BCAA supplementation has three potential benefits for patients with liver disease: 1) It may help treat hepatic encephalopathy by promoting ammonia detoxification and reducing amino acid imbalances. 2) It may support liver regeneration through stimulating protein synthesis and secretion of growth factors. 3) It may help treat hepatic cachexia by stimulating protein synthesis and inhibiting proteolysis. The document discusses the mechanisms and evidence for these proposed benefits of BCAA supplementation for different types of liver injury and disease.

1. 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 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.

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. 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

13. 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.

14.  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 accumulation of
substances that are normally removed by liver.

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.  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

18. Chronic hyperammonemia
 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 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.

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 false neuro
transmitters like octopamine,phenyl
ethanolamine,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.  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. 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-acetyl
carnitine 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 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.