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

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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 (

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BCAA

L-ALB

M-DXT

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

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11.5

22.5

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iliru

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(g

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L-ALB

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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?

ReferencesMüller, M. J., Selberg, O. & Böker, K. (1994) Are patients with liver cirrhosis hypermetabolic?. Clin. Nutr. 13:131-144. The ESPEN Consensus GroupPlauth, M., Merli, M., Kondrup, J., Weimann, A., Ferenci, P. & Muller, M. J. (1997) ESPEN guidelines for

nutrition in liver disease and transplantation. Clin. Nutr. 16:43-55. Falck-Ytter, Y., Younossi, Z. M., Marchesini, G. & McCullough, A. J. (2001) Clinical features and natural history of nonalcoholic

steatosis syndromes. Semin. Liver Dis. 21:17-26. Italian Multicentre Cooperative Project on nutrition in liver cirrhosis (1994) Nutritional status in cirrhosis. J. Hepatol. 21:317-325. Marchesini, G., Bianchi, G., Amodio, P., Salerno, F., Merli, M., Panella, C., Loguercio, C., Apolone, G., Niero, M. & Abbiati, R. (2001)

Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 120:170-178. Selberg, O., Bottcher, J., Tusch, G., Pichlmayr, R., Henkel, E. & Muller, M. J. (1997) Identification of high- and low-risk patients before

liver transplantation: a prospective cohort study of nutritional and metabolic parameters in 150 patients. Hepatology 25:652-657.

James, J. H., Ziparo, V., Jeppsson, B. & Fischer, J. E. (1979) Hyperammonaemia, plasma amino acid imbalance, and blood-brain amino acid transport: a unified theory of portal-systemic encephalopathy. Lancet 2:772-775.

Naylor, C. D., O’Rourke, K., Detsky, A. S. & Baker, J. P. (1989) Parenteral nutrition with branched-chain amino acids in hepatic encephalopathy. A meta-analysis. Gastroenterology 97:1033-1042.

Fabbri, A., Magrini, N., Bianchi, G., Zoli, M. & Marchesini, G. (1996) Overview of randomized clinical trials of oral branched-chain amino acid treatment in chronic hepatic encephalopathy. J. Parenter. Enteral Nutr. 20:159-164.

Als-Nielsen, B., Koretz, R. L., Kjaergard, L. L. & Gluud, C. (2004) Branched-chain amino acids for hepatic encephalopathy (Cochrane review). The Cochrane Library, Issue 2 2004 John Wiley and Sons Chichester, UK .

Ishiki, Y., Ohnishi, H., Muto, Y., Matsumoto, K. & Nakamura, T. (1992) Direct evidence that hepatocyte growth factor is a hepatotrophic factor for liver regeneration and has a potent antihepatitis effect in vivo. Hepatology 16:1227-1235.

Tomiya, T., Inoue, Y., Yanase, M., Arai, M., Ikeda, H., Tejima, K., Nagashima, K., Nishikawa, T. & Fujiwara, K. (2002) Leucine stimulates the secretion of hepatocyte growth factor by hepatic stellate cells. Biochem. Biophys. Res. Commun. 297:1108-1111.

Fenton, J. C., Knight, E. J. & Humpherson, P. L. (1966) Milk-and-cheese diet in portal-systemic encephalopathy. Lancet 1:164-166. Bianchi, G. P., Marchesini, G., Fabbri, A., Rondelli, A., Bugianesi, E., Zoli, M. & Pisi, E. (1993) Vegetable versus animal protein diet in

cirrhotic patients with chronic encephalopathy. A randomized cross-over comparison. J. Intern. Med. 233:385-392. Rossi-Fanelli, F., Riggio, O., Cangiano, C., Cascino, A., De Conciliis, D., Merli, M., Stortoni, M., Giunchi, G. & Capocaccia, L. (1982)

Branched-chain amino acids vs. lactulose in the treatment of hepatic coma. A controlled study. Dig. Dis. Sci. 27:929-935.

ReferencesWahren, J., Denis, J., Desurmont, P., Eriksson, L. S., Escoffier, J. M., Gauthier, A. P., Hagenfeldt, L., Michel, H. & Opolon, P., et al (1983) Is intravenous

administration of branched chain amino acids effective in the treatment of hepatic encephalopathy?. A multicenter study. Hepatology 3:475-480. Michel, H., Bories, P., Aubin, J. P., Pomier-Layrargues, G., Bauret, P. & Bellet-Herman, H. (1985) Treatment of acute hepatic encephalopathy in cirrhotics with a

branched-chain amino acids enriched versus a conventional amino acids mixture. A controlled study of 70 patients. Liver 5:282-289. Cerra, F. B., Chung, N. K., Fischer, J. E., Kaplowitz, N., Schiff, E. R., Dienstag, J. L., Bower, R. H., Mabry, C. D., Leevy, C. M. & Kiernan, T. (1985) Disease-

specific amino acid infusion (F080) in hepatic encephalopathy: a prospective, randomized, double-blind controlled trial. J. Parenter. Enteral Nutr. 9:288-295.

Fiaccadori, F., Ghinelli, F., Pedretti, G., Pelosi, G., Sacchini, D., Zeneroli, M. L., Rocchi, E., Gibertini, P. & Ventura, E. (1985) Branched-chain enriched amino acid solutions in the treatment of hepatic encephalopathy: a controlled trial. Ital. J. Gastroenterol. 17:5-10.

Strauss, E., dos Santos, W. R., da Silva, E. C., Lacet, C. M., Capacci, M.L.L. & Bernardini, A. P. (1986) Treatment of hepatic encephalopathy: a randomized clinical trial comparing branched chain enriched amino acid solution to oral neomycin. Nutr. Supp. Services 6:18-21.

Vilstrup, H., Gluud, C., Hardt, F., Kristensen, M., Køler, O., Melgaard, B., Dejgaard, A., Hansen, B. E. & Krintel, J. J., et al (1990) Branched chain enriched amino acids versus glucose treatment of hepatic encephalopathy. A double-blind study of 65 patients with cirrhosis. J. Hepatol. 10:291-296.

Eriksson, L. S., Persson, A. & Wahren, J. (1982) Branched-chain amino acids in the treatment of chronic hepatic encephalopathy. Gut 23:801-806. Sieg, A., Walker, S., Czygan, P., Gärtner, U., Lanzinger-Rossnagel, G., A., S. & Kommerell, B. (1983) Branched-chain amino acid-enriched elemental diet in

patients with cirrhosis of the liver. Z. Gastroenterol. 21:644-650. Simko, V. (1983) Long-term tolerance of a special amino acid oral formula in patients with advanced liver disease. Nutr. Rep. Int. 27:765-773. Horst, D., Grace, N. D., Conn, H. O., Schiff, E., Schencker, S., Viteri, A., Law, D. & Atterbury, C. E. (1984) Comparison of dietary protein with an oral, branched

chain-enriched amino acid supplement in chronic portal-systemic encephalopathy. Hepatology 4:279-287. Christie, M. L., Sack, D. M., Pomposelli, J. & Horst, H. (1985) Enriched branched-chain amino acid formula vs. a casein-based supplement in the treatment of

cirrhosis. J. Parenter. Enteral Nutr. 9:671-678. Egberts, E. H., Schomerus, H., Hamster, W. & Jürgens, P. (1985) Branched chain amino acids in the treatment of latent portosystemic encephalopathy. A

double-blind placebo-controlled cross-over study. Gastroenterology 88:887-895. Fiaccadori, F., Elia, G. F., Lehndorff, H., Merli, M., Pedretti, G., Riggio, O. & Capocaccia, L. (1988) The effect of dietary supplementation with branched-chain

amino acids vs. casein in patients with chronic recurrent portal systemic encephalopathy: a controlled trial. Soeters, P. B. Wilson, J.H.P. Meijer, A. J. Holm, E. eds. Advances in Ammonia Metabolism and Hepatic Encephalopathy 1988:489-497 Excerpta Medica Amsterdam, The Netherlands. .

Swart, G. R., van den Berg, W. O., van Vuure, J. K., Rietveld, D., Wattimena, D. L. & Frenkel, M. (1989) Minimum protein requirements in liver cirrhosis determined by nitrogen balance measurements at three levels of protein intake. Clin. Nutr. 8:329-336.

 

References

Marchesini, G., Dioguardi, F. S., Bianchi, G. P., Zoli, M., Bellati, G., Roffi, L., Martines, D. & Abbiati, R. & the Italian Multicenter Study Group (1990) Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized double-blind casein-controlled trial. J. Hepatol. 11:92-101.

Marchesini, G., Bianchi, G., Merli, M., Amodio, P., Panella, C., Loguercio, C., Rossi Fanelli, F. & Abbiati, R. (2003) Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial. Gastroenterology 124:1792-1801.

Lieber, C. S. (2000) Alcoholic liver disease: new insights in pathogenesis lead to new treatments. J. Hepatol. 32:113-128.

Marsano, L. & McClain, C. J. (1991) Nutrition and alcoholic liver disease. J. Parenter. Enteral Nutr. 15:337-344.

Merli, M., Nicolini, G., Angeloni, S. & Riggio, O. (2002) Malnutrition is a risk factor in cirrhotic patients undergoing surgery. Nutrition 18:978-986.

Fan, S. T., Lo, C. M., Lai, E. C., Chu, K. M., Liu, C. L. & Wong, J. (1994) Perioperative nutritional support in patients undergoing hepatectomy for hepatocellular carcinoma. N. Engl. J. Med. 331:1547-1552.

The San-in Group of Liver Surgery (1997) Long-term oral administration of branched chain amino acids after curative resection of hepatocellular carcinoma: a prospective randomized trial. Br. J. Surg. 84:1525-1531.

Poon, R. T., Yu, W. C., Fan, S. T. & Wong, J. (2004) Long-term oral branched chain amino acids in patients undergoing chemoembolization for hepatocellular carcinoma: a randomized trial. Aliment. Pharmacol. Ther. 19:779-788.

Reilly, J., Mehta, R., Teperman, L., Cemaj, S., Tzakis, A., Yanaga, K., Ritter, P., Rezak, A. & Makowka, L. (1990) Nutritional support after liver transplantation: a randomized prospective study. J. Parenter. Enter Nutr. 14:386-391.

Bilbao, I., Armadans, L., Lazaro, J. L., Hidalgo, E., Castells, L. & Margarit, C. (2003) Predictive factors for early mortality following liver transplantation. Clin. Transplant. 17:401-411.

Tietge, U. J., Bahr, M. J., Manns, M. P. & Boker, K. H. (2003) Hepatic amino-acid metabolism in liver cirrhosis and in the long-term course after liver transplantation. Transpl. Int. 16:1-8.

Charlton, M. (2003) Branched-chain amino acid-enriched supplements as therapy for liver disease: Rasputin lives. Gastroenterology 124:1980-1982.