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.     

Succinylacetone and delta-aminolevulinic acid dehydratase in hereditary tyrosinemia: immunochemical study of the enzyme

Immunochemical determinations of delta-aminolevulinic acid (ALA) dehydratase were performed in erythrocytes and in liver of a patient with hereditary tyrosinemia who underwent liver transplantation for correction of this metabolic disorder. Both erythrocytic and hepatic ALA dehydratase activities were extremely low before liver transplantation, but they appeared normal after transplantation. According to results of immunochemical quantification of ALA dehydratase, the level of the enzyme protein in erythrocytes was not different before, during, and after liver transplantation. Immunoquantifiable enzyme concentrations were not substantially different in the patient's own liver as compared with the transplanted liver. These findings indicate that although succinylacetone, an abnormal metabolite produced in tyrosinemia, is a potent inhibitor of the activity of ALA dehydratase, it has a far less effect on the synthesis of the enzyme protein.     

Rare pediatric conditions: Contribution of grey-scale ultrasonography

The authors report some unusual pediatric conditions where grey scale ultrasound was the most useful diagnostic tool. Cases of pericardial cyst, polycystic kidney disease of the adult type, hepatic hamartoma and hepatocarcinoma, gallstones, renal pseudo tumors, calcified inferior vena caval thrombus, acute pancreatitis, multicystic kidney and retroperitoneal lymphangioma are briefly described and compared to the literature. In a patient presenting with hereditary tyrosinemia, ultrasound not only disclosed evidence of hepatocarcinoma but was shown to be the procedure of choice for following the course of the disease.     

Contribution of extrahepatic tissues to biochemical abnormalities in hereditary tyrosinemia type I: study of three patients after liver transplantation

Three patients with hereditary tyrosinemia type I were examined before and after liver transplantation to assess the role of extrahepatic tissues in the biochemical disorders of this disease. Before transplantation the three patients excreted excessive amounts of succinylacetoacetate (SAA), succinylacetone (SA), tyrosyl acidic compounds, and 5-aminolevulinate (ALA). The activity of 5-aminolevulinate dehydratase (ALA-D) in red blood cells was markedly inhibited (1% to 5% of control) in the three patients. Successful liver transplantation resulted in decreased excretion of urinary SAA plus SA, tyrosyl acidic compounds, and ALA. Two of the patients continued to excrete significant amounts of SAA plus SA, whereas those compounds were undetectable in the urine of the third patient. Tyrosine loading resulted in increased excretion of SAA plus SA in two patients, but those compounds remained undetectable in the third. All three patients continued to excrete higher than normal amounts of ALA, but the activity of ALA-D in red blood cells returned to normal after transplantation, indicating marked clearance of SA from the blood. Liver transplantation may not totally correct the biochemical abnormalities of hereditary tyrosinemia. It is likely that the kidney is the source of persistent biochemical aberrations in the urine without significant effects on the blood. Our results suggest the existence of heterogeneity for renal involvement in hereditary tyrosinemia.     

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.     

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     

Kidneys of mice with hereditary tyrosinemia type I are extremely sensitive to cytotoxicity

Children with hereditary tyrosinemia type 1 (HT1) suffer from liver failure, renal tubular dysfunction, and rickets. The disease is caused by deficiency of fumarylacetoacetate hydrolase (FAH), the last enzyme of tyrosine catabolism, and leads to accumulation of the toxic substrate fumarylacetoacetate (FAA) in hepatocytes and renal proximal tubular cells. Patients are treated with 2-(2-nitro-4-trifluoro-methylbenzoyl)-1,3 cyclohexanedione (NTBC), which prevents accumulation of FAA by blocking an enzyme upstream of FAH. Liver transplantation is performed when patients do not respond to NTBC or develop hepatocellular carcinoma. This reduces the tyrosine load for the kidney but does not abolish renal exposure to locally produced FAA. To investigate the pathogenesis of liver and kidney damage induced by tyrosine metabolites, we challenged FAH-deficient mice with various doses of homogentisic acid (HGA), a precursor of FAA. Injecting NTBC-treated Fah-/- mice with low doses of HGA caused renal damage and death of renal tubular cells, as was shown by histologic analyses and deoxynucleotidyl transferase-mediated dUDP nick-end labeling (TUNEL) assay but did not lead to liver damage. In addition, kidney function, but not liver function, was affected after exposure to low doses of HGA. Administration of high doses of HGA led to massive cell death in both the liver and kidneys. Resistance to HGA-induced cell death was seen after withdrawing NTBC from Fah-/- mice. The finding that the kidneys of Fah-/- mice are especially sensitive to damage induced by low doses of HGA underscores the need to perform careful monitoring of the kidney function of tyrosinemia patients undergoing any form of treatment.     

Surgical excision of a hepatoma complicating chronic tyrosinemia (author's transl)

A girl with chronic hereditary tyrosinemia is described in whom the diet caused an immediate resolution of tubular defect and rapid healing of the rickets. However cirrhosis was not prevented and at the age of 8 she developed a hepatoma. Complete surgical excision was possible and she remained well 15 months later. The value of blood alpha-fetoprotein levels and liver echotomography to monitor the course of the disease is emphasized. The apparent ineffectiveness of the low phenylalanine and tyrosine diet in preventing hepatic complications is discussed.     

Serum type III procollagen in children with type I hereditary tyrosinemia.

BACKGROUND: Type I hereditary tyrosinemia leads to hepatic dysfunction and fibrosis and is associated with a high risk of hepatic malignancy. Serum N-terminal propeptide of type III procollagen is a sensitive marker of organ fibrosis of diverse origins. The current study was conducted to determine whether analysis of serum levels of type III procollagen in hereditary tyrosinemia would be useful in the follow-up of the progressive liver disease and eventually in detecting hepatic malignancy. METHODS: Serum N-terminal propeptide of type III procollagen was sequentially studied in 10 children with type I hereditary tyrosinemia. RESULTS: At diagnosis of type I hereditary tyrosinemia, serum N-terminal propeptide of type III procollagen ranged from 0.6 to 2.9 multiples of age-related median. During follow-up, serum N-terminal propeptide of type III procollagen decreased, yet remained elevated 0.2 to 2.6 years after diagnosis. Children with the acute type of the disease tended to have higher serum N-terminal propeptide of type III procollagen than did those with the chronic type. Porphyria crises were associated with elevated serum type III procollagen. The one patient receiving 2-(2-nitro-4-trifluoromethyl-benzoyl)-1,3-cyclohexanedione (NTBC) did not differ from the other ones in serum type III procollagen levels. Serum N-terminal propeptide of type III procollagen did not increase with developing hepatocellular carcinoma. CONCLUSIONS: Serum N-terminal propeptide of type III procollagen may be useful in monitoring the hepatopathy in type I hereditary tyrosinemia but is not useful in detecting malignant transformation in the liver.     

Homotransplantation of the liver in a patient with hepatoma and hereditary tyrosinemia.

A girl with hereditary tyrosinemia, diagnosed at 6 months of age, was treated with a diet restricted in phenylalanine and tyrosine. At 9 1/2 years of age she developed an acutely enlarged liver and spleen, and the diagnosis of hepatocarcinoma was made. The patient received a liver transplant and tyrosine metabolites became normal while she was receiving a regular diet. Three months later, an infected thrombosis of the portal vein caused her death. Liver transplant appears to be an effective method of enzyme replacement in tyrosinemia and should be considered for prevention of hepatoma.     

HEREDITARY TYROSINEMIA

The clinical and biochemical findings in the case of an infant with hereditary tyrosinemia followed from birth have been reported. The child received a low protein diet from birth and a formula diet restricted in phenylalanine and tyrosine when the diagnosis was established at 54 days of age. There was a steady progress of the disease and the baby died from liver failure complicated with septicemia when he was 5½ months old. The clinical course and the biochemical findings as well as the morphological changes were typical of the acute type of the disease. A 6½ year old brother suffers from the same disease of the chronic type and the two types of hereditary tyrosinemia therefore seem to belong to the same genotype. The biochemical data from the patient with hereditary tyrosinemia have been compared with those in a healthy looking baby with longstanding and pronounced transient tyrosinemia of early infancy. The patterns of amino acids in blood and of phenolic acids in urine were similar in the two patients and it is concluded that an early laboratory differential diagnosis between hereditary tyrosinemia and transient tyrosinemia may only be made by observing the biochemical response to a diet restricted in tyrosine and phenylalanine in combination with the results of phenylalanine tolerance tests. The clinical features of hereditary tyrosinemia can apparently not be attributed to a high serum-tyrosine concentration or to the overproduction of phenolic acids; the lack of effect of early restriction in the intake of phenylalanine and tyrosine indicates a more complex pathogenesis of hereditary tyrosinemia than a primary deficiency of p-hydroxyphenylpyruvate hydroxylase.     

Biochemical studies of a patient with hereditary hepatorenal tyrosinemia: evidence of glutathione deficiency

Metabolic and enzymatic studies in a patient with hereditary tyrosinemia demonstrated for the first time a deficiency of erythrocyte and hepatic glutathione. Markedly decreased hepatic fumarylacetoacetate hydrolase activity was demonstrated in this patient. The activities of hepatic enzymes not involved in tyrosine metabolism were also determined. Assay of mixed function oxidase activity demonstrated low levels of aryl hydrocarbon hydroxylase and 7-ethoxycoumarin deethylase, suggesting decreased hepatic detoxification capacity. 5-Aminolevulinic acid dehydratase activity was undetectable. Succinylacetone (4,6-dioxoheptanoic acid), an abnormal metabolic product secondary to fumarylacetoacetate hydrolase deficiency was found in serum and urine. Succinylacetone was demonstrated to inhibit 5-aminolevulinic acid dehydratase in vitro, as did the urine, plasma, and red cell lysates of the patient.     

Early liver transplantation is indicated for tyrosinemia type I

Liver transplantation is now accepted as the treatment of choice for tyrosinemia type I (hereditary tyrosinemia). In an effort to determine whether any factors in these patients would aid in predicting optimal timing of the transplant procedure, we evaluated several clinical, biochemical, and radiographic parameters in five successive patients undergoing liver transplant for tyrosinemia type I at the University of Minnesota. All five patients evidenced prolonged periods of clinical and metabolic stability with dietary therapy and four of five remained stable at the time of evaluation for transplantation. Nevertheless, all five suffered significant and unexpected complications of tyrosinemia prior to the time of liver transplant. Four developed renal stones, two were in liver failure, and one developed a neurologic crisis that left him completely paralyzed. Hepatocellular carcinoma was found in one of the five at transplant. We could identify no clinical, biochemical, or radiographic study that was predictive of the likelihood of significant complications of the disorder. Survival from the transplant procedure itself was 100%. The inability to predict or prevent significant complications of tyrosinemia and the favorable outcome from transplantation lead us to recommend liver transplant for all patients with tyrosinemia type I by 12 months of age.     

Liver transplantation for type I and type IV glycogen storage disease

Progressive liver failure or hepatic complications of the primary disease led to orthotopic liver transplantation in eight children with glycogen storage disease over a 9-year period. One patient had glycogen storage disease (GSD) type I (von Gierke disease) and seven patients had type IV GSD (Andersen disease). As previously reported [19], a 16.5-year-old-girl with GSD type I was successfully treated in 1982 by orthotopic liver transplantation under cyclosporine and steroid immunosuppression. The metabolic consequences of the disease have been eliminated, the renal function and size have remained normal, and the patient has lived a normal young adult life. A late portal venous thrombosis was treated successfully with a distal splenorenal shunt. Orthotopic liver transplantation was performed in seven children with type N GSD who had progressive hepatic failure. Two patients died early from technical complications. The other five have no evidence of recurrent hepatic amylopectinosis after 1.1–5.8 postoperative years. They have had good physical and intellectual maturation. Amylopectin was found in many extrahepatic tissues prior to surgery, but cardiopathy and skeletal myopathy have not developed after transplantation. Post-operative heart biopsies from patients showed either minimal amylopectin deposits as long as 4.5 years following transplantation or a dramatic reduction in sequential biopsies from one patient who initially had dense myocardial deposits. Serious hepatic derangement is seen most commonly in types I and IV GSD. Liver transplantation cures the hepatic manifestations of both types. The extrahepatic deposition of abnormal glycogen appears not to be problematic in type I disease, and while potentially more threatening in type IV disease, may actually exhibit signs of regression after hepatic allografting.     

Hereditary tyrosinemia of chronic course without rickets and renal tubular dysfunction

Three patients with hereditary tyrosinemia type 1, two brothers and one girl, studied at the age of 5, 12 and 15 years, respectively, had neither generalized hyperaminoaciduria, glucosuria nor clinical symptoms of rickets. Untreated the elder brother had only slightly elevated plasma tyrosine level (141 mumol/l, normal less than 80), and low excretion of p-hydroxyphenyllactate. He presented with pronounced thrombocytopenia (3 X 10(9)/l). At 13 years of age he contracted hepatocellular carcinoma. The younger brother presented with serum tyrosine of 318 mumol/l and thrombocyte count 48 X 10(9)/l. Succinylacetone in urine was elevated in both, 30 and 79 mumol/mmol creatinine, respectively. The female patient was investigated for hepatomegaly in infancy, atypical tyrosinemia being considered, but afterwards developed normally without diet or any other treatment until she contracted hepatoma at the age of 15 years. Her plasma tyrosine level was 600-700 mumol/l, and she excreted large amounts of p-hydroxyphenyllactate. Succinylacetone in urine was low but elevated (8 mumol/mmol creatinine). The fumarylacetoacetase activity in fibroblasts from the brothers and in lymphocytes from the girl was less than 5% and 10% of control levels, respectively. In conclusion, the chronic form of hereditary tyrosinemia may occur without evidence of renal tubular dysfunction.     

Diagnostic Problems of Disorders of Tyrosine Metabolism

Abnormalities of tyrosine metabolism have been reported in infants and children with a variety of liver diseases. Especially infants with hereditary fructose intolerance show often the very similar picture of clinical symptoms with congenital tyrosinemia. The livers of the patients, two cases of congenital tyrosinemia type 1 and three cases of hereditary fructose intolerance, were studied biochemically and compared to normal control livers. Kinetic studies of p-hydroxyphenylpyruvate oxidase revealed that crude extract of livers from patients with congenital tyrosinemia were distinctively inhibited by substrate in low concentration. It is suggested that this kinetic abnormality is closely related to the fundamental defect of congenital tyrosinemia. Activity of p-hydroxyphenylpyruvate oxidase was noted in peripheral leucocytes. The patient showed a reduced activity as low as 20% of normal. Enzyme assay in leucocytes might be useful in making the definite diagnosis prior to starting correct diagnosis for tyrosinemic state.     

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.     

Hereditary Tyrosinemia of Chronic Course without Rickets and Renal Tubular Dysfunction

ABSTRACT. Three patients with hereditary tyrosinemia type 1, two brothers and one girl, studied at the age of 5, 12 and 15 years, respectively, had neither generalized hyperaminoaciduria, glucosuria nor clinical symptoms of rickets. Untreated the elder brother had only slightly elevated plasma tyrosine level (141 μmol/l, normal <80), and low excretion of p-hydroxyphenyllactate. He presented with pronounced thrombocytopenia (3 × 10⁹/1). At 13 years of age he contracted hepatocellular carcinoma. The younger brother presented with serum tyrosine of 318 μol/l and thrombocyte count 48 × 10⁹/1. Succinylacetone in urine was elevated in both, 30 and 79 μmol/mmol creatinine, respectively. The female patient was investigated for hepatomegaly in infancy, atypical tyrosinemia being considered, but afterwards developed normally without diet or any other treatment until she contracted hepatoma at the age of 15 years. Her plasma tyrosine level was 600-700 μmol/1, and she excreted large amounts of p-hydroxyphenyllactate. Succinylacetone in urine was low but elevated (8 μmol/mmol creatinine). The fumarylacetoacetase activity in fibroblasts from the brothers and in lymphocytes from the girl was less than 5% and 10% of control levels, respectively. In conclusion, the chronic form of hereditary tyrosinemia may occur without evidence of renal tubular dysfunction.     

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.     

Neonatal hemochromatosis: a case report with unique presentation

Acute liver failure (ALF) is a relatively rare condition in neonates, and early diagnosis and treatment are crucial for the treatable conditions. Neonatal hemochromatosis (NH) is a rare clinical condition that is clinically defined as severe neonatal liver disease associated with hepatic and extrahepatic iron deposition in a distribution similar to that seen in hereditary hemochromatosis. Although a few cases have been reported with spontaneous remission, early and aggressive medical treatment is essential for improving the outcome. Despite aggressive treatment, some patients may require liver transplantation. We report a five-day-old male infant with NH and associated Duarte variant galactosemia, renal tubulopathy and hypertyrosinemia, who was successfully treated with combination medical treatment. Combination therapy may reduce the need for liver transplantation in infants with NH. Early diagnosis and aggressive treatment are important as in galactosemia or tyrosinemia for the outcome. Thus, NH may be listed as a treatable cause of ALF in neonates.