What Causes Citrulline Deficiency? A Comprehensive Overview

January 2, 2026 •

3 min read

Citrulline, an amino acid vital for ammonia detoxification and nitric oxide production, can become deficient due to several complex factors. A deeper understanding of what causes citrulline deficiency is crucial, as it often points to an underlying metabolic issue, whether inherited or acquired.

Quick Summary

Citrulline deficiency arises from genetic disorders affecting the urea cycle, such as Citrullinemia Types I and II, and acquired problems stemming from liver or intestinal dysfunction.

Key Points

Genetic Disorders: Citrullinemia, caused by gene mutations affecting urea cycle enzymes, is a primary cause of abnormal citrulline metabolism.
Urea Cycle Impairment: Both Citrullinemia Type I and Type II involve defects in the urea cycle, leading to the buildup of toxic ammonia, though their specific mechanisms differ.
Intestinal Dysfunction: Since the small intestine produces a significant amount of citrulline, conditions like short bowel syndrome can cause a deficiency.
Liver Disease: The liver's role in the urea cycle means that severe liver damage, including cirrhosis, can severely impair citrulline production.
Critical Illness: Low citrulline levels are associated with severe conditions like sepsis and Acute Respiratory Distress Syndrome (ARDS).
Distinguishing Causes: Diagnosis involves assessing plasma citrulline levels, as Type I can paradoxically show elevated levels while acquired causes lead to low levels.
Genetic Testing: For inherited causes like citrullinemia, molecular genetic testing is necessary to confirm the diagnosis and identify the specific gene mutation.

The Role of Citrulline in the Body

Before exploring the causes of its deficiency, it's important to understand citrulline's function. Citrulline is a non-essential amino acid, meaning the body can produce it, mainly within the intestines and kidneys. It is a critical intermediate in the urea cycle, a pathway that converts toxic ammonia into urea for excretion. Beyond its role in detoxification, citrulline is converted into arginine, which is a precursor for nitric oxide. Nitric oxide helps relax blood vessels, improving overall blood flow. Given its central role in these processes, a deficiency can have significant health consequences, particularly concerning ammonia buildup.

Primary Genetic Causes: Citrullinemia

Citrullinemia is the most well-known cause of a marked citrulline deficiency and is an inherited, autosomal recessive metabolic disorder. It is part of a broader class of conditions called urea cycle disorders. There are two main types, caused by different genetic mutations and with distinct presentations.

Citrullinemia Type I (CTLN1)

Citrullinemia Type I is caused by mutations in the ASS1 gene, which provides instructions for making the enzyme argininosuccinate synthetase (ASS). This enzyme is essential for a specific step in the urea cycle. A non-working or missing ASS enzyme prevents the proper removal of nitrogen, leading to an accumulation of ammonia and a corresponding increase in citrulline levels in the blood, which is counterintuitive. While this type causes elevated citrulline, problems in the urea cycle can lead to secondary issues impacting citrulline production elsewhere in the body. Symptoms can appear shortly after birth (classic neonatal form) or later in life (late-onset form).

Citrullinemia Type II (CTLN2)

Citrullinemia Type II results from mutations in the SLC25A13 gene, affecting a mitochondrial protein called citrin. This protein transports crucial molecules into the mitochondria for metabolic processes, including the urea cycle. A deficiency of citrin impairs the urea cycle's function, particularly in the liver, leading to hyperammonemia and other issues. Interestingly, patients with CTLN2 often have an aversion to carbohydrates and prefer protein and lipid-rich foods. This condition can manifest in infants as Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD) or in adults with neuropsychiatric symptoms.

Acquired Causes of Citrulline Deficiency

While genetic disorders are a major cause, low citrulline levels can also arise from a variety of acquired medical conditions that affect the body's metabolic function.

Liver Disease: Since the liver is the primary site for the urea cycle, severe liver disease, including cirrhosis and fatty liver, can impair citrulline synthesis and metabolism.
Intestinal Dysfunction: The intestines are responsible for a significant portion of the body's citrulline production. Conditions that reduce intestinal functional mass, such as short bowel syndrome, celiac disease, or chronic diarrhea, can lead to decreased citrulline levels.
Sepsis and Critical Illness: In critically ill patients, particularly those with severe sepsis and acute respiratory distress syndrome (ARDS), low citrulline levels have been observed. This is thought to be due to either reduced production or increased consumption during the body's inflammatory response.
Other Urea Cycle Disorders: Disorders affecting other enzymes in the proximal urea cycle, such as carbamoyl phosphate synthetase I (CPS1) deficiency or ornithine transcarbamylase (OTC) deficiency, can result in low citrulline concentrations.
Pancreatitis: Inflammation of the pancreas has been associated with citrulline depletion.
Medication and Lifestyle: Certain medications or prolonged catabolic states can also influence citrulline metabolism, particularly in susceptible individuals.

Comparing the Primary Genetic Causes of Citrullinemia


Feature	Citrullinemia Type I (CTLN1)	Citrullinemia Type II (CTLN2)
Affected Gene	ASS1	SLC25A13
Mechanism	Deficiency of the enzyme argininosuccinate synthetase (ASS).	Deficiency of the citrin protein, affecting mitochondrial transport.
Typical Onset	Neonatal or late-onset, variable severity.	Infancy (NICCD) or adulthood (CTLN2).
Ammonia Impact	Significant hyperammonemia due to urea cycle failure.	Recurrent hyperammonemia, especially in adult form.
Citrulline Levels	Elevated plasma citrulline, paradoxically.	May show elevated plasma citrulline.
Food Preference	Not specified, often avoid high-protein food.	Strong preference for protein/lipid-rich foods, aversion to carbohydrates.

Conclusion

In conclusion, the causes of citrulline deficiency are diverse, ranging from rare, inherited genetic conditions to more common, acquired health issues. The most notable causes are the genetic disorders known as Citrullinemia Types I and II, which disrupt the urea cycle through different metabolic mechanisms. However, factors like severe liver disease, intestinal damage, and critical illnesses can also impair the body's ability to produce or utilize citrulline effectively. Accurate diagnosis relies on understanding these complex pathways and is essential for implementing appropriate and potentially life-saving treatment strategies. For more in-depth information on genetic causes, consult the GeneReviews database from NCBI.

Frequently Asked Questions

Citrulline is a non-essential amino acid produced by the body, primarily in the intestines. Its main functions are acting as a key intermediate in the urea cycle to remove ammonia, and being converted to arginine, which increases nitric oxide to relax blood vessels.

A diet low in protein does not typically cause a direct deficiency because the body can produce its own citrulline. However, individuals with certain metabolic disorders, like Citrullinemia Type II, often develop an aversion to carbohydrate-rich foods and crave high-protein items.

Yes, many cases of citrulline deficiency are hereditary. The most common genetic causes are the autosomal recessive disorders Citrullinemia Type I and Type II, caused by mutations in the ASS1 and SLC25A13 genes, respectively.

Citrullinemia Type I involves a defective argininosuccinate synthetase enzyme, leading to a problematic buildup of citrulline and ammonia. Type II involves a defective citrin protein transporter, leading to hyperammonemia and metabolic issues, often with a preference for high-protein foods.

Symptoms vary by cause and severity but can include lethargy, poor feeding, vomiting, seizures, and neurological problems due to toxic ammonia buildup. Patients with Citrullinemia Type II may also experience psychiatric symptoms.

The small intestine is a primary site for citrulline synthesis. Therefore, conditions that reduce the functional mass of the intestine, such as short bowel syndrome, can significantly lower plasma citrulline levels.

Treatment depends on the underlying cause. For genetic disorders like citrullinemia, treatment often involves a highly restrictive low-protein diet, ammonia-scavenging medications, and sometimes a liver transplant. Management of acquired deficiencies focuses on treating the underlying medical condition.