Persistent Hypothyroidism in an Infant Receiving a Soy Formula: Case Report and Review of the Literature

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148 EXPERIENCE AND REASON

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32. Van der Poll T, Levi M, Billler HR. et al. Fibrinolytic response to tumor necrosis factor in healthy subjects. IExp Med. 1991:174:729-732

33. Emeis JJ, Kooistra T. lnterleukin-1 and lipopolysaccheride induce an inhibitor of tissue-type plasminogen activator in vivo and in cultured endothelial cells. I Er/i Med. 1986:163:1268-1266

34. Colluci M, Paramo JA, Collen D. Generation in plasma of a fast acting inhibitor of plasminogen activator in response to endotoxin stimulation.

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Persistent

Hypothyroidism

in

an

Infant

Receiving

a Soy

Formula:

Case

Report

and

Review

of

the

Literature

Soy-induced goiter was a well-known

phenorne-non before 1966, the back date used in many

corn-puterized literature databases.4 In the mid-1960s,

iodine-supplemented infant soy formulas prepared

from isolated soy protein were introduced by

commercial manufacturers.5 Since then, there have

not been any documented cases of soy

formula-associated hypothyroidism.

We present the case of a patient with congenital

hypothyroidism who remained persistently

hypo-thyroid while on a soy formula diet despite large

doses of L-thyroxine (T4). This case made us reaware of the historical data on the effects of soy on thyroid function. It also realerted us to the thoughtful use of formula preparations and close dietary monitoring of hypothyroid infants.

CASE SUMMARY

The patient was a full-term male infant born from

an uncomplicated pregnancy and delivery. Birth

weight was 3.4 kg (75%); length, 54 cm (90%); and

head circumference, 35 cm (50%). He received a soy

formula diet at his parents’ request because of a

family history of intolerance of cow’s milk in the

patient’s older siblings. Poor feeding, hypotonicity,

and continuous sleeping was noted during his first

week. An abnormal newborn screen (done on day 2

of life) was reported on day 8 of life. Serum

confir-mation of primary hypothyroidism was obtained on

day 9 of life (Table).

A physical examination showed a weight of 3.46

kg (75%), a length of 52 cm (75%), and a head

cir-cumference of 36 cm (75%). He had a mild degree of

generalized mottling. His skin was warm to the

touch. There was some wrinkling over his forehead. His anterior fontanelle was 3 X 3 cm, and his

poste-nor fontanelle was 1 X 1 cm. No lingual

protuber-ance was noted on examination of the phayrnx. His

thyroid was not palpable. A grade Il/VI systolic

ejection murmur was heard at the left sternal border.

He had a small umbilical hernia. His genitalia

were those of a healthy male infant, and he seemed

to have good muscle tone.

Bone age was compatible with 34 weeks’ gestation.

A technetium thyroid scan showed evidence of an

ectopic thyroid (lingual) gland. Treatment with L-T4,

0.05 mg (14.5 pg/kg per day), was initiated on day II of life.

One month later, the infant’s thyrotropin (TSH)

level remained markedly elevated (Table).

Compli-Received for publication May 31, 1994; accepted Sep 30, 1994.

Reprint requests to (N.J.H.) Department of Pediatrics, Division of Endocri-nology, University of Michigan, Room D3252, Medical Professional Building, Ann Arbor, MI 48109-0718.

Acad-emy of Pediatrics.

at Viet Nam:AAP Sponsored on September 1, 2020 www.aappublications.org/news

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Age T4 TSH Free 14 TBG T1 Reverse 13 Free 1, Weight L-T4 Dose

(d) (pg/dL) (pU/mL) (ng/dL) (%) (ng/mL) (ng/mL) (pg/mL) (kg) (pg/kg/d)

Soy formula

2 8.4t 201t 3.4

9 8.6 342 26 132 3.4 14.5

39 4.8 98

44 6.9 180 0.7 29

49

Nonsoy formula

57

7.8

9.3

196

58

0.9

0.83

(124+) (40+) (282+)I 5.1

5.8

12.2

10.9

64 21 1.39 200 6.2 12.1

71 11.4 0.8 157 7 8.9

120 0.98 2.1 9 8.3

180 <0.2 1.65 10.8 6.9

270 1.63 1.65 255 12.1 5.6

368 3.62 1.45 13.3 5.7

Infant Norms2#{176} 6.1-14.9 0.5-4.8 0.9-2.6 NA 85-250 10-50 NAIl

* Abbreviations: T3, tniodothyronine; NA, not available for infants; TBG, thyroid-binding globulin.

t Newborn screen (filter paper), state of Michigan.

:1:

(+), Obtained later on stored serum.

§

17-26 for children ages I to 6 years.

II260-480 for adults.

TABLE. Serial Measurements in Our Infant With Congenital Hypothyroidism

EXPERIENCE AND REASON 149

ance and nongenenic L-T4 dosing was confirmed

(Boots/Synthroid). There were no reported episodes

of emesis on spitting up after feeding. He was defe-cating five to seven times per day. He was more alert, hungrier, and less tired after the initiation of L-T4

therapy. However, his thyroid tests continued to

show a lack of TSH suppression. A new prescription

and different pharmacy were recommended to rule

out the possibility of an inactive preparation.

At 49 days of age, TSH remained high. He

weighed 5.1 kg (75%), with a length of 57.1 cm (75%)

and a head circumference of 40 cm (75%). His

pos-tenor fontanelle was closed. His L-T4 dose was

ad-justed for his weight, and he was switched to a cow’s

milk formula. After I week on the cow’s milk

for-mula, he showed significant suppression of TSH

(Table). He was noted to have a decreased stool

frequency of two to three times per day. His thyroid

function continued to normalize over time.

Subse-quent growth and development were normal

with-out a need for increase in his L-T4 dose (expressed as micrograms per kg/d). His skeletal age at 12 months was equivalent to 10 months (average of hands, feet, and knees).

DISCUSSION

In the early part of the 20th century, the goitro-genic effect of a soybean diet was well recognized in

animals.69 Animal soy diets supplemented with

io-dine in amounts double the normal daily

require-ments protected against the development of

goi-ters.911 The goiters in soy-fed rats exhibited high

uptake of iodine 131, similar to the effect of iodine 11

Van Middleworth12’13 elucidated the mechanism

for the development of goiters in animals fed soy

diets. Soy diets are associated with a large fecal mass and an accelerated rate of transport. The high-uptake goiters were caused by an increased iodine require-ment after T4 depletion from increased fecal wastage. Beck14 confirmed Van Middleworth’s12’13 findings and also speculated about the presence of a

goitro-genic factor in soy. Several investigators attempted to characterize this possible goitrogen. Konijin et a115

purified a goitnogenic substance from soybeans

de-scnibed as a glycopeptide. This glycopeptide blocked

iodine uptake by the thyroid and decreased its

or-ganification but had little effect on the formation of tniiodothynonine and T4. There have been no further reports characterizing goitrogenic factors in soy.

Relatively little is known about the effects of a soy

diet on thyroid function in humans. Before 1960,

there were several notable cases of goiters occurring

in infants fed soy formulas, which resolved after

their diets were changed to a cow’s milk

form-ulas.13’16 Similar to the findings in animals, all the

infants demonstrated an increased uptake of 131! by

the thyroid while taking a soy diet. These infants

showed normal uptake when receiving cow’s

milk diets. Stool frequency and bulk were also noted to decrease after this change.

There may be several different mechanisms by

which soybeans induce goiters. Commercial

manu-facturers have reported that different lots of soy vary widely in their goitrogenic properties. In all cases it was possible to overcome the goitrogenic activity of the soy ration by fortifying it with additional

iodine.1”1 Since commercial manufacturers began

supplementing soy formulas with iodine in 1959, no

further cases of soy formula-induced goiters have

been reported.

However, in 1965, an athyreotic cretin fed a

soy-flour formula supplemented with iodine was

described to be refractory to thyroid hormone.17

‘311-labeled T4 was measured in the feces, along with the )31J content in the urine and serum at the time the

patient was receiving the soy formula and later a

cow’s milk formula. Higher fecal 1311 excretion and

lower levels of radioactivity in the urine and serum

were found during soy feeding but not in cow’s milk

feedings. These findings provided evidence that soy

feeding interferes with exogenous T4 absorption

pni-manly by fecal wastage in humans. This is similar to

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150 EXPERIENCE AND REASON

the earlier observations of soy feeding on

endoge-nous T4 in animals.12’13

In the mid-I960s, commercial manufacturers

re-placed the high-fiber soy-flour preparation formulas with a formula prepared from isolated soy protein.5 The isolated soy protein formula is more like a cow’s

milk formula in color and odor. Most of the fiber is

removed during the protein isolation process, and

the stools of infants receiving the isolated soy protein formula were found to be similar to those of infants

fed a cow’s milk formula. This is the preparation of

the soy formula widely used today.

Our patient was found to have congenital

hypo-thyroidism from his neonatal screen, confirmed by

serum values (Table). He continued to have

persis-tent hypothyroidism despite receiving a dose of L-T4

that is usually adequate for infants with congenital

hypothyroidism. His soy formula contained 10.2 pg

of iodide/4200

J)

similar to several other commercial

soy formulas (15 to 20 pg/4200

J)

and several cow’s

milk infant formulas (6 to 9 pg/4200

J).

After the

change from a soy formula to a cow’s milk formula,

our patient’s thyroid functions normalized while he

received the same or a smaller dose of L-T4 in

micro-grams per kg/d. The patient’s stool frequency

de-creased from five to seven stools per day while

re-ceiving the soy formula to two to three stools per day

while receiving the cow’s milk formula. Although T4

excretion was not measured in this infant’s stools, his clinical course suggests that fecal bulk and

acceler-ated transit time may have played a role in the

absorption of exogenous thyroid hormone.

There is a recent report of an infant with congenital

hypothyroidism who, in the course of thyroxine

ne-placement, developed a cow’s milk protein

intoler-ance. There was a need to increase his thyroxine

replacement dose due to rising TSH levels.18 After

the patient was switched to a hydrolyzed milk diet,

his thyroid function improved. A rechallenge with

the cow’s milk formula caused subsequent decreases in the patient’s serum T4 and increases in his TSH.

Our patient was given a soy formula from birth

because of a family history of allergies to milk.

Al-lergies to soy formulas and protein intolerances do

occur.19 Although there are no reports of intolerance of a formula inducing hypothyroidism, it is theoret-ically possible that the increased stools associated

with intolerance of a formula may cause a

persis-tence of hypothyroidism in a congenital hypothyroid infant receiving replacement thyroid hormone.

In summary, soy diets are known to induce high-uptake goiters from an increased iodine requirement

after T4 depletion through fecal wastage. Other

mechanisms may be involved in the development of

goiters, and evidence exists that soy contains a

goitrogenic factor. The addition of iodine

supple-mentation to commercial soy formulas in the I960s

has eliminated the development of hypothyroidism

caused by iodine deficiency in soy-fed infants.

However, it is still necessary to reemphasize the

effects of soy diets on thyroid function, particularly

in hypothyroid infants receiving thyroid hormone.

This case presentation should realert physicians that dietary monitoring and close follow-up are necessary in hypothyroid infants.

PAULA ANN CHORAZY, MD, PHD

SETH HIMELHOCH, MD

Nmci’ J. HOPWOOD, MD

Department of Pediatrics

Division of Pediatric Endocrinology University of Michigan Medical Center Ann Arbor, MI

N.rsc G. GREGER, MD

DANIEL C. POSTELLON, MD

Department of Pediatrics

Division of Pediatric Endocrinology Children’s Hospital of Michigan

Detroit, MI

REFERENCES

1. Van Wyk JJ,Arnold MB, Wynn J, Pepper F. The effects of soybean

product on thyroid function in humans. Pediatrics. 1959;24:752-760 2. Hydovitz JD. Occurrence of goiter in an infant on a soy diet. N Engi

JMed. 1960;262:351-353

3. Shepard TH, Pyne GE, KirschvinkJF, McLean M. Soybean goiter: report

of three cases. N Engl IMed. 1960;262:1099-1103

4, Ripp JA. Soybean-induced goiter. Am JDis Child. 1961;102:106-106 5. Fomon SJ. Nutrition of Normal Infants. St Louis, MO: Mosby; 1993:20-21

6. McCarrison R. The goitrogenic action of soya-bean and ground-nut.

Indian JMed Rn. 193321:179-181

7. Sharpless GR. A new goiter producing diet for the rat. Proc Soc Exp Biol

Med. 1938;38:166

8. Wilgus HS Jr, Gassner FX, Patton AR, Gustavson RG. Goitrogenicity of soybeans. INutr. 1941;22:43-52

9. Halverson AW, Zepplin M, Hart EB. Relation of iodine to the

goitro-genic properties of soybeans. JNutr. 194938:115-129

10. Sharpless GR, PearsonsJ, Prato GS. Production of goiter in rats with raw and with treated soybean flour. INutr. 1939;17:545-.555

11. Block RJR, Mandi H, Howard HW, Bauer CD, Anderson DW. The

curative action of iodine on soybean goiter and the changes in the

distribution of iodo-amino acids in the serum and in thyroid gland

digests. Arc/i Biochem Biophys. 196L93:15-24

12. Van Middlesworth L. Thyroxine excretion, a possible cause for goiter.

Endocrinology. 1957;61 :570-573

13. Van Middlesworth L. Re-evaluation of certain aspects of iodine

metab-olism. Recent Prog Horm Res. 1957;16:405-438

14. Beck RN. Soy flour and fecal thyroxine loss in rats. Endocrinology.

1958;62:587-592

15. Konijin AM, Gershon B, Guggenjeim K. Further purification and mode of action a goitrogenic material from soybean flour. INutr. 1973;103: 378-383

16. Rawson RW, Rail JE. Endocrinology of neopiastic disease. Recent Prog

Horm Res. 1955;11:257-290

17. Pinchera A, MacGiliivray MH, Crawford JD, Freeman AG. Thyroid

refractoriness in an athyreotic cretin fed soybean formula. N EngI IMed. 1965;273:83-87

18. Franzese A, Limauro R, Ecuba P, Campanile F, De Martino F, Tenore A.

L-T4 malabsorption determined by intolerance to cow’s milk proteins

and celiac disease in a patient with hypothyroidism: a clinical case.

Minerva Pediatr. 1993;45:113-116

19. Motil KJ. Protein needs for term and preterm infants. In: Tsang RC,

Nichols BL, mis. Nutrition During Infancy. Philadelphia: Hanley and

Blefus; 1988:100-121

20. Endocrine Diagnostic Syllabus. Calabasas Hills, CA: Endocrine Sciences; 1992

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1995;96;148

Pediatrics

Postellon

Paula Ann Chorazy, Seth Himelhoch, Nancy J. Hopwood, Nancy G. Greger and Daniel C.

Review of the Literature