Sarcopenia (age-related muscle loss) represents an important burden in patients with cirrhosis (scarring of the liver caused by long-term liver damage) as it is associated with a high risk of morbidity and mortality.
Beta-hydroxy-beta-methylbutyrate (HMB) is a metabolite derived from leucine and its ketoacid alpha-ketoisocaproate (α-KIC) which has been shown to influence muscle protein turnover by stimulating protein synthesis and decreasing proteolysis.
The combination of its anabolic and anti-proteolytic properties makes HMB a potentially effective supplement for the treatment of sarcopenia in cirrhotic patients, according to the current study's authors. However, there are currently no data on the use of HMB in patients with chronic liver disease.
In a recent pilot study, the authors of the current study randomised patients after liver transplantation for supplementation with HMB (3 g/day) or placebo for 12 weeks. They observed a significant increase in appendicular lean mass and in the hand-grip strength in patients receiving supplementation, suggesting that HMB could improve the recovery of skeletal muscle in liver transplant patients.
The present monocentric, randomised pilot trial aimed to evaluate the effect of 12-week HMB supplementation vs. placebo on muscle mass and performance in a group of patients with liver cirrhosis.
Secondary endpoints were the assessment of the tolerance and safety of HMB in cirrhotic patients, changes in frailty, and changes in liver function or cognitive performance during treatment.
Twenty four outpatients (aged under 70) were recruited from the University Hospital Policlinico Umberto I, in Rome, and randomly assigned to the treatment group (HMB 3 g/day) or the placebo group (sorbitol 3 g/day) for 12 weeks (14 in the HMB group and 10 in the placebo group). Demographic data as well as weight, height and BMI were recorded.
The supplement or placebo was given to the patients as a white powder in sachets, with directions for it to be taken twice a day. All patients were given counseling for nutritional intake and moderate physical activity.
At enrolment, all patients underwent a complete physical performance battery - six-minute walk test, hand-grip test, and chair stands test, an assessment of the Liver Frailty Index (LFI), and cognitive tests.
For the evaluation of muscle mass, the patients underwent bioelectric impedance analysis (BIA) to measure the fat mass index, fat-free mass index, and phase angle. Ultrasound was also performed to measure the thickness of the quadriceps femoris muscle.
After 12 weeks (T1), the patients returned to the outpatients’ clinic to repeat measurements and tests. Subsequently, the study continued with a further observation period of 12 weeks (T2) after treatment discontinuation.
The resulting data suggest that HMB supplementation increased the muscle performance of cirrhotic patients compared to that of the placebo group.
Lean body mass as measured by BIA was not modified, but quadriceps thickness, measured using ultrasonography, improved (4.9 ± 1.8 vs. 5.4 ± 1.8 mm).
LFI was also ameliorated in the HMB group but not in the control group (4.1 ± 0.4 vs. 3.7 ± 0.4, p < 0.05). However, this improvement should be considered with caution, as the patients in the HMB group had a worse LFI at enrolment.
Patients receiving HMB supplementation achieved a significant improvement in muscle performance. Both the distance walked by patients in the six-minute walk test (6MWT: 361.8 ± 68 m vs. 409.4 ± 58 m) and the time required to get up five times from the chair (CST: 14.2 ± 5 s vs. 11.7 ± 2.6) were significantly improved vs. baseline.
The authors conclude that "adequate dietary intake and physical activity counseling alongside HMB supplementation for 12 weeks may improve muscle function in compensated cirrhotic patients. These positive results persisted for six months after discontinuation. Moreover, HMB supplementation is safe and well tolerated in compensated cirrhotic patients."
The authors note some limitations of this study include the small sample size and the under-representation of females (36% of patients).
Mechanism of action
Multiple pathways have been identified in which HMB plays a role in modulating skeletal muscle mass.
The first mechanism is the proliferation of myoblasts through the activation of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, which increases the proliferation, differentiation, and survival of myoblasts, resulting in a reduction in muscle atrophy and improvements in muscle strength.
The role of HMB in suppressing proteolysis has also been demonstrated through the inhibition of the ubiquitin–proteasome pathway in models of neoplastic cachexia as well as through the effect of attenuation of muscle atrophy secondary to steroid therapy.
Another pathway in which HMB plays a role is regulated by the enzyme mTOR, a stimulator of protein synthesis. Other effects of HMB that could potentially affect muscle growth and performance include the expression of the proliferation marker MyoD and the muscle differentiation markers MRFs, as well as the stimulation of myogenic cell proliferation via the MAPK/ERK and PI3K/Akt pathways.
In a recent systematic review, HMB was reported to improve lean muscle mass and function in older people with sarcopenia or frailty.
Lattanzi. B., Bruni. A., Di Cola. S., Molfino. A., De Santis. A., Muscaritoli. M., and Merli. M.