Update on BCAA (print).ppt

dr Iyan DarmawanMedical Department PT Otsuka Indonesia

email address: [email protected]

Is there any new guideline?

Plauth M et al. ESPEN Guidelines on Parenteral Nutrition: Hepatology Clinical Nutrition 28 (2009) 436–444

ESPEN GUIDELINES

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 2–3 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

Provide amino acids at 1.2–1.5 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

ENERGY

AMINO ACIDS

How much is needed?

• The mean requirement and population-safe level of the total BCAA were 144 and 210 mg/(kg d), respectively

Riazi et al. The Total Branched-Chain Amino Acid Requirement in Young HealthyAdult Men Determined by Indicator Amino Acid Oxidation by Useof L-[1-13C]Phenylalanine. J. Nutr. 133: 1383–1389, 2003

60 kg man requires 60 x 144 = ~ 9 g

Aminofluid500mL x

2bags （ amino acid ： 30g,BCAA

9 g ）

http://www.otsuka.co.id/?content=product_detail&id=36&lang=en

http://www.otsuka.co.id/?content=product_detail&id=36&lang=en

Metabolism in Hepatic Cirrhosis & EH

• Imbalance of Fischer’s 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 neurologicalcondition, 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. Sørensen Ammonia metabolism, the brain and fatigue; revisiting the link. Progress in Neurobiology 91 (2010) 200–219EFFECT OF BRANCHED-CHAIN AMINO ACIDS ON AMMONIAMETABOLISM IN SKELETAL MUSCLE IN PATIENTS WITH LIVER CIRRHOSIS AND HEALTHY CONTROLS MEASURED BY13N-AMMONIA PET. Journal of Hepatology 2010 vol. 52 | S59–S182

MULTIFACTORIAL MECHANISM OF EH

NH3

Direct

neural toxin

Tryptophan

Arousal(serotonin)

Excitatory glutamate

NH3

False neurotransmitters

Motor/cognitive(dopamine)

Endogeneous

BZ

Inhibitory GABA

ENCEPHALOPATHY

Sphincter of Oddi

Hepatic vein Liver

Left bile duct

Hepatic artery

Pancreas

Pactreatic duct

Portal vein

Common bile duct

Cystic ductGall bladder

Common hepatic duct

Right bile duct

Vascular system in the liver

Supervised by Akiharu Watanabe, Kawasaki University of Medical Welfare

Change in portal blood flow in liver cirrhosis- formation of collateral circulation


Paraumbilical vein

Portal veinSuperior

mesenteric

vein

Inferior mesenteric vein

Superior rectal vein

Splenic vein

Para

esoph

agea

l vein

Left gastric vein

Rectal varix

Splenomegaly

Azygos veinEsophageal varix

Stomach varix

Paraumbilical vein

Superior rectal vein

Peritonealvein

Left gastric vein

Para

esophag

eal v

ein

Inferior vena cava

Portal vein

Shunt

Liver

Rectum

Spleen

Stomach

Esophagus

liver

Rectum

Spleen

Esophagus

Stomach

NavelNavel

Normal Liver cirrhosis

Hepatic encephalopathy is indicative of hepatic failure

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.

Mild hepatic encephalopathy

Babble babble

Nod

nod

Snore snore

In severe case…

Affection lability

Night awakening and daytime sleepiness

Coma

Sensitive to stimulation

Talkative

Loss ofattention

Restlessness


Grr!

Normal liver Damaged liver (detoxication of ammonia in muscles)

尿素Urea

Ammonia

Ammonia

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


Urea(intestine)

Portal vein

Hepatic vein

Ureacycle

Ammonia

Amino acids NH4+Ammonia

Collateral circulation

Ureacycle

Amino acids

BCAA

Glutamine

Glutamic acid

Energy

Ammonia

Muscle

Yasutoshi Muto, et al.: The Saishin Igaku 1980;35(8): 1573-1582

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.

Liver cirrhosis without encephalopathy (n=40)Liver cirrhosis with encephalopathy (n=21)

* p<0.05, ** p<0.01, *** p<0.0013

**

*

***

**

**

***

*

*

***

***

*** *** ***

*** *** ***

*** ***

***

*** ***

***

***

***

***

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.

Free amino acid pattern in plasma of patients with liver cirrhosis (decompensated)

2

1

Metabolisme ProteinMetabolisme Protein

..

BCAA

AAA

BCAA

BCAA

BCAA: Branched chain amino acids

Isoleucine (Ile)

Valine (Val)

Phenylalanine (Phe)

Tyrosine

AAA: Aromatic amino acids

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

Molecular weight: 165.19

Leucine (Leu)

Structures of branched-chain amino acids and aromatic amino acids

CH3-CH2CH3

CH-CH-COOH

NH2

CH3-CH2CH3

CH-CH-COOH

NH2

CH3CH3

CH-CH2-CH-COOH

NH2

CH3CH3

CH-CH2-CH-COOH

NH2

CH3CH3

CH-CH-COOH

NH2

CH3CH3

CH-CH-COOH

NH2

HO- -CH2-CH-COOH

NH2

HO- -CH2-CH-COOH

NH2

-CH2-CH-COOH

NH2

Molecular weight: 181.19Molecular weight: 131.17



CH - CH - COOH

NH

- CH2 CH COOH

NH2NH

Tryptophan (Trp)


(Tyr)

Method for calculation of Fischer ratio and BTR

Valine Valine + Leucine + Leucine + Isoleucine + Isoleucine

Phenylalanine Phenylalanine + Tyrosine + Tyrosine ==

Fischer ratioFischer ratioBranched-chain amino acid Branched-chain amino acid

Aromatic amino acid Aromatic amino acid == (molar ratio)

Fischer ratio in patients with liver cirrhosis3)

Compensated 　　　 2.11±0.58 Decompensated 　 1.22±0.21

Reimbursementpoint1)

1300

BTRBTRBranched-chain amino acid Branched-chain amino acid

　　　　 Tyrosine Tyrosine ==

Valine Valine + Leucine + Leucine + Isoleucine + Isoleucine

　　　　　　　　　　 Tyrosine Tyrosine ==

(molar ratio)

BTR in patients with liver cirrhosis4)

Compensated 　　　 3.490.89 Decompensated 　 2.56 0.72

Reimbursementpoint1)

300

Normal range2)

4.84 - 10.00 (male)3.65 - 9.97 (female)

Normal range2)

4.84 - 10.00 (male)3.65 - 9.97 (female)

Normal range2)

2.43 - 4.40

Normal range2)

2.43 - 4.40

1): Japanese Medical Journal 2008; 4374: p84, 2): Ed. Kanai, M.: Kanai’s 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 　

BTR: Branched-chain amino acids and Tyrosine Ratio

Norepinephrine Octopamine(*)

Phenylethanolamine (*)

Serotonin

Aromatic amino acid (AAA)

Branched-chain amino acid (BCAA)

Competitive inhibition

Brain-blood barrierBrain

L-DOPA Tyr Phe Trp

Dopamine Tyramine Phenyl tyramine

(*)false neurotransmitter

ＨＶＡ

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

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

Hepatic encephalopathy

Hepatic encephalopathy

Imbalance in cerebral amino acid and increasein ammonia

Abnormality in brain neurotransmitters

Theory of false neurotransmitter in hepatic encephalopathy

Fischer’ s theory

5HIAA

: Tyrosine hydrogenase

5HTP

a) Valine + leucine + isoleucine b) (Valine + leucine + isoleucine )/(phenylalanine + tyrosine )(molar ratio)c) Normal valued) Ratio to physiological saline

L-Alanine L-Arginine hydrochloride(as L-arginine)L-Histidine hydrochloride(as L-histidine)L-ProlineL-SerineL-Cysteine hydrochloride hydrate (as L-cysteine)Glycine

L-Valine L-Leucine L-Isoleucine L-ThreonineL-Tryptophan L-MethionineL-Phenylalanine L-Lysine hydrochloride(as L-lysine)

4.20 g5.50 g4.50 g2.25 g0.35 g0.50 g0.50 g3.80 g3.04 g

3.75 g3.65 g3.02 g1.60 g1.18 g4.00 g2.50 g0.20 g

0.14 g4.50 g

Amino acidcontent

Total nitrogen

Content of branched-chain amino acida) Fischer ratiob) Specific

gravity (20C)

E/N Na+ Cl- pHc)

7.99 w/v% 6.11 g 35.5 w/w% 37.05 1.025

1.09 5.5-6.5

Composition of Aminoleban for intravenous drip infusion (500mL)

Cited from package insert revised June, 2008

Osmotic pressured)

About 7 mEq About 47 mEq About 3

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 (Davidson’s classification) was improved by one degree.

Cited from Revised Package Insert, June 2008

*: Metastatic hepatocellular carcinoma: 2, hepatic fibrosis: 3, bile duct cancer: 1, hepatic amyloidosis: 1, Eck fistula syndrome: 1

Any EBM?

Comparison 02 Sensitivity analyses - BCAA versus control (improvement), Outcome 07 Best

case scenario favouring BCAA - Improvement

Indication

Dosage and administration

Improvement of encephalopathy in chronic liver disorder

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

Indication, and dosage and administration of Aminoleban IV drip infusion

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

Therapeutic policies for hepatic encephalopathy (I)

Read the package inserts of respective products before their uses.Read the package inserts of respective products before their uses.

TATALAKSANA ENSEFALOPATI HEPATIKDiagnosis: Tes faal hati, EEG, amonia, Pembekuan darahMonitor: Tanda-tanda vital, kadar gas darah, Ventilasi, oksigenasi jaringan

DUKUNG FUNGSI ORGAN-ORGAN

Fungsi paru:Pertahankan saturasi oksigen > 90%Lindungi jalan napasPertahankan PaCO2 > 30 mmHg

Pertahankan kadar glukosa(beri glukosa hipertonik 20%)

Gunakan antasid untukmenaikkan pH > 4,5(Ranitidine)

Pertahankan Na serum >130(diuresis hati-hati)

CEGAH MEMBURUKNYAENSEFALOPATI

Nutrisi: BCAA AAA Emulsi lemak Karbohidrat

Laktulosa,neomisin

Hati-hati dalammenggunakan CNS depressant

Kontrol perdarahan GITLavage, Plasma bekusegar

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

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