Nutritional Management of Hepatic Encephalopathy

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Nutritional Management of Hepatic Encephalopathy

• Presented by
• Chris Theberge Sara Murkowski

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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

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Lets Take It From The Top

• A Physiology Review

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Functions of the LiverA 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

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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

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Aspartate Transaminase(AST)
The Urea Cycle
Alanine Transaminase (ALT)
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Liver Diseases
Classifications

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

• Viral hepatitis A, B, C, D, E (and G)
• Fulminant hepatitis
• Alcoholic liver disease
• Non-alcoholic liver disease
• Cholestatic liver disease
• Hepatocellular carcinoma
• Inherited disorders

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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

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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)

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Inherited Liver Disorders

• Hemochromatosis
• Inherited disease of iron overload
• Wilsons disease
• Autosomal recessive disorder associated with
  impaired biliary copper excretion
• a1-antitrypsin deficiency
• Causes cholestasis or cirrhosis and can cause
  liver and lung cancer

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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

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Progression of Liver Diseases
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Normal Liver
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Alcoholic Fatty Liver
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Cirrhotic Liver
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Prognosis of Cirrhosis
Child-Pugh and MELD Score Both used to determine
prognosis of Cirrhosis (mortality and
survival) Determine Need For Transplantation Use
d in studies to determine effect of treatment on
liver function
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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

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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

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And Now Our Featured Presentation
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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

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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

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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

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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

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Precipitants of Hepatic Encephalopathy

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

• Drugs
• Benzodiazepines
• Narcotics
• Alcohol

• Dehydration
• 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
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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

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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
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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

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Neurotoxic Action of Ammonia

• Readily crosses blood-brain barrier
• Increased NH3 increased glutamate
• a-ketoglutarateNH3NADH?glutamateNAD
• glutamateNH3ATP?glutamineADPPi
• 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

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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

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Abnormal plasma amino acidschronic liver disease
400
Glu
350
Phe
Asp
300
Meth
250
Tyr
of Normal
200
Try
150
Gly
100
Orn
Thr
Ser
Lys
Tau
His
Val
50
Leu
Arg
Pro
Ala
Ileu
Essential
Non-Essential
Cerra, et al JPEN, 1985
J. Y. Pang
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Pathogenesis Theories False Neurotransmitter
Hypothesis

• AAA are precursors to neurotransmitters and
  elevated levels result in shunting to secondary
  pathways

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Pathogenesis TheoriesChange In
Neurotransmitters and Receptors

• Gamma-Aminobutyric Acid (GABA)

• BCAA-Ammonia Connection

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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
• NNormal Astrocytes
• AAlzheimer type II astrocytes
• Pale, enlarged nuclei
• characterisic of HE

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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

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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 (Wernickes)

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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

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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

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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 ammonias effect on
  brain cell function
• Lactulose
• Antibiotics
• Devices to compensate for liver dysfunction
• Liver transplantation

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• Proposed
• Complex
• Feedback
• Mechanisms
• In Treatment
• Of HE

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Nutritional Management of HE

• Historical treatment theories
• Protein Restriction
• BCAA supplementation
• Goals of MNT
• Treatment of PCM associated with ESLD

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Historical Treatment TheoriesProtein Restriction

• Studies in early 1950s 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

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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

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Dispelling the Myth

• Results
• On days 2 and 14
• Similar protein synthesis among both groups
• Protein breakdown higher in low-protein group
• Conclusion
• No significant differences in course of hepatic
  encephalopathy
• Greater protein breakdown in protein-restricted
  subjects

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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 lt 40g/day contributes to
  malnutrition and worsening HE
• Increased endogenous protein breakdown NH3
• Susceptibiliy to infection increases under such
  catabolic conditions

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Other Considerations

• Vegetable Protein
• Beneficial in patients with protein intolerance
  lt1g/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?

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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 L-glutamine in
  skeletal muscle

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• Nutritional Supplementation with Branched-Chain
  Amino Acids in Advanced Cirrhosis A
  Double-Blind, Randomized Trial
• Marchesini et al.,(2004). Gastroenterology, 124,
  1792-1801

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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

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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

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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
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.
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Primary Outcome Results

• Based on ITT, time course of events was not
  different between groups (p0.101)
• 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) p0.039
• M-DXT-OR, 0.51 95 CI (0.23-1.17) p0.108
• Less frequent hospital admissions with BCAA vs
  two control arms (p 0.021)

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• 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
  (p0.108)

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Anorexia and Health-Related Quality of Life

• Increased hunger/satiety in BCAA (p0.019), while
  no change in L-ALB and M-DXT (p0.026)
• Prevalence of anorexia significantly (p0.0014)
  decreased in BCAA, while unchanged in controls
• Significant improvement in physical functioning
  in BCAA, while no change in controls
• Trend (p0.069) 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)
  (p0.001)

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Conclusions

• Long-term BCAA supplementation showed an
  advantage compared to equicaloric,
  equinitrogenous supplemenation
• Prevention of combined death
• Progressive liver failure
• Hospital rates
• Secondary Outcomes

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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?

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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

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• 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

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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

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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)

60
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

61
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)

62
Significant
63
Not significant
Combining survival data regardless of window of
f/u showed no significant Difference in survival
between BCAA and controls
64
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 p0.03
  vs p0.13 with random
• No significant effect of BCAA with worst-case
  analysis

65
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

66
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

67
TABLE 1 Randomized controlled trials of BCAA
treatment in cirrhosis1
1 bw, body weight co, crossover study pg,
parallel group design. 2 Dietary BCAA not
included. Data are in g/d except as noted. 3
Positive, BCAA significantly different negative,
BCAA not significantly different.
68
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

69
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

70
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 BCAAs
  need to be supplied
• Effects of leucine on protein turnover and HGF
  secretion
• Leucine alone might achieve similar beneficial
  results at lower total doses

71
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

72
The Child-Turcotte-Pugh Classification
73
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

74
Nutritional ImplicationsPCM associated Liver
Dz

• Nutrient malabsorption/ maldigestion
• Cholestatic non-cholestatic liver disease
• Excessive protein losses
• Pancreatic insufficiency
• Abnormal Metabolism
• Hypermetabolism
• Hyperglucogonemia
• Increased protein metabolism
• Increased lipid oxidation
• Osteopenia

• Malnutrition reported in 65-90 cirrhotic pts
• Poor Dietary Intake
• Anorexia
• Dietary Restrictions
• Ascites
• Gastroparesis
• Zinc Deficiency
• Increased proinflammatory cytokines

75
MNT in Advanced Liver Disease

• Poor Dietary Intake
• Due to poor appetite, early satiety with ascites
• Small frequent meals
• Aggressive oral supplementation
• Zinc supplementation
• Nutrient Malabsorption
• Due to bile, failure to convert to active
  forms
• ADEK supplementation
• Calcium D supplementation
• Folic Acid Supplementation

76
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

77
MNT in Advanced Liver Disease

• Standard Guidelines
• MVI with minerals
• 2gm Na restriction in presence of ascites
• Do not restrict fluid unless serum Na lt120mmol
• Low threshold for NGT in pts awaiting transplant
• TPN should be considered only if contraindication
  for enteral feeding

78
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

79
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
• BCAAs do not exacerbate encephalopathy

80
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 (lt1g/kg)

81
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

82
Thank You!

• Special Thanks to Nicole Varady
• Comments?
• Questions?

83
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