HMB Enriched Amino Acids to Reverse Muscle Loss in Cirrhosis

  • STATUS
    Recruiting
  • End date
    Dec 30, 2025
  • participants needed
    24
  • sponsor
    The Cleveland Clinic
Updated on 31 December 2021
insulin
amino acids
leucine

Summary

Loss of skeletal muscle mass or sarcopenia is the most common and potentially reversible complication in cirrhosis that increases morbidity and mortality before, during and after liver transplantation. No proven treatments exist for the prevention or reversal of sarcopenia in cirrhosis, primarily because the mechanisms responsible for this are unknown. Based on compelling preliminary studies and those of the co investigator, investigators hypothesize that the mechanism of reduced skeletal muscle mass in cirrhosis is due to a myostatin mediated impaired mTOR (mechanistic target of rapamycin) signaling resulting in reduced protein synthesis and increased autophagy. Investigators further postulate that leucine, a direct stimulant of mTOR, will reverse the impaired mTOR phosphorylation in the skeletal muscle of cirrhotics. The consequent increase in protein synthesis reduced autophagy will result in an increase in skeletal muscle mass. Investigators will test these hypotheses by quantifying the response to acute and long term (3 month) administration of hydroxymethyl butyrate (HMB) enriched essential amino acid compared with an isonitrogenous isocaloric non-essential balanced amino acid mixture (does not stimulate protein synthesis) in cirrhotic patients. Fractional protein synthesis rate (FSR) in skeletal muscle, responses of the molecular regulatory pathways of skeletal muscle protein synthesis, and autophagy flux will be quantified in the acute and long term protocols. Tracer studies using L-[D5]-phenylalanine (Phe) as a primed constant infusion (prime 2µmol.kg-1.hr-1; constant 0.05 µmol.kg-1.hr-1) with and L [ring-D2] tyrosine, forearm plethysmography, and sequential skeletal muscle biopsies (total of 3 per study subject) will be used to quantify these outcomes. Anthropometric, clinical and body composition measures will be additional outcome measures for the long term intervention. Expression of regulatory signaling proteins, myostatin, IGF-1 (insulin like growth factor) , phospho-Akt, phospho-AMPK (activated protein kinase), phospho-mTOR and phospho-p70s6k will be quantified by Western immunoblots. Autophagy flux will be measured by quantifying expression of the autophagosome proteins.

Details
Condition Cirrhosis, Liver
Treatment Hydroxy Methyl Butyrate, Balanced Amino Acids
Clinical Study IdentifierNCT05166499
SponsorThe Cleveland Clinic
Last Modified on31 December 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Diagnosis of cirrhosis of the liver
Child-Pugh score of 5-8

Exclusion Criteria

Recent gastrointestinal bleeding (<3m)
Active infection
Overt encephalopathy
Renal failure on dialysis
Pedal edema
Uncontrolled diabetes (HbA1C > 7.9mg/dL)
Advanced cardiac, lung, kidney disease
Metastatic cancer
Medications that alter muscle protein metabolism
Pregnancy
Recent bowel resection or gastric bypass surgery
INR >1.7, platelets <60,000/ml, serum creatinine >2mg/dL
Medications that interfere with blood clotting
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