dr Iyan Darmawan Medical Department PT Otsuka Indonesia email address: iyan@ho.otsuka.co.

id

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 Tryptophan

Arousal (serotonin)

NH3

False neurotransmitters
Motor/cognitive (dopamine) Endogen eous BZ

NH3

Direct neural toxin

Excitatory glutamate

Inhibitory GABA

ENCEPHALOPATHY

Vascular system in the liver

Hepatic vein Liver

Left bile duct

Hepatic artery Right bile duct Pancreas Pactreatic duct Gall bladder Cystic duct Common bile duct Sphincter of Oddi
Supervised by Akiharu Watanabe, Kawasaki University of Medical Welfare

Common hepatic duct

Portal vein

Normal

Change in portal blood flow in liver cirrhosis - formation of collateral circulation Liver cirrhosis
Azygos vein
Esophagus

Shunt
liver

Inferior vena cava

Esophageal varix Esophagus

Liver

Stomach varix

Stomach Paraumbilical vein

Stomach

Paraumbilical vein

Inferior mesenteric vein

Superior mesenteric Superior rectal vein vein

Navel

Spleen

Peritoneal vein Navel Superior rectal vein

Spleen

Splenomegaly

Rectum

Rectal varix Rectum

Supervised by Akiharu Watanabe, Kawasaki University of Medical Welfare

Hepatic encephalopathy is indicative of hepatic failure

Mild hepatic encephalopathy
Talkative
Night awakening
and daytime sleepiness

Affection lability

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

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

Normal liver
Urea
Hepatic vein
Amino acids

Damaged liver (detoxication of ammonia in muscles)

Collateral circulation

Glutamine
Amino acids

Ammonia +

NH 4

Urea cycle

Ammonia

Urea cycle

Ammonia

Glutamic acid BCAA Energy

Portal vein

Muscle
Ammonia

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)
*** *** ***

***

***

3 2

***

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

*** *** ** ***

**

* ***

**

***

***

***

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

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

*** ***

***
***

Leu.

*** ***

Tyr. Phe. Trp.

Metabolisme Protein
.
BCAA BCAA

AAA

BCAA

Structures of branched-chain amino acids and aromatic amino acids BCAA: Branched chain
amino acids
Leucine (Leu)

AAA: Aromatic amino acids

Tyrosine

CH3 CH3

CH-CH2-CH-COOH NH2
Molecular weight: 131.17

(Tyr)

HO-

-CH2-CH-COOH NH2
Molecular weight: 181.19

Isoleucine CH3-CH2 (Ile)

CH3

CH-CH-COOH NH2

Phenylalanine (Phe)

-CH2-CH-COOH NH2
Molecular weight: 165.19

Molecular weight: 131.17

Valine (Val)

CH3 CH3

CH-CH-COOH NH2

Tryptophan (Trp)

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

Molecular weight: 117.15 Akiharu Watanabe: Liver Diseases and Nutrition Therapy, Daiichi Shppab 1993: p100

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

= Phenylalanine + Tyrosine

Valine + Leucine + Isoleucine

Fischer ratio in patients with liver cirrhosis3) Compensated 2.110.58 Decompensated 1.220.21

BTR: Branched-chain amino acids and Tyrosine Ratio Branched-chain amino acid 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

BTR
Reimbursement point1) 300

= =

(molar ratio)

Tyrosine
Valine + Leucine + Isoleucine Tyrosine

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

Tyr
Tyramine

Phe
Phenyl tyramine

Trp

Dopamine

5HTP
Serotonin 5HIAA

Imbalance in cerebral amino acid and increase in ammonia

Norepinephrine

Octopamine (*)

Phenyl ethanolamine (*)

Abnormality in brain neurotransmitters

(*)
false neurotransmitter : Tyrosine hydrogenase

5HIAA: 5-hydroxy indole acetic acid HVA: Homovalic acid

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
Fischer ratiob)

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)

Amino acid content

Total nitrogen

Content of branched-chain amino acida)

7.99 w/v%

6.11 g

35.5 w/w%

37.05

1.025

E/N

Na+

Cl-

pHc)

Osmotic pressured)

1.09

About 7 mEq

About 47 mEq

5.5-6.5

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) Hepatocellular carcinoma (90) Others* (8) Total (368)

73.3% 62.2% 62.5% 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.

TATALAKSANA ENSEFALOPATI HEPATIK

Diagnosis: Tes faal hati, EEG, amonia, Pembekuan darah Monitor: Tanda-tanda vital, kadar gas darah, Ventilasi, oksigenasi jaringan DUKUNG FUNGSI ORGAN-ORGAN Fungsi paru: Pertahankan saturasi oksigen > 90% Lindungi jalan napas Pertahankan PaCO2 > 30 mmHg

Gunakan antasid untuk menaikkan pH > 4,5 (Ranitidine)

Pertahankan kadar glukosa (beri glukosa hipertonik 20%)

Pertahankan Na serum >130 (diuresis hatihati)

CEGAH MEMBURUKNYA ENSEFALOPATI

Nutrisi: BCAA AAA Emulsi lemak Karbohidrat

Laktulosa, neomisin

Hati-hati dalam menggunakan CNS depressant

Kontrol perdarahan GIT Lavage, Plasma beku segar

Ref: Demling.RH, Wilson RF. Decision making in Surgical Critical care. BC. Decker 1998. pp 229-230

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