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Chapter 7. Diabetes
5. Packer M, Anker SD, Butler J, etal. Cardiovascular and renal
outcomes with Empagliflozin in heart failure. N Engl J Med.
2020;383(15):1413–24.
6. Kristensen SL, Rørth R, Jhund PS, Docherty KF, Sattar N, Preiss
D, Køber L, Petrie MC, McMurray JJ.Cardiovascular, mortality,
and kidney outcomes with GLP-1 receptor agonists in patients
with type 2 diabetes: a systematic review and meta-analysis
of cardiovascular outcome trials. Lancet Diabetes Endocrinol.
2019;7(10):776–85.
7. National diabetes statistics report, 2020 [Internet]. Centers for
disease control and prevention. Centers for disease control and
prevention; 2020 [cited 9 Dec 2021]. https://www.cdc.gov/diabe-
tes/data/statistics- report/index.html.
8. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical Care in Diabetes—2021.
Diabetes Care. 2021;44(Supplement 1):S15–33.
9. Statistics about diabetes [Internet]. Statistics About Diabetes |
ADA. [cited 9 Dec 2021]. https://www.diabetes.org/resources/
statistics/statistics- about- diabetes
10. Davidson KW, Barry MJ, Mangione CM, Cabana M, Caughey
AB, Davis EM, Donahue KE, Doubeni CA, Krist AH, Kubik
M, Li L.Screening for prediabetes and type 2 diabetes: US preventive services task force recommendation statement. JAMA.
2021;326(8):736–43.
11. American Diabetes Association. 4. Comprehensive medical
evaluation and assessment of comorbidities: standards of medical Care in Diabetes—2020. Diabetes Care. 2020;43(Supplement
1):S37–47.
12. American Diabetes Association. 6. Glycemic targets: standards of medical care in diabetes—2021. Diabetes Care.
2021;44(Supplement 1):S73–84.
13. Garber AJ, Handelsman Y, Grunberger G, Einhorn D,
Abrahamson MJ, Barzilay JI, Blonde L, Bush MA, DeFronzo RA,
Garber JR, Garvey WT.Consensus statement by the American
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of endocrinology on the comprehensive type 2 diabetes management algorithm—2020 executive summary. Endocr Pract.
2020;26(1):107–39.
14. American Diabetes Association. 7. Diabetes technology:
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A. Geliebter
15. DeFronzo RA.From the triumvirate to the ominous octet: a new
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Chapter 8
Thyroid Dysfunction
NancyA.LaVine
Hypothyroidism
Brief Introduction
Hypothyroidism (both overt and subclinical) is one the most
common endocrine disorders, with a prevalence of 1.9% in
women and 0.1% in men [1, 2]. Prevalence increases with age
in men (0.5%) and women (5.0%) over 60. Treatment of
hypothyroidism is with levothyroxine, which accounted for
over $3.2 billion in 2016 [3].
The hallmark of hypothyroidism is the insufficient production of thyroid hormones. This can be of a primary nature
(under activity of the thyroid gland itself) or of a secondary
nature, in which the stimulation of the thyroid gland by the
pituitary or hypothalamic glands is inadequate. Primary
hypothyroidism accounts for the vast majority (>95%) of
hypothyroidism cases. In iodine-sufficient parts of the world,
Hashimoto’s autoimmune thyroiditis is the most common
N. A. LaVine (*)
Department of Medicine, Zucker School of Medicine
at Hofstra/Northwell, New Hyde Park, NY, USA
e-mail: nlavine@northwell.edu
© The Author(s), under exclusive license to Springer Nature
Switzerland AG 2022
E. Sydney et al. (eds.), Handbook of Outpatient Medicine,
https://doi.org/10.1007/978-3-031-15353-2_8
179
180
N. A. LaVine
cause of hypothyroidism, while iodine deficiency remains an
important cause worldwide [4].
Significant causes of hypothyroidism are listed below.
• Autoimmune thyroiditis
• Severe iodine deficiency
• Non-autoimmune thyroiditis (subacute, silent, and
postpartum)
• Partial or total thyroidectomy or other neck surgery
• Thyroid ablation with radioactive iodine therapy
• External radiation to the head and neck
• Infiltrative diseases of the thyroid (amyloidosis, sarcoid-
osis, hemochromatosis)
• Congenital
• Secondary hypothyroidism (pituitary adenomas, empty
sella, pituitary surgery, extra pituitary tumors, inflamma-
tory, or infiltrative diseases)
• Drugs: amiodarone, lithium, interferon, methimazole, pro-
pylthiouracil, iodine, iodinated contrast agents
Key H&P
The presentation of hypothyroidism can range from completely asymptomatic to extreme, as symptoms may be influenced by the duration and severity of disease as well as the
age of the patient and their sensitivity to thyroid deficiency.
Symptoms can be as minor as mild fatigue, cold intolerance,
constipation, or weight gain, or, in rare cases, as significant as
myxedema coma (hypothermia, coma, pleural, and pericardial effusions). The positive predictive values of varied symptoms of hypothyroidism have been as low as 8–12% in one
study [5]. Patients presenting with newly developed symptoms are more likely to have hypothyroidism [6]. Physical
exam findings of hypothyroidism can include goiter,
bradycardia, or delayed deep tendon reflexes. Given the
unreliability of history and lack of physical exam findings, the
diagnosis of hypothyroidism in adults is made on the basis of
biochemical testing. In addition to those patients presenting
Chapter 8. Thyroid Dysfunction
with symptoms, there are certain groups of patients at higher
risk for developing hypothyroidism who may need testing:
• Personal or family history of autoimmune thyroid
disorders
• Autoimmune endocrine disorders (DMI, adrenal insuffi-
ciency, ovarian failure)
• Autoimmune disorders (celiac disease, vitiligo, pernicious
anemia)
• Postpartum women
• Treatment of thyroid, pituitary, or hypothalamic glands in
the past
• Radiation to the head and neck
• Turner’s syndrome
• Down syndrome
181
Decision-Making/Diagnosis
Thyroid-stimulating hormone (TSH) is the first-line test in the
diagnosis of thyroid hormone insufficiency, with a 99% sensitivity and specificity [7]. An elevated TSH with a decreased
free T4 (FT4) level is the hallmark of primary hypothyroidism.
FT4 alone is less sensitive in detection, and free T3 levels may
not be abnormal unless there is severe hypothyroidism. The
degree of TSH elevation and the level of free T4 can help
further characterize primary hypothyroidism. Patients with
overt hypothyroidism will often have a TSH level greater than
10mU/L with a FT4 below reference range. For some patients,
TSH may be mildly elevated (5–10mU/L) with a low-serum
FT4. Other patients may have a milder elevation in TSH
(between 5 and 10mU/L) with a FT4in the normal range—
this is subclinical (or mild) hypothyroidism. The distinction
between these categories has important implications for treatment. Of note, some substances can interfere with TSH measurement, including biotin, a commonly used over the counter
supplement, which may falsely lower TSH values [8]. Patients
taking 10mg or more of biotin should hold the supplement for
2days prior to testing.
182
N. A. LaVine
Treatment
Overt Hypothyroidism
There is strong evidence to support treating patients with
overt hypothyroidism (TSH>10mU/L) with levothyroxine
(LT4) monotherapy. Treatment is generally lifelong, and as
such, a confirmatory TSH should be checked prior to initiating therapy. Adequate treatment often improves symptoms,
as well as prevents progression of disease and decreases the
risk of cardiovascular events. Untreated overt hypothyroidism can result in coronary artery disease, atherosclerosis,
heart failure, arrhythmias, and pericardial and pleural effusions, secondary to effects on lipid profiles, the vascular system, and cardiac function [9]. The goal of treatment is to
avoid such complications and restore the euthyroid state.
Levothyroxine doses should be titrated to normalize the TSH
within the reference range. Initial dosing can be based on
weight, with a dose of 1.6–1.8 μg/kg/day sufficient to reach a
euthyroid state in most patients [10, 11]. Alternatively, a dose
of 25–50μg daily can be started and titrated up. In general,
older patients (>60years old) and those patients with ischemic heart disease should be started at lower doses (25–
50μg) and titrated up over 3–6weeks.
Monitoring of the TSH level is the most sensitive way to
ensure adequate doses of levothyroxine therapy, with monitoring every 4–8 weeks between dosage changes. Patients
who have reached a euthyroid state should have TSH monitored every 6–12months to ensure stability.
Subclinical Hypothyroidism
Patients with subclinical hypothyroidism (an elevated
TSH<10 and a normal FT4) are largely asymptomatic. These
patients do have an elevated risk of developing overt hypothyroidism, and several factors have been shown to increase
the risk, including the level of TSH elevation and the presence of thyroid peroxidase (TPO) antibodies [12]. Treatment
Chapter 8. Thyroid Dysfunction
183
of subclinical hypothyroidism with levothyroxine remains
controversial and is not typically recommended for patients
with a TSH<10. For patients with a TSH≥10, treatment is
recommended [13]. Older adults with subclinical hypothyroidism do not appear to benefit from levothyroxine replacement, particularly with a TSH < 10 [14]. Patients with
subclinical hypothyroidism should be monitored yearly for
continued TSH elevation, the development of overt hypothyroidism, or the development of TPO antibodies (Fig.8.1).
Treatment Challenges
Levothyroxine absorption and metabolism can be affected by
numerous other medications and dietary intake. Both iron
and calcium supplements can interfere with absorption.
Optimal absorption occurs with fasting, and patients should
be advised to take the medication on an empty stomach.
Timing of new medication administration should be carefully
considered. In a patient with inadequate TSH levels on an
optimum weight-based dose, nonadherence (both with the
medication and with fasting) as well as absorption problems
(such as in celiac disease or previous GI surgeries) should be
considered.
Clinical Pearls
• Clinical symptoms have low positive predictive value in
the diagnosis of hypothyroidism.
• Thyroid-stimulating hormone (TSH) is the first-line test in
the diagnosis of thyroid hormone insufficiency, with a 99%
sensitivity and specificity.
• Monitoring TSH alone in patients on levothyroxine
replacement is adequate to ensure appropriate dosages.
Don’t Miss This!
• Consider nutritional and medication interactions with
levothyroxine in patients with elevated TSH despite seem-
ingly adequate levothyroxine dosing.
184
N. A. LaVine
Elevated TSH
Check Free T4
Decreased Free T4
Overt Hypothyroidism
Confirm TSH elevaion
Initiate levothyroxine
replacement
TSH >10 mU/L
Initiate levothyroxine
replacement.
Replacement may not
benefit patients >70
years old.
Normal Free T4
Subclinical
Hypothyrodism
Treatment generally
not beneficial unless
significant symptoms,
Repeat TSH in 6months
F . Treatment algorithm for hypothyroidism
TSH 5-10 mU/L
or positive TPO
antibodies
and then yearly
Chapter 8. Thyroid Dysfunction
185
Hyperthyroidism
Brief Introduction
Hyperthyroidism is increased thyroid hormone synthesis and
secretion. Thyrotoxicosis is the clinical syndrome of increased
circulating thyroid hormone. Hyperthyroidism is found in
approximately 1.3% of the US population (0.5% clinical and
0.7% subclinical) [15]. Hyperthyroidism can be overt or subclinical and both will be discussed in this section. The hallmark of hyperthyroidism is the detection of a low level of
thyroid-stimulating hormone (TSH) and elevated levels of T4
and/or T3. Subclinical hyperthyroidism is characterized by
low-serum TSH and normal levels of T3 and T4 and can be
endogenous (due to Graves’ disease, toxic multinodular goiter) or exogenous, from excessive intake of thyroid agents
(levothyroxine or desiccated thyroid) [16].
Key H&P
Symptoms of overt hypothyroidism can vary, with some of the
more prevalent symptoms including fatigue, weight loss,
tremulousness/palpitations, anxiety, and heat intolerance.
Physical exam findings can include tachycardia, palpable goiter, tremor, and proptosis, and in rare cases, patients can present with thyroid storm (tachycardia, agitation, fever, and
altered mental state).
Decision-Making/Differential Diagnosis
Graves’ disease, caused by auto-antibodies stimulating the TSH
receptor, is the most common etiology of hyperthyroidism, with
3% of women and 0.5% of men developing Graves’ disease in
their lifetime [17]. Other important etiologies of hypothyroidism include thyroiditis (subacute, silent, or postpartum), which
leads to the release of pre-formed thyroid hormone due to
186
N. A. LaVine
Check TSH and Free
T4/T3
Signs/Symptoms of
Hyperthyroidism
Subclinical
Hyperthyroidism
Elevated/Normal
TSH
Elevated Free T4
Pituitary Adenoma
(TSH Secretion)
Normal TSH
Normal Free T4/T3
Normal
Suppressed TSH
TSH Receptor
Antibodies Present
Graves Disease
No Uptake
Thyroiditis
Elevated T4
Primary
Hyperthyroidism
Check TSH
Receptor
Antibodies
Free T3 elevated Free T3 Normal
TSH Receptor
Antibodies Absent
Radionuclide
Uptake Scan
Patchy Uptake
Toxic Multinodular
Goiter or Toxic
Thyroid Nodule
Suppressed TSH
Normal Free T4
Check Free T3
Diffuse Uptake
Graves Disease
F . Diagnostic algorithm for hyperthyroidism
destruction of the thyroid follicles, and toxic nodular goiter,
which is more common in iodine deficient areas. The following
algorithm outlines a diagnostic workup for diagnosis of the
more common etiologies of hyperthyroidism (Fig.8.2).
Treatment
Graves’ Disease
The treatment options for Graves’ disease include radioactive
iodine (RAI) ablation, antithyroid drugs, and surgical removal