Enzyme defect in a case of tyrosinemia type I, acute form

We determined the activities of tyrosine aminotransferase (TAT, EC 2.6.1.5), p-hydroxyphenylpyruvate oxidase (p- HPPA oxidase, EC 1.14.2.2) and fumarylacetoacetate fumarylhydrolase ( FAH , EC 3.7.12) in cytosol of the liver and kidney tissues obtained at autopsy from a case of hereditary tyrosinemia type I. Values were compared with those from a control group of autopsied tissues from three adults and six children, who had died of other causes. In tyrosinemia, these three hepatic enzyme activities were all decreased: TAT showed approximately 35%, p- HPPA oxidase 11%, and FAH 60% of the corresponding control values. On the other hand, kidney enzymes in tyrosinemia revealed that FAH was most significantly decreased to approximately 14% of the control activity. Km values for substrate--determined for p- HPPA oxidase and FAH --were not different between the patient and controls, suggesting no altered properties of these enzymes. We conclude that in the present case of hereditary tyrosinemia type I, the activities of p- HPPA oxidase in liver and FAH in kidney were most strikingly affected. This fact may in part explain the deteriorated metabolism of tyrosine observed in this patient.     

Chromosomal instability in hereditary tyrosinemia type I

Autopsy of a 4-year-old girl with hereditary tyrosinemia type I revealed a hepatocellular carcinoma in addition to cirrhosis and renal tubular dysplasia. Cytogenetic studies performed on a skin fibroblast culture demonstrated greatly increased chromosome breakage, which affected 71% of the cells. This suggests that the development of hepatoma, which is frequent in this syndrome, and the presence of dysplastic changes of hepatocytes in nontumorous liver are related to genetic instability caused by accumulation of intermediates of tyrosine catabolism, which are natural alkylating agents (e.g., maleylacetoacetate and fumarylacetoacetate). The other microscopic structural changes seen, such as renal tubular atypia, pancreatic islet cell hyperplasia, and focal necrosis of cortical neurons, may also be partly due to DNA damage caused by the accumulation of abnormal metabolites produced in patients with type 1 tyrosinemia.     

Favorable outcome of treatment with NTBC of acute liver insufficiency disclosing hereditary tyrosinemia type I]

BACKGROUND: Hereditary tyrosinemia type I is a disease with a severe prognosis. Main causes of death are acute liver failure, neurologic crises and hepatocarcinoma. NTBC, which acts as an inhibitor of the 4-hydroxyphenylpyruvate dioxygenase, prevents the formation of toxic metabolites involved in hepatic, renal and neurologic lesions. CASE REPORTS: Results of NTBC therapy used in three infants with type I tyrosinemia who presented with acute liver failure are reported. The diagnosis relied on the finding of high plasmatic levels of tyrosine and methionine, and abnormal urinary excretion of succinyl acetone and delta aminolevulinic acid. Treatment with NTBC was initiated within 2 to 8 days from onset of symptoms. Signs of liver failure resolved after 3 weeks therapy. After 12 to 39 months of follow-up, outcome remains favorable. CONCLUSION: The results reported here highlight the efficiency of NTBC in type I tyrosinemia with early acute onset. However, the long term outcome needs to be determined with regards to prevention of hepatocarcinoma and toxicity of the drug.     

Tyrosinämie Typ I

Tyrosinemia type I is an autosomal recessive inherited defect of tyrosine metabolism. The underlying cause is a defect of fumarylacetoacetate hydrolase. The disease affects the liver (acute liver failure, liver cirrhosis, hepatocellular cancer), the kidney (tubulopathy with hypophosphatemic rickets), and the peripheral nervous system (paresthesia, vegetative symptoms, progressive paralysis). Beside the hypertyrosinemia the diagnosis can be made on the basis of urinary excretion of a pathological metabolite of the tyrosine metabolism (succinylacetone). Therapeutic options are a regulated phenylalanine/tyrosine diet, a very effective drug therapy (NTBC) that has been available for several years, and in cases of acute liver failure or end-stage liver cirrhosis a liver transplantation.     

ON THE RENAL TUBULAR DAMAGE IN HEREDITARY TYROSINEMIA AND ON THE FORMATION OF SUCCINYLACETOACETATE AND SUCCINYLACETONE1

ABSTRACT. Fällström, S.-P., Lindblad, B. and Steen, G. (Department of Paediatrics, East Hospital, University of Gothenburg, Gothenburg, Department of Paediatrics, Molndal's Hospital, Molndal, Department of Clinical Chemistry, University of Gothenburg, Gothenburg, Sweden). On the renal tubular damage in hereditary tyrosinemia and on the formation of succinylacetoacetate and succinylacetone. Acta Paediatr Scand, 70:315, 1981.–Phenylalanine and homogentisate increase the concentration of succinylacetoacetate and succinylacetone both in serum and urine in patients with hereditary tyrosinemia and therefore increase the excretion of 5-aminolevulinate. Both phenylalanine and homogentisate cause a tubular proteinuria which is in agreement with our hypothesis that their metabolites maleylacetoace-tate and fumarylacetoacetate are the toxic compounds in hereditary tyrosinemia. The patient with the highest excretion of succinylacetoacetate and succinylacetone has the slightest tubular proteinuria whereas the one with the lowest excretion of these compounds has the more pronounced tubular proteinuria. It is suggested that this is caused by a difference in the ability to reduce the presumed toxic compounds fumarylacetoacetate and maleylacetoacetate, i.e. the precursors of succinylacetoacetate.     

Tyrosinämie Typ I Klinische und biochemische Symptome bei 3 Säuglingen

Background. Tyrosinemia type I is an autosomal recessively inherited deficiency of fumarylacetoacetate hydrolase resulting in accumulation of tyrosin and its degradation products (succinylacetoacetone mainly). Typical clinical features include liver and kidney failure as well as central nervous system involvement. There are three main forms of the disease: the acute form with manifestation in newborn infants and the subacute and the chronic form in children older than one year of age. Case reports. We report on three infants with acute tyrosinemia type 1. In two patients impaired liver function with coagulopathy, hypalbuminemia and low cholinesterase as well as renal tubulopathy with urinary phosphate loss led to the diagnosis. In one patient high galactose and phenylalanine levels at routine neonatal screening gave the hint for further investigations. All patients had anemia and thrombocytopenia. Diagnosis was established by measurement of urinary succinylacetoacetone at mean age of 54.6 days. Treatment. Treatment with 2-(nitro-4-trifluoromethylbenzoyl)-1–3-cyclohexanedione (NTBC) and a diet low in tyrosine, and phenylalanine was started. Clinical improvement and normalization of laboratory findings were noted in all patients. Discussion. Tyrosinemia type I must be considered in newborns and infants with impaired hepatic synthesis of coagulation parameters, albumin and cholinesterase and with additional signs of renal tubulopathy (hypophosphatemia and rickets mainly). For diagnosis measurements of urinary succinylacetoaceton is essential.     

The kidney in children with tyrosinemia: sonographic, CT and biochemical findings

Background. Tyrosinemia relates to a deficiency of fumarylacetoacetate hydrolase and presents early in life with central nervous system and liver abnormalities. Renal function is often impaired. Little is known about the architecture and function of the kidneys. Objective. Imaging changes on US and CT are compared to the function of the kidneys in children with tyrosinemia, and followed after liver transplantation. Materials and methods. Renal sonography, CT and renal function tests in 32 children were reviewed. Renal length, volume, echogenicity and nephrocalcinosis were evaluated. Renal function was assessed by glomerular filtration rate, and the presence of aminoaciduria, acidosis and calciuria. Seventeen children had open renal biopsy during time of liver transplantation. Histology was reviewed. Statistical analyses relating renal structure to function were performed, and repeated after transplantation. Results. The kidneys were enlarged (47 %), hyperechogenic (47 %) and showed nephrocalcinosis (16 %). There was delayed excretion of contrast medium at CT in 64 %. Aminoaciduria was present in 82 % of children, hypercalciuria in 67 %, tubular acidosis in 59 %, and low GFR in 48 %. Delayed excretion of contrast was associated with low GFR (P < 0.05). Renal biopsies showed dilated tubules (81 %), interstitial fibrosis (56 %), glomerulosclerosis (56 %) and tubular atrophy (56 %). During a mean observation period of 3 years following liver transplantation, GFR improved in 50 %, tubular acidosis in 50 % and hypercalciuria in 70 %. No change was noted in renal size or sonographic architecture. Conclusion. Renal architecture and function are abnormal in the majority of children with tyrosinemia. Liver transplantation improves renal function in about 50 % of patients, but abnormal renal size and architecture persist. Received: 27 October 1997 Accepted: 4 June 1998     

Imaging features of type 1 hereditary tyrosinemia: a review of 30 patients

Hereditary tyrosinemia type 1, a common genetic disorder in the province of Quebec, is characterized by a deficiency of fumarylacetoacetate hydrolase. In this autosomal recessive disorder of tyrosine metabolism, the accumulation of succinyiacetone leads to neurologic crises, acute and chronic liver failure, complex renal tubulopathy, rickets and a hemorrhagic syndrome. Liver transplantation has dramatically modified the spontaneous course of this lethal disease. The present paper describes the imaging features of tyrosinemia in 30 patients followed from 1980 to 1995 at Hôpital Sainte-Justine, Montreal, Canada.     

Tyrosinemia I,a model for human diseases mediated by 2-oxoacid-utilizing dioxygenases: hepatotoxin suppression by NTBC does not normalize hepatic collagen metabolism

OBJECTIVES: Medical treatment of tyrosinemia I relies on the herbicide NTBC [Orfadin 2-(2-nitro-4-trifluoromethylbenzoyl)-cyclohexane-1,3-dione], an inhibitor of plant and mammalian 2-oxoacid-utilizing dioxygenases with a collective catalytic cycle ('HAG' mechanism). We hypothesize that NTBC-treated tyrosinemia I is a human model for the pathogenic role of two major enzymes in this class, 4-hydroxyphenylpyruvate dioxygenase (4-HPPD; EC 1.13.11.27) and prolyl 4-hydroxylase (P4-H; E.C. 1.14.11.2), essential for tyrosine and collagen metabolism, respectively. METHODS: In a patient with established tyrosinemia I, we monitored the in vivo activities of 4-HPPD and P4-H via five biomarkers before and during NTBC medication. Hypothesis testing at the molecular level was performed by computational modeling of NTBC binding to the crystal structure-derived active site of 4-HPPD, and then relating these findings to our experimental results and to known P4-H data. RESULTS: NTBC rapidly normalized the biomarkers for 4-HPPD activity. However, those for P4-H activity remained uniformly elevated after one hundred days on NTBC, the PIIINP biomarker even increasing above its grossly abnormal, initial level. This selective enzyme inhibition despite a collective catalytic cycle is attributed to the conformation of NTBC, which only fits the active site of 4-HPPD, as confirmed by its crystal structure. CONCLUSIONS: Normalization of hepatic collagen formation, highly desirable in all fibrotic liver diseases, is not achieved by NTBC in tyrosinemia I. By establishing the molecular cause for this failure, our results also establish a rational approach to identify inhibitors that achieve that goal, either by joint 4-HPPD / P-4H inhibition, or by inhibition of only P-4H.     

Renal Tubular Dysgenesis in Twin-Twin Transfusion Syndrome

In twin-twin transfusion syndrome (TTTS), the disparity in circulation is reflected in discordant fetal growth, urine output, and amniotic fluid accumulation. The effect of uneven shunting of the growth factor and nutrient-rich vasculature on development and differentiation of the kidney has not been well studied. We analyzed renal tubular growth and differentiation in 25 fetal autopsies with TTTS (13 donors and 12 recipients, including 9 sibling pairs) between 18 and 33 weeks gestation. Immunohistochemical markers for fumarylacetoacetate hydrolase (FAH), Leu-M1, and Lotus tetragonolobus (LTA) were used to identify proximal convoluted tubules, and epithelial membrane antigen (EMA) was used to demonstrate distal convoluted and collecting tubules. FAH appeared to be more specific and reliable than either Leu-M1 or LTA in the identification of proximal tubules. Donors tended to demonstrate a paucity of proximal tubules with crowding of glomeruli characteristic of renal tubular dysgenesis (RTD). The degree of dysgenesis was greater in later gestations and associated with more severe growth restriction. Donors in TTTS are at risk for the development of RTD. Several authors suggest ischemia as the underlying cause of “acquired” RTD. However, in this setting there is no evidence of cell death or necrosis, and we suggest that hypoperfusion leading to decreased glomerular filtration is the underlying etiology, with the severity of RTD related to the degree of shunting. Received November 12, 1997; accepted February 12, 1998.     

Clinical practice

Four patients with tyrosinemia type 1 (ages 6–32 months) were treated with 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexandion (NTBC) at Cairo University Children’s Hospital, Egypt and followed up for 12–27 months. The recommended average dose of NTBC is 1 mg/kg/day. They were started on the following doses: 0.8, 0.58, 0.5, and 0.625 mg/kg/day, respectively. Two months after start of therapy, succinylacetone was undetectable in patients 1, 2, and 4, while in case 3, it was 5.4 μM. Her NTBC dose was increased from 0.5 to 0.65 mg/kg/day, and succinylacetone was undetectable 1 month later. They were kept on NTBC doses ranging from 0.55 to 0.65 mg/kg/day. These doses allowed catch up growth, normalization of synthetic liver functions, steep drop in serum alpha fetoprotein, reduction in phosphate loss in urine, normalization of serum calcium, phosphate, and alkaline phosphatase, and healing of active rickets. Succinylacetone was undetectable in urine on these doses. In conclusion: Doses of NTBC, lower than recommended, may be helpful in treatment of tyrosinemia, on condition that succinylacetone production is suppressed, and AFP is maintained normal or showing a progressive decrease. This cost-effective dose may allow treatment of affected children from economically underprivileged countries, but longer follow up periods are needed.     

Effect of dietary treatment on the renal tubular function in a patient with hereditary tyrosinemia

In a 1 1/2-month-old girl with hereditary tyrosinemia, renal tubular function studies were done. The effect of a low tyrosine and phenylalanine formula on renal tubular functions was also studied. The tubular handling of phosphorus, uric acid, beta 2-microglobulin, and amino acids was disturbed. Low urinary osmolality was also seen. Creatinine clearance was increased during a period of the standard formula. Although treatment with the low tyrosine and phenylalanine diet produces dramatic improvement in plasma tyrosine and tyrosyluria, all tubular symptoms did not revert to normal. It is possible that tubular dysfunction of hereditary tyrosinemia may be irreversible changes.     

Tyrosinemia: A Review

Hypertyrosinemia encompasses several entities, of which tyrosinemia type I (or hepatorenal tyrosinemia, HT1) results in the most extensive clinical and pathological manifestations involving mainly the liver, kidney, and peripheral nerves. The clinical findings range from a severe hepatopathy of early infancy to chronic liver disease and rickets in the older child; gradual refinements in the diagnosis and medical management of this disorder have greatly altered its natural course, mirroring recent advances in the field of metabolic diseases in the past quarter century. Hepatorenal tyrosinemia is the inborn error with the highest incidence of progression to hepatocellular carcinoma, likely due to profound mutagenic effects and influences on the cell cycle by accumulated metabolites. The appropriate follow-up of patients with cirrhosis, the proper timing of liver transplantation in the prevention of carcinoma, and the long-term evolution of chronic renal disease remain important unresolved issues. The introduction of a new pharmacologic agent, NTBC, holds the hope of significantly alleviating some of the burdens of this disease. Mouse models of this disease have permitted the exploration of newer treatment modalities, such as gene therapy by viral vectors, including ex vivo and in utero methods. Finally, recent observations on spontaneous genetic reversion of the mutation in HT1 livers challenge conventional concepts in human genetics. Received November 15, 2000; accepted December 7, 2000.     

Tyrosinemia type I: A clinico-laboratory case report

Progressive hepatocellular dysfunction in a neonate, resulting in elevated serum α-fetoprotein together with raised blood levels of tyrosine and methionine, a generalized amino aciduria and the absence of urinary δ-aminolevulinic acid and succinylacetone, suggests a diagnosis of tyrosinemia type Ib. Classical tyrosinemia type I arises from a deficiency of fumarylacetoacetate hydrolase while the variant tyrosinemia type Ib results from a deficiency of maleylacetoacetate isomerase.     

Tyrosinemia type 1 should be suspected in infants with severe coagulopathy even in the absence of other signs of liver failure

Tyrosinemia type l is an inherited metabolic disorder attributable to deficiency of fumarylacetoacetate hydrolase, a terminal enzyme in the degradation pathway of tyrosine. Affected individuals may present with any of a number of signs and symptoms, including failure to thrive, fever, vomiting, diarrhea, hepatomegaly, ascites, jaundice, renal Fanconi syndrome, or conditions such as rickets and hepatocellular carcinoma.1 If untreated, the patient may die of acute liver failure before the second year of life, or from chronic liver failure or hepatocellular carcinoma before the end of the second decade of life.2 Although overt liver failure with coagulopathy may be part of the presentation of tyrosinemia, a significant coagulopathy in the absence of overt signs of liver disease has not been emphasized as a clue to the diagnosis of this condition. We report two tyrosinemic infants who presented with severe coagulopathies and no other signs of liver failure to stress this diagnostic point.     

Clinical syndromes with liver and kidney involvement in children and adults

Multiple pathogenetic mechanisms can lead to dysfunctions or malformations of the liver and kidneys in children and adults. The association of renal and hepatic abnormalities can be found in different congenital malformation syndromes. Hereditary metabolic disorders are capable of alternating liver and kidney function. Immunologic, toxic and septic diseases may damage both organ systems. In patients with liver cirrhosis, both glomerular and tubular dysfunctions can be observed. In the course of liver transplantations, an increased rate of renal dysfunction was observed. This survey summarizes the main clinical syndromes of renal involvement associated with liver disease.     

Rapid improvement in the renal tubular dysfunction associated with tyrosinemia following hepatic replacement.

The postoperative management of patients with hereditary tyrosinemia type I (McKusick 27670) following liver transplantation is often complicated by the renal tubular dysfunction associated with this disease. To characterize better the temporal course of the improvement in renal excretory activity following hepatic replacement, renal tubular function and metabolite excretion were studied in a 4-year-old girl with hereditary tyrosinemia during the immediate post-transplantation course. Tubular reabsorption of bicarbonate and phosphate were normal 5 days following transplantation, in contrast to glucosuria, hyperaminoaciduria, and tyrosyluria, which persisted for approximately 3 weeks. After hepatic replacement, serum amino acid concentrations returned to normal and succinylacetone was no longer detected in the urine. This is the third tyrosinemia patient reported to achieve complete resolution of urinary abnormalities following transplantation, and the only patient in whom renal tubular function was formally assessed within the first postoperative week.     

Evolution of a case of tyrosinemia type I treated with NTBC

Tyrosinemia type I is an autosomal recessive inherited disorder caused by deficient fumarylacetoacetase activity. Treatment with 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexanedione (NTBC), an inhibitor of 4-hydroxyphenylpyruvate dioxygenase, has successfully been applied for the last few years. Our aim was to evaluate the clinical and biochemical response to treatment with NTBC of a 18-year-old patient with a chronic form of tyrosinemia type I, whose main clinical feature was vitamin D-resistant rickets leading to severe osteoporosis with multiple bone fractures and skeletal deformities. After treatment, toxic metabolites became undetectable and porphobilinogen synthase activity returned to normal. Renal function improved, blood hemoglobin returned to normal and alfa-fetoprotein decreased. The patient's general condition greatly improved. However, the alfa-fetoprotein concentration slowly increased during the second year of NTBC treatment and hepatocellular carcinoma developed. NTBC treatment should be considered even in advanced cases of tyrosinemia type I, although only as a palliative therapy.     

Hereditary tyrosinemia type 1 from a single center in Egypt: clinical study of 22 cases

Background  

Hereditary tyrosinemia type 1 (HT1) is an increasingly recognized inborn error of metabolism among Egyptian children. This study was undertaken to define the presenting clinical, biochemical and imaging features and outcome of 2-(2-motrp-4-trifluoromethylbenzoyl)-1, 3-cyclohexanedione (NTBC) therapy and liver transplantation in a cohort of Egyptian children diagnosed with HT1.     

Reversibility of cirrhotic regenerative liver nodules upon NTBC treatment in a child with tyrosinaemia type I

In a male patient with hereditary tyrosinaemia type I (HTI), NTBC [2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3-cyclohexandion] treatment and a diet low in phenylalanine and tyrosine were started at the age of 4 wk. At the recommended average dosage (1 mg kg(-1)), liver failure improved transiently. After 4 mo of treatment, with increased body weight, the dose had decreased to 0.7 mg kg(-1), and diffuse cirrhotic changes in liver parenchyma and multiple nodules were visualized by ultrasonography. Multiple nodules in the liver parenchyma were differentiated from hepatocellular carcinoma by magnetic resonance imaging (MRI) using mangafodipir trisodium as a paramagnetic liver-specific contrast agent. Augmentation of NTBC dosage resulted in a decrease in serum alpha-fetoprotein levels and in significant regression of liver nodules on MRI. CONCLUSION: In HTI patients with a poor response to NTBC treatment and/or development of cirrhotic changes of liver parenchyma, augmentation of the recommended NTBC dosage may result in significant improvement of symptoms.