Nutritional Management of Hepatic Encephalopathy Presented by Chris Theberge & Sara Murkowski.
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Transcript of Nutritional Management of Hepatic Encephalopathy Presented by Chris Theberge & Sara Murkowski.
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
Alanine Transaminase (ALT)
Aspartate Transaminase(AST) The Urea Cycle
Liver Diseases 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
Classifications
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)
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)
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
Inherited Liver Disorders
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
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 decerebration
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 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
Drugs•Benzodiazepines•Narcotics•Alcohol
Increased Ammonia Production,
Absorption or Entry Into the Brain•Excess Dietary Intake of Protein•GI Bleeding•Infection•Electrolyte Disturbances (ie., hypokalemia)•Constipation•Metabolic alkalosis
Dehydration•Vomiting•Diarrhea•Hemorrhage•Diuretics•Large volume paracentesis
Portosystemic Shunting•Radiographic or surgically placed shunts•Spontaneous shunts•Vascular Occlusion•Portal or Hepatic Vein Thrombosis
Primary Hepatocellular Carcinoma
Precipitants of Hepatic Encephalopathy
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 Encephalophay
Stage Symptoms
I Mild Confusion, agitation, irritability, sleep disturbance, decreased attention
II Lethargy, disorientation, inappropriate behavior, drowsiness
III Somnolent but arousable, slurred speech, confused, aggressive
IV Coma
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
Val
Abnormal plasma amino acids:chronic liver disease
400
350
300
250
150
200
100
50Thr
Leu
Ileu
Lys
Try
Meth
Phe
Tau
Asp
Glu
Ser
Pro
Gly
Ala
Tyr
OrnHis
Arg
Essential Non-Essential
% o
f N
orm
al
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 pathways
Pathogenesis Theories:Change In Neurotransmitters and Receptors
Gamma-Aminobutyric Acid (GABA)
BCAA-Ammonia 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 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 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 in hepatic encephalopathy Differential Diagnosis
Metabolic encephalopathiesDiabetes (hypoglycemia, ketoacidosis)HypoxiaCarbon dioxide narcosis
Toxic encephalopathiesAlcohol (acute alcohol intoxication, delirium tremens, Wernicke-Korsakoff syndrome)Drugs
Intracranial eventsIntracerebral bleeding or infarctionTumorInfections (abscess, meningitis)Encephalitis
Treatment of Hepatic Encephalopathy 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
Proposed
Complex
Feedback
Mechanisms
In Treatment
Of HE
Nutritional Management of HE
Historical treatment theoriesProtein RestrictionBCAA supplementation
Goals of MNTTreatment 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 of restriction never proven within controlled trial
Dispelling the MythNormal 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 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
ConclusionNo significant differences in course of hepatic
encephalopathy 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 HE
Beneficial effect d/t high fiber content Also elevated calorie-to-nitrogen ratio
BCAA Supplementation Effective or Not?
Branched Chain Amino Acids (BCAA)
ValineLeucineIsoleucine
•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 L-glutamine in skeletal muscle
Nutritional Supplementation with Branched-Chain Amino Acids in Advanced Cirrhosis:
A Double-Blind, Randomized TrialMarchesini 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
* Significantly different from both lactoalbumin and maltodextrin. 1 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.
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
Events (death, any cause, or progression of liver failure to exclusion criteria)
9 (15.5%)* 18 (32.1%) 16 (27.1%)
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
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 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); p=0.039M-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 ConcentrationANOVA, P=0.670
22.42.83.23.6
4
Se
rum
Alb
um
in (
g/d
L)
BCAA
L-ALB
M-DXT
Total Bilirubin (g/dL)Repeated Measures ANOVAtime x treatment; P=0.0012
00.5
11.5
22.5
33.5
To
tal B
iliru
bin
(g
/dL
)BCAA
L-ALB
M-DXT
Child-Pugh ScoreANOVA, P=0.025
56789
10
Baseli
ne3-
Mo
6-M
o9-
Mo
End
Ch
ild-P
ug
h S
co
re
BCAA
L-ALB
M-DXT
Secondary OutcomesNutritional Parameters•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)
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 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
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 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 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
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 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
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)
Significant
Not significant
Combining survival data regardless of window of f/u showed no significantDifference 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
Conclusions
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
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 (65-
90% 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 MalabsorptionDue 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 GuidelinesMVI with minerals2gm Na restriction in presence of ascitesDo not restrict fluid unless serum Na <120mmolLow threshold for NGT in pts awaiting transplantTPN 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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