Tyrosinaemia type I: considerations of treatment strategy and experiences with risk assessment, diet and transplantation

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Tyrosinaemia type I: considerations of treatment strategy and experiences with risk assessment, diet and transplantation
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  J. Inher. Metab. Dis. 18 (1995) 111-114 © SSIEM and Kluwer Academic Publishers. Printed in the Netherlands Short ommunication Tyrosinaemia type I: considerations of treatment strategy and experiences with risk assessment diet and transplantation 17. j. VAN SPRONSEN*, G. P. A. SMIT, F. A. WIJBURG, Y. THOMASSE, a. VISSER and H. S. A. HEYMANS Beatrix Children s University Hospital, Groningen, The Netherlands *Correspondence: Department of Pediatrics, University Hospital of Groningen, 59 Oostersingel, 9713 EZ Groningen, The Netherlands The rapid development of new modes of treatment including organ transplantation, enzyme inhibition, enzyme replacement, liver cell transplantation and gene therapy necessitates knowledge about the results of all modes of treatment to allow decisions on treatment strategies. In hereditary tyrosinaemia type I, apart from the dietary treatment, both orthotopic liver transplantation (OLT) and treatment with 2-(2-nitro-4- trifluoromethylbenzoyl)-l,3-cyclohexanedione (NTBC) have become available (Lindstedt et al 1992). However, this disease seems clinically very heterogeneous. Therefore, we should first attempt to categorize different clinical forms since treatment strategies may be quite different. Based on clinical heterogeneity, Halvorsen (1990) divided patients with tyrosinaemia into three forms - acute, subacute and chronic - but could not report the exact outcome on dietary treatment with possible consequences for treatment strategies. We have therefore investigated the clinical course on dietary treatment of our own patients and conducted an international survey on the clinical course of patients managed by dietary treatment and/or OLT, of which the results in part are described elsewhere (van Spronsen et al 1994). The results may enable us to compare the outcome on NTBC and to decide on treatment strategy in tyrosinaemia type I patients. PATIENTS AND METHODS Patients with tyrosinaemia type I treated by the metabolic team in the Beatri× Children's Hospital in Groningen were studied for age of onset of symptoms, pre- senting symptomatology, clinical course and outcome. In addition, a questionnaire was sent to centres caring for patients with metabolic diseases throughout the world seeking data about the age of onset of symptoms, survival on dietary treatment and after OLT, and the eventual causes of death. More detailed information about the methods used in the international survey is reported elsewhere (van Spronsen et al 1994). 111  112 van Spronsen et al 1 00 li 0.75"11 ~ .... ., "-': L. °-- 0 ¢.. a. 0.50- u~ 0 25] 0.00/ 012; 1 I I L----- 1 I I I , L. i L.... I i i ~._._ I I I I I I I I I I / 5 10 15 Time from the first symptoms in years Figure 1 The survival of patients with tyrosinaemia type I on dietary treatment (censored if OLT has taken place). Age at first symptoms is indicated as 0-62 days (unbroken line), 63- 183 days (short-dashed line) or more than 183 days (long-dashed line) RESULTS In the past few years 10 patients with tyrosinaemia type I have been treated by our metabolic team. for those, the ages of onset of symptoms and symptomatology were 2 months (n = 1, liver noduli), 3 months (n = 3, liver failure; n = 1, renal tubular acidosis), 4 months (n = 1, liver failure), 9 months (n = 2, hepatomegaly), 11 months (n = 1, liver failure) and 28 months (n = 1, rickets, hepatomegaly, abdominal pain and high blood pressure). The last patient underwent surgery at 9 months for symptoms mimicking intussusception. Apart from liver noduli found in all patients surviving the first few months, one patient encountered episodes of respiratory failure due to a porphyria-like syndrome at 2 and 3 years of age. The patients presenting with liver noduli and renal tubular acidosis died because of liver failure within 1 or 2 months. All others were referred for OLT (Wijburg et al 1994). One could not be transplanted owing to hepatocellular carcinoma (HCC) with metastases. Given the promising experience with NTBC, OLT has been postponed in two cases. Data of 108 patients were available for study in the international survey. Fourteen patients developed symptoms in the first 2 weeks of life, 11 in the second half of the first month, 14 in the second month, 44 within 2-6 months, 15 within 6-12 months, and 10 after 12 months of age. Analysis of survival curves showed an improved survival for patients with an onset of symptoms at > 6 months of age compared to those presenting at <6 months (p<0.001). There was no difference in survival of patients with an onset of symptoms between 6 and 12 months and at > 12 months of age, whereas the survival of those with an onset of symptoms at < 2 months was worse than for those with an onset of symptoms between 2 and 6 months of age (p < 0.001) (Figure 1) (van Spronsen et al 1994). J. lnher. Metab. Dis. 18 (1995)  Treatment of tyrosinaemia 113 Liver failure and recurent bleeding were the most prevalent causes of death (67%), the others being HCC (17%), respiratory failure and the porphyria-like syndrome (10%), chronic rejection after OLT (2%), acute encephalopathy (2%), and unknown (2%). HCC was reported in 10 patients. The frequency of HCC in patients having lived for at least 2 years was 18%. Eight of them died, 2 after OLT. OLT was performed in 26 of the 108 patients. Three died: 2 due to HCC with metastases, one due to rejection. DISCUSSION Our experience suggests the following. (1) Patients manifesting symptoms before 6 months of age not only present with liver failure and bleeding problems as suggested previously but also with liver noduli and renal tubular acidosis. (2) The age of onset of symptoms rather than the symptomatology predicts the outcome. The major findings of the international survey were as follows. (1) the age of onset of symptoms predicts the outcome on dietary treatment. (2) Patients with tyrosinaemia type I may manifest within the first weeks of life. (3) The Halvorsen (1990) classification does not distinguish adequately between groups with different mortality risk. (4) Distinction between patients with an onset of symptoms at < 2, at 2-6 and at >6 months of age clearly distinguishes between patients with different survival probabilities. On the basis of this difference, the classification was revised: very early (symptoms <2 months), early (2-6 months) and late-presenting form (>6 months) (van Spronsen et al 1994). Concerning the reported complications in the international survey, the frequency of HCC in patients older than 2 years of age (18%) was well below the 35% reported before (Weinberg et al 1976). It was also found that porphyria is an important problem, confirming the findings of Mitchell et al (1990). The outcome after OLT was good, which is in agreement with experience of inborn errors of metabolism in general (Starzl et al 1987; van Spronsen et al 1992). However, our results should be interpreted with care, as they concerned only 26 patients and therefore were extended with 25 additional patients in the literature with detailed information on outcome after transplantation (Dehner et al 1989; Esquivel et al 1989; van Spronsen et al 1989; Mieles et al 1990; Flye et al 1990; Freese et al 1991; Sokal et al 1992; Wijburg et al 1994). The overall 2-year survival of the 51 patients was 83% (SE 5.9%). The 2-year survival in patients transplanted after 1 year of age without HCC (n=26) was 100%, but only 58% (SE 16%) in patients with HCC (n= 10). Previously, OLT was the only definitive answer to both the metabolic and the oncological problem in tyrosinaemia type I (van Spronsen et al 1989), but this may have changed after the introduction of NTBC by Lindsted et al (1992). In conclusion, experience in Groningen suggests that clinical presentation is more variable in patients presenting at < 6 months of age than previously thought and that the outcome on dietary treatment is determined by the age of onset of symptoms rather than the symptomatology. The international survey confirms the predictive value of the age of onset of symptoms for the clinical outcome and provides a new clinical classification with consequences for survival probability (van Spronsen et al 1994). The international J. Inher. Metab. Dis. 18 1995)  114 van Spronsen et al. survey, in combination with a literature study, underlines the usefulness of OLT in tyrosinaemia type I and the concern for transplantation in the presence of HCC. All these data should be compared with the results on NTBC treatment and can be used in decisions on treatment strategy in tyrosinaemia type I to improve the survival time and quality of life. ACKNOWLEDGEMENTS The authors are indebted to the contributors to the international survey, who by their generous offering of patient data made this group study possible. REFERENCES Dehner LP, Snorer DC, Sharp HL, Ascher N, Nakhleh R, Day DL (1989) Hereditary tyrosinemia type I (chronic form): pathologic findings in the liver. Hum Pathol 20: 149- 148. Esquivel CO, Mieles L, Marino IR et al (1989) Liver transplantation for hereditary tyrosinemia in the presence of hepatocellular carcinoma. Transplant Proc 21: 2445-2446. Flye MW, Riely CA, Hainline BE et al (1990) The effects of early treatment of hereditary tyrosinemia type I in infancy for orthotopic liver transplantation. Transplant 49: 916-921. Freese DK, Tuchman M, Schwarzenberg SJ et al (1991) Early liver transplantation is indicated for tyrosinemia type I. J Pediatr Gastroenterol Nutr 13: 10- 15. Halvorsen S (1990) Tyrosinemia. In Fernandes J, Saudubray J-M, Tada K, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. Berlin: Springer-Verlag, 199-209. Lindstedt S, Holme E, Lock EA, Hjalmarson O, Strandvik B (1992) Treatment of hereditary tyrosinemia type I by inhibition of 4-hydroxyphenyl-pyruvate dioxygenase. Lancet 340: 813-817. Mieles LA, Esquivel CO, Thiel DH van et al (1990) Liver transplantation for tyrosinemia. A review of 10 cases from the university of Pittsburgh. Dig Dis Sci 35: 153- 157. Mitchell G, Larochelle J, Lambert M et al (1990) Neurological crises in hereditary tyrosinemia. N Engl J Med 15:432 - 437. Sokal EM, Bustos R, van Hoof F, Otte JB (1992) Liver transplantation for hereditary tyrosinemia: early transplantation following the patient's stabilization. Transplantation 54: 937-939. Starzl TE, Esquivel C, Gordon R, Todo S (1987) Pediatric liver transplantation. Transplant Proc 19: 3230-3235. van Spronson FJ, Berger R, Smit GPA et al (1980) Tyrosinaemia type I: orthotopic liver transplantation as the only definitive answer to a metabolic as well as an oncological problem. J Inher Metab Dis 12(Supplement 2): 339-342. van Spronsen FJ, Smit GPA, Slooff MJH et al (1992) Indication and timing of liver replacement in inherited metabolic disorders, lntens Crit Care Digest 11: 23-26. van Spronsen I, Thomasse Y, Smit GPA et al (1994) Hereditary tyrosinemia type I: a new clinical classification with difference in prognosis on dietary treatment. Hepatology 20:1187-1191. Weinberg AG, Mize CE, Worthen HG (1976) The occurrence of hepatoma in the chronic form of hereditary tyrosinemia. J Pediatr 88: 434-438. Wijburg FA, Reitsma WChC, Slooff MJH et al (1994) Liver transplantation in tyrosinemia type I: the Groningen experience. J lnher Metab Dis 18:115-118. J. Inher. Metab. Dis. 18 (1995)
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