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Quick Reference
  • Normal Range: 15-45 μg/dL (9-33 μmol/L)
  • Mild Elevation: 45-80 μg/dL
  • Moderate Elevation: 80-150 μg/dL
  • Severe Elevation: >150 μg/dL (high risk of encephalopathy)
  • Critical: >200 μg/dL (emergent management required)
  • SI Units: To convert μg/dL to μmol/L, multiply by 0.587
  • Primary Use: Evaluation of hepatic encephalopathy, urea cycle disorders, altered mental status
  • Sample Type: Arterial or venous blood on ice; must be processed within 15-30 minutes
  • Key Point: Levels do not always correlate with encephalopathy grade; clinical presentation is paramount

Test Description

What is Ammonia?

Ammonia (NH3) is a toxic nitrogenous compound produced primarily from the breakdown of amino acids and the action of intestinal bacteria on dietary proteins. Under normal conditions, ammonia is efficiently converted to urea in the liver via the urea cycle and excreted by the kidneys. When hepatic function is impaired or portosystemic shunting bypasses the liver, ammonia accumulates in the blood and can cross the blood-brain barrier, causing neurological dysfunction including hepatic encephalopathy.

How is Ammonia Produced and Metabolized?

Ammonia originates from multiple sources:

  • Intestinal production: Bacterial degradation of proteins and urea in the colon (major source)
  • Protein catabolism: Deamination of amino acids in various tissues
  • Renal production: Glutamine metabolism in kidney tubules
  • Muscle metabolism: Purine nucleotide cycle and amino acid degradation

The liver converts ammonia to urea through the urea cycle (ornithine cycle), a series of enzymatic reactions occurring in hepatocytes. Urea is then excreted by the kidneys. Skeletal muscle also contributes to ammonia detoxification by converting it to glutamine.

Clinical Use

Ammonia measurement is clinically indicated for:

  • Hepatic encephalopathy: Assessing ammonia contribution to altered mental status in liver disease
  • Acute liver failure: Monitoring for cerebral edema risk (ammonia >150-200 strongly associated)
  • Urea cycle disorders: Diagnosing and monitoring inherited metabolic diseases
  • Unexplained encephalopathy: Evaluating non-hepatic causes of hyperammonemia
  • Reye syndrome: Supporting diagnosis in pediatric patients
  • Medication monitoring: Valproic acid-induced hyperammonemia
Normal Ranges

Ammonia levels vary by age, sample type, and laboratory method. Prompt processing is critical as ammonia increases rapidly in blood samples at room temperature.

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Population Reference Range (μg/dL) Reference Range (μmol/L)
Adults 15-45 μg/dL 9-33 μmol/L
Neonates (0-2 weeks) 90-150 μg/dL 64-107 μmol/L
Infants (>1 month) 40-80 μg/dL 29-57 μmol/L
Children 20-50 μg/dL 12-36 μmol/L
Arterial vs Venous: Arterial ammonia levels are typically 10-20% higher than venous levels due to muscle ammonia extraction. Either sample is acceptable for clinical use, but consistency is important for serial monitoring.
Sample Handling Critical:
  • Sample must be placed on ice immediately after collection
  • Processed within 15-30 minutes (ammonia rises ~20% per hour at room temperature)
  • Avoid tourniquet use or fist clenching (increases local ammonia)
  • Hemolysis invalidates the result
  • Recent smoking increases ammonia levels
Clinical Significance

Hyperammonemia (Elevated Ammonia)

Elevated ammonia results from decreased hepatic clearance, increased production, or portosystemic shunting. The clinical manifestations primarily affect the central nervous system.

Hepatic Causes (Most Common in Adults)

  • Cirrhosis: Reduced hepatic mass and portosystemic shunting; most common cause of hyperammonemia
  • Acute liver failure: Massive hepatocyte necrosis with severely impaired urea synthesis; ammonia >150 predicts cerebral edema
  • Acute-on-chronic liver failure: Decompensation of underlying cirrhosis
  • Portal-systemic shunts: TIPS procedure, surgical shunts, or spontaneous shunts
  • Hepatocellular carcinoma: Replacement of functional liver tissue

Precipitants of Hepatic Encephalopathy

  • GI bleeding: Increased intestinal protein load (blood = protein substrate)
  • Constipation: Increased colonic ammonia production and absorption
  • Infection/Sepsis: Increased catabolism and impaired hepatic function
  • Dehydration: Prerenal azotemia increases urea available for bacterial conversion to ammonia
  • Hypokalemia: Increases renal ammonia production
  • Alkalosis: Increases proportion of ammonia (NH3) vs ammonium (NH4+) crossing blood-brain barrier
  • Medications: Sedatives, opioids, benzodiazepines (unmask encephalopathy)
  • Dietary protein excess: Rarely a primary precipitant in modern management

Non-Hepatic Causes

  • Urea cycle disorders: Inherited enzyme deficiencies (OTC deficiency most common); present in neonates or can present in adults under stress
  • Organic acidemias: Propionic acidemia, methylmalonic acidemia (pediatric)
  • Reye syndrome: Acute encephalopathy with fatty liver following viral illness in children; associated with aspirin use
  • Valproic acid: Inhibits urea cycle enzymes; hyperammonemia can occur with normal LFTs
  • Urinary tract infections: Urease-producing organisms (Proteus, Klebsiella) convert urea to ammonia
  • Multiple myeloma: Rare cause of hyperammonemia from plasma cell ammonia production
  • Total parenteral nutrition: Amino acid overload, especially in liver dysfunction
  • Post-lung transplant: Hyperammonemia syndrome (mechanism unclear)

Hepatic Encephalopathy Grading (West Haven Criteria)

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Grade Clinical Features Typical Ammonia
Minimal (Covert) Psychometric abnormalities only; normal exam Normal-mildly elevated
Grade 1 Mild confusion, euphoria, sleep disturbance, shortened attention 45-80 μg/dL
Grade 2 Lethargy, moderate confusion, personality changes, asterixis 80-120 μg/dL
Grade 3 Marked confusion, somnolent but arousable, bizarre behavior 100-200 μg/dL
Grade 4 Coma, unresponsive to verbal or painful stimuli >150-200 μg/dL
Critical Point: Ammonia level does NOT correlate reliably with encephalopathy grade in chronic liver disease. Many patients with Grade 3-4 encephalopathy have only moderately elevated ammonia. Clinical assessment is more important than the number.
Interpretation Guidelines

Diagnostic Approach to Hyperammonemia

Step 1: Confirm the Elevated Ammonia

  • Verify proper sample collection and handling (ice, processed quickly)
  • Repeat if sample handling was questionable
  • Consider arterial sample for accuracy if venous indeterminate

Step 2: Evaluate for Known Liver Disease

  • History of cirrhosis, alcohol use, viral hepatitis
  • Signs of chronic liver disease (spider angiomata, palmar erythema, gynecomastia)
  • Check LFTs, INR, albumin, platelet count

Step 3: Identify Precipitating Factors

  • GI bleeding (check stool guaiac, H/H)
  • Infection (CBC, UA, CXR, blood cultures)
  • Electrolyte disturbances (BMP for K+, check for alkalosis)
  • Constipation (last bowel movement)
  • Medication review (sedatives, opioids, diuretics)

Step 4: Consider Non-Hepatic Causes if No Liver Disease

  • Review medications (valproic acid, chemotherapy, TPN)
  • Check urine for infection (urease-producing organisms)
  • In young patients or severe unexplained elevation: consider urea cycle disorders (plasma amino acids, urine orotic acid)

Ammonia Level Interpretation

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Ammonia Level Clinical Interpretation Action
15-45 μg/dL Normal Unlikely hyperammonemia; consider other causes of symptoms
45-80 μg/dL Mild elevation May contribute to subtle symptoms; identify and treat precipitants
80-150 μg/dL Moderate elevation Likely contributing to encephalopathy; initiate lactulose
>150 μg/dL Severe elevation High risk of cerebral edema in acute liver failure; aggressive treatment
>200 μg/dL Critical ICU monitoring; consider intracranial pressure monitoring in ALF
Serial Monitoring: Trending ammonia levels can be useful to assess treatment response. A 50% reduction typically correlates with clinical improvement. However, clinical response remains the most important endpoint.
Treatment Overview

Management of Hepatic Encephalopathy

First-Line: Lactulose

  • Mechanism: Non-absorbable disaccharide metabolized by colonic bacteria to lactic acid, lowering colonic pH and trapping ammonia as NH4+ (non-absorbable)
  • Dosing: 25-30 mL (15-30g) PO q1-2h until bowel movement, then titrate to 2-3 soft stools daily
  • Enema: 300 mL in 700 mL water retention enema for patients unable to take PO
  • Goal: 2-3 loose stools per day; avoid excessive diarrhea (causes dehydration/electrolyte disturbance)

Second-Line: Rifaximin

  • Mechanism: Non-absorbable antibiotic that reduces ammonia-producing intestinal bacteria
  • Dosing: 550 mg PO BID
  • Role: Add-on to lactulose for recurrent HE; reduces recurrence by 50%
  • Advantage: Minimal systemic absorption, well-tolerated

Adjunctive Measures

  • Identify and treat precipitants: Most important step (infection, GI bleed, constipation, electrolytes)
  • Avoid sedatives: Benzodiazepines and opioids worsen encephalopathy
  • Nutritional support: Adequate protein (1.2-1.5 g/kg/day); protein restriction is NOT recommended
  • Correct electrolytes: Treat hypokalemia, avoid alkalosis
  • Zinc supplementation: May be helpful; zinc is a cofactor in urea cycle

Management of Acute Liver Failure with High Ammonia

Cerebral Edema Risk: Ammonia >150-200 μg/dL in acute liver failure is associated with high risk of cerebral edema and intracranial hypertension.
  • ICU admission with frequent neurological checks
  • Head of bed elevation 30°
  • Avoid hyperthermia (maintain normothermia)
  • Consider prophylactic intubation for Grade 3-4 encephalopathy
  • ICP monitoring may be indicated
  • Continuous renal replacement therapy (CRRT) effectively removes ammonia
  • Urgent liver transplant evaluation

Valproic Acid-Induced Hyperammonemia

  • Can occur even with normal liver function tests
  • Treatment: Discontinue or reduce valproic acid dose
  • L-carnitine supplementation (50-100 mg/kg/day, max 3g/day) may help
  • Lactulose has limited role since mechanism is not intestinal ammonia production
Interfering Factors

Factors That Falsely Increase Ammonia

  • Improper sample handling: Room temperature storage (most common cause of falsely elevated ammonia)
  • Delayed processing: Ammonia rises ~20% per hour at room temperature
  • Hemolysis: RBC ammonia release
  • Tourniquet use: Local muscle ammonia production
  • Fist clenching: Muscle ammonia release
  • Smoking: Recent tobacco use increases ammonia
  • High-protein meal: Transient postprandial elevation
  • Intense exercise: Muscle ammonia production

Medications That Increase Ammonia

  • Valproic acid: Inhibits urea cycle; can cause hyperammonemia without liver dysfunction
  • Carbamazepine: Less common than valproate
  • Acetazolamide: Increases renal ammonia production
  • Salicylates: High doses can impair urea cycle
  • Asparaginase: Chemotherapy agent affecting amino acid metabolism
  • 5-fluorouracil: Rare association with hyperammonemia
  • Glycine (transurethral irrigation): TURP syndrome with hyperammonemia

Factors That Decrease Ammonia

  • Lactulose: Therapeutic effect
  • Rifaximin: Reduces intestinal ammonia production
  • Antibiotics: Reduce ammonia-producing bacteria (neomycin, metronidazole)
  • Low-protein diet: Reduces substrate (not recommended therapeutically)

Important Considerations

  • Arterial vs venous: Arterial levels are 10-20% higher than venous; be consistent for serial monitoring
  • Lab method variation: Different assays may have different reference ranges
  • Age-dependent ranges: Neonates and infants have higher normal ranges
Clinical Pearls
Clinical Pearl
Don't Chase the Number: In chronic liver disease, ammonia levels correlate poorly with encephalopathy grade. A patient with ammonia of 80 may be comatose, while another with 150 may be only mildly confused. Treat the patient, not the lab value.
Clinical Pearl
Acute vs Chronic Matters: In acute liver failure, ammonia >150 μg/dL is strongly predictive of cerebral edema and herniation. In chronic liver disease, patients tolerate much higher levels due to compensatory mechanisms.
Clinical Pearl
The "4 I's" of HE Precipitants: Infection, Intestinal bleeding, Intoxication (sedatives), and Imbalance (electrolytes/dehydration). Address these before simply escalating lactulose.
Clinical Pearl
Asterixis is NOT Specific: While classically associated with hepatic encephalopathy, asterixis (flapping tremor) also occurs in uremia, hypercarbia, and medication toxicity. It's a sign of metabolic encephalopathy, not liver disease specifically.
Valproate Alert: Always check ammonia in patients on valproic acid who develop encephalopathy, even if LFTs are normal. VPA-induced hyperammonemia can occur at therapeutic drug levels and requires dose reduction or discontinuation.
Lactulose Titration: The goal is 2-3 soft stools per day. More is not better—excessive lactulose causes dehydration and hypokalemia, which can paradoxically worsen encephalopathy.
Clinical Pearl
Protein Restriction is Outdated: Long-term protein restriction was once standard for HE but is now discouraged. Malnutrition worsens outcomes in cirrhosis. Patients should receive 1.2-1.5 g/kg/day of protein, including during acute HE episodes.
Hidden GI Bleed: In a cirrhotic patient with new encephalopathy and elevated ammonia, always consider occult GI bleeding even without melena or hematemesis. Check stool guaiac and hemoglobin/hematocrit.
Clinical Pearl
The Overlooked UTI: Urinary tract infections with urease-producing organisms (Proteus, Klebsiella, Ureaplasma) can cause hyperammonemia, especially with urinary retention or obstruction. Always check urinalysis in unexplained hyperammonemia.
CRRT for Severe Cases: Continuous renal replacement therapy is highly effective at removing ammonia. Consider early in acute liver failure with ammonia >150-200, or in refractory hyperammonemia from any cause.
References
  1. Kratz, A., Ferraro, M., Sluss, P. M., & Lewandrowski, K. B. (2004). Laboratory reference values. New England Journal of Medicine, 351, 1548-1564.
  2. Lee, M. (Ed.). (2009). Basic skills in interpreting laboratory data. Ashp.
  3. Farinde, A. (2021). Lab values, normal adult: Laboratory reference ranges in healthy adults. Medscape. https://emedicine.medscape.com/article/2172316-overview?form=fpf
  4. Nickson, C. (n.d.). Critical Care Compendium. Life in the Fast Lane • LITFL. https://litfl.com/ccc-critical-care-compendium/
  5. Farkas, Josh MD. (2015). Table of Contents - EMCrit Project. EMCrit Project. https://emcrit.org/ibcc/toc/
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