Hypertyrosinemia

What is Hypertyrosinemia?

Tyrosine is a necessary component in your body that helps produce certain chemicals, thyroid hormones, and melanin – the pigment that gives your skin, hair, and eyes their color. Sometimes, your body may have a higher than normal level of tyrosine in your blood, a condition known as hypertyrosinemia. This can occur due to various disorders which might be either acquired (developed after birth) or genetic (inherited from parents).

This high level can be due to a lack of certain enzymes needed to break down tyrosine, usually seen in newborn babies, or due to some issues with liver function. Too much tyrosine and its harmful byproducts in your body are what usually cause the symptoms of the illness.

The increase in tyrosine levels might be temporary, especially in newborn babies, or may be due to liver disease. The inherited forms of this condition are usually more serious and if left untreated may lead to severe health problems, including liver failure, kidney disease, liver cancer, problems with blood clotting, seizures, delayed development, and severe neurological crises.

Normally, the tyrosine level in the blood varies between 30 and 120 micromoles per liter. However, you wouldn’t notice any symptoms unless the level rises above 500 micromoles per liter. Many states in the U.S. screen newborns for inherited types of hypertyrosinemia, which allows for early diagnosis. However, in developing countries, most cases are diagnosed late. The treatment usually depends on the cause. If it’s inherited, you might need to follow a lifelong diet low in tyrosine. A medicine called Nitisinone, which helps block the formation of harmful byproducts, might also be required. In some serious cases that don’t respond to regular treatment, a liver transplant might be needed.

What Causes Hypertyrosinemia?

Hypertyrosinemia, or high levels of the amino acid tyrosine in the blood, can be divided into two main groups:

1. Birth (or congenital) enzyme deficiency, which includes three types of inherited tyrosinemia (HT1, HT2, HT3)

2. Acquired Hypertyrosinemia, which can occur transiently in newborns, from liver disease, or from other conditions like hyperthyroidism and scurvy.

Hereditary tyrosinemia type 1 (HT1) is a genetic disorder caused by a deficiency in an enzyme called fumarylacetoacetate hydrolase (FAH). This deficiency results from mutations in the FAH gene. When FAH is lacking, a harmful substance, fumarylacetoacetate (FAA), builds up in liver and kidney cells, causing damage. Too much FAA also decreases the activity of an enzyme that helps break down tyrosine, leading to higher tyrosine levels in the body. However, it’s worth noting that these levels usually aren’t as high as those seen in HT2.

Hereditary tyrosinemia type 2 (HT2), also known as Richner-Hanhart syndrome, is caused by a deficiency in the enzyme that breaks down tyrosine, leading to high levels of tyrosine and its products in the blood. In HT2, the highest tyrosine levels among the hereditary types are seen and can be used for diagnosis.

Hereditary tyrosinemia type 3 is the rarest type, caused by a deficiency of another enzyme involved in processing tyrosine. This results in increased levels of tyrosine in the blood, though these levels are usually not higher than 500 micromoles/L.

Aside from these congenital types, there are several other causes of hypertyrosinemia that can occur later in life. The most common is the “transient tyrosinemia of the newborn.” This is usually seen in preterm infants and results from either a temporary delay in the development of the above enzyme or from liver immaturity. It often doesn’t cause symptoms and usually goes away on its own. However, if tyrosine levels don’t normalize within a few weeks, further tests would be needed to rule out inherited tyrosinemia. Finally, any condition that causes liver dysfunction, such as liver disease, can lead to higher tyrosine levels because the liver isn’t able to break down tyrosine as well. Tyrosine levels are expected to go back to normal once the liver function improves.

Risk Factors and Frequency for Hypertyrosinemia

Hereditary Hypertyrosinemia type 1 (HT1) is the most widespread type of hereditary hypertyrosinemia, affecting 1 in every 100,000 people globally. However, this condition is seen more frequently in certain regions. Notably, in the Saguenay-Lac-Saint-Jean region of Quebec, Canada, it can affect as many as 1 in every 1,846 newborn babies.

Furthermore, HT1 is also more common in countries like Norway and Finland. Conversely, Hereditary Hypertyrosinemia type 2 (HT2) is less common, with cases being less than 1 in every 250,000 individuals worldwide. As for Hereditary Hypertyrosinemia type 3 (HT3), its incidence is largely unknown due to very few documented cases.

Additionally, if a child has any type of hereditary hypertyrosinemia, there is a 25% chance that their sibling might also have it, following the Mendelian patterns of inheritance.

Signs and Symptoms of Hypertyrosinemia

Hypertyrosinemia is a condition that can present differently depending on its cause. The most severe type is known as HT1 and can show itself in two ways. The acute form typically appears within the first two months of a baby’s life. Common symptoms include:

• An enlarged liver, or ‘hepatomegaly’
• Jaundice
• Bleeding
• Increased liver enzymes
• Abnormal blood clotting
• Kidney problems known as ‘renal Fanconi syndrome’
• A unique ‘cabbage smell’ in the urine

Without treatment, babies with acute HT1 can experience progressive liver failure and possibly death within the first two years. The chronic form of HT1 is less intense and is characterized by long-term liver disease and a specific form of rickets related to renal Fanconi syndrome. This can be accompanied by additional features like poor growth, heart muscle disease, peripheral neuropathy, and respiratory failure.

HT2 generally shows up in the first year of life and affects the eyes and skin. Eye symptoms include sensitivity to light and excessive tearing due to a condition called ‘dendritic keratitis.’ This condition arises from a buildup of tyrosine crystals on the cornea. Skin symptoms include painful thickened skin patches, most often on the palms, soles, elbows, knees, and ankles. Almost half of the patients with HT2 also show varying degrees of intellectual disability. A significant difference between HT1 and HT2 is that the liver and kidneys are usually unaffected in HT2.

HT3 patients present with neurological symptoms that can range from loss of coordination (ataxia) to seizures and intellectual disability. There have also been cases of an HT3 patient without any symptoms. The condition known as ‘transient tyrosinemia of the newborn’ usually doesn’t present any symptoms but is identified due to elevated blood tyrosine levels in new-born screening tests. Similarly, hypertyrosinemia related to liver dysfunction usually doesn’t have symptoms but mildly elevated tyrosine levels. The existence of liver disease may complicate the diagnosis.

Testing for Hypertyrosinemia

In the United States and a few other countries where hypertyrosinemia (a group of rare genetic diseases that affect how the body processes the amino acid tyrosine) occurs often, screenings for inherited forms are common. But such screenings are less available in many other countries, meaning the disease is often not diagnosed until later.

These screening programs use a technique called tandem mass spectroscopy to look for an excess of certain chemicals in the blood associated with tyrosinemia. For example, in the case of Type 1 tyrosinemia (HT1), this test looks for elevated levels of a chemical called succinylacetone (SA). If the doctors suspect you have hypertyrosinemia based on these screening results or your symptoms, you’ll undergo more tests to confirm the diagnosis.

In Type 1 tyrosinemia, for example, patients usually have increased levels of SA and somewhat higher than normal levels of tyrosine in their blood or urine. Elevated levels of SA are considered a clear sign of Type 1 tyrosinemia. Patients with this type also have elevated levels of a protein called alpha-fetoprotein or AFP (used to measure liver function), and their blood doesn’t clot as quickly as it should.

Patients with Type 2 tyrosinemia (HT2) have much higher levels of tyrosine in their blood, more than 1000 micromoles per liter. Their urine also contains high levels of certain chemicals, such as p-hydroxyphenylpyruvate, p-hydroxyphenyllactate, and p-hydroxyphenylacetate. On the other hand, patients with Type 3 tyrosinemia (HT3) have increased levels of tyrosine in their blood too, but they typically have less than 500 micromoles per liter.

For all three types of inherited hypertyrosinemia, doctors can also conduct molecular tests to look for specific inherited gene mutations. Acquired forms of tyrosinemia, which are not inherited but arise for other reasons, usually cause only a slight increase in blood tyrosine levels. These patients typically do not show any symptoms.

Once diagnosed with hypertyrosinemia, most patients with Type 1 or Type 2 will need care from a team of doctors. These may include a children’s doctor or newborn specialist, a kidney doctor, a heart doctor, a brain doctor, an eye doctor, a skin doctor, a genetic specialist, and a dietitian with experience in managing tyrosinemia patients. You’ll want to consult these specialists often and have regular follow-ups with them. Patients with Type 1 tyrosinemia might also need imaging of their abdomens to check for a form of liver cancer called hepatocellular carcinoma. Those with Type 2 tyrosinemia could benefit from heart imaging to check for heart disease and tests to check for nerve damage.

In terms of imaging, all patients suspected of having hypertyrosinemia should have an ultrasound scan of their liver and kidneys. If any nodules are found in the liver, they should have an MRI scan for a clearer picture. If kidney problems are confirmed, a bone x-ray of the wrist or chest might also be done.

Treatment Options for Hypertyrosinemia

Treatment for a condition known as hypertyrosinemia depends on its root cause, with the goal of reducing levels of a substance called tyrosine in the body and preventing the creation of harmful by-products. Remember, if left untreated, this condition can become very serious. Therefore, it’s advised not to delay treatment even while awaiting confirmatory tests.

A common course of treatment includes a low-protein diet and a drug called nitisinone. Nitisinone, which is approved by the Food and Drug Administration (FDA), works by inhibiting an enzyme in the body, reducing the production of harmful substances. It has proven effective in various clinical studies and can reduce the risk of a form of liver cancer when started early in the disease’s course.

Because nitisinone increases tyrosine levels by blocking its breakdown, it’s important to limit tyrosine intake in the diet. This helps prevent an excess of tyrosine, which can lead to issues like corneal ulcerations (painful sores on the eyes). In some patients, long-term use of nitisinone and a low-protein diet can cause a deficiency in phenylalanine, an essential amino acid. This deficiency might result in problems with brain development.

Thus, supplementing with phenylalanine is often recommended. Side effects of nitisinone can include temporary low white blood cell and platelet counts. Regular monitoring is important for people with hypertyrosinemia, including checking blood levels of various substances, liver and kidney function, and yearly abdominal imaging.

There can be cases where despite medical treatment, the patient continues to experience persistent liver failure or develops liver cancer. In those cases, a liver transplant could be beneficial.

For type 2 hypertyrosinemia, the goal is to keep serum tyrosine levels below a certain threshold. This is achieved with a restricted intake of tyrosine and phenylalanine. Any skin and eye problems usually improve dramatically and can fully normalize within a few weeks of starting this dietary management. Vitamin C supplementation may also be helpful.

Patients diagnosed with type 3 hypertyrosinemia are also advised to restrict their dietary intake of tyrosine and phenylalanine. However, it’s unclear whether such dietary modification can prevent or reverse the neurological abnormalities seen in these patients. There are specialized formulas available on the market with low levels of tyrosine and phenylalanine specifically intended for patients with hypertyrosinemia.

What else can Hypertyrosinemia be?

When looking at HT1, the symptoms may appear to be similar to newborn sepsis, liver failure from other causes, cystinosis, Lowe syndrome, or hereditary fructose intolerance. To confirm a diagnosis, it’s important for doctors to look at previous medical history, run physical tests, and perform the necessary lab tests.

Patients with newborn sepsis may end up showing abnormal CBC (Complete Blood Count), a C-reactive protein, or the presence of bacteria in cultures and respond well to antibiotics. Cystinosis is a genetic disorder where the body is unable to properly transport an amino acid named cystine.

The severe form of cystinosis often shows itself in infants with symptoms of Fanconi syndrome, hypophosphatemic rickets, hyperpigmentation, and deposits over the cornea seen on examination of the eye. If cystinosis is suspected, it can be diagnosed by detecting high cysteine levels in white blood cells or skin cells.

Lowe syndrome is another genetic disorder that shows up during the first year after birth. It is characterised by bilateral congenital cataracts, hypotonia, and renal Fanconi syndrome in boys. This syndrome is different from HT1 because it involves the presence of cataracts and hypotonia at birth. Genetic testing helps confirm the diagnosis in unclear cases.

Hereditary fructose intolerance is another condition that can present with renal Fanconi syndrome. But, the symptoms occur after introducing fructose or sucrose in the diet. A diagnosis can be confirmed by analyzing the Aldolase B gene.

HT2 patients show up with corneal ulcerations and dermal keratosis and can be confused with other causes of corneal ulcerations at a young age, especially in areas where Newborn Screening for the disease doesn’t exist. Both bacterial and viral infections could cause corneal ulcers in babies. Patients dealing with infectious causes usually show other signs of sepsis and often improve with proper antimicrobials. Looking at HT3, the symptoms can mimic causes of ataxia, seizures, and psychomotor retardation. The diagnosis of HT3 in unclear cases can be helped by a careful look at the patient’s history, physical tests, and the high levels of tyrosine detected.

What to expect with Hypertyrosinemia

The outlook for your condition depends on what has caused it. For HT1 (a type of metabolic disease), the outlook is generally better if treatment is started early. One study found that when treatment began within 28 days of birth for 5 patients with HT1, there were no deaths or liver failure over a 15 year period.

If the condition isn’t treated, patients might face acute (sudden) liver failure before they turn two years old, or succumb to chronic (long-term) liver failure and liver cancer during their teens.

HT2 and HT3 are similar but rare diseases, and we don’t have a lot of data on long-term survival yet. However, we do know that both of these conditions are usually milder than HT1, and starting treatment early can greatly improve the outlook. Screening programs in many developed countries have been key in detecting these disorders early, reducing the severity and death rates associated with them.

Possible Complications When Diagnosed with Hypertyrosinemia

If not treated properly, HT1, a medical condition, can lead to serious complications like liver failure, cirrhosis (a chronic liver disease), and hepatocellular carcinoma (a type of liver cancer), which may result in premature death. HT1 can also lead to various neurological issues. These can vary from a neurological condition similar to porphyria (a group of rare genetic disorders that affect the nervous system) to muscle weakness, which can, in many cases, cause respiratory failure (difficulty breathing). Kidney disorder, known as Renal Fanconi Syndrome, may result in a form of bone disease called hypophosphatemic rickets.

Even though HT2 is generally less severe than HT1, untreated patients can still face serious complications. These complications can range from corneal ulcerations (sores on the front part of the eye) and painful, hard skin growths known as keratotic plaques. It is also noteworthy to mention that up to 50% of patients with HT2 may suffer some intellectual disability.

Patients with untreated HT3, can face severe issues like ataxia (a condition affecting the coordination of movement), uncontrollable seizures, and common occurrences of intellectual disability.

Common Side Effects:

• Liver failure
• Cirrhosis
• Hepatocellular carcinoma
• Premature death
• Neurological complications (neuropathic crises to muscle weakness)
• Respiratory failure
• Renal Fanconi Syndrome resulting in hypophosphatemic rickets
• Corneal ulcerations
• Keratotic plaques
• Potential intellectual disability in HT2 and HT3 patients
• Ataxia and uncontrollable seizures in HT3 patients

Preventing Hypertyrosinemia

Providing comprehensive advice, such as guidelines on what to eat and ensuring the consistency in following the prescribed treatment, is crucial for improving health outcomes in the long run. Patients and their families should also understand the potential complications of the disease, as well as know which symptoms to keep an eye on. It’s also important to share with them potential side effects of the treatment. Families who are planning for a baby might find it helpful to receive relevant genetic counseling.