ORIGIN OF BILE CHOLESTEROL: EVIDl?NCEFOR RAPID EQUILIBRATION OF DIVERSE HEPATIC POOLS. S.J. Robins, R. Leduc, J.M. Fasulo, and G.M. Patton. Dept. Medicine, Boston Univ. and Boston VA Medical Center, Boston, MA. Biliary cholesterol derives predominantly from preformed hepatic cholesterbl stores. It bas been suggested that within the liver there is a metabolically active pool of unesterified cholesterol (UC) from which biliary cholesterol is generated (J.Clin.Invest. 76:1773. 1985). Studies were undertsken to determine if already existent hepatic UC (which is in equilibrium with al1 of plasma UC)and hepatic UC which is generated from the hydrolysis of hepatic cholesteryl esters (CE) are equally available for secretion into bile or constitute metabolically separate pools of UC. Rats with bile fistula were in cted with an iv bolus of HDLrecombinants containing [1$C]UC and [%i]CE. Plasma, liver, and bile samples were sequentially obtained for 2 h. Different degrees of radiolabeling of the liver with [14C]UC were achived by incorporating into recombinants different lecithin species which resulted in different rates of UC exchange between recombinants and liver. Results showed oier a 10-fo d range of radiolabeling with [14C]UC, that bile [l4C]UC secretion was constant and linear proportion of the whole liver [16C]UC pool; that the secretion of bile [3H]UC was in direct proportion to the rate of hydrolysis of hepatic [3H]CE; when biliary cholesterol secretion as calculated C]UC and [3H]UC using the specific activities of [11; in the whole liver to determine the size of the biliary precursor UC pool, that the rate of secretion Was essentially the same (453.4+79.2(SE) and 44O.y+81.2 nmol/h, respectively); and that cholesterol secretion, calculated using either isotope, was virtually identical to the mass of UC directly measured in bile (443.y+77.6 nmol/h). These results indicate that irrespective of its origins, the totality of preformed UC is in metabolic equilibrium in the liver. Thus, rather than a special "biliary" pool of hepatic UC, it would appear that al1 hepatic UC exists in one single kinetic pool and that al1 hepatic UC is potentially available for secretion into bile.
IMPR(lVED GROWTH IN CHILDREN FOLLOWING ORTHOTOPIC LIVER JV Spolidoro, E Pehlivanoglu, WE TRANSPLANTATION (OLT). University of Berquist, JH Vargas, R Busuttil, ME Ament. California, Los Ange.les, CA. Failure to gain weight and grow normally is characteristic of most patients with end stage liver disease. We assessed height, weight, height velocity and weight/height ratio before and periodically after OLT to determine the effect of the procedure and of the steroids on growth of these pts. 46 pts had OLT performed between 2/84 and l/B7. Data was analyzed on 29 pts who had the mean post bperative End stage liver period of 15.2 mo (range 5 to 31 mo). disease was secondary to biliary atresia in 15, alpha-lantitrypsin deficiency in 5. familial cirrhosis in 2, idiopathic cirrhosis ih 2, fulminant hepatitis in 2, The mean chronic active hepatitis in 1, and tumor in 2. age was 5 yrs, and the median age was 3 yrs. There were 17 Al1 received cyclosporin A and prednisone; 10 females. Predniione dosage was als0 received azqthioprine. gradually reduced from 20 mg/day to ideally below 0.5 mg/kg/day, to mlnimize the growth suppressing effect of 83% had height velocity above the corticosteroids. expected for age, and 12 of these increased percentile of 79% had weight acceleration. Only 1 pt height for age. had a growth deceleration: she is receiving 10 mg/day of 5 pts have height velocity prednisohe (0.68 mglkglday). Two of these are receiving more below the normal for age. than 0.5 mg/kg/day of prednisone and have chronic rejec86% of pts have an increased weight/height ratio; 2 tion. Al1 pts maintained the same ratio, and in 1 it decreased. with chronic liver disease had low albumin prior to. OLT; afterwards. it was normal in all. CONCLUSIONS: (1) OLT allows pts with failure to thrive secondary to end stage liver disease to accelerate growth;(2) ldw dose prednisone (0.5 mglkglday or less) as one of the imnunosuppressive drugs did not suppress growth.
Vol. 92. No. 6
cRAI~GIRGPBBSSUBB-FLOU RRLATIOWSHIPS &ROSS TliRBILIARY ~PIT?IRLI~R~ 111RRSPORSB TO PILIARY OBSTRUCTIOU IR TUR RAT. BOSS R.J. Stlmpson, Steven E. Rapet, Carlos A. Pellerrini, Lawrenca w. uey. Surgical Service, VA lledicalCenter and Departmemt of Surgery, Univ of California, SF, 4150 Clement St. (112). San Fráncisco, CA 94121. Bile duet obstruation leed6 to structural change6 in the canalicular tight junctions, which may altér the reflux of bile toxins responsible for clinical chqlangitis. To detecmine the relationship of these changes to resistance (R) to flow across the biliary epithelium, we studied 16 rats, before (Day 0). and up to 14 days after bile duet obstruction. Using isoflurane anesthesia, a PR 50 poly ethylene catheter was secured in the cossnonduet and the catheter was occluded, completely obstructing bile flow. On the day of the study, restlng preesure (Po) was detennined; then, salina Was infused into the bile duet at various flox rates (F) to elavate ductal pressure (P) by increments to an absolute of 35 cm H20. Because there was no flow at Po, Po equalled dounstream pressure. Flow occurred at pressures above Po, 80 P-Po equalled the driving pressure, and at steady state conditions (P-Po)/F was proportionate to R. Two rats were studied on each day and were then sacrificed. The relationship of P to F was best represented by a straight lina (p<.OOl), 80 R could be calculated as the slape (AP/AF). The Y intercepts of the P-F lines were not significantly different from the resting pressures. The results were: 1 DAY OF STUDY 0 2 4 8 14 15.1 20.3* PR(cmli20) 23.5* 22.8* 22.8* 27.5* kl.0 fl.4 0.7 0.4 kl.1 kl.4 R(cm H20/ 70.6 69.0 67.9 mllmin 61.3 67.1 63.7 +7.2 27.0 -5.4 +14 0 24.4 +11.5 * Denotes SiRnificant differente (P < .OOl) from Day 0. These data show that:(l) Po increases bv 30% within the first 24 hours after bile duet obstruction and continues to increase at a sloper rate thereafter; and (21 R remains unchanged as Po (the dounstream pressure in the resistance equation) increases. Therefore, a higher absolute pressure is required to cause reflux from the bile duet in the presenca of chronic obstruction, but this is the result of highcr outflow pressures,_pc& increased resmce.
TREATMENT OF CLINICAL SELENIUM DEFICIENCY IN PATIENTS ON LONGTERM TOTAL PARENTERAL NUTRITION (TPN). NE Vinton, KA Oahlstrom, CT Strobel. ME Ament. UCLA Medical Center, Los Angeles, CA and East Tennesee Children's Hospital, Knoxville, TN. We previously reported a new syndrome associated with and erythrocyte macroctyosis selenium deficiency 34:139A). We now routinely add pseudo-albinism (Clin Res selenium to our TPN solutions for both C and adults (A). Since then, darkening of hair color has been seen in 5C and 2A, correction of macrocytosis as measured by changes in MCV in 3C and 5A, decreases in elevated liver transaminases (2C, 1A) or CPK (2C, IA), improvement in muscle strength (lC, lA), and strengthening of nails (2C). Of our longterm TPN patients (17C, 42A), these findings have been observed in 6C and 7A on TPN 1-7 years. Before After -3Zl7-lm (0% Selenium - serum (ng/mL) + 3 0.34kO.23 1.02fl.34 <0.025 - hair (p/g) < 0.05 8 109flO MCV (fL) 92f8 < 0.05 4 132&41 60t17 SGOT (U/L) 4 < 0.05 lolt18 44&22 SGPT (U/L) 0.08 4 82t24 56&13 CPK (U/L) Deficiency states were repleted with intravenous selenious acid at 2 pg/kg/d for C and 100 ug/d for A, returning most doses in TPN serum levels to normal. With maintenance solutions (0.5-1 pg/kg/d for C, 40 pg/d for A), serum levels fel1 below normal in many patients, even after 6-12 months of repletion therapy. In one C, a dose of 3.5 ug/kg/d for 6 weeks resulted in a toxic leve1 of 335 1) the need for selenium ug/dL. These data indicate: repletion in longterm TPN patients for prolonged periods and 2) the dosage range is critically narrow requiring careful monitoring.