Is there any new guideline?

ESPEN GUIDELINES
ENERGY
Provide energy to cover 1.3 x REE (C)
Give glucose to cover 50 % - 60 % of non-protein energy
requirements. (C )
Reduce glucose infusion rate to 23 g kg/day in case of hyperglycemia
and use consider the use of i.v. insulin. (C)
Use lipid emulsions with a content of n-6 unsaturated fatty acids
lower than in traditional pure soybean oil emulsions

AMINO ACIDS
Provide amino acids at 1.21.5 g kg1 d1. C
In encephalopathy III or IV, consider the use of solutions rich in BCAA
and low in AAA, methionine and tryptophane. A
Plauth M et al. ESPEN Guidelines on Parenteral Nutrition: Hepatology Clinical Nutrition 28 (2009) 436444

How much is needed?

The mean requirement and population-safe
level of the total BCAA were 144 and 210
mg/(kg d), respectively
Aminofluid
500mL x 2bags
amino acid
30g,BCAA 9 g

60 kg man requires 60 x 144 = ~ 9 g

Riazi et al. The Total Branched-Chain Amino Acid Requirement in Young Healthy
Adult Men Determined by Indicator Amino Acid Oxidation by Use
of L-[1-13C]Phenylalanine. J. Nutr. 133: 13831389, 2003

Metabolism in Hepatic Cirrhosis & EH

Imbalance of Fischers BCAA/AAA ratio
increased pseudoneurotransmitters
Ineffective removal of ammonia
Hyperammonemia
Insulin resistance
Fasting hypoglycemia due to impaired
gluconeogenesis
Etc.

Hyperammonemia is linked to
impairment of normal brain function
and the onset of the neurological
condition, hepatic encephalopathy
BCAA increases removal rate of
Ammonia from muscle
Daniel J. Wilkinson *, Nicholas J. Smeeton, Peter W. Watt G. Dam, O.L. Munk, P. Ott, S. Keiding, M. Srensen Ammonia
metabolism, the brain and fatigue; revisiting the link. Progress in Neurobiology 91 (2010) 200219
EFFECT OF BRANCHED-CHAIN AMINO ACIDS ON AMMONIA
METABOLISM IN SKELETAL MUSCLE IN PATIENTS WITH LIVER CIRRHOSIS AND HEALTHY CONTROLS MEASURED BY
13N-AMMONIA PET. Journal of Hepatology 2010 vol. 52 | S59S182

MULTIFACTORIAL MECHANISM OF EH

NH3

Tryptophan

NH3

Arousal
(serotonin)

Direct
neural toxin

False
neurotransmitters
Motor/cognitive
(dopamine)

Excitatory
glutamate

Inhibitory
GABA

ENCEPHALOPATHY

Endogen
eous
BZ

Vascular system in the liver

Hepatic vein

Liver

Left bile duct

Hepatic artery
Right bile duct
Pancreas

Common hepatic duct

Pactreatic duct
Gall bladder

Cystic duct

Portal vein

Common bile duct

Sphincter of Oddi
Supervised by Akiharu Watanabe, Kawasaki University of Medical Welfare

Normal

Change in portal blood flow in liver cirrhosis

- formation of collateral circulation
Liver cirrhosis
Azygos vein

Liver

Stomach

Esophagus

liver

Stomach varix

Stomach

Peritoneal
vein
Navel

Spleen

Superior
rectal vein

Rectum

Spleen

Esophageal varix

Paraumbilical vein

Inferior mesenteric vein

Superior
mesenteric
Superior rectal vein
vein

Paraumbilical vein

Navel

Shunt

Inferior vena cava

Esophagus

Splenomegaly

Rectal varix
Rectum
Supervised by Akiharu Watanabe, Kawasaki University of Medical Welfare

Hepatic encephalopathy is indicative of hepatic failure

Mild hepatic encephalopathy
Talkative

Affection lability

Night awakening
and daytime
sleepiness

Sensitive to stimulation

Loss of
attention

In severe case
Coma

Restlessness

Severity of hepatic encephalopathy (consciousness disturbed) varies from very slight (degree I) to coma (degree IV or
V). Initial symptoms in particular may not be noticed even by family members without careful watching.

Supervised by Akiharu Watanabe, Kawasaki University of Medical Welfare

Classification of coma in hepatic encephalopathy

Degree of
coma

Psychiatric symptoms

Reference notes

Inversion of sleep-awake rhythm

Euphoric mood and sometimes depressive state
Sloppy and ignorant

Only retrospective
judgment is possible in
many cases

II

Disorientation (time, place), confusion

Abnormal behavior (such as scattering money, discarding
cosmetics)
Sometimes somnolence state (eye-opening by usual
calling and conversation is possible)
Impolite behaviors but observes physicians instructions

Absence of excitement
Absence of
urinary/fecal
incontinence
Presence of flapping
tremor

III

Often excitement or delirium is accompanied and reflective

attitude is shown.
Lethargic state (mostly asleep); the eyes may be opened to
external stimulus but physicians instructions are not
followed or cannot be followed (response to a simple order)

Presence of flapping
tremor (if cooperation of
a patient is obtained)
Severe disorientation

IV

Coma (total loss of consciousness)

Response to pain stimulus

Reactions such as
shaking off and frowning
are observed.

Deep coma
No response even to pain stimulus

12th Inuyama Symposium: Hepatitis A and fulminant hepatitis, Chugai Igakusha, 1982: pp.116-125
Supervised by Akiharu Watanabe, Kawasaki University of Medical Welfare

Inducing factors of hepatic encephalopathy

1

Excessive
consumption of
dietetic proteins

Production of toxic nitrogen compounds such as

ammonia is increased in the intestines.

Constipation

Contact between intestinal flora and nitrogen compounds

is prolonged resulting in increased production/absorption
of toxic substances such as ammonia.

Gastrointestinal
hemorrhage

100 mL of blood is equivalent to 15-20 g of proteins.

Shock and hypoxia due to decreased circulating blood
deteriorate hepatic, cerebral and renal functions.

Diuretics

Hypokalemic alkalosis is induced (NH4++OH- NH3+H2O),

increasing production of ammonia in the kidneys and
accelerating transportation of ammonia to the brain.

Medication
(sedatives,
analgesics),
infections

Potent inhibitory action on sensitive brain is exhibited.

Catabolism of tissue protein is accelerated.

Akiharu Watanabe: Clinical pathology of hepatic failure, Nagai Shoten, 1994: pp.255-257
Supervised by Akiharu Watanabe, Kawasaki University of Medical Welfare

Processing of ammonia and amino acid metabolism in patients with liver cirrhosis
(decompensated)

Damaged liver (detoxication of ammonia in muscles)

Normal liver

Collateral circulation

Urea

Hepatic vein

Glutamine

Amino acids

Urea
cycle

Ammonia

Ammonia+

NH 4

Amino acids

Urea
cycle

Ammonia

Glutamic acid
BCAA

Portal vein

Ammonia

Energy

Muscle
Ammonia

Urea
(intestine)
Supervised by Akiharu Watanabe, Kawasaki University of Medical Welfare

Free amino acid pattern in plasma of patients with liver

cirrhosis (decompensated)

***

***

***

***

***

***

Liver cirrhosis without encephalopathy (n=40)

Liver cirrhosis with encephalopathy (n=21)

* p<0.05, ** p<0.01, *** p<0.001

***
***

*
***

**

**
***

**

***

***

***

*
***

***

***

***

***

***

Orn. Lys. His. Arg. Thr. Ser. Glu. Pro. Gly. Ala. Met. Val. Ile.

Leu.

Tyr. Phe. Trp.

Aromatic amino acids (AAA) such as Tyr and Phe increase whereas branched-chain amino acids (BCAA) such as Val,
Ile and Leu decrease showing a decreased BCAA/AAA ratio.

The concentration of each amino acid in the plasmas of 13 healthy subjects was
defined as 1 and its multiple number was plotted along the horizontal axis.
Yasutoshi Muto, et al.: The Saishin Igaku 1980;35(8): 1573-1582

Metabolisme Protein
.
BCAA
BCAA

AAA

BCAA

Structures of branched-chain amino acids and aromatic amino acids

BCAA: Branched chain
amino acids
Leucine
(Leu)

CH3
CH3

CH-CH2-CH-COOH

AAA: Aromatic amino acids

Tyrosine
HO(Tyr)

NH2

CH3

CH-CH-COOH

Valine
(Val)

CH3
CH3

Phenylalanine
(Phe)

NH2

Molecular weight: 131.17

CH-CH-COOH
NH2

Molecular weight: 117.15

Akiharu Watanabe: Liver Diseases and Nutrition Therapy,
Daiichi Shppab 1993: p100

NH2
Molecular weight: 181.19

Molecular weight: 131.17

Isoleucine
CH3-CH2
(Ile)

-CH2-CH-COOH

-CH2-CH-COOH
NH2
Molecular weight: 165.19

Tryptophan
(Trp)

- CH2 -CH
CH -COOH
COOH
N
NH2
H
Molecular weight: 204.23

Method for calculation of Fischer ratio and BTR

Fischer ratio

Reimbursement
point1)
1300

Branched-chain amino acid

Aromatic amino acid

(molar ratio)

Normal range2)
2.43 - 4.40

Fischer ratio in patients with liver

cirrhosis3)
Compensated
2.110.58
Decompensated
1.220.21

Valine + Leucine + Isoleucine

= Phenylalanine + Tyrosine

BTR: Branched-chain amino acids and Tyrosine Ratio

BTR
Reimbursement
point1)
300

=
=

Branched-chain amino acid

Tyrosine

Valine + Leucine + Isoleucine

Tyrosine

(molar ratio)

Normal range2)
4.84 - 10.00 (male)
3.65 - 9.97 (female)
BTR in patients with liver cirrhosis4)
Compensated
3.490.89
Decompensated 2.56 0.72

1): Japanese Medical Journal 2008; 4374: p84, 2): Ed. Kanai, M.: Kanais Manual of Chemical Laboratory Medicine, Kanahara Shppan 2005: p510-513,
3): Fujisawa R.: KAN-TAN-SUI 1983; 6(6): 867-8724): Hiyama, Y.: Frontiers in Gastroenterology 4(4), 1999 409-419

Theory of false neurotransmitter in hepatic encephalopathy

Fischer s theory
Aromatic amino acid
(AAA)

Branched-chain amino acid

(BCAA)

Competitive inhibition
Brain-blood barrier

Brain

L-DOPA

Dopamine

Norepinephrine

Tyr

Phe

Tyramine

Octopamine
(*)

Trp

Phenyl tyramine

Imbalance in cerebral amino

acid and increase
in ammonia

5HTP

Phenyl
ethanolamine (*)

Serotonin

5HIAA

Abnormality in brain
neurotransmitters
(*)
false neurotransmitter

5HIAA: 5-hydroxy indole acetic acid

HVA: Homovalic acid

: Tyrosine hydrogenase

Hepatic
encephalopathy

Fischer, J.E, et.al.: Surgery 1975;78(3): 276-290

Composition of Aminoleban for intravenous drip infusion (500mL)

L-Valine
L-Leucine
L-Isoleucine
L-Threonine
L-Tryptophan
L-Methionine
L-Phenylalanine
L-Lysine hydrochloride
(as L-lysine)

4.20 g
5.50 g
4.50 g
2.25 g
0.35 g
0.50 g
0.50 g
3.80 g
3.04 g

L-Alanine
L-Arginine hydrochloride
(as L-arginine)
L-Histidine hydrochloride
(as L-histidine)
L-Proline
L-Serine
L-Cysteine hydrochloride
hydrate (as L-cysteine)
Glycine

Amino acid
content

Total
nitrogen

Content of branched-chain
amino acida)

7.99 w/v%

6.11 g

35.5 w/w%

Fischer ratiob)

37.05

E/N

Na+

Cl-

pHc)

1.09

About 7 mEq

About 47 mEq

5.5-6.5

3.75 g
3.65 g
3.02 g
1.60 g
1.18 g
4.00 g
2.50 g
0.20 g
0.14 g
4.50 g
Specific
gravity (20C)

1.025

Osmotic pressured)

About 3

a) Valine + leucine + isoleucine

b) (Valine + leucine + isoleucine )/(phenylalanine + tyrosine )(molar ratio)
c) Normal value
Cited from package insert revised June, 2008
d) Ratio to physiological saline

Efficacy of Aminoleban IV on hepatic encephalopathy

Disease (n)

Efficacy rate

Liver cirrhosis (270)

73.3%

Hepatocellular carcinoma (90)

62.2%

Others* (8)

62.5%

Total (368)

70.4%

The efficacy of Aminoleban intravenous drip infusion was examined in patients with
chronic hepatic failure complicated by hepatic encephalopathy (76 facilities in total, 368
patients). The product was judged effective when decreased consciousness level was
resolved or improved definitely or the degree of coma (Davidsons classification) was
improved by one degree.
*: Metastatic hepatocellular carcinoma: 2, hepatic fibrosis: 3, bile duct cancer: 1, hepatic amyloidosis: 1, Eck
fistula syndrome: 1
Cited from Revised Package Insert, June 2008

Any EBM?

Comparison 02 Sensitivity analyses - BCAA versus control

(improvement), Outcome 07 Best
case scenario favouring BCAA - Improvement

Indication, and dosage and administration of Aminoleban IV drip

infusion

Indication
Improvement of encephalopathy in chronic liver disorder

Dosage and administration

The usual adult dosage is 500 to 1000 mL to be intravenously infused.
The normal infusion speed is 180 to 300 minutes per 500 mL in adults.
Intravenous hyperalimentation may be performed by mixing 500 to 1000 mL of this
product with carbohydrate infusion, etc. and injecting the mixture by drip infusion
into the central vein over 24 hours.
The dose may be increased or decreased according to age, symptoms or body
weight.
<<Precautions concerning the dosage and administration>>
This product contains about 14 mEq/L of sodium ion and about 94 mEq/L of
chlorine ion. Therefore, electrolyte balance should be checked carefully when it is
administered in a mass dose or an electrolyte solution is co-administered.
Cited from Revised Package Insert, June 2008

Therapeutic policies for hepatic encephalopathy (I)

A. Coma degree II or lower and oral intake is possible
(i) Dietetic restriction of proteins (40 50 g)
(ii) Oral administration of lactulose solution or Monilac solution, 30 60 mL in 3
divided doses
(iii) Oral intake of lactitol (Portolac), 18 36 g in 3 divided doses
(iv) Enema of lactulose (mix 100 mL of lactulose with 100 mL of physiological saline or
lukewarm water and administer once or twice a day
Administer (v) together with the above.
(v) Aminoleban injection (or Morihepamin injection), 400 1000 mL (daily dosage)
An intravenous drip infusion of Aminoleban alone or with glucose from a
peripheral vein (over 2 3 hours)
24-hour drip infusion into the central vein
(vi) Intravenous drip infusion of Argimate injection, 200 mL (over 2 3 hours)
B. Coma degree II or higher and oral intake is impossible
(i) Under fasting
(ii) Administration of Aminoleban (or Morihepamin injection), 400 1000 mL from the
central vein
(iii) After awakening from coma, switching to oral administration of enteral nutrient
for hepatic failure
Kazuyuki Suzuki: Therapeutic Guidance Today, 2000 (ed. By Yukio Tagasu, Etsuro Ogata), Igaku Shoin 2000: pp.429-430
Read the package inserts of respective products before their uses.

TREATMENT OF HEPATIC ENCEPHALOPATHY

Diagnosis: LFT, EEG, ammonia, Blood coagulation
Monitor: Vital signs, ABG,
Ventilation, tissue exygenation
SUPPORT VITAL SIGNS

Lung function:
Maintain oxygen saturation> 90%
Protect airway
Maintain PaCO2 > 30 mmHg

Use antacid to increase pH > 4,5

(H2 blocker, PPI)
maintain serum
Na >130
(careful diuresis)

Treat Hypoglycemia if present

(hypertonic glucose (20%))
PREVENT WORSENING
OF ENCEPHALOPATHY

LOLA
Nutrition:
BCAA
AAA
Fat emulsion
Carbohydrate

Lactulose,
Neomisin/
Rifamycin

Control GIT bleeding

Lavage, Fresh frozen plasma
Watch out
CNS depressant

THANK YOU