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Nutritional Management

of Hepatic

Presented by
Chris Theberge & Sara Murkowski

Copyright © 2007, The Nutrition and Food Web Archive (, All rights reserved.
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
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
 Duration Viral hepatitis A, B, C, D, E (and G)
 Acute vs Chronic
Fulminant hepatitis
 Pathophysiology
 Hepatocellular vs Alcoholic liver disease
Cholestasic Non-alcoholic liver disease
 Etiology
 Viral Cholestatic liver disease
 Alcohol Hepatocellular carcinoma
 Toxin
Inherited disorders
 Autoimmune
 Stage/Severity
 Cirrhosis
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
 At least 6-month course of hepatitis or biochemical
and clinical evidence of liver disease with
confirmatory biopsy findings of unresolving hepatic
 Multiple causes: autoimmune, viral, metabolic, toxic
Liver Diseases
Cholestatic Liver Diseases
 Primary biliary cirrhosis (PBC)
 Immune-mediated chronic cirrhosis of the liver due to obstruction
or infection of the small and intermediate-sized intrahepatic bile
 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
 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
 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
 Complications more frequent than in well-nourished (44% vs
 Usually more of a clinical problem than hepatic encephalopathy
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 &
 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
What is Hepatic Encephalopathy?
 Broadly defined
 All neurological and psychological symptoms in patients with liver
disease that cannot be explained by presence of other pathologies
 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
 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
 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
 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
 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
Portosystemic Shunting
•Radiographic or surgically placed shunts
•Spontaneous shunts
•Vascular Occlusion
•Portal or Hepatic Vein Thrombosis
Dehydration Increased Ammonia Production,
Absorption or Entry Into the Brain
•Excess Dietary Intake of Protein
•GI Bleeding
•Large volume paracentesis
•Electrolyte Disturbances (ie., hypokalemia)
Primary Hepatocellular
•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”
 Most frequent neurological disturbance
 Not associated with overt neuropsychiatric symptoms
 Subtle changes detected by special psychomotor tests
Stages of Hepatic
Stage Symptoms
I Mild Confusion, agitation, irritability, sleep disturbance,
decreased attention
II Lethargy, disorientation, inappropriate behavior,
III Somnolent but arousable, slurred speech, confused,
IV Coma
Pathogenesis Theories
 Endogenous Neurotoxins
 Ammonia
 Mercaptans
 Phenols
 Short-medium fatty acids
 Increased Permeability of Blood-Brain Barrier
 Change in Neurotransmitters and Receptors
 Altered BCAA/AAA ratio
 Other
 Zinc
 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
350 Phe Asp
300 Meth
% of Normal

250 Tyr
100 Thr Ser
Lys Tau His
50 Va Leu Arg
Pro Ala
Essential Non-Essential
Cerra, et al; JPEN, 1985 J. Y. Pang
Pathogenesis Theories:
False Neurotransmitter Hypothesis
 AAA are precursors to neurotransmitters and
elevated levels result in shunting to secondary
Pathogenesis Theories:
Change In Neurotransmitters and Receptors
 Gamma-Aminobutyric  BCAA-Ammonia
Acid (GABA) Connection
Increase Permeability of Blood-
Brain Barrier
 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  Course muscle
state, consciousness tremors
 Confusion,  Muscle stiffness or
disorientation rigidity
 Delirium
 Loss of small hand
 Dementia (loss of
memory, intellect)
 Mood swings
 Decreased altertness,
 Seizures (rare)
responsiveness  Decreased self-care
 Coma 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
 Alcoholic liver disease (Wernicke’s)
Diagnostic Criteria
 Asterixis (“flapping tremor”)
 Hx liver disease
 Impaired performance on neuropsychological tests
 Visual, sensory, brainstem auditory evoked potentials
 Sleep disturbances
 Fetor Hepaticus
 Slowing of brain waves on EEG
 PET scan
 Changes of neurotransmission, astrocyte function
 Elevated serum NH3
 Stored blood contains ~30ug/L ammonia
 Elevated levels seen in 90% pts with HE
 Not needed for diagnosis
Table 3. Differential diagnostic considerations
Differential Diagnosis
in hepatic encephalopathy

Metabolic Intracranial
encephalopathies events
Diabetes Intracerebral
(hypoglycemia, bleeding or
Carbon dioxide narcosis Tumor
Toxic Infections
encephalopathies (abscess,
Alcohol (acute alcohol meningitis)
intoxication, delirium Encephalitis
tremens, Wernicke-
Treatment of Hepatic
 Various measures in current treatment of HE
 Strategies to lower ammonia production/absorption
 Nutritional management
 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
In Treatment
Nutritional Management of HE
 Historical treatment theories
 Protein
 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
 Lack of Valid Evidence
 Efficacy of restriction never proven within controlled
Dispelling the Myth
Normal Protein Diet for Episodic Hepatic
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
 No protein first 3 days, increasing q3days until 1.2g/kg daily
for last 2 days
 10 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
 Greater protein breakdown in protein-
restricted 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
 Beneficial effect d/t high fiber content
 Also elevated calorie-to-nitrogen ratio
 BCAA Supplementation
 Effective or Not?
Branched Chain
Amino Acids (BCAA)
•Important fuel sources for skeletal
muscle during periods of metabolic
•Metabolized in muscle & brain, not
-promote protein synthesis
-suppress protein catabolism
-substrates for gluconeogenesis

Catabolized to L-alanine and L-

glutamine in skeletal muscle
Nutritional Supplementation with Branched-
Chain 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 (Child-
Pugh scores)
 Anorexia and health-related quality of life
 Therapy needs
Study Profile of BCAA Trial BCAA umin Maltodextrin

Total number 59 56 59
Lost to follow-up 1 — —
Intention-to-treat analysis 58 56 59
Events (death, any cause, or 9 (15.5%)* 18 (32.1%) 16 (27.1%)
progression of liver failure to
exclusion criteria)
Removed from systematic follow-up1 7 4 4
    Development of HCC2 1 1 2
    Noncompliance to treatment3 5 (1) 2 (1) 0
    Side effects3 44 (1) 2 (1) 2
    Treatment-unrelated diseases — 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)
    Admission rate (patients/y) 0.6 ± 0.2* 2.1 ± 0.5 1.9 ± 0.4
    Total no. d in hospital 195* 327 520
Significantly different from both lactoalbumin and maltodextrin.
Some individuals were removed based on more than 1 criterion.
Cases with HCC were censored at the time of HCC diagnosis.
The number of withdrawn patients who died or progressed to exclusion criteria within 12 mo
from entry into the study is reported in parentheses.
Including the patient lost to follow-up.
Primary Outcome Results
 Based on ITT, time course of events
was not different between groups
 A benefit of BCAA only found when non-
liver 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);
M-DXT-OR, 0.51; 95% CI (0.23-1.17);
Less frequent hospital
admissions with BCAA vs two
control arms (p = 0.021)
Secondary Outcomes
Nutritional Parameters
Albumin Concentration
•No change in serum albumin among
ANOVA, P=0.670

Serum Albumin (g/dL)

•Significant interaction between BCAA and 4
•Significant reduction in prevalence and 2.8
severity of ascites in BCAA vs controls 2.4 M-DXT
•No significant improvement in HE based 2

on Reitan Test)





•Trend for superiority of BCAA over M-DXT

Child-Pugh Score Total Bilirubin (g/dL)
ANOVA, P=0.025 Repeated Measures ANOVA
time x treatment; P=0.0012
Child-Pugh Score


Total Bilirubin
9 BCAA 3.5
8 3

L-ALB 2.5
7 2
1.5 BCAA
6 M-DXT 1




l in









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)
 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
 Ascertainment bias for event rates
 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
 Mortality was lower, but BCAA group had similar number of
deaths compared to the other groups
 Mean admission rate lower in BCAA compared to
 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
Als-Nielsen B, Koretz RI, Kjaergard LL, Gluud C. The
Cochrane Database of Systematic Reviews, 2003, 1-55
Branched-Chain Amino Acids For Hepatic
 Meta-Analysis of randomized-controlled trials on the treatment of HE
with IV or oral BCAA
 Objective
 To evaluate the beneficial and harmful effects of BCAA or BCAA-
enriched interventions for patients with hepatic encepalopathy
 Review Criteria
 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
 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
 Types of Interventions
 Experimental Group
 BCAA or BCAA-enriched solutions given in any mode, dose, or duration with
or without other nutritive sources
 Control Group
 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
 Data Collection and Analysis
 Trial inclusion and data extraction made independently by two
 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
 Median 17 days (range 6 to 30 days)
 Compared to control regimens, BCAA significantly increased the
number of patients improving from HE at end of treatment
 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)
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
 Higher quality vs lower quality
 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
 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
 No convincing evidence that BCAA had a significant
beneficial effect on improvement of HE or survival in
patients with HE
 Small trials with short f/u and most of poor quality
 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
 Effect size and “small study bias”
 No significant association between dose or duration and
the effect of BCAA
 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
 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
 Scales and items used for defining and
assessing HE are arbitrary and not tested for
reliability or validity
Implications For Future
 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
 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  Hepatic-Aid II
Nutrition (Nestle) (Hormel Health Labs)
 1.5 kcal/mL  1.2 kcal/mL
 Fat (12%) MCT  Fat (28%) No MCT
(66%)  Protein: 46% BCAA,
 Protein: 50% low AAA
BCAA, low MET  CHO: 58%
 CHO: 77%  Vitamin and
 RDI: 100% Electrolyte-free
 Gluten-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 (65-
90% with PCM)
 Severity of pcm positively correlated with mortality
Nutritional Implications:
PCM associated Liver Dz
 Malnutrition reported in  Nutrient malabsorption/
65%-90% cirrhotic pts maldigestion
 Cholestatic & non-cholestatic
 Poor Dietary Intake
liver disease
 Anorexia  Excessive protein losses
 Dietary Restrictions  Pancreatic insufficiency
 Ascites
 Gastroparesis
 Abnormal Metabolism
 Hypermetabolism
 Zinc Deficiency
 Hyperglucogonemia
 Increased proinflammatory
cytokines  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
 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
 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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