1. Protein-Energy Malnutrition
The optimum BCAA for pharmaco-nutritional solution…”
Protein-Energy Malnutrition

2. Malnutrition in Liver Cirrhosis
Occurs in 50-90% of patients with liver cirrhosis
Commonly undiagnosed due to liver disease complications such as edema and ascites
Independent risk factor for predicting clinical outcomes
ES, et al. Middle east Journal of Digestive Diseases Vol 5 No 2, April 2013

3. Malnutrition in Liver Cirrhosis
Associated with an increased risk of morbidity/mortality, biochemical dysfunction, compromised immune and respiratory functions, decreased muscle mass, increased recovery time and delayed wound healing
Higher rates of refractory ascites, SBP, HRS, variceal hemorrhage and post-transplant mortality in patients with PCM
ES, et al. Middle east Journal of Digestive Diseases Vol 5 No 2, April 2013

4. Cause of PEM in cirrhosis is multifactorial
Poor oral intake
(anorexia, GI symptoms, zinc deficiency)
Increased resting energy expenditure (REE) “hypermetabolic state”
Malnutrition is present in 80% of cirrhotics
Malabsorption of fats
(inadequate bile production)
Poor liver synthetic capacity
The pathogenesis of malnutrition in liver cirrhosis is not fully understood but poor dietary intake[8,18], increased energy expenditure[11,19-21], malabsorption[8,22] and poor synthetic capacity of the cirrhotic liver may be involved.
Kalaitzakis, et al. World J Gastro 2014

5. Pathogenesis of Protein Calorie Malnutrition (PCM) in Liver Disease
Multifactorial
Changes that are known to affect nutrition status include
1. Decreased intake
2. Metabolic alterations
3. Increased B-adrenergic activity
4. Malabsorption of fats due to inadequate production of bile
ES, et al. Middle east Journal of Digestive Diseases Vol 5 No 2, April 2013

6. Decreased intake
Anorexia secondary to changes in the liver’s control of appetite
GI symptoms such as early satiety, nausea, vomiting, diarrhea, constipation, indigestion, abdominal pain/distention, ascites and reflux
Zinc deficieny that leads to anorexia and dysgeusia or taste or smell changes or both
ES, et al. Middle east Journal of Digestive Diseases Vol 5 No 2, April 2013

7. Metabolic changes
Early occurrence of ‘fasting state’ which uses glycerol and amino acids and other non-carbohydrate sources for the synthesis of glucose
Constant breakdown of fat and muscle
Insulin resistance
ES, et al. Middle east Journal of Digestive Diseases Vol 5 No 2, April 2013

8. Increased B-adrenergic activity
“Hypermetabolism” attributed to increased B-adrenergic activity by 25% which leads to muscle breakdown
Increased plasma catecholamines and activation of sympathetic nervous system (SNS) in cirrhosis
ES, et al. Middle east Journal of Digestive Diseases Vol 5 No 2, April 2013

9. Metabolic Alterations in Cirrhosis result in Protein Depletion
Impaired hepatic glycogen synthesis & storage
Response to fasting similar to STARVED individuals for 2-3 days
Early & excessive lipolysis
Switch from glycogenolysis to gluconeogenesis
ESPEN/AASLD = kcal/kg/d
Proteolysis to support splanchnic glucose
The final result of the metabolic alterations present in patients with cirrhosis is the depletion of protein stores in the body, also termed sarcopenia. This slide will show you the underlying processes that occur and contribute to this final outcome.
In cirrhosis, because of the decrease in hepatic synthetic function, glycogen synthesis and storage in the liver is impaired. The response of cirrhotic patients to an Overnight fast result in a cascade of metabolic processes that is equivalent to the response of normal individuals to 2-3 days fasting.
Excessive lipolysis occurs early and there is a switch from glycogenolysis, which is an energy producing process, to gluconeogenesis, which is a energy requiring process. This is why cirrhotic patients have increased resting energy expenditure and is also the reason why both the European and American guidelines recommend that cirrhotic patients should be provided with kcal/kg/day.
The resulting catabolic processes however is not enough to provide enough splanchnic glucose to the patient and proteolysis now ensues in order to provide enough energy. There is therefore loss of amino acids in the body and an increase in protein requirements. This is why it is recommended that protein intake should be maintained at g/kg/d
ESPEN/AASLD
G Protein/kg/d
Loss of amino acids
Increase in protein requirements & ammonia production
AASLD guidelines on nutrition in HE: Hepatology 2013
ESPEN guidelines on nutrition in Liver disease: Nutrition 2006

10. Oxidation Ratio of Energy Substrates
100%
32.0
***
58.3
Carbohydrates
50%
49.5
***
25.7
Fats
To prove that patients are in hypermetabolic state and that oxidation of fats is higher to patients with cirrhosis, here is a clinical study from Moriwaki showing the oxidation ratio of energy substrates.
In healthy subjects, approximately 16% of oxidation energy is generated from proteins, approximately a little less than 60% from carbohydrates (glucose) and approximately 25% from fats as sources.
However, in liver cirrhosis, the oxidation ratio of carbohydrates as an energy source is decreased since the efficiency of glucose utilization is deteriorated due to glucose intolerance.
13.5
16.0
Proteins
Liver Cirrhosis
(n=98)
Healthy Subjects
(n=20)
*** : p<0.001 Student’s t-test
Moriwaki,H et al.: Gastroenterology, 26 (5): , 1988

11. Energy Metabolism of Cirrhotics
REE/BMR
npRQ
* *
* * *
1.3
1.0
1.2
0.9
1.1
0.8
1.0
0.7 :
p<0.001
*** :
p<0.01 **
Since patients consume mostly on fats, npRQ is affected and decreased in patients with cirrhosis. Another problem in energy metabolism among patients with liver cirrhosis is an insufficient utilization of carbohydrates or glucose as an energy source due to insulin insensitivity, while they need more energy.
As you can see in the right graph, npRQ in patients with liver cirrhosis is lower than 0.85, compared to that in healthy subject, which is higher than 0.85.
When npQR becomes less than 0.85, it means that fats are more predominantly utilized as an energy source than carbohydrates.
Liver
Healthy
Liver
Healthy
Cirrhosis
Subjects
Cirrhosis
Subjects
(n=98)
(n=20)
(n=98)
(n=20)
REE: Resting Energy Expenditure
Student’s t-test
npRQ: Non-protein Respiratory Quotient
BMR: Basal Metabolic Rate
Moriwaki,H et al.: Gastroenterology, 26 (5): , 1988

12. Correlation Between Protein Intake and Nitrogen Balance
Normal
Cirrhosis
Cirrhosis + HCC 6
Normal 4
Cirrhosis 2
Nitrogen Balance (g/day)
Amount of Protein needed to
maintain Nitrogen Balance
Normal
Cirrhosis
Cirrhosis + HCC ：
1.0
g/kg/day
1.3g/kg/day
1.5g/kg/day - 2
Another aspect in protein malnutrition among patients with liver cirrhosis is that they need more protein intake in order to achieve positive nitrogen balance, as shown in this slide. While normal individuals only need 1g of protein/kg/day to maintain positive nitrogen balance, patients with liver cirrhosis need more than 1.3g of protein/kg/day or 80g of protein/day based on an average body weight of 60 kg. - 4
Cirrhosis + HCC - 6
0.5
1.0
1.5
2.0
2.5
Amount of Protein Intake (g/kg/day)
Okita, K.: Nutrition-Assessment & Treatment, 8 (3), , 1991

13. Liver disease and BCAA
Higher levels of aromatic amino acids (AAA) and lower branched chain amino acids (BCAA) (reversal of Fischer’s ratio)
Supplementation of BCAA has been used to normalize this ratio
ASPEN recommends the use of BCAA for HE, improvement of muscle cramps, immune function and inhibition of hepatocarcinogenesis.

14. Fischer’s ratio in Chronic liver disease
Fischer’s Ratio is the ratio of BCAA over AAA
Fischer’s Ratio
1.0
2.0
3.0
4.0
Normal (20)
Liver Cirrhosis (20)
Liver cirrhosis is a typical disease showing Fischer’s ratio below 1.8.
Fischer’s ratio is the molar ratio of BCAA’s over AAAs.
The decrease in Fischer’s ratio among patients with liver cirrhosis is due to two reasons and these are …….
Hepatocellular Carcinoma (10)
Liver Cirrhosis with HCC (30)
Inoue, Y. et. al. J. Iwate Med. Assoc., 40 (3), 351, 1988

15. Cumulative Survival Rates (%)
Plasma Fischer’s ratio (BCAA/AAA) Determines Survival Rate in Cirrhotics
100
1.8≦FR
Cumulative Survival Rates (%) 50
1.0≦FR＜1.8
This data shows that Fischer’s ratio really can determine the prognosis of patients with liver cirrhosis. With those data I have shown, I hope that it is now clear to you the importance of improving Fischer’s ratio in patients with liver cirrhosis by supplying them with BCAAs. The question now is whether Fishcer’s ratio in patients with liver cirrhosis be improved through diet alone?
FR＜1.0 1 2 3 4 5
years
(Poverall<0.05 by the log rank test)
Yoshida, T. et.al. Gastroenterologica Japonica, Vol 24, No. 6, 1989

16. Effects of BCAA on Survival Rate in Decompensated Liver Cirrhosis
59.4
10.3
2.8
0.4
Control
59.2
10.7
2.9
Age
Albumin (g/ dL )
Liver Cirrhosis
100
BCAA (45 cases)
Control
(39 cases)
Survival rate (%) 50
The patients who were given BCAA’s had a better prognosis as seen in this study. By taking high amount of protein of 80 g/day in the combination of low protein diet and 3 sachets of Aminoleban EN per day, we can expect an improvement in the protein nutritional condition of these patients as evidenced by an increase in the serum albumin level, without precipitating hepatic encephalopathy. With this nutritional management, prognosis of patients with liver cirrhosis can be improved.
P<0.05
Years 1 2 3 4 5
Matsuzaki, S. et. al., Hepatology. Vol.38 (5), 809,1999

17. Nutritional supplementation with BCAAs in advanced cirrhosis: a double-blind randomized trial
METHODS:
A multicenter, randomized study comparing 1-year nutritional supplementation with BCAA against lactoalbumin or maltodextrins was performed in 174 patients with advanced cirrhosis.
Primary outcomes were the prevention of a combined end point (death and deterioration to exclusion criteria), the need for hospital admission, and the duration of hospital stay.
Secondary outcomes were nutritional parameters, laboratory data and Child-Pugh score, anorexia, health-related quality of life, and need for therapy.
Giulio Marchesini et al. Gastroenterology 2003;124;

18. Nutritional supplementation with BCAAs in advanced cirrhosis: a double-blind randomized trial
RESULTS:
Treatment with BCAA significantly reduced the combined event rates compared with lactoalbumin (odds ratio, 0.43; 95% confidence interval, ; P = 0.039) and nonsignificantly compared with maltodextrins (odds ratio, 0.51; 95% confidence interval, ; P = 0.108).
The average hospital admission rate was lower in the BCAA arm compared with control treatments (P = and P = 0.003, respectively). In patients who remained in the study, nutritional parameters and liver function tests were, on average, stable or improved during treatment with BCAA and the Child-Pugh score decreased (P = 0.013). Also, anorexia and health-related quality of life (SF-36 questionnaire) improved. Long-term compliance with BCAA was poor.
Giulio Marchesini et al. Gastroenterology 2003;124;

19. Nutritional supplementation with BCAAs in advanced cirrhosis: a double-blind randomized trial
CONCLUSIONS:
In advanced cirrhosis, long-term nutritional supplementation with oral BCAA is useful to prevent progressive hepatic failure and to improve surrogate markers and perceived health status.
New formulas are needed to increase compliance.
Giulio Marchesini et al. Gastroenterology 2003;124;

20. Cumulative event-free rate of Aminoleban
1.0
0.9
BCAA
0.8
Cumulative Event-free Rates
M-DXT; P = 0.108
0.7
BCAA、L-ALB又はM-DXTを服用した肝硬変患者におけるイベントフリー率のKaplan-Meier分析です。全原因による死亡及び除外基準に至る悪化をイベントと見なしています。肝細胞癌を発症した患者４名は診断時に試験から除外されています。
BCAA群のイベント発生率はL-ALB群に比べ有意に低かったが
（P = 0.039）、M-DXT群との差は統計学的に有意なレベルに達しなかった（P = 1.108）
＜参考＞
試験期間中、BCAA群の入院頻度は対照群より低かった（BCAA群15名、L-ALB群27名、M-DXT群28名；P = 0.021）。
入院回数はBCAA群及びL-ALB群で０～３回、M-DXT群で０～６回であった。
延べ入院回数はBCAA群で20回、L-ALB群で35回、M-DXT群で56回であった（P = 0.026、Kruskal-Wallisの検定）。
平均入院率はBCAA群で0.60.2患者/年、L-ALB群で2.10.5、M-DXT群で1.90.4であった(vs. BCAA、それぞれP = 0.006と0.003)。
入院率を試験前の12カ月間に記録された値と比べると、BCAA群で減少したが有意ではなく（-0.2患者/年；P = 0.286、対応のあるt検定）、対照２群では増加した（L-ALB、+1.2；P = 0.023；M-DXT、+0.8；P = 0.047）。
試験期間中、在院期間はBCAA群で０～24日間、L-ALB群で０～31日間、M-DXT群で０～77日間であった。しかし入院が必要であった患者では、入院率及び平均在院期間について３群間に差は認められなかった。
0.6
L-ALB; P = 0.038
0.5 3 6 9 12 15
Months
Giulio Marchesini et al. Gastroenterology 2003;124;

21. Take Home Messages
Malnutrition is very common among patients with liver cirrhosis and is commonly undiagnosed.
Malnutrition is an independent risk factor for predicting clinical outcomes.
Addition of a carbohydrate and protein-rich evening snack with use of BCAA may help nitrogen balance and improve survival.
Longterm use of BCAA may improve survival and prevent decompensation among cirrhotic patients.

22. Objectives of dietary intervention in decompensated liver cirrhosis
1. Support residual liver function
2. Provide supportive treatment for ascites and liver failure
3. Promote liver regeneration and healing
4. Prevent fat stasis and fatty stools
5. Correct nutritional deficiencies
6. Prevent or correct protein intolerance, by supplementing with BCAA preparation
7. Provide adequate glucose for brain metabolism

23. Nutritional intervention in patients with cirrhosis
ASPEN and ESPEN Recommendations: kcal/kg/day based on dry weight; g/kg protein to prevent muscle catabolism
Patients with acute episodes of HE: g/kg/day until cause of HE is determined and eliminated
Advised to consume small frequent meals throughout the day
Addition of a carbohydrate and protein-rich evening snack (LES) may help nitrogen balance

24. ESPEN 2006 Guidelines on Enteral Nutrition : Liver Cirrhosis
Subject
Recommendations
Grade
General
Use simple bedsisde methods such as the Subjective Global Assessment (SGA) or anthropometry to identify at risk of nutrition.
Use phase angle or Body cell mass measured by bioelectric impedance analysis to quantitate undernutrition, despite some limitations in patients with ascites.
Recommended energy intake: kcal/kgBW/day ( kJ/kgBW/day)
Recommended protein intake: g/kgBW/day C B
Application
Use supplemental EN when patients cannot meet their caloric requirements through oral food despite individualized nutritional advise. A
Aside from the recommendation of kcal/kg/d and g protein/kg/d,
The European guidelines recommend BCA

25. ESPEN 2006 Guidelines on Enteral Nutrition : Liver Cirrhosis
Subject
Recommendations
Grade
Route
If patients are not able to maintain adequate oral intake from normal food, use
Oral nutritional supplements or
Tube feeding (even in the presence of esophageal varices)
PEG placement is not recommended since it is associated with a higher risk of complications C A
Type of Formula
Generally recommended: Whole protein formula
Patients with ascites: consider more concentrated high-energy formula
Patients with hepatic encephalopathy arising during EN: use BCAA-enriched formula
BCAA can improve clinical outcomes in advanced cirrhosis B
Aside from the recommendation of kcal/kg/d and g protein/kg/d,
The European guidelines recommend BCA

26. PRODUCT DIFFERENTIATION

28. THANK YOU!