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MINICASE 2
Hyperosmolar Hyperglycemia State Secondary to Uncontrolled
Type 2 Diabetes Mellitus
Jimmy C. is a 63- year- old African American man with a 19- year
history of type 2 DM, hypertension, and dyslipidemia. He lives alone.
His medication list includes metformin 1,000 mg BID, simvastatin
20 mg daily at bedtime, lisinopril 20 mg daily, hydrochlorothiazide
25 mg daily, and ASA 325 mg daily. He monitors his blood glucose
once a day, and his results have ranged from 215 to 400 mg/dL. His
fasting blood glucose has averaged 200 mg/dL over the last week.
He reports frequent urination throughout the day and night, which
has increased over the last 6 days. He denies any nausea or vomiting
but states he has not had much of an appetite lately. His daughter
accompanies him to the doctor’s office because she thinks he has
not been his usual self lately.
The physical examination reveals a disoriented and confused man
with vital signs including BP 120/60mm Hg (which decreased to
100/60 when standing); HR 100 beats/min; RR 20 breaths/min (deep
and regular); and oral temperature 101.4°F (38.6°C). His skin turgor
is poor, and his mucous membranes are dry. His laboratory results
are as follows:
• Sodium, 139 mEq/L (136 to 142 mEq/L)
• Potassium, 4.6 mEq/L (3.8 to 5 mEq/L)
• Chloride, 102 mEq/L (95 to 103 mEq/L)
• BUN, 50 mg/dL (8 to 23 mg/dL)
• SCr, 1.2 mg/dL (0.6 to 1.2 mg/dL)
• Phosphorus, 2.7 mg/dL (2.3 to 4.7 mg/dL)
• pH, 7.38 (7.36 to 7.44)
• Bicarbonate, 26 mEq/L (21 to 28 mEq/L)
• Hct, 39% (42% to 50%)
• WBC count, 9.4 × 10
3
10
cells/mm3)
• Calcium, 9 mg/dL (9.2 to 11 mg/dL)
• Glucose, 715 mg/dL (70 to 110 mg/dL)
• Ketones, 0 (normal = 0)
• Osmolality, 335 mOsm/kg (280 to 295 mOsm/kg)
• Triglycerides, 174 mg/dL (10 to 150 mg/dL)
• Lipase, 1.4 units/mL (<1.5 units/mL)
• Magnesium, 2 mEq/L (1.3 to 2.1 mEq/L)
• Hemoglobin A1c, 9.5 (4% to 5.6%)
QUESTION: Based on the subjective and objective data provided,
what is the most likely diagnosis for this patient? What signs and
symptoms support the diagnosis? What could have precipitated
this disorder?
3
cells/mm3 (4.8 to 10.8 ×
DISCUSSION: Jimmy C. is older than 60 years. HHS occurs most
frequently in patients older than 60 years. He reports symptoms
for more than 5 days. He has decreased skin turgor, dry mucous
membranes, tachycardia (HR 100 beats/min), and orthostatic
hypotension (a fall of systolic BP 20mm Hg after 1 minute of
standing), which are consistent with dehydration. He is lethargic,
confused, and disoriented. Patients with HHS are generally more
dehydrated than patients with DKA; therefore, mentation changes
are more commonly seen in patients with HHS than in DKA. Elderly
persons often have an impaired thirst mechanism that increases
the risk of HHS. Jimmy C.’s plasma glucose level is >600 mg/dL;
bicarbonate concentration is normal; and pH is normal. Negative
ketone bodies <2+ in 1:1 dilution confirms the diagnosis of HHS
(and not DKA, in which ketones are present in the blood and urine
of patients). Insulin deficiency is less profound in HHS; therefore,
lipolysis resulting in the production of ketone bodies does not occur.
His plasma osmolarity can be estimated using a formula:
The estimated osmolality is (2 × 139) + (715/18) + 50/2.8 =
335 mOsm/kg, which is the same as the actual laboratory value.
Massive fluid loss due to prolonged osmotic diuresis secondary to
hyperglycemia may have precipitated the onset of HHS.
The patient should be given IV fluids for hydration because of
the mental status changes. An IV insulin drip should also be
administered. Although his sodium and potassium are within normal
limits, the presence of orthostatic hypotension is consistent with
decreased intravascular volume, causing hemoconcentration of
sodium and potassium. These levels may decline when the patient
is rehydrated with fluids. Potassium replacement is required.
Phosphorus is also within normal limits but may decrease after
rehydration and insulin. Decreased intravascular volume has led to
hemoconcentration of Hct and BUN, which is also elevated because
of decreased renal perfusion (prerenal azotemia), although intrinsic
renal causes should be considered if SCr is also elevated.
Given the patient’s symptoms and diagnosis of HHS, metformin
in combination with a onceadministered at breakfast or bedtime is a reasonable option because
he did not obtain glycemic control on oral agent(s). Metformin can
be continued if glomerular filtration rate >30 mL/min/1.73m2 and
long- acting insulin can be administered at bedtime.
pOsm = (2 × serum sodium) + glucose/18 + BUN/2.8
daily injection of long- acting insulin
Based on results of landmark studies, the ADA recommends
angiotension- converting enzyme (ACE) inhibitors or angiotension receptor blockers (ARBs) for the treatment of both
moderately increased albuminuria (previously termed micro-
albumuria and dened as a urinary albumin excretion 30 to
299 mg/day) and severely increased albuminuria (previously
termed macroalbuminuria and dened as a urinary albumin
excretion >300 mg/day). If one class is not tolerated, the other
should be substituted.
e leading cause of death in patients with DM is cardiovascular disease. Control of hypertension and dyslipidemia is
necessary to decrease the risk of macrovascular complications.
Under the new American College of Cardiology and American
Heart Association lipid guidelines, patients should be placed on
statin medications based on risk stratication and treated with
varying intensity statin dosing regimens.
51,52
Patients with DM and hypertension should be treated with
pharmacologic therapy regimen that includes either an ACE
CHAPTER 9 • EndoCRinE disoRdERs 177
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inhibitor or an ARB.50 Although ARBs have been shown to
delay the progression of nephropathy in patients with type 2
DM, hypertension, moderately increased albuminuria, and renal
insuciency, ACE inhibitors are the initial agents of choice in
patients with type 1 DM with hypertension and any degree of
albuminuria. iazide diuretics, β- blockers, or calcium channel
blockers should be used as an add- on agent to further decrease
BP (blood pressure). Avoidance of nephrotoxic drugs and use
of SGLT2i therapy is also recommended.
50
Anatomy and Physiology
e thyroid gland is a buttery- shaped organ composed of two
connecting lobes that span the width of the trachea. e thyroid
produces the hormones thyroxine (T4) and triiodothyronine
(T3). Approximately 80 and 30 mcg of T4 and T3, respectively, are
produced daily in normal adults. Although T4 is produced solely
by the thyroid gland, only about 20% to 25% of T3 is directly
secreted by this gland. Approximately 80% of T3 is formed by
hepatic and renal deiodination of T4.
T4 has a longer half- life than T3, approximately 7 days versus
1day, respectively. At the cellular level, however, T3 is three to
four times more active physiologically than T4.49 When the conversion of T4 to T3 is impaired, a stereoisomer of T3, known as
reverse T3, is produced; reverse T3 has no known biological eect.
yroid hormones have many biological eects, both at the
molecular level and on specic organ systems. ese hormones
stimulate the basal metabolic rate and can aect protein, carbohydrate, and lipid metabolism. ey are also essential for normal growth and development. yroid hormones act to do the
following tasks:
• Stimulate neural and skeletal development during fetal life
• Stimulate oxygen consumption at rest
•
Stimulate bone turnover by increasing bone formation and
resorption
• Promote conversion of carotene to vitamin A
• Promote chronotropic and inotropic eects on the heart
•
Increase number of catecholamine receptors in heart muscle
cells
• Increase basal body temperature
• Increase production of RBCs
• Increase metabolism and clearance of steroid hormones
• Alter metabolism of carbohydrates, fats, and protein
• Control normal hypoxic and hypercapnic respiratory drives
e synthesis of thyroid hormones depends on iodine and
the amino acid tyrosine. e thyroid gland, using an energyrequiring process, transports dietary iodide (I—) from the circulation into the thyroid follicular cell. Iodide is oxidized to iodine
(I2), and then combined with tyrosyl residues within the thyroglobulin molecule to form thyroid hormones (iodothyronine).
us, thyroid hormones are formed and stored within the thyroglobulin protein for release into the circulation.
53
54,55
Both T4 and T3 circulate in human serum bound to three proteins: thyroxine- binding globulin (TBG); transthyretin, previously known as thyroid- binding prealbumin; and albumin. Of the
three proteins, 80% of T4 and T3 is bound to TBG. Only 0.02%
of T4 and 0.2% of T3 circulate unbound, free to diuse into tissues. e “free” fraction is the physiologically active component.
Total and free hormones exist in an equilibrium state in which
the protein- bound fraction serves as a reservoir for making the
free fraction available to tissues.
55
yroid hormone secretion is regulated by a feedback mechanism involving the hypothalamus, anterior pituitary, and thy
roid gland itself (Figure9-2). e release of T4 and T3 from
the thyroid gland is regulated by thyrotropin, also called thyroid
stimulating hormone (TSH), which is secreted by the anterior
pituitary. e intrathyroidal iodine concentration also inuences
thyroid gland activity, and TSH secretion primarily is regulated
by a dual negative feedback mechanism:
yrotropin- releasing hormone (TRH), or protirelin, is
released by the hypothalamus, which stimulates the synthesis
and release of TSH from the pituitary gland. Basal TSH concentrations in persons with normal thyroid function are 0.3 to
5milliunits/L. e inverse relationship between TSH and free
T4 is logarithmic. A 50% decrease in free T4 concentrations leads
to a 50- fold increase in TSH concentrations and vice versa.49
Unbound T4 and T3 (mainly the concentration of intracellular
T3 in the pituitary) directly inhibit pituitary TSH secretion. Consequently, increased concentrations of free thyroid hormones
cause decreased TSH secretion, and decreased concentrations
of T4 and T3 cause increased TSH secretion.
55
Prolonged exposure to cold and acute psychosis may activate
the hypothalamic- pituitary- thyroid axis, whereas severe stress
may inhibit it. Although TRH stimulates pituitary TSH release,
somatostatin, corticosteroids, and dopamine inhibit it. Small
amounts of iodide are needed for T4 and T3 production, but
large amounts inhibit their production and release. Evidence
from the most sensitive assays suggests that no physiologically
relevant change in serum TSH concentrations occurs in rela-
T3T4
54
Hypothalamus
TRH (+)
(–)
Pituitary
Thyroid
TSH (+)
T3T4
(+)
tion to age.
FIGURE 9-2. The hypothalamic- pituitary- thyroid axis.
-
178 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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Thyroid Disorders
Patients with a normally functioning thyroid gland are said to be
in a euthyroid state. When this state is disrupted, thyroid disease
may result, which occurs four times more oen in women
than in men. yroid disease may occur at any age but peaks
between the third and sixth decades of life. A family history of
this disease oen is present, especially for autoimmune thyroid
diseases. Diseases of the thyroid usually involve an alteration in
the quantity or quality of thyroid hormone secretion and may
manifest as hypothyroidism or hyperthyroidism. In addition to
the signs and symptoms discussed next, thyroid disease may
produce an enlargement of the thyroid gland known as goiter.
Hypothyroidism
Hypothyroidism results from a deciency of thyroid hormone
production, causing the body metabolism to slow down. is
condition aects about 2% of women and 0.2% of men, and
the incidence increases with age. Symptoms include lethargy;
constipation; dry, coarse skin and hair; paresthesias and slowed
deep tendon reexes; facial puness; cold intolerance; decreased
sweating; impaired memory, confusion, and dementia; slow
speech and motor activity; and anemia and growth retardation
in children. Interestingly, these typical signs and symptoms
have been observed in as little as 25% of elderly hypothyroid
patients.
57
Hypothyroidism is usually caused by one of three mechanisms. Primary hypothyroidism is a failure of the thyroid to produce thyroid hormone; secondary hypothyroidism is failure of
the anterior pituitary to secrete TSH; and tertiary hypothyroidism is failure of the hypothalamus to produce TRH. e classication is commonly referred to as primary (problem originating
within the thyroid gland) or secondary (disease originating from
the pituitary or hypothalamus).
Most patients with symptomatic primary hypothyroidism have TSH concentrations >20 milliunits/L. Patients with
mild signs or symptoms (usually not the reason for the visit to
the doctor) have TSH values of 10 to 20 milliunits/L. Patients
with secondary and tertiary hypothyroidism may have a low or
normal TSH. In such patients, other pituitary hormones (eg,
adrenocorticotropic hormone [ACTH], antidiuretic hormone
[ADH], prolactin, growth hormone, and luteinizing hormone/
follicle- stimulating hormone [LH/FSH]) should be measured to
rule out other pituitary hormone deciencies. Table9-3 outlines
the numerous etiologies of hypothyroidism.
57
Thyrotoxicosis
Thyrotoxicosis results when excessive amounts of thyroid
hormones are circulating and is usually due to hyperactivity
of the thyroid gland (hyperthyroidism). Signs and symptoms
include nervousness; fatigue; weight loss; heat intolerance;
increased sweating; tachycardia or atrial brillation; muscle
atrophy; warm, moist skin; and, in some patients, exophthalmos.58 ese signs and symptoms occur much less frequently in
elderly persons, except for atrial brillation, which occurs three
times more oen.59 Table9-4 summarizes the specic causes of
hyperthyroidism.
51
TABLE 9-3.
Etiology
Primary
Excessive iodide intake (eg, kelp and contrast dyes)
Thyroid ablation: surgical removal of the thyroid,
131
post
I (radioactive iodine
131
I) treatment of
thyrotoxicosis, radiation of neoplasm
Hashimoto (autoimmune) thyroiditis
Subacute thyroiditis
Genetic abnormalities of thyroid hormone synthesis
Medications: propylthiouracil, methimazole,
thiocyanate, lithium, amiodarone, alfa- interferon,
some antineoplastic agents (ipilimumab, bexarotene,
sunitinib, nivolumab)
Food: excessive intake of goitrogenic foods (eg, cabbage
and turnips)
Secondary
Hypopituitarism: adenoma, ablative therapy, pituitary
destruction, sarcoidosis hypothalamic dysfunction
Other
Abnormalities of T
T4 = thyroxine.
Source: Adapted from Cryer PE. Hypoglycemia: pathophysiology,
diagnosis and treatment. New York: Oxford University Press;
1997; Grundy SM, Stone NJ, Bailey AL, et
AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/
PCNA Guideline on the Management of Blood Cholesterol: a
report of the American College of Cardiology/American Heart
Association Task Force on Clinical Practice Guidelines. Circulation.
2019;139(25):e1082– e1143.
receptor
4
al. 2018 AHA/ACC/
Nonthyroid Laboratory Tests in Patients with
Thyroid Disease
Thyroid disease may present with a wide range of signs,
symptoms, and abnormal laboratory results. Table 9-5 lists
nonthyroid laboratory tests that may indicate a thyroid disorder.
e inuence on these tests reects the widespread eects of
thyroid hormones on peripheral tissues. Findings from these
tests cannot be used alone to diagnose a thyroid disorder.
However, they may support a diagnosis of thyroid dysfunction
when used with specic thyroid function tests and the patient’s
presenting signs and symptoms.
60
Thyroid Function Tests
Tests more specic for thyroid status or function can be categorized as those that (1) measure the concentration of products
secreted by the thyroid gland, (2) evaluate the integrity of the
hypothalamic- pituitary- thyroid axis, (3) assess intrinsic thyroid
gland function, and (4) detect antibodies to thyroid tissue.60
CHAPTER 9 • EndoCRinE disoRdERs 179
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TABLE 9-4.
Etiology
Overproduction of thyroid hormone
Graves disease
TSH- secreting pituitary adenomas
Hydatidiform moles/choriocarcinomas
Multinodular goiter
“Leaking” thyroid hormone due to thyroid destruction
Lymphocytic thyroiditis
Granulomatous thyroiditis
Subacute thyroiditis
Radiation
Medications: thyroidamiodarone, iodinated radiocontrast agents, iodine
excess, kelp
Ovarian teratomas with thyroid elements
Metastatic thyroid carcinoma
a
Most frequent cause. The mechanism is production of thyroidstimulating antibodies; usually associated with diffuse goiter and
ophthalmopathy.
b
Tumor production of chorionic gonadotropin, which stimulates the
thyroid.
c
Patients at risk for hyperthyroidism from these agents usually have
some degree of thyroid autonomy.
Source: Adapted from Cryer PE. Hypoglycemia: Pathophysiology,
Diagnosis and Treatment. New York: Oxford University Press; 1997;
American Diabetes Association. Cardiovascular disease and risk
management: standards of medical care in diabetes: 2020. Dia betes
Care. 2020;43(suppl 1):S111–S134.
Tests that directly or indirectly measure the concentrations of
T4 and T3 include the following:
• Free T
4
• Total serum T
• Serum T3 resin uptake
• Free T4 index
• Total serum T
Test results that are higher than normal are consistent with
hyperthyroidism, whereas test results that are lower than normal
indicate hypothyroidism.
e integrity of the hypothalamic- pituitary- thyroid axis is
assessed by measuring TSH and TRH. A radioactive iodine
uptake test assesses intrinsic thyroid gland function, and
an antithyroid antibodies test detects antibodies to thyroid
tissue.
a
b
replacement drugs (excessive),
c
4
3
TABLE 9-5. Nonthyroid Laboratory Tests
Consistent with Thyroid Disorders
HYPOTHYROIDISM HYPERTHYROIDISM
Decreased
Hgb/Hct
Serum glucose
Serum sodium
Urinary excretion of
17- hydroxysteroids
Urinary excretion of
17- ketosteroids
Increased
AST/SGOT
Capillary fragility
LDH
pCO
Serum carotene
Serum cholesterol
CPK
Serum prolactin
Serum triglycerides
AST = aspartate aminotransferase; CPK = serum creatine
phosphokinase; Hgb = hemoglobin; LDH = lactate dehydrogenase;
pCO
oxaloacetic transaminase.
a
Associated with normocytic and macrocytic anemias.
Source: Adapted from Grundy SM, Stone NJ, Bailey AL, et al.
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/
ASPC/NLA/PCNA Guideline on the Management of Blood
Cholesterol: a report of the American College of Cardiology/
American Heart Association Task Force on Clinical Practice
Guidelines. Circulation. 2019;139(25):e1082– e1143; American
Diabetes Association. Cardiovascular disease and risk
management: standards of medical care in diabetes: 2020.
Diabetes Care. 2020;43(suppl 1):S111–S134.
and 9-7). Several methods are available to determine free T4
concentrations. Some methods perform well only in otherwise
healthy hypothyroid and hyperthyroid patients and in euthyroid patients with mild abnormalities of TBG. However, in
patients with severe alterations of T4 binding to carrier proteins
(eg, severe nonthyroidal illness), only the direct equilibrium
dialysis method maintains accuracy (Table9-7).
a
Granulocytes
Serum cholesterol
Serum triglycerides
Alkaline phosphatase
Lymphocytes
Serum ferritin
Urinary calcium excretion
2
= partial pressure of carbon dioxide; SGOT = serum glutamic-
2
61
Free T
4
Normal range: 0.9 to 2.3 ng/dL (11.6 to 29.6 pmol/L)
is test measures the unbound T4 in the serum and is the
most accurate reection of thyrometabolic status (Tables9-6
Total Serum T
4
Normal range: 5.5 to 12.5 mcg/dL (71 to 161 nmol/L)
In most patients, the total serum T4 level is a sensitive test for
the functional status of the thyroid gland. It is high in 90% of
180 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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TABLE 9-6. Free T4 and TSH in Thyroidal and
Nonthyroidal Disorders
FREE T4 INDEX
OR DIRECT
EQUILIBRIUM
DIALYSIS
DIAGNOSIS
FREE T
4
Hypothyroidism
Primary Normal
On dopamine or
↓ ↑
↓ ↓
glucocorticoids
Secondary or
↓ ↓
tertiary: functional
hypopituitarism
Recent thyroid
↓ <0.1
supplement
withdrawal
Recently treated
↓ <0.1
hyperthyroidism
Hyperthyroidism
With severe
↑ <0.1
↓/WNL/↑
b
nonthyroidal illness
Euthyroid states WNL WNL
Low total T
4
of
↓/WNL/↑
c
nonthyroidal illness
After T
After T4 therapy
High total T
therapy
3
4
of
↓ WNL/↓
WNL WNL
↑ WNL/↑
nonthyroidal illness
High total T
from
4
↑ ↑
amiodarone or
iodinated contrast
media
Decreased T
- binding
4
↑/WNL
d
proteins
↑ = increased; ↓ = decreased; T3 = triiodothyronine; T4 = thyroxine;
WNL = within normal limits.
a
Usually absent TSH response to TRH; also may be normal with
hyperthyroidism from TSH- secreting tumors.
b
Normal or low using free T4 index estimation; increased using the
direct equilibrium dialysis free T
c
Decreased using free T4 index estimation; normal to high using the
direct equilibrium dialysis free T
d
Decreased using free T4 index estimation; normal using the direct
equilibrium dialysis free T
Source: Adapted from Jenklass J, Talbert RL. Thyroid disorders.
In: DiPiro JT, Talbert RL, Yee GC, eds. Pharmacotherapy: A
Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill;
2014:1191–1216; Mokshagundam S, Barzel US. Thyroid disease in
the elderly. J Am Geriatr Soc. 1993;41(12):1361–1369.
assay.
4
assay.
4
assay.
4
TSH
(milliunits/L)
a
a
<0.1
WNL/↑
WNL
patients with hyperthyroidism and low in 85% of patients with
hypothyroidism. is test measures both bound and free T4 and
is, therefore, inuenced by any alteration in the concentration
or binding anity of thyroid- binding protein.
56
Conditions that increase or decrease thyroid- binding protein
result in an increased or decreased total serum T4, respectively,
but do not aect the amount of metabolically active free T4 in the
circulation. erefore, thyrometabolic status may not always be
truly represented by the results. Table9-8 lists factors that alter
thyroid- binding protein.
61
Increased total serum T4. An increased total serum T4 may
indicate hyperthyroidism, elevated concentrations of thyroidbinding proteins (as seen in pregnancy or in women receiving
oral contraceptive therapy), or nonthyroid illness. Total serum
T4 elevations have been noted in patients, particularly elderly
persons, with relatively minor illnesses. ese transient elevations may be due to increased TSH secretion stimulated by a
low T3 concentration. Similarly, up to 20% of all patients admitted to psychiatric hospitals have had transient total serum T4
elevations on admission.61 us, the dierential diagnosis for
a patient with this elevation must include nonthyroid illness
versus hyperthyroidism if other signs and symptoms of thyroid
disease are absent or inconsistent.
61
Decreased total serum T4. A decreased total serum T4 may
indicate hypothyroidism, decreased concentrations of thyroidbinding proteins, or nonthyroid illness (also called euthyroid
sick syndrome). Nonthyroid illness may lower the total serum
T4 concentration with no change in thyrometabolic status.
Typically in this syndrome, total serum T4 is decreased (or normal), total serum T3 is decreased, reverse T3 is increased, and
TSH is decreased (or normal). Neoplastic disease, DM, burns,
trauma, liver disease, renal failure, prolonged infections, and
cardiovascular disease are nonthyroid illnesses that can lower
total serum T4 concentrations.
61
Several mechanisms probably contribute to this low T4 state.
Diminished T4 in nonthyroid illness may be due to low TBG
concentrations caused by protease cleavage at inammatory sites
during acute inammatory illness. In some, but not all, patients
with chronic illness, a desialylated form of TBG is synthesized
by the liver, which has one- tenth the binding capacity of that of
normal TBG. is results in a fall in the circulating levels of total
thyroid hormone as a consequence of the diminished thyroid
hormone- binding capacity. In addition, peripheral deiodination
of T4 to T3 is impaired because of diminished activity of type I
deiodinase enzyme. Diminished enzyme activity accounts for
decreased deiodination of T4 to T3 and an increase in the production of reverse T3.
60,61
In general, a correlation exists between the degree of total
serum T4 depression and the prognosis of the illness (ie, the
lower the total serum T4, the poorer the disease outcome).
Because severely ill patients may appear to be hypothyroid, it
is important to dierentiate between patients with serious nonthyroid illnesses and those who are truly hypothyroid.61 Aer
recovery from a nonthyroid illness, thyroid function test result
abnormalities should be completely reversible.
CHAPTER 9 • EndoCRinE disoRdERs 181
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TABLE 9-7. Performance and Availability of Free T4 Methods
% OF EUTHYROID PATIENTS WITH
SEVERE TBG DEPRESSION OR SEVERE
NONTHYROIDAL ILLNESS IN WHICH
ASSAY
Free T
indexa or single- step 50%–80% Available in most clinical laboratory tests
4
Immunoextraction or RIA
Direct equilibrium dialysis
a
Corrects total T4 values using an assessment of T4- binding proteins.
b
Uses a T4 analog or two- step- back titration with solid- phase T4 antibody but does not use membranes to separate free from bound hormone.
c
Uses minimally diluted serum that separates free T4 from bound T4 using a semipermeable membrane.
d
May be underestimated in 25% of patients on dopamine. A decreased direct equilibrium dialysis free T4 with an elevated TSH is
diagnostic of primary hypothyroidism, even in patients with severely depressed TBG. Conversely, an increased direct equilibrium dialysis
free T
with a TSH of <0.10 milliunit/L is consistent with nonpituitary hyperthyroidism.53 Decreased direct equilibrium dialysis free T4 with
4
normal or decreased TSH concentrations may be seen in patients on T
available (Table
Source: Adapted from Walsh JP. Managing thyroid disease in general practice. Med J Aust. 2016;205(4):179–184; Kaptein EM. Clinical
application of free thyroxine determinations. Clin Lab Med. 1993;13:653–672.
d
9-12), most clinicians initially rely on the traditional total serum T
ASSAY UNDERESTIMATES FREE T
b
10%–30% Available in some clinical laboratory tests
c
0%–5% Available in reference laboratory tests and large
4
COMMENTS
medical center laboratory tests; gold standard
0%–5% Available only in research laboratory tests
therapy (Table 9-8). Although free T4 assays are becoming widely
3
measurement by RIA.
4
TABLE 9-8. Factors Altering Thyroid-Binding
Protein
FACTORS THAT
INCREASE THYROIDBINDING PROTEIN
Acute infectious hepatitis
Acute intermittent porphyria
Chronic active hepatitis
Estrogen-
containing oral
contraceptives
Estrogen- producing tumors
Estrogen therapy
Genetic excess of total
binding protein
Heroin
Methadone maintenance
Perphenazine
Pregnancy
Tamoxifen
Source: Adapted from Walsh JP. Managing thyroid disease in general
practice. Med J Aust. 2016;205(4):179–184; Mokshagundam S,
Barzel US. Thyroid disease in the elderly. J Am Geriatr Soc. 1993;
41(12):1361–1369; Klee GG, Hay ID. Role of thyrotropin
measurements in the diagnosis and management of thyroid disease.
(review). Clin Lab Med. 1993;13(3):673–682.
FACTORS THAT
DECREASE THYROIDBINDING PROTEIN
Acromegaly
Androgen therapy
- asparaginase
Cirrhosis
Danazol
Salsalate
Glucocorticoid therapy
(high dose)
Furosemide (high dose)
Hypoproteinemia
Malnutrition
Nephrotic syndrome
Phenytoin
Salicylates
Testosteronetumors
producing
Drugs causing true alterations in total serum thyroxine.
Medications can cause a true alteration in total serum T4 and
a corresponding change in free T4 concentrations (Tables9-9
and 9-10).62 In such cases, the total serum T4 (and free T4) result
remains a true reection of thyrometabolic status. High- dose
salicylates and phenytoin also may lower total serum T4 signicantly via decreased protein binding in vivo. Salicylates inhibit
binding of T4 and T3 to TBG. An initial increase in serum free T4
is followed by return of free T4 to normal levels with sustained
therapeutic serum salicylate concentrations, although total T4
levels may decrease by as much as 30%. Phenytoin displaces
T4 and T3 from serum binding proteins, resulting in an initial
increase in free T4 and T3 and a decrease in total T4 levels.
62,63
Iodides may also increase thyroid function. A previously
euthyroid patient may develop thyrotoxicosis from exposure
to increased quantities of iodine. Supplemental iodine causes
autonomously functioning thyroid tissue to produce and secrete
thyroid hormones, leading to a signicant increase in T4 and
T3 concentrations. is phenomenon commonly occurs during
therapeutic iodine replacement in patients who live in areas of
endemic iodine deciency.
Similarly, patients with underlying goiter who live in iodinesucient areas may develop hyperthyroidism when given
pharmacological doses of iodide. e heavily iodinated antiarrhythmic medication amiodarone may induce hyperthyroidism (1% to 5% of patients) as well as hypothyroidism (6% to
10% of patients).64 Propylthiouracil and methimazole are used
in patients with hyperthyroidism to decrease hormone concentrations. Both T4 and T3 concentrations decrease more rapidly
with methimazole than propylthiouracil.
65
Serum T3 Resin Uptake
Normal range: 25% to 38%
Although rarely used, the serum T3 resin uptake test indirectly
estimates the number of binding sites on thyroid- binding
182 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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TABLE 9-9. Medications That Cause a True
Alteration in Total Serum T
a
Measurements
MECHANISM
Interference in
central regulation
of TSH secretion
at hypothalamicpituitary level
Interference with
thyroid hormone
synthesis or
release from
thyroid gland
Altered thyroid
hormone
metabolism
Inhibition of
GI absorption
of exogenous
thyroid hormone
a
In true alterations, the concentration change is not due to assay
interference or alteration in thyroid-
the potential to inhibit thyroid hormone release and impair the
1 to 2 weeks. However, individuals with subclinical hypothyroid
disease may develop clinical hypothyroidism after treatment with
iodides. Iodide- induced hypothyroidism has also been noted in
b
May increase or decrease total serum T4 and free T4.
Source: Compiled, in part, from references 55,57,58.
protein occupied by T3. is result is also referred to as the
thyroid hormone- binding ratio. e T3 resin uptake is usually low
when the concentration of thyroid- binding proteins is high.
In this test, radiolabeled T3 is added to a specimen that
contains endogenous hormone. An aliquot of this mixture
is then added to a resin that competes with endogenous
thyroid- binding proteins for the free hormone. Radiolabeled
T3 binds to any free endogenous thyroid- binding protein; at
INCREASE
TOTAL SERUM
T4 AND FREE T
Amphetamines Glucocorticoids
Amiodarone,
lithium
Amiodarone,
iopanoic
acid, ipodate,
propranolol (high
dose)
and Free T4
4
DECREASE TOTAL
SERUM T4 AND
FREE T
4
4
(acutely)
Octreotide
Dobutamine
Dopamine
b
b
Aminoglutethimide,
amiodarone,b
6- mercaptopurine,
sulfonamides
b
Iodides
Thionamides
Lithium
Phenobarbital
Carbamazepine
Rifampin
Phenytoin
Antacids, orlistat
cholestyramine,
colestipol, iron,
sodium polystyrene
sulfonate, soybean
formulas), sucralfate
Omeprazole
lansoprazole
binding proteins. As noted in
57
b
60
TABLE 9-10. Iodine-Containing Compounds That
Oral radiopaque agents
Diatrizoate
Iocetamic acid
Iopanoic acid
Ipodate
Tyropanoate
Expectorants
Iodinated glycerol
Potassium iodide solution
SSKI
Parenteral radiopaque agents
Diatrizoate meglumine
Iodamide meglumine
Iopamidol
Iothalamate meglumine
Metrizamide
Miscellaneous compounds
Amiodarone
containing nutritional supplements
Kelp-
SSKI = supersaturated potassium iodide.
a
No longer available; most products reformulated with guaifenesin.
Source: Compiled, in part, from references 58 and 59.
the saturation point, the remainder binds to the resin. e
amount of thyroid- binding protein can be estimated from the
amount of radiolabeled T3 taken up by the resin. e T3 resin
uptake result is expressed as a percentage of the total radiolabeled T3 that binds to the resin. e T3 resin uptake can verify
the clinical signicance of measured total serum T4 and T3
concentrations because it is an indicator of thyroid- binding
protein- induced alterations of these measurements; however,
it is rarely used in contemporary practice because of the availability of the free T4 test.
Elevated T3 resin uptake concentrations are consistent with
hyperthyroidism, whereas decreased concentrations are consistent with hypothyroidism. However, this test is never used
alone for diagnosis. e T3 resin uptake is low in hypothyroidism because of the increased availability of binding sites on the
TBG. However, in nonthyroidal illnesses with a low T4, the T3
resin uptake is elevated. erefore, the test may be used to dierentiate between true hypothyroidism and a low T4 state caused
by nonthyroid illness.
All of the disease states and medications listed in Table9-11
can inuence thyroid- binding protein and, consequently, alter T3
a
60
60
CHAPTER 9 • EndoCRinE disoRdERs 183
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resin uptake results. Radioactive substances taken by the patient
also interfere with this test. In practice, the T3 resin uptake test
is used only to calculate the free T4 index.
61,62
Free T4 Index
Normal range: 1 to 4 units
e free T4 index is the product of total serum T4 multiplied by
the percentage of T3 resin uptake:
free T4 index = total serum T4(mcg/dL) ×
T3 resin uptake (%)
e free T4 index adjusts for the eects of alterations in
thyroid- binding protein on the total serum T4 assay. e index
is high in hyperthyroidism and low in hypothyroidism. Patients
taking phenytoin or salicylates have low total serum T4 and high
T3 resin uptake with a normal free T4 index. Pregnant patients
have high total serum T4 and low T3 resin uptake with a normal
free T4 index. Patients taking therapeutic doses of levothyroxine may have a high free T4 index because total serum T4 and
T3 resin uptake are high. In addition to aecting total serum T4
and free T4, propranolol and nadolol block the conversion of T4
to T3, which may cause mild elevations in the free T4 index.
Total Serum T
3
Normal range: 80 to 200 ng/dL (1.2 to 3.1 nmol/L)
Using radioimmunoassay (RIA), highly active thyroid hormone
T3 is measured. Like T4, almost all of T3 is protein bound.
60
erefore, any alteration in thyroid- binding protein inuences
this measurement. As with the total serum T4 test, changes in
thyroid- binding protein increase or decrease total serum T3
but do not aect the metabolically active free T3 in the circulation. erefore, the patient’s thyrometabolic status remains
unchanged.
60
Total serum T3 is primarily used as an indicator of hyperthyroidism (Minicase 3). is measurement is usually made to detect
T3 toxicosis when T3, but not T4, is elevated. Generally, the serum
T3 assay is not a reliable indicator of hypothyroidism because
of the lack of reliability of the assay in the low to normal range.
Drugs that aect T4 concentrations have a corresponding eect
on T3 concentrations. Additionally, propranolol, propylthiouracil,
and glucocorticoids inhibit the peripheral conversion of T4 to T3
and cause decreased T3 concentration (T4 usually stays normal).
60
Total serum T3 concentrations can be low in euthyroid
patients with conditions (eg, malnutrition, cirrhosis, and uremia) in which the conversion of T4 to T3 is suppressed. T3 is low
in only half of hypothyroid patients because these patients tend
to produce relatively more T3 than T4. A patient with a normal
total serum T4, a low T3, and a patient with high reverse T3 has
euthyroid sick syndrome.
60
Thyroid-Stimulating Hormone
Normal range: 0.5 to 5.0 milliunits/L
yroid stimulating hormone (TSH) is a glycoprotein with
two subunits: α and β. e α subunit is similar to those of
TABLE 9-11. Test Results Seen in Common Thyroid Disorders and Drug Effects on Test Results
TOTAL
DISEASE
Hypothyroidism
Hyperthyroidism
SERUM T
↓ ↓ ↓ ↓ ↓ ↑/↓
↑ ↑ ↑ ↑ ↑ ↓
T3 thyrotoxicosis No change
Euthyroid sick
Corticosteroids
Phenytoin/aspirin
Radiopaque media
↑ = increased; ↓ = decreased; RAIU = radioactive iodine uptake test.
a
Increased TSH diagnostic of primary hypothyroidism. TSH is decreased in secondary and tertiary types.
Source: Adapted from Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med. 1995;333(25):1688–1694; Kaptein EM. Clinical
application of free thyroxine determinations. Clin Lab Med. 1993;13(3):653–672.
No change/↓ ↓ ↑
↓ No change/↓ ↑
↓ ↓ ↑
No change/↑ No change/↓
4
TOTAL
SERUM T
↑
3
T3 RESIN
UPTAKE
FREE T4
INDEX RAIU TSH COMMENT
No change No change No change
Variable No change No change
No change
No change
No change
No change/↑ ↓
a
↓
syndrome
↓ No change/↓
↓
No change Large
No change
T3 resin
uptake may
be slightly
increased
salicylate
dose
184 BASIC SKILLS IN INTERPRETING LABORATORY DATA
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MINICASE 3
A Patient with Hyperthyroidism
A 35- year- old nurse complains of nervousness, mood swings,
weakness, and palpitations with exertion for the past 6 months.
Recently, she noticed excessive sweating and wanted to sleep
with fewer blankets than her husband. Menstrual periods had been
regular, but there was less bleeding. She has lost 20 lb over the last
6 months despite eating twice as much as she did 1 year ago. Her
HR is 92 beats/min and BP is 150/90mm Hg. She appears anxious.
She has smooth, warm, moist skin; she has a fine tremor; and she
cannot rise from a deep knee bend without aid. Upon physical exam,
her thyroid contains three nodules— two on the right and one on
the left with a total gland size of 60g (three times normal size). All
nodules are of firm consistency, and there is no lymphadenopathy.
• Sodium, 145 mEq/L (136 to 142 mEq/L)
• Potassium, 4 mEq/L (3.8 to 5 mEq/L)
• Chloride, 101 mEq/L (95 to 103 mEq/L)
• Carbon dioxide, 26 mEq/L (21 to 28 mEq/L)
• BUN, 10 mg/dL (8 to 23 mg/dL)
• SCr, 0.8 mg/dL (0.6 to 1.2 mg/dL)
• Hemoglobin, 12 g/dL (12 to 16 g/dL)
• Hct, 36% (36% to 45%)
• RBC count, 3.5 M/mm
3
(4 to 5.2 M/mm3)
other hormones secreted from the anterior pituitary: folliclestimulating hormone, human chorionic gonadotropin (hCG),
and luteinizing hormone. e β subunit of TSH is unique and
renders its specic physiologic properties.
61,62
Although the older “rst- generation” TSH assays have
been useful in diagnosing primary hypothyroidism, they
have not been useful in diagnosing hyperthyroidism. Almost
all patients with symptomatic primary hypothyroidism have
TSH concentrations >20 milliunits/L; those with mild signs
or symptoms have TSH values of 10 to 20 milliunits/L. Oen,
TSH concentrations become elevated before T4 concentrations
decline. All assays can accurately measure high concentrations of TSH.
61,66
e rst- generation TSH assays, however, cannot distinguish low- normal from abnormally low values because their
lower limit of detection is 1 milliunit/L, whereas the lower
limit of basal TSH is 0.2 to 0.3 milliunits/L in most euthyroid
persons. is distinction can usually be ascertained with the
second- generation assays, which can accurately measure TSH
concentrations as low as 0.05 milliunits/L. Occasionally, some
euthyroid patients have levels of 0.05 to 0.5 milliunits/L. erefore, supersensitive, third- and fourth- generation assays have
been developed; they can detect TSH concentrations as low as
0.005 milliunits/L and 0.004 milliunits/L, respectively. Although
third- generation assays are usually not required to make or conrm this diagnosis, they provide a wider margin of tolerance
so that discrimination at 0.1 milliunit/L can be ensured even
when the assay is not performing optimally. Concentrations
• Antithyroid antibodies, 1:200
• Mean cell (corpuscular) volume, 104 mm
• WBC count, 16 × 10
• Calcium, 9 mg/dL (9.2 to 11 mg/dL)
• Glucose, 96 mg/dL (70 to 110 mg/dL)
• Free T
• T
• TSH, 0.3 microunits/mL (0.5 to 5 microunits/mL)
QUESTION: How should these results be interpreted? Are
confirmatory tests needed?
DISCUSSION: This patient presents with many of the clinical features
of hyperthyroidism, including rapid heart rate, weight loss, and heat
intolerance. Her thyroid gland is visibly enlarged (goiter). She also
has elevated BP and complains of nervousness, sweating, and
hand tremors. The diagnosis of hyperthyroidism can be confirmed
by her laboratory results of a high T4 and a below- normal TSH
value. She has a toxic multinodular goiter that should be treated
with radioactive iodine or surgery with antithyroid drug and iodine
pretreatment.
<0.05milliunits/L are almost always diagnostic of primary
hyperthyroidism in patients <70 years.
Use in therapy. In patients with primary hypothyroidism,
TSH concentrations are also used to adjust the dosage of thyroid hormone replacement therapy. In addition to achieving a
clinical euthyroid state, typically the goal should be to lower
TSH into the midnormal range (Minicase 4). e exception
is in patients with recently diagnosed papillary or follicular
thyroid cancer, where the goal TSH level may be in the 0.1 to
0.2milliunits/L range. Although TSH concentrations reect
long- term thyroid status, serum T4 concentrations reect acute
changes. Patients with long- standing hypothyroidism oen
notice an improvement in well- being two to three weeks aer
starting therapy. Signicant improvements in heart rate (HR),
weight, and puness are seen early in therapy, but hoarseness, anemia, and skin/hair changes may take many months
to resolve.
rational to wait at least 6 to 8 weeks aer starting or changing
therapy to repeat TSH and T4 concentrations to rene dosing.56
e hypothalamic- pituitary- axis requires this time to respond
fully to changes in circulating thyroid hormone concentrations.
For example, noncompliant patients with hypothyroidism who
wait to take their thyroid hormone replacement therapy until
days before their appointment may have elevated TSH concentrations despite a normal T4 concentration.
suppressive therapy, usually levothyroxine. e therapeutic
3
3
3
10
cells/mm3)
, 4.6 ng/dL (0.9 to 2.3 ng/dL)
4
, 250 ng/dL (80 to 200 ng/dL)
3
66
cells/mm3 (4.8 to 10.8 ×
(80 to 100 mm3)
61
Unless undesirable changes in signs or symptoms occur, it is
61
Patients with thyroid cancer are oen treated with TSH
CHAPTER 9 • EndoCRinE disoRdERs 185
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MINICASE 4
A Case of Possible Hypothyroidism
Diane G. is a 45- year- old homemaker who presents to clinic
complaining of progressive weight gain of 20 lb in 1 year, fatigue,
postural dizziness, loss of memory, slow speech, deepening of
her voice, dry skin, constipation, and cold intolerance. Her HR is
58 beats/min, and her BP is 110/70mm Hg. Her physical exam
is normal, except for a mildly enlarged thyroid gland, pallor, and
diminished tendon reflexes. She denies taking any medications or
changing her diet. Diane G.’s chemistry results are as follows:
• Sodium, 130 mEq/L (136 to 142 mEq/L)
• Potassium, 3.8 mEq/L (3.8 to 5 mEq/L)
• Carbon dioxide, 28 mEq/L (21 to 28 mEq/L)
• Calcium, 9.5 mg/dL (9.2 to 11 mg/dL)
• Magnesium, 2 mEq/L (1.3 to 2.1 mEq/L)
• Glucose, 80 mg/dL (70 to 110 mg/dL)
• BUN, 20 mg/dL (8 to 23 mg/dL)
• SCr, 1.1 mg/dL (0.6 to 1.2 mg/dL)
• Cholesterol, 255 mg/dL (<200 mg/dL)
The cholesterol concentration is elevated since a screening
6months ago. A test for mononucleosis is negative. Hct is low
at 36% (36% to 45%)— close to her usual. Her total serum T
3.8mcg/dL (5.5 to 12.5 mcg/dL), her T3 resin uptake is 15% (25% to
38%), her free T4 index is 1.0 (1 to 4), and her TSH is 65 milliunits/L
(0.3 to 5 milliunits/L).
QUESTION: How should these results be interpreted?
DISCUSSION: Clinically, all of the history and physical findings point
to hypothyroidism. The pallor and weakness are also consistent with
anemia, but an Hct of 35% is unlikely to cause such significant symptoms.
Her cholesterol recently became elevated, consistent with primary
hypothyroidism.93 Both the total serum T4 and T3 resin uptake are low
and TSH level is high.
4
is
QUESTION: Does this information help to elucidate the diagnosis?
DISCUSSION: An elevated TSH confirms primary hypothyroidism.
Diane G. is started on levothyroxine 0.2 mg/day, and her TSH is
6 milliunits/L 3 weeks later. Clinically, she improves but is not fully
back to normal. Six weeks after starting therapy, she complains
of jitteriness, palpitations, and increased sweating. Her TSH is
<0.3 milliunit/L. Her physician lowers the dose of levothyroxine to
0.1 mg/day, and she becomes asymptomatic after about 2 weeks.
Eight weeks later, her TSH is 1.5 milliunits/L, and she remains
asymptomatic. Her cholesterol is 200 mg/dL, sodium is 138 mEq/L,
and Hct is 40%.
QUESTION: Which test(s) should be used to determine proper dosing
of levothyroxine? How long after a dosage change should clinicians
wait before repeating the test(s)?
DISCUSSION: Although total serum T4, T3 resin uptake, and free
T
index can be used to monitor and adjust doses of thyroid
4
supplements in patients with a hypothyroid disorder, the highly
sensitive TSH test is most reliable. Chemically, the goal is to achieve
a TSH in the normal range, as was ultimately achieved in this patient
(TSH of 1.5 milliunits/L).
The TSH is the standard for adjusting thyroid replacement therapy.
The 0.2- mg levothyroxine dose is excessive for this patient, as
evidenced by her “hyperthyroid” symptoms and the fully suppressed
TSH. Eight weeks later, after T4 steady state has been reached on
the 0.1- mg/day dose and after the hypothalamic- pituitary- thyroid
axis reached homeostasis, TSH is within the desired range. Her
cholesterol, sodium, and Hct also normalized when she became
euthyroid.
endpoint is a basal TSH concentration of about 0.1 milliunit/L.
Some clinicians suggest more complete suppression with TSH
concentrations <0.005 milliunit/L, whereas others think that it
leads to toxic eects of overreplacement (eg, accelerated bone
loss, new onset atrial brillation).
61,66
Potential misinterpretation and drug interference. Some
TSHassays may yield falsely elevated results whenever hCG
concentrations are high (eg, pregnancy) due to the similarity
in structure of these two proteins. Most patients who have secondary or tertiary hypothyroidism have low or normal TSH
concentrations. In patients with nonthyroid illness, TSH may
be suppressed by factors other than thyroid hyperfunction. As
mentioned previously, the TSH concentration typically is normal in patients with euthyroid sick syndrome.
62,66
yroid function tests are known to be altered in depressed
patients. With the advent of the third- generation TSH assays,
it was hoped that TSH concentrations could help to determine
various types of depression and response to therapies. Unfortunately, TSH has not proven useful in this way.66 Because
endogenous dopamine inhibits the stimulatory eects of TRH,
any drug with dopaminergic activity can inhibit TSH secretion. erefore, levodopa, glucocorticoids, bromocriptine, and
dopamine are likely to lower TSH results. e converse is also
true— dopamine antagonists (metoclopramide) may increase
TSH concentrations.
62,63
Radioactive Iodine Uptake Test
is test is used to detect the ability of the thyroid gland to trap
and concentrate iodine and, thereby, produce thyroid hormone.
In other words, this test assesses the intrinsic function of the
thyroid gland. is test is not specic, and its reference range
must be adjusted to the local population. erefore, its use is
declining. In patients with a normal thyroid gland, 12% to 20%
of the radioactive iodine is absorbed by the gland aer 6hours
and 5% to 25% is absorbed aer 24 hours. e radioactive iodine
uptake test is an indirect measure of thyroid gland activity
and should not be used as a basic screening test of thyroid
function. is test is most useful in distinguishing causes of
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