Branched Chain Aminoacids

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Three targets of branched-chain aminoacid
supplementation in the treatment of liver
disease.

• M.Prasad Naidu
• MSc Medical Biochemistry,
• Ph.D.Research Scholar

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• 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.

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• 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.

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• 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

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• 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

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• 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.

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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.

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• 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.

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• 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

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

• 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

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

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• 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.

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• 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

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• 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

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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

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• Results of several studies have indicated that
  preservation of hepatic glycogen increases the
  livers tolerance to oxidative and ischaemic
  damage
• Perioperative glucose/insulin infusion may
  prevent or attenuate hepatic dysfunction after
  extensive liver resection

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• 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

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

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• 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.

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• 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.

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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

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• 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

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• 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

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• 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 ßcells 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.

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• 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.

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• 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

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• 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.

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• 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

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• 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.

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• 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

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

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• 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.

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Thank you