What are the causes of non-cirrhotic hyperammonemia?

Causes of Non-Cirrhotic Hyperammonemia

Non-cirrhotic hyperammonemia results from four major categories: primary urea cycle disorders, secondary metabolic defects (organic acidemias and fatty acid oxidation defects), drug-induced inhibition (particularly valproic acid), and acquired urea cycle dysfunction from infections or metabolic stressors. 1, 2

Primary Causes: Urea Cycle Disorders

Congenital enzyme deficiencies represent the most common inherited cause of hyperammonemia:

• Ornithine transcarbamylase (OTC) deficiency is the most frequent urea cycle disorder, occurring in 1 in 56,500 births 1
• Other enzyme deficiencies include N-acetylglutamate synthase (NAGS), Carbamoyl phosphate synthase I (CPS), Argininosuccinate synthetase (ASS), Argininosuccinate lyase (ASL), and Arginase 1 deficiency 1
• Partial enzyme deficiencies can remain undiagnosed until adulthood, manifesting only when triggered by metabolic stressors such as illness, increased protein intake, or pregnancy 1
• Previously undiagnosed inborn errors of metabolism accounted for 17% of adult-onset non-cirrhotic hyperammonemia cases in recent studies 2

Secondary Metabolic Causes

Organic acidemias disrupt ammonia metabolism indirectly:

• Methylmalonic acidemia, isovaleric acidemia, propionic acidemia, and multiple carboxylase deficiency occur in approximately 1 in 21,000 births 1, 3
• These disorders cause hyperammonemia through inhibition of N-acetylglutamate synthase and impaired urea cycle function 4
• Fatty acid oxidation defects can also present with hyperammonemia, particularly during catabolic stress 4, 5

Drug-Induced Hyperammonemia

Valproic acid (Depakene) is the most clinically significant drug cause:

• Valproate directly inhibits the urea cycle and can cause hyperammonemia even with normal liver function 1, 6
• Asymptomatic ammonia elevations are common with valproate and require close monitoring 6
• The combination of valproate with topiramate significantly increases hyperammonemia risk, even in patients who tolerated either drug alone 6
• If unexplained lethargy, vomiting, or mental status changes occur in valproate-treated patients, measure ammonia levels immediately and discontinue valproate if elevated 6

Acquired Urea Cycle Dysfunction

Infections with urease-producing organisms represent a critical and potentially reversible cause:

• Urease-producing bacterial infections (particularly Proteus, Klebsiella, and Ureaplasma species) accounted for 22% of adult non-cirrhotic hyperammonemia cases 2
• These organisms convert urea to ammonia in the urinary tract or other sites, overwhelming normal ammonia clearance mechanisms 2
• Empiric antibiotic treatment targeting urease-splitting organisms should be initiated promptly in patients with unexplained hyperammonemia 2

Unexplained acquired urea cycle dysfunction (uaUCD):

• This represented 35% of adult non-cirrhotic hyperammonemia cases, characterized by biochemical signatures of urea cycle dysfunction without genetic or clear clinical causes 2
• Severe protein malnutrition appears to be a reversible risk factor for acquired urea cycle dysfunction 2
• Clinical exposures causing acquired dysfunction (such as chemotherapy, total parenteral nutrition, or critical illness) accounted for 26% of cases 2

Transport and Amino Acid Defects

• Dibasic amino acid transport defects can impair ornithine availability for the urea cycle, leading to hyperammonemia 7
• These disorders affect the transport of lysine, arginine, and ornithine across cell membranes 7

Acute Kidney Injury

• Renal impairment reduces ammonia excretion capacity, as kidneys normally excrete ammonia both directly and as glutamine 1
• This becomes particularly problematic when combined with other risk factors for hyperammonemia 1

Critical Clinical Pitfalls

Do not assume cirrhosis is the only cause of hyperammonemia in adults:

• In a retrospective study, inherited metabolic disorders, infections, and acquired dysfunction accounted for all cases of adult-onset hyperammonemia without cirrhosis 2
• Mortality was 39% overall, with 13% dying before hyperammonemia resolution, emphasizing the urgency of diagnosis and treatment 2

Consider underlying metabolic disorders in patients with:

• Unexplained neurological symptoms with respiratory alkalosis (a key distinguishing feature from other encephalopathies) 1, 3
• Family history of liver disease or neurological disorders 8
• Low protein tolerance or migraine-like headaches as subtle indicators 1
• Psychiatric manifestations including learning disabilities, delusion, or psychosis 1

Measure ammonia levels urgently when ammonia >200 μmol/L (341 μg/dL), as this threshold is associated with poor neurological outcomes and may require renal replacement therapy 1, 8, 2