Citrin Deficiency

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Citrin deficiency is an inborn error of metabolism that appears to affect both the urea cycle and energy generation. Proteins taken through the diet are broken down into amino acids during digestion. Amino acids are the building blocks for cells. Excess amino acids are further broken down to produce energy. This generates ammonia which is a toxic waste product that is excreted by the body. Some of this is excreted in the urine by the kidneys and the rest is converted by a series of reactions into urea. In Citrin Deficiency there is a problem with the supply of L-Aspartate into the cycle which leads to complications. 

Citrin Deficiency can present within the first few weeks of life. If this is the case the condition is known as Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (or NICCD). It can also present in childhood as Failure to Thrive and Dyslipidemia caused by Citrin Deficiency (FTTDCD) or in adulthood in which case it is known as Citrullinaemia Type II (or CTLN2). 

Citrin Deficiency is thought to be one of the most common inherited metabolic disorders. It has a particularly high prevalence in Asia where the carrier frequency is 1 in 65. In China, between 60,000-80,000 people are thought to have the disorder. In Japan, Citrullinaemia type 2 affects 1 in every 100,000 people and NICCD affects 1 in 19,000.  Although most common in Asia, Citrin Deficiency is reported worldwide. Citrullinaemia type 2 is more common in males. 

Symptoms and severity vary between individuals. This section describes an overview of the signs and symptoms associated with Citrin Deficiency and the different forms. Every individual is different and therefore you may not have all the symptoms listed. 

Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD) 

Those with NICCD present with a low birth weight and growth problems. Symptoms include: 

• Liver problems 
• An enlarged liver  
• Problems clearing bile 
• An accumulation of fat in the liver.  
• Anaemia
• Low blood sugar 

Symptoms are usually not severe and often disappear by the age of one with appropriate treatment. There have been rare reports where this form has been fatal or where the child has required a liver transplant. As a child reaches two years of age they may start to have a great preference for high protein foods and those high in fats (lipids). This is accompanied by a great dislike or aversion to foods high in sugar or carbohydrates.  

A small number may go on to develop Citrullinaemia type II (CTLN2) in their 20’s or 30’s after appearing relatively healthy for some time. 

Failure to Thrive and Dyslipidemia caused by Citrin Deficiency (FTTDCD) 

More is still being discovered about this form. It has been proposed as a new type which causes a significant impact on quality of life in some people during the typically “silent” period before the onset of Citrullinaemia type 2 (CTLN2).  

Symptoms occur between the ages of one to eleven and may include: 

• Dislike of high carbohydrate foods 
• Delayed/restricted growth 
• Severe fatigue  
• Low blood sugar (hypoglycaemia) 
• High levels of lipids in the blood (hyperlipidaemia)
• Inflammation of the pancreas (pancreatitis) 
• An accumulation of fats in the liver 
• Weight loss 

Citrullinaemia type 2 (CTLN2) 

Not everyone with Citrin Deficiency will go on to develop Citrullinaemia type 2. Most people who are receiving the correct treatment and management do not develop it. 

Symptoms of the severe form of Citrullinaemia Type II are recurrent short episodes of illness known as metabolic crises which are characterised by high levels of ammonia (hyperammonaemia). Symptoms of this may include: 

• Altered behaviour 
• Aggression 
• Irritability 
• Disorientation, 
• Hyperactivity  
• Delusions 
• Altered level of consciousness 
• Drowsiness 
• Loss of memory 
• Seizures  
• Coma (severe cases) 

Other forms of CTLN2 may include:  

• Low BMI 
• High levels of triglycerides (lipids) in the blood 
• Inflammation of the pancreas (pancreatitis) 

Many of these individuals are fond of protein and foods high in fats (lipids) whilst also having a strong dislike or aversion to sugary carbohydrate rich foods. 

Symptoms can come on suddenly and be precipitated by alcohol intake, medications, high sugar intake, and surgery.  

This disorder can be diagnosed through blood tests to determine raised ammonia levels and raised levels of citrulline. Liver function tests may be used in the diagnosis of NICCD. Genetic testing is available. In some countries, like some states in the USA this disorder is routinely screened for at birth as part of newborn screen programmes. It is not currently screened for at birth in the UK. 

Treatment will be overseen by a metabolic consultant and specialist dietitian. Regular follow ups should be attended as required and advised. Dietary changes should not be made without consulting your metabolic team. It is important to note that although Citrin Deficiency belongs to a group called the Urea Cycle Disorders, the dietary management followed in these disorders is dangerously unsuitable for those with Citrin Deficiency. Always follow the advice of your metabolic team. 

Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD) 

Treatment includes fat-soluble vitamin supplements and lactose-free and MCT-enriched formulas. Symptoms for most resolve by one year of age. Vitamin D and/or zinc supplementation may be required. In rare severe cases, liver transplant may be required. 

Failure to Thrive and Dyslipidemia caused by Citrin Deficiency (FTTDCD) 

There is currently no defined treatment yet due to a lack of information. However, dietary management using high protein/high fat (lipids) and low carbohydrate/sugar diet has been beneficial in some. Sodium pyruvate may be used to counteract restricted growth. 

Citrullinaemia type 2 (CTLN2).  

Liver transplant has been the most successful treatment until recently. Citrullinaemia type 2 can now be managed using arginine, sodium pyruvate, and medium chain triglyceride (MCT) oil. 

Treatment also aims to prevent high ammonia and promote growth. This can be achieved through a high protein/high fat (lipids) and low carbohydrate diet. A specialist dietitian will advise on diet and make any changes where required. High-carbohydrate meals and alcohol should be avoided. Arginine may be prescribed to help prevent high ammonia.  

Your metabolic team will give you an emergency regimen to follow for times of illness. In the case of the onset of symptoms switch to a high protein diet and contact your metabolic team. If the person is unable to eat/tolerate food and is vomiting or have a deteriorating level of consciousness, then emergency admission to hospital is needed. It is advised that those with Citrullinaemia type 2 wear a medic alert bracelet and carry a card containing details of their illness and contact details for their metabolic consultant. 

Certain medications like paracetamol painkillers, acetaminophen and tablets for gastritis e.g. rabeprozole should be avoided as they can precipitate symptoms.  During hospital visits, glucose containing intravenous fluids should be avoided. Saline is the preferred fluid for intravenous infusion. Small bolus doses of glucose may be given to reverse hypoglycaemia confirmed on blood tests. 

Generally, it is true to say that we all carry two copies of each gene. Citrin deficiency is passed down by an autosomal recessive mode of inheritance. A person who has one normal gene and one gene for the disease is termed a carrier for the disease and does not show any symptoms. The condition arises when an infant inherits a gene for the disease from both parents.  

The risk to the offspring of a couple who are both carriers is 25%. There is a 50% chance that their child will be a carrier. There is a 25% chance that the child will not carry the abnormal gene. This risk is the same for each pregnancy. This is a general description of autosomal recessive inheritance.  

For further information a genetic counselling service should be consulted. 

All information accurately referenced by Metabolic Support UK, however, should you require access to our references, please contact us by email: contact@metabolicsupportuk.org