Andrew Sass-Kortsak

The State of Copper in Human Serum: Evidence for an Amino Acid-bound Fraction *

In addition to copper bound to ceruloplasmin and to albumin, there is a third small fraction of copper in human serum that is bound to amino acids. The amino acid-bound fraction of copper is in equilibrium with albumin-bound copper, and both fractions are probably in equilibrium with ionic copper. Of the 23 amino acids that are known to be in human serum, a substantial number were shown (in physiological concentrations) to compete effectively with albumin for the binding of copper. In this respect, histidine had the most marked effect followed by glutamine, threonine, cystine, and others. The effect of the combined presence of 23 amino acids on the state of copper in human serum could not be explained on the basis of their individual abilities to compete with albumin for the binding of copper. It is suggested that copper may also be present in serum in the form of mixed amino acid-copper complexes consisting of one atom of copper and two different amino acids. Under normal conditions, histidine is the amino acid primarily involved in the formation of mixed amino acid-copper complexes in serum. In combination with histidine and copper, threonine, glutamine, and asparagine are the other amino acids that are most likely to be the third members of these mixed complexes. The first binding site for copper on human albumin is different from subsequent ones in that its binding affinity to copper is much higher. We propose that the amino acid-bound fraction of copper in serum may have a physiological role in the biological transport of copper.

Jaundice associated with severe bacterial infection in young infants.

The study is based on observations made on 24 young infants who developed jaundice in the course of a proved bacterial infection. Enteric bacilli, E. coli in particular, were the most frequently encountered etiological agents. Urinary infection occurred commonly. The sudden onset of jaundice and an elevated white blood count should make one suspicious of an infection. Bacterial cultures will establish the diagnosis. Treatment with an appropriate antibiotic results in rapid improvement of the jaundice. The theory is advanced that a hemolytic process leading to anemia and a retention type of jaundice is present initially. This is followed by toxic liver damage resulting in a regurgitation type of jaundice in most of these patients.

Persistent jaundice in infancy

I have collected the opinions of a number of pediatricians and pediatric pathologists regarding the causes of persistent jaundice during infancy. Most would discard the term “inspissated bile syndrome”, but there is less unanimity regarding the meaning of “neonatal hepatitis”, the significance of giant cells in the liver, and the value of needle biopsies. The many causes of infantile jaundice are mentioned, and hepatic physiology during the neonatal period is discussed. Finally, a program is outlined for the study of the infant with persistent jaundice. The value of the determination of the excretion of radioactive rose bengal in differentiating complete biliary atresia from other causes of jaundice is emphasized.

Liver disease associated with alpha1-antitrypsin deficiency in childhood

Liver disease in children with alpha1-antitrypsin deficiency and protease inhibitor type ZZ does not necessarily carry a bad prognosis. Fourteen of our 18 patients presented with the neonatal hepatitis syndrome and four had hepatomegaly without jaundice. Although four patients have died of cirrhosis and its complications, and three have severe liver disease, most of the 11 others, of whom four are over 13 years of age, have relatively little clinical, biochemical, or histologic evidence of liver disease. Persistent elevation of SGOT during the third year of life and renal or pulmonary problems were associated with a poor prognosis. Liver biopsy early in the course of the disease was not helpful prognostically but was useful in assessment of the severity of liver disease and demonstration of alpha1AT storage, alpha1AT deficiency was found in 29% of our patients who presented with the neonatal hepatitis syndrome. One of seven apparently healthy Pi type ZZ sibs of our patients had significant liver disease which had not been suspected previously.

The Influence of Amino Acids on Copper Uptake by Rat Liver Slices

Addition of physiological concentrations of 20 l-amino acids to the incubation medium facilitates the uptake of copper by liver slices. This effect can be observed in a wide range of initial concentrations of copper in the medium, including the low physiological concentrations. The uptake of copper was not influenced by the addition of sodium lactate or d-glucose to the incubation media. The facilitation of copper uptake by amino acids is abolished under anaerobic conditions. It is not affected by the presence of 2,4-dinitrophenol. The type of transport and its exact mechanism have not been established, but this type of transport does not fulfill the criteria for classification as simple diffusion.

Biochemical and genetic studies in cystinuria: observations on double heterozygotes of genotype I/II

10 families with cystinuria were investigated by measuring: (a) quantitative 24 hr urinary excretion of amino acids by column chromatography; (b) endogenous renal clearances of amino acids and creatinine; (c) intestinal uptake of (34)C-labeled L-cystine, L-lysine, and L-arginine using jejunal mucosal biopsies; (d) oral cystine loading tests. All four of these were studied in the probands and the first two in a large number of the family members.49 members of 8 families were found to have a regular genetic pattern as described previously by Harris, Rosenberg, and their coworkers. Clinical or biochemical differences between the homozygotes type I (recessive cystinuria) and homozygotes type II (incompletely recessive cystinuria) have not been found. Both types excreted similarly excessive amounts of cystine, lysine, arginine, and ornithine, and had high endogenous renal clearances for these four amino acids. Some homozygotes of both types had a cystine clearance higher than the glomerular filtration rate. Jejunal mucosa from both types of homozygotes exhibited near complete inability to concentrate cystine and lysine in vitro. This was also documented in vivo with oral cystine loads. The heterozygotes type I were phenotypically normal with respect to the above four measurements. The heterozygotes type II showed moderate but definite abnormalities in their urinary excretion and their renal clearances of dibasic amino acids. Of the four amino acids concerned, cystine was the most reliable marker to differentiate between the heterozygotes type II and the homozygous normals. In this study, type III cystinuria, as described by Rosenberg, was not encountered. In two additional families, double heterozygotes of genotype I/II were found. The disease affecting these is clinically and biochemically less severe than that affecting homozygotes of either type I or type II. With respect to the four parameters used in this study, the double heterozygotes type I/II have results which are intermediate between those of the homozygotes type I and II and those of the heterozygotes type II.

Wilson's disease. A treatable liver disease in children.

The clinician is reminded of when Wilson’s disease should be suspected in children and how to treat the patient after diagnosis is made. Attention is concentrated on the hepatic diseases with which Wilson’s disease presents most frequently in the pediatric age group.