The efficacy of liver transplantation in malignant liver tumors associated with tyrosinemia: clinical and laboratory findings of five cases

To evaluate clinical and laboratory findings of these patients and the efficacy of liver transplantation in children with hepatocellular carcinoma (HCC) and hepatoblastoma (HB) associated with tyrosinemia. Among 113 children with liver tumors diagnosed between 1972 and 2004 five patients had HCC or HB associated with tyrosinemia. The age at diagnosis of the HCC or HB ranged from 9.5 to 17 yr and male:female ratio was 1:4. During regular clinic visits for tyrosinemia, elevated alpha-fetoprotein (AFP) was detected in all patients. AFP levels ranged between 13.7 and 29 340 IU/mL. Radiological studies including ultrasound, computed tomography and magnetic resonance imaging showed heterogeneous parenchyma and nodules in the liver. The patients did not have any metastatic disease. The time from diagnosis of tyrosinemia to HCC or HB ranged from 9.25 to 15.25 yr. Histopathologically, four patients have been diagnosed as HCC and one patient had HB. All patients were given chemotherapy including cisplatin and adriamycin. In three patients, living-related liver transplantation was performed. They had no treatment after transplantation. All of them are disease free. One patient was treated with chemotherapy and right hepatectomy. She had no suitable donor for living-related liver transplantation. Three months after completing chemotherapy, she had recurrent tumor in the left lobe of the liver and she died with progressive disease. The last patient whose parents were not suitable as donors for living-related liver transplantation is waiting for a deceased donor graft. All patients had limited disease to liver due to close clinical and radiological follow up for tyrosinemia. In these patients liver transplantation is curative both for liver tumor and tyrosinemia.     

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.     

Hereditary tyrosinemia type I: lack of correlation between clinical findings and amount of immunoreactive fumarylacetoacetase protein.

Immunoblot analyses with bovine fumarylacetoacetase antibodies have been performed in fibroblast extracts from 28 patients with hereditary tyrosinemia of various clinical phenotypes, in one healthy individual homozygous for a "pseudodeficiency" gene for fumarylacetoacetase, and in three tyrosinemia families in which one or both parents are compound heterozygotes for the tyrosinemia and pseudodeficiency genes. Liver extracts from two chronic patients were also investigated. None of the patients with the acute type of tyrosinemia had detectable immunoreactive protein in fibroblast extracts. Only two of seven patients with typical chronic tyrosinemia had definite immunoreactivity in fibroblasts. In liver tissue, one of the patients had cross-reactive material and the other had no immunoreactivity. Four of 13 patients with intermediate clinical findings showed immunoreactivity in fibroblasts. There was no relationship between severity of symptoms and amount of cross-reactive material in this group. The pseudodeficiency gene product gave almost no detectable immunoreactivity in fibroblasts. The results indicate that chronic tyrosinemia may be due to at least two protein variants, and immunoblotting does not classify tyrosinemia patients according to clinical findings.     

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.     

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.     

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.     

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.     

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.     

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.     

Long-term survival after liver transplantation in children with metabolic disorders

BACKGROUND: Liver transplantation for inherited metabolic disorders aims to save the patient's life when the disorder is expected to progress to organ failure, and to cure the underlying metabolic defect. METHODS: We retrospectively analyzed 146 pediatric liver transplants (28 metabolic; 118 non-metabolic) performed between 1986 and 2000. RESULTS: Twenty-eight transplants were performed in 24 children with metabolic disease (8 females; 16 males; age range 3 months to 17 yr). Indications included alpha-1-antitrypsin deficiency (n = 8), two cases each of hyperoxaluria type 1, Wilson's disease, hereditary tyrosinemia type I, citrullinemia, methylmalonic acidemia, and one case each of propionic acidemia, Crigler-Najjar syndrome type I, neonatal hemachromatosis, hemophilia B, Niemann-Pick disease type B, and cystic fibrosis. Eighteen transplants were whole organ grafts and 10 were lobar or segmental. Auxiliary liver transplants were performed in two patients and three received combined liver-kidney transplants. There were three deaths from sepsis, two from chronic rejection, and one from fulminant hepatitis. Seven of 10 patients currently of school age are within 1 yr of expected grade and three who had pretransplant developmental delay have remained in special education. Actuarial survival rates at 5 and 10 yr are 78% and 68%, respectively, with mean follow-up in excess of 5 yr. These results compare favorably to 100 pediatric patients transplanted for non-metabolic etiologies (65% and 61%, respectively) (p= NS). CONCLUSIONS: Pediatric liver transplantation for metabolic disorders results in excellent clinical and biochemical outcome with long survival and excellent quality of life for most recipients.     

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.     

Diagnosis and treatment of hereditary tyrosinemia in Japan

Hereditary tyrosinemia is an autosomal recessive inherited disease that manifests as three types (types I–III). We conducted a nationwide survey of this disease in Japan, and here review the results in relation to prevalence, clinical characteristics, and treatment and diagnosis. A definitive diagnosis of tyrosinemia type I is difficult to obtain based only on blood tyrosine level. Detection of succinylacetone using dried blood spots or urinary organic acid analysis, however, is useful for diagnosis. In tyrosinemia type I, dietary therapy and nitisinone (Orfandin®) are effective. Prognosis is greatly affected by the complications of liver cancer and hypophosphatemic rickets; even patients that are treated early with nitisinone may develop liver cancer. Long‐term survival can be expected in type I if nitisinone therapy is effective. Prognosis in types II and III is relatively good.     

Hepatocellular carcinoma in children and effect of living-donor liver transplantation on outcome

Hepatocellular carcinoma (HCC) is primarily observed in the older children and in most cases it develops in association with liver cirrhosis. Liver transplantation offers a good chance for long-term cure. To evaluate the outcome of children with HCC and the impact of living-donor orthotopic liver transplantation (OLT) on survival a retrospective review of radiographic, laboratory, pathologic, and therapeutic data in 13 children (six female and seven male) with chronic liver disease accompanied with HCC were studied. The patients were divided into two groups according to therapeutic modality: transplanted and non-transplanted patients. Kaplan-Meier survival curves in various therapeutic groups were plotted. The mean age of patients was 6.4 +/- 4.8 yr. Pediatric end-stage liver disease score was adapted to model for end-stage liver disease score for HCC and ranged between 1-44 and 18-44, respectively. The underlying liver diseases were tyrosinemia type 1 (n = 6), chronic hepatitis B infection (n = 6), glycogen storage disease type 1 (n = 1). Alfa-feto protein levels were elevated in all patients except one. Median number of tumor nodules was three (1-10), median maximal diameter of tumor nodules was 3.4 cm (0.5-8). Eleven patients were eligible for OLT whereas two patients were not eligible. Seven of the 11 patients considered for transplantation underwent living-donor OLT. Remaining four patients died while waiting on cadaveric transplant list. Overall 1 and 4-yr survival rates for all patients were 53.3 and 26.6%, respectively, and were found significantly higher in transplanted children than non-transplanted children (72%, 72% vs. 33% and 16.6%). No patient had tumor recurrence at median of 36-month follow-up after OLT. OLT is a life-saving procedure for children with chronic liver disease accompanying with HCC. Living-donor OLT avoids the risk of tumor progression and transplant ineligibility in these children.     

A new hepato-pancreato-renal disorder resembling tyrosinemia involving neuropathy and abnormal metabolism of polyunsaturated acids

This report describes a new disorder resembling hereditary tyrosinemia (HT) but differing from it in several respects. Similarities include failure to thrive with hypoproteinemia, micronodular cirrhosis, alpha-fetoprotein positive hepatocellular carcinoma, renal Fanconi syndrome with renal tubular ectasia, hypermethioninemia, and hypoglycemia associated with islet cell hyperplasia. However, the tyrosine metabolic pathway was intact. Unique findings include optic atrophy, cerebellar degeneration, and exocrine pancreatic hypoplasia. Polyunsaturated fatty acid (PUFA) status was evaluated in the serum and liver. Initial PUFA profile to serum phospholipids revealed grossly elevated linoleic acid and subnormal linolenic acid. All PUFAs derived from these precursors were absent suggesting gross abnormalities in the utilization of these two essential fatty acids for synthesis of longer chain highly unsaturated structural PUFA. Analysis of liver phospholipids indicated that linoleic acid was lower and w3 and monenoic acids were higher than in the liver specimens from two cases of HT. The gross abnormalities in PUFA pattern, although perhaps secondary to another cause, represent serious structural and functional abnormalities of essential membrane lipids and potentially of eicosanoids derived from them.     

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.     

Tyrosinemia type 1 in Spain: Mutational analysis,treatment and long‐term outcome

Background: Tyrosinemia type 1 (HT1) is a rare but treatable disease. The aim of the present study was to review the efficacy of long‐term treatment of HT1 with nitisinone, expand knowledge about the clinical spectrum of the disease and assess a possible genotype–phenotype correlation. Methods: A retrospective multicenter study was carried out based on questionnaires on genotype, phenotype, therapy and outcome in 34 Spanish patients with HT1. Results: The main manifestations that led to the diagnosis were acute liver failure (55.8%), asymptomatic hepatomegaly (44.1%) and renal tubular dysfunction (29.4%). Laboratory analysis indicated a marked increase of α‐fetoprotein and coagulopathy. The most common mutation was IVS6‐1(G > T; 66.6% of 24/34 patients for whom mutation analysis was available) and these patients presented less nephrocalcinosis and more hepatomegaly at diagnosis; two novel mutations (c.974C>T, c.398A>T) were found. The mean duration of treatment was 6.73 years. Dietary compliance was very good in 47.1% and good in 20.6%; nitisinone treatment adherence was very good in 85.2% of cases. Mean dose of nitisinone was 0.87 mg/kg per day with average plasma levels of 45.67 µmol/L. Only one patient required liver transplantation after nitisinone and none had hepatocellular carcinoma. Conclusions: Treatment with nitisinone has improved the prognosis of HT1, and compliance is good. In Spain, screening for HT1 by plasma tyrosine and urine succinylacetone determination may be implemented with IVS6‐1(G > T) mutational analysis. A correlation between low frequency of nephrocalcinosis and IVS6‐1(G > T) mutation was observed.     

Live donor liver transplantation for type 1 tyrosinemia: An analysis of 15 patients

Type 1 tyrosinemia is a rare metabolic disorder of the tyrosine degradation pathway. Due to the rarity of the disease, the best evidence literature offers is limited to guidelines based on expert opinions and optimal treatment is still a debate. LT serves as a definitive treatment of the defective metabolic pathway in the liver along with other serious disease manifestations such as LF and HCC. Nitisinone is a relatively new agent that is currently recommended for the medical management of the disease. Its mechanism of action is well understood, and efficacy is well established when started presymptomatically. This study aims to evaluate outcomes of 15 patients with type 1 tyrosinemia who underwent LT in nitisinone era and discuss its effect on prevention of HCC. A LT database of 1037 patients was reviewed. Data from 15 patients with type 1 tyrosinemia were retrospectively analyzed. All the patients except one were treated with nitisinone prior to LT. Most common indications for LT were LF and suspicious nodules. Seven patients had HCC. Mortality rate was 20% (n = 3). Nitisinone treatment has opened new horizons in the management of type 1 tyrosinemia, but LT still remains the only option for the patients developing LF and in the event of HCC. Neonatal screening programs utilizing blood succinyl acetone as the marker should be encouraged especially in the countries, such as Turkey, with high prevalence of consanguineous marriages.     

Tyrosinemia type 1 in pediatric nephrology: Not always straightforward

The main clinical features of tyrosinemia type 1 usually appear in the first months of life, including fever, diarrhea, vomiting, liver involvement, growth failure, and renal proximal tubulopathy with subsequent hypophosphatemic rickets. An early diagnosis is crucial in order to provide specific management and to prevent complications. Here, we report on two cases referred primarily to pediatric nephrologists for the diagnosis of “neonatal tubulopathy” and management of “X-linked hypophosphatemia (XLH),” respectively. Our aim is to emphasize that (1) even a mixed tubulopathy can reveal tyrosinemia, and (2) tyrosinemia is a classic differential diagnosis of XLH that should not be forgotten, especially in the era of the anti-FGF23 burosumab.     

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 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.