Type I tyrosinemia
| Classification according to ICD-10 | |
|---|---|
| E70.2 | Tyrosine metabolism disorders Tyrosinemia |
| ICD-10 online (WHO version 2019) | |
As a Type I tyrosinemia is called a rare inherited metabolic disease from the group of Tyrosinämien . The inherited defect of an enzyme in the breakdown of the amino acid tyrosine ensures the formation of harmful metabolic products. It is also known as hepato - renal tyrosinemia, since damage to the liver and kidneys are the leading factors. The disease manifests itself in early childhood or infancy and can be treated with medication, diet or liver transplantation .
distribution
The disease is autosomal - recessive inherited. It generally occurs in around 1: 100,000 to 1: 120,000 newborns and is therefore rare. Regions of frequent occurrence are Québec and Scandinavia .
root cause
The disease is based on a mutation on chromosome 15 . The mutation causes a deficiency in the enzyme fumarylacetoacetase (FAA), which catalyzes the last step in the breakdown metabolism of the amino acid tyrosine to the two end products acetoacetic acid and fumaric acid . Instead, succinylacetone , succinylacetoacetate and maleyl acetoacetate are formed, and these defective metabolic products ultimately damage cells in the liver, kidneys and brain. In addition, the incorrect metabolite succinylacetone blocks the function of the enzyme δ-aminolevulinic acid dehydratase . When the enzyme fails, δ-aminolevulinic acid increasingly accumulates in the body, which damages the nerves and can lead to attacks similar to those of porphyria .
The affected FAA gene consists of a total of 35,000 base pairs . It contains 14 exons and codes for an mRNA of 1260 base pairs. Several mutations leading to the disease have been described. The most common mutation is the exchange of guanine to adenosine , which leads to incorrect splicing of the mRNA. So far, no connection has been established between the various mutations and the actual severity of the disease.
In some cases, spontaneous weakening of the symptoms has also been described. These are attributed to the formation of a genetic mosaic in the body's cells. Healthy cells without a genetic defect exist alongside diseased cells with a genetic defect in the same body. The healthy cells have a survival advantage over the sick and so increase in proportion. This is also named as a possible explanation for the different severity of the disease.
Clinical manifestations
liver
A distinction can be made between an acute and a chronic course of the disease. In the acute course, liver failure usually develops within months after birth . Depending on the severity of the organ failure , the affected infants show edema , enlarged liver , general failure to thrive, blood coagulation disorders and hepatic encephalopathy . The failure of the organ is often triggered by an infection , as the immune response creates a catabolic metabolic situation in which body proteins are broken down and many amino acids, including tyrosine, are released. Acute liver failure is the first manifestation of the disease in around 80% of patients.
In the chronic form or after surviving acute liver failure, liver damage is very likely to develop, which leads to liver cirrhosis . With both forms of the course, the risk of liver cell carcinoma is enormously increased. The youngest patients described with such a type I tyrosinemia cancer were 15 to 25 months old.
kidney
The disease shows damage to the kidney cells, which first manifests itself in a failure of the kidney tubules . The damage can lead to damage to the kidney corpuscles and loss of kidney function. On the basis of this process, renal tubular acidosis , aminoaciduria , enlargement of the kidneys and finally a reduction in the glomerular filtration rate can develop.
Neurological damage
The damage caused by the disease to the nervous system traditionally takes place in two phases. In the first phase, the focus is on painful abnormal sensations, increased muscle tone up to intestinal obstruction and an increase in heart rate ( tachycardia ). Paralysis can occur less often at this stage . After a short recovery phase, paralysis affects the whole body, which can lead to the need for artificial respiration .
heart
The patients rarely show cardiomyopathy , which, however, usually does not lead to impaired cardiac function.
pancreas
In the pancreas , tyrosinemia type I can lead to hyperplasia of the islet cells via a previously unexplained mechanism . This change then leads to a drop in blood sugar levels ( hypoglycaemia ) via an increased production of the hormone insulin .
Investigation methods
In Germany, the only routine method for screening newborns is to determine the tyrosine level in the blood. However, this method only covers 90% of the sick, as 10% only develop an increased level of the amino acid in the later course. In some states of the USA , methionine , succinylacetone and δ-aminolevulinic acid are still routinely determined in the blood.
For prenatal diagnosis , succinylacetone can be determined from the umbilical cord blood as part of an umbilical cord puncture . Another possibility is to determine the activity of the FAH enzyme in amniocytes or chorionic cells as part of a chorionic villus sampling .
If a patient with type I tyrosinemia is suspected, there are several methods of detecting the disease. On the one hand, tyrosine and methionine can be determined in plasma and urine. Likewise, δ-aminolevulinic acid and its metabolites can be determined in the urine. The enzyme defect itself can be traced by detecting the FAH activity in lymphocytes , erythrocytes or fibroblasts . Succinylacetone can also be detected in the urine.
Differential diagnosis
Numerous other conditions can also cause increased levels of tyrosine in the blood. This includes transient tyrosinemia in newborns, which is based on the immaturity of an enzyme. This usually regresses without consequences. Type II and type III tyrosinemia also lead to increased levels of the amino acid. In addition, scurvy or hyperthyroidism can lead to an increase in tyrosine. In healthy people, tyrosine levels are usually elevated after a meal.
treatment
diet
The goal of the diet is to minimize the amount of tyrosine in the body. First, it should avoid the ingestion of tyrosine and phenylalanine , which the body metabolizes to tyrosine. Second, conditions in which the metabolism becomes catabolic should be avoided, as the body would otherwise mobilize amino acids and thus also tyrosine from its proteins, for example from muscle tissue . After the diagnosis, the diet should consist of special products free of tyrosine and phenylalanine and be rich in energy for several days. With the former, practically no tyrosine is released through exogenous intake. The high nutritional value avoids catabolic conditions. You can then switch to normal foods that contain only very small amounts of the two amino acids. Catabolic situations such as prolonged hunger should be avoided. Therefore, meals should be distributed evenly and regularly throughout the day. To avoid tyrosine and phenylalanines, patients have to limit their consumption of dairy, egg and meat products very severely. As the sole therapeutic measure, however, the diet is inadequate and cannot stop the progression of the disease. However, it seems to have a positive influence on the course of kidney damage. The plasma levels of tyrosine should be below 500 μmol / l as part of the diet.
Medical therapy
With the help of nitisinone (NTBC), the disease can also be treated with medication. NTBC blocks the enzyme 4-hydroxyphenylpyruvate dioxigenase, which catalyzes an early breakdown step in the tyrosine metabolism. As a result of the blockade, there are no longer any substrates available for the formation of toxic metabolites. The diet should also be maintained under NTBC treatment, otherwise symptoms of type II tyrosinemia may occur. No serious side effects were observed with an adequate diet, but leukopenia (lack of white blood cells) and thrombopenia (lack of blood platelets) do occur occasionally . It is not certain whether these are triggered by the active ingredient NTBC or are due to the pre-existing damage to the patient's liver. Around 90% of patients respond to medication with NTBC, even if they are already in the acute liver failure stage.
The success of the therapy can be monitored by determining the amount of succinylacetone in the plasma. The biggest problem with drug therapy is that NTBC cannot prevent the occurrence of liver cell carcinoma. In a mouse model it could be shown that malignant neoplasms continue to occur in the liver despite the treatment. Since most patients have already developed severe liver damage - often with cirrhosis - at the time of diagnosis, the early diagnosis of liver cancer is difficult, since cirrhosis nodules and carcinomas can only be distinguished very poorly in imaging procedures. As a makeshift, the tumor marker alpha-1-fetoprotein (AFP) is determined. The level is usually very high in the sick due to liver damage, so this marker is by no means specific for tumors. If the level of AFP does not fall during therapy, or if it rises again during therapy, hepatocellular carcinoma can be assumed. Imaging of the liver using sonography or MRI is currently recommended every six to twelve months. The AFP level should be determined quarterly and monitored over time. In addition, some authors recommend several studies on the development of the child, since NTBC therapy can lead to developmental delays, which have not yet been proven.
For better detection of liver cell carcinomas, reliable means of detection are currently being sought for a sub-fraction of AFP that react with lectin . This marker should be able to differentiate more specifically between non-malignant liver damage and malignant neoplasm. However, detailed studies and marketable solutions are still pending.
Liver transplant
Until the introduction of NTBC, liver transplantation was the only promising treatment for tyrosinemia type I. One indication for transplantation is non-response to NTBC, which affects around 10% of patients. So far, no reliable predictive options have been found to estimate the probability of non-response in an individual case before the start of treatment. According to current recommendations, liver transplantation should be considered if the AFP level rises again or does not fall under NTBC therapy. In the rarer case that the patient's liver has not yet been remodeled cirrhotically, new nodular changes in the liver can be seen as an indication of hepatocellular carcinoma and a transplant of the organ can be considered.
Prospect of healing
Due to the rarity of the disease, there are few studies on the long-term course of the disease. A study of French patients on NTBC therapy found a survival rate of 97.8% for an average of four years and nine months after treatment with NTBC. A Dutch study in the 1990s reported a survival rate of 83% after two years in patients who had received a liver transplant. Likewise, in contrast to NTBC therapy, liver transplantation does not improve kidney function in patients. In addition, there is no longer any clinically relevant damage to the nerves under successful NTBC therapy. The authors of the French long-term study point out, however, that there are indications of a worsened school development of the patients, even if this has not yet been meaningfully quantified.
Research history
In Québec , effective screening of all newborns has been in place since the 1970s. Since diet was the only therapy available at the time, most patients died of the disease within a few years. In the early 1990s, liver transplantation was established as a therapeutic method. In 1992 a Swedish research group from the University of Gothenburg used NTBC, which had actually been developed as a herbicide , for the first time on a life-threatening child and four others . The drug was in the following years in many countries as off-label use used. It was finally approved in the US in 2002 and in the EU in 2005 .
Individual evidence
- ↑ a b c d e f g h i j k l m n o p q B. Rodeck, U. Baumann: Tyrosinemia Type I. In: Monthly Pediatric Medicine. 2004, 152, pp. 1095-1101.
- ^ A b Anthony Killeen, Emanuel Rubin, David Strayer: Developmental and Genetic Diseases. In: Raphael Rubin, David Strayer: Rubin's Pathology. 5th edition. Philadelphia 2008, ISBN 978-0-7817-9516-6 , p. 213.
- ↑ Guideline of the German Society for Child and Adolescent Medicine Tyrosinemia Type I. last updated 11/1997; than online ; last accessed on November 22, 2007.
- ↑ a b c d e f g h i j P. J. McKiernan: Nitisinone in the Treatment of Hereditary Tyrosinaemia Type 1. In: Drugs. 2006; 66 (6), pp. 743-750, PMID 16706549
- ↑ a b c d e f g h U. Baumann, B. Rodeck: Liver transplantation in tyrosinemia type I. In: Monthly Pediatric Medicine. 2004, 152, pp. 1102-1107.
- ↑ M. Al-Dhalimy, K. Overturf, M. Finegold, M. Grompe: Long-term therapy with NTBC and tyrosine-restricted diet in a murine model of hereditary tyrosinemia type I. In: Mol Genet Metab. 2002 Jan; 75 (1), pp. 38-45, PMID 11825062
- ↑ a b c A. Masurel-Paulet, J. Poggi-Bach, MO Rolland, O. Bernard, N. Guffon, D. Dobbelaere, J. Sarles, HO de Baulny, G. Touati: NTBC treatment in tyrosinaemia type I: long-term outcome in French patients. In: J Inherit Metab Dis. 2008 Feb; 31 (1), pp. 81-87, PMID 18214711
- ^ S. Lindstedt, E. Holme, EA Lock, O. Hjalmarson, B. Strandvik: Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase. In: The Lancet . 1992 Oct 3; 340 (8823), pp. 813-817, PMID 1383656
