Clinical and Therapeutic Implications of BCAAs Metabolism during Chronic Liver Disease in Humans: Crosstalk between Skeletal Muscle and Liver
Abstract
:1. Introduction
2. Metabolism of BCAAs: Interplay between Skeletal Muscle and Liver
2.1. BCAAs Transamination
2.2. BCAAs Oxidation
3. Clinical Insights into CLD: Role of BCAAs in Musculoskeletal Health
3.1. BCAAs Concentration in Patients with CLD
3.2. Correlation of Muscle Health and BCAAs in Patients with CLD
3.3. Interplay of BCAAs, mTOR Signaling, Ammonia, and Mitochondrial Dysfunction in the Skeletal Muscle during CLD
4. Interventions with BCAAs Supplementation in Patients with CLD: Implications for the Skeletal Muscle
4.1. Effects of BCAAs on Skeletal Muscle Mass and Skeletal Muscle Strength
Reference | Type of Study | Intervention | Treatment Composition | Inclusion Criteria | Sample Size | Treatment Duration | Findings |
---|---|---|---|---|---|---|---|
[35] | Open-label prospective study. | Oral supplementation with BCAAs (4.5 g/day) as a late evening snack, compared to a combination of BCAAs supplementation with unsupervised walking exercise, or unsupervised walking exercise alone. | BCAAs 4.5 g, containing: Leu 3 g Ile 0.75 g Val 0.75 g | CLD with CP score A or B | 127 patients: BCAAs group, n = 42 Walking exercise, n = 43 Walking exercise plus BCAAs, n = 42 | 3 months. | -Walking exercise plus BCAAs significantly increased grip strength and SMI, reducing sarcopenia prevalence. -Albumin significantly increased in all groups. |
[68] | RCT. | Oral supplementation with BCAAs (10.85 g/day) against regular diet. | BCAAs 5.425 g, containing: Leu 2.03 g Ile 1.76 g Val 1.635 g | CLD in frail patients with CP score A or B | 54 patients (27 in the BCAAs group). | 4 months. | -Increased SMI in the intervention group. -Improvement in all 4 domains of the physical component score of the SF-36 questionnaire in the BCAAs group. -Improvement in the LFI, BMI and serum albumin compared to controls. |
[69] | RCT. | Oral supplementation with BCAAs (12 g/day) against placebo, in adition to a home-based exercise program (30 min/day), dietary counselling and standard medical therapy. | CLD with CP score A or B and sarcopenia | 60 patients (30 in the BCAAs group). | 6 months. | No changes in muscle mass with the addition of BCAAs to exercise, dietary counselling and standard medical therapy. | |
[66] | RCT. | Oral supplementation with BCAAs (7.2 g/dose) against lactoalbumin (6.3 g/dose). | BCAAs 8.1 g, containing: Leu 1.2 g Ile 0.6 g Val 0.6 g | CLD, with portal hypertension and sarcopenia | 138 patients (69 in the BCAAs group) | 6 months. | -Improvement of the hand grip strength. -Improvement of the gait speed score from before treatment with BCAAs to after treatment. -Increased in the TAMA, TSF, and MAMC. -Lower progression of HE. |
[70] | RCT. | Oral supplementation with BCAAs (5.24 g/day) and physical activity against nutritional and physical activity intervention. | Each 100-g sachet contained: Leu 2.61 g Ile 1.01 g Val 1.62 g | CLD and sarcopenia | 32 patients (15 in the BCAAs group) | 3 months. | -Improvement in muscle mass and serum albumin levels compared to controls. -Improvement in the LFI in the global cohort. |
[36] | Cohort study. | Oral supplementation with BCAAs (4 g/dose) three times daily. | BCAAs 4 g, containing: Leu 1.9 g Ile 0.9 g Val 1.14 g | CLD with serum albumin levels of ≤3.5 g/dL | 21 patients. | 12 months. | -Decreased IMAC in patients with ameliorated hypoalbuminemia associated with BCAAs supplementation. -Higher liver-related event-free survival rates in patients with decreased IMAC. |
[65] | RCT. | Oral supplementation with BCAAs (110 g/day) against high-fiber and high-protein diet. | BCAAs 110 g, containing: Leu 3.38 g Ile 2.75 g Val 2.5 g | CLD and CP score A or B | 72 patients (73 in the BCAAs group) | 6 months. | -Increased muscle mass and decreased fat mass compared to control. -No differences in ammonia and glucose levels. -No significant changes in the Psychometric HE Score or the Critical Flicker–Frequency score results. |
[37] | RCT. | Single oral BCAAs mixture (15 g) enriched with Leu, and a primed constant (0.05 µmol.kg−1.min−1) infusion of L-[ring-2H5]-phenylalanine. | BCAAs 15 g, containing: Leu 7.5 g Ile 3.75 Val 3.75 g | CLD due to ALD, with CP score A, and alcohol abstinence for at least 6 months | 6 patients. 8 controls. | 7 h. | -BCAAs/Leu acutely reversed impaired mTOR1 signaling and increased autophagy in skeletal muscle of cirrhotic ALD patients. -Plasma BCAAs increased similarly in cirrhotic patients and controls after oral intake. -Muscle synthesis rate was slightly higher in controls. -BCAAs/Leu supplementation reduced elevated protein breakdown in cirrhosis patients. |
[67] | RCT. | Oral supplementation with BCAAs (30 g) or maltodextrin twice a day. | BCAAs 30 g, containing: Leu 13.5 g Ile 9 g Val 7.5 g | CLD and a previous episode of HE | 116 patients (58 in the BCAAs group). | 14 months. | -Increased MAMC in the BCAAs group. -No difference in the risk of remaining free of HE among groups. |
4.2. Role of BCAAs in Frailty and Nutritional Status
4.3. Role of BCAAs on Skeletal Muscle Protein Metabolism
4.4. Combining BCAAs with Exercise
5. Clinical Perspectives
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ALD | alcohol-associated liver disease. |
BCAAs | Branched-chain Amino Acids. |
BCAT | branched-chain aminotransferase. |
BCKAs | branched-chain α-ketoacids. |
BCKDH | branched-chain α-keto acid dehydrogenase. |
CFS | Clinical Frailty Scale. |
CLD | Chronic Liver Disease. |
HBV | hepatitis B virus. |
HBV | hepatitis C virus. |
HCC | hepatocellular carcinoma. |
HPLC | high-performance liquid chromatography. |
Ile | isoleucine. |
IMAC | intramuscular adipose tissue content. |
Leu | leucine. |
LFI | liver frailty index. |
MAMC | mid-arm muscle circumference. |
MASLD | Metabolic Dysfunction-Associated Steatotic Liver Disease. |
MELD | Model for End-Stage Liver Disease. |
mTOR | mammalian target of rapamycin. |
NMR | Proton (1H) nuclear magnetic resonance. |
PT | prothrombin time. |
RCT | randomized controlled trial. |
SMI | skeletal muscle mass index. |
TAMA | total abdominal muscle area. |
TCA | citric acid cycle. |
TSF | triceps skinfold. |
Val | valine. |
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Reference | Type of Study | Population | Etiology | BCAAs Analysis | Liver Function | Skeletal Muscle Function |
---|---|---|---|---|---|---|
[32] | Comparative study | 14 adults with CLD (12 males, 2 females) and 9 healthy controls. | 11-ALD 3-cryptogenetic | Spectrophotometry ↑ BCAAs (μM/kg) controls: Leu 132, Val 215, T. BCAAs 423. ↓ BCAAs (μM/kg) patients: Leu 84, Val 54, T. BCAAs 278. | Patients profile: -Albumin (gm/L): 28.6 ± 5.1 -PT (%): 67 ± 14 -Ammonia (µg/dL): 125 ± 50 -Ascites: 7 patients -Malnutrition: 7 patients | Intracellular muscle Val: Patients: 222 μM/kg (↓) Control: 368 μM/kg. |
[33] | Cohort design | 14 patients with CLD (13 males, 1 female) and 7 healthy subjects (5 males, 2 females). | Non specify | HPLC with fluorescence detection. ↑ BCAAs (μM/kg) controls: Leu 132, Val 215, T. BCAAs 423. ↓ BCAAs (μM/kg) patients: Leu 84, Val 54, T. BCAAs 278. | Patients profile: -Albumin (μmol/L): 520 ± 21 -Total bilirubin (μmol/L): 21.8 ± 3.2-PT index: 0.58 ± 0.03 -CP score: A: 6; B: 8; C: 0 patients. Healthy profile: -Albumin (μmol/L): 639 ± 27 -Total bilirubin (μmol/L): 7.14 ± 1.1 -PT index: 0.94 ± 0.05 | Uptake of BCAAs across muscle leg (femoral artery): Control: 196 ± 67 μmol/min Patients: −84.7 ± 110 μmol/min). |
[34] | Cohort design, retrospective | 13 patients with CLD and 6 patients with an episode of alcoholic hepatitis (16 males, 4 females) and 6 healthy controls (2 females, 5 males) | 6-ALD 13-Other | ↑ BCAAs (μmol/L) controls: Leu 244 ± 19, Val 256 ± 19, T. BCAAs 646 ± 44. ↓ BCAAs (μmol/L) patients: Leu 185 ± 18, Val 201 ± 15, T. BCAAs 535 ± 42. | ALD patients profile: -Albumin (μmol/L): 469 ± 42 -Total bilirubin (μmol/L): 380 ± 42 -PT index: 0.24 ± 0.04 -CP score: A: 0; B: 2; C: 4 patients. CLD patients profile: -Albumin (μmol/L): 520 ± 21 -Total bilirubin (μmol/L): 21.8 ± 3 -PT index: 0.58 ± 0.03 -CP score: A: 6; B: 7; C: 0 patients | Leg muscle BCAAs uptake: Patients with alcoholic hepatitis: Total BCAAs 0.48 ± 23 μmol/L Stable cirrhosis: Total BCAAs 32 ± 22 μmol/L Controls: Total BCAAs −11.9 ± 22 μmol/L |
[35] | Prospective control trial | 127 patients with CLD (81 males, 43 females) | 68-HBV 23-ALD 26-MASLD 7-Other | Colorimetric method Average of BCAAs 453.73 +/− 40.17 (μmol/L) | Patients profile: -Albumin (g/dL): 32.48 ± 4.53 -Total bilirubin (μmol/L): 36.65 ± 13.16 (μmol/L) -PT (%) 62.48 ± 10.45 -CP score: A: 71; B: 53 patients. | Patients had decreased handgrip strength (kg): 25.47 ± 5.84 and SMI (cm2/m2): 49.61 ± 8.84. 37 patients with sarcopenia. |
[36] | Case control | 21 patients with CLD (9 males, 12 females) | 18-HCV 2-HBV 1-ALD | Patients with Albumin improvement (11): ↓ Total BCAAs 377.4 ± 102.2 μmol/L Patients with no Albumin improvement (10): ↑ Total BCAAs 413.4 ± 89.2 μmol/L. | Patients profile: -Albumin (g/dL): 3.2 ± 0.4 -Total bilirubin (mg/dL): 1.2 ± 0.5 -Ammonia (μg/dL) 57.7 ± 30.1 -CP score: A: 10; B: 11; C: 12 patients. | SMI area: 12.4 ± 2.7 cm2/m2. IMAC: −0.11 ± 0.16. |
[37] | Control trial | 8 healthy controls (4 males, 4 females). 6 patients with CLD (5 males, 1 female). | ALD cirrhosis | Ion exchange chromatography ↑ BCAAs (μmol/L) controls: Leu 119.13 ± 9.35, Ile 77.02 ± 5.78, Val 245.70 ± 18.69. ↓ BCAAs (μmol/L) patients: Leu 81.33 ± 7.75, Ile 55.15 ± 4.12, Val 166.99 ± 12.44. | Patients profile: -Albumin (μmol/L): 4.20 ± 0.12 -CP score: 5.17 ± 0.15 -MELD score: 6.21 ± 0.23 -Ammonia (μg/dL) 98.24 ± 6.75 | Patients muscle tissue: -Lower activation of mTOR-related proteins (p70S6K, S6, 4EBP1) -↑ Intracellular amino acid sensor (GCN2) and myostatin protein. |
[38] | Cross-sectional, single-center analysis. | 92 patients with CLD (60 males, 32 females). | 7-Viral hepatitis 24-Autoimmune 28-MASLD 20-ALD 2-Storage disorder 3-Malignancy 8-Other | NMR spectroscopy platform Control group: ↑ T. BCAAs (μmol/L): -Men: 412.7 -Women: 339.7 Patients group: ↓ T. BCAAs (μmol/L): -Men: 307.0 -Women: 213.5 | Patients profile: -Albumin (g/L): 32.7 ± 6.5 -Total bilirubin (µmol/L): 41 -Ammonia (µmol/L) 68.8 ± 33.4 -MELD score 15 ± 6. | -Lowest BCAAs tertile had higher CP scores (7 ± 2) -The 4 m walking test, standing balance test and CFS were not significantly different between BCAAs tertiles -Inverse correlations of the Timed up and go performance test with total BCAAs, Val and Ile. -Total BCAAs, Val and Leu were inversely related in the sit-to-stand test |
[39] | Comparative study | 8 healthy subjects (6 males, 2 females) and 8 patients with CLD (4 males, 4 females) | 6-HCV 1-HBV 1-Other | Patients group: Fischer’s ratio 0.68–2.31 | Patients profile: -Albumin (g/dL): 2.8–3.4 -Total bilirubin (mg/dL): 0.6–2.1 -Ammonia (µg/dL): 46–122 -PT (%): 58–77 | After exercise loading intramuscular ⊿pH: -Controls 0.20 ± 0.18 -Patients 0.49 ± 0.16 Creatine phosphate: -Controls 0.35 ± 0.19 -Patients 0.55 ± 0.12 |
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Trillos-Almanza, M.C.; Martinez-Aguilar, M.; Arroyave-Ospina, J.C.; van Vilsteren, F.; Blokzijl, H.; Moshage, H. Clinical and Therapeutic Implications of BCAAs Metabolism during Chronic Liver Disease in Humans: Crosstalk between Skeletal Muscle and Liver. Muscles 2024, 3, 71-87. https://doi.org/10.3390/muscles3010008
Trillos-Almanza MC, Martinez-Aguilar M, Arroyave-Ospina JC, van Vilsteren F, Blokzijl H, Moshage H. Clinical and Therapeutic Implications of BCAAs Metabolism during Chronic Liver Disease in Humans: Crosstalk between Skeletal Muscle and Liver. Muscles. 2024; 3(1):71-87. https://doi.org/10.3390/muscles3010008
Chicago/Turabian StyleTrillos-Almanza, Maria Camila, Magnolia Martinez-Aguilar, Johanna C. Arroyave-Ospina, Frederike van Vilsteren, Hans Blokzijl, and Han Moshage. 2024. "Clinical and Therapeutic Implications of BCAAs Metabolism during Chronic Liver Disease in Humans: Crosstalk between Skeletal Muscle and Liver" Muscles 3, no. 1: 71-87. https://doi.org/10.3390/muscles3010008