Citrin deficiency (CD) is a rare, inherited metabolic disorder that primarily affects the liver’s ability to process and detoxify certain substances. CD belongs to a group of urea cycle defects, which interfere with the clearance of toxic nitrogen waste from the body. Because CD presents differently across a patient’s lifespan, early identification is necessary to prevent severe, life-threatening complications. Understanding the underlying cellular mechanism helps explain why the symptoms manifest and how the condition must be managed.
The Underlying Genetic and Metabolic Defect
The cause of Citrin Deficiency lies in a mutation of the SLC25A13 gene, which creates the citrin protein. Citrin is an aspartate-glutamate carrier protein located on the inner membrane of the mitochondria. Its function is to serve as a component of the Malate-Aspartate Shuttle (MAS), a system that transports molecules between the mitochondrial space and the cytosol.
The citrin protein facilitates the transport of aspartate out of the mitochondria into the cytosol, a step essential for the urea cycle. The urea cycle is the liver’s primary detoxification pathway, converting excess, toxic ammonia into harmless urea for excretion. When citrin is deficient, the supply of aspartate to the urea cycle is hindered, impairing the body’s ability to effectively remove ammonia.
Impairment of the MAS also creates a chronic energy deficit within the liver cells. The shuttle moves high-energy electrons into the mitochondria for ATP production, and its failure disrupts multiple metabolic pathways. Consequently, the liver struggles to process carbohydrates and fatty acids for energy. This leads to a build-up of metabolic byproducts that contribute to the disorder’s clinical symptoms.
Clinical Presentation: Citrin Deficiency Across the Lifespan
The clinical manifestations of citrin deficiency are highly variable and categorized into three age-dependent phenotypes. The first presentation, usually occurring between one and five months of age, is Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD). Infants with NICCD display symptoms of liver dysfunction, including prolonged jaundice, cholestasis (impaired bile flow), and growth failure.
This phase can be severe, sometimes progressing to liver failure, but symptoms often resolve spontaneously in most patients by the age of one. Following this initial period, patients enter a latent phase, sometimes termed Failure to Thrive and Dyslipidemia caused by Citrin Deficiency (FTTDCD). This stage, spanning childhood and adolescence, is characterized by a strong, self-selected dietary preference.
During the FTTDCD phase, affected individuals frequently show an aversion to carbohydrate-rich foods like rice or sweets, preferring high-protein and high-fat foods instead. This preference is a compensatory mechanism, as fats and proteins are metabolized through pathways less dependent on the citrin protein. Patients in this stage may still experience persistent issues such as dyslipidemia (abnormal fat levels in the blood), mild growth delays, or fatigue.
The most severe manifestation is Citrullinemia Type II (CTLN2), the adult-onset form that typically appears between 20 and 50 years of age. CTLN2 is a life-threatening condition marked by episodes of hyperammonemia, or dangerously high ammonia levels in the blood. These episodes can be triggered by factors like alcohol consumption, high-carbohydrate meals, or illness. Symptoms are primarily neurological, including confusion, disorientation, irritability, seizures, and potentially coma.
Diagnostic Procedures and Early Detection
Early diagnosis of citrin deficiency is important for preventing severe complications. Diagnosis often begins with newborn screening (NBS) in regions where the condition is included on the standard panel. NBS involves measuring amino acid levels in a dried blood spot collected shortly after birth. Elevated levels of citrulline, an amino acid that builds up when the urea cycle is impaired, are the primary indicator used to screen for CD.
Relying solely on citrulline levels can result in missed diagnoses, as some infants with CD may have normal results. Therefore, biochemical analysis of plasma amino acids is used to confirm suspicion, looking for a pattern that includes elevated citrulline, threonine, and methionine. Liver function tests showing elevated enzymes like AST and ALT, especially in a jaundiced infant, can also point toward NICCD.
The definitive method for confirming a diagnosis of citrin deficiency is genetic sequencing of the SLC25A13 gene. This test identifies the specific mutations responsible for the non-functional citrin protein, providing an unambiguous diagnosis. Genetic confirmation is considered the gold standard, particularly for individuals who present later in life with milder symptoms.
Treatment and Long-Term Management
The management of citrin deficiency centers on dietary modification to bypass the metabolic block and prevent the accumulation of toxic substances. The standard recommendation is a high-protein, high-fat, and low-carbohydrate diet, which contrasts with advice for other urea cycle disorders. This nutritional strategy decreases the metabolic burden on the impaired Malate-Aspartate Shuttle and limits the production of toxic byproducts.
For infants with NICCD, treatment includes lactose-free formulas supplemented with medium-chain triglycerides (MCT) oil. MCTs are a specific type of fat that provides an alternative energy source to the liver, as they are metabolized through a pathway that does not require the citrin protein. MCT oil supplementation remains an effective therapeutic measure throughout all phases of life to supply energy to the compromised liver cells.
Pharmacological support addresses specific symptoms and metabolic imbalances. Supplements such as L-arginine may be administered to assist the impaired urea cycle by providing a substrate for the remaining functional steps. Sodium pyruvate is also used in some cases to help restore proper energy production within the cells.
Long-term management requires continuous medical monitoring, including regular checks of liver function, plasma amino acid levels, and ammonia levels, especially during periods of illness or stress. For patients who develop severe adult-onset CTLN2 and do not respond to dietary and pharmacological interventions, liver transplantation is the only curative option. The transplanted liver contains healthy SLC25A13 genes and produces functional citrin, resolving the underlying metabolic defect.