Tyrosinemia type 1 (TT1), also referred to as hepatorenal tryosinosis, is caused by an inborn error of metabolism. This genetic disorder affects the liver, kidney, and central nervous system. Without treatment, patients usually die in childhood.
This metabolic disease may present in infancy, early childhood, or beyond   and the symptomology varies from one patient to another. TT1 occurs in one of three forms: acute, subacute, or chronic.
This type manifests either congenitally or in early infancy, as the more severe cases develop in the first two months . The most common clinical picture includes severe liver disease, which progresses to liver failure and coagulopathy. Infants will typically have a rapid and dramatic onset of fever, emesis, diarrhea, epistaxis, and melena. They also have the failure to thrive and appear lethargic and irritable. Furthermore, these children are also predisposed to developing infections . Patients also exhibit a developmental delay.
Patients with chronic variant are older than the age of one. The onset is more gradual and typically presents with the failure to thrive. The features include cirrhosis, renal disease, and developmental delay. Also, cardiomyopathy is common although it is benign in these patients .
Acute liver failure is one of the most ominous diseases that occurs in patients with TT1. It evolves into cirrhosis, the formation of liver nodules, and possibly hepatocellular carcinoma. Liver dysfunction leads to hypoglycemia , coagulopathy, hypoalbuminemia with the resultant ascites, and jaundice. Liver impairment is nearly always present to some extent.
Another common complication is a renal disease such as Fanconi syndrome. The severity of this disorder is variable and is typically characterized by tubular acidosis, aminoaciduria, glycosuria, and/or phosphaturia. Kidney disease may progress into glomerulosclerosis and eventually chronic failure. Furthermore, patients at risk for rickets due to low serum phosphate levels.
Affected individuals may also experience a neurological crisis, described as a porphyria-like syndrome, after an infection. These episodes feature pain in the abdomen and lower extremities, hypertonia, tachycardia, hypertension, and weakness. This may be life-threatening as it can cause a condition known as ascending motor neuropathy, which is often accompanied by respiratory failure that necessitates assisted ventilation.
Newborns who screen positive for TT1 and symptomatic individuals suspected to have this disorder warrant a thorough assessment of the personal and family history, a physical exam, and the pertinent studies.
The diagnosis is established by measurement of the biomarker SA in the plasma, urine, or DBS (through mass spectrometry). This demonstrates high specificity and sensitivity. Note that plasma testing offers more accuracy since urine organic acid analyses may not detect SA or the levels of the metabolite may be too low.
A comprehensive evaluation includes coagulation studies, complete blood count (CBC), electrolyte and mineral panel, renal function tests, liver function tests (LFTs), alpha-fetoprotein (AFP), quantitative serum analysis of amino acids, organic acid analysis, urinalysis, and other pertinent tools to understand the clinical picture.
The liver and kidneys should be promptly evaluated by ultrasonography at initial presentation and periodically afterward. Specifically, this tool can identify nodular lesions and provide details regarding the liver parenchyma. Additionally, the color doppler mode will help assess the vasculature. Nodules warrant further investigation with magnetic resonance imaging (MRI) or computed tomography (CT).
Also, wrist x-rays are used for diagnosing rickets.
Early detection of TT1 followed by immediate treatment is paramount . Newborn screening should be done with SA, although screening for this disease is not widely available.
Therapy should be initiated as soon as a patient is diagnosed with TT1. Additionally, asymptomatic infants identified through newborn screening should be treated before they even develop a clinical picture. There are two main components of treatment which include the use of medication and dietary modification. Patients should be managed by a team of pediatricians, hepatologists, nephrologists, specialized nutritionists, and other professionals.
The treatment of critically ill patients should include stabilization with respiratory support, fluid resuscitation, and blood transfusions as needed.
The Food and Drug Administration (FDA) approved Nitisinone for the treatment of this disease in 2002 . This agent inhibits parahydroxyphenylpyruvic acid dioxygenase (p-HPPD), which is an enzyme that participates in tyrosine degradation. Blocking this enzyme thereby prevents the production of FAA and SA . This medication should be given promptly after confirmation of the diagnosis. The standard dose is 1.0 mg/kg/day, which is adjusted to attain the therapeutic range as measured by blood concentration. Adverse reactions are rare and may include transient thrombocytopenia and photophobia.
Upon diagnosis, all children should be immediately placed on a low protein diet with a limited intake of phenylalanine and tyrosine. The patient's nutritional requirements should be carefully managed and adjusted as needed for growth and overall well-being. Specialized food products may be needed to ensure that essential requirements are fulfilled.
Liver transplantation is considered for patients with severe liver failure that is refractory to treatment with Nitisinone, or those who have liver malignancy  . There is at least a 10% mortality rate in children who undergo transplantation.
Prior to current therapy, untreated patients exhibited a poor prognosis that typically resulted in childhood death. Treatment has profoundly improved the survival and the quality of life in affected children . Furthermore, medical therapy may also prevent manifestations from emerging. However, complications such as hepatocellular carcinoma pose a lifelong risk for these patients despite treatment .
This autosomal recessive disorder results from mutations in the FAH gene, which is located on chromosome 15 . FAH codes for the FAH enzyme which plays a key role in the final step of the tyrosine degradation pathway. Hence, a deficiency in FAH leads to an accumulation of tyrosine and numerous toxic products such as SA in the tissues of the liver, kidney, and the CNS.
The estimated global incidence of TT1 is 1 in 100,000 to 120,000 births . With regards to patient demographics, this metabolic disorder is more prevalent in the Canadian province, Quebec  . Additionally, cases have been identified in the Middle East where there are high rates of consanguinity . As for gender, there is no preference.
Children with TT1 develop this disorder as a result of a defect in the tyrosine catabolic pathway. Specifically, the FAH enzyme is absent or insufficient to catalyze tyrosine degradation. As a result, the buildup of tyrosine causes its conversion to upstream products such as SA, succinylacetoacetate (SAA), fumarylacetoacetate (FAA), and maleylacetoacetate (MAA). The accumulation of these toxic metabolites is responsible for the diseases to occur .
These substances are implicated in the pathological features of TT1. SA inhibits heme synthesis, which leads to neurotoxicity  while FAA and MAA are damaging to hepatocytes and can cause hepatocellular carcinoma open link . Additionally, MAA causes damage to the tubules and results in kidney disease . These toxic products are considered to be carcinogenic.
This disease is inherited and therefore cannot be prevented. However, newborn screening can identify affected children earlier, thereby introducing treatment prior to manifestation.
Genetic counseling is offered to affected individuals and their family members to provide them with education about what the disease entails, its mode of inheritance, expectations, and other specific details. Carrier and prenatal testing are available to relatives at risk if the mutation has been identified. Additionally, a fetus can be diagnosed by the presence of SA in the amniotic fluid.
Tyrosinemia type 1 (TT1) is a rare metabolic disorder that results from a mutation in the gene that codes for fumarylacetoacetate hydrolase (FAH), which is an enzyme that catalyzes the final step of the tyrosine catabolism pathway. This deficiency leads to an accumulation of tyrosine and tyrosine-derived compounds which cause damage to sites such as the liver, kidneys, and central nervous system.
The devastating condition features liver and renal disease, coagulopathy, possibly rickets , and neuropathy. In untreated children, TT1 progresses to liver and kidney failure, and other complications that ultimately lead to death. Furthermore, patients are at risk for developing hepatocellular carcinoma. TT1 manifests as either acute, subacute, or chronic in which earlier presentations are associated with greater severity. Children typically fail to grow appropriately and suffer from fever, vomiting, epistaxis, and other symptoms.
The workup is comprised of the patient and family history, physical exam, and the appropriate studies. The confirmatory diagnostic tool for TT1 is the measurement of the pathognomonic marker succinylacetone (SA) in blood, urine, or dried blood spot (DBS). To clarify the complete clinical picture, further laboratory tests are indicated. There are various biochemical abnormalities that are typically observed in these patients. Moreover, imaging is required for the evaluation of the liver and kidney pathologies.
Treatment consists of a diet restricted in protein, tyrosine, and phenylalanine in conjunction with nitisinone. The latter is a drug that inhibits the formation of the toxic metabolites such as SA and others . The therapeutic regimen along with the implementation of modified newborn screening programs have profoundly improved survival and reduced most effects of TT1 .
What is Tyrosinemia Type 1?
What are the causes?
Tyrosinemia type 1 is caused by a mutation in a gene that normally produces an enzyme known as fumarylacetoacetate hydrolase. This enzyme breaks tyrosine down. When this enzyme is absent, tyrosine and other toxic substances build up. Therefore, these products go on to cause liver disease, kidney disease, and even nerve damage.
This disease is inherited in an autosomal recessive pattern. This means that affected individuals inherit a bad copy from each parent. In other words, each parent is a carrier.
What are the signs and symptoms?
This disease presents in early infancy or childhood. Patients are affected with:
Patients are also at high risk of developing liver cancer known as hepatocarcinoma.
How is it diagnosed?
Patients presenting with symptoms suggestive of this disease or newborns with positive screening should be assessed immediately for this disease. The clinician will obtain the patient and family history, perform a physical exam, and conduct the appropriate studies such as:
Additionally, the liver and kidneys should be evaluated with imaging techniques such as ultrasonography.
How is it treated?
There are two main components that are used for treatment and management of patients with this disorder:
These patients should be treated by a team of pediatricians, liver and kidney specialists, and a specialized nutritionist.
Can it be prevented?
This disease is inherited and therefore cannot be prevented. However, newborn screening can identify affected children earlier and therefore these infants can be treated before the effects of the disease emerge.
Also, genetic counseling is offered to patients and relatives at risk. A geneticist can educate the patients, parents, at-risk relatives about the disease, how it is inherited, and many other details. Genetic testing is available for relatives at risk in cases where the genetic mutation is known.
What is the prognosis?
The current treatment has significantly improved the prognosis of patients with this disease. It has increased survival and the quality of life. Also, it can prevent many of the diseases that develop in these patients. The earlier the diagnosis, the sooner the patients receives treatment. Hence, newborn screening is very crucial because this can diagnose patients before they develop symptoms.