NONTRANSPLANT TREATMENT OF TYROSINEMIA

doi:10.1016/S1089-3261(05)70142-2

Clinics in Liver Disease

Volume 4, Issue 4, 1 November 2000, Pages 805-814

https://doi.org/10.1016/S1089-3261(05)70142-2 Get rights and content

Tyrosinemia type I (OMIM 276700) is a recessive inherited metabolic liver and kidney disease caused by deficiency of fumarylacetoacetate hydrolase (FAH)(Fig. 1). The enzyme block causes accumulation of the reactive metabolites fumarylacetoacetate and maleylacetoacetate and their reduced derivatives succinylacetoacetate and succinylacetone.¹ Succinylacetone is a potent inhibitor of porphobilinogen synthase. The clinical spectrum of the disorder is highly variable and includes acute liver failure in infancy, slowly progressive liver cirrhosis complicated by a high incidence of childhood hepatocellular carcinoma (HCC),21, 23 hypophosphatemic rickets caused by kidney tubular dysfunction, and porphyrialike neurologic crisis.¹⁶ Tyrosinemia type I was recognized as an entity during the 1960s. Since then and until the late 1980s, when pediatric liver transplantation was successfully established, treatment of tyrosinemia was confined to treatment with a diet restricted in tyrosine and phenylalanine. Although dietary treatment may relieve acute symptoms and resolve the kidney disease, the prognosis remained poor.²¹ When pediatric liver transplantation was established a decade ago, it became widely accepted as the only successful treatment, which was to be performed early enough to prevent the fatal complications of the disorder.4, 15, 20 At this time, a new principle for treatment of tyrosinemia type I based on inhibition of tyrosine degradation at the level of 4-hydroxyphenylpyruvate dioxygenase (Fig. 1) was reported.¹³ Since then, the number of patients treated by the inhibitor 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) has steadily increased, and NTBC treatment has become a first-line treatment of tyrosinemia type I.7, 8, 9

Section snippets

NTBC

NTBC was primarily studied at Zeneca Central Toxicology Laboratory, Alderley Park, Cheshire, UK because of its herbicidal effects.¹⁴ During the toxicologic evaluation, it was found that NTBC had a moderate to low acute toxicity, but about 80% of rats exposed to NTBC, at a dose of 0.05–40 mg/kg body weight (bw) per day for 3 months, developed eye lesions. These lesions were found to result from increased tyrosine levels caused by inhibition of 4-hydroxyphenylpyruvate dioxygenase. The eye lesions

NTBC–INITIAL TRIAL IN TYROSINEMIA

In 1991, NTBC was made available for a trial in a 2-month-old infant in liver failure caused by tyrosinemia.¹³ A biochemical improvement was readily detectable after an initial dose of 0.05 mg/kg bw. This dose was then progressively increased to 0.6 mg/kg bw per day, at which point there were no signs of succinylacetone production. In parallel with the biochemical improvement, there was a remarkable clinical improvement. Encouraged by these results, four other patients between 2 and 7 years of

NTBC–EXTENDED STUDY

After publication of the first trial, a multicenter protocol for an extended study was established. Until 1996, all patients received NTBC from Gothenburg. The protocol required that laboratory and clinical data be reported to a common database in Gothenburg and that urine and blood samples be sent there for measurement of critical variables. After 1996, Swedish Orphan AB, which had been licensed by Zeneca to commercialize NTBC, assumed the responsibility for providing the drug. The NTBC study

METABOLIC EFFECTS OF NTBC AND ASSESSMENT OF METABOLIC CONTROL

Based on the findings in rats, 0.1 mg NTBC/kg bw per day was chosen as the initial dose for the first patient. This dose was then increased to 0.6 mg/kg bw per day and after further experience to 1.0 mg/kg bw per day, which is the currently recommended initial dose. In most patients, this dose is sufficient for normalization of the metabolic profile, but occasionally (especially in infants) an increased dose up to 2 mg/kg bw may be required. The aim of the treatment is to block completely the

NTBC IN ACUTE TYROSINEMIA

The patient with acute tyrosinemia presents during the first 6 months of age with signs of liver failure. Jaundice is moderate, and serum aminotransferase levels are usually only moderately increased, but coagulopathy is generally pronounced even when other signs of liver failure are moderate. In addition to high plasma tyrosine levels, there may be a greatly elevated methionine concentration. There are also often signs of renal tubular dysfunction, such as hypophosphatemia, and greatly

NTBC IN PATIENTS WHO RECEIVED TREATMENT AFTER 2 YEARS OF AGE

The group of patients who first received NTBC treatment after 2 years of age is quite heterogeneous and includes both newly diagnosed patients and patients who have been on restricted diet for many years. There are patients with a mild chronic phenotype, patients with advanced liver disease with missed diagnosis, and patients who have been on restricted diet since infancy. There are several reasons to divide the patients into subgroups based on the age at start of treatment. The most important

ADVERSE EVENTS

Adverse effects or possible adverse effects of NTBC have been few, and no patient has been withdrawn from the study because of such effects. Symptoms related to the eyes, which are known targets of high tyrosine levels, have been reported on 17 occasions and are the most commonly reported adverse effects. The symptoms include itching, burning, photophobia, corneal erosion, and corneal clouding. The symptoms have been transient but have recurred on several occasions in a few patients. The

SUMMARY

NTBC treatment has greatly improved the survival of patients with acute tyrosinemia and has reduced the need for liver transplantation during early childhood. In patients in whom treatment with NTBC was started early in life, 2 cases (1%) of HCC have occurred during the first year of treatment, but no further cases have occurred among these patients, who have been followed for up to 9 years. In patients with late start of NTBC treatment, there is a considerable risk for liver malignancy. The

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Inhibition of 4-hydroxyphenylpyruvate dioxygenase by 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione and 2-(2-chloro-4-methanesulfonylbenzoyl)-cyclohexane-1,3-dione
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Treatment of hereditary tyrosinaemia type I by inhibition of 4-hydroxyphenylpyruvate dioxygenase
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Occurrence of hepatoma in chronic form of hereditary tyrosinemia
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Tyrosinaemia type II
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Tyrosinemia type I with early metastatic hepatocellular carcinoma: Combined treatment with NTBC, chemotherapy and surgical mass removal
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D.K. Freese et al.
Early liver transplantation is indicated for tyrosinemia type I
J Pediatr Gastroenterol Nutr
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Peripheral neuropathy as the presenting feature of tyrosinemia type I and effectively treated with an inhibitor of 4-hydroxyphenylpyruvate dioxygenase
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Detection of succinylacetone and the use of its measurement in mass screening for hereditary tyrosinemia
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Treatment of tyrosinemia type I with an enzyme inhibitor
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Diagnosis and management of tyrosinemia type I
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E. Holme et al.

Tyrosinaemia type I and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione)

J Inherit Metab Dis

(1998)

Cited by (148)

Developmental and Inherited Liver Disease
2023, MacSween's Pathology of the Liver, Eighth Edition
A section on the approach to diagnostic histological interpretation is the overture to this chapter on inherited and developmental disorders. This initial section is split chronologically into the early neonatal and infantile period and later childhood and adulthood, with the intention of reflecting clinical practice as closely and succinctly as possible. Disorders of the biliary tree, bile formation and secretion and hepatocyte metabolism are the core of this chapter, a merger of Chapters 3 and 4 of previous editions. Considerations on the pathogenetic and/or clinical overlap among developmental, genetic and metabolic disorders were the rationale behind this change. The complexity of hepatocyte metabolism is reflected into the myriad of related pathological conditions. Two short new paragraphs on disorders of manganese metabolism and DNA repair and nuclear envelope have been added. Recent technological advances, particularly in genomics in the last 5 years, have resulted in a plethora of new entities and changes in terminology, challenging the authors to balance detail and application to clinical practice. Tables and figures from the previous edition have been largely kept due to their quality and contemporary relevance, and updated where necessary. Liver involvement in immunodeficiency and miscellaneous disorders precede the final section on anatomical anomalies. Vascular anomalies are now included in the chapters on vascular disorders.
Initial presentation, management and follow-up data of 33 treated patients with hereditary tyrosinemia type 1 in the absence of newborn screening
2022, Molecular Genetics and Metabolism Reports
Citation Excerpt :
There is evidence that treatment within the first two months of life with nitisinone and a low-protein diet prevents liver and renal complications in most patients with shorter and fewer hospital admissions, and a reduced need for liver transplant [6,12,13]. Holme and Lindstedt described improvement in liver function in 90% of patients treated with nitisinone before the age of six months [14]. However, the treatment can fail, as we saw in two very young patients (patients 29 and 32, Fig. 1), and emergency liver transplantation remains a life-saving procedure in these rare cases (patient 32) [4,15].
Hereditary tyrosinemia type 1 (HT1) is a rare autosomal recessive disorder of phenylalanine and tyrosine catabolism due to a deficiency of fumarylacetoacetate hydrolase. HT1 has a large clinical spectrum with acute forms presenting before six months of age, subacute forms with initial symptoms occurring between age 6 and 12 months, and chronic forms after 12 months of age. Without treatment, HT1 results in the accumulation of toxic metabolites leading to liver disease, proximal tubular dysfunction, and porphyria-like neurological crises. Since the early nineties, the outcome of HT1 has dramatically changed due to its treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC, nitisinone). In some countries, HT1 is included in the newborn screening program based on the analysis of succinylacetone concentration on dried blood spots.
In the present study, we report clinical and laboratory parameters data on 33 HT1 patients focusing on clinical presentation and therapeutic management at the time of diagnosis. Eighteen patients were diagnosed with the acute form (median age at presentation 2.5 months), 6 with the subacute form (median age at presentation 10 months), and 5 with the chronic form of HT1 (median age at presentation 15 months). Four patients were diagnosed pre-symptomatically in the setting of a family history of HT1. Among the 29 symptomatic patients, hepatomegaly was found in 83% of patients and prolonged coagulation times due to hepatocellular insufficiency was observed in 93% of patients. HT1 diagnosis was confirmed by increased urine succinylacetone in all patients. All patients but 2 were treated with nitisinone immediately at diagnosis. During follow-up, 2 patients received liver transplant for high grade dysplasia or hepatocellular carcinoma, 10 patients exhibited some form of neurocognitive impairments.
Our data confirm that HT1 is a severe treatable liver disease that should be detected at the earliest, ideally by newborn screening and appropriately treated.
In vivo quantitative photoacoustic evaluation of the liver and kidney pathology in tyrosinemia
2022, Photoacoustics
Hereditary tyrosinemia type Ⅰ (HT1) is a severe autosomal recessive inherited metabolic disease, which can result in severe damage of liver and kidney. Photoacoustic imaging (PAI) uses pulsed laser light to induce ultrasonic signals to facilitate the visualization of lesions that are strongly related to disease progression. In this study, the structural and functional changes of liver and kidney in HT1 was investigated by cross-scale PAI. The results showed that the hepatic lobule and renal tubule were severely damaged during HT1 progression. The hemoglobin content, vessel density, and liver function reserve were decreased. The metabolic half-life of indocyanine green declined from 59.8 s in health to 262.6 s in the advanced stage. Blood oxygen saturation was much lower than that in health. This study highlights the potential of PAI for in vivo evaluation of the liver and kidney lesions in HT1.
mRNA-based therapy proves superior to the standard of care for treating hereditary tyrosinemia 1 in a mouse model
2022, Molecular Therapy Methods and Clinical Development
Hereditary tyrosinemia type 1 is an inborn error of amino acid metabolism characterized by deficiency of fumarylacetoacetate hydrolase (FAH). Only limited treatment options (e.g., oral nitisinone) are available. Patients must adhere to a strict diet and face a life-long risk of complications, including liver cancer and progressive neurocognitive decline. There is a tremendous need for innovative therapies that standardize metabolite levels and promise normal development. Here, we describe an mRNA-based therapeutic approach that rescues Fah-deficient mice, a well-established tyrosinemia model. Repeated intravenous or intramuscular administration of lipid nanoparticle-formulated human FAH mRNA resulted in FAH protein synthesis in deficient mouse livers, stabilized body weight, normalized pathologic increases in metabolites after nitisinone withdrawal, and prevented early death. Dose reduction and extended injection intervals proved therapeutically effective. These results provide proof of concept for an mRNA-based therapeutic approach to treating hereditary tyrosinemia type 1 that is superior to the standard of care.
Nitisinone: two decades treating hereditary tyrosinaemia type 1
2021, The Lancet Diabetes and Endocrinology
Long-term safety and outcomes in hereditary tyrosinaemia type 1 with nitisinone treatment: a 15-year non-interventional, multicentre study
2021, The Lancet Diabetes and Endocrinology
Since the EU approval of nitisinone in 2005, prognosis for patients with hereditary tyrosinaemia type 1 has changed dramatically, with patients living with the disease now reaching adulthood for the first time in history. This study aimed to assess the long-term safety and outcomes of nitisinone treatment in patients with hereditary tyrosinaemia type 1.
We did a non-interventional, non-comparative, multicentre study in 77 sites across 17 countries in Europe and collected retrospective and prospective longitudinal data in patients with hereditary tyrosinaemia type 1 who were treated with oral nitisinone during the study period (Feb 21, 2005, to Sept 30, 2019). There were no specific exclusion criteria. Patients were followed-up with an investigator at least annually for as long as they were treated, or until the end of the study. The primary endpoints, occurrence of adverse events related to hepatic, renal, ophthalmic, haematological, or cognitive or developmental function, were assessed in the complete set (all patients already receiving treatment at the index date [Feb 21, 2005] or starting treatment thereafter) and the index set (the subset of patients who had their first dose on the index date or later only).
315 patients were enrolled during the study period (complete set). Additionally, data from 24 patients who had liver transplantation or died during the post-marketing surveillance programme were retrieved (extended analysis set; 339 patients). Median treatment duration was 11·2 years (range 0·7–28·4); cumulative nitisinone exposure was 3172·7 patient-years. Patients who were diagnosed by neonatal screening started nitisinone treatment at median age 0·8 months versus 8·5 months in those who presented clinically. Incidences of hepatic, renal, ophthalmic, haematological, or cognitive or developmental adverse events were low. Occurrence of liver transplantation or death was more frequent the later that treatment was initiated (none of 70 patients who started treatment at age <28 days vs 35 [13%] of 268 patients who started treatment at age ≥28 days). 279 (89%) of 315 patients were assessed as having either very good or good nitisinone treatment compliance. Treatment and diet compliance declined as patients aged. Suboptimal plasma phenylalanine and tyrosine levels were observed. The majority of patients were reported to have good overall clinical condition throughout treatment; 176 (87%) of 203 during the entire study, 98% following 1 year of treatment.
Long-term nitisinone treatment was well tolerated and no new safety signals were revealed. Life-limiting hepatic disease appears to have been prevented by early treatment start. Neonatal screening was the most effective way of ensuring early treatment. Standardised monitoring of blood tyrosine, phenylalanine, and nitisinone levels has potential to guide individualised therapy.
Swedish Orphan Biovitrum (Sobi).

View all citing articles on Scopus

Address reprint requests to Elisabeth Holme, MD, PhD Department of Clinical Chemistry Sahlgrenska University Hospital S-413 45 Gothenburg Sweden e-mail: [email protected]

This work was supported by the Swedish Cancer Foundation, the Children's Cancer Foundation of Sweden, the Swedish Medical Research Council (project no. 585) and Swedish Orphan AB.

^*: Department of Clinical Chemistry, Göteborg University, Sahlgrenska University Hospital, Gothenburg, Sweden

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NONTRANSPLANT TREATMENT OF TYROSINEMIA

Section snippets

NTBC

NTBC–INITIAL TRIAL IN TYROSINEMIA

NTBC–EXTENDED STUDY

METABOLIC EFFECTS OF NTBC AND ASSESSMENT OF METABOLIC CONTROL

NTBC IN ACUTE TYROSINEMIA

NTBC IN PATIENTS WHO RECEIVED TREATMENT AFTER 2 YEARS OF AGE

ADVERSE EVENTS

SUMMARY

Toxicol Appl Pharmacol

Lancet

J Pediatr

Tyrosinaemia type II

Tyrosinemia type I with early metastatic hepatocellular carcinoma: Combined treatment with NTBC, chemotherapy and surgical mass removal

J Inherit Metab Dis

Early liver transplantation is indicated for tyrosinemia type I

J Pediatr Gastroenterol Nutr

Peripheral neuropathy as the presenting feature of tyrosinemia type I and effectively treated with an inhibitor of 4-hydroxyphenylpyruvate dioxygenase

J Neurol Neurosurg Psychiatry

Detection of succinylacetone and the use of its measurement in mass screening for hereditary tyrosinemia

Clin Chim Acta

Treatment of tyrosinemia type I with an enzyme inhibitor

International Pediatrics

Diagnosis and management of tyrosinemia type I

Curr Opin Pediatr

Tyrosinaemia type I and NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione)

J Inherit Metab Dis