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After liver transplantation in children, growth is often impaired, but the underlying mechanisms are unknown. Glucocorticoids used for immunosuppression are believed to be partly responsible. After renal transplantation in children, reduced growth hormone (GH) secretion and increased serum insulin-like growth factor-binding protein-3 (IGFBP-3) levels have been reported. We attempted to find endocrine factors predicting growth in 18 prepubertal children followed for more than 1 y (mean 2.4 y) after liver transplantation. Spontaneous and stimulated GH secretion, serum IGF-I, IGFBP-3 concentrations, and endogenous Cortisol production were measured. GH secretion was reduced in only two patients. Serum IGF-I concentration was normal, but serum IGFBP-3 was elevated or 1 SD above the mean for age in 62% of the patients. Endogenous Cortisol production was reduced in most patients during the first year and improved later in only a few. Growth velocity after transplantation did not correlate with GH secretion, scrum IGF-I or IGFBP-3 concentration, or with methylprednisolone dose, but correlated positively with serum basal (rs = 0.44, p < 0.05) and stimulated (rs = 0.53, p < 0.005) Cortisol concentration. In conclusion, after liver transplantation 1) the normal pulsatile character of nocturnal GH secretion is sustained, and the GH response to stimulation is reduced in only a few patients; 2) serum IGF-I concentrations are normal; 3) serum IGFBP-3 concentrations are elevated or in the upper part of the normal range in most patients; and 4) endogenous Cortisol production is reduced in most patients and correlates positively with growth velocity.

Prior to 1987 all pts with HT in Finland died in early years. In 1987 OLT on children was introduced in our country and since then 5 pts wirh HT have been diagnosed by high plasma tyrosine and urinary succinyl acetone (SAA) concentrations and enzyme analysis. In one pt, HT manifested acutely with bleeding, ascites and edema at 6 wks. Four presented with liver insufficiency and tubulopathy at 3 to 7 mos. Serurm α-fetoprotein (AFP) was 130-11000 times age matched median and liver CT showed tumor like nodules in most pts. The pts were treated by low tyrosine + low phenylalanine diet. In the pt with acute HT, blood exchanges and i.v. glutathione were used. One pt had several porphyria episodes which responded well to i.v. hemiarginate.

GA is an autosomal recessive disease involving the eyes and type II muscle fibers. In the eyes, progressive atrophy of the choroid and retina starts by age 5-9 years and leads to virtual blindness in 20-40 years. Muscular involvement is clinically mild. The patients have 10-20-fold increased plasma ornithine concentrations, caused by lack of ornithine amino-transferase. Elevation of ornithine strongly inhibits arginine-glycine amidinotransferase, and decreases subsequently production of guanidinoacetic acid and creatine. We gave to 6 GA patients per os creatine 0.75-1.5 g divided in 3 daily doses. Muscle biopsies before treatment showed tubular aggregates and atrophy of type II muscle fibers in all but one subject. In control biopsies after 1 year of treatment, the atrophy was almost absent and very few cells contained tubular aggregates. The changes in cell size were highly significant. There was some progression in the choroidoretinal atrophies justified by photographs, but the Goldman visual fields showed some improvement. The treatment caused no side effects in the patients.

HOGA is an autosomal recessive disease, which is clearly enriched in Finland. Our 30 patients have a 10-20-fold elevation of ornithine levels in plasma and urine. The clinical disease appears at the age of 5-9 years with an impairment of vision, myopia and dark blindness, and proceeds to practically total blindness by age 30 years. A defect in ornithine transaminase has been demonstrated in the patients' fibroblasts and lymphocytes. We have studied the muscles of 20 patients. Clinically they had a varying degree of muscle atrophy but normal strength. Most of them reported a moderately decreased capacity to fast muscular performance. Needle biopsies revealed a decreased proportion of type II fibres; in some specimens they were almost absent. In electron microscopy, subsarcolemmal sites of type II fibres showed tubular aggregates. Light microscopy revealed corresponding histochemical alterations. In electromyography, myopathic patterns were constantly obtained from a part of the proximal muscle fibres. The muscular pathology showed no clear correlation with the severity of visual impairment. Presumably it arises by the same mechanism as the retinal and choroidal atrophies. Muscle is easy to sample and presents a model for studies on the pathogenesis of the progressive atrophy which appears to be a process characteristic of the disease. Our findings also emphasize the generalized nature of the disease in HOGA.

GA is an autosomal recessive disorder with characteristic chorioretinal degeneration; atrophy and tubular aggregates in type II muscle fibers; 10-20 fold increase in ornithine concentration in body fluids; and deficient activity of ornithine-δ-aminotransferase. Based on the inhibition by high ornithine concentration of the rate-limiting enzyme of creatine synthesis, the low excretion of the reaction product (guanidinoacetic acid), and low serum and urinary concentrations of creatine and creatinine in the patients, creatine and creatine phosphate deficiency has been suggested to be involved in the pathogenesis of GA. We supplemented 13 patients (age 6-31 years) with creatine, 0.5 g × 3 daily for 36-72 months. Deterioration of visual function tests and fundus photographs was seen during the treatment, apparently with similar velocity as in untreated cases. Deterioration varied considerably among individuals, being fastest in the youngest patients. Muscle abnormalities decreased or disappeared within months of the initiation of the therapy; changes reappeared in two who discontinued supplementation. Differences in creatine responses in the two organs may depend on too small creatine dosage, impermeability of blood-eye barrier for creatine, or on different mechanisms of the atrophy in muscle and eye.

Gyrate atrophy (GA) patients exhibit chorioretinal degeneration and histologic muscle abnormalities. Due to autosomal recessive deficiency of ornithine aminotransferase they accumulate ornithine to levels, which are 10× normal and well above the K, of arginine-glycine transamidinase of rat kidney. We have previously shown inadequate synthesis of guanidinoacetate and low creatine concentration in plasma, urine, erythrocytes, and muscle tissue of GA patients. Supplementary creatine corrected the atrophic muscle pathology but the chorioretinal atrophy continued. We alleged that this discrepancy was due to ineffective transport of creatine across the blood-eye barrier and sought for synthesis of guanidinoacetate in ocular tissues. We developed a new assay for measuring the arginine-glycine transamidinase activity in bovine eye tissues with a new assay based on the detection of formed guanidinoacetate with alkaline ninhydrin reaction. We found transamidinase activity only in the neuroretina (NR) and retinal pigment epithelium (RPE). The pH optimum was 7.5 in NR and 7.9 in RPE and the apparent Km for arginine was 1.10 in NR and 4.96 mM in RPE, and for glycine 1.03 and 0.95 mM, respectively. Our results indicate that a potential energy-rich phosphagen compound can be formed in eye tissues. Reduction of the ornithine concentration in ocular tissues can possibly enable the transamidination also in gyrate atrophy.

It has been suggested that lysine inhibits urea cycle function both in vivo and in vitro mainly by decreasing arginase activity. We gave an L-alanine load to a patient with hyperlysinemia (fasting plasma lysine 860 μM on a 1.5 g protein/kg diet) at age 5 and 10 years, and to a patient with saccharopinuria (and hyperlysinemia) at age 3, 12.5 and 16 years. The alanine was given as a 5% aqueous i.v. infusion (6.6 mmol/kg) over 90 min and changes in blood ammonia, serum urea urinary orotic acid were measured. In healthy subjects, serum urea increases rapidly, but blood ammonia and urinary orotic acid remain unchanged after such a load. The patient with hyperlysinemia developed hyperammonemia (peak values 760 and 210 μM at 5 and 10 years of age), and orotic aciduria increased 10-fold in the first 6-h collection. Serum urea increased slowly. The saccharopinuric patient's peak ammonias were 60, 280 and 410 μM at 3, 12.5 and 16 years of age, respectively; serum urea increased always slowly. Orotic acid excretion in the latest test increased 320-fold. Addition of 1.1 mmol/kg of l-ornithine to the alanine loads abolished the hyperammonemic response totally in both, and urinary orotic acid increased only 2-3 fold. The findings suggest that patients with constant hyperlysinemia or with saccharopinuria have decreased nitrogen tolerance and may benefit from ornithine supplementation.

Guanidinoacetate (GAA) excretion and plasma amino acids after an arginine load in patients with hyperornithinemia and gyrate atrophy of the choroid and retina (GA): 70

We studied a male patient (K.L.) aged 5 years, who had had feeding difficulties during infancy after weaning, and was later found to be slightly mentally and motorically retarded. The presenting symptom was speech difficulty with marked dysarthria and dysphasia. The liver and spleen were normal in size, leukocyte and platelet counts have always been normal, as have the liver enzymes and function tests. There was a clear aversion against berries and sweet food, but not against proteins. Plasma lysine was continuously 10-20 times higher than normal, and urinary excretion of lysine and homocitrulline were elevated. Blood ammonia was normal during fast, but moderately increased after meals. In an i.v. L-alanine load, 6.6 mmoles/kg of body weight given in 5 or 90 min, the patient developed marked hyperammonemia (peak values 465 uM and 760 uM, respectively) and vomited. Serum urea rose slowly and less than in the controls. Urinary orotic acid excretion was increased during the hyperammonemia but not on a self-chosen diet. Oral load with L-lysine-HC1, 0.5 mmoles/kg of body weight, caused a normal molar increase in plasma lysine and blood ammonia remained normal. The patient apparently has a new possibly inherited hyperammonemic disease, linked to constant hyperlysinemia and homocitrullinuria.