Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec

doi:10.1016/j.ymgme.2012.05.022

Molecular Genetics and Metabolism

Volume 107, Issues 1–2, September–October 2012, Pages 49-54

https://doi.org/10.1016/j.ymgme.2012.05.022 Get rights and content

Abstract

Background

Hepatorenal tyrosinemia (HT1, fumarylacetoacetate hydrolase deficiency, MIM 276700) can cause severe hepatic, renal and peripheral nerve damage. In Québec, HT1 is frequent and neonatal HT1 screening is practiced. Nitisinone (NTBC, Orfadin ®) inhibits tyrosine degradation prior to the formation of toxic metabolites like succinylacetone and has been offered to HT1 patients in Québec since 1994.

Methods

We recorded the clinical course of 78 Québec HT1 patients born between 1984 and 2004. There were three groups: those who never received nitisinone (28 patients), those who were first treated after 1 month of age (26 patients) and those treated before 1 month (24 patients). Retrospective chart review was performed for events before 1994, when nitisinone treatment began, and prospective data collection thereafter.

Findings

No hospitalizations for acute complications of HT1 occurred during 5731 months of nitisinone treatment, versus 184 during 1312 months without treatment (p < 0.001). Liver transplantation was performed in 20 non-nitisinone-treated patients (71%) at a median age of 26 months, versus 7 late-treated patients (26%, p < 0.001), and no early-treated patient (p < 0.001). No early-treated patient has developed detectable liver disease after more than 5 years. Ten deaths occurred in non-nitisinone treated patients versus two in treated patients (p < 0.01). Both of the latter deaths were from complications of transplantation unrelated to HT1. One probable nitisinone-related event occurred, transient corneal crystals with photophobia.

Interpretation

Nitisinone treatment abolishes the acute complications of HT1. Some patients with established liver disease before nitisinone treatment eventually require hepatic transplantation. Patients who receive nitisinone treatment before 1 month had no detectable liver disease after more than 5 years.

Highlights

► A 25-year record of hepatorenal tyrosinemia (HT1) in Québec is presented. ► 71% of non-nitisinone treated HT1 patients required liver transplantation (median age, 26 m). ► Nitisinone treatment abolished the acute complications of HT1 and reduced HT1-related deaths. ► Some late-treated patients, who had liver findings before treatment, required transplantation. ► Screened newborns with early nitisinone treatment had no detectable liver disease after ≥ 5 y.

Introduction

We report the outcome of treatment of hepatorenal tyrosinemia (HT1, MIM 276700) [1], a severe hereditary metabolic disorder of childhood, with nitisinone, which specifically inhibits an early step of tyrosine degradation (Fig. 1) [2]. The setting is the province of Québec, Canada, which is suited for clinical studies of HT1 because the disease is frequent due to high prevalence of a founder mutation, IVS12 + 5G > A [3], in the French-Canadian population [4], [5] and because of a universal newborn screening program which refers all patients to a small number of physicians, allowing for treatment to be started before the development of clinical symptoms.

HT1 patients typically present in infancy with acute liver failure, cirrhosis, neurologic crises with pain and paralysis [1] and renal tubular dysfunction with hypophosphatemic rickets. Interpatient variability is great. With age, there is increasing risk of hepatocellular carcinoma [6]. Patients who survive beyond infancy may develop chronic renal failure. We compare the outcome of children born during the first ten years that nitisinone was available in Québec with that of patients born in the preceding decade, during which all current treatment options except nitisinone were available, including newborn screening, diet therapy and liver transplantation.

Section snippets

Patient groups

All known HT1 patients in Québec born between February 1984 and February 2004 (Fig. 2) were identified. In all patients, the diagnosis of HT1 was confirmed by the presence of elevated levels of succinylacetone in blood or urine. The clinical course of patients was recorded until hepatic transplantation, death, or August 1, 2009, whichever came first. Data for events before 1994 were obtained from retrospective chart review; subsequent data, by prospective recording. Three patient groups were

Definition of variables and analysis

All hospitalizations related to the acute complications of HT1 were noted, including hospitalizations for preventive treatment and observation during infections. Hospitalizations with neurologic crises, defined as in [8], were noted separately. For descriptive purposes, the total length of hospital stays and the total length of time studied were noted. For comparative statistics, the course of each patient was divided into calendar months. Each month was classified as to whether the patient had

Patient characteristics

Fig. 2 summarizes the clinical course of the 78 HT1 patients. Twenty-eight patients never received nitisinone, 26 were first treated after 30 days of age and 24, before 30 days. A total of 1312 patient-months without nitisinone treatment were registered (777 months from the non-nitisinone group and 535, late-treated) and 5731 months with treatment (3138, late-treated group; 2593, early-treated group).

Clinical course

Acute complications of HT1 were frequent before nitisinone treatment (Fig. 2, Table 1). Patients in

Discussion

Nitisinone treatment dramatically improved the course of HT1. Before the availability of nitisinone, patients and their families lived in uncertainty because of the unpredictable but frequent and often-fatal acute neurologic crises and episodes of acute hepatic failure (Fig. 2, Table 1). Conversely, none of 24 patients treated from the neonatal period and followed for over 5 years developed detectable liver disease, while in patients not treated with nitisinone, 20/28 (71%) required

Conclusions

Nitisinone treatment effectively prevents acute hepatic and neurologic crises in compliant HT1 patients. The reductions of succinylacetone and ALA excretion within 12 h following the first dose of nitisinone are consistent with a near-immediate therapeutic effect. In this series, the liver function of all patients markedly improved on nitisinone treatment, but some late-treated patients developed cirrhosis with high grade dysplasia or hepatocarcinoma. In contrast, all patients detected by

Acknowledgments

Khazal Paradis, Jean-Claude Jéquier, Marie-France Goyer, Manon Bouchard, Nicole Labbé, Louise Longtin, Martyne Gosselin, Yolande Lefèvre, Linge Pan, Danièle Régimbald, Hanyi Su and Shu Pei Wang made key contributions to this study. Funded in part by the Garrod Society of Canada, the Groupe d'Aide aux Enfants Tyrosinémiques du Québec (GAETQ), the Faculty of Medicine of the Université de Montréal (to GM), the Swedish Cancer Society (to EH and SL), the Food and Drug Administration USA (Grant

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Citation Excerpt :
Our study presents data on 33 patients with HT1. Clinical presentation at diagnosis was in line with previous reports [6,7]. At diagnosis, liver dysfunction with PT ratio < 70% occured in 93% of patients reflecting hepatocellular insufficiency as a major finding in HT1 prior to treatment.
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.
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¹: The Québec NTBC Study Group.

²: Deceased.

³: The International NTBC Study Group.

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Effect of nitisinone (NTBC) treatment on the clinical course of hepatorenal tyrosinemia in Québec

Abstract

Background

Methods

Findings

Interpretation

Highlights

Introduction

Section snippets

Patient groups

Definition of variables and analysis

Patient characteristics

Clinical course

Discussion

Conclusions

Acknowledgments

Lancet

Toxicol. Appl. Pharmacol.

Clin. Liver Dis.

Clin. Biochem.

Hypertyrosinemia

A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I

N. Engl. J. Med.

Human genetics: lessons from Quebec populations

Annu. Rev. Genomics Hum. Genet.

Population history and its impact on medical genetics in Quebec

Clin. Genet.

Hepatocellular carcinoma despite long-term survival in chronic tyrosinaemia I

J. Inherit. Metab. Dis.

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

J. Inherit. Metab. Dis.