HMB + Amino Acids for Liver Cirrhosis

Overseen By Annette Bellar

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: The Cleveland Clinic

Must not be taking: Muscle metabolism drugs, Blood thinners

Disqualifiers: Recent bleeding, Infection, Encephalopathy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

24 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Will I have to stop taking my current medications?

The trial requires that you stop taking medications that alter muscle protein metabolism or interfere with blood clotting.

What data supports the effectiveness of the treatment HMB + Amino Acids for Liver Cirrhosis?

Research shows that HMB (a compound that helps build muscle) can improve muscle strength and liver function in patients with liver cirrhosis, and it may help prevent minimal hepatic encephalopathy (a brain disorder caused by liver disease). However, the effects on muscle mass are not clearly demonstrated, and more studies are needed to confirm these benefits. ^{1 2 3 4 5}

Is HMB and amino acids treatment safe for humans?

The research articles provided do not contain specific safety information about HMB and amino acids treatment for humans, including those with liver cirrhosis. ^{6 7 8 9 10}

How does the treatment HMB + Amino Acids differ from other treatments for liver cirrhosis?

HMB (beta-hydroxy-beta-methylbutyrate) is unique because it is a derivative of the amino acid leucine and is used to potentially improve muscle mass and strength, which is often reduced in liver cirrhosis. Unlike standard treatments, HMB may help increase certain amino acids in the blood and improve muscle function, although its effects on liver cirrhosis are not yet fully established and may vary. ^{1 2 3 4 5}

Eligibility Criteria

This trial is for individuals with a moderate level of liver cirrhosis, as indicated by a Child-Pugh score of 5-8. Participants must not have had recent severe complications like gastrointestinal bleeding or infections, and should not be on dialysis or have uncontrolled diabetes among other exclusions.

Inclusion Criteria

I have been diagnosed with cirrhosis of the liver.

My liver function is moderately impaired.

Exclusion Criteria

My cancer has spread to other parts of my body.

I have been diagnosed with severe brain function problems.

I am on dialysis for kidney failure.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Acute Treatment

Participants receive acute administration of hydroxymethyl butyrate (HMB) enriched essential amino acids

1 day

1 visit (in-person)

Long-term Treatment

Participants receive long-term administration of hydroxymethyl butyrate (HMB) enriched essential amino acids for 3 months

12 weeks

Multiple visits (in-person) for muscle biopsies and assessments

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Balanced Amino Acids
• Hydroxy Methyl Butyrate

Trial Overview The study is testing whether HMB enriched amino acids can reverse muscle loss in people with cirrhosis. It compares this intervention to a balanced amino acid mixture that doesn't stimulate protein synthesis, over an acute phase and then long-term for three months.

Participant Groups

Group I: Balanced Amino Acid Mixture Experimental Treatment 1 Intervention

Group II: Hydroxy Methyl Butyrate Active Control 1 Intervention

Who Is Running the Clinical Trial?

The Cleveland Clinic

Lead Sponsor

Trials

1,072

Recruited

1,377,000+

Findings from Research

BCAA supplementation in liver cirrhosis has been shown to slightly increase muscle mass and improve symptoms of hepatic encephalopathy, making it a useful second-line therapy.

While HMB supplementation may help increase muscle mass in chronic diseases, its effectiveness in liver cirrhosis is not well established, and it currently has no clinical indication for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of Branched-Chain Amino Acids and Their Derivative β-Hydroxy-β-Methylbutyrate in Liver Cirrhosis. Espina, S., Sanz-Paris, A., Bernal-Monterde, V., et al.[2022]

In a study of 43 patients with liver cirrhosis and malnutrition, those receiving HMB supplementation showed trends towards improved handgrip strength and reduced minimal hepatic encephalopathy over 12 weeks, although fat-free mass did not change.

Both HMB and non-HMB supplements led to increased fat mass and improved liver function scores, indicating that while HMB may have specific benefits, overall nutritional support is crucial for patients with cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized Clinical Trial: Effects of β-Hydroxy-β-Methylbutyrate (HMB)-Enriched vs. HMB-Free Oral Nutritional Supplementation in Malnourished Cirrhotic Patients. Espina, S., Sanz-Paris, A., Gonzalez-Irazabal, Y., et al.[2022]

In a pilot study involving 24 patients with liver cirrhosis, 12 weeks of beta-hydroxy-beta-methylbutyrate (HMB) supplementation significantly improved muscle function and increased quadriceps muscle mass compared to a placebo.

HMB supplementation was well tolerated with no reported adverse events, and it also led to a reduction in the Liver Frailty Index, indicating potential benefits for frailty in cirrhotic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effects of 12-Week Beta-Hydroxy-Beta-Methylbutyrate Supplementation in Patients with Liver Cirrhosis: Results from a Randomized Controlled Single-Blind Pilot Study. Lattanzi, B., Bruni, A., Di Cola, S., et al.[2021]

In a study of 43 malnourished cirrhotic patients, oral nutritional supplements enriched with ß-Hydroxy-ß-methylbutyrate (HMB) significantly increased plasma levels of branched chain amino acids (BCAA) compared to a high-protein control, suggesting a potential therapeutic benefit in managing hepatic encephalopathy.

The HMB-enriched supplements improved the amino acid profile without raising harmful levels of ammonia, indicating a safe approach to potentially prevent minimal hepatic encephalopathy (MHE) in patients with liver cirrhosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amino Acid Profile in Malnourished Patients with Liver Cirrhosis and Its Modification with Oral Nutritional Supplements: Implications on Minimal Hepatic Encephalopathy. Espina, S., Gonzalez-Irazabal, Y., Sanz-Paris, A., et al.[2021]

In healthy rats, HMB supplementation improved muscle mitochondrial function and increased levels of branched-chain amino acids (BCAAs) in the blood, although it did not significantly affect muscle mass or protein content.

In rats with liver cirrhosis induced by carbon tetrachloride, HMB supplementation led to negative outcomes, including higher mortality and lower body weight, suggesting that HMB may have harmful effects in the context of liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of beta-hydroxy-beta-methylbutyrate supplementation on skeletal muscle in healthy and cirrhotic rats. Holeček, M., Vodeničarovová, M.[2021]

In a study involving Wistar rats with induced cholestasis, butyrate treatment significantly reduced harmful inflammatory cytokines and increased protective IL-10 levels, suggesting its potential to improve intestinal inflammation in cirrhosis.

Butyrate also enhanced the expression of tight junction proteins in the ileum and promoted the growth of beneficial gut bacteria, indicating its role in maintaining gut barrier integrity and microbiota diversity in liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Butyrate administration strengthens the intestinal epithelium and improves intestinal dysbiosis in a cholestasis fibrosis model. Peña-Rodríguez, M., Vega-Magaña, N., García-Benavides, L., et al.[2021]

Patients with cirrhosis experience unpredictable changes in how their bodies process medications, leading to potential drug accumulation and adverse effects, especially for drugs primarily cleared by the liver.

Certain medications, like aminoglycosides and ACE inhibitors, should be avoided in patients with cirrhosis due to increased risks of toxicity and complications, while drugs like furosemide may cause electrolyte disturbances without significantly altering their disposition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug administration in chronic liver disease. Westphal, JF., Brogard, JM.[2022]

In a study of 5618 patients with cirrhosis followed for a median of 3 years, nearly 60% of patients were prescribed potentially unsafe drugs, highlighting a significant risk for adverse drug reactions (ADRs).

The most commonly used medications included proton pump inhibitors and diuretics, with almost half of all prescriptions falling under safety recommendations, indicating a need for personalized pharmacotherapy to enhance safety in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevalence of Drug Prescriptions and Potential Safety in Patients with Cirrhosis: A Retrospective Real-World Study. Weersink, RA., Taxis, K., Drenth, JPH., et al.[2020]

In a study of 400 patients with liver cirrhosis, 20% of prescribed drugs were inadequately dosed, leading to a significant number of adverse drug reactions (ADRs), with 78% of these being preventable.

Patients receiving inadequately dosed medications experienced more ADRs and were more likely to be hospitalized, resulting in an additional 94 hospital days, highlighting the critical need for careful drug dosing in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dose adjustment in patients with liver cirrhosis: impact on adverse drug reactions and hospitalizations. Franz, CC., Hildbrand, C., Born, C., et al.[2021]

Medicine-related problems (MRPs) are common in patients with liver cirrhosis, with reported frequencies ranging from 14% to 23.4% across various studies, highlighting a significant concern in this patient population.

The causes of MRPs include drug interactions, inappropriate dosing, and the use of contraindicated medications, along with patient-related factors and healthcare system issues, indicating that effective management should address both medication therapy and patient behavior.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Medicine use and medicine-related problems in patients with liver cirrhosis: a systematic review of quantitative and qualitative studies. Cheema, E., Al-Aryan, A., Al-Hamid, A.[2020]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Role of Branched-Chain Amino Acids and Their Derivative β-Hydroxy-β-Methylbutyrate in Liver Cirrhosis. [2022]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Randomized Clinical Trial: Effects of β-Hydroxy-β-Methylbutyrate (HMB)-Enriched vs. HMB-Free Oral Nutritional Supplementation in Malnourished Cirrhotic Patients. [2022]

3. Switzerland pubmed.ncbi.nlm.nih.gov

The Effects of 12-Week Beta-Hydroxy-Beta-Methylbutyrate Supplementation in Patients with Liver Cirrhosis: Results from a Randomized Controlled Single-Blind Pilot Study. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Amino Acid Profile in Malnourished Patients with Liver Cirrhosis and Its Modification with Oral Nutritional Supplements: Implications on Minimal Hepatic Encephalopathy. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Effects of beta-hydroxy-beta-methylbutyrate supplementation on skeletal muscle in healthy and cirrhotic rats. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Butyrate administration strengthens the intestinal epithelium and improves intestinal dysbiosis in a cholestasis fibrosis model. [2021]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Drug administration in chronic liver disease. [2022]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Prevalence of Drug Prescriptions and Potential Safety in Patients with Cirrhosis: A Retrospective Real-World Study. [2020]

9. Germany pubmed.ncbi.nlm.nih.gov

Dose adjustment in patients with liver cirrhosis: impact on adverse drug reactions and hospitalizations. [2021]

10. Germany pubmed.ncbi.nlm.nih.gov

Medicine use and medicine-related problems in patients with liver cirrhosis: a systematic review of quantitative and qualitative studies. [2020]