Beruflich Dokumente
Kultur Dokumente
of Hepatic
Encephalopathy
Presented by
Chris Theberge & Sara Murkowski
Copyright © 2007, The Nutrition and Food Web Archive (www.nafwa.org), All rights reserved.
Presentation At A Glance
Background on Liver Dysfunction
Review of liver physiology
Diseases of the liver
Development of Hepatic Encephalopathy
Pathogenesis Theories
Incidence, Prognosis, Diagnostic Criteria
Clinical manifestations, Nutritional manifestations
Treatment: Medical Management
Case Study
Nutritional Management
Historical Treatment Theories/Practice
Protein Restriction & BCAA Supplementation
Goals of MNT
Let’s Take It From The Top
A Physiology Review
Functions of the Liver:
A Brief Overview
Largest organ in body, integral to most
metabolic functions of body, performing over
500 tasks
Only 10-20% of functioning liver is required to
sustain life
Removal of liver will result in death within 24
hours
Functions of the Liver
Main functions include:
Metabolism of CHO, protein, fat
Storage/activation vitamins and minerals
Formation/excretion of bile
Steroid metabolism, detoxifier of drugs/alcohol
Action as (bacteria) filter and fluid chamber
Conversion of ammonia to urea
Gastrointestinal tract significant source of ammonia
Generated from ingested protein substances that are
deaminated by colonic bacteria
Ammonia enters circulation via portal vein
Converted to urea by liver for excretion
The Urea Cycle Aspartate Transaminase(AST)
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
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
Portosystemic Shunting
Drugs
•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
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
250 Tyr
200
Try
150
Gly
100 Thr Ser
Orn
Lys Tau His
50 Va Leu Arg
Pro Ala
l
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
Mood swings
(handwriting)
Decreased altertness,
Seizures (rare)
responsiveness Decreased self-care
Coma ability
Speech impairment
Diagnosing HE
Metabolic Intracranial
encephalopathies events
Diabetes Intracerebral
(hypoglycemia, bleeding or
ketoacidosis)
infarction
Hypoxia
Carbon dioxide narcosis Tumor
Toxic Infections
encephalopathies (abscess,
Alcohol (acute alcohol meningitis)
intoxication, delirium Encephalitis
tremens, Wernicke-
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
Protein
Restriction
BCAA supplementation
Goals of MNT
Treatment of PCM associated with ESLD
Historical Treatment Theories:
Protein Restriction
Studies in early 1950’s showed cirrhotic pts
given “nitrogenous substances” developed
hepatic “precoma”
Led to introduction of protein restriction
Began with 20-40g protein/day
Increased by 10g increments q3-5 days as tolerated
with clinical recovery
Upper limit of 0.8-1.0 g/kg
Was thought sufficient to achieve positive nitrogen
balance
Lack of Valid Evidence
Efficacy of restriction never proven within controlled
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
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
Lactoalb
Study Profile of BCAA Trial BCAA umin Maltodextrin
Total number 59 56 59
Lost to follow-up 1 — —
Intention-to-treat analysis 58 56 59
Events (death, any cause, or 9 (15.5%)* 18 (32.1%) 16 (27.1%)
progression of liver 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
*
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.
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
on Reitan Test)
nd
in
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
8 3
(g/dL)
L-ALB 2.5
7 2
1.5 BCAA
6 M-DXT 1
0.5
0
5 L-ALB
M-DXT
d
o
o
d
e
e
En
l in
lin
En
M
M
3-
6-
3-
6-
9-
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)
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
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
Comments?
Questions?
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