I. What is Citrin Deficiency Disease?
Citrin deficiency disease is a disease in which the body, mainly in the liver, does not make the protein called “Citrin” very well.
The symptoms of Citrin Deficiency Disease are completely different in childhood and in adulthood, so they are referred to by the following names.
Children (especially infants): Neonatal intrahepatic cholestasis caused by citrin deficiency, NICCD (neonatal intrahepatic cholestasis caused by citrin deficiency)
Adult disease name: adult onset citrullinemia type II: CTLN2 (adult-onset type II citrullinemia)
What are the manifestations of Citrin deficiency disease?
Infancy: NICCD
Children with NICCD may present with yellow urine, persistent yellowing of the skin and sclera (jaundice), frequent feeding, poor weight gain, or fatness. The diagnosis can be confirmed by performing more detailed tests (blood, ultrasound, liver biochemistry, genetic tests). In our country, many people are misdiagnosed with cytomegalovirus (CMV) hepatitis.
Treatment can be done with special formulas and symptomatic drugs, etc. There are also cases where the symptoms disappear on their own without any treatment. However, the use of targeted treatment will greatly accelerate the pace of improvement while potentially reducing the chances of progression to liver failure.
Toddler? School-age? Adolescence?
Although there will be a period of time when it does not look like you have the disease, some patients may present with the features and symptoms described below. One of the characteristics is a partial diet, with some foods being very much loved and others very little. They tend to prefer high protein and high fat foods such as beans (tofu, beans), eggs, cheese, salad dressings, etc., but not sugary foods such as fruits, juices, and desserts, which are generally enjoyed by children. In addition, there are children who hate bread and rice.
This characteristic is thought to be a physical response to effectively cope with illness. Do not reprimand the child for being “excessively picky and disobedient” and do not indiscriminately force the child to eat the same foods as everyone else (especially sugary foods).
The following symptoms may also occur: easy fatigue, lethargy, low blood sugar, frequent diarrhea, diagnosis of pancreatitis due to abdominal pain, and seizures.
Adolescence? Adulthood: CTLN2
CTLN2 shows completely different symptoms than NICCD. cTLN2 can manifest as sudden forgetting how to get home, not knowing what you are doing, loss of consciousness, irritability, and seizures. The diagnosis can be made based on elevated ammonia and citrulline in the blood.
Nowadays, the confirmed effective treatment is liver transplantation. Early detection through regular checkups is expected to be treated with medication and avoid liver transplantation.
Recently, some problems have been identified in the previously used medical treatment of CTLN2. Because CTLN2 causes hyperammonemia, symptomatic treatment often involves low protein foods, high energy fluids, and anti-cerebral edema drugs, but these treatments may worsen CTLN2 symptoms.
Not all patients with Citrin deficiency disease (2 SLC25A13 gene abnormalities) develop CTLN2, and it is possible to live a healthy life. It is now believed that the development of this disease is related to lifestyle habits and hormonal effects. However, the exact cause is still unknown and is currently under investigation.
Important points to note
About diet
As mentioned earlier, patients with citrin deficiency have a special diet that is averse to sugary foods. This can be seen as a response to the body’s struggle with citrin deficiency. It is better to talk to the school teacher in advance and tell them that your child “may not be able to eat the same food as others at school, etc.”.
About alcohol consumption
Most patients are not allowed to drink alcohol. It is important to be careful because alcohol consumption can be a trigger for the onset of the disease.
About high concentration glucose solution drip
Next, hospitals and doctors should be aware that patients with citrin deficiency may have other medical conditions, such as respiratory infections, or may undergo surgery as a result of an accident. At that time, medical staff should be aware of the following things.
In patients with citrin deficiency disease, the use of large amounts of highly concentrated glucose solutions (high-energy infusions, glycerin injections, etc.) can lead to a worsening of symptoms and can be very dangerous, so care is necessary.
Of course, patients themselves and their families should also keep this in mind, and it is vital to make this clear to doctors and hospitals. This can be considered as an important part of disease prevention measures. In addition, it is not considered necessary to worry about low concentration glucose drips of about 5% in pediatrics, etc. for the treatment of vomiting, diarrhea and hypoglycemia.
IV. Why do I get sick (genetic aspects)?
Here, a brief explanation of genetic problems is provided. If you would like a more detailed explanation, please consult with your doctor or a genetic counselor.
The human body is made up of many kinds of proteins. Genes are like design drawings for the various proteins, written in a text called DNA.
Citrin is also an important protein, mainly in the liver, and the design drawing for Citrin is called the SLC25A13 gene (the notation for the gene is difficult to understand and is referred to here as the citrin gene). Each person carries 2 design drawings of the citrin gene. One is from the father and the other is from the mother. These genes (design drawings) are often written incorrectly (called variants or mutations in genetics).
In the case of Citrin deficiency disease, if only one of the two design drawings is incorrectly written and the other is not abnormal, the person will not get sick (this state is called a carrier). The majority of parents of Citrin deficiency patients are carriers, and the father and mother of Citrin deficiency patients are carriers of both the normal gene [A] and the faulty gene [a], denoted by Aa. The probability of inheritance of a child born to two parents with the same Aa is:
Carrying 2 normal genes AA 1/4
Carriers with one normal gene and one faulty gene Aa 1/2
Patients with 2 faulty genes aa 1/4
The combination of two faulty genes, aa (mutant purets), leads to Citrin deficiency disease because of the inability to make functional citrin. Such a form of inheritance is known as autosomal recessive inheritance.
An actual survey of the frequency of Citrin mutations showed that the same mutations were detected in the Chinese as in the Japanese, especially in the area south of the Yangtze River in China, with a carrier rate of 1 in 40 people.
However, it is not quite clear whether NICCD and CTLN2 occur in all people who are genetically pure of the mutation.
V. What is Citrin?
Citrin is a functional protein embedded in the inner membrane of mitochondria and is called an aspartate (Asp)-glutamate (Glu) carrier. citrin deficiency disease is associated with a lack of aspartate in the cytoplasm of the liver and a decrease in energy production in the mitochondria, resulting in poor weight gain and fatigue.
VI. Need for long-term follow-up investigations
There is still a lot of uncertainty about this disease (Citrin deficiency disease). In order to better understand this disease, long-term follow-up is necessary.
By following up, the following points are possible.
(i) avoid dangerous treatment of the disease due to misdiagnosis of other diseases
(2) Adopt internal medication without liver transplantation and appropriate food therapy
③Take countermeasures to prevent the occurrence of serious diseases