Hepatic conversion of amino-nitrogen to urea in thyroid diseases. II. A study in hyperthyroid patients.

Conflicting data have been reported on the influence of thyroid hormones on hepatic nitrogen metabolism and on liver metabolic activity. We studied the urea-nitrogen synthesis rate (UNSR) and the kinetics of the process of hepatic amino-nitrogen to urea-nitrogen conversion in response to constant alanine infusion (ie, the functional hepatic nitrogen clearance [FHNC]) in five hyperthyroid female patients before and after the achievement of a stable euthyroid status. In the same patients, galactose elimination capacity and antipyrine clearance were also measured as quantitative indices of hepatic function. The basal urea synthesis rate was nearly doubled in hyperthyroid patients (35.6 +/- 8.5 mmol.h-1 v 17.6 +/- 7.7 in euthyroid patients, P < .05) and increased linearly with increasing alpha-amino-nitrogen (alpha-AN) concentrations in both conditions. The urea synthesis rate during alanine infusion was still higher by approximately 30 mmol.h-1 in hyperthyroid subjects. The FHNC, calculated as the slope of the linear relation between the UNSR in each time interval and the corresponding average alpha-AN concentration, was not different (hyperthyroidism, 30.6 +/- 7.2 L.h-1; euthyroidism, 28.5 +/- 4.4; normal values > 25). The hepatic microsomal and cytosolic activities (antipyrine clearance and galactose elimination) were normal in hyperthyroid patients and did not change significantly after therapy. Our data show that the hepatic nitrogen metabolism of hyperthyroid patients is characterized by an upregulation of amino-nitrogen catabolism and loss of the sparing mechanism at low plasma amino acid levels, without any change in different metabolic activities.

Hepatic conversion of amino nitrogen to urea nitrogen in hypothyroid patients and upon L-thyroxine therapy.

Conflicting studies have been reported regarding the influence of thyroid hormones on hepatic nitrogen metabolism and liver metabolic activity. We studied urea N synthesis rate (UNSR), functional hepatic N clearance (FHNC), galactose elimination capacity, and antipyrine clearance in six hypothyroid female patients before and after achievement of a stable euthyroid status. In both conditions, UNSR measured at intervals in response to constant alanine infusion was linearly related to the average alpha-amino N concentrations. In the hypothyroid state, peak UNSR was decreased by 31% in comparison with values measured in euthyroidism, which were in the normal range. FHNC (ie, the slope of the linear relation between UNSR and blood alpha-amino N concentration) is a measure of the kinetics of the process of hepatic amino N to urea N conversion; it was 19.8 +/- 4.0 L.h-1 in hypothyroid patients and increased to normal values after L-thyroxine replacement (30.4 +/- 3.3 L.h-1, P < .01; normal values > 25 L.h-1). Hepatic microsomal and cytosolic activities (antipyrine clearance and galactose elimination) were normal in hypothyroid patients and did not change significantly after therapy. Our data show a specific defect in hepatic handling of amino acids in hypothyroid patients, leading to reduced alpha-amino N to urea N conversion, in the absence of any detectable impairment in different hepatic metabolic activities.

Effects of beta-blockade on hepatic conversion of amino acid nitrogen and on urea synthesis in cirrhosis.

beta-Blockers are widely used to prevent gastrointestinal hemorrhage in cirrhosis. The metabolic effects of treatment are scarcely studied: hepatic function reportedly does not change significantly, but beta-adrenoceptors have been reported to regulate protein and amino acid metabolism. We studied hepatic nitrogen metabolism in response to constant alanine infusion in seven patients with cirrhosis before and 7 to 10 days after treatment with oral propranolol (60 to 100 mg/d). Beta-blockade was effective: it decreased heart rate by 25%, abolished orthostatic tachycardia, and reduced portal blood flow by 20%. Alanine-stimulated urea nitrogen synthesis rate (UNSR) was higher in patients with propranolol treatment, without any difference in aminonitrogen concentration. The kinetics of hepatic conversion of amino acid nitrogen into urea--ie, functional hepatic nitrogen clearance (FHNC)--increased by 30%, from (mean +/- SD) 17.0 +/- 4.1 to 22.0 +/- 6.6 L/h (P < .01). Increased urea production during alanine infusion resulted in negative nitrogen exchange even at the peak of alpha-aminonitrogen concentration. Basal insulin level was only slightly reduced during propranolol treatment, whereas the insulin response to alanine was significantly blunted. No differences in glucagon and cortisol were demonstrated. Epinephrine and norepinephrine levels were high-normal and did not vary after treatment. Increased urea production and stimulation of hepatic nitrogen clearance during beta-blockade may be mediated by relative hypoinsulinemia or by direct involvement of beta-adrenoceptors in the control of nitrogen metabolism, possibly by regulation of amino acid uptake and release in peripheral tissues.

Cytogenetic survey of 31 patients treated with bone marrow transplantation for acute nonlymphocytic and acute lymphoblastic leukemias.

The authors report on a sequential cytogenetic study carried out on 31 patients with acute leukemia (20 with acute lymphoblastic leukemia and 11 with acute non-lymphocytic leukemia) who underwent bone marrow transplantation (BMT). Engraftment was documented in all patients with sex-mismatched donors and with donor constitutional aberrations. During the follow-up, ranging from 6 to 110 months, clinical and hematologic relapse was observed in 11 patients (35.5%). Five of these cases showed a normal karyotype, 3 were of undefined relapse origin, 2 were aneuploid karyotypes, and one was donor (male) metaphases. Cytogenetic and immunologic data in the latter patient were suggestive of relapse in donor cells.

Elimination of infused branched-chain amino-acids from plasma of patients with non-obese type 2 diabetes mellitus.

Increased plasma levels of branched-chain amino-acids (BCAA) have been demonstrated in poorly controlled diabetes mellitus, and related to absolute or relative insulin deficiency. To study the pathogenesis of this alteration, the elimination of BCAA from plasma was measured in 8 patients with non-obese type 2 diabetes mellitus and in 8 age-matched control subjects during steady-state BCAA concentrations induced by a primed-continuous infusion. Fasting BCAA levels were increased by 40-50% in patients with diabetes. The plasma clearances of valine, isoleucine, and leucine, calculated as infusion rate divided by steady-state concentration, were reduced by 20% in diabetics, despite 50% hyperinsulinemia (P < 0.01). Basal BCAA levels and BCAA clearance were negatively correlated (r(2) = 0.46 - 0.56). The endogenous basal appearance rates of BCAA, estimated by the basal concentrations multiplied by the plasma clearances, were normal in diabetics, and there was no difference in the apparent volumes of distribution of BCAA. The increased basal concentration of BCAA in poorly controlled type 2 diabetics (693 [SD 114; n = 8] mumol/l vs 479 [88; n = 8] in controls (P < 0.005) is attributable to changes in plasma clearances, without any change in the efflux of BCAA into plasma. This may be due to insulin resistance.

Relationship between intrathyroid calcifications and thyroglobulin in endemic goiter.

Intrathyroid calcifications represent a common finding within simple or nodular goiters, but, as far as they can be found also inside papillary and medullary thyroid carcinomas, an ultrasonographic detection of intrathyroid calcifications stands as a different diagnosis problem. We have been looking for the presence of parameters associated with thyroid calcifications in patients affected by simple or nodular goiter, either sporadic or endemic. We studied 284 euthyroid subjects, 250 females, ageing from 24 to 90 years, affected by a simple goiter, in the 9.51% of the cases, and by a nodular goiter in the remaining part. 69.37% of the patients came from an endemic goiter area, while the others were affected by sporadic goiter. We tested fT3, fT4, TSH, hTG, Ab-TG, Ab-TPO and performed an ultrasonography in all the subjects, 57.75% of patients shown intrathyroid calcifications in the 57.75% of them. We applied a multistep discriminant analysis taking for the presence/absence of calcifications as dependent variable and we tried to find which variable, by itself or in combination with others, could foretell its presence. We also created a new variable (TG1) to differentiate normal from supraphysiologic concentrations of hTG (< 60 ng/ml). The variable with the highest significance F originated from endemic goiter area (F = 96.36), followed by TG1 (F = 24.46) and age (F = 10.61). On the contrary hTG did not relate to calcifications, due to non-proportionally direct relationship between these two parameters, afterwards we used the multistep logistic regression that gave overlapping significances. This means that supraphysiologic hTG rates are sufficient to predict the possible presence of intrathyroid calcifications. In conclusion, as far as a follicular hyperstimulation can be assumed, especially if long-lasting, the presence of intrathyroid calcifications should rise a clinical suspect toward an old goiter rather than a neoplastic lesion.

Oral BCAA supplementation in cirrhosis with chronic encephalopathy: effects on prolactin and estradiol levels.

The effects of oral BCAA supplementation on fasting levels of prolactin and estradiol were retrospectively analyzed in frozen plasma samples of patients with cirrhosis and chronic hepatic encephalopathy, taking part in a 3-month randomized, double-blind trial. Twenty-five patients had received 0.24g of BCAA per kg body weight, 24 had received an equinitrogenous amount of casein, in addition to a diet providing 0.7-1.0 g/kg of protein. Thirty-eight were males, 11 post-menopausal women. Fasting prolactin did not show any change in the BCAA group, where mental state significantly improved. In the casein group plasma prolactin increased by nearly 50% during the 3-month period. Similarly, estradiol concentrations were unchanged during BCAA supplementation, and increased during casein treatment. The analysis of variance demonstrated significant differences between the 2 treatments. Liver function tests and nutritional parameters (albumin, transferrin, urinary creatinine) supported a superiority of BCAA over casein. These data suggest that the favorable effects of BCAA on mental state are not mediated by changes in cerebral neurotransmission, but are due mainly to maintained liver function, possibly related to improved nutrition.

Mathematical model to analyse urea synthesis following alanine infusion in control subjects and in patients with liver cirrhosis.

A three-compartment model was used to analyse the urea response to an alanine infusion in control subjects and patients with liver cirrhosis. Discriminant analysis showed a good separation between model coefficients of the two groups. A single parameter was derived, able to quantify the liver functional capacity. The method provides a useful diagnostic tool in patients with liver disease.

May peripheral and central fatigue be correlated? Can we monitor them by means of clinical laboratory tools?

BACKGROUND: A laboratory-based model which links regional and central fatigue during physical exercise has not yet developed. Today we can assay the oxypurines, a specific and sensible marker of muscle cell-energy exhaustion during strenuous physical exercise, thus allowing us to insight in peripheral fatigue mechanisms. Prolonged physical exercise modifies plasma free amino acids and fatty acids levels, increases plasma free tryptophan (fTrp) and, conversely, probably serotonin, an amine involved in the genesis of central fatigue. We tried to verify if there is a correlation between central and peripheral fatigue. EXPERIMENTAL DESIGN: We studied 29 male marathon runners before marathon, at the arrival, one and three days after the run. MEASURES: Plasma samples were assayed for amino acids, fTrp serotonin, xanthine, hypoxanthine inosine, cortisol. Urine samples were assayed for serotonin and hydroxyin-doleacetic acid (5HIAA). RESULTS: After the competition we observed a decrease in plasma fTrp but an increased ratio fTrp/sum of neutral amino acids with a normalization after 24 hours. No significant changes were observed in plasma and urinary serotonin and 5HIAA. Hypoxanthine and inosine increased at the end of the trial and returned to basal levels the day after. Cortisol increased at the end of the run but was reduced after 24 and 72 hours. CONCLUSIONS: In our athletes we observed only indirect signs of fTrp involvement in the genesis of central fatigue. Oxypurines seem to be a good marker of regional muscular fatigue. Plasma cortisol expresses the stress reaction to the competition and its exhaustion after a prolonged physical exercise.

Can oxypurines plasma levels classify the type of physical exercise?

BACKGROUND: A laboratory-based model able to describe muscle energy status during physical exercise and changes in myofibrillar composition in response to training would be desirable. Lactate and ammonia concentrations are not sufficient for a comprehensive knowledge of these systems. All muscle fibres, irrespective of the type, show ATP depletion and IMP accumulation following exhausting muscular exercise with quantitative differences due to the different concentrations of deaminase. We studied the plasma concentration of metabolites of oxypurine cascade to test their reliability to classify different exercises. METHODS: We studied 52 athletes, measuring plasma metabolites at the beginning and at the end of their specific field exercise (cycle pursuers, 8 cases; soccer players, 19; marathon runners, 25). K3EDTA-blood samples were assayed for plasma hypoxanthine, xanthine, and inosine, using an HPLC technique, as well as ammonia and lactate by means of enzymatic methods. RESULTS AND CONCLUSIONS: Basal oxypurines levels were not different in relation to any specific physical exercise. Post-exercise oxypurines, namely hypoxanthine, were more precise predictors of muscle energy exhaustion than strain intensity or duration. Plasma levels of hypoxanthine may be elevated also in the presence of normal xanthine and uric acid concentrations, due to an exhaustion of the enzymatic pathway, to a reduced activity of xanthine-oxidase or finally to a substrate-dependent inhibition of the process.

[General considerations and modern views on the surgical treatment of recurrent dislocation of the shoulder (author's transl)]. / Considerazioni generali e moderne acquisizioni sul trattamento chirurgico della lussazione recidivante di spalla.

The authors discuss the treatment of recurrent dislocation of the shoulder joint in a synthetic review of methods so far proposed and tried out; the they offer a critical description of the method currently representing the best one available according to their experience made at Milan's Istituto Ortopedico G. Pini.

[Transcutaneous electrostimulation in the treatment of benign somatic chronic pain: evaluation of a new stimulator]. / L'elettrostimolazione transcutanea nel trattamento del dolore cronico somatico benigno: valutazione di un nuovo stimolatore.

40 patients affected by chronic orthopaedic syndromes, outlasting 6 months, have been treated by transcutaneous electrical stimulation. Has beem employed a new commercial stimulator with these impulse parametres: 50 Hz, 0,2 msec of length, 30 mA. Rubber electrodes on trigger points or myalgic areas were used. Authors obtained the following results: in 14 patients any change, in 10 patients mild improvement but of short effect, in 16 patients a good and long term improvment. skin lesions were not observed during electrical stimulation treatment.

[Treatment of chronic lumbosacral pain by transcutaneous electrical stimulation in laminectomized patients: preliminary results (author's transl)]. / Trattamento del dolore cronico lombosacrale con elettrostimolazione transcutanea in pazienti laminectomizzati: risultati preliminari.

The authors have tried transcutaneous electrical stimulation for the treatment of chronic lumbosacral pain in 27 patients already treated by laminectomy without benefit. Six patients experienced a 55% mean reduction of pain; another six had a 35% reduction; and the remaining 15 a 16% reduction of pain severity. From these results and a review of published data the authors conclude that the method is of limited value in alleviating chronic lumbosacral pain in laminectomized patients.

[Chylothorax in a newborn infant]. / Chilotorace in neonato.

A case of chylothorax in newborn is described. A the fifteenth day a sudden respiratory distress for chylothorax has appeared. A continuous drainage, after thoracenteses, has been placed; the clinic course has been favourable and, at five day, we have started with MCT feeding.

[A case of stenosing ureteritis in Schoenlein-Henoch purpura]. / Su un caso di ureterite stenosante in porpora di Schönlein-Henoch.

A case of stenosing ureteritis in a 6 years old girl with Schönlein-Henoch purpura is described. In a careful review of the literature only a few cases results described. The authors discuss the problems concerning this rare and potentially serious complication of Schönlein-Henoch purpura.

["Dense deposits" glomerulonephritis: description of a case]. / Glomerulonefrite "a depositi densi": descrizione di un caso.

The authors report a case of "dense deposits" glomerulonephritis in a girl who showed the first symptoms of asintomatic microhematuria at the age of 3 years during an ambulatorial examination which had been requested from her family doctor. After 1 year and 10 months the girl has been hospitalized and during her stay in the hospital it appeared that she still suffered of microhematuria with very low levels of serum complement. Being these results the same after the various check-ups made after her dismission from the hospital it has been decided to execute a renal biopsy, comprehending also the examination with an electronic microscopy which showed intramembranous "dense deposits" glomerulonephritis. In literature no similar cases under 4 years of age are reported.

Thyroid involvement in patients with active inflammatory bowel diseases.

Previous studies have documented an association between systemic diseases and disorders of the thyroid gland, expressed by an enlargement of the thyroid and by the presence of anti-thyroid antibodies. Chronic inflammatory bowel diseases (IBD, ulcerative colitis and Crohn's disease) may also present a multi-organ involvement, including the biliary tree, joints and uvea. To detect a possible subclinical thyroid involvement, thyroid volume and function were assessed in 31 patients with IBD in active phase and in 50 control subjects. Thyroid volume was calculated by ultrasonography on the basis of the three maximum diameters of the 2 lobes. A blood sample was taken to determine free thyroid hormones, TSH, and anti-thyroid antibodies. In patients with IBD, thyroid volume was increased on average by 35%, and the prevalence of thyroid enlargements (antero-posterior diameter > 20 mm) was 3 times higher (45% vs 16%). Free thyroxine was increased by nearly 50%, but only 10% of patients had anti-thyroid antibodies. Alterations of thyroid volume and function are present in IBD, even in the absence of clinically-detectable thyroid disease. The association of IBD with thyroid disorders, as well as the involvement of various organs, confirms the view that IBD is a systemic disease.

Model-derived assessment of urea appearance in response to alanine infusion: a quantitative measure of liver function in cirrhosis.

A three compartment mathematical model was used to analyse the urea response to an alanine infusion in six control subjects, and in 15 patients with liver cirrhosis and variable degree of hepatocellular failure. Model-derived coefficients were used to calculate two parameters (Ymax and Tmax), able to describe the theoretical response of the conversion of amino acid derived nitrogen into urea, in response to a unit impulse in alanine concentration. They correspond to the maximum rate of conversion of nitrogen from an intermediary pool into urea and to the time delay between the impulse and Ymax, respectively. In cirrhosis, the apparent volume of distribution of infused alanine was smaller than in controls, while the conversion of alanine nitrogen into an intermediary pool of nitrogen and finally into urea nitrogen were both reduced. Also Ymax was reduced by 50% in cirrhosis, whereas Tmax was increased by 50%, and both significantly correlated with galactose elimination capacity (GEC; R2 = 0.706 and R2 = 0.505, respectively) and with antipyrine clearance (Ap Cl; R2 = 0.823 and R2 = 0.576, respectively). Model-derived assessment of urea appearance in response to alanine infusion is able to quantify the functional liver cell mass, and may prove useful for the study of nitrogen metabolism in cirrhosis, mainly in relation to encephalopathy.

Reduced ubiquinone plasma levels in patients with liver cirrhosis and in chronic alcoholics.

Ubiquinone (CoQ10 coenzyme) is part of the respiratory chain in mitochondria, and acts as a scavenger in oxidative stress in cell membranes. Ubiquinone is mainly synthesized in the liver and partly derived from the diet; its plasma levels significantly correlate with tissue levels in experimental animals and in pathological states in man. By means of an original high-performance liquid chromatography technique, we measured ubiquinone plasma levels in 10 healthy subjects, in 27 patients with cirrhosis and in 22 chronic alcoholics with normal liver function. Ubiquinone levels were markedly reduced in cirrhosis (0.25 [SD 0.21] microgram/ml vs. 0.92 [0.38] in controls; P < 0.001), without any difference between alcohol- and non-alcohol-related disease. Also, in chronic alcoholics ubiquinone levels were nearly halved (0.49 [0.24]). In cirrhosis, ubiquinone plasma levels significantly correlated with cholesterol (P < 0.05), and with total bilirubin levels (P < 0.01). Our study highlights a remarkable deficiency in ubiquinone levels in patients with cirrhosis and in chronic alcoholics, to which both reduced hepatic synthesis and nutritional defects may contribute.