Why do ammonia levels increase in liver disease?

Why Ammonia Increases in Liver Disease

Ammonia levels increase in liver disease primarily because the liver loses its ability to convert ammonia to urea through the urea cycle, leading to systemic hyperammonemia and associated neurological complications. 1

Pathophysiology of Ammonia Accumulation

Normal Ammonia Metabolism

• Ammonia is produced through:

  • Protein metabolism (deamination of amino acids)
  • Intestinal bacterial action on nitrogenous compounds
  • Deamination of AMP during exercise in skeletal muscle
  • Kidney, pancreas, and brain metabolism 1

• In healthy individuals:

  • Most ammonia enters the hepatic urea cycle
  • Converted to urea and excreted in urine
  • Some is converted to glutamine

Disrupted Metabolism in Liver Disease

1. Impaired Urea Cycle Function:

   • Liver disease reduces the functional capacity of hepatocytes
   • Decreased activity of urea cycle enzymes (N-acetylglutamate synthase, carbamoyl phosphate synthase I, ornithine transcarbamylase, argininosuccinate synthetase, argininosuccinate lyase, and arginase 1) 1
   • Results in reduced conversion of ammonia to urea

2. Portosystemic Shunting:

   • Portal hypertension creates collateral circulation
   • Blood bypasses the liver, preventing ammonia detoxification
   • Ammonia-rich blood from intestines enters systemic circulation directly 1

3. Altered Intestinal Function:

   • Bacterial overgrowth in the intestines
   • Enhanced ammonia production by intestinal bacteria
   • Increased intestinal permeability 2

4. Muscle Wasting and Sarcopenia:

   • Skeletal muscle serves as an alternative site for ammonia detoxification through glutamine synthesis
   • Sarcopenia (common in cirrhosis) reduces this compensatory mechanism
   • Ammonia itself is myotoxic, creating a vicious cycle 1
   • Ammonia causes decreased protein synthesis, increased autophagy, and mitochondrial dysfunction in muscles 1

5. Renal Contribution:

   • Kidneys play a role in ammonia excretion
   • Renal dysfunction (common in advanced liver disease) further impairs ammonia clearance 1

Clinical Implications

Hyperammonemia and Hepatic Encephalopathy

• Normal blood ammonia: ≤35 µmol/L (≤60 µg/dL)
• Toxic levels: >200 µmol/L (>341 µg/dL) associated with poor neurological outcomes 1
• Hyperammonemia defined as:

  • 100 µmol/L (>170 µg/dL) in neonates

  • ≥50 µmol/L (≥85 µg/dL) in term infants, children, and adults 1

Neurological Effects

• Ammonia crosses the blood-brain barrier and is metabolized to glutamine by astrocytes
• Increased intracellular glutamine causes:
  • Astrocyte swelling
  • Cerebral edema
  • Release of inflammatory cytokines
  • Increased extracellular potassium
  • Neuronal damage 1, 2

Progression of Symptoms

• Early: Lethargy, loss of appetite, vomiting
• Progressive: Hyperventilation (respiratory alkalosis), hypotonia, ataxia, disorientation
• Severe: Seizures, coma, death if untreated 1

Disease-Specific Considerations

• Alcohol-associated liver disease: Particularly high prevalence of sarcopenia (80% in decompensated cirrhosis), accelerating ammonia accumulation 1
• NASH-related cirrhosis: Insulin resistance and systemic inflammation compound ammonia-related issues 1
• Cholestatic liver diseases: Elevated bile acids may contribute to muscle atrophy, further reducing ammonia clearance capacity 1

Important Clinical Pearls

• Blood ammonia levels correlate with hepatic encephalopathy severity but are not diagnostic alone 2
• A normal ammonia level has high negative predictive value for hepatic encephalopathy diagnosis 2
• Proper collection technique is critical for accurate ammonia measurement (fasting patient, avoiding venous stasis, EDTA-containing tube, immediate placement on ice) 2
• Ammonia measurement may help evaluate treatment efficacy but is not routinely used to guide therapy 2

Understanding the complex pathophysiology of ammonia accumulation in liver disease is essential for developing effective treatment strategies targeting hyperammonemia and its consequences.