Transcript Nutritional Management of Hepatic Encephalopathy

Nutritional Management
of Hepatic
Encephalopathy
Presented by
Chris Theberge & Sara Murkowski
Presentation At A Glance

Background on Liver Dysfunction
 Review
of liver physiology
 Diseases of the liver

Development of Hepatic Encephalopathy
 Pathogenesis
Theories
 Incidence, Prognosis, Diagnostic Criteria
 Clinical manifestations, Nutritional manifestations
 Treatment: Medical Management


Case Study
Nutritional Management
 Historical Treatment Theories/Practice
 Protein Restriction & BCAA Supplementation
 Goals
of MNT
Let’s Take It From The Top

A Physiology Review
Functions of the Liver:
A Brief Overview



Largest organ in body, integral to most metabolic
functions of body, performing over 500 tasks
Only 10-20% of functioning liver is required to
sustain life
Removal of liver will result in death within 24
hours
Functions of the Liver

Main functions include:
 Metabolism
of CHO, protein, fat
 Storage/activation vitamins and minerals
 Formation/excretion of bile
 Steroid metabolism, detoxifier of drugs/alcohol
 Action as (bacteria) filter and fluid chamber
 Conversion of ammonia to urea




Gastrointestinal tract significant source of ammonia
Generated from ingested protein substances that are
deaminated by colonic bacteria
Ammonia enters circulation via portal vein
Converted to urea by liver for excretion
The Urea Cycle
Aspartate Transaminase(AST)
Alanine Transaminase (ALT)
Liver Diseases
Classifications




Duration
 Acute vs Chronic
Pathophysiology
 Hepatocellular vs
Cholestasic
Etiology
 Viral
 Alcohol
 Toxin
 Autoimmune
Stage/Severity
 ESLD
 Cirrhosis
Viral hepatitis A, B, C, D, E (and G)
Fulminant hepatitis
Alcoholic liver disease
Non-alcoholic liver disease
Cholestatic liver disease
Hepatocellular carcinoma
Inherited disorders
Liver Diseases

Fulminant Hepatic Failure (“Shocked Liver”)
 Rapid, severe acute liver injury with impaired function
and encephalopathy in someone with a previously
normal liver or with well-compensated liver disease




Encephalopathy within 8 weeks of symptom onset or within 2
wks of developing jaundice
Multiple causes (ie, drug toxicity, hepatitis)
Malnutrition often not major issue
Chronic Hepatic Failure (“Subfulminant" Hepatic
Failure)
 At least 6-month course of hepatitis or biochemical
and clinical evidence of liver disease with
confirmatory biopsy findings of unresolving hepatic
inflammation
 Multiple causes: autoimmune, viral, metabolic, toxic
Liver Diseases
Cholestatic Liver Diseases

Primary biliary cirrhosis (PBC)


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Immune-mediated chronic cirrhosis of the liver due to obstruction
or infection of the small and intermediate-sized intrahepatic bile
ducts
90% of patients are women
Nutritional complications


Osteopenia, hypercholesterolemia, fat-soluble vitamin deficiencies
Sclerosing cholangitis


Fibrosing inflammation of segments of extrahepatic bile ducts,
with or without involvement of intrahepatic ducts
Nutritional complications

Inflammatory bowel disease, fat soluble vitamin deficiencies,
hepatic osteodystrophy (steatorrhea)
Inherited Liver Disorders

Hemochromatosis
 Inherited

disease of iron overload
Wilson’s disease
 Autosomal
recessive disorder associated with
impaired biliary copper excretion

α1-antitrypsin deficiency
 Causes
cholestasis or cirrhosis and can cause
liver and lung cancer
Liver Diseases

Alcoholic Liver Disease, Alcoholic hepatitis, and
Cirrhosis
 Diseases resulting from excessive alcohol ingestion
characterized by fatty liver (hepatic steatosis),
hepatitis, or cirrhosis (fibrous tissue)
 Prognosis depends on degree of abstinence and
degree of complications
 Malnutrition often an issue in these patients
 Most common liver disease in US
Progression of Liver Diseases
Normal Liver
Alcoholic Fatty Liver
Cirrhotic Liver
Prognosis of Cirrhosis
Child-Pugh and MELD Score
Both used to determine prognosis of
Cirrhosis (mortality and survival)
Determine Need For Transplantation
Used in studies to determine effect
of treatment on liver function
Malnutrition In Liver Disease

Malnutrition is an early and typical aspect of hepatic
cirrhosis


Contributes to poor prognosis and complications
Degree of malnutrition related to severity of liver
dysfunction and disease etiology (higher in alcoholics)



Mortality doubled in cirrhotic patients with malnutrition (35% vs
16%)
Complications more frequent than in well-nourished (44% vs
24%)
Usually more of a clinical problem than hepatic encephalopathy
itself
Cirrhosis is common
end result of many
chronic liver disorders
Severe damage to structure &
function of normal cells


Inhibits normal blood flow

Decrease in # functional hepatocytes
Results in portal hypertension &
ascites


Portal systemic shunting
Blood
bypasses the liver via shunt,
thus bypassing detoxification
Toxins
remain in circulating blood
Neurtoxic
substances can precipitate
hepatic encephalopathy
And Now Our Featured
Presentation…
What is Hepatic Encephalopathy?

Broadly defined

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Brain and nervous system damage secondary to severe
liver dysfunction (most often chronic disease) resulting from
failure of liver to remove toxins
Multifactorial pathogenesis with exact cause unknown
Symptoms vary from nearly undetectable, to coma with
decerebration


All neurological and psychological symptoms in patients with liver
disease that cannot be explained by presence of other pathologies
Characterized by various neurologic symptoms
 Cognitive impairment
 Neuromuscular disturbance
 Altered consciousness
Reversible syndrome
Incidence & Prognosis

Incidence
 10-50%
of cirrhotic pts and portal-systemic shunts
(TIPS) experience episode of overt hepatic
encephalopathy
 True incidence/prevalence of HE unknown



Lack of definitive diagnosis
Wide spectrum of disease severity
Prognosis
 40%
survival rate 1 year following first episode
 15% survival rate 3 years following first episode
Clinical Manifestations of HE
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Cerebral edema
Brain herniation
Progressive, irreversible coma
Permanent neurologic losses (movement,
sensation, or mental state)
Increased risk of:
 Sepsis
 Respiratory
failure
 Cardiovascular collapse
 Kidney Failure
Variants of Hepatic Encephalopathy

Acute HE
 Associated with marked cerebral edema seen in
patients with the acute onset of hepatic failure (FHF)

Hormonal disarray, hypokalemia, vasodilation (ie,
vasopressin release)
 Quick
progression: coma, seizures, and decerebrate
rigidity
 Altered mental function attributed to increased
permeability of the blood-brain barrier and impaired
brain osmoregulation
 Results in brain cell swelling and brain edema
 Can occur in cirrhosis, but usually triggered by
precipitating factor
 Precipitating factors usually determine outcome
Precipitants of Hepatic
Encephalopathy
Drugs
•Benzodiazepines
•Narcotics
•Alcohol
Dehydration
•Vomiting
•Diarrhea
•Hemorrhage
•Diuretics
•Large volume paracentesis
Primary Hepatocellular
Carcinoma
Portosystemic Shunting
•Radiographic or surgically placed shunts
•Spontaneous shunts
•Vascular Occlusion
•Portal or Hepatic Vein Thrombosis
Increased Ammonia Production,
Absorption or Entry Into the Brain
•Excess Dietary Intake of Protein
•GI Bleeding
•Infection
•Electrolyte Disturbances (ie., hypokalemia)
•Constipation
•Metabolic alkalosis
Variants of Hepatic Encephalopathy

Chronic HE

Occurs in subjects with chronic liver disease such as cirrhosis and
portosystemic shunting of blood (Portal Systemic Encepalopathy [PSA])
 Characterized by persistence of neuropsychiatric symptoms despite
adequate medical therapy.
 Brain edema is rarely reported

Refractory HE
 Recurrent episodes of an altered mental state in absence of
precipitating factors
Persistent HE
 Progressive, irreversible neurologic findings: dementia,
extrapyramidal manifestations, cerebellar degeneration,
transverse cordal myelopathy, and peripheral neuropathy

Subclinical or “Minimal HE”


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Most frequent neurological disturbance
Not associated with overt neuropsychiatric symptoms
Subtle changes detected by special psychomotor tests
Stages of Hepatic
Encephalophay
Stage
I
Symptoms
II
Lethargy, disorientation, inappropriate behavior,
drowsiness
III
Somnolent but arousable, slurred speech, confused,
aggressive
IV
Coma
Mild Confusion, agitation, irritability, sleep disturbance,
decreased attention
Pathogenesis Theories

Endogenous Neurotoxins
 Ammonia
 Mercaptans
 Phenols
 Short-medium


fatty acids
Increased Permeability of Blood-Brain Barrier
Change in Neurotransmitters and Receptors
 GABA
 Altered

BCAA/AAA ratio
Other
 Zinc
defficiency
 Manganese deposits
Neurotoxic Action of Ammonia


Readily crosses blood-brain barrier
Increased NH3 = increased glutamate




α-ketoglutarate+NH3+NADH→glutamate+NAD
glutamate+NH3+ATP→glutamine+ADP+Pi
As a-ketoglutarate is depleted TCA cycle activity halted
Increased glutamine formation depletes glutamate stores
which are needed by neural tissue
 Irrepairable cell damage and neural cell death ensue.
 In liver disease, conversion of ammonia to urea and
glutamine can be reduced up to 80%
Pathogenesis Theories:
False Neurotransmitter Hypothesis

Liver cirrhosis characterized by altered
amino acid metabolism
Increased Aromatic Amino Acids in plasma and
influx in brain
 Decrease in plasma Branched Chain Amino Acids
 Share a common carrier at blood-brain barrier

BCAAs in blood may result in
AAA transport
to brain

Abnormal plasma amino acids:
chronic liver disease
400
Glu
% of Normal
350
Phe
Asp
Meth
300
250
Tyr
200
Try
150
Gly
100 Thr
50 Val Leu
Lys
Tau
Orn
Ser
Pro
His
Ala
Arg
Ileu
Essential
Cerra, et al; JPEN, 1985
Non-Essential
J. Y. Pang
Pathogenesis Theories:
False Neurotransmitter Hypothesis
 AAA are
precursors to neurotransmitters and
elevated levels result in shunting to secondary
pathways
Pathogenesis Theories:
Change In Neurotransmitters and Receptors

Gamma-Aminobutyric
Acid (GABA)

BCAA-Ammonia
Connection
Increase Permeability of BloodBrain Barrier
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

Astrocyte (glial cell) volume is controlled by
intracellular organic osmolyte
Organic osmolyte is glutamine.
glutamine levels in the brain result in volume
of fluid within astrocytes resulting in cerebral
edema (enlarged glial cells)
Neurological impairment
 N=Normal Astrocytes
 A=Alzheimer
type II astrocytes
 Pale, enlarged nuclei
 characterisic of HE
Symptoms of HE

Changes in mental
state, consciousness
 Confusion,
disorientation
 Delirium
 Dementia (loss of
memory, intellect)
 Mood swings
 Decreased altertness,
responsiveness
 Coma






Course muscle
tremors
Muscle stiffness or
rigidity
Loss of small hand
movements
(handwriting)
Seizures (rare)
Decreased self-care
ability
Speech impairment
Diagnosing HE

No single laboratory test is sufficient to
establish the diagnosis
 No

Gold Standard
Pt brains cannot be studied with
neurochemical/neurophysiologic methods
 Data
on cerebral function in HE usually derived
from animal studies

Underlying cause of liver disease itself
may be associated with neurologic
manifestations
 Alcoholic
liver disease (Wernicke’s)
Diagnostic Criteria

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Asterixis (“flapping tremor”)
Hx liver disease
Impaired performance on neuropsychological tests
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Sleep disturbances
Fetor Hepaticus
Slowing of brain waves on EEG
PET scan

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Visual, sensory, brainstem auditory evoked potentials
Changes of neurotransmission, astrocyte function
Elevated serum NH3
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

Stored blood contains ~30ug/L ammonia
Elevated levels seen in 90% pts with HE
Not needed for diagnosis
Table 3. Differential diagnostic considerations in hepatic
encephalopathy
Differential Diagnosis
Metabolic encephalopathies
Diabetes (hypoglycemia,
ketoacidosis)
Hypoxia
Carbon dioxide narcosis
Toxic encephalopathies
Alcohol (acute alcohol
intoxication, delirium tremens,
Wernicke-Korsakoff syndrome)
Drugs
Intracranial events
Intracerebral bleeding or
infarction
Tumor
Infections (abscess,
meningitis)
Encephalitis
Treatment of Hepatic
Encephalopathy

Various measures in current treatment of HE
 Strategies to lower ammonia
 Nutritional management



production/absorption
Protein restriction
BCAA supplementation
Medical management
 Medications
to counteract ammonia’s effect on brain
cell function


Lactulose
Antibiotics
 Devices
to compensate for liver dysfunction
 Liver transplantation
Proposed
Complex
Feedback
Mechanisms
In Treatment
Of HE
Nutritional Management of HE

Historical treatment theories
 Protein
Restriction
 BCAA supplementation

Goals of MNT
 Treatment
of PCM associated with ESLD
Historical Treatment Theories:
Protein Restriction


Studies in early 1950’s showed cirrhotic pts
given “nitrogenous substances” developed
hepatic “precoma”
Led to introduction of protein restriction
 Began
with 20-40g protein/day
 Increased by 10g increments q3-5 days as tolerated
with clinical recovery
 Upper limit of 0.8-1.0 g/kg
 Was thought sufficient to achieve positive nitrogen
balance

Lack of Valid Evidence
 Efficacy
trial
of restriction never proven within controlled
Dispelling the Myth
Normal Protein Diet for Episodic Hepatic
Encephalopathy
Cordoba et al. J Hepatol 2004; 41: 38-43


Objective: To test safety of normal-protein diets
Randomized, controlled trial in 20 cirrhotic
patients with HE
 10
patients subjected to protein restriction, followed
by progressive increments

 10
No protein first 3 days, increasing q3days until 1.2g/kg daily
for last 2 days
patients followed normal protein diet (1.2g/kg)
 Both groups received equal calories
Dispelling the Myth

Results
 On
days 2 and 14:
Similar protein synthesis among both groups
 Protein breakdown higher in low-protein group


Conclusion
 No
significant differences in course of hepatic
encephalopathy
 Greater protein breakdown in proteinrestricted subjects
Protein and HE Considerations




Presence of malnutrition in pts with cirrhosis and
ESLD clearly established
No valid clinical evidence supporting protein
restriction in pts with acute HE
Higher protein intake required in CHE to
maintain positive nitrogen balance
Protein intake < 40g/day contributes to
malnutrition and worsening HE
 Increased

endogenous protein breakdown
NH3
Susceptibiliy to infection increases under such
catabolic conditions
Other Considerations

Vegetable Protein
 Beneficial in patients with protein intolerance <1g/kg
 Considered to improve nitrogen balance without worsening
HE
 Beneficial effect d/t high fiber content
 Also elevated calorie-to-nitrogen ratio

BCAA Supplementation
 Effective
or Not?
Branched Chain
Amino Acids (BCAA)
Valine
Leucine
Isoleucine
•Important fuel sources for skeletal
muscle during periods of metabolic
stress
•Metabolized in muscle & brain, not
liver
-promote protein synthesis
-suppress protein catabolism
-substrates for gluconeogenesis
Catabolized to L-alanine and Lglutamine in skeletal muscle
Nutritional Supplementation with BranchedChain Amino Acids in Advanced Cirrhosis:
A Double-Blind, Randomized Trial
Marchesini et al.,(2004). Gastroenterology, 124, 1792-1801
Nutritional Supplementation with Branched-Chain Amino Acids
in Advanced Cirrhosis: A Double-Blind, Randomized Trial


Multi-Center, randomized, controlled study involving 15
centers with interest in patients with liver disease
Inclusion Criteria




A diagnosis of liver cirrhosis documented by histology and
confirmed lab data
Child-Pugh score ≥ 7 (Class B or C)
Sonographic and endoscopic evidence of portal hypertension
Exclusion Criteria

Active alcohol consumption, overt HE, refractory ascites,
reduced renal function (Cre ≥ 1.5 mg/dL), Child-Pugh score ≥ 12,
suspected hepatocellular carcinoma, previous poor compliance
to pharmacological treatment of nutrition counseling
Nutritional Supplementation with Branched-Chain Amino Acids
in Advanced Cirrhosis: A Double-Blind, Randomized Trial

Primary Outcomes
 Combined
survival and maintenance of liver function,
as assessed by death (any reason), deterioration to
exclusion criteria, or transplant
 Number of hospital admissions
 Duration of hospital stay

Secondary Outcomes
 Nutritional
parameters and liver function tests (ChildPugh scores)
 Anorexia and health-related quality of life
 Therapy needs
Study Profile of BCAA Trial
BCAA
Lactoalbumin
Maltodextrin
Total number
59
56
59
Lost to follow-up
1
—
—
Intention-to-treat analysis
58
56
59
9 (15.5%)*
18 (32.1%)
16 (27.1%)
7
4
4
1
1
2
Noncompliance to treatment3
5 (1)
2 (1)
0
Side effects3
44 (1)
2 (1)
2
—
1
—
Regular 3-mo follow-up
42 (71.2%)*
34 (60.7%)
39 (66.1%)
Admission to hospital
15 (35.7%)*
27 (79.4%)
28 (71.8)
0.6 ± 0.2*
2.1 ± 0.5
1.9 ± 0.4
195*
327
520
Events (death, any cause, or progression of liver
failure to exclusion criteria)
Removed from systematic follow-up1
Development of HCC2
Treatment-unrelated diseases
Admission rate (patients/y)
Total no. d in hospital
Significantly different from both lactoalbumin and maltodextrin.
Some individuals were removed based on more than 1 criterion.
2 Cases with HCC were censored at the time of HCC diagnosis.
3 The number of withdrawn patients who died or progressed to exclusion criteria within 12 mo from entry into the study is reported
in parentheses.
4 Including the patient lost to follow-up.
*
1
Primary Outcome Results

Based on ITT, time course of events
was not different between groups
(p=0.101)

A benefit of BCAA only found when nonliver disease-related events excluded
from analyses compared to L-ALB
BCAA significantly reduced the
combined event rates compared
with L-ALB, but not with M-DXT

L-ALB-OR,
0.43; 95% CI (0.19-0.96);
p=0.039
M-DXT-OR,
0.51; 95% CI (0.23-1.17);
p=0.108
Less frequent hospital
admissions with BCAA vs two
control arms (p = 0.021)

Albumin Concentration
ANOVA, P=0.670
4
3.6
3.2
2.8
2.4
2
nd
E
o
9M
o
6M
d
En
o
9M
o
6M
o
BCAA
3M
se
lin
e
3.5
3
2.5
2
1.5
1
0.5
0
Ba
Total Bilirubin
(g/dL)
d
En
o
9M
o
6M
o
BCAA
L-ALB
M-DXT
3M
se
lin
e
10
9
8
7
6
5
Ba
o
Total Bilirubin (g/dL)
Repeated Measures ANOVA
time x treatment; P=0.0012
Child-Pugh Score
ANOVA, P=0.025
Child-Pugh Score
3M
as
el
in
e
BCAA
L-ALB
M-DXT
B
•No change in serum albumin among
groups
•Significant interaction between BCAA and
M-DXT
•Significant reduction in prevalence and
severity of ascites in BCAA vs controls
•No significant improvement in HE based
on Reitan Test)
•Trend for superiority of BCAA over M-DXT
(p=0.108)
Serum Albumin (g/dL)
Secondary Outcomes
Nutritional Parameters
L-ALB
M-DXT
Anorexia and Health-Related Quality of Life

Increased hunger/satiety in BCAA (p=0.019), while no
change in L-ALB and M-DXT (p=0.026)

Prevalence of anorexia significantly (p=0.0014)
decreased in BCAA, while unchanged in controls

Significant improvement in physical functioning in BCAA,
while no change in controls

Trend (p=0.069) towards better scoring of health in
subjects with BCAA only

After 1 year, the percentage of subjects who felt their
health improved increased (29% to 52%) and who felt it
had worsened decreased (43% to 18%) (p=0.001)
Conclusions

Long-term BCAA supplementation showed an
advantage compared to equicaloric,
equinitrogenous supplemenation
 Prevention
of combined death
 Progressive liver failure
 Hospital rates
 Secondary Outcomes
The Mother of All BCAA Trials?
Randomized Study Limitations

Poor subject compliance and adverse reactions 3 times
more common in BCAA (15%) arm compared to controls
(5% combined) resulting in greater withdrawal


Only 115 of 174 subjects had regular f/u at end of study,
reducing power


May explain lack no difference in time course of events
A benefit of BCAA supplementation only found when
non-liver-related deaths were excluded from analysis


Ascertainment bias for event rates
Mortality was lower, but BCAA group had similar number of
deaths compared to the other groups
Mean admission rate lower in BCAA compared to
controls


No cost-effectiveness analysis done
Reasons for hospital admission?
The Mother of All BCAA Trials?
Further Study Limitations

No differences in encephalopathy test scores, including
Reitan testing seen among treatment groups, but
significant improvement in nutritional status in BCAA
compared to others
 Most likely this attributed to reduced admission rates
Branched-Chain Amino Acids For Hepatic
Encephalopathy
Als-Nielsen B, Koretz RI, Kjaergard LL, Gluud C. The
Cochrane Database of Systematic Reviews, 2003, 1-55
Branched-Chain Amino Acids For Hepatic
Encephalopathy

Meta-Analysis of randomized-controlled trials on the treatment of HE
with IV or oral BCAA

Objective


Review Criteria




To evaluate the beneficial and harmful effects of BCAA or BCAAenriched interventions for patients with hepatic encepalopathy
All randomized trials included, irrespective of blinding, publication
status, or language
Data from first period of crossover trials and unpublished trials included
if methodology and data accessible
Excluded trials in which patients allocated by quasi-random method
Participants

Patients with HE in connection with acute or chronic liver disease or
FHF
 Patients of either gender, any age and ethnicity included irrespective of
etiology of liver disease or precipitating factors of HE
Branched-Chain Amino Acids For Hepatic
Encephalopathy

Types of Interventions

Experimental Group


Control Group


BCAA or BCAA-enriched solutions given in any mode, dose, or duration with
or without other nutritive sources
No nutritional support, placebo support, isocaloric support, isonitrogenous
support, or other interventions with a potential effect on HE (ie., lactulose)
Outcome Measures

Primary


Improvement of HE (number of patients improving from HE using definitions
of individual trials)
Secondary



Time to improvement of HE (number of hours/days with HE from the time of
randomization to improvement)
Survival (number of patients surviving at end of treatment and at max f/up
according to trial)
Adverse events (number and types of events defined as any untoward
medical occurrence in a patient, not necessarily causal with treatment)
Branched-Chain Amino Acids For Hepatic
Encephalopathy

Data Collection and Analysis



Trial inclusion and data extraction made independently by two
reviewers
Statistical heterogeneity tested using random effects and fixed
effect models
Binary outcomes reported as risk ratios (RR) based on random
effects model
Branched-Chain Amino Acids For Hepatic
Encephalopathy: Results

Eleven randomized trials (556 patients)



Trial types: BCAA versus carbohydrates, neomycin/lactulose, or
isonitrogenous controls
Median number of patients in each trial: 55 (range 22 to 75)
Follow-up after treatment reported in 4 trials


Compared to control regimens, BCAA significantly increased the
number of patients improving from HE at end of treatment


Median 17 days (range 6 to 30 days)
RR 1.31, 95% CI 1.04 to 1.66, 9 trials
No evidence of an effect of BCAA on survival


RR 1.06, 95% CI 0.98 to 1.14, 8 trials
No adverse events (RR 0.97, 95% CI 0.41 to 2.31, 3 trials)
Significant
Not significant
Combining survival data regardless of window of f/u showed no significant
Difference in survival between BCAA and controls
Branched-Chain Amino Acids For Hepatic
Encephalopathy: Results

Sensitivity Analyses

Methodological quality had a significant impact on results




In trials with adequate generation of allocation sequence,
allocation concealment, and adequate double-blinding, BCAA
had no significant effect on improvement or survival
In trials with unclear generation of allocation sequence,
allocation concealment, and inadequate double-blinding a
significant effect of BCAA on HE was found
BCAA had no significant effect on survival when given
parenterally to acute HE or enterally to chronic HE


Higher quality vs lower quality
Discrepancy between each applied model (fixed vs random)
Trend towards beneficial effect of BCAA using best-case
analysis with fixed model only [p=0.03 vs p=0.13 with random]

No significant effect of BCAA with worst-case analysis
Conclusions

No convincing evidence that BCAA had a significant
beneficial effect on improvement of HE or survival in
patients with HE


Primary analysis showed a significant benefit of BCAA
on HE, but significant statistical heterogeneity was
present and result not robust to sensitivity analysis


Low methodological quality source of heterogeneity (=bias)
Benefits of BCAA on HE only observed when lower
quality studies included


Small trials with short f/u and most of poor quality
Effect size and “small study bias”
No significant association between dose or duration and
the effect of BCAA
Conclusions

In general, BCAAs were more effective when
given enterally to subjects with chronic
encephalopathy, then when given IV to patients
with acute encephalopathy
 Most
likely through improved nutrition
Limitations




Significant heterogeneity among studies (ie.,
patient populations, settings, routine care)
making a meta-analysis decipherable
Division of HE into categories is arbitrary and
precipitating factors not always identified
The definition of “improvement” different among
studies
Scales and items used for defining and
assessing HE are arbitrary and not tested for
reliability or validity
Implications For Future
Research




The absence of evidence for an effect of BCAA does not
mean there is evidence of lack of effect
Future randomized trials warranted
Trials could randomize according various types of HE to
BCAA versus placebo
All trials should use parallel group design



Spontaneously fluctuating nature of HE
Need for assessing outcomes (improvement, recovery, mortality,
and adverse events) after end of treatment
There is substantial need for clear diagnostic criteria of
HE, as well as reassessment and validation of scales
and items used for measuring its course
Implications For Future
Research



New studies are awaited to identify patients at higher risk
where BCAA is probably the only way to prevent
catabolic losses and improve prognosis
Dose-finding studies are needed to detect optimum
dosage, safe limits of administration, and whether higher
doses will show more benefit
Studies needed to define whether all 3 BCAA’s need to
be supplied


Effects of leucine on protein turnover and HGF secretion
Leucine alone might achieve similar beneficial results at lower
total doses
BCAA Enteral Formulations

NutriHep Enteral
Nutrition (Nestle)
 1.5
kcal/mL
 Fat (12%) MCT
(66%)
 Protein: 50%
BCAA, low MET
 CHO: 77%
 RDI: 100%
 Gluten-free,
lactose-free

Hepatic-Aid II
(Hormel Health Labs)
 1.2
kcal/mL
 Fat (28%) No MCT
 Protein: 46% BCAA,
low AAA
 CHO: 58%
 Vitamin and
Electrolyte-free
The Child-Turcotte-Pugh Classification
Goals of MNT for HE

Treatment of PCM associated with Underlying
Liver Disease
 Suppression
of endogenous protein breakdown to
reduce stress placed on de-compensated liver
 Achieve positive nitrogen balance without
exacerbating neurological symptoms


PCM associated with morbidity and mortality in cirrhosis (6590% with PCM)
Severity of pcm positively correlated with mortality
Nutritional Implications:
PCM associated Liver Dz


Malnutrition reported in
65%-90% cirrhotic pts
Poor Dietary Intake






Anorexia
Dietary Restrictions
Ascites
Gastroparesis
Zinc Deficiency
Increased proinflammatory
cytokines

Nutrient malabsorption/
maldigestion




Cholestatic & non-cholestatic
liver disease
Excessive protein losses
Pancreatic insufficiency
Abnormal Metabolism





Hypermetabolism
Hyperglucogonemia
Increased protein metabolism
Increased lipid oxidation
Osteopenia
MNT in Advanced Liver Disease

Poor Dietary Intake
 Due
to poor appetite, early satiety with ascites
Small frequent meals
 Aggressive oral supplementation
 Zinc supplementation


Nutrient Malabsorption
 Due
to
bile, failure to convert to active forms
ADEK supplementation
 Calcium + D supplementation
 Folic Acid Supplementation

MNT in Advanced Liver Disease

Abnormal Fuel Metabolism
 Increased


perioxidation, gluconeogenesis
Bedtime meal to decrease
Protein Deficiency

protein catabolism, repeat paracentesis
High protein snacks/supplements
 1.2-1.5 gms/day

MNT in Advanced Liver Disease

Standard Guidelines
 MVI
with minerals
 2gm Na restriction in presence of ascites
 Do not restrict fluid unless serum Na <120mmol
 Low threshold for NGT in pts awaiting transplant
 TPN should be considered only if
contraindication for enteral feeding
How Much Protein:
That is the Question

Grade III to IV hepatic encephalopathy
 Usually
no oral nutrition
 Upon improvement, individual protein tolerance can
be titrated by gradually increasing oral protein intake
every three to five days from a baseline of 40 g/day
 Oral protein not to exceed 70 g/day if pt has hx if
hepatic encephalopathy
 Below 70 g/day rarely necessary, minimum intake
should not be lower than 40 g/day to avoid negative
nitrogen balance
MNT Specifically in HE


Non-protein energy: 35-45 kcal/kg/day
Up to 1.6g/kg/day protein as tolerated
 Low-grade
HE (minimal, I, II) should not be
contraindication to adequate protein supply

40g temporary restriction if considered protein
intolerant, but gradual increase q3-5 days
 30-40g

Vegetable protein/day for these pts
In patients intolerant of a daily intake of 1 g
protein/kg, oral BCAA up to 0.25 g/kg may be
beneficial to create best possible nitrogen balance
 BCAA’s
do not exacerbate encephalopathy
MNT Specifically in HE

HE coma (grade III-IV)
 Usually
no oral nutrition
 Upon improvement, individual protein tolerance can
be titrated by gradually increasing oral protein intake
every three to five days from a baseline of 40 g/day
 Enteral and parenteral regimens providing 25-30
kcal/kg/day non-protein energy
 1.0g/kg/day protein, depending on degree of muscle
wasting
 BCAA-enriched solutions may benefit protein
intolerant (<1g/kg)
Conclusions in HE Management




Intervention directed against the precipitating
cause(s) will lead to improvement or
disappearance of acute hepatic encephalopathy
Our understanding of pathogenesis is improving,
but much work remains
Link between liver and brain still only partially
understood
No evidence supporting standard use of BCAA
formulations, but may benefit small subgroup
 Cost analysis not conducted in trials
 Cost outweigh benefits for standard protocol
Thank You!

Special Thanks to Nicole Varady
Comments?
 Questions?

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