Documents
Resources
Learning Center
Upload
Plans & pricing Sign in
Sign Out

Nutritional Management of Hepati

VIEWS: 14 PAGES: 85

									         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
The Urea Cycle    Aspartate Transaminase(AST)




                 Alanine Transaminase (ALT)
                    Liver Diseases
Classifications
   Duration               Viral hepatitis A, B, C, D, E (and G)
      Acute vs Chronic
                           Fulminant hepatitis
   Pathophysiology
      Hepatocellular vs   Alcoholic liver disease
       Cholestasic         Non-alcoholic liver disease
   Etiology
      Viral               Cholestatic liver disease
      Alcohol             Hepatocellular carcinoma
      Toxin
                           Inherited disorders
      Autoimmune
   Stage/Severity
      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
   Hemochromatosis
     Inherited   disease of iron overload
   Wilson’s disease
     Autosomal recessive   disorder associated with
      impaired biliary copper excretion
   α1-antitrypsin deficiency
     Causes   cholestasis or cirrhosis and can cause
      liver and lung cancer
Liver Diseases

   Alcoholic Liver Disease, Alcoholic hepatitis, and
    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
  Precipitants of Hepatic
  Encephalopathy
 Drugs                        Portosystemic Shunting
                              •Radiographic or surgically placed shunts
 •Benzodiazepines
                              •Spontaneous shunts
 •Narcotics
                              •Vascular Occlusion
 •Alcohol
                              •Portal or Hepatic Vein Thrombosis
 Dehydration                  Increased Ammonia Production,
 •Vomiting
                              Absorption or Entry Into the Brain
 •Diarrhea
                              •Excess Dietary Intake of Protein
 •Hemorrhage
                              •GI Bleeding
 •Diuretics
                              •Infection
 •Large volume paracentesis
                              •Electrolyte Disturbances (ie., hypokalemia)
Primary Hepatocellular
                              •Constipation
Carcinoma
                              •Metabolic alkalosis
Variants of Hepatic Encephalopathy
   Chronic HE
     Occurs in subjects with chronic liver disease such as cirrhosis and
      portosystemic shunting of blood (Portal Systemic Encepalopathy [PSA])
     Characterized by persistence of neuropsychiatric symptoms despite
      adequate medical therapy.
     Brain edema is rarely reported
   Refractory HE
      Recurrent episodes of an altered mental state in absence of
       precipitating factors
   Persistent HE
      Progressive, irreversible neurologic findings: dementia,
       extrapyramidal manifestations, cerebellar degeneration,
       transverse cordal myelopathy, and peripheral neuropathy
   Subclinical or “Minimal HE”
       Most frequent neurological disturbance
       Not associated with overt neuropsychiatric symptoms
       Subtle changes detected by special psychomotor tests
Stages of Hepatic
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
         defficiency
     Zinc
     Manganese deposits
Neurotoxic Action of Ammonia
   Readily crosses blood-brain barrier
   Increased NH3 = increased glutamate
       α-ketoglutarate+NH3+NADH→glutamate+NAD
       glutamate+NH3+ATP→glutamine+ADP+Pi
   As a-ketoglutarate is depleted TCA cycle activity halted
   Increased glutamine formation depletes glutamate stores
    which are needed by neural tissue
      Irrepairable cell damage and neural cell death ensue.
      In liver disease, conversion of ammonia to urea and
       glutamine can be reduced up to 80%
Pathogenesis Theories:
False Neurotransmitter Hypothesis
   Liver cirrhosis characterized by altered
    amino acid metabolism
        Increased Aromatic Amino Acids in plasma and
         influx in brain
        Decrease in plasma Branched Chain Amino Acids

        Share a common carrier at blood-brain barrier

            BCAAs in blood may result in  AAA transport
         to brain
                     Abnormal plasma amino acids:
                         chronic liver disease
               400                                     Glu
               350                Phe            Asp
               300                      Meth
 % of Normal




               250                                                           Tyr
               200
                                           Try
               150
                                                                 Gly
               100 Thr                                   Ser
                                                                             Orn
                                          Lys    Tau                            His
                50 Val Leu                                     Pro     Ala            Arg
                           Ileu
                       Essential                               Non-Essential
Cerra, et al; JPEN, 1985                                                              J. Y. Pang
Pathogenesis Theories:
False Neurotransmitter Hypothesis
 AAA are  precursors to neurotransmitters and
elevated levels result in shunting to secondary
pathways
Pathogenesis Theories:
Change In Neurotransmitters and Receptors

   Gamma-Aminobutyric      BCAA-Ammonia
    Acid (GABA)              Connection
Increase Permeability of Blood-
Brain Barrier
   Astrocyte (glial cell) volume is controlled by
    intracellular organic osmolyte
   Organic osmolyte is glutamine.
     glutamine levels in the brain result in volume
    of fluid within astrocytes resulting in cerebral
    edema (enlarged glial cells)
   Neurological impairment
     N=Normal   Astrocytes
     A=Alzheimer type II astrocytes
     Pale, enlarged nuclei
     characterisic of HE
Symptoms of HE
   Changes in mental            Course muscle
    state, consciousness          tremors
     Confusion,                 Muscle stiffness or
      disorientation              rigidity
     Delirium
                                 Loss of small hand
     Dementia (loss of
      memory, intellect)
                                  movements
                                  (handwriting)
     Mood swings
     Decreased altertness,
                                 Seizures (rare)
      responsiveness             Decreased self-care
     Coma                        ability
                                 Speech impairment
Diagnosing HE

   No single laboratory test is sufficient to
    establish the diagnosis
     No   Gold Standard
   Pt brains cannot be studied with
    neurochemical/neurophysiologic methods
     Data on cerebral function in HE usually derived
      from animal studies
   Underlying cause of liver disease itself
    may be associated with neurologic
    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
Differential Diagnosis
encephalopathy


Metabolic encephalopathies             Intracranial events
   Diabetes (hypoglycemia,                Intracerebral bleeding or
   ketoacidosis)                          infarction
   Hypoxia
                                          Tumor
   Carbon dioxide narcosis
                                          Infections (abscess,
Toxic encephalopathies
   Alcohol (acute alcohol                 meningitis)
   intoxication, delirium tremens,        Encephalitis
   Wernicke-Korsakoff syndrome)
   Drugs
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 theories
            Restriction
     Protein
     BCAA supplementation

   Goals of MNT
     Treatment   of PCM associated with ESLD
Historical Treatment Theories:
Protein Restriction
   Studies in early 1950’s showed cirrhotic pts
    given “nitrogenous substances” developed
    hepatic “precoma”
   Led to introduction of protein restriction
     Began   with 20-40g protein/day
     Increased by 10g increments q3-5 days as tolerated
      with clinical recovery
     Upper limit of 0.8-1.0 g/kg
     Was thought sufficient to achieve positive nitrogen
      balance
   Lack of Valid Evidence
     Efficacy of   restriction never proven within controlled
      trial
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
   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
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)
       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
Nutritional Supplementation with Branched-
 Chain Amino Acids in Advanced Cirrhosis:
      A Double-Blind, Randomized Trial
   Marchesini et al.,(2004). Gastroenterology, 124, 1792-1801
Nutritional Supplementation with Branched-Chain Amino Acids
  in Advanced Cirrhosis: A Double-Blind, Randomized Trial

    Multi-Center, randomized, controlled study involving 15
     centers with interest in patients with liver disease
    Inclusion Criteria
        A diagnosis of liver cirrhosis documented by histology and
         confirmed lab data
        Child-Pugh score ≥ 7 (Class B or C)
        Sonographic and endoscopic evidence of portal hypertension
    Exclusion Criteria
        Active alcohol consumption, overt HE, refractory ascites,
         reduced renal function (Cre ≥ 1.5 mg/dL), Child-Pugh score ≥ 12,
         suspected hepatocellular carcinoma, previous poor compliance
         to pharmacological treatment of nutrition counseling
Nutritional Supplementation with Branched-Chain Amino Acids
  in Advanced Cirrhosis: A Double-Blind, Randomized Trial

    Primary Outcomes
      Combined   survival and maintenance of liver function,
       as assessed by death (any reason), deterioration to
       exclusion criteria, or transplant
      Number of hospital admissions
      Duration of hospital stay
    Secondary Outcomes
                 parameters and liver function tests (Child-
      Nutritional
       Pugh scores)
      Anorexia and health-related quality of life
      Therapy needs
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          9 (15.5%)*            18 (32.1%)              16 (27.1%)
failure to exclusion criteria)
Removed from systematic follow-up1                              7                     4                       4
     Development of HCC2                                        1                     1                       2
     Noncompliance to treatment3                              5 (1)                 2 (1)                     0
     Side effects3                                           44 (1)                 2 (1)                     2
     Treatment-unrelated diseases                              —                      1                      —
Regular 3-mo follow-up                                    42 (71.2%)*            34 (60.7%)              39 (66.1%)
     Admission to hospital                                15 (35.7%)*            27 (79.4%)               28 (71.8)
     Admission rate (patients/y)                           0.6 ± 0.2*             2.1 ± 0.5               1.9 ± 0.4
     Total no. d in hospital                                  195*                  327                      520
 * Significantlydifferent 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.
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=0.039
    M-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)
                   Secondary Outcomes
                   Nutritional Parameters
                                                                                                          Albumin Concentration
                   •No change in serum albumin among
                                                                                                             ANOVA, P=0.670
                   groups




                                                                   Serum Albumin (g/dL)
                   •Significant interaction between BCAA and                                4
                   M-DXT                                                                  3.6                                          BCAA
                                                                                          3.2
                   •Significant reduction in prevalence and                               2.8
                                                                                                                                       L-ALB
                   severity of ascites in BCAA vs controls                                2.4                                          M-DXT
                   •No significant improvement in HE based                                  2




                                                                                                                                  nd
                   on Reitan Test)




                                                                                                          o


                                                                                                                    o


                                                                                                                              o
                                                                                                   e
                                                                                                 in


                                                                                                         M


                                                                                                                    M


                                                                                                                              M


                                                                                                                                  E
                                                                                              el


                                                                                                       3-


                                                                                                                  6-


                                                                                                                            9-
                   •Trend for superiority of BCAA over M-DXT




                                                                                           as
                                                                                          B
                   (p=0.108)
                                   Child-Pugh Score                                                        Total Bilirubin (g/dL)
                                   ANOVA, P=0.025                                                      Repeated Measures ANOVA
                                                                                                        time x treatment; P=0.0012
Child-Pugh Score




                   10

                                                                      Total Bilirubin
                    9                                      BCAA                                  3.5

                                                                          (g/dL)
                    8                                                                              3
                                                           L-ALB                                 2.5
                    7                                                                              2
                                                                                                 1.5                                   BCAA
                    6                                      M-DXT                                   1
                                                                                                 0.5
                                                                                                   0
                    5                                                                                                                  L-ALB




                                                                                                                                   d
                                                                                                              o

                                                                                                                        o

                                                                                                                              o
                                                                                                      e                                M-DXT
                                                       d
                               o


                                       o


                                              o
                         e




                                                                                                   lin




                                                                                                                                  En
                                                                                                            M

                                                                                                                     M

                                                                                                                              M
                      lin




                                                      En
                               M


                                      M


                                             M




                                                                                                          3-

                                                                                                                   6-

                                                                                                                            9-
                             3-


                                    6-


                                           9-




                                                                                                 se
                    se
                   Ba




                                                                                                Ba
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 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
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        Hepatic-Aid II
        Nutrition (Nestle)       (Hormel Health Labs)
         1.5 kcal/mL             1.2 kcal/mL
         Fat (12%) MCT           Fat (28%) No MCT
          (66%)                   Protein: 46% BCAA,
         Protein: 50%             low AAA
          BCAA, low MET           CHO: 58%
         CHO: 77%                Vitamin and
         RDI: 100%                Electrolyte-free
         Gluten-free,
          lactose-free
The Child-Turcotte-Pugh Classification
Goals of MNT for HE
   Treatment of PCM associated with Underlying
    Liver Disease
     Suppression  of endogenous protein breakdown to
      reduce stress placed on de-compensated liver
     Achieve positive nitrogen balance without
      exacerbating neurological symptoms
          PCM associated with morbidity and mortality in cirrhosis (65-
           90% with PCM)
          Severity of pcm positively correlated with mortality
Nutritional Implications:
PCM associated Liver Dz
   Malnutrition reported in           Nutrient malabsorption/
    65%-90% cirrhotic pts               maldigestion
                                           Cholestatic & non-cholestatic
   Poor Dietary Intake
                                            liver disease
       Anorexia
                                           Excessive protein losses
       Dietary Restrictions
                                           Pancreatic insufficiency
       Ascites
       Gastroparesis
                                       Abnormal Metabolism
                                           Hypermetabolism
       Zinc Deficiency
                                           Hyperglucogonemia
       Increased proinflammatory
        cytokines                          Increased protein metabolism
                                           Increased lipid oxidation
                                           Osteopenia
MNT in Advanced Liver Disease
   Poor Dietary Intake
     Due   to poor appetite, early satiety with ascites
        Small frequent meals
        Aggressive oral supplementation

        Zinc supplementation

   Nutrient Malabsorption
     Due   to   bile, failure to convert to active forms
        ADEK supplementation
        Calcium + D supplementation

        Folic Acid Supplementation
MNT in Advanced Liver Disease
   Abnormal Fuel Metabolism
     Increased     perioxidation, gluconeogenesis
           Bedtime meal to decrease
   Protein Deficiency
           protein catabolism, repeat paracentesis
         High protein snacks/supplements
         1.2-1.5 gms/day
MNT in Advanced Liver Disease
   Standard Guidelines
     MVI with minerals
     2gm Na restriction in presence of ascites
     Do not restrict fluid unless serum Na <120mmol
     Low threshold for NGT in pts awaiting transplant
     TPN should be considered only if
      contraindication for enteral feeding
How Much Protein:
That is the Question
   Grade III to IV hepatic encephalopathy
     Usually  no oral nutrition
     Upon improvement, individual protein tolerance can
      be titrated by gradually increasing oral protein intake
      every three to five days from a baseline of 40 g/day
     Oral protein not to exceed 70 g/day if pt has hx if
      hepatic encephalopathy
     Below 70 g/day rarely necessary, minimum intake
      should not be lower than 40 g/day to avoid negative
      nitrogen balance
MNT Specifically in HE
   Non-protein energy: 35-45 kcal/kg/day
   Up to 1.6g/kg/day protein as tolerated
     Low-grade  HE (minimal, I, II) should not be
      contraindication to adequate protein supply
   40g temporary restriction if considered protein
    intolerant, but gradual increase q3-5 days
     30-40g   Vegetable protein/day for these pts
   In patients intolerant of a daily intake of 1 g
    protein/kg, oral BCAA up to 0.25 g/kg may be
    beneficial to create best possible nitrogen balance
     BCAA’s do   not exacerbate encephalopathy
MNT Specifically in HE
   HE coma (grade III-IV)
     Usually  no oral nutrition
     Upon improvement, individual protein tolerance can
      be titrated by gradually increasing oral protein intake
      every three to five days from a baseline of 40 g/day
     Enteral and parenteral regimens providing 25-30
      kcal/kg/day non-protein energy
     1.0g/kg/day protein, depending on degree of muscle
      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?
References
Müller, 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. 2 1:317-325.
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 branche d-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.
 References
Wahren, 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 requ irements 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 surg ery. 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 und ergoing 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.

								
To top