BRANCHED CHAIN AMINOACIDS

1. Three targets of branched-chain aminoacid supplementation in the treatment of liver disease. M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar

2. 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 encephalopathy 2.Liver regeneration 3.Hepatic cachexia.

4. The BCAA may ameliorate hephaticencephalopathyby promoting ammonia detoxification,correction of plasma aminoacid imbalance and by reduced brain influxof AAA • The favourable effect of BCAA on liverregeneration 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.

5. 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

12. Acuteliverinjury • 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

13. Chronic injury • Decreased blood conc of BCAA and increased conc of AAA and methionine are characteristic of chronic liver disease esp.,cirrhosis • The abnormalities 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.

14. BCAA and hepatic encephalopaty • 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.

15. 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 accumulationofsubstancesthatarenormallyremovedbyliver.

16. 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

17. Hyperammonemia affects neurotransmission associated with n-MDA receptors(acute effects) • Impaired mitochondrial respiration • ATP depletion • Contributing to ammonia induced death in acute liver failure • Activation ofn-MDA receptors • Intracellular excess of calcium • Increased NO formation • Increased production of free radicals

18. Chronichyperammonemia • Seems to induce impaired signal transduction associated with n-MDA receptors • Thereby contributing to some neurological alterations observed in hepatic encephalopathy

19. Indirectly , hyper ammonemia may contribute to hepatic encephalopathy 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.

20. 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 falseneurotransmitters like octopamine,phenylethanolamine,andtyramine

21. 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

22. BCAA and liver regeneration • 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

23. 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

24. 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

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

26. 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.

27. 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.

28. BCAA and hepatic cachexia 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

29. 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

30. 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

31. 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.

32. 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.

33. 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

35. Conclusions and suggestions Most 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.

36. 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

37. 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.

38. 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-acetylcarnitine revealed improvement of neurologic symptoms and serum ammonia in cirrhotic patients

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

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

41. Thank you