A Closer Look at What is Nitisinone Used For
Nitisinone (brand names Orfadin, Nityr, Harliku) is a specialized medication for managing severe, inherited metabolic diseases, primarily hereditary tyrosinemia type 1 (HT-1) and alkaptonuria (AKU). It works by interrupting the tyrosine degradation pathway, but requires medical supervision and strict dietary adherence.
Nitisinone for Hereditary Tyrosinemia Type 1 (HT-1)
HT-1 is a rare genetic disorder where a missing enzyme, fumarylacetoacetate hydrolase (FAH), causes toxic substances like succinylacetone to build up, severely damaging the liver, kidneys, and nervous system. Nitisinone helps by blocking an earlier enzyme, 4-hydroxyphenylpyruvate dioxygenase (HPPD), preventing the formation of these toxins. This treatment has significantly improved survival and outcomes for HT-1 patients, who previously had a very poor prognosis. However, because nitisinone increases plasma tyrosine levels, it must be used with a strict, lifelong diet low in tyrosine and phenylalanine to avoid side effects affecting the eyes, skin, and nervous system.
Nitisinone for Alkaptonuria (AKU)
AKU is another rare genetic disorder caused by a deficiency in the enzyme homogentisate 1,2-dioxygenase (HGD), leading to the accumulation of homogentisic acid (HGA). This buildup causes problems like arthritis, ochronosis (tissue discoloration), and kidney stones. Nitisinone is also effective in AKU by inhibiting HPPD, reducing HGA levels and potentially slowing the progression of joint damage and ochronosis. The EMA approved nitisinone for adult AKU patients in 2020. While not a cure, it can improve quality of life. As with HT-1, nitisinone can increase tyrosine levels in AKU patients, requiring monitoring and sometimes dietary restrictions to manage potential side effects, such as eye issues.
Dosage and Administration
Nitisinone dosage is tailored to the individual and depends on factors like body weight and biochemical response. It is available under various brand names, including Orfadin, Nityr, and Harliku, and comes in capsules, tablets, and an oral suspension, each with specific instructions. Dosage adjustments are based on disease markers, while high tyrosine levels are managed through diet.
Potential Side Effects and Monitoring
Side effects of nitisinone are primarily linked to increased plasma tyrosine levels, making a restricted diet crucial. These can include skin issues like dryness and thickened palms/soles, and eye problems like light sensitivity and corneal clouding. Lowered white blood cell and platelet counts have also been reported, requiring regular blood monitoring. The oral suspension may cause gastrointestinal issues. In rare cases, high tyrosine levels have been associated with neurological concerns.
Comparison of Nitisinone Treatment for HT-1 vs. AKU
| Feature | Hereditary Tyrosinemia Type 1 (HT-1) | Alkaptonuria (AKU) |
|---|---|---|
| Primary Enzyme Deficiency | Fumarylacetoacetate hydrolase (FAH) | Homogentisate 1,2-dioxygenase (HGD) |
| Mechanism of Nitisinone | Blocks an upstream enzyme, HPPD, preventing the buildup of toxic metabolites like succinylacetone. | Also blocks HPPD, preventing the formation of homogentisic acid (HGA). |
| Therapeutic Goal | Prevents life-threatening liver and kidney damage and neurological crises. | Slows or prevents the progression of ochronosis and arthritis. |
| Primary Monitoring Biomarker | Succinylacetone levels in blood and/or urine. | Homogentisic acid (HGA) levels in urine. |
| Dietary Restriction | Strict, lifelong restriction of tyrosine and phenylalanine is essential. | Restriction is implemented or intensified if high plasma tyrosine levels develop and cause side effects. |
| Typical Patient Age | Treatment usually initiated in infancy or early childhood following newborn screening. | Treatment typically starts later in life, especially in adulthood, once complications begin. |
Conclusion
Nitisinone is a vital medication for treating hereditary tyrosinemia type 1 and alkaptonuria. By inhibiting HPPD, it stops the formation of toxic byproducts that cause severe damage in these genetic disorders. Successful treatment requires nitisinone therapy combined with a strict low-protein diet to manage elevated tyrosine levels. Early diagnosis and careful monitoring are key to maximizing effectiveness and minimizing tyrosine-related side effects. Nitisinone has significantly improved the lives and long-term outlook for individuals with these rare conditions.
For more in-depth information, you can consult the National Center for Biotechnology Information's LiverTox resource.
