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Biomedical subjects

J E Heubi

Publications and source records attributed to J E Heubi.

At least 73 records · Page 4Linked to original sources
PubMed1985

Postnatal development of intestinal bile salt transport. Relationship to membrane physico-chemical changes.

The postnatal development of intestinal bile salt transport in the rat was examined using the villus technique. Jejunal uptake of taurocholate was linear with respect to incubation concentration at all study ages. Ileal uptake was linear with taurocholate concentration during the first 2 postnatal weeks; a curvilinear relationship indicating the presence of saturable transport appeared during the third week. With the appearance of ileal active transport at age 3 weeks, the Km (app) was constant at 0.49 mM, 0.59 mM, and 0.50 mM in 3-week, 4-week, and adult animals, respectively. The V(app) was 14.65 nmol X mg-1 (dry wt) X min-1 at 3 weeks and declined with age to 11.40 and 10.51 nmol X mg-1 (dry wt) X min-1 in 4-week and adult animals, respectively. The role of physico-chemical changes in the microvillus membrane in the development of ileal active transport was examined. With increasing postnatal age, microvillus membrane cholesterol content rose while the phospholipid content remained unchanged in both ileum and jejunum. Corresponding rises in the cholesterol/phospholipid ratio were observed in both sites. Simultaneously, the microvillus membrane fatty acid composition was changing from predominantly saturated to unsaturated species in both ileum and jejunum. The microvillus membrane fluorescence anisotropy (r) increased with postnatal age in jejunum when measured at 25 degrees C and 37 degrees C and ileum when measured at 25 degrees C; however, no change was noted in ileum when measured at 37 degrees C. Ileal active bile salt transport develops during the third postnatal week, and is associated with concurrent changes in membrane lipid composition and fluidity when measured at 25 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1984

Grade I Reye's syndrome--outcome and predictors of progression to deeper coma grades.

We studied 83 biopsy-proved cases of Grade I Reye's syndrome to determine the outcome, possible clinical or laboratory predictors of progression to deeper coma grades, and hepatic ultrastructural findings. Seventy-eight patients had no change in coma grade during hospitalization, whereas five (6 per cent) had progression to deeper coma grades. All the patients survived without sequelae except one who sustained severe brain damage. The mean (+/- S.E.) level of serum ammonia on admission was significantly higher (P = 0.005) in patients whose disease progressed to deeper neurologic grades (291 +/- 42 micrograms per deciliter) than in those whose disease did not so progress (53 +/- 5 micrograms per deciliter), and the corrected prothrombin time was significantly more prolonged (P = 0.005) in patients with progressing coma (3.9 +/- 0.5 seconds) than in those whose coma grade did not change (1.6 +/- 0.2 seconds). The combination of a prothrombin time 3 seconds or longer than that of the control and a serum level of ammonia on admission of 100 micrograms per deciliter or more correctly predicted progression in 71.5 per cent of the cases (sensitivity, 100 per cent; specificity, 97.6 per cent). Our findings suggest that the prognosis is excellent for survival without sequelae in Grade I Reye's syndrome (98.8 per cent) when management includes hospital surveillance and intravenous glucose and electrolyte infusion.

Ammonia↗
PubMed1984

Vitamin E deficiency with normal serum vitamin E concentrations in children with chronic cholestasis.

We studied serum vitamin E levels and the ratio of serum vitamin E to serum lipid levels in 11 children with chronic cholestasis complicated by vitamin E deficiency, as defined by characteristic neurologic signs or sural-nerve histopathology in addition to impaired intestinal absorption of vitamin E. Eight of the children had low levels of serum vitamin E, as well as low ratios of serum vitamin E to total lipids and to cholesterol. However, three patients had normal serum vitamin E levels but low ratios of serum vitamin E to total lipids (two of the three had normal ratios of vitamin E to cholesterol). In four patients who were not vitamin E-deficient, all three values were normal. We conclude that vitamin E deficiency may exist in a child with a normal serum vitamin E concentration and that the ratio of serum vitamin E to total serum lipids is the most reliable biochemical index of vitamin E status during chronic childhood cholestasis.

Adult↗
PubMed1984

Chenodeoxycholic acid pool size determination from children using isotope dilution mass spectrometry.

An isotope dilution mass spectrometry method is described for determining chenodeoxycholic acid pool size in children. The stable isotopically labeled tracer, (11,12-2H2) chenodeoxycholic acid, was administered orally to children, and the enrichment of bile was measured by selected ion monitoring gas chromatography mass spectrometry. The level of (11,12-2H2)chenodeoxycholic acid enrichment found in the patient samples was in the range of 0.5 to 5%. Data are presented illustrating the duplication of this method in two independent laboratories using standard quadrupole mass spectrometers. This procedure provides the clinician with a non-radioactive method for determining chenodeoxycholic acid pool size which is especially beneficial in studies involving children and pregnant women.

Chenodeoxycholic Acid↗
PubMed1983

Grade I Reye's syndrome. A frequent cause of vomiting and liver dysfunction after varicella and upper-respiratory-tract infection.

In a one-year prospective study we assessed the incidence of Reye's syndrome in children presenting with the acute onset of vomiting after a prodromal upper-respiratory-tract infection or varicella, and with serum alanine or aspartate aminotransferase levels at least three times higher than normal, and a paucity of neurologic findings. Of 25 patients meeting the above criteria, 19 had liver biopsies yielding adequate tissue for diagnostic purposes. Biopsy specimens from 14 of these 19 patients (74 per cent) were diagnostic of Reye's syndrome, according to rigorous light-microscopical, histochemical, and ultrastructural criteria. None of the biopsy specimens contained evidence of other acute pathologic processes, including hepatitis. A wide spectrum of mitochondrial alterations existed at the ultrastructural level, ranging from mild to severe lesions that were indistinguishable from those seen in comatose patients with Reye's syndrome. Our findings suggest that the clinical complex of vomiting, hepatic dysfunction, and minimal neurologic impairment after varicella or an upper-respiratory-tract infection usually represents Reye's syndrome. This syndrome occurs more frequently than previously recognized.

Adolescent↗
PubMed1983

Hypocalcemia and steatorrhea--clues to etiology.

Two boys with idiopathic hypoparathyroidism had extensive studies of gastrointestinal function during hypocalcemia accompanied by steatorrhea. No evidence of generalized gastrointestinal moniliasis or abnormal mucosal structure or function was observed. Studies of pancreatic function and bile salt metabolism during hypocalcemia demonstrated deficient meal-stimulated intraluminal pancreatic enzyme concentrations in both subjects and reduced bile salt concentrations in one subject. However, following stimulation with exogenous octapeptide of cholecystokinin, intraluminal pancreatic enzyme and bile salt concentrations were normal in both. Cholic acid pool sizes were markedly increased in both subjects during hypocalcemia (9 and 12 times larger than during normocalcemia) and cholic acid turnover was reduced during hypocalcemia in one subject. Our findings suggest that during hypocalcemia, insufficient endogenous cholecystokinin is released by the duodenal mucosa during a meal stimulus to stimulate normal gallbladder contraction and pancreatic enzyme secretion.

Adolescent↗
PubMed1983

Vitamin E deficiency during chronic childhood cholestasis: presence of sural nerve lesion prior to 2 1/2 years of age.

Vitamin E malabsorption and deficiency during chronic childhood cholestasis has been associated with a progressive ataxic neurologic syndrome. Hyporeflexia, the first sign of neurologic dysfunction, may begin prior to age 2 years, but severe symptoms do not develop until age 5 to 10 years. To establish the age of onset of neuropathologic lesions, we prospectively evaluated four young children with severe cholestasis. Malabsorption and deficiency of vitamin E were documented by low serum vitamin E concentrations, low serum vitamin E to total serum lipids ratios, elevated hydrogen peroxide hemolysis, and impaired absorption of a pharmacologic dose of alpha-tocopherol. Abnormal neurologic findings in two patients were limited to areflexia, ptosis, mild truncal ataxia, and hypotonia; two patients had minimal signs of neurologic dysfunction. Sural nerve histology at age 6 to 25 months revealed a degenerative axonopathy involving large-caliber myelinated fibers, but without quantitative axonal loss. Muscle histology and histochemistry tests yielded normal results. Our study suggests that neurologic injury may occur during the first two years of life in vitamin E-deficient children with cholestatic hepatobiliary disease, obligating aggressive attempts at correcting this deficiency state at a very young age.

Child, Preschool↗
PubMed1983

Intrahepatic "cholestasis facies": is it specific for Alagille syndrome?

In 1975 Alagille described in the English literature a syndromatic form of intrahepatic biliary hypoplasia associated with characteristic facial features (prominent forehead, deep-set eyes, mild hypertelorism, straight nose, and small pointed chin). To test the specificity of the facies for Alagille syndrome, close-up facial photographs of 15 children and young adults with various forms of intrahepatic cholestasis (including seven with Alagille syndrome) were examined by 13 pediatric hepatologists from the United States and Canada and by Dr. Alagille and eight of his co-workers from France, without knowledge of the individual diagnoses. Each examiner was asked to identify the patients with facies characteristic for Alagille syndrome. Fifty-one percent of the U.S./Canadian group's matchings and 49% of the French group's matchings of facies to underlying liver disease (presence or absence of Alagille syndrome) were incorrect. The sensitivity of the facies for diagnosing Alagille syndrome was 54% and 32%, the specificity 44% and 68%, and the predictive value 46% and 47% based on the U.S./Canadian and French groups, respectively. "Cholestasis facies" does not appear specific for Alagille syndrome; rather, it seems to be a general feature of congenital intrahepatic cholestatic liver disease.

Adolescent↗
PubMed1983

Comparison of vitamin E and 25-hydroxyvitamin D absorption during childhood cholestasis.

To characterize differences in intestinal absorption of fat-soluble vitamins during cholestasis, intestinal absorption of vitamin E was compared with that of 25-hydroxyvitamin D in eight infants and young children with prolonged neonatal cholestasis. Oral tolerance tests were performed using 100 IU/kg/dose dl-alpha-tocopherol and 10 micrograms/kg/dose 25-hydroxyvitamin D. Mean vitamin E absorption was only 1.0% to 1.9% of that of control children, whereas 25-hydroxyvitamin D absorption was 22.5% to 25.1% of that of controls. Although intestinal absorption of both vitamins is impaired during cholestasis, the severity of vitamin E malabsorption far exceeds that of 25-hydroxyvitamin D.

Calcifediol↗
PubMed1983

The role of human growth hormone in the regulation of cholesterol and bile acid metabolism.

Cholesterol and bile acid metabolism was studied in 16 children with human GH (hGH) deficiency (11 with isolated hGH deficiency and 5 with multiple trophic hormone deficiency) before and after 6 months of hGH therapy. We measured plasma lipid concentrations, biliary lipid composition, and cholesterol saturation indices; calculated the bile acid pool size measured by the isotopic dilution technique using the stable isotope chenodeoxycholic-[11,12-d2] acid; and measured cholesterol and bile acid synthetic rates by sterol balance techniques. In all 16 patients, plasmas lipid concentrations were unchanged after hGH therapy; total plasma cholesterol was 182 +/- 10 (+/-SEM) mg/dl before and 179 +/- 9 mg/dl after treatment, high density lipoprotein-cholesterol was 47 +/- 2 mg/dl before and 49 +/- 3 mg/dl after treatment, low density lipoprotein-cholesterol was 112 +/- 10 mg/dl before and 111 +/- 8 mg/dl after therapy, and triglyceride was 113 +/- 13 mg/dl before and 107 +/- 10 mg/dl after hGH therapy. Biliary lipid composition and cholesterol saturation in 10 patients were similar to those in controls and unchanged with hGH therapy. Cholesterol synthesis (n = 14) was unchanged (7.6 +/- 1.4 vs. 9.6 +/- 1.2 mg/kg X day); however, bile acid synthesis (n = 15) increased from 3.1 +/- 0.4 to 4.3 +/- 0.6 mg/kg X day (P less than 0.025) after therapy. The chenodeoxycholate pool size (n = 8) was significantly reduced (P less than 0.025) before hGH treatment (416 +/- 64 mg/m2) compared to that in controls (617 +/- 45 mg/m2) and increased to 620 +/- 72 mg/m2 after hGH therapy (P less than 0.05). Chenodeoxycholate pool size expansion during hGH therapy was, at least in part, caused by an increase in hepatic bile acid synthesis. These findings suggest that hGH may indirectly modulate cholesterol metabolism through regulation of hepatic cholesterol 7 alpha-hydroxylase activity, the rate-limiting enzyme of bile acid synthesis.

Adolescent↗
PubMed1983

Mechanism causing vitamin E deficiency during chronic childhood cholestasis.

In order to characterize the mechanism(s) causing vitamin E deficiency during chronic childhood cholestasis, we studied 6 vitamin E-deficient cholestatic children with clinical evidence of neurologic dysfunction (group A), 4 vitamin E-sufficient cholestatic children and young adults with normal neurologic status (group B), and 6 vitamin E-sufficient noncholestatic children (group C). Intestinal absorption of dl-alpha-tocopherol (assessed by an oral tolerance test) was markedly impaired (p less than 0.001) in group A compared with groups B and C, which did not differ from each other. Intraluminal total bile acid concentrations were markedly depressed in group A compared with age-matched controls (0.50 vs. 7.00 mM, p less than 0.001), whereas concentrations were low normal in group B. Intramuscular dl-alpha-tocopherol was well absorbed in 4 group A subjects and corrected abnormal hydrogen peroxide hemolysis. Our data suggest that low intraluminal bile acid concentrations result in malabsorption and deficiency of vitamin E in children with prolonged, severe cholestasis. Intact plasma transport and tissue uptake of vitamin E during cholestasis suggest that intramuscular vitamin E should be utilized for prevention and therapy of the neurologic abnormalities caused by vitamin E deficiency.

Adolescent↗
PubMed1982

Postnatal development of intestinal bile salt transport in the guinea pig.

The postnatal development of intestinal bile salt transport was examined in the guinea pig. Using an in vitro technique, mucosal uptake of taurocholate was measured in jejunum and ileum at five monomeric concentrations from fetal, 1-day-old, 5-day-old, 10-day-old, 21-day-old, and adult animals. Jejunal taurocholate uptake was linear with respect to concentration and was not inhibited by taurochenodeoxycholate at all ages studied. In fetal and 1-day-old animals, ileal taurocholate uptake was linear and was not inhibited by taurochenodeoxycholate. A curvilinear relation between uptake and taurocholate concentration, which was inhibited by taurochenodeoxycholate, was observed in 5-day-old and older animals. These findings indicate that, in the guinea pig, passive diffusion of taurocholate is the only mode of intestinal transport in fetuses and newborns and the sole mode of jejunal transport at all ages. By 5 days, however, active ileal transport appears, which persists into adulthood and contributes to the development of an efficient enterohepatic circulation of bile salts.

Animals↗
PubMed1982

Intestinal bile acid malabsorption in cystic fibrosis: a primary mucosal cell defect.

Bile acid malabsorption in cystic fibrosis reduces intraluminal bile acid concentration and may impair fat absorption. The cause of this malabsorption is unknown but it is believed due to intraluminal inhibition of uptake by undigested dietary nutrients. The purpose of this study was to determine the bile acid absorptive capability of cystic fibrosis intestine in a physiologic environment. Direct ileal mucosal taurocholic acid uptake was examined in vitro in seven patients with cystic fibrosis, and seven children and adolescents with ileostomies as controls. Jejunal uptake was studied in five normal individuals. A Crosby-Kugler biopsy capsule was used to obtain all tissues. Tissue was incubated in Krebs buffer, 10 mM glucose, and taurocholic acid at 0.1, 1.0 and 10.0 mM with shaking at 37 degrees C. Significant reduction of taurocholic acid uptake was present in every cystic fibrosis patient with mean uptake rates being 24%, 38%, and 29% of control ileum, respectively, at the three concentrations. Values paralleled those for passive jejunal taurocholic acid uptake in controls. These data illustrate a marked reduction in taurocholic acid uptake capability of cystic fibrosis ileal mucosa and may indicate a cellular defect suggestive of a primary lesion in this disease.

Adolescent↗