8. • The Food and Nutrition Board (FNB) of the U.S. Institute of Medicine
set RDAs for leucine 42 mg/kg/d; for isoleucine 19 mg/kg/d; for valine
24 mg/kg/d (total 85mg/kg/d).
Riazi et al., 2003
For 60 Kg ~ 5 g/d
9. Most of the commonly used protein supplements contains BCAA 15- 20% of the crude protein
11. Fischer et al (1976) were the first to
propose that the primary treatment of
hepatic encephalopathy in cirrhosis might
be enhanced by normalising circulating
amino acid profiles in their patients
Devised a specially
formulated AA solution for IV
use that contained
decreased amounts of
phenylalanine, tyrosine,
tryptophan, methionine and
glycine and
survival in encephalopathic dogs
receiving this
formulation was appreciably
increased compared
with dogs receiving a standard IV
formulation
of AA
Based on
finding that
12. Plasma level of BCAA in Cirhhotic Pt
• The decrease in BCAA concentration, occurs in liver cirrhosis and UCD, is a
characteristic feature of hyperammonemia
• Pt with mild liver disease however show minor or no abnormalities in plasma
amino acid conscentrations
• In patients with diseases, serum concentrations of BCAAs are
decreased, while the concentrations of AAAs are increased, resulting in a low
ratio of BCAAs to AAAs, a ratio called the Fischer ratio.
Holecek et al. 2011
13. The BCAA/AAA (Fischer) ratio of plasma amino acids in 3 different groups of cirrhotics
Healthy
(3.9 +/- 0.3)
compensated
Decomp-
ensated
HE
(0.8 +/- 0.07)
(1.7 +/- 0.3)
(2.9 +/- 0.2)
14. Main role in the pathogenesis of
decreased BCAA levels in
hyperammonaemic states is increased
ammonia detoxification to Glutamine
in muscles.
15. • BCAAs act as the main donor of
amino nitrogen to α-KG to form
Glutamate (GLU)
• which is used for ammonia
detoxification to Glutamine(GLN) in
the Glutamine synthetase reaction
16. Aromatic amino acids (AAA; phenylalanine, tyrosine,
and tryptophan) and methionine increases due to
portosystemic shunts and reduced ability of diseased
liver to catabolise these AA
17. BCAA in HE
Elevated Ammonia is
main pathogenic factors
for the development of
HE.
18. • A low Fischer ratio has been associated with hepatic
encephalopathy. The imbalance of amino acids tends to become
more marked with the progression of liver diseases.
• Correcting this ratio may have therapeutic potential, not only
for nutritional improvement, but also for HE, in patients with
advanced liver diseases
19. 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
normalizing plasma amino acid concentrations
20. • Although there is a good theoretical basis for
recommending BCKAs for the treatment of patients with
liver disease, the number of reports is very small.
21.
22.
23. Effects of BCAA Supplementation on the Progression of Advanced Liver
Disease: A Korean Nationwide, Multicenter, Prospective, Observational, Cohort
Study
25. • 11 randomised trials (556 patients) assessing BCAA versus controls
were included
• The median amount of BCAA was 28 gram/day (range 11 to 57 gram)
and the median duration of treatment was seven days (range four to 90
days).
• The control therapies were glucose (one trial), isonitrogenous control
(four trials), neomycin or lactulose (five trials), or placebo (one)
BCAA had no significant
beneficial
effect on hepatic encephalopathy
when trials with adequate
generation
of the allocation sequence,
adequate allocation
concealment,
or adequate double-blinding were
analysed
27. • The trials included 827 participants with hepatic encephalopathy
• The type of hepatic encephalopathy was minimal in 4 trials and overt
in the remaining 11 trials
• The dose of BCAA ranged from 11 g/day to 57 g/day (median 20 g/day)
and treatment duration from one to 104 weeks (median four weeks).
28. • BCAA, and
BCAA had beneficial
effect
in trials on overt hepatic
encephalopathy, but not on
minimal hepatic
encephalopathy.
BCAA had a beneficial effect
on hepatic encephalopathy
when excluding trials with a
lactulose or neomycin
control group, but not in an
analysis limited to trials with
these
two type of controls.
29. • Skeletal muscle hyperammonemia in cirrhosis induces transcriptional up-
regulation of myostatin and increases autophagy.
is a TGFβ superfamily member that
inhibits protein
synthesis via impaired mTOR signaling
Since impaired mTOR signaling decreases protein synthesis as well as increased
autophagy, activation of mTOR is a potential approach to reverse impaired
muscle protein synthesis in cirrhosis
BCAA in Sarcopenia
30. • BCAAs, particularly Leucine, activate
the mTOR and subsequently
upregulates mRNA translation and
synthesis of albumin.
• Leu also stimulates the nuclear import
of polypyrimidine-tract (PBT) –binding
protein, which binds to albumin mRNA
and increases its translation
31. Exclusion criteria- were, overt hepatic encephalopathy, refractory ascites, reduced renal function
(defined as serum creatinine level >1.5 mg/dL), Child–Pugh score >12,
Marchesini G, Bianchi G, Merli M, et al. Nutritional sup-plementation with branched-chain amino acids in advancedcirrhosis: a double-blind, randomized trial.
Gastroenterology.2003;
32. • Clinical and blood biochemical data of 130 patients with LC who
underwent abdominal CT scan were analyzed in this retrospective study
• Cirrhotic patients who were treated with BCAA supplementation of 12
g/d for ≥ 1 y were defined as the BCAA group, and the effect of BCAA
on sarcopenic LC was evaluated.
• BCAA supplementation(12 g/d for ≥ 1 yr) was associated with better
survival in sarcopenic but
35. •
Since inflammatory
response blunts the
anabolic response after
BCAA administration
BCAA supplementation is more
effective in compensated
cirrhosis with decreased plasma
BCAA concentrations
and without symptoms of an
inflammatory response of
the body
Lang CH, Frost RA. muscle. J Cell Physiol 2005
39. • In total, 78 of 367 participants in the BCAA group versus 89 of 393
participants in the control group died.
• Random-effects meta-analysis showed no difference between the
groups (RR 0.88, 95% CI 0.69 to 1.11; 760 participants; 15 trials.
40. Oral Branched-Chain Amino Acids Have a Beneficial Effect on
Manifestations of Hepatic Encephalopathy in a Systematic Review with
Meta-Analyses of Randomized Controlled Trials
2013 American Society for Nutrition
• Asystematic review on the effects of oral BCAAs compared with
control supplements or placebo for patients with cirrhosis and recurrent
overt or minimal HE.
• The quantitative analyses included data from 8 trials (n = 382 pts).
• BCAA supplements had no effect on mortality or markers of nutritional
status.
41. Lactulose, rifaximin or branched chain amino acids
for hepatic encephalopathy: what is the evidence?
A meta-analysis of randomized trials
• The review has revealed that supplementation of oral BCAAs in
cirrhotic patients inhibits the manifestation of HE, especially in
patients with overt HE rather than those with minimal HE
but showed no effect on the survival of those patients.
42. Over 2 years 307 (166 in the BCAA group and 141 in the control group) were analyzed.
The BCAA group was divided into 3 subgroups, whose patients consumed
• 4.15 g
• 8.3 g
• 12.45g of BCAAs daily for the analysis
Medicine (2017) 96:24(e6580)
43. • The MELD and CTP score significantly improved in the BCCA-12.45g
group compared to the matched control group (P=.004)
• In the subgroup analysis of the entire BCAA group treated with BCAAs,
the CTP score did not improve in patients treated with < 12.45g of
BCAAs
44. Dose and Recomendation
• BCAA is recomended at dose of 0.25 g/kg/d in cirrhotic pt
(15gm in 60kg Pt) according to European Society for Clinical
Nutrition and Metabolism 2019
45.
46. BCAA supplements and leucine enriched amino acid supplements
should be considered in patients
. (Grade II-1,
C1)
47. • In cirrhotic patients who are protein “intolerant”, vegetable proteins or
BCAA (0.25 g/kg/d) should be used by oral route to facilitate adequate
protein intake.
Grade of recommendation B,Consensus (89% agreement)
49. BCAA is associated with Insulin resistance and Diabetes
• Circulating levels of BCAAs tend to be increased in individuals with
obesity and are associated with worse metabolic health and future insulin
resistance or T2DM.
• A hypothesized mechanism linking increased levels of BCAAs and
T2DM involves leucine-mediated activation of the mTORC1, which
leads to serine phosphorylation of IRS-1 and IRS-2(insulin
receptorsubstrate), which interferes with insuin signalling.
50.
51. • In clinical studies, increased
blood levels of BCAAs positively
correlate with insulin resistance
and levels of HbA1c
52. • Correlation between plasma
levels of leucine and fasting
levels of HbA1c in African–
American women with obesity
and T2DM (blue circles) and
those with obesity but noT2DM
(green circles)
55. BCAA and Cancer
• enzymes catalyzing the first step in BCAA degradation-
BCAT1 are overexpressed in many cancers.
• In 2013 Tonjes et al. reported overexpression of BCAT1 in
gliomas
56.
57.
58. • BCAAs were increased in patients with breast cancer
(compared with healthy controls), in both peripheral blood
serum and cancer tissue, and BCAT1 was also overexpressed.
• From a therapeutic standpoint, knockdown of BCAT1 in a
mouse model of CML improved survival
Hattori A, Tsunoda M, Konuma T, et al. Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia. Nature 2017; 545:500–504.
59. Why BCAA
supplementation is
required in cirrhosis
Is plasma level is decreased
For correction of Sacrcopenia
For Treatment of Hepatic
Encephalopathy
Progression free survival or
improvement in quality of life
?
yes, but in other
hyperammonemic
conditions also
No benefit
Only in decompensated
cirrhosis without
features of SIRS
conflicting results, that too
in overt HE and no benefit
when compared to
Lactulose/Neomycin
Added risks of
many adverse
effects
