van Spronsen, Francjan J.*; Bijleveld, Charles M. A.†; van Maldegem, Bianca T.‡; Wijburg, Frits A.‡
*Section of Metabolic Diseases, †Liver transplantation Team, Beatrix Children's Hospital, University Medical Center of Groningen; ‡Department of Pediatrics, Academic Medical Center, University of Amsterdam, The Netherlands
Address correspondence and reprint requests to Dr. F.J. van Spronsen, Beatrix Children's Hospital, University Hospital of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands (e-mail: email@example.com).
Hereditary tyrosinemia type I (McKusick 27670) is an autosomal recessive inborn error of tyrosine catabolism caused by a deficiency of the enzyme fumarylacetoacetase that results in liver failure, hepatocellular carcinoma (HCC), renal tubular dysfunction and acute intermittent porphyria (1). Dietary treatment, once the cornerstone of treatment, results in a poor outcome and does not prevent the development of liver failure and HCC in all patients (2,3). Therefore, orthotopic liver transplantation was considered the only definitive answer to both the metabolic and the oncological problem (2-5).
Perceptions of treatment changed completely in 1992, when Lindstedt et al. reported their first experiences with 2-(2 nitro-4-3 trifluoro-methylbenzoyl)-1,3-cyclohexanedione (NTBC) (6), an inhibitor of the enzyme 4-hydroxy-phenylpyruvate dioxygenase (7). This enzyme is located upstream of fumarylacetoacetase in the catabolic pathway of tyrosine (Fig. 1), preventing the formation of maleylacetoacetate and fumarylacetoacetate and consequently, of succinylacetoacetate and succinylacetone also. Fumarylacetoacetate is the metabolite considered pathogenic and mutagenic in tyrosinemia type I (8,9).
With NTBC, liver failure, renal tubular dysfunction and acute porphyria, tyrosinemia type I patients can be treated and prevented adequately (6,10-13). The development of HCC, however, is of concern. Development of HCC has been reported after relatively small periods of NTBC treatment, the longest period being 3 years (13-15). Dionisi-Vici et al. reported their experiences with one patient who developed HCC with lung metastases at 15 months of age while being on NTBC treatment during 10 months (14). As liver transplantation was not indicated because of the metastases, treatment included chemotherapy and partial hepatectomy.
We present an additional patient with tyrosinemia type I who developed HHC without metastases despite NTBC treatment for 6 years, stressing the importance of ongoing strict follow-up for possible development of HCC.
A boy, presented at the age of 2 years with slow motor development, failure to thrive, hepatosplenomegaly and signs and symptoms of rickets. Laboratory studies revealed hypophosphatemia, normal concentrations of calcium, albumin, total protein, urea and creatine, as well as glucose, and increased alkaline phosphate concentration in blood. Aspartate amino transferase (ASAT), alanine amino transferase (ALAT) and total bilirubin levels were normal. Studies in urine revealed increased loss of phosphate, suggestive of tubular dysfunction. Alpha-1-foetoprotein (AFP) concentration in plasma was increased (8440 μg/l, normal <20). Ultrasound studies of the liver showed inhomogeneity suggestive of cirrhosis. At 2 years and 3 months, the diagnosis of tyrosinemia type I was made based on the findings of increased urinary excretion of succinylacetone, decreased activity of fumarylacetoacetase in liver tissue, and homozygous IVS6-1 G > T mutation. Directly after diagnosis he started on a phenylalanine-tyrosine restricted diet. NTBC treatment was started 4 weeks later at a dose of 0.6 mg/kg body weight/d. The dose was gradually increased to 0.9-1.0 mg/kg body weight/d in the following weeks.
There was clear clinical improvement and AFP decreased from 8440 μg/l to 25 μg/l and remained at this level for the next 5 years without succinylacetone detection in the urine. At the almost 8 years of age, more than 5.5 years after the start of NTBC treatment, AFP increased to 372 μg/l. NTBC was increased to 2.0 mg/kg, but AFP rose to 428 μg/l in 3 months time. Ultrasound studies of the liver showed no abnormalities on two subsequent studies. MRI of the liver, however, revealed a subcapsular nodule with a diameter of 1.3 cm in the right lobe with increased circular signal intensity in the wall after intravenous contrast, compatible with development of HCC. The nodule was surgically removed with a wide margin without complications. HCC was confirmed by histopathologic examination, which revealed a radically removed, well-delineated node with atypical hepatocytes with enlarged polymorphic nuclei and prominent nucleoli. Immunohistochemistry demonstrated a high expression of AFP. Liver tissue outside the nodule showed cirrhotic transformation without other nodules. After surgery, AFP decreased to 18 μg/l. Further studies did not show any signs of metastases.
Because of the potential risk of developing HCC in the remaining liver, he was referred for liver transplantation. Liver transplantation was performed. Histopathologic examinations of the explanted liver revealed cirrhosis without HCC. The first three liver transplants failed due to thrombosis of the hepatic artery, a Budd Chiari syndrome and primary non-functioning respectively. The fourth transplant was successful and he was discharged from the hospital 8 weeks after the first transplantation. At 1.5 years after transplantation, the patient is in good physical condition, although his mental development shows mild retardation probably due to the stormy course of the transplantation procedures.
At present, NTBC is the cornerstone of treatment of tyrosinemia type I. About 10 years ago, the international survey on tyrosinemia type I patients treated with diet and/or liver transplantation showed that dietary treatment carries a high risk of development of HCC (2,3). Of the 122 patients 11 patients had HCC, resulting in 17% of the reported deaths. Data from the international NTBC study revealed that NTBC treatment may prevent liver failure and may prolong life both in very early, early and late presenting patients and may decrease the risk of development of HCC when compared to dietary treatment (13). Since the introduction of NTBC, a few cases with HCC have been reported despite NTBC treatment, the longest treatment period being 3 years (13,15).
We present a patient with tyrosinemia type I who developed HCC after the longest treatment period of NTBC reported. The patient was on longterm NTBC but also started with NTBC at a later age than most reported cases. The longer the period of NTBC treatment before HCC develops, the more the questions arise as to whether NTBC really prevents the development of HCC.
When NTBC treatment is introduced, AFP levels decrease immediately. Suspicion about HCC arises after an increase in AFP. AFP is a well-known tumor marker for the development of HCC in pre-existing liver cirrhosis (16). AFP can also rise due to derangement of the tyrosinemia type I itself (5,13). Therefore, in our patient, the dosage of NTBC was increased to determine whether the metabolic derangement of the tyrosinemia type I itself was the possible cause of the rise in AFP. At the same time a thorough investigation for the presence of development of HCC was performed. The fact that urinary succinylacetone was not detectable and increasing the NTBC dosage did not produce a decrease in AFP strongly suggested that treatment with NTBC was adequate and that HCC was present.
Although the nodule with HCC was radically removed and AFP returned to pre-malignant concentrations, we decided to perform an orthotopic liver transplantation because of the high probability of the development of HCC in other segments of the cirrhotic liver in the future. In addition, a study on the cost effectiveness of partial hepatectomy versus liver transplantation in patients with liver cirrhosis and resectable HCC revealed a more favorable outcome in the patients who underwent orthotopic liver transplantation (17).
Concerning the effect of NTBC on HCC development, the observation in this patient that AFP levels never completely normalized during NTBC treatment-without detectable succinylacetone in urine- may indicate at least three possibilities.
First, NTBC can not prevent the start of the development of HCC in some tyrosinemia type I patients. Such a hypothesis is in line with the observations in fumarylacetoacetase deficient knockout mice in which even high doses of NTBC in combination with dietary restriction of phenylalanine and tyrosine did not prevent HCC (18,19).
Second, the development of HCC can not be stopped by NTBC if HCC is present before NTBC is introduced. This hypothesis underscores the importance of both the early recognition of tyrosinemia type I and intensive prolonged surveillance for the development of HCC even in cases apparently adequately treated with NTBC. In this regard, the development of adequate neonatal screening is greatly needed. Screening procedures, however, can not rely on genetic screening for mutations that are only frequent in specific areas such as Quebec (20), blood AFP or blood tyrosine concentrations (21-23). The most promising measurement is probably the succinylacetone concentration in blood or urine. Blood testing will require further refining of the method to decrease the limit of detection, while urine screening will require a major change in neonatal screening procedures.
Third, the difference between the positive reaction on NTBC at the start of the treatment and the lack of a positive reaction some years later may also suggest the development of resistance to NTBC by at least some liver cells.
Concerning the intensive follow-up for HCC in patients with tyrosinemia type I, the fact that increased AFP may be due to reasons other than development of HCC decreases the specificity of this test. The causes of elevated AFP include the development of adenoma and regeneration as observed in less adequately treated tyrosinemia type I patients. In addition, the possibility that HCC is developing in patients with very mild elevations of AFP must be considered. Patients in whom normal concentrations of AFP are not reached, therefore, should be monitored even more intensively. In general, the hepatic ultrasound is sufficient for detecting even very small nodules (24). Our patients case suggests that if an elevated AFP is detected and if the ultrasound of the liver is normal, other diagnostic modalities should be employed to screen for HCC.
Development of biochemical markers to monitor for HCC in tyrosinemia type I other than AFP is an issue of ongoing research. Other methods investigated to date have had drawbacks (25). However, new techniques such as proteonomic signatures in blood may hold promise (26).
In conclusion, NTBC is the treatment of choice for patients with very early, early and late presenting forms of tyrosinemia. Treatment should be started as early as possible suggesting that reliable neonatal screening should be a priority world-wide. Liver transplantation carries high morbidity and mortality and should be reserved for patients with failure to respond to NTBC in case of acute liver failure and those with possible development of HCC. Early recognition of tyrosinemia type I and adequate treatment should always be followed by intensive follow up for the risk of development of HHC both at the short and the long term. There is a need for development of methods other than AFP such as proteonomic signatures in blood to monitor treated patients. It remains to be shown whether NTBC is sufficient to prevent the development of HCC or only retard the growth of HCC already present.
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