It has long been recognized that certain ordinarily salutary drugs may produce an acute hemolytic anemia in some susceptible individuals. The 8-aminoquinoline antimalarial, pamaquine (plasmoquine), was such a medication. It was the investigation of the hemolytic effect of pamaquine and its derivatives which led to the recognition that hereditary red cell enzyme deficiencies could produce hemolytic disease.

Glucose-6-phosphate dehydrogenase deficiency.

This article is adapted from a published evidence report concerning neonatal hyperbilirubinemia with an added section on the risk of blood exchange transfusion (BET). Based on a summary of multiple case reports that spanned more than 30 years, we conclude that kernicterus, although infrequent, has at least 10% mortality and at least 70% long-term morbidity. It is evident that the preponderance of kernicterus cases occurred in infants with a bilirubin level higher than 20 mg/dL. Given the diversity of conclusions on the relationship between peak bilirubin levels and behavioral and neurodevelopmental outcomes, it is apparent that the use of a single total serum bilirubin level to predict long-term outcomes is inadequate and will lead to conflicting results. Evidence for efficacy of treatments for neonatal hyperbilirubinemia was limited. Overall, the 4 qualifying studies showed that phototherapy had an absolute risk-reduction rate of 10% to 17% for prevention of serum bilirubin levels higher than 20 mg/dL in healthy infants with jaundice. There is no evidence to suggest that phototherapy for neonatal hyperbilirubinemia has any long-term adverse neurodevelopmental effects. Transcutaneous measurements of bilirubin have a linear correlation to total serum bilirubin and may be useful as screening devices to detect clinically significant jaundice and decrease the need for serum bilirubin determinations. Based on our review of the risks associated with BETs from 15 studies consisting mainly of infants born before 1970, we conclude that the mortality within 6 hours of BET ranged from 3 per 1000 to 4 per 1000 exchanged infants who were term and without serious hemolytic diseases. Regardless of the definitions and rates of BET-associated morbidity and the various pre-exchange clinical states of the exchanged infants, in many cases the morbidity was minor (eg, postexchange anemia). Based on the results from the most recent study to report BET morbidity, the overall risk of permanent sequelae in 25 sick infants who survived BET was from 5% to 10%.

American academy of pediatrics subcommittee on hyperbilirubinemia. an evidence-based review of important issues concerning neonatal hyperbilirubinemia

https://pediatrics.aappublications.org/content/pediatrics/114/1/e130.full.pdf

An evidence-based review of important issues concerning neonatal hyperbilirubinemia.

Zinc protoporphyrin (ZnPP) is a normal metabolite that is formed in trace amounts during heme biosynthesis. The final reaction in the biosynthetic pathway of heme is the chelation of iron with protoporphyrin. During periods of iron insufficiency or impaired iron utilization, zinc becomes an alternative metal substrate for ferrochelatase, leading to increased ZnPP formation. Evidence suggests that this metal substitution is one of the first biochemical responses to iron depletion, causing increased ZnPP to appear in circulating erythrocytes. Because this zinc-for-iron substitution occurs predominantly within the bone marrow, the ZnPP/heme ratio in erythrocytes reflects iron status in the bone marrow. In addition, ZnPP may regulate heme catabolism through competitive inhibition of heme oxygenase, the rate-limiting enzyme in the heme degradation pathway that produces bilirubin and carbon monoxide. Physiological roles, especially relating to carbon monoxide and possibly nitric oxide production, have been suggested for ZnPP. Clinically, ZnPP quantification is valuable as a sensitive and specific tool for evaluating iron nutrition and metabolism. Diagnostic determinations are applicable in a variety of clinical settings, including pediatrics, obstetrics, and blood banking. ZnPP analytical methodologies for clinical studies are discussed. In addition to diagnostic tests and metabolic studies, ZnPP has a potential therapeutic application in controlling bilirubin formation in neonates as a preventive measure for hyperbilirubinemia. Biochemical research techniques, both in vivo and in vitro, are described for further studies into the role of ZnPP in metabolism and physiology.

Zinc protoporphyrin: A metabolite with a mission.

G6PD: Population genetics and clinical manifestations

Hyperbilirubinemia among glucose-6-phosphate dehydrogenase-deficient infants in Singapore is a common and serious problem. Sixty-nine G-6-PD-deficient newborns were studied throughout the neonatal period. A total of seven infants (10%) required exchange transfusions or developed kernicterus. Kernicterus occurred in two infants. The incidence of similarly severe hyperbilirubinemia in G-6-PD-normal newborns of Singapore is probably less than 0.3%. Hyperbilirubinemia in G-6-PD-deficient Chinese infants appears to result from slightly excessive hemolysis superimposed upon a moderately severe hyperbilirubinemia of a nonhemolytic type. In the average infant excessive hemolysis contributes relatively little to the total bilirubinemia. Exposure to exogenous agents occasionally may be important. Neonatal hyperbilirubinemia may vary considerably among ethnic groups, and it is suggested that the incidence of severe hyperbilirubinemia in G-6-PD-deficient members of an ethnic group may be influenced by their "baseline" or "physiologic" hyperbilirubinemia. Early-detection of G-6-PD deficiency and close surveillance of affected newborns has substantially reduced the incidence of kernicterus associated with G-6-PD deficiency in Singapore.

Hyperbilirubinemia and kernicterus in glucose-6-phosphate dehydrogenase-deficient infants in singapore

In full-term Chinese, Malay, and Indian infants of Singapore neonatal hyperbilirubinemia generally is more severe and of longer duration than in Singapore-born British infants. The ethnic group differences in neonatal bilirubin levels might be the expression of previously unrecognized genetic differences in bilirubin metabolism, although the importance of some environmental factors is not completely understood. The ordinary definitions of "physiologic" jaundice, which have evolved principally from observations in Western countries, are not appropriate to Singapore-born Asian infants and may not be appropriate to infants in many parts of the world. Further geographic studies of neonatal bilirubinemia are indicated.

Wong Hock Boon

Papers

Hyperbilirubinemia and kernicterus in glucose-6-phosphate dehydrogenase-deficient infants in singapore

Ethnic group differences in plasma bilirubin levels of full-term, healthy singapore newborns