Goiter in Children

Thomas P. Foley, Jr, MD*

Enlargement of the thyroid gland males. The very high female-to-male

has been recorded in Western civili- ratio in autoimmune thyroid disease
EDUCATIONAL OBJECTIVES
zation for at least 2,000 years. Sculp- is the reason for the higher incidence
tures of dwarfs with goiter in the of goiter in females; there is an ap- 6. Appropriate knowledge to man-
southwestern Andean region of Go- proximately equal male-female ratio age children and adolescents with
lombia, South America, date back to among the other diseases associated a mass in the anterior neck region
400 B.C. Until the present century, with goiter during childhood and ad- and an ability to differentiate
enlargement of the thyroid gland usu- olescence. Enlargement of the thy- among Hashimoto thyroiditis with
ally was caused by a deficient dietary roid gland may develop in utero and goiter, Graves disease, simple goi-
intake of iodine associated with hy- may be present at any age. The peak ter, adenoma or carcinoma of the
pothyroidism or euthyroidism. This incidence of goiter before maturity thyroid gland, branchial cleft cyst,
remains the most common cause of occurs during early to midpuberty; subacute thyroidits, colloid cyst of
goiter in the world today. lodine-defi- goiter is uncommon before the age the thyroid gland, and lymph node
cient goiter has been a rare occur- of 4 years. enlargement, and the ability to de-
rence in Western civilization since the The hypothalamic-pituitary-thyroid velop an appropriate plan for man-
introduction of iodized salt during the axis controls thyroid hormone secre- agement (Topics 83/84).
first half of this century. Caleb Perry, tion and maintains normal circulating
and tissue concentrations of thyroid 100. Appropriate knowledge to
in 1825, was the first to describe
hormones through feedback mecha- evaluate goiter in children and an
goiter with hyperthyroidism, and
nisms. The synthesis and release of awareness of recent studies which
since then this clinical association has
the major thyroid hormones, thyrox- are diagnostic of chronic lympho-
been noted with greater frequency.
In North America, autoimmune thy- me (T4) and triiodothyronine (T3), be- cytic thyroiditis (83/84).
roid diseases cause more than 90% gin with stimulation of the thyroid
of cases of goiter during childhood gland by the pituitary glycoprotein,
and adolescence. These diseases in- thyroid-stimulating hormone, thyro-
dude chronic lymphocytic thyroiditis tropin (TSH). When the free or un- the most sensitive test of primary
S (Hashimoto thyroiditis) and the dif- bound concentration
serum
of T4 and T3 in
decreases, the secretion of
hypothyroidism.
Steps in the synthesis and release
fuse toxic goiter of Graves disease.
In a survey of children aged 1 1 to 18 TSH bythe pituitary gland increases of T4 and T3 are shown in Fig 1.
years between 1 965 and 1 971 in the and TSH stimulates the thyroid gland Adequate dietary intake and absorp-
southwestern United States, chronic to increase the synthesis and release tion of iodide are important for normal
lymphocytic (Hashimoto) thyroiditis of T4 and T3. When the serum con- synthesis of T4 and T3. TSH stimu-
(CLT) was identified in 1 .2%. This centrations of T4 and T3 increase, the lates various steps of thyroid hor-
high prevalence of CLI was also circulating concentrations of TSH de- mone synthesis and release. Iodide
found in a survey of schoolchildren crease to undetectable levels. When in plasma is concentrated by an ac-
aged 6 to 18 years in Japan. The failure of the thyroid gland (primary tive transport process and rapidly ox-
prevalence rate in the Japanese chil- hypothyroidism) occurs, there is an idized by a peroxidase-dependent
dren was 0.3%;
it was higher in a initial slight decrease in the concen- system to organic iodine. Residues
costal city (0.53%) than in an inland tration of T4 in serum. This is of tyrosine within the large colloid
urban city (0.1 4%). Autoimmune thy- promptly recognized by the pituitary, protein, thyroglobulin, are iodinated
roid diseases occur with increased which begins to secrete increased to form monoiodotyrosine (MIT) and
frequency in patients with insulin-de- amounts of TSH even before the se- diiodotyrosine (DII). Two tyrosyl res-
pendent diabetes mellitus (IDDM), an- rum T4 value has decreased below idues are coupled by an ether linkage
other probable autoimmune disease. the normal range. The serum concen- to form the iodothyronines, T3 and T4.
As autoimmune thyroid diseases may tration of T3 remains normal except T4 and T3 are stored in colloid drop-
occur in more than one third of pa- in severe, advanced hypothyroidism lets and released into the circulation
tients with IDDM (which has a fre- when the T3 level falls below normal. following proteolytic enzymatic diges-
quency of 1/700 children), autoim- In hyperthyroidism of nonpituitary or- tion under TSH stimulation. The ma-
mune thyroid disease is clearly the igin, the serum concentrations of T3 jor portion of the circulating concen-
most common endocrine disorder of and usually T4 are increased, and the trations of T3 is derived from the mon-
childhood and adolescence. serum TSH concentrations are low or odeiodination of T4 to T3 by peripheral
Enlargement of the thyroid gland undetectable. Except in patients with tissues, principally the liver.
occurs more often in females than poor nutritional intake or severe sys- An abnormality at any step in the
temic illnesses, the serum T3 concen- T4 and T3 biosynthetic pathway re-
. * Professor

of the University
of Pediatrics,
of Pittsburgh;
School of Medicine
Director, Clinical
tration is increased in hyperthyroid-
ism, and it is the single most sensitive
sults in diminished iodothyronine
duction, increased secretion of TSH
pro-

Research Center, Childrens Hospital of Pitt s- test for the diagnosis of hyperthyroid- and an enlarged thyroid gland. A spe-
burgh, 125 DeSoto St, Pittsburgh, PA 15213. ism. The serum TSH concentration is cific clinical disease has been re-

pediatrics in review #{149} vol. 5 no. 9 march 1984 PIR 259

Goiter

infection. In bacterial infections, the

thyroid gland is exquisitely tender.
Viral diseases
associated
of the thyroid gland are
with tenderness in some
S
but not all patients.
Thyroid function and the clinical
presentation-hyperthyroidism, eu-
thyroidism, and hypothyroidism-are
dependent upon the underlying dis-
ease process. Stimulation of the thy-
roid gland by TSH is usually the result
of an inhibition in the synthesis and
release of thyroid hormones which
results in varying degrees of mild to
severe hypothyroidism. Rarely TSH,
but often TSAb stimulates the thyroid
gland to cause thyromegaly and hy-
perthyroidism. Neoplastic or granu-
lomous infiltration of the thyroid gland
is almost always associated with nor-
mal thyroid function, except for the
rare, hyperfunctioning thyroid tumor.
Inflammatory disease of the thyroid
gland may be associated with tran-
sient toxic thyroiditis during the initial
DEIODINATION >T3
weeks of the disease, when cellular
*4, damage from the inflammatory proc-
URINE
ess releases large amounts of thyroid
PTU
hormone into the circulation. During
the recovery phase of the disease,
Fig 1.
Diagnosis
Biosynthesis
and Therapy,
of thyroid hormones
ed 14. Rahway,
(Reprinted
NJ, Merck,
with permission from
1982, chap 86, p 998).
Merck Manual or thyroid function
gress into transient
will be normal or pro-
or permanent hy-
S
pothyroidism.
ported as the result of an abnormality hibited by the antithyroid drugs that Thyromegaly during childhood may
at most of the steps in the biosyn- are used in the treatment of hyper- present either as diffuse, symmetrical
thesis and release of the iodothyro- thyroidism. enlargement of the gland or nodular,
nines. These diseases are known col- irregular, and asymmetrical enlarge-
lectively as familial dyshormonoge- PATHOGENESIS OF ment (Table 2). In most instances the
nesis and are inherited as autosomal THYROMEGALY history and careful physical exami-
recessive traits. In addition, certain Enlargement of the thyroid gland nation will suggest the nature of the
steps in hormonogenesis are in- may occur as a result of stimulation, disease and enable the clinician to
infiltration, and/or inflammation of the select those thyroid tests that will
thyroid gland (Table 1 ). Diffuse, sym- confirm the etiology and determine
metrical enlargement of the thyroid the state of thyroid function.
ABBREVIATIONS
gland occurs when the thyroid gland
CLT Chronic lymphocytic (Hash- is stimulated by TSH and thyroid-
imoto) thyroiditis AUTOIMMUNE THYROID
stimulating antibodies (TSAb). Thy-
DIT Diiodotyrosine DISEASES
roid tumors, cysts, and inflammatory
IDDM Insulin-dependent diabetes diseases cause asymmetrical, local-
mellitus Immunologic Mechanisms in
ized enlargement. More than one
MEN Multiple endocrine neopla- Pathogenesis of Autoimmune
mechanism for development of thy-
sia Thyroid Disease
MIT Monoiodotyrosine romegaly may be involved in a single
T3 Triiodothyronine disease process; for example, in au- For more than 25 years, experi-
T4 Thyroxine toimmune thyroid disease, the thyroid mental and clinical evidence has ac-
TRH Thyrotropin-releasing hor- gland is commonly both infiltrated by cumulated that implicates abnormali-
mone lymphocytes and lymphoid follicles ties of the immune system in the
TSAb Thyroid-stimulating anti- and stimulated by TSH (in CLI) or by pathogenesis of chronic lymphocytic
bodies TSAb (in Graves disease). thyroiditis and Graves disease. The
TSH Thyroid-stimulating hor- The enlarged thyroid gland is usu- term autoimmunity refers to a
mone, thyrotropin
ally nontender except when the in- pathologic mechanism involving fail-
flammatory process is caused by an ure of the organism to recognize its

PIR 260 pediatrics in review #{149} vol. 5 no. 9 march 1984

 ENDOCRINOLOGY

TABLE 1. Pathogenesis of TABLE 2. Differential Diagnosis of Ihyromegaly

Ihyromegaly
Etiology of diffuse thyromegaly
Stimulation Hashimoto thyroiditis
Ihyrotropin (TSH) Thyrotoxicosis
Inhibition of hormonogenesis Graves disease
Excessive pituitary secretion Toxic thyroiditis
Thyroid-stimulating antibodies TSH secreting pituitary adenoma
(ISAb) Pituitary resistance to thyroid hormone
Infiltration Goitrogen ingestion
Neoplastic Antithyroid drugs
Adenoma Other antithyroid agents and foods
Carcinoma Iodine deficiency
Lymphoma Dyshormonogenesis
Histiocytosis Acute and subacute thyroiditis (bacterial or viral)
Nonneoplastic Idiopathic (simple) goiter
Cysts Etiology of nodular thyromegaly
Inflammation Hashimoto thyroiditis
Infectious Thyroid cyst
Bacterial Thyroid adenoma
Viral Hyperfunctioning (hot): thyrotoxicosis or euthyroidism
Other pathogens Nonfunctioning (cold)
Noninfectious Thyroid carcinoma
Lymphocytic (autoimmune) Other thyroid tumors
thyroiditis Nonthyroidal masses
Lymphadenopathy
Branchial cleft cyst
Thyroglossal duct cyst

own tissues, as a result of which it

sets up an immune assault on its own
S tissues as though they were foreign.
In most instances, the autoimmune
TSH-receptor
receptor
antibody
and mimics TSH by stimu-
binds to the immune regulation in patients
CLI and Graves disease is unknown.
with

process impairs the function of the lating adenyl cyclase activity; this In genetically predetermined individ-
tissue or is directly cytotoxic. In the TSAb stimulates the production of uals, the normal balance between Is
case of Graves disease, however, the thyroid hormone and mediates the and Ih cells is altered either by de-
immunologic assault is stimulatory to hyperthyroidism of Graves disease. creased Is cell function or by in-
the tissue rather than inhibitory or Finally, evidence suggests that there creased Ih cell function. On presen-
destructive. Abnormalities of T-Iym- are antibodies that cause growth of tation of the thyroid antigen to pre-
phocyte response (cell-mediated im- thyroid follicular cells but do not stim- cursor I lymphocytes, there is differ-
munity) and B-lymphocyte response ulate the production of hormone. entiation of the precursor I lympho-
(humoral immunity) have been dem- There may be two types of antibodies cytes to antigen-specific Is and Ih
onstrated in patients with autoim- affecting thyroid growth: one that cells. In Graves disease the antigen-
mune thyroid disease. The B lympho- stimulates and another that blocks specific Ih cells proliferate and inter-
cytes are precursors of the plasma follicular cell growth. act with B lymphocytes, which differ-
cells that produce antibodies. Several Cellular immunity is mediated by T entiate into plasma cells and produce
thyroid antibodies have been found in lymphocytes and is responsible for thyroid-stimulating antibodies. This
the sera of patients with autoimmune graft-versus-host reactions, delayed mechanism is also responsible for the
thyroid disease. The serum anti- hypersensitivity reactions, and direct production of other antibodies seen
bodies useful in the diagnosis of au- cytotoxicity. The subsets of T lym- in autoimmune thyroid diseases. In
toimmune thyroid disease are dem- phocytes are as follows: (1) suppres- CLI, the sensitized le lymphocytes
onstrated by hemagglutination tech- sor I lymphocytes (Is) act to limit the produce cytotoxicity by direct inter-
niques and are directed against spe- immune reaction to foreign antigens; action with thyroid follicular cells (Figs
cific thyroid autoantigens, usually thy- (2) helper T lymphocytes (Th) cause 2 and 3). In addition, thyroid follicular
roglobulin and thyroid microsomes. B lymphocytes to differentiate into cell toxicity may be mediated by an-
There are several types of thyrotro- plasma cells and are controlled by tibody-dependent killer lymphocytes
pin-receptor antibodies (Fig 2), which specific Is cells; and (3) effeCtor I and by direct cytotoxic action of com-
have different mechanisms of action cells (Te) cause direct cytotoxicity plement-fixing thyroid antibody. The
determining specific biologic re- and are also suppressed by Is cells presence of these sensitized I lym-

S sponses. One type of antibody

to the TSH receptor
binds
and blocks the
(Fig 3). Patients
thyroid disease
with autoimmune
have abnormalities in
phocytes and
against thyroid follicular
specific antibodies
cells will de-
binding of TSH to prevent the action both humoral and cell-mediated im- termine whether the predominant dis-
of TSH on the cell. A second type of munity. The specific abnormality of ease process is to be stimulation (hy-

pediatrics in review #{149} vol. 5 no. 9 march 1984 PIR 261

Goiter

of thyroiditis may be the initial clinical

presentation in patients with CLI or
THYROID FOLLICLE
subacute
known
thyroiditis.
as toxic thyroiditis,
This disease,
is often
S
difficult to distinguish from early, mild
Graves disease since the clinical
symptomatology and serum levels of
thyroid hormones are similar. The
toxic phase of the disease usually
Direct Te cell resolves within four to eight weeks,
cytotoxicity
and the patient subsequently mani-
fests euthyroid goiter, a compen-
sated or clinical hypothyroidism with
I goiter. Infrequently, the patient may
initially have coexisting Graves dis-
TRAb that ease and CLI. Goiter is present and
binds and blocks the coexistence of these diseases is
suspected on the presence of exo-
J TSH
1 phthalmus in the patient who is mildly
hyperthyroid or euthyroid with the
characteristic features of thyroiditis
on physical examination. Such pa-
tients have circulating ISAb, but din-
ical thyrotoxicosis does not develop
because the thyroid gland is incapa-
ble of responding to stimulation, ow-
ing to coexisting CLI. Similarly, pa-
tients who have received antithyroid
? Thyroid growth antibody, which may be a type of drug therapy for Graves disease may
TRAb that binds and stimulates follicular cell growth
enter permanent remission as a result

of the development of CLI; in fact, in S

Fig 2. Immune-mediated mechanisms that may be pathogenic in Graves disease and Hashimoto some patients the disease will pro-
thyroiditis (Reprinted with permission from Strakosch et al). gress to primary hypothyroidism. Pa-
tients with euthyroid or hypothyroid
perthyroidism of Graves disease), in- goiter and normal thyroid function goiter caused by CLI will not develop
hibition (CLI with goiter), or cytotox- tests. Very infrequently will these pa- clinical thyrotoxicosis at a later age.
icity (CLI with hypothyroidism). The tients progress in subsequent years
onset of the disease may be triggered to the development of decreased thy-
Chronic Lymphocytic Thyroiditis
by other factors, such as psychologic roid reserve and compensated hypo-
(Hashimoto Thyroiditis)
stress or biologic stress (for example, thyroidism. If this entity is not de-
by a viral infection or by glucocorti- tected, the patient may progress to During childhood and adolescence,
coids, catecholamines, or thyroid hor- clinically overt, primary hypothyroid- most patients with CLI will have
mones which depress the function of ism. If the patient at the time of initial asymptomatic enlargement of the
Is lymphocytes). examination has compensated hy- thyroid gland. Patients will occasion-
pothyroidism, it is likely that clinical ally have signs of hypothyroidism
hypothyroidism will subsequently de- with or without goiter, or infrequently
Spectrum of Autoimmune Thyroid
velop. there are signs of toxic thyroiditis.
Disease
During childhood and adolescence The disease rarely occurs before the
Graves disease and CLI usually the majority of patients with Graves age of 3 years and has a peak inci-
present distinct clinical disorders. The disease have exophthalmic goiter dence during early and middle ado-
two diseases may coexist, however, and hyperthyroidism. Mild thyrotoxi- lescence. The child who has euthy-
at the time of clinical presentation, or cosis with an elevation of serum 13 roid goiter may have a history of sev-
during the course of Graves disease but normal serum 14 concentrations eral weeks to months of symptoms
CLI may develop and later become is rare during childhood. This entity, suggestive of toxic thyroiditis. Occa-
the predominant clinical disease. Ac- known as 13 toxicosis, occurs either sionally, a patient will have had recur-
cordingly, the clinician may encounter very early in the course of Graves rent sore throats, discomfort on swal-
a spectrum of thyroid function at var- disease or as the presenting clinical lowing or on palpation of the neck, or
ious times during the course of au- symptoms in the patient with a toxic dysphagia. The thyroid gland may be
toimmune
Most patients
thyroid disease
with autoimmune
(Table 3).
thy-
hyperlunctioning
ated with autoimmune
nodule not associ-
thyroid dis-
symmetrically
larged. Usually
or asymmetrically
both lobes
en-
are in-
S
roid disease initially have euthyroid ease. The transient, thyrotoxic phase volved. In most patients, the gland is

PIR 262 pediatrics in review #{149} vol. 5 no. 9 march 1984

 ENDOCRINOLOGY

firm in consistency and nontender.

S The surface
either a fine, isgranular often irregular
texture with a
or HLA-D
Influences

immune regulation genes

Precursor cell

Microphage
more lumpy, pebbly feel due to small
stress via steroids.
discrete nodules within the gland.
This nodular or crenated texture re-
suIts from lymphocytic infiltration and
lymphoid follicles. There may be re-
gional lymphadenopathy that is non-
tender, freely movable and discrete,
and firm but not hard. On inspection
and palpation the thyroid gland in chil-
dren should not be affixed to adjacent
tissues and should move freely on
swallowing. Rarely, the child with
CLI may have a single nodule that is
difficult to differentiate from a thyroid
neoplasm. Such patients require ad-
ditional diagnostic studies to exclude
malignancy.
Usually the only necessary labora- Cell mediated
tory studies are serologic tests of immunity
Humoral Immunity
thyroid function and thyroid antibody (antibodies)
determinations. A significantly ele-
vated titer of thyroid microsomal
and/or thyroglobulin-hemagglutinat-
ing antibodies in serum is found in
most patients with CLI at the time of
initial presentation. Infrequently, the
S child with CLI
tests for thyroid
will have negative
antibodies, but the
Thyroid follicular cells

titer will be significantly elevated four Fig 3. Postulated mechanisms for maintenance or loss of control of immune response in
to six months later. In children, a titer autoimmune thyroid disease (Reprinted with permission from Strakosch et al).
of 1 :4 for hemagglutinating anti-
bodies is considered to be significant, coexisting euthyroid sick syndrome most patients with euthyroid or hy-
whereas in normal adults a titer up to or the low 13 syndrome in which the pothyroid goiter and positive titers of
1 :1 00 may be found. On the other serum 13 level is normal in the pres- thyroid antibodies should not have
hand, children with other types of ence of hyperthyroidism. In Graves radionudlide studies, thyroid scans or
thyroid disease may have low titers disease, the four- to six-hour and 24- radioiodine uptake tests. Only for the
of thyroid hemagglutinating anti- hour uptake of [1231]iodide will be el- very unusual patient with toxic thy-
bodies in serum; therefore, a positive evated whereas patients with toxic roiditis, familial dyshormonogenesis,
titer of thyroid antibodies may mdi- thyroiditis and CLI will have a normal or a solitary thyroid nodule will radio-
date CLI but does not exclude other or low uptake of radioiodide during nudlide studies be indicated.
thyroid disease. the transient, toxic phase of the dis- The anticipated clinical course of
Only rarely will the patient with din- ease. the patient with CLI will depend upon
ical thyroiditis and high titers of thy- The euthyroid patient with a soli- the clinical presentation and confirm-
roid antibodies require additional di- tary thyroid nodule will require addi- atory laboratory studies. The child
agnostic tests. If the clinical symp- tional laboratory tests to exclude thy- with primary hypothyroidism may ex-
toms and initial thyroid function tests roid malignancy. These tests will be perience a brief period of remission,
support a presumptive diagnosis of discussed later. If the patient with a but clinical hypothyroidism will recur
toxic thyroiditis in association with solitary nodule has a high titer of thy- and such patients should be main-
CLI, it may be necessary to distin- roid antibodies and thyroid function tained indefinitely on L-thyroxine re-
guish this entity from early Graves tests that are diagnostic of hypothy- placement therapy. Those patients
disease by a radioactive iodine up- roidism, additional diagnostic tests who have mild, symmetrical thyro-
take test. In both diseases, the serum should be delayed until after a trial of megaly and normal thyroid function
13 concentration will be elevated ex- oral L-thyroxine replacement therapy. tests will usually remain euthyroid.
cept in those children with other se- An exception to this rule would be The size of the thyroid gland will grad-
S vere systemic
have experienced
illnesses or those who
very poor to negli-
the patient
thyroid malignancy,
with a familial history
with prior cervical
of ually return to normal over a period
of months to years, and the titer of
gible nutritional intake for several irradiation, or with a rapidly enlarging thyroid antibodies will decrease. The
days. Severely ill children may have mass. It is important to stress that child who has a firm thyroid gland

pediatrics in review #{149} vol. 5 no. 9 march 1984 PIR 263

Goiter

eral weeks to months, and are often

mistaken by parents and health
TABLE 3.
Lymphocytic
Variation of Thyroid Function in Graves
(Hashimoto) Thyroiditis (CLT)*
Disease and Chronic
professionals for psychologic prob- S
lems. Changes in behavior and poor
Serum TSH
Serum Serum Serum academic performance in school may
Clinical Presentation Response
T4 T3 TSH be the initial features that bring the
toTRH
Thyrotoxicosis patient to a physician. Often there is
I I 0 Absent
c T3 toxicosis N I 0 Absent a history of restless sleep and insom-
Toxic thyroiditis 0 Absent nia that are associated during the day
I I
3 0 Thyrotoxicosis with Mild I 0 Absent with easy fatigability and lethargy.
.a >
limited thyroid reserve The complaint of nervousness is
Nonsuppressible euthy- N N N Blunted very common. Approximately two
.2
roid goiter thirds of patients will have an in-
3 creased appetite; weight loss may
- Euthyroid goiter N N N Normal not occur if the patients caloric in-
Euthyroid goiter with de- N N N Exaggerated
take meets or exceeds the increased
creased thyroid re-
metabolic needs of the disease proc-
serve
>- Compensated hypothy- N N I Exaggerated ess.
roidism Almost invariably, thyromegaly is
Primary hypothyroidism or N I Exaggerated present. In most patients, the thyroid
*0 denotes undetectable value for TSH; N denotes normal value for T4, I3, or gland is symmetrically enlarged, non-
TSH. tender, soft, and smooth on palpa-
tion. A continuous bruit may be heard
when the stethoscope is placed over
the enlarged lobes of the gland. If
that is more than three times the L-thyroxine therapy may be initiated CLI coexists at the time of presen-
normal size will usually remain euthy- at that time. If the size of the thyroid tation of Graves disease, as occa-
roid, but may develop hypothyroidism gland decreases to normal and thy- sionally occurs, the thyroid gland will
at a later age. As most patients will roid antibodies are no longer present, be firm, and may be asymmetrical
not subsequently
roidism
develop
if they have normal
hypothy-
thyroid
thyroid
necessary.
function tests are no longer and have the other characteristic
tures of thyroiditis. Approximately
fea-
S
function tests initially, it is not advis- 80% of children and adolescents will
able to initiate L-thyroxine therapy if have tachycardia and an increased
Graves Disease
the serum ISH concentration is nor- pulse pressure at the time of diag-
mal. Furthermore, thyroxine replace- Graves disease during childhood nosis. A fine tremor of the out-
ment therapy in affected children will and adolescence is much less com- stretched hands is seen in approxi-
usually not cause significant diminu- mon than CLI; it occurs with a peak mately half of the children. Fortu-
tion in the size of the thyroid gland incidence during puberty with a fe- nately, exophthalmus during child-
for several months after the initiation male-to-male ratio of approximately hood and adolescence is usually mild;
of therapy. Therefore, so long as the 6: 1 ; and it rarely presents before the it may be associated with ocular
patient remains clinically euthyroid age of 3 years except in the neonatal symptoms of lid lag, increased lacri-
and the serum TSH concentration is form of the disease. Exophthalmic mation, conjunctival injection, and
normal, replacement therapy with L- goiter with hyperthyroidism is present edema. Ocular muscle involvement is
thyroxine is not necessary and should at the time of diagnosis in approxi- uncommon, and the severe, progres-
be discouraged. Some pediatric en- mately two thirds of patients. By the sive form of exophthalmus seen in
docrinologists, however, would treat time the patient has developed dlini- the adult with Graves disease rarely
these patients for a limited interval of cal symptoms and signs of hyperthy- occurs during childhood and adoles-
time to determine whether therapy roidism, enlargement of the thyroid cence. In most patients the exo-
causes a decrease in the size of the gland is detectable on clinical exami- phthalmus will improve with therapy.
gland. nation. Other causes of hyperthyroid- Very few laboratory tests are re-
L-thyroxine therapy may be helpful ism should be investigated if the pa- quired to confirm the diagnosis of
in the child who is self-conscious tient has thyrotoxicosis in the ab- Graves disease in the patient with the
about a very large thyroid gland even sence of thyromegaly. classic picture of exophthalmic goiter
though a decrease in the size of the In some patients, the onset of and hyperthyroidism. In these pa-
gland during thyroxine therapy may Graves disease may follow an emo- tients, the only tests of thyroid fund-
not occur for months or years. The tional or a biologic stress, such as tion that are necessary are the serum
child with CLI and euthyroid goiter bereavement over the death of a total 14 and either a direct or indirect
should have a yearly clinical exami- close relative or friend, a viral infec- measurement of free thyroxine. The
nation,
14 and ISH
with determination
concentrations.
of serum
If the
tion, or trauma. The clinical
toms and signs of nervousness
symp-
and
resin 13 uptake
and an indirect
is readily measured
estimate of the free
S
serum ISH concentration is elevated, irritability develop gradually over sev- thyroxine can be made. The latter

PIR 264 pediatrics in review #{149} vol. 5 no. 9 march 1984

 ENDOCRINOLOGY

procedure confirms that an elevated existing Graves disease and CLI, two acceptable methods of mainte-
usually with high titers of thyroid anti- nance therapy for children and ado-
S total thyroxine of level
an elevation is not caused
the thyroxine bindingby bodies, and such a patient may have lescents: (1 ) the full blocking dose of
proteins, but represents a true hyper- limited thyroid reserve that will pre- the antithyroid drug is continued until
thyroxinemia. A complete blood vent the development of progressive biochemical hypothyroidism occurs,
count and differential count are im- hyperthyroidism. Such patients, in at which time L-thyroxine therapy is
portant base line tests for patients fact, may have a clinical course simi- initiated in a once-daily dose of 1 zg/
treated with antithyroid drugs since lar to that seen in patients with toxic kg; or (2) the antithyroid drug dose is
granulocytopenia may occur as a side thyroiditis, with resolution of hyper- reduced by 30% to 50% in order to
effect of therapy. No other laboratory thyroidism within a few weeks to maintain serum 14 and 13 values
procedures are necessary prior to months following the onset of the within the normal range. The use of
treatment of the patient with the clas- disease. combined antithyroid drug and L-thy-
sic symptoms and signs of exoph- The symptomatic patient should be roxine therapy has the theoretical ad-
thalmic Graves disease. treated. Prompt relief of the uncom- vantage of completely blocking the
For patients who have hyperthy- fortable and distressing adrenergic disease process and avoiding the in-
roidism in the absence of exophthal- symptoms can be achieved by the sidious development of hypothyroid-
mus, other diagnostic tests may be use of fl-adrenergic blocking drugs ism, an undesirable side effect during
necessary to determine the cause. such as propranolol, using reasona- the growth period. In the child whose
When the thyroid gland is nontender bly low doses of 1 0 to 20 mg every compliance with the drug regimen is
to palpation, early, mild Graves dis- six to eight hours. The drug should poor, the antithyroid drug may be
ease may be difficult to differentiate not be used in patients with coexist- effective in a once- or twice-daily
from toxic thyroiditis associated with ing diseases in which (-adrenergic dose, but a higher total dose may be
CLI or subacute thyroiditis. The ra- blockade is contraindicated. The required to control the disease.
dioactive iodine uptake test (not a dose of propranolol should be ta- If the antithyroid drug has effec-
thyroid scan) using [123I]iodide is a pered and the drug discontinued tively controlled the disease and the
useful, discriminating test since the when remission is achieved. size of the thyroid gland has de-
patients with toxic thyroiditis will have The currently acceptable modes of creased, the dose medication may be
normal or very low uptake whereas therapy for Graves disease include: slowly tapered or a 13 suppression
patients with Graves disease will (1 ) antithyroid drugs, (2) surgery, and test may be performed. In patients
S have elevated
should be measured
uptakes. The uptake
both at four to
(3) radioiodine
stances
ablation.
the antithyroid
In most in-
drugs are
with active Graves
administration
disease
of 13 (1 .5 ag/kg/day
the oral
in
six hours and at 24 hours after inges- used as the initial method of long- three divided doses) will not produce
tion of the isotope. The thyrotropin- term therapy in children. These drugs the decrease in the serum 14 concen-
releasing hormone (TRH) test may be include propylthiouracil (PTU), methi- tration that occurs in normal persons.
an additional, useful test in the patient mazole (MMZ), and carbimazole Remission of Graves disease is char-
with mild hyperthyroidism and mini- (CMZ). The last drug is not available acterized by the return of normal sup-
mal elevation of the serum 13 concen- in the United States at the present pressibility of serum 14 levels to con-
tration. Following TRH administration time. None of the antithyroid drugs centrations below the normal range
there will be no increase in serum has greater therapeutic effectiveness with two to three weeks of oral ad-
ISH values in patients with hyperthy- than the others, but most clinicians ministration of 13. The test can be
roidism in association with Graves begin therapy with PIU since it has performed either after antithyroid
disease, toxic thyroiditis, thyrotoxi- been reported to block the peripheral drug therapy is discontinued or dur-
cosis associated with a hyperfunc- conversion of 14 to 13 and to reduce ing antithyroid drug therapy (after L-
tioning thyroid adenoma, or factitious levels of ISAb. For the older child thyroxine has been discontinued). In
hyperthyroidism. The otherwise nor- and adolescent, PTU is administered the latter situation, if the serum 14
mal patient with an elevation of serum initially in a dose of 300 to 450 mg/ value is suppressed below normal
thyroxine binding proteins will have a day in three divided doses at eight- while the patient is receiving both
normal ISH response to TRH; such hour intervals. In the young child, a exogenous 13 and an antithyroid
patients usually do not have thyro- dose between 150 and 200 mg/day drug, the antithyroid therapy can be
megaly. ISH concentrations will in- in three divided doses is usually ef- discontinued. The patient should be
crease following the administration of fective. The dose for MMZ and CMZ given exogenous 13 for an additional
IRH to patients with the rare disorder is approximately one tenth that of two weeks to confirm that normal
of inappropriate pituitary secretion of PTU. Within four to eight weeks the suppressibility of the thyroid persists
ISH, the disorder known as selective serum concentration of 14 usually de- after the cessation of antithyroid drug
pituitary resistance to thyroid hor- creases into the normal range, al- therapy.
mone. though the size of the thyroid gland Between 5% and 10% of patients
The course of Graves disease is may increase slightly. Such an in- receiving antithyroid drugs will expe-
S unpredictable. In most untreated pa- crease
continuation
should not discourage
of antithyroid drugs
the
if
rience minor side effects;
quently, major toxic side effects
very infre-
oc-
tients, the disease persists and hy-
perthyroidism progresses in severity. the patient shows clinical and bio- cur (Table 4). The most frequent side
Occasionally, a patient may have co- chemical improvement. There are effects are nonspecific erythematous

pediatrics in review #{149} vol. 5 no. 9 march 1984 PIR 265

Goiter

surgery (permanent hypoparathyroid- ment of the thyroid gland other than

that caused by autoimmune thyroid
TABLE 4. Toxic Reactions
Produced by Antithyroid Drugs
ism or damage to the recurrent
geal nerve) occur infrequently
laryn-
when disease occurs infrequently. Goitro- S
subtotal thyroidectomy is performed gens in the environment and goitro-
Erythematous rash I by an experienced surgeon. The fre- genic medications rarely cause thy-
Urticana romegaly during childhood. Iodine de-
quency of side effects increases with
Granulocytopenia
I each successive surgical interven- ficiency, the most common cause of
Arthralgia
Arthritis tion. For this reason, another mode goiter worldwide, rarely occurs in
Lymphadenopathy of therapy is recommended when hy- North America where food products
Edema perthyroidism recurs following sub- are supplemented with iodide. The
Fever total thyroidectomy. various types of familial dyshormon-
Conjunctivitis Ablation of the thyroid gland by the ogenesis account for approximately
Lupus-like syndrome administration of [1311]iodide is an- 5% to 1 0% of cases of congenital
Hepatitis other acceptable method of therapy hypothyroidism and thyromegaly is
Thrombocytopenia of juvenile Graves disease. Recent present infrequently during later
Hypoprothrombinemia
, reports of long-term follow-up of pa- childhood or adolescence. Acute thy-
Disseminated intravascular coagu-
tients treated with radioiodine during roiditis is rare except in Japan, and
lation
Peripheral neuritis childhood indicate that there is nei- few cases of subacute or presumed
Sensorineural hearing impairment ther an increased risk of thyroid can- viral thyroiditis have been reported
Toxic psychosis cer nor any teratogenic effect among during childhood and adolescence.
Loss of taste sensation I the progeny of treated patients. Prior Although the silent or subclinical form
to the present time the use of radioi- of subacute thyroiditis may be more
, odine therapy was limited by most common during childhood and ado-
clinicians to thyrotoxic patients who lescence than the number of reported
rashes, arthralgia, and granulocyto- were poor candidates for surgery, cases would indicate, the fact that it
penia. Antithyroid drug therapy who had suffered a relapse following infrequently is identified would sug-
should be discontinued promptly if surgical therapy, or who had experi- gest that the course of the disease is
symptoms or signs of drug toxicity enced toxic reactions to the antithy- self-limited, that the insult of the thy-
develop. Once the side effects have roid drugs. Ablative doses of radioi- roid gland is minimal, and that the
abated, an alternate antithyroid
may be initiated if the initial side effect
drug odine are recommended;
induce remission
they usually
within a few months
disease
symptoms
produces
of thyroid
few, if any, clinical
disease. It is S
was not a severe, systemic reaction. and frequently induce hypothyroidism important that the clinician be aware
The patient, however, must be within several years. The incidence of of the clinical features of subacute
closely monitored for the develop- hyperparathyroidism may be in- thyroiditis because the asymptomatic
ment of the same or different toxic creased following radioiodine therapy form of the disease may account, in
effects of the second antithyroid drug for Graves disease. part, for the high frequency of goiter
since there may be cross-toxicity in Until the present time, it has not during later childhood and adoles-
some patients. been possible to select the patients cence that has been attributed to au-
If relapse occurs following the des- who will best respond to a specific toimmune thyroid disease. There are
sation of antithyroid drug therapy, the method of therapy. A recent report a group of patients seen during ado-
patient may resume antithyroid drug indicated that relapse occurred fol- lescence, usually girls, who have
therapy or may select an alternate lowing the cessation of antithyroid mild, diffuse enlargement of the thy-
method of treatment. Subtotal thy- drug therapy in 95% of adult patients roid gland with no biochemical evi-
roidectomy by a surgeon with expe- who were both HLA-DRw3 positive dence of autoimmune thyroid dis-
rience in performing thyroid surgery and had detectable levels of ISAb ease. Their disorder, idiopathic goi-
in children is effective therapy for following six months of antithyroid ter, may occur at any age but is most
Graves disease. Surgery should be drug therapy. As such laboratory common during adolescence. Thy-
delayed until hyperthyroidism is con- techniques become more widely roid function tests are normal and the
trolled by the use of antithyroid drugs available and if the relationship is diagnosis is made when the clinical
and propranolol; potassium iodide or found applicable in juvenile Graves and biochemical evaluation of thyro-
Lugol solution (5% iodine and 10% disease, we may be able to select at megaly reveals no specific cause.
iodide) should be started between ten an earlier time during the course of These patients may have mild CLI
and 14 days before surgery in order their disease those patients for whom without positive serum thyroid anti-
to reduce the vascularity of the gland more definitive therapy such as sur- bodies. In adults, subacute thyroiditis
at surgery and inhibit iodothyronine gery or radioiodine wilI be appropri- is seen both as symptomatic (pain
release from the gland. Although re- ate. and tenderness) and asymptomatic
lapse of hyperthyroidism after sur- thyromegaly. As symptomatic sub-
OTHER CAUSES OF DIFFUSE
acute thyroiditis is rare during adoles-
gery is uncommon,
of hypothyroidism
the development
is frequent, but THYROMEGALY cence, it seems unlikely that only the S
easily treated with a single daily dose asymptomatic clinical disease would
of L-thyroxine. The side effects of In North America, diffuse enlarge- cause idiopathic goiter.

PIR 266 pediatrics in review #{149} vol. 5 no. 9 march 1984

 ENDOCRINOLOGY

Iodine Deficiency and Goitrogens When a mother is receiving high lated thyroid disease. Patients with
doses of these medications for the CLI or with a thyroid gland that is
Endemic goiter remains a major treatment of Graves disease, the partially destroyed by radioiodine or
worldwide public health problem that drugs may cause goiter and hypothy- thyroidectomy may develop hypothy-
is caused by deficient dietary intake roidism in the fetus, neonate, or roidism with a daily iodine intake be-
of iodine, and in some areas by nat- breast-fed infant. Iwo additional an- tween 1 50 and 200 mg. A similar
urally occurring goitrogens in the wa- tithyroid drugs, iodide and lithium, are effect occurs in patients with cystic
ter supply or food. Iodine deficiency used in the treatment of other disor- fibrosis who have no documented
occurs when the daily iodine intake is ders and may cause thyromegaly in thyroid disease. Infrequently patients
less than 50 ag/day. The optimal daily children without known preexisting with euthyroid Graves disease or au-
iodine requirement is estimated to be thyroid disease. Iodides were fre- tonomous thyroid nodules will de-
between 1 50 and 300 zg/day, and a quently used in the treatment of velop mild hyperthyroidism when
nutritional intake of iodine between asthma and other chronic lung dis- large amounts of iodine are ingested.
50 and 1,000 pg/day is adequate. ease. Patients receiving iodide-con- It should be emphasized, however,
The iodine content of foods is gen-
taming expectorants may ingest as that most normal children and adoles-
erally low except in fish, and to a much as 500 to 1 ,000 mg/day. Many cents will tolerate a large intake of
lesser extent in milk, eggs, spinach,
iodine-substituted organic chemicals iodine without untoward effects.
and meat. The principal nutritional
used as x-ray contrast dyes contain
source of iodine is the supplementa- between 5 to 40 gm of iodine, and
tion of salt and milk for public health Acute and Subacute Thyroiditis
sufficient iodine may be released dur-
reasons and the addition of iodide in Acute thyroiditis, a rare disease, is
ing metabolism to affect thyroid io-
certain drugs and foods such as the dine metabolism. The chronic inges- easy to recognize but difficult to man-
use of iodates as preservatives for tion of up to 4 mg of iodine per day age. Among the 29 cases reported
breads. In areas of low iodine intake, has failed to reveal detrimental ef- since 1 950, there is equal sex distri-
clinical studies of populations sug- fects in normal persons. The inges- bution, usually the left lobe of the
gest a genetic predisposition to the tion of larger amounts, however, may thyroid is affected, and there have
development of goiter. Familial clus- interfere with normal thyroid iodine been several aerobic and anaerobic
ters of goiter occur in populations in metabolism. A transient, clinically un- organisms identified on culture. Most
which comparably low nutritional in- important interference with thyroid of the recent cases have been re-
S take of iodine occurs.
Although the ingestion of foods
hormone synthesis,
koff effect, occurs
the Wolff-Chai-
in normal individ-
ported from Japan where the disease
was found to be associated with a
that contain goitrogenic substances left pyriform sinus fistula. The orga-
uals. In a small portion of the popu-
usually does not result in thyrome- lation, however, there is a genetic nisms most commonly cultured from
galy, the use of these foods in areas inability to escape from this inhibition the lesions are Staphylococcus au-
of low dietary intake of iodine is as- when the blood iodide level exceeds reus, Streptococcus hemolyticus,
sociated with an increased incidence 20 zg/dl over a prolonged period; and pneumococcus. The patient has
of goiter. The goitrogenic substance a history of an antecedent upper res-
goiter and hypothyroidism result, the
in members of the genus Brassicae piratory infection followed by the ab-
so-called iodide goiter. The inges-
(family Cruciferae) of plants that in- tion of 1 0 to 200 mg of iodine per rupt onset of a very painful thyroid
dude cabbage is goitrin (l-5-vinyl-2- day, primarily from kelp or seaweed, gland associated with fever, chills,
thiooxazolidone). A similar effect may dysphagia, hoarseness, and sore
causes goiter in approximately 10%
be expected in patients from areas of of the population in one coastal area throat. The patients are in a toxic
low dietary intake of iodine who re- state from the infectious disease, but
of Japan, but rarely is hypothyroidism
ceive goitrogenic drugs such as p- seen. The fetal thyroid gland is sus- they are not thyrotoxic. Results of
aminosalicylic acid, lithium, and sulfis- ceptible to the inhibitory effects of thyroid function tests are usually nor-
oxazole (Gantrisin). Prior to the sup- iodine on thyroid hormone synthesis mal. Antimicrobial therapy should be
plementation of artificial infant for- and release. Hypothyroidism during instituted promptly once appropriate
mulas with iodide, thyromegaly was fetal life with irreversible damage to cultures are obtained. The presence
found in infants receiving soybean- the CNS will occur if there is exces- or development of an abscess of the
based formulas, as a result of the sive maternal intake of iodine during thyroid gland may be promptly iden-
binding of iodide in the intestinal tract pregnancy. At birth, the neonate will tified by ultrasonography of the thy-
and preventing absorption. This prob- have a goiter which may be large and roid. Thyroid function remains normal
lem has been prevented by iodide in most patients throughout the
compromise respiration. Although
supplementation.
biochemical hypothyroidism is rapidly course of the disease, and full recov-
corrected in the first few days of post- ery is expected.
natal life, thyromegaly may persist for Nonsuppurative, presumedly viral
Antithyroid Drugs
several weeks. inflammatory disease of the thyroid
The ingestion of excessive gland is referred to as subacute or
S The ofantithyroid
ment drugs for
Graves disease (PIU,the MMZ,
and CMZ) are not used in the long-
treat- amounts of iodine can result in goiter
with hypothyroidism or hyperthyroid-
granulomatous
ease is rarely reported
thyroiditis. The dis-
during child-
term treatment of other diseases. ism in patients with a second, unre- hood, occurring more frequently be-

pediatrics in review #{149} vol. 5 no. 9 march 1984 PIR 267

 Goiter

TABLE 5. Familial Dyshormonogenesis

Goiter 1231 Uptake Additional Diagnostic dnteria
S
Impaired thyroid response to 0 Normal or low No in vivo response to TSH
TSH
Iodide transport defect + Low No concentration of iodide by salivary glands
Oxidation defects + High Rapid [123l]iodide discharge from thyroid after oral
perchlorate
Pendred syndrome + High Nerve deafness; partial [1231]iodide dischargefrom thy-
roid after oral perchlorate
Thyroglobulin defects + Normal or high Exclusion of other defects; biopsy: absent or abnor-
mal thyroglobulin; low iodothyronine content
lodotyrosine deiodinase defect + High MIT and DIT in plasma and urine; no deiodination of
injected MIT or DIT
Thyroid hormone unresponsive- + Normal or high TSH basal levels and response to TRH inappropriate
ness defects (small) for high serum 14 and I3 levels; subnormal re-
sponses to large doses of T4 or T3

tween the third and fifth decades of inflammatory process recovers, there thyroidism at birth or at any age dur-
life and in women. The history usually is a gradual diminution in iodothyron- ing childhood or adolescence. An en-
reveals a recent upper respiratory in- me concentrations, gradual rise in se- larged thyroid gland is a characteris-
fection followed by constitutional rum ISH concentration and the up- tic feature of each disease except in
symptoms of an inflammatory proc- take of radioiodine, and an increase those patients with impaired thyroid
ess with tenderness of the thyroid in the titer of thyroid antibodies. The response to TSH. The patients with
gland. The disease may occur with- transient phase of hypothyroidism the group of thyroid hormone unre-
out pain or tenderness of the thyroid during recovery will vary in length and sponsiveness defects have either
gland, which may be a reason why it severity, but full recovery is expected small goiters or normal thyroid
is not frequently identified during and the detectable titers of thyroid glands. The serum levels of TSH are
childhood
ical examination
and adolescence. On phys-
the patient with sub-
antibodies
Symptomatic
eventually
therapy
disappear.
may be neces-
elevated
roid hormone
or, in patients with the thy-
unresponsiveness de- S
acute thyroiditis during childhood and sary during the initial phase of the fects, are inappropriate for the ele-
adolescence has either asympto- disease, and will include propranolol vated serum levels of 14 and 13. Ra-
matic goiter or has pain, swelling, and if symptoms of hyperthyroidism are dionudlide studies with [123I]iodide are
tenderness in the region of the thy- present and therapeutic doses of sa- important in distinguishing among the
roid gland. The patient will be euthy- licylates if local pain and tenderness various disease entities (Table 5). The
roid or have clinical symptoms of of the thyroid gland persist. Predni- uptake of radioiodine is normal or low
toxic thyroiditis indistinguishable from sone therapy is infrequently neces- in patients with impaired thyroid re-
those of toxic thyroiditis associated sary to control symptoms. A short- sponse to ISH and the iodide trans-
with CLI. Constitutional symptoms term course of L-thyroxine therapy port defect; the remaining defects be-
of a systemic inflammatory disease may be required if the serum 14 con- yond the ability of the thyroid gland
may be present and include fatigabil- centrations decrease below the nor- to concentrate iodide are associated
ity, malaise, weakness, and a low mal range. Permanent hypothyroid- with sometimes normal but usually
. grade fever. ism rarely occurs. elevated uptakes of radioiodine.
The expected results of laboratory Many of the diagnostic tests for
tests during the early phase of the Familial Dyshormonogenesis definitive diagnosis of the biochemical
disease include elevated levels of to- defect are not available except in re-
tal and free 14 and of 13, an unde- Our knowledge of the biosynthesis search laboratories. Some tests may
tectable level of ISH, either negative of thyroid hormones has been de- be performed by the clinician when
or low titers of thyroid antibodies, a rived to a large extent from the study the diagnosis of familial dyshormon-
low or absent uptake of radioactive of patients with the various types of ogenesis is suspected. If the radioio-
iodine, an elevated ESR, and a familial goiter known collectively as dine uptake is normal or low when
blunted or absent serum ISH re- familial dyshormonogenesis (Table measured two hours after administra-
sponse to IRH administration. 5). When sufficient data from the tion of the isotope, the simultaneous
The clinical course of subacute thy- study of families are available, they collection of saliva and plasma can
roiditis is variable, but it often prog- suggest an autosomal recessive be used to count the amount of radi-
resses through three phases (toxic mode of inheritance. Clinically af- oiodine in equal volumes of the two
thyroiditis, euthyroid goiter, and mild fected patients have either varying specimens to identify the iodide
hypothyroidism) before the patient fi- degrees
pensated
of hypothyroidism
hypothyroidism.
or com-
The clinical
transport defect (normally radioiodine S
nally has completely normal thyroid is concentrated tenfold or greater by
function. Relapse is common. As the disease may present goitrous hypo- saliva compared with plasma). If the

PIR 268 pediatrics in review #{149} vol. 5 no. 9 march 1984

 ENDOCRINOLOGY

uptake of radioiodine at two hours is TRH and the level of TSH can be

S elevated,
potassium theperchlorate
oral administration
will identify of
suppressed by exogenous
tration of thyroxine.
adminis-
The latter obser-
TABLE 6.
Dose of L-Thyroxine
Guidelines for Daily
in Patients
those patients with the defects in the vation suggests that the suppression with Hypothyroidism
oxidation of iodide to iodine since the of ISH secretion by thyroid hormone
uptake of radioiodide will be rapidly occurs only at higher than normal A e Dose Range Dose
g (pg) (,g/kg)
discharged from the thyroid gland of levels of 14 and 13, and that the pi-
0-6 mo 25-50 8-10
patients with this defect and, to a tuitary thyrotroph is partially resistant 6-12 mo 50-75 6-8
lesser extent, in patients with to the normal suppressive effects of 1-5 yr 75-1 00 5-6
Pendred syndrome. In patients with 14 and 13. In patients with pituitary 6-12 yr 100-150 4-5
high radioiodine uptake in whom the adenoma and hyperthyroidism, the >12 yr 100-200 2-3
diagnosis of iodine deficiency has basal levels of ISH are moderately * Specific dose must be individual-
been excluded, the administration of increased, do not increase further ized for each patient according to
potassium iodide to the patient with after IRH administration, and do not clinical and biochemical responses.
iodotyrosine deiodinase defect will re- suppress following exogenous thy- Patients with hypothalamic or pitui-
suIt in clinical and biochemical euthy- roxine administration. These findings tary hypothyroidism usually require
roidism and return of the thyroid suggest autonomous secretion of lower doses of L-thyroxine to main-
gland to normal size. These patients ISH by the adenoma. These dis- tam euthyrodism.
will also have increased concentra- eases are to be suspected in those
tions of MIT and DII in plasma and patients with mild hyperthyroidism;
urine. As these patients have either minimal, diffuse enlargement of the
clinical hypothyroidism or compen- thyroid gland; and increased concen-
sated hypothyroidism, they should be trations of ISH, 14, and 13. TABLE 7. Classification of
treated with oral L-thyroxine once Cancer of Thyroid
daily in a dose appropriate for age Carcinoma
(Table 6). With adequate thyroxine THYROID NEOPLASMS AND Papillary adenocarcinoma
replacement therapy, the size of the CYSTS Follicular carcinoma
thyroid gland will decrease to normal. Clear cell carcinoma
Local enlargements of the thyroid
Oxyphil carcinoma
gland may occur in specific areas of Mixed papillary and follicular
Hyperthyroidism Secondary to one or both lobes or in the isthmus carcinoma
Excessive Secretion of TSH of the gland. The most common Medullary carcinoma
cause of an asymmetrical, localized MEN syndrome Ila
Rarely, patients will develop mild MEN syndrome lIb
enlargement of the thyroid gland is
hyperthyroidism and mild, diffuse thy- Hashimoto thyroiditis. Solitary and Undifferentiated carcinoma
romegaly as a result of inappropriate multiple nodules must be evaluated, Small cell carcinoma
secretion of ISH. Affected patients however, in order to evaluate the Giant cell carcinoma
may or may not have an identifiable possibility of malignant or benign tu- Epidermoid carcinoma
pituitary adenoma; both sexes are Other malignant tumors
mor or cyst. Benign lesions that
involved with equal frequency. Hy- Lymphoma
cause anterior cervical masses during Sarcoma
perthyroidism is usually mild, associ- childhood include papillary or follicular
ated with minimal enlargement of the Malignant teratoma
adenoma or teratoma of the thyroid Secondary tumor
thyroid gland, and resistant to ther- gland, branchial cleft cyst, heman-
apy, with frequent recurrence of the gioma, neurofibroma, lymphangioma,
disease. In patients with pituitary ad- hemangioma, lymph nodes, or thy-
enoma, visual field defects may oc- roid cyst. Most malignant lesions of tients with thyroidal and nonthyroidal
cur, and clinical features associated the thyroid gland are carcinomas, but cysts.
with excessive secretion of other pi- other malignant tumors occur (lable
tuitary hormones such as growth hor-
7).
mone and prolactin have been re-
Diagnostic Evaluation
ported. In patients without demon-
Clinical Manifestations
strable pituitary adenoma, the map- The assessment of thyroid function
propriate secretion of ISH that The solitary mass of the thyroid and the examination for thyroid anti-
causes hyperplasia of the thyroid gland usually presents as an asymp- bodies are important tests for the
gland and hypersecretion of 14 and tomatic, nontender lesion. In the child diagnosis of Hashimoto thyroiditis as
13 is thought to occur as a result of with a solitary mass of the thyroid the cause of a solitary nodule of the
selective, partial pituitary resistance gland, there are certain historical fea- thyroid gland. The presence of pri-
to 14 and 13. In these patients, basal tures, symptoms, and signs that in- mary hypothyroidism and positive
S levels of ISH are slightly increased crease the suspicion
is malignant
that the lesion
(Table 8). The history of
tests for thyroid antibodies
evidence against the diagnosis
are strong
of a
above normal in association with high
circulating free 14 and 13 levels. There an increase and decrease in the size malignant lesion of the thyroid gland.
is an exaggerated ISH response to of the mass is characteristic for pa- Similarly, an elevated serum 13 level

pediatrics in review #{149} vol. 5 no. 9 march 1984 PIR 269

 Goiter

strates a small cystic lesion (less than to determine whether there is pul-
2 cm in diameter) the lesion is almost monary metastasis. In all instances,
TABLE 8. Thyroid Carcinoma:
Symptoms and Signs invariably benign and may be treated
by either periodic clinical evaluation
the patient must be maintained on S
thyroid suppressive therapy utilizing
History of previous cervical irradia-
and repeated ultrasonography at a dose of L-thyroxine that maintains
tion
Family history of thyroid tumors four- to six-month intervals, or by fine the serum 14 value slightly above the
Rapidly enlarging mass in region of needle aspiration and cytologic ex- upper limit of the normal range and
thyroid gland amination. An enlarging cystic mass the serum ISH value suppressed to
Midcervical and supraclavicular ad- of the thyroid gland or a mixed cystic undetectable levels.
enopathy and solid nodular mass should be Patients with medullary carcinoma
Hoarseness and/or dysphagia excised. of the thyroid should have total thy-
Enlarging mass on suppressive roidectomy and periodic evaluation
doses of L-thyroxine for the development of other tumors
Clinical Course and Management associated with the multiple endo-
crine neoplasia (MEN) syndromes Ila
Patients with primary hypothyroid- and lIb. These tumors include pitui-
in a patient with symptoms of mild ism and positive titers of thyroid anti- tary adenoma, parathyroid adenoma,
hyperthyroidism is suggestive of a bodies in association with asymmet- pheochromocytoma, and adrenocor-
functioning, benign thyroid adenoma, rical, nodular thyromegaly need no tidal tumors for MEN Ila and gastroin-
particularly if the size of the lesion is further diagnostic procedures; L-thy- testinal neuromas and pheochromo-
greater than 2.5 cm. A hyperfunction- roxine therapy should be started (Ta- cytoma in MEN lIb. The secretion of
ing thyroid carcinoma is exceedingly ble 6). If the histologic diagnosis of calcitonin following pentagastrin
rare. In addition to the determination an excised thyroid nodule shows a stimulation is a useful test for the
of thyroid function, it is imperative lymphoid follicule and chronic lym- presence of residual tumor following
that diagnostic procedures to deter- phocytic thyroiditis, and if thyroid surgery. Similar tests should be per-
mine the structure and consistency function tests are normal, the patient formed in members of the immediate
of the mass be obtained. Ultrasonog- should be followed for the develop- family since the disease is inherited
raphy can readily differentiate be- ment of primary hypothyroidism. Sur- as an autosomal dominant trait. Pa-
tween solid and cystic masses. The gical excision of a benign tumor or tients should be examined at six-
radionuclide scan is the most impor- cyst is usually curative and requires month intervals following surgery; the
tant diagnostic test for a solid mass no additional
The management
therapy.
and prognosis
prognosis for children and adoles- S
lesion of the thyroid gland. The pre- cents with papillary carcinoma, mixed
ferred isotope for the thyroid scan for the child with a malignant tumor follicular-papillary carcinoma, and fol-
should be [1231]iodide. The absence of the thyroid vary with the histology licular carcinoma of the thyroid is gen-
of uptake of the isotope in the area of the tumor, the presence and extent erally very good. Long-term survival
of the nodule (cold nodule) is sugges- of local or distant metastatic tumors, is expected with these tumors unless
tive of a malignant lesion of the thy- and the ability of the tumor to con- extensive metastatic disease is pres-
roid gland, and surgical excision of centrate iodide. Surgical excision of ent at the time of initial diagnosis.
the lesion is indicated. If the nodule malignant lesions of the thyroid is
is the only area that accumulates the generally accepted as the initial
isotope (hot nodule), the treatment of method of therapy, but the extent of
SUMMARY
the patient will depend on the results the surgical procedure remains con-
of thyroid function tests and clinical troversial. Some advocate lobectomy The diagnostic evaluation of the
symptomatology. If the patient is din- and subtotal thyroidectomy if an iso- patient with thyromegaly will be de-
ically hyperthyroid, the mass lesions lated lesion of papillary carcinoma is termined by the clinical history and
will usually exceed 2 cm in diameter identified and the regional lymph an examination of the thyroid gland
and the serum 13 level will be ele- nodes do not contain metastatic tu- (Table 9). In most instances the di-
vated. Surgical excision of the lesion mor. When there is metastatic dis- agnosis will not be in doubt, and only
is the preferred method of treatment ease, ablative therapy with radioio- a few tests will be necessary. For
for the toxic hot nodule. When the dine following thyroidectomy and sur- example, the euthyroid adolescent fe-
thyroid nodule on scan is neither a gical excision of metastatic disease male with an asymmetrically or sym-
hot nor a cold nodule and thyroid is indicated. metrically enlarged, firm thyroid gland
function tests are normal, the patient In follicular carcinoma or mixed has a presumptive diagnosis of CLI,
should be observed for six months or papillary-follicular carcinoma, total and only tests of thyroid function (14
be given suppressive doses of L-thy- thyroidectomy, excision of regional and ISH) and thyroid antibodies may
roxine. During suppressive L-thyrox- lymph nodes for the detection of met- be needed for confirmation. Similarly,
me therapy, the mass should regress astatic disease, and ablative therapy the patient with clinical symptoms
in size over a 12-month period. If the with radioiodine approximately three and signs of hyperthyroidism, exo-
size of the lesion does not decrease,
the nodule should be excised.
months
mended.
later are generally
A chest roentgenogram
recom- phthalmus, and a diffusely
soft thyroid gland has a presumptive
enlarged, S
When ultrasonography demon- should be performed preoperatively diagnosis of Graves disease. The

PIR 270 pediatrics in review #{149} vol. 5 no. 9 march 1984

 ENDOCRINOLOGY

TABLE 9. Diagnostic Evaluation of Thyromegaly

Clinical . Thyroid Additional
Presentation Etiology Function Tests Diagnostic Tests
Smooth symmetrical, dif- 1. Family history 1 . Serum 13 (thyrotoxicosis) 1. 1231[iodide] uptake at 4-6
fuse enlargement 2. Goitrogen and drug his- 2. Serum T4 (hypothyroid- and 24 hours
tory ism and hyperthyroidism) 2. TRH test
3. Serum thyroid antibodies 3. Serum TSH (hypothyroid- 3. 13 suppression test
ism) 4. Perchlorate discharge test
Firm, irregular enlarge- 1. Family history 1 . Serum TSH (hypothyroid- 1 . Perchlorate discharge test
ment 2. Serum thyroid antibodies ism)
2. Serum 14 (hypothyroid-
ism and hyperthyroidism)
Thyroid nodule 1 . Radiation exposure 1 . Serum 13 (thyrotoxicosis) 1 . 13 suppression test to eval-
2. Ultrasonography of neck 2. Serum I4 (hypothyroid- uate autonomous hyperse-
3. 1231[iodide] or technetium ism and hyperthyroidism) cretion
scan 3. Serum TSH (hypothyroid- 2. Serum thyroglobulin
4. Serum thyroid antibodles ism) 3. Serum calcitonin response
5. Biopsy to pentagastrin

necessary tests include only a meas- and a tender or nontender enlarged may give abnormal results in patients
urement of 14, an estimate of free 14, thyroid gland may have subacute thy- with CLI is the perchlorate discharge
and WBC and differential counts prior roiditis; a low or absent uptake of test.
to the initiation of antithyroid drug radioiodine with high-normal or ele- The approach to the patient with
therapy. vated 14 and 13 concentrations will the solitary thyroid nodule differs
In the absence of an obvious diag- be suggestive of that diagnosis. from that of the previously described
nosis, the clinician will select the spe- In patients with thyromegaly and clinical presentations. The most im-
cific diagnostic tests depending upon mild symptoms of hyperthyroidism, a portant studies for the patient with a
S the examination
The cause of smooth,
of the thyroid gland.
symmetrical,
TRH test will help to discriminate
perthyroxinemia secondary
hy-
to in-
thyroid nodule are those designed
determine the structure and consist-
to

diffuse enlargement of the thyroid creased or abnormal serum thyroxine ency of the thyroid gland, namely,
gland can be suspected with careful binding proteins from early Graves ultrasonography to distinguish be-
history for familial disease, history of disease, factitious hyperthyroidism, tween solid and cystic lesions, and
exposure to goitrogens and goitro- toxic thyroiditis, and ISH-mediated the radionudlide scan to determine
genic drugs, and the determination of hyperthyroidism. Ihe 13 suppression whether the nodule is functioning
thyroid antibodies in serum. If the test is a definitive diagnostic test for (hot) or nonfunctioning (cold). To as-
clinical history is suggestive of hyper- early, mild Graves disease. sure that the thyroid nodule is not
thyroidism, the tests of thyroid func- The euthyroid patient with mild-to- associated with a nonsurgical lesion
tion should include determination of moderate thyromegaly and tests that such as Hashimoto thyroiditis, serum
serum 13 concentration; if the history are negative for thyroid antibodies thyroid antibody determinations are
is compatible with euthyroidism or usually deserves no further diagnos- important. As malignancy of the thy-
hypothyroidism, thyroid function tic evaluation, but should be followed roid gland is usually not associated
tests should include determination of with a presumptive diagnosis of idio- with abnormalities of thyroid function,
serum ISH concentration for the pathic goiter or mild CLI. On follow- it is important to perform laboratory
presence of compensated primary up evaluation, initially at six-month tests to exclude hyperthyroidism (a
hypothyroidism. If results of these intervals and subsequently at yearly serum 13 determination) and hypo-
tests are normal, no additional tests intervals, the patient should have a thyroidism (a serum ISH determina-
are necessary, and the patient should clinical and biochemical assessment tion) at the time of initial evaluation.
be reassured and seen again in six until thyromegaly regresses and the Additional tests are usually not nec-
months. gland is normal in size and consist- essary unless the patient had mild
If the patient has a test that is ency. hyperthyroidism with an autono-
negative for thyroid antibodies and The patient with a nontender, firm, mously functioning nodule, in which
an elevation of serum TSH concen- irregular enlargement of the thyroid case the 13 suppression test and
tration, a radioactive [123l]iodide up- gland usually has CLI. If results of IRH test are often useful; rarely, the
take and perchlorate discharge test thyroid function tests are normal and ISH stimulation test is helpful in de-
will be helpful in the diagnosis of fa- tests for thyroid antibodies are neg- terming whether thyroid tissue
S milial dyshormonogenesis. The pa- ative, the patient should be seen throughout the remainder of the
tient with constitutional symptoms of again in four to six months and serum gland is suppressed. A solitary, solid,
inflammatory disease, history of a re- thyroid antibody determinations nonfunctioning (cold) nodule requires
cent upper tract respiratory infection, again performed. Another test that excisional biopsy.

pediatrics in review #{149} vol. 5 no. 9 march 1984 PIR 271

Goiter

SUGGESTED READING roiditis, inKaplan SA (ed): Clinical Pediatric 1975

and Adolescent Endocrinology. Philadelphia, Stanbury JB, Dumont JE: Familial goiter and
Clayton GW: Thyrotoxicosis in children, in Ka-
plan SA (ed): Clinical Pediatric and Adoles-
WB Saunders Go, 1982, pp 96-109
Hopwood NJ, Rabin BS, Foley TP Jr, et al:
related disorders, in Sanbury JB, Wyngaar-
den JB, Fredrickson DS (eds): The Metabolic
S
cent Endocrinology. Philadelphia, WB Saun- Thyroid antibodies in children and adoles- Basis of Inherited Disease, ed 5. New York,
ders Go, 1982, pp 110-117 cents with thyroid disorders. J Pediatr 93:57, McGraw-Hill Book Go, 1983, chap 11, pp
Fisher DA, Oddie TH, Johnson DE, et al: The 1978 231-269
diagnosis of Hashimoto thyroiditis. J Clin lngbar SH, Woeber KA: The thyroid gland, in Strakosch CR, Wenzel BE, Row VV, et al:
Endocrinol Metab 40:795, 1975 Williams RH (ed): Textbook of Endocrinology, Immunology of autoimmune thyroid disease.
Fisher DA, Sack J, Oddie TH, et al: Serum T4, ed 6. Philadelphia, WB Saunders Go, 1981, N EngI J Med 307:1499-1 507, 1982
TBG, T3 uptake, T3, reverse T3 and TSH chap 4 Werner SC, Ingbar SH (eds): The Thyroid, ed
concentration in children 1 to 15 years of Rallison M, Dobyns B, Keating F, et al: Occur- 4. New York, Harper and Row Publishers,
age. J C/in Endocrinol Metab 45:191, 1977 rence and natural history of chronic lympho- nc, 1978
Foley TP Jr: Acute, subacute and chronic thy- cytic thyroiditis in children. J Pediatr 86:675,

Department of Additional Information

Rectal Bleeding
After reading Rectal Bleeding in Childhood by Hillemeier (PIR 5:35, 1983), I would
like to raise a question concerning the child with lower rectal bleeding and a demon-
strable anal fissure.
In the article, the statement is made, Once the determination has been made that
the child has rectal bleeding from the lower GI tract, an endoscopic procedure is
required. I would question the necessity of endoscopy with its additional complexity
and definite increased costs as a requirement in the treatment of children with anal
fissures. Obviously, some clinical judgment is necessary as the presence of an anal
fissure does not rule out disease above, but in many clinical situations, a diagnosis
can be made and appropriate therapy can be initiated without endoscopy. An additional
problem, which has occurred frequently in my experience, is that many of the children
with anal fissures have considerable constipated stool present at the time of their visit
and the endoscopy requires an additional visit.
In the absence of abdominal
clinical setting that is confirmatory
pain or any evidence of significant
of an anal fissure, I would suggest
strable fissure may be treated without endoscopy.
bleeding and in a
that a demon- S
E. IDE SMITH, MD
Oklahoma City
Dr Hillemeier answers: I certainly appreciate the point that the child with an anal
fissure demonstrable on physical examination would not necessarily have to have a
sigmoidoscopy if the lesion was responding to appropriate therapy. The statement,
Once the determination has been made that the child has rectal bleeding from the
lower Gl tract, an endoscopic procedure is required, was made in reference to the
child who has an acute rectal bleeding episode of unknown etiology. If a nasogastric
tube and/or upper panendoscopy have failed to reveal the source of bleeding in a
patient who has significant amounts of blood per rectum, then an endoscopic proce-
dure should be required.

Other Causes of Red Urine

I am writing in reference to Hematuria in Childhood by Kaplan (PIR 5:99, 1983).
In Table 1 are listed several causes for red urine. Under discolored urine, external
pigments, drugs, I would like to suggest that rifampin be included. This is particularly
important because many physicians are using this drug as prophylaxis in the treatment
of Haemophilus influenzae type B carriers. This drug produces red urine in almost all
who take the substance. I suspect that currently, at a national level, this single agent
is presently more responsible for red urine than all of the other agents added together.
Fortunately, this is a totally reversible process, despite possible other harmful side
effects.
D. C. HEFELFINGER, MD
University, Alabama
I wondered, as I went through Kaplans fine review, whether from oversight, or
perhaps experience different from my own, he mentioned only en passant viral
trigonitis, for which serveral serotypes of adenoviruses have been accused, and which
we seem to see in a brief flurry of cases here in Washington,
They are characterized by dysuria, and gross hematuria,
DC area most years.
often worse at the termination S
of micturition. They have sterile urine and a benign course. We have tended, especially

PIR 272 pediatrics in review #{149} vol. 5 no. 9 march 1984