benzodiazepine Hypothesis Increased inhibitory GABA-ergic
neurotransmission in the CNS due to excess GABA in the brain or elevated
endogenous benzodiazepines causes HE
Flumazenil has been showing to be more effective in reversing HE than
placebo
Research in determining what these benzodiazepines are and where they
come from is ongoing

G. Other Hypotheses
Manganese hypothesis
Abnormal manganese deposits have been found in certain brain
regions (can also be seen on MRI)
Manganese induces astrocyte swelling in-vivo
Endogenous opiate hypothesis
Case reports of reversal of HE by opiate antagonists
Fatigue and pruritus, to some extent, can be linked to excessive
endogenous opiates
Inflammatory cytokines mediate both decrease in heart rate variability and
HE
3

Severe zinc deficiency

V. Diagnosis
A. There are 2 major components of HE, altered mental status and generalized motor
disturbance.
B. Rule out other causes of encephalopathy

Metabolic CNS Toxins Infection
Hypoxia / Hypercapnea CVA Alcohol Sepsis
Hyper / Hypo-natremia Wernicke-Korsakoff
syndrome
CNS
depressants
Meningitis
Hypoglycemia / Ketoacidosis Seizure / Postictal Encephalitis
Hyper / Hypo-thyroidism Intracranial or
subdural hemorrhage
Intracranial
abscess
Hypercalcemia Delirium tremens
Adrenal dysfunction CNS infection
Uremia CNS neoplasm
C. Search for precipitating factors every advanced cirrhotic patient displaying a
change in mental status is septic until proven otherwise
Why does GI bleeding precipitate HE?
Hemoglobin is deficient in isoleucine, and when hemoglobin is
digested and absorbed it causes an unbalanced amino acid profile
that ultimately leads to disproportionate production of ammonia
Conceivably, infusion of isoleucine to cirrhotic patients after
bleeding may reduce ammonia levels
Sepsis / Infections hypercatabolic state increased precursors for
ammonia synthesis
Hypokalemic alkalosis induces renal ammoniagenesis
Renal failure decreased renal ammonia excretion
4
HCC, Portosystemic shunt increases ammonia delivery to CNS

Definite Less Certain
Gastrointestinal bleeding CNS-active drugs Zinc deficiency
Sepsis / Infections Constipation Beta-blockers
Hypokalemia High protein load Anemia
Renal failure / Urinary
obstruction
Portosystemic shunt Oral methionine
Hyponatremia Superimposed liver injury Hypernatremia (free water
depletion)
Dehydration Hepatocellular carcinoma

D. Grade / Stage the severity of disease
Overt HE is a clinical diagnosis
West Haven Criteria for Semi-quantitative grading of mental status
The major grading system used for the past 3 decades
Focuses on mental status

West Haven Criteria for Semi-quantitative Grading of Mental Status
Grade 1 Trivial lack of awareness
Euphoria or anxiety
Shortened attention span
Impaired performance of addition
Grade 2 Lethargy or apathy
Minimal disorientation for time or place
Subtle personality change
Inappropriate behavior
Impaired performance of subtraction
Grade 3 Somnolence to semi-stupor, but responsive to verbal stimuli
Confusion
Gross disorientation
Grade 4 Coma (unresponsive to verbal or noxious stimuli)
Glasgow Coma Scale
Useful for patients with Grade 3-4 HE
Incorporates motor components

Glasgow Coma Scale
1 2 3 4 5 6
Eyes Does not
open eyes
Opens eyes to
painful stimuli
Opens eyes to
voice
Opens eyes
spontaneously
NA NA
Verbal No sounds Incomprehensible
sounds
Inappropriate
words
Confused Oriented NA
Motor No
movements
Extension posturing
to painful stimuli
Flexion
posturing to
painful stimuli
Withdraws to
painful stimuli
Localizes
painful
stimuli
Obeys
commands

Other grading systems have been devised in an attempt to incorporate both
the West Haven criteria and the GCS, but none have been validated in
large multi-center trials
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HESA (Hepatic Encephalopathy Scoring Algorithm) Courtesy of Dr. Hassanein



E. Motor Abnormalities
Hyperreflexia, asterixis, extensor plantar reflexes are often seen
Asterixis is not specific to HE, but its presence in a patient with known
liver disease is a fairly reliable sign presence signifies grade 2 HE, may
be diminished in grade 3 HE
Localizing motor signs may be seen in patients with HE without any
imaging abnormalities, though stroke and hemorrhage must be ruled out
first. These resolve without sequelae as HE resolves.

F. Laboratory and Imaging Assessment
Blood Ammonia Testing
Recently, some studies have shown a correlation (r>0.6) of
ammonia levels with degree of encephalopathy, however this is not
sufficient proof to use ammonia testing for diagnosis.
Major problem: Frequent false positives and false negatives
Falsely high levels can occur with inappropriately collected
samples (must be placed on ice and processed within 30 minutes)
The only clinical scenario where ammonia testing may be helpful
is in the patient without clear underlying liver disease but with
marked mental status changes
Brain imaging
Useful for ruling out other causes of encephalopathy
Imaging findings in HE patients
o CT
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Cortical atrophy (worse in alcoholic liver dz)
Subtle suggestion of cerebral edema
Rarely frontal cerebral edema can be seen
o MRI
Hyperintensity of basal ganglia on T1 weighted
images (due to manganese deposits)
Cerebral and cerebellar atrophy
Cerebral edema

G. Assess the rare patient with HE but no obvious chronic liver disease
Long-standing, undiagnosed, well compensated cirrhosis
Unlike alcoholic cirrhosis, where portal-systemic shunting and loss
of liver function progress at roughly the same rate, patients with
hep C or NASH cirrhosis develop large shunts and may exhibit HE
before major loss of liver function is observed
Congenital portal-systemic shunts
Portal-systemic shunts due to splanchnic venous thrombosis (ie, portal
vein thrombosis)
Non-cirrhotic portal hypertension
Coincidental partial urea cycle enzyme deficiency
Mild liver disease with other entities such as zinc deficiency, Addisons
disease, or hypothyroidism

VI. Minimal Hepatic Encephalopathy (MHE)
A. Definition
Previously known as subclinical HE
No clinically discernable symptoms but at least one abnormal
neuropsychologic or neurophysiologic test

B. Why is this important?
5,6

Studies show that patients have impairments in daily functioning, quality
of life, and may be unsafe to drive cars
MHE predicts the occurrence of overt H
Patients who are treated show a significant reduction in blood ammonia
levels and improvement in Child-Turcotte-Pugh class

C. Pathogenesis
Mainly a dysfunction of subcortical systems: attention, visual-spatial, fine
motor movements
May have impaired immediate memory due to poor cognitive ability, not
an impairment in anterograde memory like Alzheimers

D. Diagnosis Not yet widely used clinically, mostly for research purposes
No consensus on how best to diagnose or how often patients should be
evaluated
2009 ISHEN guidelines
7
recommend 1 of the 2 following battery of tests,
takes 20-40 minutes to complete
PSE-Syndrome Test designed especially for MHE, but only
available in German
7
o Serial dotting test 10 rows of 10 circles each, patient is
timed on how quickly he/she can draw a dot in the center of
each circle
o Line drawing test patient scored on how quickly and
accurately he/she can draw a continuous line between 2
winding lines
o Digit symbol test involves coding-substitution of symbols
for numbers
o Number connection tests A and B known as connect the
dots in elementary school
RBANS used for all forms of dementia and neurocognitive
impairment; also includes tests for memory and language fluency
Electrophysiological studies not readily available
EEG can see triphasic spikes
Visual / auditory evoked potentials
Flicker fusion detection

E. Treatment - ? lactulose, ? probiotics; not currently standard of care

VII. Treatment - Overview
A. 4-pronged approach to treatment
Supportive care
Search for and correct precipitating factors
Exclude and treat other causes of altered mental status
Start empiric therapy for HE

Reduction of ammonia
production and absorption
Lactulose, Lactitol, Lactose
Dietary protein restriction
Poorly absorbed antibiotics
Disaccharide inhibitors
Probiotics
Promotion of waste nitrogen
excretion
L-Ornithine-aspartate (LOLA)
Sodium benzoate
Correction of neurotransmitter
abnormalities in the brain
Flumazenil
Branched-chain amino acid-enriched formulations
Dopaminergic agents
Narcotic antagonists
Zinc repletion
Portosystemic shunt
suppression

Liver support systems
Liver transplantation

B. Historical issues
The first treatments were with antibiotics such as tetracyclines to reduce
production of ammonia by gut flora
Later, poorly absorbed antibiotics, mainly neomycin, became standard of
treatment in the 1960s. However, the first placebo-controlled trials for
neomycin didnt occur until the early 1990s, and they showed equal
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efficacy of neomycin and placebo! Despite this, it continued to be used as
a comparison drug for other agents in the years that followed.
Lactulose first appeared in 1966, and was featured in a number of RCTs in
the 1970s. Two early placebo-controlled trials did not show any efficacy.
Following, major RCTs were done comparing lactulose to neomycin, and
found that neomycin was equivalent to slightly superior to lactulose
(possibly due to concomitant use of sorbital to induce diarrhea). The two
were marked eqiavalent, and thus lactulose came into favor due to fewer
side effects.
Modern trials are complicated by several factors, first lactulose is
considered the necessary comparison arm (despite evidence lacking as to
its efficacy), IRBs consider it unethical to not treat HE (ie, unable to do
placebo controlled trials), and hospitalized patients are always being
treated supportively. It is not known what the spontaneous recovery rate
from HE is, but some studies have suggested 40-70%.
In a recent study by Sharma et al
4
comparing lactulose to placebo in the
secondary prevention of HE in 140 patients, lactulose was found to be
superior (19.6% vs 46.8%, p=0.001)

VIII. Treatments that reduce ammonia production and absorption in the gut
A. Non-absorbed disaccharides lactulose (and lactitol-not available in US)
Mechanism of action complex
Osmotic laxative
Acidifies lumen of colon, which converts ammonia to ammonium
and traps it in the colon and promotes its incorporation into
bacterial proteins
Gut acidity inhibits ammoniagenic bacteria and promotes growth
of nonammoniagenic bacteria
Possibly inhibits intestinal glutaminase activity
Efficacy: Consistently shown to be superior compared to no treatment for
minimal HE, proof of efficacy is lacking for overt HE
Dose: lactulose 30cc bid-qid titrated to goal 2-4 soft BMs/day or retention
enema 300cc lactulose + 700cc tap water retained for 1 hour
Pros: cheap, has been used for a long time
Cons: sweet, increases intestinal gas production, electrolyte disturbances,
particularly hypernatremia (with dehydration)
Contraindications: ileus

B. Poorly absorbed antibiotics rifaximin (and neomycin-FDA approved for acute HE
only, not chronic HE)
Mechanism of action
Suppresses growth of aerobic intestinal bacteria, which reduces
ammonia production in the gut
Induces malabsorption and villous atrophy in the small intestines
Possibly reduces glutaminase activity
Possibly treats small bowel bacterial overgrowth
Efficacy: Rifaximin has been found to be equivalent or superior to
lactulose
Dose:
First Line
Second Line
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Rifaximin 400mg PO tid marginally better than lower doses
(400mg-550mg bid)
Neomycin 1gm PO q6h for up to 6 days (if used chronically, 1-
2gm/day)
Pros: no diarrhea
Cons: rifaximin is expensive; neomycin can cause ototoxicity and
nephrotoxicity
Other antibiotics
Metronidazole not FDA approved for HE, but found to be
equivalent to neomycin
o Dose: 250mg PO bid
o Cons: Risk of accumulation in patients with advanced liver
dz, leading to CNS toxicity, peripheral neuropathy; ?risk of
antibiotic resistance, fungal infection
Vancomycin one report showed efficacy in lactulose-resistant
HE, but popularity faded with outburst of VRE
Nitazoxanide pilot study in 2008 looked promising

C. Dietary protein restriction no longer recommended
Protein restriction below maintenance level (0.8g/kg/day) may lead to lean
body mass catabolism and may ultimately increase nitrogen load in the
circulation
Recent studies have shown that recovery from HE was not delayed if a
normal protein diet was delivered in addition to standard HE therapy
If oral dietary protein intolerance is truly documented, then patients can be
placed on a vegetable protein diet. Branched-chain amino acid enriched
supplements are useful in highly elect protein-intolerant patients, but are
expensive.
Recommended protein intake: 0.8-1.5 g/kg/day

D. Disaccharide inhibitors Acarbose
Used for treatment of diabetes
Mechanism of action: inhibits alpha glucosidase activity in the intestines
and induces carbohydrate malabsorption; inhibits colonic proteolytic flora
Efficacy: randomized controlled crossover trial of 107 cirrhotic patients
showed significant reduction of ammonia and improvement in HE
symptoms over placebo
10

Cons: not used because package insert says Acarbose is contraindicated in
patients with cirrhosis

E. Probiotics
Mechanism of action: attempts to promote nonammoniagenic bacteria in
the gut
Lactobacillus acidophilus
Enterococcus SF, Enterococcus faecium pilot studies equivocalent to
lactulose
Cons: concerns about introducing live bacteria into patients who are
immunosuppressed

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F. Combination of lactulose + rifaximin Frequently used for difficult to treat cases,
but no prospective studies to date
IX. Treatments that promote waste nitrogen excretion
A. LOLA (L-Ornithine-L-Aspartate) available for research only
Mechanism of action:
Promotes ureagenesis and glutamine synthetase activity in the liver
Promotes glutamine synthesis and possibly protein anabolism in
skeletal muscle
Efficacy: Shown in placebo-controlled trials to have significant effect in
grade II HE
Available in enteral and parenteral forms
Pros: well tolerated, only minor GI side effects reported

B. L-Ornithine Phenylacetate animal studies only
Theoretically, phenylacetate component can conjugate with glutamine and
be excreted by the kidneys

C. Sodium Benzoate and Sodium Phenylacetate
Mechanism of action benzoate conjugates with glycine and
phenylacetate conjugates with glutamine (both contain nitrogen from
ammonia)
Approved for use in patients with urea cycle enzyme deficiencies
Efficacy: Only 1 trial done so far comparing sodium benzoate to lactulose,
judged to be equivalent
Dose: start low, titrate to effect, max 5g PO BID
Pros: Available in enteral and parenteral forms, cheap
Cons: Bad taste, high sodium content, GI side effects (esp nausea)

D. L-Carnitine stimulates urea cycle; animal studies only

X. Correction of neurotransmitter abnormalities in the brain
A. Flumazenil
Mechanism of action: Endogenous and exogenous benzodiazepine
receptor antagonist
Efficacy: Shown to reverse HE in animal models. In human trials,
systemic review showed good short term benefit, but no long term benefit
and no change in survival
Cons: No long acting formulation available, can cause seizures, agitation,
dizziness, nausea/vomiting

B. Branched-chain amino acid (BCAA)-enriched formulations
Parenteral formula not useful
Enteral formula may possibly be useful in select protein-sensitive patients
for prevention or treatment of HE
Cons: high cost, some studies showed increased mortality ?

C. Dopaminergic agents L-Dopa, bromocriptine
Limited role in HE
Third Line
Third Line
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May be helpful for the patient with extrapyramidal symptoms refractory to
other therapy (bromocriptine dose 30mg bid)

D. Opiate antagonists
Animal studies show reversal of HE with naloxone; no RCTs have been
done in humans

E. Zinc repletion
Zinc deficiency is common in cirrhotics, particularly alcoholics
Efficacy: Only small studies, and results equivocal, but case reports exist
of resistant HE responding only to zinc
Dose: elemental zinc 11mg/day for adult males, 8mg/day for adult females
Pros: cheap, over the counter
Cons: acute or chronic zinc toxicity can lead to nausea, vomiting, diarrhea,
poor appetite, abdominal cramps, headache

XI. Other Treatments
A. Liver support systems covered in more detail in Cristinas and Dr. Hassaneins
grand rounds
MARS (albumin dialysis), biologic systems
Appear to improve HE, but ? survival benefit, very expensive

B. Closure or downsizing of portosystemic shunts (spontaneous or artificial)
TIPS is relatively contra-indicated in patients with grade 2 or higher HE
Episodes of HE may occur within the first few months after TIPS and can
be managed medically
TIPS downsizing or closure is necessary for severe and intractable HE.
One study showed critical low threshold for portal pressure gradient was
<5mm Hg
8

Splenic artery embolization (to reduce shunting) can be helpful for highly
select cases

C. Total colectomy - decreases colonic absorption of nitrogenous substances; described
in the literature in the 1970s-1980s

D. Liver transplantation Largely reverses HE, but may have permanent mild residual
symptoms

E. AST-120 currently undergoing phase II trial
An oral adsorbent used in Japan to delay initiation of dialysis in patients
with ESRD. Binds ammonia, bile acids, inflammatory mediators.

F. NMDA-receptor antagonists animal studies only
Theory: ammonia leads to overstimulation of NMDA receptors
Efficacy: Rats given ammonia developed sx of HE which were reversed
by administration of NMDA-receptor antagonists

XII. HE resistant to treatment - It is actually very rare to be unable to arouse a patient (at least
temporarily) from severe HE, no matter how bad their liver function has become. Look for
other reasons of AMS in these patients.
Third Line
Fourth Line
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References
1) Mullen KD. Hepatic Encephalopathy. In Editors Boyer TD, Wright TL, Manns MP. Hepatology, 5
th

edition. Saunders Elsevier 2006. Chapter 18.
* All studies mentioned in this handout that were discussed in this textbook are not listed separately
here.
2) Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy definition, nomenclature,
diagnosis, and quantification: final report of the working party at the 11
th
World Congress of
Gastroenterology, Vienna, 1998. Hepatology 2002;35:716-721.
3) Mani AR, Montagnese S, Jackson CD, et al. Decreased heart rate variability in patients with cirrhosis
relates to the presence and degree of hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol
2009. 296(2):G330-8. Epub 2008 Nov 20.
4) Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis of hepatic encephalopathy: an
open-label randomized controlled trial of lactulose versus placebo. Gastroenterology 2009.
137(3):885-91.
5) Das A, Dhiman RK, Saraswat VA, Verma M, Naik SR. Prevalence and natural history of subclinical
hepatic encephalopathy in cirrhosis. J Gastroenterol Hepatol. 2001. 16(5):531-5.
6) Bustamante J, Rimola A, Ventura PJ, et al. Prognostic significance of hepatic encephalopathy in
patients with cirrhosis. J Hepatol. 1999. 30(5):890-5.
7) Randolph C, Hilsabeck R, Kato A et al. Neuropsychological assessment of hepatic encephalopathy:
ISHEN practice guidelines. International Society for Hepatic Encephalopathy and Nitrogen
Metabolism (ISHEN). Liver Int. 2009. 29(5):629-35.
8) Chung HH, Razavi MK, Sze DY, et al . Portosystemic pressure gradient during transjugular
intrahepatic portosystemic shunt with Viatorr stent graft: what is the critical low threshold to avoid
medically uncontrolled low pressure gradient related complications? J Gastroenterol Hepatol 2008.
23(1):95-101.
9) Al Sibae MR, McGuire BM, et al. Current trends in the treatment of hepatic encephalopathy. Ther
Clin Risk Manag 2009. 5(3):617-26.
10) Gentile S, Guarino G, Romano M, et al. A randomized controlled trial of acarbose in hepatic
encephalopathy. Clin Gastroenterol Hepatol 2005. 3(2):184-91.
Some Common Reasons for HE Resistant to Treatment

Excess purgation leading to dehydration / free water loss
Failure to identify and treat sepsis
Ileus, especially in association with azotemia (may need dialysis)
Long-acting sedative use
Undiagnosed concomitant CNS problem (eg, hypothyroidism, hemorrhage)
Overly efficacious portosystemic shunt procedure
Profound zinc deficiency (can sometimes occur with excessive small bowel purge)