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Biomedical subjects

J E Heubi

Publications and source records attributed to J E Heubi.

At least 55 records · Page 3Linked to original sources
PubMed1990

Resistance to the growth-promoting and metabolic effects of growth hormone in children with chronic liver disease.

Because growth failure is a frequent complication of chronic liver disease in childhood, we examined the growth hormone/insulin-like growth factor type I axis and its relationship to growth disturbances, nutritional status, and carbohydrate metabolism in nine children (2.1 to 18.6 years of age) with chronic cholestatic liver disease. Seven had cholestasis associated with splenomegaly and histologic findings of cirrhosis; two patients had Alagille syndrome. Stature was less than or equal to 15th percentile in all except the youngest subject and less than 5th percentile in five subjects. Ten-hour, nocturnal, integrated serum concentrations of growth hormone were considerably higher in patients with cholestasis than in control subjects (mean +/- SD) 9.7 +/- 3.8 vs 4.7 +/- 1.9 ng/ml; p less than 0.02). Serum concentrations of insulin-like growth hormone type I were less than 95th percentile confidence intervals for age- and sex-matched norms in five patients and at the lower limits of normal in the remaining four patients. Insulin sensitivity, determined with the minimal model intravenous glucose tolerance test, was not decreased in five patients despite elevated levels of circulating growth hormone. The estimated mean caloric and protein intake exceeded the recommended dietary allowance and the weight-for-height index was greater than 90% for six of nine patients. Triceps and subscapular skin-fold thicknesses, indicators of body fat stores, were greater than 25th percentile for five of nine and eight of nine patients, respectively, suggesting deficient lipolytic action of GH. We conclude that children with cholestatic liver disease have a resistance to the growth-promoting, diabetogenic, and lipolytic properties of growth hormone.

Adolescent↗
PubMed1990

Comparison of total serum lipids measured by two methods.

To accurately assess vitamin E status, the ratio of serum vitamin E to total serum lipids is required. We compared two methods of measuring total serum lipids: (a) the calculated sum of measured cholesterol, triglycerides, and phospholipids, and (b) the colorimetric method. Over the entire range of total lipid concentrations (151-1,728 mg/dl), there was an excellent correlation between methods (r = 0.930; p less than 0.001). No significant differences between measurements by these methods were found over the entire range and between 0 and 1,000 mg/dl; however, between 1,000 and 1,728 mg/dl, the measured total lipid concentration was higher (p = 0.023) than the added total lipid measurements. Despite this discrepancy, the methods appear comparable for clinical use in assessing vitamin E/total lipid status; the measured total lipids would be the preferred method because of the low cost and ease of performance of the test.

Adult↗
PubMed1990

Neonatal jaundice: clinical and ultrasonographic findings.

We reviewed the laboratory parameters, clinical information including presence or absence of stool pigmentation, and ultrasonographic findings in 67 patients with neonatal conjugated hyperbilirubinemia and liver biopsies. Hepatobiliary nuclear scintigraphy was done in 14 of the patients. Final diagnoses included extrahepatic biliary atresia, neonatal hepatitis, cystic fibrosis, metabolic liver disease, alpha 1-antitrypsin deficiency, bile duct stenosis, Alagille syndrome (arteriohepatic dysplasia), choledochal cyst, panhypopituitarism, and miscellaneous causes of intrahepatic cholestasis. A single diagnostic criterion is insufficient to distinguish the various causes of neonatal jaundice. Clinical laboratory values varied widely among patients with medical and surgical causes of jaundice. Absence of stool pigmentation was not specific for biliary atresia and was found in patients with medical causes of jaundice. Conversely, two patients with biliary atresia had pigmented stools at presentation. Ultrasonography was diagnostic only for choledochal cyst and bile duct stenosis. Nonvisualization of the gallbladder by either ultrasonography or nuclear hepatobiliary scintigraphy was nonspecific in the discrimination of medical from surgical causes of jaundice. A multidisciplinary approach to the evaluation of neonatal jaundice is necessary, since no single test or imaging modality can reliably define the cause in all cases.

Bile Duct Diseases↗
PubMed1990

Bone disease in chronic childhood cholestasis. II. Better absorption of 25-OH vitamin D than vitamin D in extrahepatic biliary atresia.

Infants with extrahepatic biliary atresia (EHBA) commonly develop rickets in infancy, whereas long-term survivors with EHBA commonly develop osteopenia with increasing age. We evaluated baseline vitamin D (D2 and D3), 25-OH vitamin D2 and D3, 1,25(OH)2 vitamin D, bone mineral content, and vitamin D2 and 25-OH vitamin D3 absorption in six infants and children (age 4-22 mo) with EHBA whose portoenterostomy failed to produce bile flow (group 1) and five infants and children (age 10/12 to 8-4/12 y) with EHBA whose portoenterostomy repair led to good postoperative bile flow (group 2). Baseline serum vitamin D2 and D3 were undetectable in all subjects in group 1 despite supplements of 2500-5000 IU/day, whereas all group 2 subjects given supplements (doses 400-5000 IU/d) had measurable levels. Baseline serum 25-OH vitamin D was less than 15 ng/mL in five of six (three with rickets) in group 1, whereas only one in group 2 had concentrations less than 15 ng/mL. A significantly blunted rise of vitamin D2 above baseline and reduced area under the absorption curve after 1000 IU/kg vitamin D2 were found in group 1 patients compared to group 2 (both p less than 0.01), and five pediatric controls (both p less than 0.01). The peak change and area under the absorption curve for serum 25-OH vitamin D3 from baseline after 10 micrograms/kg 25-OH vitamin D3 were significantly reduced for group 1 (both at least p less than 0.05) and group 2 compared to controls (both p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Biliary Atresia↗
PubMed1990

Absence of relationship between the postnatal development of ileal active taurocholate transport and microvillus membrane fluidity.

Concurrent measurements of ileal microvillus membrane vesicle transport and fluorescence anisotropy were performed on magnesium precipitated membranes from rats of various ages during the third postnatal week. At age 14 and 18 days, taurocholate uptake was comparable in the presence of NaCl and KCl gradients. At age 20 days, a 'sodium effect' and at age 21 days an 'overshoot' were observed in the presence of NaCl gradients. No significant change in fluorescence anisotropy was observed between postnatal days 14 and 21. These studies suggest it is unlikely that changes in microvillus membrane fluidity modulate the postnatal development of ileal active bile salt transport.

Animals↗
PubMed1989

Bone disease in chronic childhood cholestasis. I. Vitamin D absorption and metabolism.

Metabolic bone disease is common in children and adults with chronic cholestasis. We evaluated baseline vitamin D (vitamin D2 and D3), 25-OH vitamin D2 and D3, 1,25(OH)2 vitamin D, vitamin D-binding protein, bone mineral content and dietary mineral content in six children (mean age: 12.1 years) with cholestasis since infancy. Absorption of 25-OH vitamin D3 and vitamin D2 was evaluated by measuring serial serum concentrations after a test dose. Bone mineral content was reduced by greater than 2 S.D. in five of six subjects compared to age-specific controls; none had radiographic evidence of rickets but all had osteopenia. Dietary Ca and P content in the subjects was comparable to the recommended daily allowance for age-specific children. Baseline serum vitamin D2 concentrations were undetectable in all but one cholestatic subject despite oral supplementation with 2,500 to 50,000 IU per day vitamin D2. Baseline serum 25-OH vitamin D was 33.2 +/- 6.0 ng per ml (mean +/- S.E.) and comparable to our laboratory norms (15 to 50 ng per ml). Serum 1,25(OH)2 vitamin D and "free" 1,25(OH)2 vitamin D were both significantly (p less than 0.05) reduced compared to controls. A significantly blunted rise and reduced area under the absorption curve (both p less than 0.001) after 1,000 IU per kg vitamin D2 was found in cholestatic children (0.8 ng +/- 0.5 ng per ml and 18.0 +/- 14.3 ng hr per ml, respectively) compared to controls (59.5 +/- 10.0 ng per ml and 1,780 +/- 253 ng hr per ml, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

25-Hydroxyvitamin D 2↗
PubMed1989

Vitamin E deficiency in primary biliary cirrhosis: gastrointestinal malabsorption, frequency and relationship to other lipid-soluble vitamins.

In contrast to deficiencies of vitamins A, D and K, little is known of the prevalence, clinical manifestations and mechanisms of vitamin E deficiency in adult patients with cholestasis. We measured serum vitamin E levels in 45 patients with primary biliary cirrhosis, 20 with primary sclerosing cholangitis, 9 with cryptogenic cirrhosis and 12 with alcoholic cirrhosis. To correct for the hyperlipidemia often found in patients with primary biliary cirrhosis and primary sclerosing cholangitis, total serum lipids were measured and vitamin E levels were expressed as the vitamin E/total serum lipid ratio. Serum vitamin A and D levels and prothrombin time were also determined. Six of 45 patients with primary biliary cirrhosis (13%) but none of the patients with sclerosing cholangitis, cryptogenic cirrhosis or alcoholic cirrhosis and subnormal vitamin E/total serum lipids ratios. Vitamin E deficiency was found in two of eight patients with asymptomatic primary biliary cirrhosis. There was no correlation between standard liver biochemical tests, fasting serum cholylglycine and vitamin E levels. Patients with primary biliary cirrhosis and primary sclerosing cholangitis had significantly lower vitamin E/total serum lipids ratios than patients with either cryptogenic or alcoholic cirrhosis. Twenty-three percent of patients with primary biliary cirrhosis were vitamin D deficient and 14% had low vitamin A levels. Two of the six patients with vitamin E deficiency were also deficient in vitamin D, only one was vitamin A deficient and none had prolonged prothrombin time. We also investigated the gastrointestinal absorption of vitamin E in nine patients with primary biliary cirrhosis and normal vitamin E levels as well as in six normal controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholesterol↗
PubMed1989

Intestinal malabsorption of vitamin E in primary biliary cirrhosis.

We studied intestinal absorption of vitamin E in 26 adults with primary biliary cirrhosis (PBC) and 6 control subjects. Seven (27%) PBC patients were vitamin E-deficient based on the ratio of serum vitamin E to serum total lipid concentrations. An oral vitamin E tolerance test was performed in all patients and control subjects using a loading dose of 2000 IU alpha-tocopheryl acetate with measurement of serial serum vitamin E concentrations over 24 h. Vitamin E absorption was expressed as the maximal rise in serum vitamin E above baseline, the area under the oral tolerance test curve, and these two values divided by the fasting total serum lipid concentration. Absorption of vitamin E was significantly impaired in all PBC patients vs. control subjects (p less than 0.01), in vitamin E-deficient vs. vitamin E-sufficient PBC patients (p less than 0.05 to p less than 0.01), and in PBC patients with serum vitamin E levels below 10 micrograms/ml vs. those with serum vitamin E levels above 10 micrograms/ml (p less than 0.01). Vitamin E absorption was inversely related to stage of PBC, serum cholylglycine, total bilirubin, cholesterol, alkaline phosphatase, aspartate aminotransferase, and prothrombin time. Patients with serum vitamin E below 10 micrograms/ml, serum total bilirubin above 3 mg/dl, serum cholylglycine above 600 micrograms/dl, or serum alkaline phosphatase above 1000 IU/L had severe malabsorption of vitamin E and would be at high risk for the development of vitamin E deficiency. Therefore, vitamin E supplementation should be considered not only in patients in whom overt vitamin E deficiency is present, but also in PBC patients meeting these criteria.

Cholestasis↗
PubMed1987

Treatment of vitamin E deficiency during chronic childhood cholestasis with oral d-alpha-tocopheryl polyethylene glycol-1000 succinate.

Treatment of vitamin E deficiency during chronic childhood cholestasis is hampered by the poor intestinal absorption of available oral preparations of vitamin E when bile flow is severely impaired; thus parenteral vitamin E has been the only effective therapy for many children with this problem. We studied the intestinal absorption, efficacy, and safety of a water-soluble oral form of vitamin E, d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), in 22 children (7 mo to 19 yr old) with severe cholestasis and vitamin E deficiency who were unresponsive to massive oral doses (100-200 IU/kg.day) of dl-alpha-tocopherol. The results of oral vitamin E tolerance tests showed that TPGS was well absorbed in virtually all study subjects, that TPGS intestinal absorption was superior to that of dl-alpha-tocopherol, and that TPGS absorption in teenage children with chronic cholestasis was similar to that of normal adults. In addition, 1.7% +/- 1.6% (mean +/- SD) of the administered polyethylene glycol 1000 contained in the TPGS was absorbed and excreted in the urine of the 13 subjects analyzed, compared with 3.0% +/- 1.3% in 4 normal adults. A chronic oral dose of 15-25 IU/kg.day of TPGS corrected the biochemical vitamin E deficiency state over 1-19 mo (mean, 10.6 mo) of TPGS therapy. No clinical or biochemical evidence of gastrointestinal, renal, hepatic, or hematologic toxicity was demonstrated. This study suggests that TPGS administered orally in a dose of 15-25 IU/kg.day may be a safe and effective form of vitamin E for prevention and correction of vitamin E deficiency during severe childhood cholestasis.

Administration, Oral↗
PubMed1987

A morphometric study of Reye's syndrome. Correlation of reduced mitochondrial numbers and increased mitochondrial size with clinical manifestations.

Morphometric analysis of liver ultrastructure in 14 children with Reye's syndrome (RS) of varying morphologic severity was compared with that of 6 children with normal livers. Results showed reduced numbers of enlarged mitochondria in RS. Multivariant analysis identified correlations between increased mitochondrial size, decreased mitochondrial number, and severity of neurologic disease (stage). A disproportionate increase in mitochondrial area and perimeter in the RS cases with the most depressed mitochondrial number distinguished the 4 children with residual neurologic damage or death. Serum salicylate concentrations were negatively correlated with severity of morphologic alteration. Two cases of non-RS salicylate toxicity showed normal or near-normal mitochondrial size and number. In fatty liver from an autopsy specimen from a child, a child with carnitine deficiency, and a child on therapy for dermatomyositis, mitochondrial numbers were also normal. Decreased mitochondrial numbers are characteristic of RS and imply a pathophysiologic mechanism, possibly related to impaired mitochondrial replication. Synergism with other forms of mitochondrial injury, such as salicylates, hypoglycemia, or shock may influence clinical severity, progression, and outcome.

Analysis of Variance↗
PubMed1986

Ontogeny of bile acid transport in brush border membrane vesicles from rat ileum.

We studied the postnatal development of bile acid transport in rat ileum, using brush border membrane vesicles prepared by a Ca2+ precipitation method. Membrane vesicles from developing (day 14-21) and adult Sprague-Dawley rats were enriched to a similar degree in brush border membrane marker enzyme activities (sucrase or lactase) compared with homogenate. Uptake of 25 microM [3H]taurocholate by adult membrane vesicles was markedly accelerated in the presence of an inwardly directed 100 mM Na+ gradient compared with a K+ gradient, and there was a transient intravesicular accumulation of isotope above equilibrium ("overshoot"). In contrast, at 14 and 16 days of age there was no difference in taurocholate uptake in the presence of a Na+ or a K+ gradient, and uptake was not saturable. The integrity of the vesicle preparation from 14- and 16-day-old rats was confirmed by the demonstration of Na+-dependent uphill transport of 100 microM L-[3H]alanine. Stimulation of taurocholate uptake by a Na+ compared with a K+ gradient ("sodium effect") was first observed at age 17 days, but an overshoot was not present until 18 days of age. The initial rate of Na+-dependent taurocholate (25 microM) uptake increased sixfold between 17 and 21 days of age (24.36 +/- 6.11 to 148.59 +/- 8.56 pmol X mg-1 protein X 5 s-1). Absent or decreased Na+-dependent taurocholate uptake was not due to increased permeability or "leakiness" of vesicles from younger animals to Na+. Ileal brush border membrane vesicles demonstrated saturable kinetics at 21 days, but the Vmax was significantly lower (10.15 +/- 0.44 vs. 13.42 +/- 0.59 nmol X mg-1 protein X min -1, p less than 0.001) and the apparent Km higher (130.6 +/- 18.9 vs. 70.1 +/- 12.6 microM, p less than 0.007) than the adult. We conclude that (a) saturable, Na+-bile acid coupled transport is absent in rat ileum throughout most of the suckling period and (b) kinetic analysis suggests that maturation occurs near weaning, primarily through an increase in functional bile acid carriers within the ileal brush border membrane.

Animals↗
PubMed1986

Role of thyroxine on postnatal development of ileal active bile salt transport.

The role of thyroid hormone on the postnatal development of ileal active taurocholate transport uptake was measured by an in vitro incubation technique in Sprague-Dawley rats. In 16-day-old rats treated with pharmacological doses of L-thyroxine (50 micrograms X 100 g body wt-1 X day-1 on days 10-13), ileal active transport appeared precociously whose Km was 1.60 +/- 0.48 mM and Vapp (apparent maximal velocity) was 8.09 +/- 1.14 nmol X min-1 X mg dry wt-1, while age-matched shams had only passive diffusion of taurocholate. To determine whether enhanced endogenous secretion of thyroxine was capable of stimulating development of ileal active taurocholate transport, thyrotrophic stimulating hormone (TSH) (0.5 U/100 g body wt twice daily) was given on days 10-13, with uptake measured on day 16. Following TSH treatment, only passive transport for taurocholate was observed in the ileum; uptake rates were consistently higher than those for untreated controls at each study concentration. Thyroidectomy performed at age 14 days with uptake measured at age 21 days did not ablate development of ileal active transport but resulted in a significant reduction (P less than 0.001) in the Vapp (7.39 +/- 1.10 nmol X min-1 X mg dry wt-1) and a significant increase (P less than 0.014) in Km (1.72 +/- 0.53 mM) compared with age-matched controls. Thyroid hormone does not appear to be obligatory for the postnatal development of ileal active taurocholate transport.

Animals↗
PubMed1985

Improved neurologic function after long-term correction of vitamin E deficiency in children with chronic cholestasis.

We studied the effect of long-term correction of vitamin E deficiency on neurologic function in 14 children with chronic cholestasis. Vitamin E repletion was achieved in all, either by large oral doses (up to 120 IU per kilogram of body weight per day) or by intramuscular administration of dl-alpha-tocopherol (0.8 to 2.0 IU per kilogram per day). With early institution of therapy, neurologic function remained normal in two asymptomatic children below the age of three years after 15 and 18 months of therapy. Neurologic function became normal in three symptomatic children below age three after 18 to 32 months of therapy. Restitution of neurologic function was more limited in nine symptomatic children 5 to 17 1/2 years old after 18 to 48 months of therapy. We conclude that vitamin E repletion therapy should be initiated at an early age in children with chronic cholestasis complicated by vitamin E deficiency, to prevent irreversible neurologic injury.

Adolescent↗
PubMed1985

Frequency and clinical progression of the vitamin E deficiency neurologic disorder in children with prolonged neonatal cholestasis.

To determine the frequency of biochemical vitamin E deficiency and of the clinical signs of the vitamin E deficiency neurologic syndrome in children with prolonged neonatal cholestatic disorders, we studied 46 children (aged 1 month to 17.0 years) with chronic forms of intrahepatic neonatal cholestasis and 47 children (aged 4 months to 8.0 years) with extrahepatic biliary atresia. Based on serum vitamin E concentrations and the ratios of serum vitamin E concentration to total serum lipid concentration, 64% of the intrahepatic and 77% of the extrahepatic cholestasis groups were vitamin E deficient. Prior to age 1 year, neurologic function was normal in all children. Between ages 1 and 3 years, neurologic abnormalities were present in approximately 50% of the vitamin E-deficient children; after age 3 years, neurologic abnormalities were present in all vitamin E-deficient children. Areflexia was the first abnormality to develop between ages 1 and 4 years; truncal and limb ataxia, peripheral neuropathy, and ophthalmoplegia developed between ages 3 and 6 years. Neurologic dysfunction progressed to a disabling combination of findings by ages 8 to 10 years in the majority of vitamin E-deficient children. Neurologic function was normal in the vitamin E-sufficient children. We conclude that vitamin E status should be evaluated in infants in whom cholestasis is diagnosed, and effective therapy should be initiated to prevent or treat vitamin E deficiency at an early age.

Adolescent↗
PubMed1985

Reye syndrome in children receiving salicylate therapy for connective tissue disease.

Concern that salicylates may play a role in the pathogenesis of Reye syndrome has raised the question of whether children receiving salicylate therapy for connective tissue disease are at risk for development of Reye syndrome. Of 176 patients with biopsy-confirmed Reye syndrome studied between January 1969 and June 1983, six had connective tissue disease at the time of development of Reye syndrome, and all six were receiving salicylates. Compared with the general population, children receiving salicylate therapy for connective tissue disease may be at increased risk for the development of Reye syndrome.

Biopsy↗
PubMed1985

The role of glucocorticoids in the postnatal development of ileal active bile salt transport.

The role of glucocorticoids in the regulation of the postnatal development of ileal active bile salt transport was examined in the rat using the villus technique. Ileal taurocholate uptake was initially by passive transport alone on day 14 and 16 which changed to an active and passive transport mechanism at 18 days which persisted thereafter. The Michaelis-Menten constant (Km, mM) was unchanged between days 18 (0.67 +/- 0.12 mM), 20 (0.84 +/- 0.25 mM), 21 (0.49 +/- 0.05 mM), 28 (0.59 +/- 0.06 mM), and 49 (0.50 +/- 0.05 mM) whereas the apparent maximal velocity nmol/mg(dry wt)/min declined after a peak at 18 days (18.17 +/- 1.92 on day 18, 16.14 +/- 1.89 on day 20, 14.65 +/- 0.52 on day 21, 11.40 +/- 0.35 on day 28, and 10.51 +/- 0.32 on day 49). Adrenalectomy performed in sucklings on day 14 with taurocholate transport studies on day 21 and in adults on day 42 studied on day 49 resulted in reductions in uptake at most study concentrations but no change in the Km (1.33 +/- 0.54 in sucklings and 0.75 +/- 0.14 mM in adults) or apparent maximal velocity [11.78 +/- 2.06 in sucklings and 9.24 +/- 0.65 nmol/mg (dry wt)/min in adults]. Treatment of sucklings with corticosterone (5 mg/100 g body weight) on days 10-13 with study on day 14 and 16 did not produce precocious development of ileal active taurocholate transport; however, corticosterone treatment led to apparent increases in ileal permeability to taurocholate in both sucklings and adults. Glucocorticoids appear to play a minor, if any, role in the physiologic postnatal development of ileal active bile salt transport.

Adrenal Glands↗