Nutritional Management of Hepatic Encephalopathy

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 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
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

Duration  Acute vs Chronic Pathophysiology  Hepatocellular vs Cholestasic Etiology  Viral  Alcohol  Toxin  Autoimmune Stage/Severity  ESLD  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 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)

Inherited Liver Disorders
 

 Inherited

disease of iron overload

Wilson’s disease
 Autosomal

recessive disorder associated with impaired biliary copper excretion cholestasis or cirrhosis and can cause liver and lung cancer

α1-antitrypsin deficiency
 Causes

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

bypasses the liver via shunt, thus bypassing detoxification

remain in circulating blood


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

 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

 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

Precipitants of Hepatic Encephalopathy
•Benzodiazepines •Narcotics •Alcohol

Portosystemic Shunting
•Radiographic or surgically placed shunts •Spontaneous shunts •Vascular Occlusion •Portal or Hepatic Vein Thrombosis

•Vomiting •Diarrhea •Hemorrhage •Diuretics •Large volume paracentesis

Increased Ammonia Production, Absorption or Entry Into the Brain
•Excess Dietary Intake of Protein •GI Bleeding •Infection •Electrolyte Disturbances (ie., hypokalemia) •Constipation •Metabolic alkalosis

Primary Hepatocellular Carcinoma

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 I II III IV Symptoms
Mild Confusion, agitation, irritability, sleep disturbance, decreased attention Lethargy, disorientation, inappropriate behavior, drowsiness Somnolent but arousable, slurred speech, confused, aggressive 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

 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
400 350
Phe Meth Tyr Try Gly Lys Tau Ser Pro Ala Orn His Arg Asp Glu

% of Normal

300 250 200 150 100 Thr Va Leu 50
l Ileu

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 BloodBrain 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 Stored blood contains ~30ug/L ammonia Elevated levels seen in 90% pts with HE Not needed for diagnosis

Elevated serum NH3
  

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-

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 production/absorption

Nutritional management
Protein restriction BCAA supplementation

Medical management

 Medications

cell function
 

to counteract ammonia’s effect on brain

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


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
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

 On

days 2 and 14:

Similar protein synthesis among both groups  Protein breakdown higher in low-protein group 

 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


Susceptibiliy to infection increases under such catabolic conditions

Other Considerations

Vegetable Protein
 Beneficial

in patients with protein intolerance <1g/kg effect d/t high fiber content

Considered to improve nitrogen balance without worsening HE Also elevated calorie-to-nitrogen ratio

 Beneficial

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 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

Exclusion Criteria

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
Total number Lost to follow-up Intention-to-treat analysis Events (death, any cause, or progression of liver failure to exclusion criteria) Removed from systematic follow-up1     Development of HCC2     Noncompliance to treatment3     Side effects3     Treatment-unrelated diseases Regular 3-mo follow-up     Admission to hospital     Admission rate (patients/y)     Total no. d in hospital
* 1

59 1 58 9 (15.5%)* 7 1 5 (1) 44 (1) — 42 (71.2%)* 15 (35.7%)* 0.6 ± 0.2* 195*

Lactoalb umin
56 — 56 18 (32.1%) 4 1 2 (1) 2 (1) 1 34 (60.7%) 27 (79.4%) 2.1 ± 0.5 327

59 — 59 16 (27.1%) 4 2 0 2 — 39 (66.1%) 28 (71.8) 1.9 ± 0.4 520

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.

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


p=0.039 p=0.108

0.43; 95% CI (0.19-0.96); 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
•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)
Child-Pugh Score ANOVA, P=0.025 Child-Pugh Score
Serum Albumin (g/dL) 4 3.6 3.2 2.8 2.4 2
el in e

Albumin Concentration ANOVA, P=0.670

o o o 9M nd E




Total Bilirubin (g/dL) Repeated Measures ANOVA time x treatment; P=0.0012

Total Bilirubin (g/dL)

10 9 8 7 6 5
se l in e o o o En 3M 6M 9M

3.5 3 2.5 2 1.5 1 0.5 0


o o o 9M d En

se lin e





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 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


To evaluate the beneficial and harmful effects of BCAA or BCAAenriched 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

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 No nutritional support, placebo support, isocaloric support, isonitrogenous support, or other interventions with a potential effect on HE (ie., lactulose)

Control Group

Outcome Measures


Improvement of HE (number of patients improving from HE using definitions of individual trials) 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 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)

No evidence of an effect of BCAA on survival
 


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 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

Hepatic-Aid II (Hormel Health Labs)
 1.2

kcal/mL  Fat (12%) MCT (66%)  Protein: 50% BCAA, low MET  CHO: 77%  RDI: 100%  Gluten-free, lactose-free

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
     

Nutrient malabsorption/ maldigestion
  

Anorexia Dietary Restrictions Ascites Gastroparesis Zinc Deficiency Increased proinflammatory cytokines

Cholestatic & non-cholestatic liver disease Excessive protein losses Pancreatic insufficiency Hypermetabolism Hyperglucogonemia Increased protein metabolism Increased lipid oxidation Osteopenia

Abnormal Metabolism
    

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


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

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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