Author
Summary: Gabi Niethammer, as published in Alpha1 Journal 1/2023.
Reenactment of a consultation after the initial diagnosis based on the questions that most frequently concern families: How does the disease develop, how does it "work"?
In very simple terms, the body contains proteins (proteases) that are needed during inflammatory responses to break down tissue. Inflammatory cells enter tissue, defend against pathogens, isolate viruses, and attack harmful substances. However, a mechanism is also needed to stop proteases. This is where antagonists (inhibitors) like alpha-1-antitrypsin come in. These bind to the proteases and thus halt the breakdown process. If alpha-1 is deficient, the proteases "eat their way through" the tissue and don't even stop at healthy lung tissue. Alpha-1-antitrypsin deficiency is caused by a simple mutation of a single amino acid.
The term AAT deficiency is somewhat misleading, since alpha-1 is produced in the liver in most people, but it folds incorrectly there and therefore cannot leave the liver. With Z-molecules, the alpha-1 that remains in the liver clumps together and forms chains (polymerization). So there is too much alpha-1 in the liver, and since it cannot be eliminated, too little reaches the lungs via the bloodstream, resulting in a deficiency.
Where does the alpha-1 antitrypsin deficiency come from and what was its purpose?
It is assumed that the deficiency variants originated approximately 2,500 years ago, with PI*Z being attributed to Scandinavia and PI*S to Spain. Furthermore, it is believed that under the living conditions of that time, with their high prevalence of infections, having at least one alpha-1 deficiency gene, i.e., being heterozygous affected, offered a certain survival advantage. This would explain the spread over a relatively short period in historical terms.
Why is my child affected? Is the diagnosis certain?
The information for alpha-1 antitrypsin is located on chromosome 14. Basically, every person has two copies of the gene, one of which they pass on to their child. Two mutated genes in the body mean being homozygous affected; the most common variant here is PI*ZZ. If only one gene is affected, this is called heterozygous affected (PI*MZ), and the person is a carrier of the deficient gene.
In a family with a homozygous affected child, both parents must carry at least one mutated gene, meaning they themselves are at least heterozygous affected. Statistically, the risk for further children is simple: 25 % (healthy) to 50 % (heterozygous) to 25 % (homozygous). However, biology doesn't follow this pattern, and the outcome is determined anew in each individual case.
In an exemplary family constellation with a homozygous affected father and a homozygous healthy mother, all children can only be heterozygous, meaning they carry the defective variant. The situation is different if the mother is not healthy but is herself a carrier; then the children can be either heterozygous or homozygous affected. If she herself is PI*ZZ, the children can only be homozygous affected, since only one Z gene can be passed on from each parent.
What are the symptoms of the illness?
This serious condition primarily affects the liver and affects very young children. In early infancy, AATD can manifest as prolonged jaundice, pale stools, liver enlargement, failure to thrive, elevated liver enzymes, and, in rare but dangerous cases, vitamin K deficiency bleeding. In toddlerhood, liver and spleen enlargement may develop, accompanied by abdominal swelling and itching.
Elevated liver enzyme levels are often an incidental finding because routine laboratory tests are performed on younger children during a completely different examination or, for example, an ENT procedure, and the elevated liver enzyme levels are then noticed in previously completely healthy children.
Later in school, children who have remained healthy until then very, very rarely become ill. However, it can occur occasionally and then manifests itself, for example, through itching, general weakness, and growth retardation, or again through abnormal liver function tests. In extremely rare cases, dramatic symptoms such as vomiting blood, bloody stools, or shortness of breath with cyanosis upon exertion occur. This hepatopulmonary syndrome is not the lung disease in adult Alpha syndrome, but rather lung problems resulting from liver cirrhosis.
Alpha-1 antitrypsin deficiency (AATD) can also be detected if a child already has a liver disease such as cystic fibrosis, biliary atresia, or viral hepatitis, and the course of that disease is atypical and significantly worse. Unfortunately, fatty liver disease in children is also increasing dramatically, and it is feared that affected children will experience a worse prognosis if they also have alpha-1 antitrypsin deficiency.
It is important to note that in children and adolescents there is no actual lung manifestation and this topic does not usually fall within the remit of the pediatrician.
Is the diagnosis certain?
For diagnosis, it is important that the serum levels of healthy individuals (MM) and affected individuals (ZZ) do not overlap. If a level is very low, e.g., 0.3 g/l, it is unlikely to be MM. Conversely, a higher level, e.g., 1.5 g/l, cannot indicate a homozygous affected individual. Previously, this initial measurement was usually followed by PI determination (phenotyping), in which the protein in the blood is characterized. Nowadays, genotyping is more commonly performed directly to detect the gene mutation through a genetic test. This test can be carried out using a cheek swab, which is free of charge for the physician and analyzed at the Alpha1 Center in Marburg.
The question of a liver biopsy for diagnosis does not arise in most cases for children and is only indicated in doubtful cases, for example, if there is suspicion of another liver disease.
If my child becomes (seriously) ill, what is the risk (prognosis)?
In the 1970s, 200,000 children in Sweden were screened and their health development was monitored for more than 30 years. By far the most common finding was that the children had significantly elevated liver enzyme levels as infants, but these levels decreased and normalized during childhood. Only a maximum of 3–5 of these children experienced more serious complications.
It is almost impossible to give a prognosis in individual cases. Significantly elevated values of some laboratory parameters (platelets, bilirubin, PTT, GGT, CHE, GOT) indicate that the course of the disease could be more severe; a marked enlargement of the liver and spleen after the first year of life could also point in this direction. Very rare and serious is the development of portal hypertension (blood from the abdominal cavity can no longer flow through the already scarred liver, the pressure in the blood increases in the abdominal cavity, and the blood flows elsewhere).
If everything is healthy at around four years of age and the liver appears normal except for slightly elevated liver enzyme levels, then it is very unlikely that anything will happen during childhood and adolescence.
„"Therapy is usually not necessary!"“
Are there treatment options?
What can I do for my child? Therapy is usually not necessary! Symptomatic treatment for affected infants can be provided with the bile acid preparation ursodeoxycholic acid. In the very rare cases of advanced disease, a deficiency in fat-soluble vitamins (A, D, E, K) may need to be addressed, a high-energy diet may be required, or various anti-itch measures may be necessary.
As a preventative measure, a healthy weight should be the goal, and the child should participate in sports and be generally active. Early intervention for fever and inflammation is advisable. The vulnerable liver should be protected with the recommended vaccinations, plus additional hepatitis A vaccination, and liver-damaging substances should be avoided. Regarding the lungs, the most important message remains: no exposure to smoke and dust – and this must be consistently maintained from childhood onward!
The only curative therapy is a liver transplant. In only 3–4 of the children who receive a liver transplant is the cause AATD, and there are only a few indications where a liver transplant is considered. Long-term survival is over 90%.
Therapeutic approaches such as future gene therapy and others are still far from being foreseeable. Corresponding medications that are under discussion are currently still in the theoretical stage and will first undergo trials in adults before being used in children. Augmentation therapy (substitution of alpha-1) also plays no role in the treatment of affected children, as previously stated.
What checks are required?
- Regular blood tests
- Regular ultrasound examinations
Initially every few weeks/months, then less frequently, and from school age onwards it is usually sufficient to present the child to the attending pediatrician every one to two years.
What should I do if my child's alpha-1 level is only slightly reduced?
If a pediatrician were to test every child seen for AATM, they would certainly discover a heterozygous affected child now and then, as it is estimated that one in 40 to 50 people carries the deficiency variant. However, since there is fortunately no actual risk of illness in childhood and adolescence, no further measures are necessary beyond advising them to quit smoking.
How can I learn more about the connections?
In 2022, a group of pediatricians caring for children with Alpha-1 antitrypsin deficiency wrote an update on the condition in the journal Monatsschrift Kinderheilkunde.
An overview of possible liver diseases in children and adolescents is provided by the Association for Children with Liver Disease.
