IM BOARD REVIEW DAVID L. LONGWORTH, MD, JAMES K.
STOLLER, MD, EDITORS
G R E G G H . FA I M A N , MD CHARLES FAIM AN,
Department of Endocrinology, Chairman, Department of
Cleveland Clinic. Endocrinology, Cleveland Clinic.
A 29'year-old man
with abnormal thyroid function tests
0 29-YEAR-OLD CAUCASIAN
referred to a tertiary care outpatient
clinic for evaluation of hyperthyroidism.
MAN
Earlier, during an investigation of diarrhea, he
had been found to have a total serum thyroxine
(T 4 ) value of 20.9 pg/dL (normal: 4-5-12.0),
and a total triiodothyronine ( T j ) value of 299
ng/dL (normal: 60-181). His primary care
physician had prescribed propylthiouracil,
which the patient had not taken.
T h e patient denies symptoms erf tempera-
ture intolerance, tremor, edema, visual abnor-
malities, or weight change. He takes cisapride
for gastrointestinal reflux, but no other med-
ications. He does not know of any family
members with thyroid abnormalities.
Physical examination reveals a euthyroid
man, 178 cm in height and 106.4 kg in weight.
His blood pressure is 124/80 mm Hg sitting, and
his resting heart rate is 66 beats per minute. His
thyroid gland is nontender and normal in size,
shape, and texture. There is no evidence of
exophthalmos, tremor, or hyperreflexia.
WHEN IS HYPERTHYROXINEMIA
NOT HYPERTHYROIDISM?
1 W h a t single test would be most helpful in
delineating the patient's thyroid status?
• T S H (thyroid-stimulating hormone)
•
• Thyroid receptor antibodies
Radioactive iodine uptake and scan
J T 3 resin uptake ( T 3 R U )
• None of the above
A n ultrasensitive T S H assay is the single best
indicator of thyroid function and should be
used as the initial screening test in patients
suspected of having either hypo- or hyperthy-
C L E V E L A N D C L I N I C J O U R N A L OF M E D I C I N E
A SELF-TEST
OF CLINICAL
MD
RECOGNITION
is roidism. T h e patient's laboratory report came
back the next day showing a T S H level of 0.6
pU/mL (normal: 0.4-5.5). In addition, his free
T4 value was 1.4 ng/dL (normal: 0.8-1.8).
• WHAT IS THE NEXT STEP?
You should now do which of the following?
• Order a radioactive iodine uptake
and scan
• Order thyroid receptor antibodies
• Observe and reassure the patient
• Start propylthiouracil
• Consult an endocrinologist
Serum T4
T h e correct approach is observation and reas-
surance. This patient has no symptoms or clin-
measures
ical signs of hyperthyroidism, and his T S H and both free T4
free T 4 levels are normal. The most likely
explanation for the elevations in total T 4 and
and protein-
T 3 is an elevation in a thyroid-binding protein. bound L
m T 4 and T 3 , BOUND AND FREE
O f the T4 and T3 in the circulation, more than
99% is bound to proteins, primarily thyroxine-
binding globulin ( T B G ) and transthyretin
(also called thyroxine-binding prealbumin).
Normally, 7 5 % to 80% of T 4 binds to T B G ,
with nearly all of the remainder binding to
transthyretin and albumin. 1 Only free T 4 and
T3 are biologically active; the bound T 4 and T3
serve as reservoirs for the free hormones. T h e
serum T 4 value is a measure of both free T 4 and
the T 4 that is bound to protein.
Because T B G binds both T4. and T 3>
whereas transthyretin binds T 4 alone, the bio-
chemical findings in this patient support the
VOLUME 65 • NUMBER 3 MARCH 1998 123
 EUTHYROID HYPERTHYROXINEMIA FAI M A N A N D FAI M A N

TABLE 1

Conditions associated with alterations

in thyroxine-binding globulin (TBG) concentration
CONDITION INCREASED TBG DECREASED TBG

Genetic Inherited TBG excess Inherited TBG deficiency (complete and partial)
Hormonal Hyperestrogenic states Androgen and anabolic steroid use
Choriocarcinoma
Estrogen-producing tumors
Estrogen therapy
Newborn state
Pregnancy (especially molar)
Drug use Clofibrate Glucocorticoids
5-Fluorouracil L-Asparaginase
Heroin
Methadone
Nicotinic acid
Perphenazine
Tamoxifen
Diseases Acute intermittent porphyria Acromegaly (active)
Acute viral hepatitis Carbohydrate deficient glycoprotein syndrome
Only free T3
Chronic active hepatitis Cirrhosis of liver
and T4 are
Collagen diseases Galactosemia
biologically
Hepatocellular carcinoma Hyperthyroidism
active
HIV infection Major illness
Hypogammaglobulinemia Nephrotic syndrome
Hypothyroidism Protein-calorie malnutrition
Myeloma Protein-losing enteropathy
Primary biliary cirrhosis

SOURCE: MODIFIED F R O M REFETOFF A N D NICOLOFF, REFERENCE 1

diagnosis of euthyroid hyperthyroxinemia due • WHAT CAN CAUSE AN EXCESS

to T B G excess. This condition was confirmed OF THYROXINE-BINDING GLOBULIN?
by obtaining a T B G level, which was elevated
at 70 pg/mL (normal: 12.2-33.0). N o further T h e serum T B G concentration can increase
evaluation was required, and the patient was or decrease with use of a variety of drugs, and
advised against taking the antithyroid medi- in many diseases and hormonal conditions
cine recommended by the referring doctor. ( T A B L E N ) . 1.2

124 C L E V E L A N D C L I N I C J O U R N A L OF MEDICINE V O L U M E 65 • N U M B E R 3 MARCH 1998

 Hereditary T B G excess was first described TABLE 2
in 1959. 3 T B G is a 54-kDa acidic glycoprotein Causes of euthyroid
encoded by a single gene copy, mapping to the
hyperthyroxinemia
q22.2 band region of the long arm of the
human X chromosome.4 Numerous analyses A l t e r e d T4 b i n d i n g
have indicated that all inherited T B G abnor- Increased TBG level
malities are X-chromosome linked. 5 - 9 G e n e Liver diseases
amplification has recently been reported to be Acute Intermittent porphyria
the cause of hereditary T B G excess in two Hepatitis
families. 10 However, other causes remain pos- Primary biliary cirrhosis
sible. 1 - 11 T h e prevalence of euthyroid hyper- Drugs
thyroxinemia caused by hereditary excess of Narcotics
T B G in the general population is 1 in 25,000 5-Fluorouracil
live births. 12 Clofibrate
N o direct relationship exists between Hyperestrogenlsm
defective types of T B G and other diseases. Estrogen therapy
T B G defects have been reported in patients Estrogen-producing tumors
with mental retardation, Turner's syndrome Pregnancy
and mosaic variants, goiter, ectopic thyroid, Chorionic gonadotropln-produclng tumors
asthma, pernicious anemia, herpes infection, Newborns
hyperlipoproteinemia, and hereditary anhy- Lymphosarcoma
drotic ectodermal dysplasia, but the associa- X-llnked hereditary excess
tions were thought to coincidental. 1 1 Familial dysalbumlnemla
Increased transthyretin (binds T 4 alone)
• T 4 A N D T 3 UPTAKE TESTING Hereditary or acquired
IN HEREDITARY TBG EXCESS Thyroid hormone binding autoantibodies

A l t h o u g h many causes of euthyroid hyper- T h y r o x i n e resistance

thyroxinemia have been described (TABLE 2 ) , 1 2
Generalized A TSH assay
a careful history and physical examination, Selective resistance to intracellular transport of T4
coupled with the prudent use of laboratory
is the best
N o n t h y r o i d a l illness
evaluations, should yield the correct diagno- Medical or surgical indicator of
sis. Physicians should consider the diagnosis
of hereditary T B G excess to avoid unneces-
Psychiatric thyroid
sary and potentially harmful treatment. Drugs function
Because the results of thyroid uptake tests Oral cholecystography agents
are frequently misinterpreted, we include a Amlodarone
brief summary below. Amphetamines
T 4 u p t a k e ( T 4 U ) is the amount of fluo- Heparin
rescein-labeled T4 that binds to serum pro- Propranolol (high doses)
tein. T h e result is expressed as a binding ratio
High altitude
compared with a control serum pool. T h e nor- SOURCE: F R O M TUCKER, REFERENCE 12
mal range varies from laboratory to laboratory;
at our hospital, it is 0.7 to 1.2. mmmmmmmmmmmmmmmmmmmmmmmHmmBmmmmmmm
T h e free thyroxine index ( F T 1 ) is the
total T4 level divided by the T4U. Thus, an
elevated total T 4 level caused by T B G excess beled T 3 instead of fluorescein-labeled T4)
would be adjusted downwards by the con- and measures the proportion of trace ligand
comitant elevation in the T | U , yielding a unbound to serum protein and trapped by an
normal FT1 value (ie, 6.4 to 10.7 pg/dL). added resin sponge. Results are usually
T 3 resin u p t a k e ( T 3 R U ) , in contrast to expressed as a percentage bound to the resin,
T4U, makes use of a different ligand (radiola- and a new value, termed T7, is derived: T3RU

C L E V E L A N D C L I N I C J O U R N A L OF M E D I C I N E VOLUME 65 • NUMBER 3 MARCH 1998 1 2 7

 . _ . FAIMAN AND FAIMAN

L J
T H E C L E V E L A N D CLINIC FOUNDATION

X total T 4 ) . Similar to the T 4 U test described

above, values may also be expressed as a ratio
to a control serum pool. In this case, however,
1 Oth Annual the FT1 is calculated in an obverse manner:
FTI = total T 4 x T 3 R U ratio.

INTENSIVE Patients with hereditary T B G excess have

elevations in T 4 , and T 4 U , and decreased

REVIEW T^RU values. These abnormalities are often

found incidentally. However, their values for
T S H , FTI, free T 4 , and free T 3 are normal.

OF Clinically, the patients are euthyroid and fre-

quently have a family history of abnormal thy-

INTERNAL roid function tests.

• REFERENCES
^

MEDICINE 1. R e f e t o f f S, N i c o l o f f JT. T h y r o i d h o r m o n e t r a n s p o r t a n d
m e t a b o l i s m . In: D e g r o o t U , Besser M , B u r g e r H G , e t a l ,
editors. Endocrinology, 3rd ed. Philadelphia: W B
Saunders, 1995:560-582.
2. S e l l m e y e r D E , G r u n f e l d C. E n d o c r i n e a n d m e t a b o l i c dis-
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3. B e l e r w a l t e s W H , R o b b l n s J. F a m i l i a l i n c r e a s e in t h e t h y -
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4. M o r l Y, Y o s h i t a k a M , O l s o Y , H i s a o S, T a k a z u m i K.
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g l o b u l i n g e n e t o c h r o m o s o m e X q 2 2 . 2 by f l u o r e s -
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June 7-12, 1998

6. R e f e t o f f S, R o b i n N l , A l p e r C A . S t u d y o f f o u r n e w k i n -
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Renaissance Cleveland Hotel 8.

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t w o J a p a n e s e families. J Clin E n d o c r i n o l M e t a b 1995;
80:3758-3762.

T h e Cleveland Clinic Educational Foundation 11. R e f e t o f f S. I n h e r i t e d t h y r o x i n e - b i n d i n g globulin

a b n o r m a l i t i e s in m a n . E n d o c r i n e R e v 1 9 8 9 ;
Continuing Education Department 10:275-293.
9 5 0 0 Euclid Avenue, T T - 3 1 12. Tucker W S . Euthyroid hyperthyroxinemla d u e to familial
Cleveland, O H 4 4 1 9 5 excess o f t h y r o x l n e - b i n d i n g g l o b u l i n . S o u t h M e d J 1 9 8 9 ;
82:368-371.
216-444-5695
800-762-8173 ADDRESS: Charles Faiman, MD, Department of Endocrinology,
A30, The Cleveland Clinic Foundation, 9500 Euclid Avenue,
216-445-9406 (FAX) Cleveland, OH 44195.

C L E V E L A N D C L I N I C J O U R N A L OF M E D I C I N E VOLUME 65 • NUMBER 3 MARCH 1998