THYROID Volume 2, Number Mary Ann Liebert,
2, 1992 Inc., Publishers
Commentary Fetal and Neonatal
Hyperthyroidism
INDER J. CHOPRA
NEONATAL offspring occurring typically (AITD),
Human TSH receptor responds to TSH (and by inference to TSI) by about 20-25 weeks of gestation. Fetal serum IgG concentration is low (~5%—8% that of maternal serum) at 15
adenylate cyclase-stimulating activity, a receptor-blocking activity, and a TSH-binding enhancing activity (10). The TSH receptor-stimulating activity of a particular serum apparently is a function of relative affinity and concentration of these various IgG-associated activities. A difference in the relative concentration of various activities in serum has been considered to explain the observed difference in the thyroid-stimulating activity in the mother and the fetus (11). These issues, infrequent occurrence of neonatal hyperthyroidism, and the high cost (—$150-200) of TSI measurement are some factors that argue against the use of routine (or repeated) measurements of TSI in pregnant women, even in those mothers with AITD concurrently or in the past.
weeks of gestation, but by 30 weeks of gestation it increases to values comparable to those in the mother (11). This explains why fetal hyperthyroidism occurs some time in the second half of pregnancy. Its occurrence may, however, be delayed to the postnatal period if the mother is taking thionamide drugs, which cross the placenta readily. As opposed to thionamides, thyroid hormones (T4 and T3) and TSH cross the placenta poorly. The occurrence of hyperthyroidism in the fetus also could be delayed if the TSH receptor blocking activity of maternal IgG were able to block the effect of maternal TSI. Clinical features of fetal and neonatal hyperthyroidism include tachycardia (heart rate > 160/min), goiter, growth retardation, arrhythmias, congestive heart failure, enhancement of bone age, craniostenosis, mental retardation, premature delivery, irritability, and death. Exophthalmos, failure to thrive, hepatosplenomegaly, jaundice, and thrombocytopenia are other features detected in the neonate. The mortality rate is approximately 20% (12-15). The duration of the disorder has been related to the metabolic clearance of maternal IgG with TSI activity from the serum of the neonate. It was less than 48 weeks in about 70% of the patients. A longer duration of the disease in the remaining 30% has been related to the syndrome of congenital Graves' disease in the newborn rather than to transplacental passage of TSIs from the mother to the fetus (12). The diagnosis of neonatal hyperthyroidism can be made by finding elevated serum total and free thyroxine (T4) and 3,5,3'triiodothyronine (T3) levels and suppressed serum TSH levels (16). The diagnosis of fetal hyperthyroidism may be suspected on the basis of history of AITD in the mother, fetal tachycardia, sonographic evidence of fetal goiter, and enhancement of bone age (1-4). Thyroid hormone (or TSH) measurement in amniotic fluid is not reliable in estimating fetal thyroid status (17). Recently, cordocentesis has been used to diagnose thyroid dysfunction in the fetus (18-21). Demonstration of elevated
HYPERTHYROIDISM IS AN UNCOMMON DISORDER
of patients with autoimmune thyroid disease Graves' disease, or chronic (Hashimoto's) thyroiditis. The mother herself may be hyperthyroid, euthyroid, or hypothyroid. The prevalence of Graves' disease in pregnant women is approximately 0.2% (1-3). The frequency of neonatal hyperthyroidism in the offspring of women with Graves' disease has been estimated to be about 1 % (4). These data suggest that the prevalence of neonatal hyperthyroidism approximates 1/50,000 pregnancies. As clearly described by McKenzie and Zakarija, fetal (and neonatal) hyperthyroidism is a result of transplacental passage of thyroid-stimulating immunoglobulins (TSIs) from the mother to the fetus (5,6). It occurs in the offspring of mothers with an especially high titerof TSI. However, the definition of this high titer is unclear. The methods of measurement of TSI have changed markedly over the years from those using animal (mouse) thyroids (6,7) to human thyroid slices (8) to those currently available commercially that employ human or rat thyroid cells in culture (9). Few data are available with the currently popular TSI assay concerning a level of TSI in maternal serum that is predictive of intrauterine or neonatal hyperthyroidism. Furthermore, sera of several patients with autoimmune thyroid disease demonstrates a variety of activities at the level of TSH receptor, including (but not limited to) an in the
Department of Medicine,
UCLA Center for Health Sciences. Los
Angeles, California. 161
162 serum total and free T4 and T3 levels in the fetal blood will confirm the diagnosis. Serum rT3 also is elevated in fetal hyperthyroidism (18,19). Measurement of TSI in the fetal blood would be interesting if sensitive assay techniques were available. Cordocentesis is not without risk. It may be associated with fetal bleeding, bradycardia, infection, and death in about 1% of cases (22,23). As experience with cordocentesis improves, it will be applied more frequently to the diagnosis and management of hyperthyroidism in utero. Treatment of hyperthyroidism in utero requires treatment of the mother with antithyroid drugs. Propylthiouracil (PTU) and methimazole (Tapazole) are used interchangeably in treatment of hyperthyroidism in nonpregnant individuals. However, PTU is preferred over methimazole in pregnant patients because of evidence that treatment with the latter may be associated aplasia cutis in the fetus ( 1 ). The initial dose of PTU in the mother of a hyperthyroid fetus approximates 300 mg/day in divided doses. The maintenance dose of PTU may be as low as 25-50 mg/day. The maternal serum free T4 should be maintained in the high normal range. Funipuncture (cordocentesis) has been used in the follow-up of fetal hyperthyroidism and for adjustment of the dose of PTU (19). Treatment of hyperthyroidism in the neonatal period requires antithyroid drugs (PTU, 5-10 mg/kg/day, or methimazole, 0.5-1.0 mg/kg/day) in divided doses with or without iodide [saturated solution of potassium iodide, 1 drop/day (—48 mg iodine/drop) or Lugol's iodine (1-3 drops/day, —8 mg iodide/ drop] and beta blockers (e.g., propranolol 2 mg/kg/day in divided doses). Glucocorticoids (e.g., prednisone 2 mg/kg/day) may be helpful in some severe cases. Thyroid hormone levels should be monitored at 2-week intervals and TSH levels at 1-month intervals (1-3). Measurement of TSI at 1-2-month intervals may assist in predicting the duration of neonatal
hyperthyroidism (5). Hyperthyroidism of Graves' disease tends to become more severe in the postpartum period, and mothers may require an increase in the dose of antithyroid medication (PTU or methimazole). Questions often raised are whether thionamides are secreted in milk, whether mothers taking thionamides can safely breastfeed their newborns, and whether the dose of thionamide drugs should be adjusted in neonatal hyperthyroidism when the mother is also receiving treatment with
thionamides. Several recent studies have addressed these issues. It is clear that both PTU and methimazole are detected in maternal milk. However, PTU excreted in milk in a 4-h period approximated only 0.025% (or 99 p,g) of a dose of 400 mg administered to the mother (24,25). Such amounts in milk are too low to influence the thyroid status of the neonate, who may require 5-10 mg PTU/kg/day to control hyperthyroidism. Similarly, the amount of methimazole excreted in milk approximated 70 p,g in an 8-h period following administration of 40 mg methimazole to the mother (25,26). This amount of methimazole also is quite low in a neonate who may require 0.5-1.0 mg/kg/day of methimazole for the treatment of hyperthyroidism. In any case, when a nursing mother is receiving thionamides, neonatal thyroid function should be monitored at 2-4-week intervals, and the dose of the antithyroid drug given to the mother (or the neonate when hyperthyroid) should be adjusted appropriately to ensure euthyroid status.
CHOPRA
ACKNOWLEDGMENT This work was from the NIH.
supported in part by USPHS Grant DK-16155
REFERENCES 1. Burrow GN 1988 Thyroid Disease. In: Burrow GN, Ferris TF (eds) Medical Complications During Pregnancy, 3rd ed. WB Saunders, Philadelphia, pp 224-253. 2. Mestman JH 1980 Thyroid and parathyroid diseases in pregnancy. In: Quilligan EJ, Kretchmer N (eds) Fetal and Maternal Medicine John Wiley & Sons, New York, pp 489-531. 3. Fisher DA 1986 Neonatal thyroid disease in the offspring of women with autoimmune thyroid disease. Thyroid Today 9:1-7. 4. Ramsay I, Kaur S, Krassas G 1983 Thyrotoxicosis in pregnancy: Results of treatment by antithyroid drugs combined with T4. Clin Endocrinol 18:73-85. 5. McKenzie JM, Zakarija M 1992 Fetal and neonatal hyper- and hypothyroidism due to maternal TSH receptor antibodies. Thyroid
2:155-159.
SM,
Munro DS 1975 Placental transmission of thyroidBr Med J 2:665-666. 7. McKenzie JM 1964 Neonatal Graves' disease. J Clin Endocrinol Metab 24:660-668. 8. Zakarija M. McKenzie JM 1983 Pregnancy-associated changes in thyroid-stimulating antibody of Graves' disease and the relationship to neonatal hyperthyroidism. J Clin Endocrinol Metab 6. Dirmikis
stimulating immunoglobulin.
57:1036-1040.
9.
Rapoport B, Filetti, Takai N, Seto P, Halverson G 1982 Studies on cyclic AMP response to thyroid-stimulating immunoglobulin (TSI) and thyrotropin (TSH) in human thyroid monolayers. Metabthe
10.
11.
12.
13.
14.
15. 16.
17.
18.
19.
olism 31:1159-1167. McKenzie JM 1985 Studies on multiple thyroid cell membrane-directed antibodies in Graves' disease. J Clin Invest 76:1885-1891. Bernales R, Bellanti X 1980 Fetal and neonatal immunology. In: Quilligan EJ. Kretchmer N (eds) Fetal and Maternal Medicine. John Wiley & Sons, New York, pp 267-314. Hollingsworth DR, Mabry CC 1976 Congenital Graves' disease. Four familial cases with long-term follow-up and perspective. Am J Dis Child 130:148-155. Riggs W, Wilroy RS, Etteldorf JN 1972 Neonatal hyperthyroidism with accelerated skeletal maturation, craniosynostosis and brachydactyly. Radiology 105:621-625. Daneman D. Howard NJ 1980 Neonatal thyrotoxicosis: Intellectual impairment and craniosynostosis in later years. J Pediatr 97:257-259. Kapelman AE 1983 Delayed cerebral development in twins with congenital hyperthyroidism. Am J Dis Child 137:842-845. Smallridge RC, Wartofsky L, Chopra IJ, Marinelli PV, Broughton RO, Dimond RC, Burman KD 1978 Neonatal thyrotoxicosis: Alterations in serum concentrations of LATS protector, T4, T3, reverse T3 and 3,3'-T2. J Pediatr 93:118-120. Hollingsworth DR. Alexander NM 1983 Amniotic fluid concentrations of iodothyronines and thyrotropin do not reliably predict fetal thyroid status in pregnancies complicated by maternal thyroid disorders or anencephaly. J Clin Endocrinol Metab 57:349-355. Wenstrom KD, Weiner CP, Williamson RA, Grant SS 1990 Prenatal diagnosis of fetal hyperthyroidism using funipuncture. Obstet Gynecol 76:513-517. Porreco RP. Block CA 1990 Fetal blood sampling in the management of intrauterine thyrotoxicosis. Obstet Gynecol 76:509-512.
Zakarija M, Jin S,
FETAL AND NEONATAL HYPERTHYROIDISM 20. Perelman AH, Johnson RL, Clemons RD, Fineberg HJ, Clewell WH, Trujillo L 1990 Intrauterine diagnosis and treatment of fetal goitrous hypothyroidism. J Clin Endocrinol Metab 71:618-621. 21. Davidson KM, Richards DS, Schatz DA, Fisher DA 1991 Successful in utero treatment of fetal goiter and hypothyroidism. N Engl J Med 324:543-546. 22. Weiner CP 1988 The role of cordocentesis in fetal diagnosis. Clin Obstet Gynecol 31:285-292. 23. Daffos F 1989 Fetal blood sampling. Annu Rev Med 40:319-329. 24. Kampamnn JP, Hansen JM, Johansen K, Helweg J 1980 Propylthiouracil in human milk, revision of a dogma. Lancet 1:736-737.
163 25. 26.
Cooper DS 1984 Antithyroid drugs. N Engl J Med 311:1353-1362. Cooper DS, Bode HH, Nath B, Saxe V, Maloof F, Ridgway EC 1984 Carbimazole pharmacology in man: Studies using a newly developed radioimmunoassay for methimazole. J Clin Endocrinol Metab 58:473-479.
Address reprint requests to: Inder J. Chopra, M.D. Department of Medicine UCLA Center for Health Sciences Los Angeles, CA 90024
2, 1992 Inc., Publishers
Commentary Fetal and Neonatal
Hyperthyroidism
INDER J. CHOPRA
NEONATAL offspring occurring typically (AITD),
Human TSH receptor responds to TSH (and by inference to TSI) by about 20-25 weeks of gestation. Fetal serum IgG concentration is low (~5%—8% that of maternal serum) at 15
adenylate cyclase-stimulating activity, a receptor-blocking activity, and a TSH-binding enhancing activity (10). The TSH receptor-stimulating activity of a particular serum apparently is a function of relative affinity and concentration of these various IgG-associated activities. A difference in the relative concentration of various activities in serum has been considered to explain the observed difference in the thyroid-stimulating activity in the mother and the fetus (11). These issues, infrequent occurrence of neonatal hyperthyroidism, and the high cost (—$150-200) of TSI measurement are some factors that argue against the use of routine (or repeated) measurements of TSI in pregnant women, even in those mothers with AITD concurrently or in the past.
weeks of gestation, but by 30 weeks of gestation it increases to values comparable to those in the mother (11). This explains why fetal hyperthyroidism occurs some time in the second half of pregnancy. Its occurrence may, however, be delayed to the postnatal period if the mother is taking thionamide drugs, which cross the placenta readily. As opposed to thionamides, thyroid hormones (T4 and T3) and TSH cross the placenta poorly. The occurrence of hyperthyroidism in the fetus also could be delayed if the TSH receptor blocking activity of maternal IgG were able to block the effect of maternal TSI. Clinical features of fetal and neonatal hyperthyroidism include tachycardia (heart rate > 160/min), goiter, growth retardation, arrhythmias, congestive heart failure, enhancement of bone age, craniostenosis, mental retardation, premature delivery, irritability, and death. Exophthalmos, failure to thrive, hepatosplenomegaly, jaundice, and thrombocytopenia are other features detected in the neonate. The mortality rate is approximately 20% (12-15). The duration of the disorder has been related to the metabolic clearance of maternal IgG with TSI activity from the serum of the neonate. It was less than 48 weeks in about 70% of the patients. A longer duration of the disease in the remaining 30% has been related to the syndrome of congenital Graves' disease in the newborn rather than to transplacental passage of TSIs from the mother to the fetus (12). The diagnosis of neonatal hyperthyroidism can be made by finding elevated serum total and free thyroxine (T4) and 3,5,3'triiodothyronine (T3) levels and suppressed serum TSH levels (16). The diagnosis of fetal hyperthyroidism may be suspected on the basis of history of AITD in the mother, fetal tachycardia, sonographic evidence of fetal goiter, and enhancement of bone age (1-4). Thyroid hormone (or TSH) measurement in amniotic fluid is not reliable in estimating fetal thyroid status (17). Recently, cordocentesis has been used to diagnose thyroid dysfunction in the fetus (18-21). Demonstration of elevated
HYPERTHYROIDISM IS AN UNCOMMON DISORDER
of patients with autoimmune thyroid disease Graves' disease, or chronic (Hashimoto's) thyroiditis. The mother herself may be hyperthyroid, euthyroid, or hypothyroid. The prevalence of Graves' disease in pregnant women is approximately 0.2% (1-3). The frequency of neonatal hyperthyroidism in the offspring of women with Graves' disease has been estimated to be about 1 % (4). These data suggest that the prevalence of neonatal hyperthyroidism approximates 1/50,000 pregnancies. As clearly described by McKenzie and Zakarija, fetal (and neonatal) hyperthyroidism is a result of transplacental passage of thyroid-stimulating immunoglobulins (TSIs) from the mother to the fetus (5,6). It occurs in the offspring of mothers with an especially high titerof TSI. However, the definition of this high titer is unclear. The methods of measurement of TSI have changed markedly over the years from those using animal (mouse) thyroids (6,7) to human thyroid slices (8) to those currently available commercially that employ human or rat thyroid cells in culture (9). Few data are available with the currently popular TSI assay concerning a level of TSI in maternal serum that is predictive of intrauterine or neonatal hyperthyroidism. Furthermore, sera of several patients with autoimmune thyroid disease demonstrates a variety of activities at the level of TSH receptor, including (but not limited to) an in the
Department of Medicine,
UCLA Center for Health Sciences. Los
Angeles, California. 161
162 serum total and free T4 and T3 levels in the fetal blood will confirm the diagnosis. Serum rT3 also is elevated in fetal hyperthyroidism (18,19). Measurement of TSI in the fetal blood would be interesting if sensitive assay techniques were available. Cordocentesis is not without risk. It may be associated with fetal bleeding, bradycardia, infection, and death in about 1% of cases (22,23). As experience with cordocentesis improves, it will be applied more frequently to the diagnosis and management of hyperthyroidism in utero. Treatment of hyperthyroidism in utero requires treatment of the mother with antithyroid drugs. Propylthiouracil (PTU) and methimazole (Tapazole) are used interchangeably in treatment of hyperthyroidism in nonpregnant individuals. However, PTU is preferred over methimazole in pregnant patients because of evidence that treatment with the latter may be associated aplasia cutis in the fetus ( 1 ). The initial dose of PTU in the mother of a hyperthyroid fetus approximates 300 mg/day in divided doses. The maintenance dose of PTU may be as low as 25-50 mg/day. The maternal serum free T4 should be maintained in the high normal range. Funipuncture (cordocentesis) has been used in the follow-up of fetal hyperthyroidism and for adjustment of the dose of PTU (19). Treatment of hyperthyroidism in the neonatal period requires antithyroid drugs (PTU, 5-10 mg/kg/day, or methimazole, 0.5-1.0 mg/kg/day) in divided doses with or without iodide [saturated solution of potassium iodide, 1 drop/day (—48 mg iodine/drop) or Lugol's iodine (1-3 drops/day, —8 mg iodide/ drop] and beta blockers (e.g., propranolol 2 mg/kg/day in divided doses). Glucocorticoids (e.g., prednisone 2 mg/kg/day) may be helpful in some severe cases. Thyroid hormone levels should be monitored at 2-week intervals and TSH levels at 1-month intervals (1-3). Measurement of TSI at 1-2-month intervals may assist in predicting the duration of neonatal
hyperthyroidism (5). Hyperthyroidism of Graves' disease tends to become more severe in the postpartum period, and mothers may require an increase in the dose of antithyroid medication (PTU or methimazole). Questions often raised are whether thionamides are secreted in milk, whether mothers taking thionamides can safely breastfeed their newborns, and whether the dose of thionamide drugs should be adjusted in neonatal hyperthyroidism when the mother is also receiving treatment with
thionamides. Several recent studies have addressed these issues. It is clear that both PTU and methimazole are detected in maternal milk. However, PTU excreted in milk in a 4-h period approximated only 0.025% (or 99 p,g) of a dose of 400 mg administered to the mother (24,25). Such amounts in milk are too low to influence the thyroid status of the neonate, who may require 5-10 mg PTU/kg/day to control hyperthyroidism. Similarly, the amount of methimazole excreted in milk approximated 70 p,g in an 8-h period following administration of 40 mg methimazole to the mother (25,26). This amount of methimazole also is quite low in a neonate who may require 0.5-1.0 mg/kg/day of methimazole for the treatment of hyperthyroidism. In any case, when a nursing mother is receiving thionamides, neonatal thyroid function should be monitored at 2-4-week intervals, and the dose of the antithyroid drug given to the mother (or the neonate when hyperthyroid) should be adjusted appropriately to ensure euthyroid status.
CHOPRA
ACKNOWLEDGMENT This work was from the NIH.
supported in part by USPHS Grant DK-16155
REFERENCES 1. Burrow GN 1988 Thyroid Disease. In: Burrow GN, Ferris TF (eds) Medical Complications During Pregnancy, 3rd ed. WB Saunders, Philadelphia, pp 224-253. 2. Mestman JH 1980 Thyroid and parathyroid diseases in pregnancy. In: Quilligan EJ, Kretchmer N (eds) Fetal and Maternal Medicine John Wiley & Sons, New York, pp 489-531. 3. Fisher DA 1986 Neonatal thyroid disease in the offspring of women with autoimmune thyroid disease. Thyroid Today 9:1-7. 4. Ramsay I, Kaur S, Krassas G 1983 Thyrotoxicosis in pregnancy: Results of treatment by antithyroid drugs combined with T4. Clin Endocrinol 18:73-85. 5. McKenzie JM, Zakarija M 1992 Fetal and neonatal hyper- and hypothyroidism due to maternal TSH receptor antibodies. Thyroid
2:155-159.
SM,
Munro DS 1975 Placental transmission of thyroidBr Med J 2:665-666. 7. McKenzie JM 1964 Neonatal Graves' disease. J Clin Endocrinol Metab 24:660-668. 8. Zakarija M. McKenzie JM 1983 Pregnancy-associated changes in thyroid-stimulating antibody of Graves' disease and the relationship to neonatal hyperthyroidism. J Clin Endocrinol Metab 6. Dirmikis
stimulating immunoglobulin.
57:1036-1040.
9.
Rapoport B, Filetti, Takai N, Seto P, Halverson G 1982 Studies on cyclic AMP response to thyroid-stimulating immunoglobulin (TSI) and thyrotropin (TSH) in human thyroid monolayers. Metabthe
10.
11.
12.
13.
14.
15. 16.
17.
18.
19.
olism 31:1159-1167. McKenzie JM 1985 Studies on multiple thyroid cell membrane-directed antibodies in Graves' disease. J Clin Invest 76:1885-1891. Bernales R, Bellanti X 1980 Fetal and neonatal immunology. In: Quilligan EJ. Kretchmer N (eds) Fetal and Maternal Medicine. John Wiley & Sons, New York, pp 267-314. Hollingsworth DR, Mabry CC 1976 Congenital Graves' disease. Four familial cases with long-term follow-up and perspective. Am J Dis Child 130:148-155. Riggs W, Wilroy RS, Etteldorf JN 1972 Neonatal hyperthyroidism with accelerated skeletal maturation, craniosynostosis and brachydactyly. Radiology 105:621-625. Daneman D. Howard NJ 1980 Neonatal thyrotoxicosis: Intellectual impairment and craniosynostosis in later years. J Pediatr 97:257-259. Kapelman AE 1983 Delayed cerebral development in twins with congenital hyperthyroidism. Am J Dis Child 137:842-845. Smallridge RC, Wartofsky L, Chopra IJ, Marinelli PV, Broughton RO, Dimond RC, Burman KD 1978 Neonatal thyrotoxicosis: Alterations in serum concentrations of LATS protector, T4, T3, reverse T3 and 3,3'-T2. J Pediatr 93:118-120. Hollingsworth DR. Alexander NM 1983 Amniotic fluid concentrations of iodothyronines and thyrotropin do not reliably predict fetal thyroid status in pregnancies complicated by maternal thyroid disorders or anencephaly. J Clin Endocrinol Metab 57:349-355. Wenstrom KD, Weiner CP, Williamson RA, Grant SS 1990 Prenatal diagnosis of fetal hyperthyroidism using funipuncture. Obstet Gynecol 76:513-517. Porreco RP. Block CA 1990 Fetal blood sampling in the management of intrauterine thyrotoxicosis. Obstet Gynecol 76:509-512.
Zakarija M, Jin S,
FETAL AND NEONATAL HYPERTHYROIDISM 20. Perelman AH, Johnson RL, Clemons RD, Fineberg HJ, Clewell WH, Trujillo L 1990 Intrauterine diagnosis and treatment of fetal goitrous hypothyroidism. J Clin Endocrinol Metab 71:618-621. 21. Davidson KM, Richards DS, Schatz DA, Fisher DA 1991 Successful in utero treatment of fetal goiter and hypothyroidism. N Engl J Med 324:543-546. 22. Weiner CP 1988 The role of cordocentesis in fetal diagnosis. Clin Obstet Gynecol 31:285-292. 23. Daffos F 1989 Fetal blood sampling. Annu Rev Med 40:319-329. 24. Kampamnn JP, Hansen JM, Johansen K, Helweg J 1980 Propylthiouracil in human milk, revision of a dogma. Lancet 1:736-737.
163 25. 26.
Cooper DS 1984 Antithyroid drugs. N Engl J Med 311:1353-1362. Cooper DS, Bode HH, Nath B, Saxe V, Maloof F, Ridgway EC 1984 Carbimazole pharmacology in man: Studies using a newly developed radioimmunoassay for methimazole. J Clin Endocrinol Metab 58:473-479.
Address reprint requests to: Inder J. Chopra, M.D. Department of Medicine UCLA Center for Health Sciences Los Angeles, CA 90024
