Can hyperammonemia occur without cirrhosis?

Hyperammonemia Without Cirrhosis: Yes, It Definitely Occurs

Yes, hyperammonemia can absolutely occur without cirrhosis, and recognizing this is critical because it should prompt investigation for alternative diagnoses beyond hepatic encephalopathy. 1

Key Principle from Guidelines

The EASL 2022 guidelines explicitly state that "patients without manifest HE and even without liver disease can display hyperammonaemia." 1 This is a crucial clinical pearl that should fundamentally change your diagnostic approach when encountering elevated ammonia levels.

Non-Cirrhotic Causes of Hyperammonemia

Congenital Portosystemic Shunts

• Congenital portosystemic shunts should be investigated in patients with unexplained hyperammonemia, mental retardation, and/or clinical picture compatible with hepatic encephalopathy in the absence of cirrhosis. 1
• These rare developmental abnormalities (both extrahepatic and intrahepatic types, including patent ductus venosus) bypass the liver where ammonia is normally metabolized. 1
• Patients may remain asymptomatic until the sixth or seventh decades, presenting with fatigue, cognitive deficits, or recurrent encephalopathy episodes. 1
• The shunt diameter determines clinical course: large shunts cause persistent symptoms from childhood, while small intrahepatic shunts may cause recurrent adult-onset episodes. 1
• MRI is the recommended diagnostic modality for identifying and classifying these shunts. 1

Urinary Tract Infections with Urease-Producing Bacteria

• Urease-splitting bacteria in the urinary tract (such as Bacteroides ureolyticus) can cause severe hyperammonemia without any liver dysfunction. 2, 3
• The mechanism involves bacterial urease degrading urinary urea in the bladder, producing ammonia that is absorbed into the blood circulation from the bladder venous plexus, particularly when dysuria is present. 2
• This diagnosis should be suspected when patients with hyperammonemia show marked alkalinuria on urinalysis and fail to respond to conventional hepatic encephalopathy treatment. 2
• Treatment requires urinary drainage and antimicrobials, which rapidly normalizes ammonia levels and urine pH. 2, 3

Inherited Metabolic Disorders

• For severe hyperammonemia (>100 µmol/L) with normal liver enzymes, consider inherited metabolic disorders, especially with family history of liver disease, neurological disorders, or severe neurological impairment. 4

Other Splenogonadal Shunts

• Non-cirrhotic hyperammonemia can occur due to rare vascular anomalies such as splenogonadal shunts. 5

Clinical Implications for Diagnosis

When to Suspect Non-Hepatic Hyperammonemia

• Normal liver enzymes with elevated ammonia should immediately trigger investigation for non-hepatic causes. 4
• Failure to respond to standard hepatic encephalopathy treatment (lactulose, rifaximin) warrants urinalysis and consideration of alternative diagnoses. 2
• Look specifically for: marked alkalinuria, obstructive uropathy with neurogenic bladder, history of mental retardation from childhood, or family history of unexplained neurological disease. 1, 2, 3

The Diagnostic Value of Normal Ammonia

• Conversely, a normal ammonia level in a patient with suspected hepatic encephalopathy should prompt renewed differential diagnostic work-up for other causes of delirium. 1
• Normal ammonia has high negative predictive value for hepatic encephalopathy—if ammonia is normal, the patient likely does not have sufficient hepatic failure and/or portosystemic shunting to justify a diagnosis of HE. 1

Critical Measurement Considerations

To avoid false-positive results that could mislead your diagnostic reasoning:

• Collect from fasting patients when possible, avoiding venous stasis (no tourniquet or fist clenching). 6, 4
• Use EDTA-containing tubes, place immediately on ice, and transport to laboratory within 60-90 minutes. 6
• Sample hemolysis, high lipemia, jaundice, high-protein diet, smoking, and exercise can all falsely elevate results. 6, 4

Common Pitfalls to Avoid

• Do not assume all hyperammonemia is due to liver disease—this assumption delays diagnosis of treatable conditions like urinary tract infections or congenital shunts. 1, 2, 3
• In cirrhotic patients with hyperammonemia who fail standard treatment, always check urinalysis for alkalinuria and culture for urease-producing bacteria. 2
• Remember that even in cirrhosis, one-third of patients with acute encephalopathy may have normal ammonia levels (NonHep E), yet still have similarly severe prognosis as those with elevated ammonia. 7