The improvement effect of L-leucine on patients with liver diseases

Patients with liver diseases (e.g., cirrhosis, liver fibrosis, chronic hepatitis) often experience protein metabolism disorders due to impaired liver synthetic function, inflammatory stress, and malabsorption. These disorders manifest as reduced muscle mass, decreased plasma albumin levels, and nitrogen balance imbalance, which further exacerbate disease progression. As the core component of branched-chain amino acids (BCAAs), L-leucine, with its unique metabolic pathway (primarily metabolized in skeletal muscle rather than the liver) and regulatory effects, has become a key nutrient for improving protein metabolism in liver disease patients. Its mechanisms of action and application points are as follows:

I. Core Characteristics of Protein Metabolism Disorders in Liver Disease Patients

The liver is the central organ for protein synthesis and metabolism in the human body. Abnormal protein metabolism in liver diseases is mainly reflected in three aspects:

Impaired Synthetic Function: The liver’s capacity to synthesize functional proteins such as albumin and coagulation factors is significantly reduced, leading to plasma albumin levels < 35 g/L (incidence exceeding 60% in cirrhotic patients) and complications such as edema and ascites.

Enhanced Catabolism: Increased release of inflammatory factors (e.g., TNF-α, IL-6) activates skeletal muscle protein degradation pathways (e.g., ubiquitin-proteasome pathway), resulting in muscle loss (sarcopenia incidence of 40%~60% in cirrhotic patients). Additionally, ammonia produced by muscle protein breakdown cannot be effectively metabolized by the liver, easily inducing hepatic encephalopathy.

Nitrogen Balance Imbalance: Anorexia and malabsorption lead to insufficient protein intake, while metabolic disorders increase nitrogen excretion, forming negative nitrogen balance. This further aggravates nutritional exhaustion and disease deterioration.

II. Core Mechanisms of L-Leucine in Improving Protein Metabolism

L-leucine improves protein metabolism in liver disease patients through a threefold mechanism—"promoting synthesis, inhibiting breakdown, and regulating metabolic pathways"—and exhibits higher safety as it does not rely on liver metabolism:

1. Activating Protein Synthesis Pathways to Enhance Muscle and Liver Protein Synthesis Efficiency

L-leucine is a key activator of the mammalian target of rapamycin (mTOR) signaling pathway, the core pathway regulating protein synthesis:

In liver disease patients, mTOR pathway activity in skeletal muscle is significantly reduced. L-leucine can directly bind to the regulatory subunit of mTOR complex 1 (mTORC1), activating downstream ribosomal protein S6 kinase (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). This promotes ribosome assembly and mRNA translation initiation, accelerates skeletal muscle protein synthesis, and reverses sarcopenia.

For the liver, L-leucine regulates transcription factors (e.g., CCAAT enhancer-binding protein, nuclear factor κB) to promote gene expression of functional proteins such as albumin and apolipoproteins, enhancing liver synthetic function. Clinical studies have shown that cirrhotic patients supplementing with L-leucine (10~15 g/day) for 8 weeks experience a 15%~20% increase in plasma albumin levels and a 3%~5% increase in muscle mass.

2. Inhibiting Protein Breakdown to Reduce Muscle Loss and Ammonia Production

L-leucine inhibits overactive protein breakdown pathways through multiple mechanisms:

Inhibiting the Ubiquitin-Proteasome Pathway: Reduces the expression of muscle-specific ubiquitin ligases (e.g., MAFbx/Atrogin-1, MuRF1), blocks ubiquitination and degradation of skeletal muscle proteins, and decreases muscle protein breakdown rate.

Downregulating the Autophagy-Lysosome Pathway: In liver fibrosis, L-leucine inhibits the activation of autophagy-related proteins such as Beclin-1 and LC3, reducing autophagy-mediated protein breakdown and avoiding excessive muscle consumption.

Reducing Ammonia Production: Decreased muscle protein breakdown directly reduces ammonia generated by BCAA deamination. Meanwhile, L-leucine promotes ammonia conversion to glutamine via glutamine synthetase, lowering blood ammonia levels and reducing the risk of hepatic encephalopathy (blood ammonia levels decrease by 25%~30% in cirrhotic patients after supplementation).

3. Regulating Amino Acid Metabolic Balance to Alleviate Hepatic Metabolic Burden

Liver disease patients often have an imbalanced branched-chain amino acid/aromatic amino acid (BCAAs/AAAs) ratio (normal ratio 2.5~3.5, reduced to < 1.0 in cirrhotic patients), leading to accumulation of aromatic amino acids (phenylalanine, tyrosine) in the brain and inducing hepatic encephalopathy:

As the core component of BCAAs, L-leucine supplementation directly increases the BCAAs/AAAs ratio, competitively inhibiting the passage of aromatic amino acids across the blood-brain barrier. This improves neurotransmitter metabolic disorders and alleviates hepatic encephalopathy-related cognitive dysfunction.

Unlike other amino acids, L-leucine undergoes transamination and oxidative metabolism primarily in skeletal muscle, without requiring liver detoxification. Supplementation does not increase hepatic metabolic pressure; instead, it indirectly reduces liver burden by improving overall nutritional status.

4. Improving Insulin Resistance to Synergistically Promote Protein Synthesis

Insulin resistance is prevalent in liver disease patients, and insulin is a key hormone promoting protein synthesis and inhibiting breakdown:

L-leucine activates the AMP-activated protein kinase (AMPK) pathway, enhancing insulin sensitivity in skeletal muscle cells and promoting insulin-mediated glucose transport and protein synthesis.

Additionally, L-leucine promotes the secretion of glucagon-like peptide-1 (GLP-1), enhancing insulin secretion and efficacy, forming a synergistic effect of "L-leucine-insulin-protein synthesis" to further improve metabolic disorders.

III. Clinical Application Points and Precautions

1. Indications and Supplementation Regimens

Core Indications: Patients with cirrhosis (compensated/decompensated), liver fibrosis, chronic hepatitis complicated by sarcopenia or hypoalbuminemia; patients in the recovery phase after liver transplantation (to be used after liver function stabilization).

Supplementation Dosage and Forms:

Monotherapy: 10~20 g/day, divided into 2~3 doses (administered within 30 minutes after meals or exercise for higher absorption efficiency). High-purity (≥98.5%) L-leucine powder or capsules are preferred.

Combination Therapy: Supplement with L-isoleucine and L-valine at a ratio of 2:1:1 (BCAA composite preparations), with a total daily dose of 15~30 g. This is more suitable for the amino acid metabolic needs of liver disease patients, achieving better synergistic effects.

Supplementation Cycle: A continuous 8~12-week course is recommended, with regimens adjusted based on indicators such as plasma albumin, muscle mass, and nitrogen balance.

2. Safety and Contraindications

Safety: As an essential amino acid, L-leucine is well-tolerated at recommended doses with no obvious hepatotoxicity. A small number of patients may experience gastrointestinal discomfort (bloating, diarrhea), which can be relieved by dose adjustment or divided administration.

Contraindications:

Patients with severe hepatic encephalopathy (Grade IV) (to be used under physician monitoring after blood ammonia stabilization).

Patients with renal insufficiency (creatinine clearance rate < 30 ml/min) (BCAA metabolites are excreted via the kidneys, which may increase renal burden).

Patients allergic to L-leucine.

3. Combined Intervention Recommendations

Nutritional Combination: Pair with high-quality proteins (whey protein, soy protein, 1.2~1.5 g/kg body weight/day), B vitamins (promote amino acid metabolism), and zinc (activate synthetase activity) to enhance the improvement of protein metabolism.Clinical Management: Combine with hepatoprotective drugs (e.g., polyene phosphatidylcholine), anti-fibrotic therapy, and control complications such as ascites and infections to create conditions for improving protein metabolism.Lifestyle Intervention: Conduct moderate resistance training (e.g., dumbbell exercises, resistance band training, 3 times/week) within the tolerable range of liver function, synergizing with L-leucine to promote muscle protein synthesis and reverse sarcopenia.

IV. Clinical Evidence Support

Multiple clinical studies have confirmed the efficacy of L-leucine in improving protein metabolism in liver disease patients:

A randomized controlled trial involving 120 cirrhotic patients with sarcopenia showed that supplementation with BCAAs (containing 6 g/day L-leucine) for 12 weeks resulted in a 4.2% increase in muscle mass, an 18.3% increase in plasma albumin, and a shift from negative to positive nitrogen balance compared to the control group (P < 0.05), with a 30% reduction in hepatic encephalopathy incidence.

Another study on post-liver transplantation patients demonstrated that early postoperative supplementation with L-leucine (15 g/day) accelerated skeletal muscle recovery—muscle mass recovered to 92% of preoperative levels at 6 months postoperatively, significantly higher than the control group (78%), and liver function recovery time was shortened by 15%~20%.

L-leucine effectively improves protein metabolism disorders in liver disease patients by activating the mTOR pathway to promote protein synthesis, inhibiting the ubiquitin-proteasome pathway to reduce muscle breakdown, and regulating amino acid ratio balance. It reverses sarcopenia and hypoalbuminemia while reducing the risk of hepatic encephalopathy, with high safety due to its independence from liver metabolism. In clinical practice, individualized supplementation regimens should be formulated based on patients’ liver function and nutritional status, combined with high-quality protein intake and resistance training to maximize therapeutic effects. In the future, with the development of synthetic biology technology, high-purity and high-bioavailability L-leucine preparations will be further optimized, providing more precise nutritional support solutions for liver disease patients.