Three targets of branched-chain aminoacid supplementation in the

treatment of liver disease.

M.Prasad NaiduMSc Medical Biochemistry,

Ph.D.Research Scholar

The BCAA & protein metabolism in various forms of hepatic injury & it is suggested that the main cause of decrease in plasma BCAA conc in liver cirrhosis is hyperammonemia

Three possible targets of BCAA supplementation in liver disease are suggested

1. Hepatic encephalopathy2.Liver regeneration 3.Hepatic cachexia.

The BCAA may ameliorate hephatic encephalopathy by promoting ammonia detoxification,correction of plasma aminoacid imbalance and by reduced brain influx of AAA

The favourable effect of BCAA on liver regeneration and nutritional state of the body is related to their stimulatory effect on protein synthesis,secretion of hepatocyte growth factor ,glutamine production and inhibitory effect on proteolysis.

Presumably the beneficial effect of BCAA on hepatic cachexia is significant in compensated liver disease with decreased plasma BCAA conc ,where as it is less pronounced in hepatic diseases with inflammatory complications and enhanced protein turn over.

Introduction

The BCAAs valine,leucine and isoleucine are indispensible aminoacids of special interest

Several studies have demonstrated the stimulatory effect of BCAAs and/or their metabolites on protein synthesis and/or inhibitory effect on proteolysis

They play a major role in muscle and most other tissues because they are major AAs that can be oxidised in tissues

Acute liver injury Is a clinical condition resulting from damage of

liver cells One characteristic feature of acute liver

failure is a marked increase in aminoacidemia The main cause of increased AA concentrations

is due to their leaking from the dying hepatocytes.

The changes in BCAA conc are less pronounced (compared to other AA s) because they are catabolised significantly in extrahepatic tissues

Chronic injury Decreased blood conc of BCAA and increased

conc of AAA and methionine are characteristic of chronic liver disease esp.,cirrhosis

The abnorm alities in BCAA and AAA levels in cirrhosis are expressed as molar ratio (BCAA/AAA)

Physiologically ,the ratio is 3.0 -3.5.,where as in patients with hepatic cirrhosis it is significantly lower.

It is a serious neuropsychiatric abnormality associated with chronic or acute liver injury

Signs Impaired cognition A flapping tremor Decreased level of consciousness,including

coma, cerebral edema and ultimately death.

BCAA and hepatic encephalopaty

Substances contributing to symptoms of hepatic encephalopathy include

AMMONIA Mercaptans Short chain FAs Increased conc of AAAs GABA Endogenous benzodiazepines etc.,In the pathogenesis of HE ,changes induced by

impaired liver function and portal systemic shunting interact,resulting in accumulation of substances that are normally removed by liver.

Presumed mechanism of the direct effect of hyperammonemia on brain functions include

-Its effect on inhibitory post synaptic potentials by blocking the chloride pump

-Impairment of brain ATPsynthesis due to depletion of krebs cycle intermediates

-Cell swelling by ammonia induced blood flow and

synthesis

-Accumulation of glutamine in astrocytes

Activation ofn-MDA receptors

Intracellular excess of calcium

Increased NO formation

Increased production of free radicals

Impaired mitochondrial respiration

ATP depletion Contributing to

ammonia induced death in acute liver failure

Hyperammonemia affects neurotransmission associated with n-MDA receptors(acute effects)

Chronic hyperammonemia Seems to induce impaired signal

transduction associated with n-MDA receptors

Thereby contributing to some neurological alterations observed in hepatic encephalopathy

Indirectly , hyper ammonemia may contribute to hepatic encepha lopathy by

A decrease in BCAA levels in the blood

Alterations in AA transport across the BBB.

AAAs flood the CNS due to high blood plasma conc of AAA and low conc of BCAAs,which compete for entry by the L-system(system that serves for transport of neutral AAs) across the BBB.

Augmented uptake of AAAs results in An imbalance in the synthesis of dopamine,

noradrenaline and serotonin in the brain.

Inaddition, increased availability of AAAs may cause the formation of false neuro transmitters like octopamine,phenyl ethanolamine,andtyramine

The rationale of BCAAs in the treatment of hepatic encephalopathy was based on assumptions that providing BCAAs

Would facilitate ammonia detoxification by supporting glutamine synthesis in skeletal muscle and brain

Would normalise plasma AA concentrations and

Decrease brain influx of AAAs

The survival of patients with liver injury of varying etiology depends on the ability of the remaining hepatocytes to regenerate

Nutritional and metabolic support of liver regeneration seem to be very important

Carbohydrate source, primarily glucose, is recommended

BCAA and liver regeneration

Results of several studies have indicated that preservation of hepatic glycogen increases the liver’s tolerance to oxidative and ischaemic damage

Perioperative glucose/insulin infusion may prevent or attenuate hepatic dysfunction after extensive liver resection

The mechanism of the favourable effect of BCAAs on hepatic tissue repair is multifactorial

The well known synergestic effect of glucagon and insulin on liver regeneration

The stimulatory effect of leucine on protein synthesis

The stimulatory effect of leucine on hepatocyte growth factor by hepatic stellate cells may be involved.

Some effects of BCAAs may be associated with enhanced production of glutamine

BCAA treatment promoted recovery of serum albumin and lowered bilirubin levels after partial hepatectomy for liver cancer and improved patient’s prognosis after livertransplantation

Glucose administation inhibits

Inhibition of Hs lipase by insulin

Decreased mobilization of fattyacids

Increase in insulin / glucagon quotient

Infusion of fatty emulsion stimulates

Regenerating liver generates ATP primarily by FA oxidation

The beneficial effect of carnitine

FAs act as substrates for synthesis of phospholipids and esterification of cholesterol.

Many studies have demonstrated that lipids are well tolerated ,even in cirrhotic patients , if administered parenterally

Clinical trials will have to determine whether lipid therapy can improve liver regeneration and function after liver resection and in hepatic disease.

Cachexia is defined as a complex metabolic syndrome associated with underlying illness and characterised by loss of fat mass.

Prevalence 20% in patients with compensated liver

disease 100% in patients with acute alcoholic

hepatitis 50% in patients with liver cirrhosis

BCAA and hepatic cachexia

Pathogenesis Poor dietary intake Malabsorption Maldigestion Metabolic

disturbances Resulting in changes

in protein synthesis and proteolysis

Characterised by Impaired glucose

tolerance- -DM Impaired post prandial

glucose utilization – -decreased glycogen contents in the liver and skeletal muscle

Enhanced utilization of lipids and proteins for energy

BCAA taken up from plasma and muscle proteins are the important energy substrate in liver cirrhosis

In the first step of their catabolism they are used for glutamate synthesis in mitochondria to clear blood ammonia by enhanced production of glutamine

In the second step, most BCKAs produced in BCAAT reaction are oxidised, probably mostly in skeletal muscle

The mechanism of favourable effect of BCAAs on protein metabolism and nutritional state of pts with hepatic disease is related to

Stimulatory effect on protein synthesis and inhibitory effect on proteolysis

Leucine stimulates insulin release from βcells of pancreas

Leucine also stimulates protein synthesis through phosphorylation of translation initiation factors and ribosomal proteins

These effects may contribute to the improvement of insulin resistance and beta cell function in chronic liver disease.

BCAA supplementation is more effective in compensated cirrrhosis with decreased plasma BCAA conc and with out SIR

The nutritional and immune status of the pt

should be carefully evaluated before BCAA supplementation to confirm the signs of inflammation and cachexia.

The assessment of changes in body weight Apetite Muscle strength Fat free mass index Inflammatory markers(CRP and IL-6) Albumin Aminoacid concentrations …seems to be

particularly important

Conclusions and suggestionsMost experimental studies have revealed the

favourable effects of BCAAs on nutritional status, development of liver illness and quality of life

.This favourable effect is related to their

stimulatory effect on protein synthesis ,insulinsecretion and liver regeneration

These favourable effects BCAA supplementation seem to be more apparent when BCAA concentration decrease as in liver cirrhosis with portasystemic shunts and particularly when not complicated by a systemic inflammatory response.

Formulas for oral,enteral and parenteral BCAA supplementation are commercially available and the appropriate administration should be considered.

Oral route is advantageous than parenteral feeding eg; danger of liver steatosis

impaired gut hormonal and immunological responses phlebitis or thrombosis of veins

An adverse property of BCAAs is their extremely bitter taste,and the low palatability of nutritive drinks is a major problem with respect to patient compliance.

BCAA enriched mixtures should contain not only BCAAs but also glucose,lipids, and other nutrients that should have beneficial effects on the course of hepatic illness.

Coadministration of BCAA s with carnitine or zinc has a beneficial effect.

BCAA with zinc supplementations showed greater ability to metabolise ammonia and higher efficacy in correcting AA alterations

The aministration of BCAA with L-acetyl carnitine revealed improvement of neurologic symptoms and serum ammonia in cirrhotic patients

Dietary supplementationwith BCAA improved the impaired transthyretin turnover in rats with liver cirrhosis

In conclusion ,although critical objections regarding the effects of BCAA supplementation can still be raised..,

the rationale of BCAA in chronic hepatic illness their favourable effect on nutritional state Repair and regeneration of hepatic tissue Safety of their administration Positive results of several randomised trials

conducted in recent years …. Are strong arguments for BCAA supplementation as a standard nutritional approach in treating pts with hepatic disease ,particularly cirrhosis.

Thank you