Carol B. Hyman

THE PRESENT STATUS OF THE HETEROGENEITY OF FETAL HEMOGLOBIN IN β‐THALASSEMIA: AN ATTEMPT TO UNIFY SOME OBSERVATIONS IN THALASSEMIA AND RELATED CONDITIONS*

t Laboratory o f Protein Chemistry, Department of Cell and Molecular Biology, Medical College of Georgia and Veterans Administration Hospital Augusta, Georgia 30902

Carbohydrate Metabolism and Pancreatic Islet-cell Function in Thalassemia Major

Division of Chetnistry and Chemical Engineering,

dl‐α‐TOCOPHEROL, IRON, AND LIPOFUSCIN IN THALASSEMIA*

California Institute of Technology Pasadena, California 91 109 5 Department of Physiology and Biochemistry, Faculty o f Agriculture Department of Pediatrics, Faculty of Medicine University of Skopje Skopje, Yugoslavia Childrens Hospital of Los Angeles and Department of Pediatrics School of Medicine, University of Southern California Los Angeles. California 90027 * * Department of Hematology, Hadassah Medical School Hadassah University Hospital, Hebrew University Jerusalem, Israel

An Unusual Hemoglobin Anomaly and Its Relation to α-Thalassemia and Hemoglobin-H Disease

To investigate the development of diabetes mellitus in patients with thalassemia major, plasma glucose and immunoreactive insulin (IRI) levels following oral glucose and intravenous tolbutamide and glucose disappearance rates following intravenous insulin were measured in 10 patients before and during five years on a high transfusion program (HTP). Plasma immunoreactive glucagon (IRG) levels following oral glucose, intravenous insulin, and arginine were measured during the sixth year. Serial percutaneous liver biopsies were performed on seven patients. The oral glucose tolerance tests (OGTT) and mean peak IRI levels were normal in nine of 10 patients before HTP. After HTP was begun a progressive deterioration of OGTT occurred despite normal IRI levels. Following tolbutamide, the mean per cent fall in plasma glucose in the patients before HTP was significantly less than in controls (p < 0.01) and similar to that of controls during five years of HTP in spite of higher than normal peak IRI levels. Of seven survivors after six years of HTP, three had normal OGTT and four had chemical diabetes; mean peak IRI levels were normal, but fasting IRG levels were significantly higher than in controls (p < 0.05). In all seven patients, plasma IRG failed to increase following insulin-induced hypoglycemia and was significantly higher than in controls after arginine (p < 0.01); after oral glucose, plasma IRG fell significantly below that of fasting only in the patients with chemical diabetes (p < 0.03). Following intravenous insulin, the mean per cent fall in glucose before and during HTP was significantly less than in controls (p < 0.01). Hemosiderosis and cirrhosis were present in all biopsied patients. Four patients died; two had chemical and two had nonketotic insulin-dependent diabetes. These data suggest that diabetes mellitus occurs frequently in patients with thalassemia on HTP and that insulin resistance and hyperglucagonemia, possibly due to cirrhosis, are important etiologic factors.

ENDOCRINE FUNCTION IN THALASSEMIA

Extract: The fetal hemoglobin of 10 infants has been examined serially from birth to several hundred days of age. In the normal child, the ratio of Gγ to Aγ chain alters from about 7:3 at birth to about 2:3 at 150–200 days. In children with abnormalities of hemoglobin synthesis, the ratio changes as expected from data from adults with the particular abnormality. Thus, little change in ratio was shown by two β-thalassemia homozygotes, whereas two β-thalassemia heterozygotes showed the same behavior as a normal child; the latter behavior is expected from one of the two classes of β-thalassemia heterozygotes. A heterozygote from the GγAγ class of hereditary persistence of fetal hemoglobin behaved much like a normal child, but two heterozygotes from the Gγ class showed the expected change from approximately 9:1 at birth to 10:0 postnatally. Two children with sickle cell anemia resembled a normal child in change of ratio whereas the third, not unexpectedly, did not show a change in ratio.Speculation: The mechanisms involved in the gradual change from γ chain synthesis to β and δ chain synthesis are complex and ill defined. The results of analyses of the ratio between the products of the Gγ and Aγ structural genes in infants with distinct genetic disorders at birth and during the postnatal period underscore the complexity of the changeover. However, differences in the postnatal change in the Gγ to Aγ ratio in infants with an apparent identical condition may help to further define these mechanisms, and to delineate the conditions involved.

The clinical significance of magnesium depletion in thalassemia.

In 1969 we started a multidisciplined longitudinal study of the physiologic effects of preventing intertransfusion anemia in 1 3 patients with @-thalassemia major in whom the pretransfusion hemoglobin level was increased from approximately <7 g % to > 11 g %. The protocol included annual biopsies of skin, liver, thyroid, and testes to determine whether there was acceleration of iron deposition or other pathologic changes in these tissues. The biopsy material was examined with a variety of stains, including Sudan Black, and was also examined for autofluorescence. In this way, the observation was made by one of us (B.L.) that lipofuscin was present in abnormal amounts in many of the specimens. The distribution of the lipofuscin deposits, including presence in the smooth muscle of small blood vessels as well as in epithelial and reticuloendothelial cells, resembles that seen in vitamin E deficiency.’ This is a preliminary report of a study designed to determine whether these patients are deficient in vitamin E, and to evaluate the effects, if any, on their tissues of chronic administration of vitamin E in pharmacologic doses.

An individual with “Miyada”-like hemoglobin indistinguishable from hemoglobin A2

Abstract A Chinese family with hemoglobin H in the propositus has been reinvestigated. Although the original propositus is now deceased, a sister has the same hematological manifestations. Her hemoglobin, like that of the deceased sister, contains hemoglobins A, H, and Barts. In addition, however, two minor components have been detected. These minor components appear to have abnormal α-chains and are also present in the maternal grandmother, the mother, a maternal aunt, and three other siblings but only in about one-tenth the amount. One of the minor components may be the same as Hb-Thai (25). The father has the characteristics of classical α-thalassemia. These results are discussed in relation to current concepts of α-thalassemia as they relate to “silent” and “classical” α-thalassemia and to possible multiple α-chain loci.

Gas exchange during exercise in children with thalassemia major and Diamond-Blackfan anemia.

Endocrine function was evaluated in 16 patients 5-28 yrs old on high transfusion therapy for 1-7 yrs. Growth hormone responses to insulin-induced hypoglycemia (ITT) and/or arginine were normal in 13/14. Serum TSH ranged from <1.7-8.2 μU/ml (normal <5); Adj T4 (RIA) was low in one and normal in the others; T3 (RIA) was elevated in 2 and normal in 8/10. Morning ACTH ranged from 21-118 pg/ml (normal 15-100) and cortisol (F) from 7.2-27.8 ug/dl. Peak F level after ITT and Cosyntropin (0.25 mg i.m) were normal (> 18 μg/dl) in 8/13 and 16/16 respectively. Urinary 17 ketogenic steroids after Metyrapone were normal in 10/13. In 5 patients puberty occurred between 16-20 yrs; 1/5 developed secondary hypogonadism (LH and FSH < 2.0 mIU/ml, testosterone 50 ng/dl). In 5 patients, 18-26 yrs old with bone age > 14, LH and FSH were < 2.0 mIU/ml; 2/5 had a normal rise in gonadal steroids following human chorionic gonadotropin (1000 U × 10). Parathyroid hormone (PTH) ranged from 29-89 μlEq/ml, calcium and phosphorus from 8-10 and 2.8-5.6 mg/dl respectively. One patient had hypocalcemia and required vit D (PTH not measured). Glucose tolerance (OGTT) was normal in 6 patients and abnormal in 9. Of those with abnormal OGTT 4 developed insulin-dependent diabetes.The data suggest that patients with thalassemia have: 1) pituitary/vs hypothalamic dysfunction with gonadotropin deficiency and possibly reduced ACTH reserve 2) primary gonadal failure and 3) increased incidence of chemical and insulin-dependent diabetes.

Induction of remission in acute leukemia with prednisone and intravenous methotrexate

(1) Mg depletion in a population of 14 patients with thalassemia was documented by low serum Mg levels, abnormal Mg tolerance tests, and/or symptoms responsive to Mg therapy. (2) The observation that some degree of Mg depletion was present even in younger asymptomatic patients needs further investigation and suggests that monitoring of Mg status should be included in the routine care of patients with thalassemia. (3) Careful consideration should be given to the possibility that in patients with thalassemia early continuous supplementation with Mg is needed and may have a beneficial influence on the hearts response to chronic Fe overload and chronic hypoxemia.