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Biomedical subjects

J E Heubi

Publications and source records attributed to J E Heubi.

At least 91 records · Page 5Linked to original sources
PubMed1982

Biliary lipid composition in healthy and diseased infants, children, and young adults.

Biliary lipid composition and cholesterol saturation were measured in 17 infants and children (age, 4 mo to 9 yr) who had recovered from chronic diarrhea (control subjects), 9 infants and children (age, 4 mo to 9 yr) with interruption of the enterohepatic circulation of bile salts from birth, and in 20 healthy young adults (age, 21-35 yr). The cholesterol molar fraction in pediatric controls was 3.7 +/- 0.2% (mean +/- SE), and in patients with ileal dysfunction or resection was 3.4 +/- 0.4%. Both values were significantly lower than that found in adults (5.7 +/- 0.5%, p less than 0.01). Cholesterol saturation, calculated using the method of Thomas and Hofmann, was significantly reduced in patients with ileal dysfunction or resection (0.60 +/- 0.10; p less than 0.01) and juvenile controls (0.72 +/- 0.04; p less than 0.05) compared with adults (1.08 +/- 0.09). It appears that proportionately larger bile salt pools (adjusted to body size) in both pediatric groups compared with their normal and diseased adult counterparts contribute to the observed reduction in the biliary molar fraction of cholesterol and reduced cholesterol saturation. However, both normal and diseased infants and children primarily have reduced biliary cholesterol/bile salt excretion ratios such that, even at low rates of secretion, bile is not saturated with cholesterol. Therefore, age-related differences in biliary lipid secretory rates seem to produce unsaturated bile in both normal and diseased prepubertal humans.

Adult↗
PubMed1982

Primary bile acid malabsorption: defective in vitro ileal active bile acid transport.

Two boys with congenital diarrhea, steatorrhea, and growth failure were studied. Preliminary investigations indicated that the enterohepatic circulation of bile acids was interrupted. Radiographically, ileal structure was normal; ileal function was normal when assessed by vitamin B12 absorption. To confirm our clinical suspicion that the patients had an isolated defect of ileal active bile acid transport, peroral terminal ileal biopsies were performed. Ileal mucosa was incubated in vitro in oxygenated Krebs-Ringer bicarbonate buffer containing 10 mM glucose and 0.1, 1.0, or 10.0 mM taurocholic acid at 37 degrees C. Ileal uptake from the patients was 0.10 and 0.34 mumol/g dry wt . min in 0.1 mM taurocholic acid, 1.20 and 2.39 mumol/g dry wt . min in 1.0 mM taurocholic acid, and 21.19 and 11.14 mumol/g dry wt . min in 10.0 mM taurocholic acid. At every concentration, significant (p less than 0.05) reductions were present compared with ileum from 7 ileostomy controls, 0.5 to 27 yr old whose uptake was 1.40 +/- 0.28 mumol/g dry wt . min (mean +/- SEM) at 0.1 mM; 6.36 +/- 1.33 mumol/g dry wt . min at 1.0 mM, and 76.20 +/- 19.30 mumol/g dry wt . min at 10.0 mM taurocholic acid. Ultrastructural examination of the ileal mucosa failed to demonstrate a significant structural abnormality. Significant reduction in ileal uptake of taurocholic acid accompanying clinical and biochemical findings of interruption of the enterohepatic circulation in the absence of mucosal disease suggests that these children have a previously undescribed, congenital transport defect that includes absence of active ileal bile acid transport presenting as diarrhea in infancy.

Bile Acids and Salts↗
PubMed1982

Bile salt metabolism in the first year of life.

Bile salt metabolism was examined in 12 infants (ages 7 weeks to 10 months) who had recovered from protracted infantile diarrhea. Cholic acid kinetics were measured with the isotopic dilution technique. Cholate pool size was 938 +/- 89 mg/m2 (means +/- S.E.), synthetic rate was 478 +/- 52 mg/m2/day, and the fractional turnover rate was 0.537 +/- 0.060 day -1. Estimated chenodeoxycholate pool size was 607 +/- 103 mg/m2. similar cholic acid pool sizes were previously observed in older children; however, the synthetic and turnover rates were significantly lower, p less than 0.05 and 0.025, respectively. A significant inverse relationship between age and fractional turnover rate (r = -0.577, p less than 0.05) was observed in the first 10 months of life. Fasting serum cholylglycine measured by radioimmunoassay was significantly higher (p less than 0.01) in infants than in children. Peak postprandial concentrations were higher in infants than in older children. Accelerated hepatic bile salt synthesis rapidly increases the size of small pools at birth. Intraluminal bile salt concentrations concurrently increase, thereby normalizing fat solubilzation. Slow maturation of intestinal transport mechanisms may result in normal cycling of bile salts by 3 to 7 months of age. Persistent immaturity of hepatic uptake and/or excretion of bile salts leads to intrahepatic retention of a portion of the pool, with resultant regurgitation into the serum during the first months of life.

Adult↗
PubMed1981

Pathologic versus physiologic cholestasis: elevated serum concentration of a secondary bile acid in the presence of hepatobiliary disease.

Serum levels of the primary bile acids cholic and chenodeoxycholic acid are transiently elevated in normal neonates and infants; this represents a state of "physiologic cholestasis." In this study we determined, using specific radioimmunoassay, the concentration of a secondary bile acid, sulfated lithocholate, in serum obtained from healthy infants and from those with various hepatobiliary diseases. The serum levels of sulfated lithocholate were low in 69 neonates (less than 5 days of age: mean +/- SEM = 0.45 +/- 0.05 mumoles/L) and in 78 normal infants (less than one year of age: 0.49 +/- 0.02); there was no postprandial rise. These values were similar to those seen in 95 older children (0.56 +/- 0.03) and in maternal (0.49 +/- 0.04) and cord blood (0.44 +/- 0.03) of the neonates. In contrast, in patients with neonatal cholestasis of any nature there was a consistent marked rise in serum concentrations of sulfated lithocholate (mean = 4.46 +/- 0.39, P less than 0.001). In infants monitored during the course of parenteral nutrition, elevated values of sulfated lithocholate often occurred in the presence of normal results of other liver function tests. Serum sulfated lithocholate concentration is an accurate index of neonatal hepatobiliary disease; the sensitivity and specificity of this test remain to be further defined.

Biliary Tract Diseases↗
PubMed1981

The effect of continuous enteral feeding on cholic acid kinetics in a child.

Continuous enteral feeding is utilized for nutritional support and specific therapy for several pediatric diseases, including protracted infantile diarrhea. Its effects on the enterohepatic circulation of bile acids were studied in a boy during continuous intragastric feeding of a high fat diet at age 42 months and after recovery while on bolus feedings at age 51 months. Cholic acid kinetics measured by the isotopic dilution technique using cholic-COOH-14C acid and meal stimulated intraluminal bile acid concentrations were measured. Cholic acid pool size was unaltered (1294 mg/m(2)) during continuous feeding compared to 999 mg/m(2) during bolus feeds and 1072 plus or minus 243 mg/m(2) (mean plus or minus SE) in nine control children. However, the cholic acid fractional turnover rate was increased 3-fold (0.912 days(-1)) during continuous feeds compared to 0.309 days(-1) during bolus feeding and 0.365 plus or minus 0.163 in controls. Similarly, synthesis rate was increased 3-4 fold during continuous feeds (1180 mg/m(2)/day) compared to controls (363 plus or minus 193 mg/m(2)/day) and the patient during bolus feeding (309 mg/m(2)/day). The intraluminal bile salt concentration was apparently reduced both during treatment (3.86 mM) and when bolus fed (3.85 mM) but were significantly different from controls (7.12 plus or minus 1.74 mM). During continuous enteral feeding with a high fat diet, effective homeostatic mechanisms in the enterohepatic circulation of bile salts ensured intraluminal bile salt concentrations adequate for normal fat solubilization and, consequently, normal fat absorption.

Bile↗
PubMed1981

Physiologic cholestasis: elevation of the primary serum bile acid concentrations in normal infants.

Immaturity of hepatic excretory function resulting in a period of "physiologic cholestasis" may occur during early life. Serum bile acids should accurately reflect maturation of the enterohepatic circulation; we therefore determined serum concentrations of the primary bile acids in normal infants to define age-related changes. There was a striking rise in serum cholylglycine and conjugates of chenodeoxycholate during the first few days of life over levels detected in cord sera; the values attained were significantly greater than maximal postprandial concentrations found in children over 1 yr of age (p less than 0.01). There was a gradual decline in bile acid concentration; however cholylglycine remained higher than the postprandial values of older children until 4 mo and chenodeoxycholate until 6 mo of age. In 12 infants a liquid feeding stimulated a greater maximal postprandial cholylglycine concentration and integrated area under the meal curve than that achieved in children (p less than 0.01). There was no difference in the postprandial response in chenodeoxycholate in these infants compared with the older subjects. We conclude that serum bile acids are elevated in normal infants and that the subsequent decline to levels of the child and adult demonstrates the evolving maturation of liver function during infancy.

Age Factors↗
PubMed1980

Serum bile acid response to a test meal stimulus: a sensitive test of ileal function.

We assessed ileal functional integrity, as reflected in the capacity to reabsorb the bile acid, cholylglycine, by sequential measurement of postprandial serum levels of this compound. A consistent increase in cholylglycine concentration (mean +/- SEM, peak above fasting baseline = 1.86 +/- 0.14 microM) occurred in eight normal children. Five patients with ileal resection and two with primary bile acid malabsorption had a minimal postprandial increase (0.27 +/- 0.08 microM; P less than 0.005 vs controls) and excess bile acid loss in feces. Similarly, in seven patients with Crohn disease involving the ileum the postprandial increase (0.38 +/- 0.06) was less than controls (P less than 0.001). In eight patients with cystic fibrosis, the administration of pancreatic enzymes normalized the blunted response demonstrated when enzymatic therapy was interrupted suggesting an intact ileal active transport mechanism. Meal-stimulated response of serum cholylglycine concentration is a sensitive indicator of altered ileal integrity and bile acid malabsorption due to ileal resection, inflammation, or dysfunction.

Adolescent↗
PubMed1980

Bile salt metabolism in infants and children after protracted infantile diarrhea.

Ten infants and children (mean age, 44 months), who had recovered from protracted infantile diarrhea with no sequelae, underwent detailed investigations of cholate metabolism using the isotope dilution technique. Cholate pool size was 1011 +/- 73 mg/m2, (mean +/- S.E.), synthetic rate was 358 +/- 58 mg/m2/day, and the fractional turnover rate was 0.359 +/- 0.049 days-1. Pool size, uncorrected for body surface area differences, was shown to increase directly with body size (r = 0.827; P = 0.002) and age (r = 0.724; P = 0.009). The fractional turnover rate varied inversely with age (r = -0.656; P = 0.02), surface area (r = 0.642; P = 0.023), and pool size (r = -0.703; P = 0.012) and directly with synthesis (r = 0.878; P < 0.001). Infants and children have an intact enterohepatic circulation of cholate; the pool size and the mechanisms which regulated synthesis are similar to adults. The progressive enlargement of pool size with age is associated with an age-related increase in intraluminal bile salt concentrations which ensures normal intraluminal fat digestion and solubilization.

Bile↗
PubMed1980

Enterohepatic circulation of bile acids in infants and children with ileal resection.

Seven children who had undergone ileal resection of varying lengths as neonates were studied to determine later gastrointestinal function with specific emphasis on the enterohepatic circulation of bile acids. Fecal homogenate and aqueous supernatant bile acid concentrations and serum bile acids were analyzed. Cholic acid kinetics were measured by the isotopic dilution technique, with multiple duodenal bile samples obtained within 48 hr after intravenous 14C--cholic acid. As compared to those of age-matched controls, significantly increased fecal homogenate bile acid concentrations (p less than 0.05) and fecal aqueous supernatant bile acid concentrations (p less than 0.01) were present. Fasting and postcibal serum bile acid concentrations were significantly reduced (p less than 0.001). Increased FTRs for cholic acid (p less than 0.001) were present in children with resection. The FTR correlated significantly with resection length (p = 0.012). Fasting pool sizes of chenodeoxycholic and cholic acid measured after an overnight fast were variable. Three children had significantly reduced cholic acid and chenodeoxycholic acid pools, and one had a reduction in the cholic acid pool only. The cholic acid pool size correlated directly with the postprandial rise in serum CG concentration (p = 0.003). The fecal coefficient of fat excretion and fecal weights were only moderately increased. Although rapid turnover of bile acids was present following neonatal ileal resection, efficient compensatory mechanisms during infancy and childhood allowed adequate intraluminal bile salt concentrations for normal fat solubilization throughout the day and resultant mild steatorrhea and diarrhea in our study patients.

Bile Acids and Salts↗
PubMed1979

Refractory infantile diarrhea due to primary bile acid malabsorption.

A boy is described who had severe, refractory diarrhea beginning soon after birth. Prolonged parenteral alimentation was required to support life. Investigations of bile acid metabolism showed impaired intestinal absorption of bile acids. Contracted bile acid pool sizes resulted, with low intraluminal bile acid concentrations and severe, malabsorption of water and fat. Bile acid malabsorption is a cause of refractory infantile diarrhea.

Bile Acids and Salts↗
PubMed1979

1,25-Dihydroxyvitamin D3 in childhood hepatic osteodystrophy.

Osteodystrophy frequently accompanies severe childhood hepatobiliary disease. Proposed causes include malabsorption of vitamin D and calcium, and diminished 25-hydroxylation of vitamin D. Two children, ages 23 and 35 months, with radiographic and biochemical evidence of rickets with extrahepatic biliary atresia, were treated with 1,25-dihydroxyvitamin D3. The minimal effective therapeutic dose and efficacy of 1,25-(OH)2D3 in the treatment of rickets associated with severe childhood hepatic disease were determined. Oral 1,25-(OH)2D3 was ineffective at doses of 0.10 microgram/kg/day. Parenteral doses of 0.20 microgram/kg/day effectively produced radiographic, bone mineral (photon absorptiometric), and biochemical evidence of healing. The need for four times the physiologic dose of 1,25-(OH)2D3 by the parenteral route suggested enhanced catabolism of, or end-organ resistance to, 1,25-(OH)2D3 in our patients with severe cholestatic liver disease treated with phenobarbital.

Bile Ducts↗
PubMed1979

Small intestinal mucosal fatty acid uptake and esterification in infants and children.

Oleic acid uptake and esterification in intact intestinal mucosa were studied in 14 infants and children with chronic non-specific diarrhea, but histologically normal small intestinal mucosal biopsies, using an in vitro technique. The uptake rate was 5.876 +/- 1.942 nmol fatty acid/mg Nigrogen/minute and the esterification rate was 4.060 +/- 1.010 nmol fatty acid/mg Nitrogen/minute, comparable to previous adult esterification studies. No effect of age on either esterification or uptake was present. Mucosal injury resulted in significant reductions in esterification (p less than 0.001) and uptake (p less than 0.05) compared to controls. Bile acid deficiencies led to reductions in mucosal esterification (p less than 0.05) but not uptake.

Bile Acids and Salts↗
PubMedDate not supplied

Correction of vitamin E deficiency in children with chronic cholestasis. II. Effect on gastrointestinal and hepatic function.

Although secondary vitamin E deficiency causes a reversible neurologic disorder in children with chronic cholestasis, the effect of this deficiency state on other organ systems is unknown. We studied the effects of vitamin E therapy on selected gastrointestinal and hepatic functions in five children with chronic cholestasis and well-documented biochemical and neurologic evidence of vitamin E deficiency. After 2 to 3 years of oral or parenteral vitamin E therapy, there was no improvement in fecal fat losses, severity of vitamin E malabsorption (as measured by an oral vitamin E tolerance test) or total serum fatty acid concentrations. Serial analyses of liver function blood tests demonstrated a marked decline in fasting serum cholylglycine concentrations during 18 to 31 months of vitamin E therapy, while other liver function tests showed no consistent changes. We conclude that vitamin E deficiency does not appear to alter intestinal absorption of fat or vitamin E; however, vitamin E deficiency may further impair already compromised hepatic function during pathologic conditions such as cholestasis.

Child↗
PubMedDate not supplied

Reye's syndrome: current concepts.

Despite greater than 23 years of study, an incomplete understanding of the etiology, epidemiology and pathogenesis of Reye's syndrome persists. Better understanding of the disease has been hampered by the lack of a good animal model on which hypotheses of its pathogenesis could be tested. Human studies indicate that a primary mitochondrial injury may lead to complex metabolic disturbances that produce the observed pathophysiology. Specific directions regarding avenues for future research should pursue two lines: a good animal model still needs to be developed in which the biochemical and morphologic alterations identified in Reye's syndrome are duplicated. This model should include an antecedent viral illness but may not require aspirin exposure as an essential ingredient. With the identification of a satisfactory model, specific questions about the roles of environmental toxins or medications may be answered. Study of noncomatose cases of Reye's syndrome should continue. The specific emphasis should be to delineate what factors (NH3, free fatty acids and dicarboxylic acids) may be implicated in the pathogenesis of the CNS disease with the hopes of devising strategies for more effective treatment of encephalopathy and its attendant morbidity and mortality.

Adolescent↗