Type I tyrosinemia
As a type I tyrosinemia is called a rare inherited metabolic disease from the group of Tyrosinämien. Here, the inherited defect of an enzyme in the degradation of the amino acid tyrosine in the formation of harmful metabolites provides. It is also known as hepato -renal tyrosinemia because it does damage to the liver and kidneys are the leaders. The disease manifests in early childhood or infancy, and is medically treatable by diet or by a liver transplant.
- 6.1 diet
- 6.2 Drug therapy
- 6.3 Liver Transplantation
Dissemination
The disease is inherited as an autosomal recessive trait. Generally, it occurs in about 1:100,000 to 1:120.000 neonates and is therefore rare. Regions are heaped occurrence Quebec and Scandinavia.
Cause
The disease is a mutation based on chromosome 15. The mutation makes for a deficiency of the enzyme Fumarylacetoacetase (FAA ), which catalyzes the last step to the two end products of acetoacetic and fumaric acid in the catabolism of the amino acid tyrosine. Instead, succinylacetone, succinylacetoacetate and maleylacetoacetate are formed, and these false products of metabolism ultimately lead to cell damage in liver, kidney and brain. In addition, the Fehlmetabolit succinylacetone blocks the function of the enzyme δ -aminolevulinic acid dehydratase. Due to the failure of the enzyme δ -aminolevulinic acid accumulates progressively in the body which causes damage to the nerves and can cause the similar symptoms of porphyria to attacks.
The affected FAA gene consists of a total of 35,000 base pairs. It contains 14 exons and encodes a mRNA of 1260 base pairs. There are described several leading to disease mutations. The most common mutation is the substitution of guanine for adenosine, leading to a defective splicing of the mRNA. So far no correlation could be established between the different mutations and the actual severity of the disease.
In some cases, spontaneous attenuation of symptoms are described. These are attributable to the formation of a genetic mosaic in the body cells. This healthy cells exist without genetic defect next to diseased cells with genetic defect in the same body. The healthy cells have a survival advantage over the sick and take so in proportion. This is also named as a possible explanation to the difference in disease severity.
Clinical manifestations
Liver
One can differentiate between a acute and chronic disease. In acute course usually forms within months after birth, liver failure from. The affected infants show depending on the severity of organ failure edema, liver enlargement, a general failure to thrive, disorders of blood coagulation and hepatic encephalopathy. Often the failure of the organ is caused by an infection, since in the context of the immune response results in a catabolic situations, degraded proteins in the body and thus, many amino acids, including tyrosine, are released. About 80 % of patients, acute liver failure is the first manifestation of the disease.
In the chronic form or after überstandenem acute liver failure most likely forms of liver damage, which leads to cirrhosis of the liver. In both progressive forms, the risk is greatly increased for hepatocellular carcinoma. The youngest patient described with such a cancer in the context of tyrosinemia type I were 15 to 25 months old.
Kidney
The disease is damage to the kidney cells, which first manifests itself in a failure of the renal tubules. The damage can lead to a loss of renal corpuscles and to the loss of kidney function. On the basis of this event may result in a renal tubular acidosis, a aminoaciduria, an enlargement of the kidneys, and finally, a limitation of the glomerular filtration rate.
Neurological damage
The damage of the disease to the nervous system extends classical example in two phases. In the first phase are painful paresthesia, increased tone of the muscles to intestinal obstruction and an increase in heart rate ( tachycardia) in the foreground. Less commonly, the paralysis may occur at this stage. After a short recovery phase uses a outreaching to the whole body paralysis, which can lead to the need for artificial ventilation.
Heart
Rarely, patients present with cardiomyopathy, which does not, however, usually to a debilitating limitation of cardiac function.
Pancreas
At the pancreas tyrosinemia type I can cause over a still unexplained mechanism to a hyperplasia of the islet cells. This change leads via an increased production of the hormone insulin to waste in blood sugar levels (hypoglycemia ).
Methods of investigation
In Germany is carried in the blood as the only routine method for screening of newborns to determine the Tyrosinspiegels. However, this method detects only 90 % of patients, as 10 % develop elevated levels of the amino acid until later. In some states of the USA methionine, succinylacetone and δ -aminolevulinic acid in the blood can be determined routinely yet.
For prenatal diagnosis succinylacetone can be determined from the umbilical cord blood as part of an umbilical cord puncture. A further possibility is to determine the activity of the enzyme in FAH amniocytes or chorion in a chorionic villus.
With a suspicion of the existence of a patient with tyrosinemia type I, there are several methods to detect the disease. Firstly, tyrosine and methionine in plasma and urine can be determined. Similarly, δ -aminolevulinic acid and its metabolites are determined in the urine. The enzyme defect itself can be traced by the detection of FAH activity in lymphocytes, erythrocytes or fibroblasts. Likewise succinylacetone can be detected in urine.
Differential Diagnosis
Many other conditions can cause an elevated tyrosine levels in the blood. This includes the transient neonatal tyrosinemia, based on the immaturity of an enzyme. These forms are usually inconsequential back. The Tyrosinämien of type II and type III lead to increased levels of the amino acid. In addition, scurvy or hyperthyroidism can lead to an increase of tyrosine. In healthy humans after ingestion of a meal of tyrosine is normally increased.
Treatment
Diet
The goal of the diet is to leave as little as possible tyrosine arise in the body. First, it is the absorption of tyrosine and phenylalanine, which is metabolized by the body to tyrosine avoid. Second, to states in which the metabolism is catabolic, be avoided as the body else, for example, mobilizes amino acids tyrosine and thus also of its proteins from the muscle tissue. The diet should be done several days with tyrosine and phenylalanine specialty products and be high-calorie after diagnosis. By the former no tyrosine is released by exogenous supply handy. Due to the high nutritional value catabolic states are avoided. Thereafter can be changed in the normal food, which contains only very small quantities of the two amino acids. Catabolic situations such as after prolonged starvation should be avoided. Therefore, the meals should be spread evenly and regularly throughout the day. For the avoidance of tyrosine and phenylalanine, patients must restrict greatly the consumption of milk, egg and meat products. As the sole therapeutic measure but the diet is inadequate and can not stop the progression of the disease. However, you seem to have a positive influence on the course of renal damage. The plasma levels of tyrosine in the diet should be less than 500 micromol / l.
Drug therapy
With the help of nitisinone ( NTBC ), the disease can be treated with medication. NTBC blocks the enzyme 4- Hydroxyphenylpyruvatdioxigenase that catalyzes an early degradation step Tyrosinemia. As a result of the blockade are no longer substrates for the formation of toxic metabolites available. The diet should be maintained but also under NTBC treatment, otherwise you may experience symptoms of tyrosinemia type II. Given adequate diet, no serious side effects were noted, but sometimes occur leukopenia ( lack of white blood cells) and thrombocytopenia ( low platelet counts ) on. It is not certain whether these are triggered by the drug NTBC or are due to the existing pre-damage the liver of patients. About 90% of patients respond to the medication with NTBC, even if they are already at the stage of acute liver failure.
The success of treatment can be monitored by the determination of succinylacetone in plasma. The biggest problem of drug therapy is that NTBC can not prevent the occurrence of hepatocellular carcinoma. In a mouse model it was shown that despite treatment continue to occur malignant neoplasms in the liver. Since most patients already at diagnosis a serious liver damage - often with cirrhosis - have developed the timely diagnosis of liver cancer is difficult as can be only very poorly differ in imaging cirrhosis node and carcinomas. As makeshift tumor marker alpha -1 -fetoprotein ( AFP) is determined. The mirror is on the sick due to the liver damage usually very high, thus this marker is not specific for tumors. If the levels of AFP not under therapy, or design it comes under treatment for a rebound, can be expected from a hepatocellular carcinoma. Currently, an imaging display of the liver using ultrasound or MRI is recommended every six to twelve months. The AFP levels should be determined on a quarterly basis and monitored over time. In addition, several studies on the development of the child are considered by some authors recommended because it could cause development delays under NTBC therapy, but which are not yet proven ..
For better detection of hepatocellular carcinoma present reliable means of detection for a subfraction of AFP are searched for, which react with lectin. This marker is specific to distinguish between a non - malignant liver damage and a malignant neoplasm. Detailed studies and market-ready solutions are, however, far from even.
Liver transplantation
Until the introduction of NTBC liver transplantation was the only promising treatment for tyrosinemia type I. An indication for transplantation is the lack of response to NTBC, which affects around 10 % of patients. So far, no reliable prediction options were found to estimate the probability of non- response in the individual case before treatment. According to current recommendations, a liver transplantation should be considered in a rebound or a non- drop of AFP levels under NTBC therapy. In the rare event that the patient's liver is not cirrhotic rebuilt, you can also see Emerging nodular changes of the liver as an indication of hepatocellular carcinoma and draw a transplantation of the organ considered.
Cure views
Due to the rarity of the disease, there are few studies on the long-term course of the disease. A study of French patients treated with NTBC therapy resulted in a survival rate of 97.8 % in an average period 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. Similarly, the liver transplantation, the patients' renal function does not improve in contrast to NTBC therapy. It also comes with successful NTBC therapy no longer clinically relevant damage to the nerves. However, the authors of the French long-term study suggest that there is evidence of a deteriorated educational development of patients, although this has not been quantified meaningful.
History of Research
In Québec, an effective screening process of all newborns has been conducted since the 1970s. Since then stood the diet is the only treatment methods are available, most patients died within a few years of the disease. In the early 1990s, liver transplantation has been established as a method of therapy. In 1992, a Swedish research group at the University of Gothenburg in a life-threatening affected child and four other for the first time NTBC, which was originally developed as a herbicide. The drug was used in subsequent years in many countries as off- label use. In 2002 it was finally approved in the U.S. and 2005 in the EU.