Citrulline is an amino acid derived from ornithine and carbamoyl phosphate in a key reaction of the urea cycle, where it helps convert ammonia into urea for excretion. It’s also produced as a by-product when the enzyme family NOS (Nitric Oxide Synthase) catalyzes reactions involving arginine, leading to nitric oxide (NO) production.
The name "citrulline" originates from its high concentration in watermelon (Citrullus vulgaris). In the human body, citrulline plays a central role in arginine production. In the kidneys, it combines with aspartic acid through the action of the enzyme argininosuccinate synthetase (ASS) to form argininosuccinate. This compound then degrades into fumarate and arginine, helping to maintain plasma arginine levels. In the liver, ASS is similarly involved in the urea cycle, facilitating ammonia detoxification.
Clinically, plasma citrulline levels are valuable as a biomarker. They serve as indicators of small intestinal function and mass, intestinal injury, and rejection in small bowel transplants. Citrulline production occurs mainly in enterocytes, the cells lining the small intestine, where it reflects the unique capacity of these cells to convert glutamine into citrulline. Consequently, plasma citrulline levels correlate with enterocyte mass.
Both classic and type II citrullinemia are linked to specific genetic mutations that disrupt the urea cycle, resulting in elevated plasma citrulline. Additionally, increased plasma citrulline is used as a marker of postoperative intestinal failure.
In contrast, low citrulline levels can indicate reduced NO synthesis, as citrulline is a by-product of this process. Lowered NO availability may stem from the inactivation of NO or inhibition of its synthesis, both of which can reduce citrulline production and signal impaired NO pathways.
Reference:
Fragkos KC, Forbes A. Citrulline as a marker of intestinal function and absorption in clinical settings: A systematic review and meta-analysis. United European Gastroenterol J. 2018 Mar;6(2):181-191. doi: 10.1177/2050640617737632. Epub 2017 Oct 12. PMID: 29511548; PMCID: PMC5833233. [L]
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Elevated levels of citrulline in a plasma amino acids panel can signal various underlying conditions, often related to metabolic, liver, kidney, or intestinal health. Citrulline is an amino acid involved in the urea cycle—a critical process in the liver that removes excess ammonia from the body. High citrulline levels are commonly linked to urea cycle disorders (UCDs), liver dysfunction, kidney impairment, or certain metabolic and intestinal conditions. The symptoms, underlying causes, and treatment options for elevated citrulline depend on the specific health issue.
Possible Symptoms of Elevated Citrulline Levels
Symptoms associated with elevated citrulline levels often arise from excess ammonia or disruptions in nitrogen metabolism. Common symptoms can include:
Treatment Options for Elevated Citrulline
Treatment depends on identifying and addressing the underlying cause of the elevated citrulline:
Urea Cycle Disorders (UCDs)
UCDs, such as citrullinemia, result from enzyme deficiencies in the urea cycle, causing citrulline and ammonia to accumulate:
Liver Dysfunction
Conditions like cirrhosis or hepatitis impair liver function, which can disrupt the urea cycle and lead to elevated citrulline:
Kidney Dysfunction
Since the kidneys play a role in clearing citrulline, kidney impairment can lead to elevated levels:
Intestinal Health and Malabsorption Disorders
Citrulline is produced in the small intestine, so conditions affecting intestinal health, such as short bowel syndrome, can alter citrulline levels:
Metabolic Conditions (e.g., Mitochondrial Disorders)
Metabolic disorders affecting energy production and nitrogen metabolism, such as mitochondrial disorders, can lead to elevated citrulline:
Symptomatic and Preventative Management
Elevated citrulline levels can point to a range of health issues, and managing these levels often requires a multidisciplinary approach involving dietary changes, medications, and careful monitoring. A tailored treatment plan developed in collaboration with healthcare specialists—such as metabolic specialists, hepatologists, or nephrologists—can effectively manage symptoms and address the underlying cause of elevated citrulline levels.
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If aspartic acid, citrulline, and to a lesser extent, arginine are on the low side, these results would be consistent with an elevated rate of consumption of amino acids for fuel. They are all involved in the urea cycle, which converts ammonia to urea. Ammonia is generated when amino acids are burned as fuel.
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What fantastic service and great, easy-to-follow layouts! I love your website; it makes it so helpful to see patterns in my health data. It's truly a pleasure to use. I only wish the NHS was as organized and quick as Healthmatters.io. You've set a new standard for health tracking!
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As a PRO member and medical practitioner, Healthmatters.io has been an invaluable tool for tracking my clients' data. The layout is intuitive, making it easy to monitor trends and spot patterns over time. The ability to customize reports and charts helps me present information clearly to my clients, improving communication and outcomes. It's streamlined my workflow, saving me time and providing insights at a glance. Highly recommended for any practitioner looking for a comprehensive and user-friendly solution to track patient labs!
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