What is the role of L-carnitine in treating hyperammonemia in Non-Alcoholic Steatohepatitis (NASH) patients?

Role of L-Carnitine in NASH Patients with Hyperammonemia

Primary Recommendation

L-carnitine cannot be routinely recommended for NASH patients at this time, despite preliminary evidence showing benefits in reducing inflammation, improving liver function, and ameliorating histological manifestations of NASH. 1

Evidence Summary and Clinical Context

Current Guideline Position

The 2020 ESPEN guidelines explicitly state that L-carnitine cannot be recommended yet for NAFLD/NASH treatment, despite promising preliminary results. 1 This conservative stance is based on:

• Limited trial data: Only small studies have evaluated L-carnitine in NASH, with oral supplementation (1 g twice daily for 24 weeks) showing reductions in TNF-α, CRP, improved liver function, glucose levels, lipid profiles, HOMA-IR, and histological improvements. 1

• Diabetic NAFLD subgroup: In diabetic NAFLD patients specifically, carnitine-orotate (3 × 824 mg for 12 weeks) demonstrated significant improvements in ALT, hepatic steatosis, and HbA1c in a double-blind placebo-controlled trial. 1

Mechanism of Action in Liver Disease

L-carnitine plays a crucial role in mitochondrial fatty acid oxidation, a process that is impaired by ammonia and central to mitochondrial function and energy metabolism. 1 In NASH, mitochondrial dysfunction appears to drive progression from simple steatosis to steatohepatitis. 2

Specific Role in Hyperammonemia Management

When L-Carnitine IS Indicated

L-carnitine should be administered specifically for organic acidemias at a loading dose of 50 mg/kg over 90 minutes, followed by 100-300 mg/kg daily. 1, 3 This indication is distinct from NASH treatment and applies when hyperammonemia results from organic acidemias rather than liver disease itself.

When L-Carnitine is NOT Indicated

• Urea cycle disorders: L-carnitine is explicitly not needed for urea cycle disorders, where primary interventions include nitrogen-scavenging agents (sodium benzoate, sodium phenylacetate) and urea cycle intermediates (L-arginine). 3

• Routine NASH management: Current guidelines do not support routine use despite mechanistic rationale. 1

Evidence for Hyperammonemia in Cirrhosis

Potential Benefits in Cirrhotic Patients

In cirrhotic patients with hepatic encephalopathy, L-carnitine administration has been associated with:

• Dose-related lowering of blood ammonia levels 1
• Lower rate of muscle loss and reversal of existing sarcopenia 1
• Increased levels of physical activity 1

A 2002 randomized trial in cirrhotic patients showed oral L-carnitine (6 g/day for 4 weeks) caused rapid and sustained reductions in ammonia levels (mean reduction 60.1 μmol/L vs 1.4 μmol/L in controls), with 14 of 16 patients achieving normal ammonia levels. 4

Limitations of Current Evidence

The 2021 AASLD guidelines note that a recent systematic review did not show benefit of acetyl-L-carnitine for hepatic encephalopathy treatment, limiting its availability for clinical practice management of frailty and sarcopenia. 1

Clinical Algorithm for L-Carnitine Use

In NASH Patients WITHOUT Hyperammonemia

• Do not routinely prescribe L-carnitine 1
• Focus on weight loss (≥7-10% body weight), which remains the most effective intervention for improving steatosis, inflammation, and fibrosis 1

In NASH Patients WITH Hyperammonemia

1. Determine the cause of hyperammonemia:

   • If due to organic acidemia: Administer L-carnitine (50 mg/kg loading dose, then 100-300 mg/kg daily) 3
   • If due to urea cycle disorder: Do not use L-carnitine; use nitrogen scavengers and L-arginine instead 3
   • If due to decompensated cirrhosis with hepatic encephalopathy: Consider L-carnitine as adjunctive therapy after standard treatments (lactulose, rifaximin) have been optimized 1

2. For cirrhotic NASH with hepatic encephalopathy:

   • First-line: Non-absorbable disaccharides (lactulose) 1
   • Second-line: Add rifaximin 1
   • Adjunctive options: Oral BCAAs, intravenous L-ornithine L-aspartate, or albumin 1
   • L-carnitine may be considered but is not guideline-recommended 1

Important Caveats and Pitfalls

Safety Considerations

• Gastrointestinal side effects (nausea, vomiting, abdominal cramps, diarrhea) occur at approximately 3 g/day 5
• Fishy body odor may occur with high doses 5
• Insufficient evidence exists to support routine use in maintenance dialysis patients 1, 5

Clinical Pitfalls to Avoid

• Do not delay standard hyperammonemia treatment while considering L-carnitine; immediately discontinue protein intake, provide adequate calories (≥100 kcal/kg daily), and initiate nitrogen scavengers when indicated 3
• Do not use L-carnitine as monotherapy for hyperammonemia in any setting 3
• Do not prolong protein restriction beyond 48 hours to avoid catabolism 3

Monitoring Requirements

If L-carnitine is used off-label in NASH with hyperammonemia:

• Check plasma ammonia levels every 3-4 hours until normalized 3
• Assess neurological status regularly for encephalopathy signs 3
• Monitor liver function tests and metabolic parameters 1

Future Directions

Animal models suggest combined rifaximin and L-ornithine L-aspartate (not L-carnitine alone) may lower plasma and muscle ammonia while improving muscle mass and function. 1 However, human data specifically evaluating benefit on muscle contractile function or mass in cirrhosis are lacking. 1