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.     

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.     

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.     

Phenotypes of Peripheral Blood Lymphocytes during Acute Hepatitis A

ABSTRACT. We investigated peripheral blood lymphocyte phenotypes of 74 patients at weekly intervals during the course of acute hepatitis A. In the second week after onset of jaundice, a significant elevation of total lymphocytes was observed (4096 × 10⁶± 1003 × 10⁶/l vs. controls 3038 × 10⁶± 1208 × 10⁶/l, p < 0.005). However, no change in the relative percentages of B-cells (CD20+), T-cells (CD3+ or CD2+), or T-cell subpopulations (CD4+ helper cells and CD8+ suppressor cells) could be demonstrated during the course of the disease. Activated T-cells (CD3+DR+) were elevated during the first week (204 × 10⁶± 134 × 10⁶/l vs. normal 91 × 10⁶± 54 × 10⁶/l, p <0.005) and during the second week (202 × 10⁶± 82 × 10⁶/l, p < 0.0005) after onset of disease and returned to normal values until the third week. Cells expressing phenotypes of lymphocytes capable of exerting non-MHC-restricted cellular cytotoxicity, i.e. Natural Killer cell activity (CD57+, CD16+, and CD56+) were significantly elevated in percentage in the first week of disease, as compared to controls (CD57: 14.5 ± 7.0% vs. 9.3 ± 5.8%, p <0.05; CD16: 13.4 ± 7.3 vs. 9.5 ± 5.1%, p < 0.05; CD56: 10.5 ± 3.5% vs. 8.0 ± 1.5%, p < 0.005). Also the absolute numbers of these lymphocyte subpopulations were found to be elevated during the first and second week. The increase in NK cells in the initial phase of acute hepatitis A suggests an important role of these cells in the first line of defence in this disease.     

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.     

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.     

Soluble receptors to tumour necrosis factor and interleukin-6 in urine during acute pyelonephritis

We compared the urinary concentrations of soluble TNF-I (sTNF-RI), TNF-II receptors, and soluble IL-6 receptor (sIL-6R) standardized to urinary creatinine concentrations, in children with acute pyelonephritis, in children with non-renal fever and in healthy controls. These levels were related to the acute inflammatory response in the kidneys and later renal scarring, as determined by acute and 1-y follow-up with ^99mTC-dimercaptosuccinic acid scintigraphy (DMSA). The concentrations of the soluble receptors were measured using enzyme immunoassay (EIA). The urinary levels of sTNF-RI were significantly higher in children with acute pyelonephritis (median 1320 pg/mmol) than in children with non-renal fever, children 6 weeks after acute pyelonephritis and healthy controls (873, 251 and 477 pg/μmol, respectively). Median sTNF-RII urine levels were also higher in acute pyelonephritis (4123 p/μmol) than in the three control groups (2000, 964 and 1850 pg/μmol, respectively). In contrast, the highest urinary sIL-6R concentrations were found in healthy children (median 420 pg/μmol). compared to those with acute pyelonephritis (235 pg/μmol), children with non-renal fever and children 6 weeks after pyelonephritis (137 and 50 pg/μmol, respectively). No significant difference was found in any of the urinary soluble receptor levels in children with or without DMSA uptake defects at the acute or the 1-y follow-up scintigraphy. In conclusion, although the urinary soluble TNF receptor levels were higher during acute pyelonephritis, this observation was not useful for deciding which children needed follow-up after acute pyelonephritis.     

COPPER DEFICIENCY AND HYPOCALCEMIC RICKETS IN A SMALL-FOR-DATE INFANT

ABSTRACT. A case of copper deficiency associated with hypocalcemia, radiological features of rickets and hyperparathyroidism is described in a small-for-date infant (gestational age 39 weeks, B.W. 1240 g). Neonatal serum copper (Cu) levels were found between 223 and 138 μmol/l. She was given daily 2 400 U of vitamin D₂ and a load dose of 80 000 IU at the age of 55 days. At the age of 79 days, X-rays of the legs and wrist showed spread, cupped and frayed metaphyses. Serum Ca was 1.35 mmol/1, P=0.99 mmol/1 with high alkaline phosphatases (A.P.) 590 II/ml. But plasma level of 25 hydroxycholecalciferol (25-OH-CC) was normal = 10.8 ng/ml. Serum Cu was low=3.14 μmol/l and serum immunoreactive parathormone (iPTH) level was elevated: 520 μlEq/ml (N±100). Administration of vitamin D₂ (15 mg) induced an immediate normalization of serum Ca, normal serum iPTH (68 μlEq/ml) in one month, normal X-rays in two months and normal A.P. in four months. Serum Cu and ceruloplasmin levels increased slowly without any supplementation to subnormal levels at the age of eight months (14.9 and 1.65 μmol/1. Serum Cu concentrations were found to be normal (16.0–33.7 μmol/1) in five children with hypocalcemic rickets. These results suggest a role of Cu deficiency in the occurrence of this transient vitamin D-resistant rickets.     

Pemphigus vulgaris as a possible cause of protein-losing gastroenteropathy: a case report

Abstract:   We present a case of pemphigus vulgaris (PV) accompanied with protein-losing gastroenteropathy (PLE). A 9-year-old girl developed multiple oral ulcerations and erosions. She was first treated with oral antibiotics and a topical steroid without improvement. Laboratory data showed eosinophilia (absolute eosinophil count 1.08 × 10⁹/L) and hypoproteinemia (total serum protein 3.9 g/dL, albumin 2.2 g/dL). A biopsy specimen from the ileum showed intense eosinophil infiltration and albumin scintigraphy demonstrated protein exduation from the same site. Endoscopic examination of the oesophagus showed multiple ulcerations and erosions, and biopsy specimen showed eosinophilic spongiosis and immunohistologic staining demonstrated deposits of IgG and C3 in the intercellular space. Antidesmoglein-3 antibody elevated, she was diagnosed as PV complicated with PLE. Immunofluorescence study of a biopsy specimen from the terminal ileum showed no significant immunoglobulin or complement deposition, and autoantibody against intestinal mucosa was unclear in this case. Gastrointestinal evaluations should be considered in patients with hypoproteinemia associated with PV.     

Estimation of Digoxin Dosage in VLBW Infants Using Serum Creatinine Concentrations

ABSTRACT. Digoxin steady state plasma concentrations (C_ss) and the corresponding serum creatinine concentrations were studied in 17 VLBW infants. Birth weight was in the range of 760-1500 g (mean 1068 g), gestational age ranged from 26 to 32 weeks (mean 28.7 weeks). Digoxin steady state plasma concentrations were found in the range of 0.5-6.5 μg/ml (mean 1.88 μg/ ml) during maintenance therapy with 1.6-8.4 μg/kg BW/24 h (mean 4.4 μg/kg BW724 h) given in two divided doses intravenously. No digoxin-like immunoreactive substance could be detected in the plasma of 18 infants (10 patients with a birth weight <1500 g, 8 patients with a birth weight of 2100-4 730 g) that were not treated with digoxin. The calculated digoxin clearance ranged from 0.38-4.03 ml/min/kg BW. Serum creatinine concentrations were found in the range of 35-274 μmol/l (0.4-3.1 mg/100 ml). A hyperbolic correlation may be derived from the digoxin clearance and the corresponding serum creatinine concentration. A linear relationship was observed between the dose normalized digoxin concentrations (y=C_ss/dose in 24 h) and the respective creatinine concentrations x (v=0.52x-0.05; n=17; 5=0.24; r=0.86; p<0.01). According to this equation we suggest a dosing schedule for digoxin in VLBW infants with impaired renal function. Digoxin maintenance dose is derived from the digoxin target and the creatinine serum concentration. This dose recommendation proved reliable on four VLBW infants (birth weight 770-1260 g) with decreased renal function.     

LOW MOLECULAR WEIGHT ORGANIC ACIDS IN THE URINE OF THE NEWBORN

Abstract The urinary excretion of seven selected low molecular weight organic acids in normal neonates was measured by gas chromatography. First and third to fourth day of life excretion of the following compounds was significantly unchanged: 3-OH-butyric acid (<13 μmol/mmol creatinine), succinic acid (approx. 43 μmol/mmol creatinine), adipic acid (approx. 12 μmol/mmol creatinine), 2-OH-glutaric acid (approx. 23 μmol/mmol creatinine), 3-OH-3-Me-glutaric acid (approx. 25 μmol/mmol creatinine) and citric acid (approx. 115 μmol/mmol creatinine). The excretion of 4-OH-phenyl-acetic acid increased during the first four days of life (from <8 μmol/mmol creatinine to approx. 20 μmol/mmol creatinine). It is postulated that urinary organic acid excretion in the neonate, which is clearly different from the adult urinary pattern, is a reflection of the specific neonatal metabolic situation, including a high fatty acid utilisation and a low protein catabolism.     

METHOTREXATE IN THE PLASMA AND CEREBROSPINAL FLUID OF CHILDREN TREATED WITH INTERMEDIATE DOSE METHOTREXATE

ABSTRACT. Rechnitzer, C, Scheibel, E. and Hendel, J. (University Clinic of Paediatrics, Rigshospitalet and Department of Clinical Chemistry, Finsen Institute, Copenhagen, Denmark). Methotrexate in the plasma and cerebrospinal fluid of children treated with intermediate dose methotrexate. Acta Paediatr Scand, 70:615,.–Serious complications can follow treatment with intermediate dose methotrexate of acute lymphoblastic leukemia in childhood. Toxicity has been shown to be correlated to plasma methotrexate concentrations. During intravenous infusions of methotrexate (500 mg/m²) the mean concentrations achieved 1 to 4¹/₂ hours after the start of infusion were 1.3×10^-7 mol/l in cerebrospinal fluid and 1.7×10^-5 mol/1 in plasma. At 72 hours after start of methotrexate infusion, plasma methotrexate concentrations were significantly higher in cases with symptoms of toxicity. In all the children who developed toxic symptoms 72-hour plasma methotrexate concentration was above 1×10^-7 mol/l. Assuming that leucovorin is given 48 hours after the start of methotrexate infusion, 72-hour plasma methotrexate is suitable for detection of patients at risk for toxicity. In children treated with intermediate dose methotrexate we therefore recommend estimating plasma methotrexate concentration 72 hours after the start of infusion, and instituting supplementary leucovorin when plasma methotrexate concentration exceeds 1×10^-7 mol/l.     

Screening for PTLD in lung and heart-lung transplant recipients by measuring EBV DNA load in bronchoalveolar lavage fluid using real time PCR

Abstract:  Pediatric L-HLTx recipients are at risk for developing PTLD with the lung being a primary site of disease. We hypothesized that BALF is a better sample than peripheral blood for measuring EBV DNA load in this high-risk population. Archived BALF specimens from pediatric L-HLTx recipients with and without PTLD were assayed for EBV DNA load using a quantitative real time TaqMan PCR assay. These values were compared with values determined in peripheral blood by a competitive PCR assay. Fifty-five BALF specimens from 16 L-HLTx patients were evaluated. Three patients with PTLD had mean BALF EBV DNA load values almost 50-fold higher than subjects without PTLD (4.6 × 10⁵ copies/mL vs. 1.0 × 10⁴ copies/mL). Patients who were EBV seronegative pretransplantation (i.e., high risk for PTLD) had elevated EBV DNA load values vs. patients who were EBV seropositive pretransplantation, regardless of the diagnosis of PTLD (mean values of 3.2 × 10⁵ copies/mL vs. 1.1 × 10⁴ copies/mL). Lastly, BALF analysis identified all subjects with PTLD, whereas peripheral blood analysis identified only one of these cases. Therefore, it can be concluded that monitoring EBV DNA load in BALF following L-HLTx facilitates detection of PTLD in high-risk patients and may be superior to peripheral blood assays.     

Combined Human Chorionic Gonadotropin (HCG) and Human Menopausal Gonadotropin (HMG) Treatment in Gonadotropin-Deficient Males with Pituitary Dwarfism

The effects of hCG-hMG treatment in 13 boys with pituitary dwarfism associated with gonadotropin deficiency, were assessed.
No patients except one showed signs of puberty at a bone age of 13 years or above. The one patient with some signs of puberty did not become fully mature. The hCG-hMG was started at a mean age of 20.4 years. The hCG at a dose of 5,000 IU was injected intramuscularly twice a week and the hMG at a dose of 75 IU was given once a week at first. During treatment, the frequency of hMG injections was increased to twice a week in six patients who still had not produced normal sperm counts. After a mean duration of 19.23 months, spermatozoa appeared in eight patients, of whom four showed more than 20 × 10⁶ sperm/ml. Among six patients who did not have normal sperm counts and had increased hMG injections, one produced a pregnancy and four achieved sperm counts of more than 35 × 10⁶/ml. One patient had refractory azoospermia. In 13 boys with growth hormone and gonadotropin deficiency, hCG-hMG treatment produced normal spermatogenesis in nine patients, one of whom fathered a girl. Thus, hCG-hMG treatment, especially twice-a-week injections of both hCG and hMG, appears to be effective for gonadotropin deficiency in males.     

Parathyroid hormone resistance and B cell lymphopenia in propionic acidemia

The mechanisms of hypocalcemia, recurrent infections and hypogammaglobulinemia associated with metabolic decompensation of propionic acidemia due to propionyl-CoA carboxylase deficiency have not been defined. A 7-week-old infant with this disorder presented with severe hypocalcemia and B cell lymphopenia during an episode of metabolic acidosis and hyperammonemia. Hypocalcemia (1.1 mmoll ¹) was associated with elevated serum intact parathyroid hormone (122 ng 1 ¹), hyperphosphatemia, hypophosphaturia and hypercalcuria, indicating parathyroid hormone resistance. B cell lymphopenia (20 cells μl^-1) was associated with transient neutropenia, anemia and subsequent hypogammaglobulinemia (IgG < 294mgdl^-1, IgM < 8mgdl^-1, IgA < 8mgdl ¹), while T cells were normal. Parathyroid hormone resistance and B cell lymphopenia resolved following treatment with hemodialysis, diet and carnitine. These complications may be due to interference with parathyroid hormone renal tubular action and B cell maturation/proliferation by accumulated organic acids.     

Metabolic studies of transient tyrosinemia in premature infants.

The recently developed technique of gas chromatography-mass spectrometry supported by computer has considerably improved the analysis of physiologic fluids. This study attempted to demonstrate the value of this system in the investigation of metabolite patterns in urine in two metabolic problems of prematurity, transient tyrosinemia and late metabolic acidosis. Serial 24-hr urine specimens were analyzed in 9 infants. Transient tyrosinemia, characterized by 5-10-fold increases over basal excretion of tyrosine, p-hydroxyphenyllactate, and p-hydroxyphenylpyruvate in urine, was noted in five of the infants. Several infants had fluctuating levels of tyrosine metabolites in urine although dietary protein intake remained constant at 3-4 g/kg/24 hr and ascorbic acid at 50 mg/24 hr. Late metabolic acidosis was seen in four infants, but bore no relation to transient tyrosinemia. The ratio of net acid to urea excretion in urine increased with increasing base deficit, implying a nonprotein origin of the metabolic acid. No unique metabolic patterns were characteristic of late metabolic acidosis.     

Tyrosinemia associated with perinatal infection with cytomegalovirus.

A premature infant presented with elevated concentrations of tyrosine in blood and urine, evidence of hepatocellular damage, demineralization of the bones, and a renal Fanconi syndrome. This is the clinical picture found in hereditary tyrosinemia. The infant also had a perinatal infection with cytomegalovirus.     

Interleukin-1α and interleukin-1 receptor antagonist in the urine of children with acute pyelonephritis and relation to renal scarring

Urinary concentrations of interleukin-lα (IL-lα) and interleukin-l receptor antagonist (IL-Ira) standardized to urinary creatinine concentrations were studied. The median standardized IL-1α creatinine quotient in children with first-time acute pyelonephritis was 3.6 pg/μmol, but was non-detectable in children with recurrent pyelonephritis, children with non-renal febrile conditions and children convalescent after acute pyelonephritis ( p < 0.05–0.01). IL-lra levels were also significantly higher in children with acute first-time pyelonephritis (median of 239 pglpmol) compared to these three groups of children ( p < 0.01–0.001). The highest urinary 1L-lra levels, however, were found in the healthy controls (median value 1.019; p < 0.001). Both cytokines were higher among children younger than one year compared to older children. The acute IL-lα creatinine quotients were lowest in children with uptake defects on ^99mTC-dimercaptosuccinic acid (DMSA) scintigraphy both during the acute infection (reflecting the acute inflammation) ( p < 0.001) and 1 year after the acute infection (reflecting permanent kidney scarring) ( p < 0.01). In conclusion, persisting high urinary levels of 1L-lα were associated with less renal inflammation and scarring.     

Combined tetrahydrobiopterin-phenylalanine loading test in the detection of partially defective biopterin synthesis

Deficiency in the synthesis of biopterin causes neonatal hyperphenylalaninemia. We report a 10-year-old girl of normal appearance with a partial defect in biopterin synthesis, normal intelligence and normal serum phenylalanine levels (95 mol/l) (1.6 mg/dl). During her 1st year of life srum phenylalanine levels were 250 mol/l (4 mg/dl) and phenylalanine loading performed at 6 months and 1 year of age was not followed by an increase in serum tyrosine. At 9 years of age she had developed a severely abnormal EEG with focal spike activity but no observable clinical abnormalities. Determination of urinary pterins showed abnormal low levels of biopterin and high levels of neopterin. Phenylalanine loading combined with oral administration of tetrahydrobiopterin (BH₄) was followed by a normal increase in serum tyrosine and a normal decrease in serum phenylalanine.Considering the importance of BH₄ for the synthesis of dopamine, catecholamines, and serotonin we suggest that these cases should be followed carefully. If neurological symptoms appear, e.g., epilepsy, it may be worthwhile to consider treatment with BH₄ and neurotransmitter precursors.