2917Pituitary Tumor Syndromes CHAPTER 380

amounts of intact gonadotropins (usually FSH) as well as uncombined

α, LH β, and FSH β subunits. Tumor secretion may lead to elevated α

and FSH β subunits and, very rarely, to increased LH β subunit levels. Some adenomas express α subunits without FSH or LH. A TRH

stimulation test often induces an atypical increase of tumor-derived

gonadotropins or subunits.

Presentation and Diagnosis Clinically nonfunctioning tumors

often present with optic chiasm pressure and other symptoms of local

expansion or may be incidentally discovered on an MRI performed for

another indication (incidentaloma). Rarely, menstrual disturbances or

ovarian hyperstimulation occur in women with large tumors that produce FSH and LH. In these cases, ovaries may have features that resemble polycystic ovarian syndrome and may produce very high levels of

estrogen. More commonly, adenoma compression of the pituitary stalk

or surrounding pituitary tissue leads to attenuated LH and features of

hypogonadism. PRL levels are usually slightly increased, also because

of stalk compression. It is important to distinguish this circumstance

from true prolactinomas, as nonfunctioning tumors do not shrink in

response to treatment with dopamine agonists.

Laboratory Investigation The goal of laboratory testing in clinically nonfunctioning tumors is to classify the type of tumor, identify

hormonal markers of tumor activity, and detect possible hypopituitarism. Free α subunit levels may be elevated in 10–15% of patients with

nonfunctioning tumors. In female patients, peri- or postmenopausal

basal FSH concentrations are difficult to distinguish from tumorderived FSH elevation. Premenopausal women have cycling FSH levels,

also preventing clear-cut diagnostic distinction from tumor-derived

FSH. In men, gonadotropin-secreting tumors may be diagnosed

because of slightly increased gonadotropins (FSH > LH) in the setting

of a pituitary mass. Testosterone levels are usually low despite the normal or increased LH level, perhaps reflecting reduced LH bioactivity

or the loss of normal LH pulsatility. Because this pattern of hormone

test results is also seen in primary gonadal failure and, to some extent,

with aging (Chap. 391), the finding of increased gonadotropins alone

is insufficient for the diagnosis of a gonadotropin-secreting tumor. In

the majority of patients with gonadotrope adenomas, TRH administration stimulates LH β subunit secretion; this response is not seen in

normal individuals. GnRH testing, however, is not helpful for making

the diagnosis. For nonfunctioning and gonadotropin-secreting tumors,

the diagnosis usually rests on immunohistochemical analyses of surgically resected tumor tissue, as the mass effects of these tumors usually

necessitate resection.

Although acromegaly or Cushing’s disease usually presents with

unique clinical features, clinically inapparent (silent) somatotrope or

corticotrope adenomas may only be diagnosed by immunostaining of

resected tumor tissue. These silent tumors usually grow more aggressively and account for up to 20% of all nonfunctioning adenomas. If

PRL levels are <100 μg/L in a patient harboring a pituitary mass, a

nonfunctioning adenoma causing pituitary stalk compression should

be considered.

TREATMENT

Nonfunctioning and Gonadotropin-Producing

Pituitary Adenomas

Asymptomatic small nonfunctioning microadenomas with no

threat to vision may be followed with regular MRI and visual field

testing without immediate intervention. However, for macroadenomas, transsphenoidal surgery is indicated to reduce tumor size

and relieve mass effects (Fig. 380-10). Although it is not usually

possible to remove all adenoma tissue surgically, vision improves

in 70% of patients with preoperative visual field defects. Preexisting

hypopituitarism that results from tumor mass effects may improve

or resolve completely. Beginning ~6 months postoperatively, MRI

scans should be performed yearly to detect tumor regrowth. Within

5–6 years after successful surgical resection, ~15% of nonfunctioning tumors recur. When substantial tumor remains after transsphenoidal surgery, adjuvant radiotherapy may be indicated to prevent

tumor regrowth. Radiotherapy may be deferred if no postoperative

residual mass is evident. Nonfunctioning pituitary tumors respond

poorly to dopamine agonist treatment, and SRLs are largely ineffective for shrinking these tumors. The selective GnRH antagonist

Nal-Glu GnRH suppresses FSH hypersecretion but has no effect on

adenoma size.

■ TSH-SECRETING ADENOMAS

TSH-producing macroadenomas are very rare but are often large and

locally invasive when they occur. Patients usually present with thyroid

goiter and hyperthyroidism, reflecting chronic overproduction of TSH.

Diagnosis is based on demonstrating elevated serum free T4

 levels,

inappropriately normal or high TSH secretion, and MRI evidence of a

pituitary adenoma. Elevated free glycoprotein hormone α subunits are

seen in many patients.

Low risk of

 visual loss

Nonfunctioning Pituitary Mass

Differential diagnosis based on MRI and clinical features

Dynamic pituitary reserve testing

Exclude aneurysm

Follow-up: MRI MRI Trophic hormone

 testing and

 replacement

May require

 disease-specific

 therapy

MRI Trophic hormone

 testing and

 replacement

Surgery

Histologic diagnosis

Other sellar mass (not adenoma)

Microadenoma Macroadenoma

Observe Surgery

Nonfunctioning adenoma

FIGURE 380-10 Management of a nonfunctioning pituitary mass. MRI, magnetic resonance imaging.

2918 PART 12 Endocrinology and Metabolism

It is important to exclude other causes of inappropriate TSH secretion, such as resistance to thyroid hormone, an autosomal dominant

disorder caused by mutations in the thyroid hormone β receptor

(Chap. 382). The presence of a pituitary mass and elevated β subunit

levels are suggestive of a TSH-secreting tumor. Dysalbuminemic

hyperthyroxinemia syndromes, caused by mutations in serum thyroid

hormone binding proteins, are also characterized by elevated thyroid

hormone levels, but with normal rather than suppressed TSH levels.

Moreover, free thyroid hormone levels are normal in these disorders,

most of which are familial.

TREATMENT

TSH-Secreting Adenomas

The initial therapeutic approach is to remove or debulk the tumor

mass surgically, usually using a transsphenoidal approach. Total

resection is not often achieved as most of these adenomas are large

and locally invasive. Normal circulating thyroid hormone levels

are achieved in about two-thirds of patients after surgery. Thyroid

ablation or antithyroid drugs (methimazole and propylthiouracil)

can be used to reduce thyroid hormone levels. SRL treatment

effectively normalizes TSH and α subunit hypersecretion, shrinks

the tumor mass in 50% of patients, and improves visual fields in

75% of patients; euthyroidism is restored in most patients. Because

SRLs markedly suppress TSH, biochemical hypothyroidism often

requires concomitant thyroid hormone replacement, which may

also further control tumor growth.

■ AGGRESSIVE ADENOMAS

Despite the rarity of malignant transformation and metastatic lesions,

a subset of pituitary adenomas undergoes aggressive local growth

and central nervous system invasion with high Ki67 levels (>4%).

Silent corticotrope and somatotrope tumors, as well as prolactinomas

occurring in middle-aged men, are particularly prone to aggressive

growth and recurrence. Patients with these tumors usually require

an integrated management approach including repeat surgeries and

irradiation. Temozolomide has also been used with variable responses.

■ FURTHER READING

Coopmans EC et al: Multivariable prediction model for biochemical

response to first-generation somatostatin receptor ligands in acromegaly. J Clin Endocrinol Metab 105:2964, 2020.

Elbelt U et al: Efficacy of temozolomide therapy in patients with

aggressive pituitary adenomas and carcinomas: A German survey.

J Clin Endocrinol Metab 105:e660, 2020.

Freda PU et al: Pituitary incidentaloma: An Endocrine Society clinical

practice guideline. J Clin Endocrinol Metab 96:894, 2011.

Melmed S: Pituitary-tumor endocrinopathies. N Engl J Med 382:937,

2020.

Melmed S et al: Diagnosis and treatment of hyperprolactinemia: An

Endocrine Society clinical practice guideline. J Clin Endocrinol

Metab 96:273, 2011.

Neou M et al: Pangenomic classification of pituitary neuroendocrine

tumors. Cancer Cell 37:123, 2020.

Nieman LK: Cushing’s syndrome: Update on signs, symptoms and

biochemical screening. Eur J Endocrinol 173:M33, 2015.

Ntali G et al: Clinical review: Functioning gonadotroph adenomas.

J Clin Endocrinol Metab 99:4423, 2014.

Pivonello R et al: The treatment of Cushing’s disease. Endocr Rev

36:385, 2015.

Samson SL et al: Maintenance of acromegaly control in patients

switching from injectable somatostatin receptor ligands to oral octreotide. J Clin Endocrinol Metab 105:e3785, 2020.

Theodoropoulou M et al: Tumor-directed therapeutic targets in

Cushing disease. J Clin Endocrinol Metab 104:925, 2019.

The neurohypophysis, or posterior pituitary, is composed of large

neuronal axons that originate in cell bodies in the supraoptic and paraventricular nuclei of the hypothalamus, project through the diaphragm

sella, and terminate as bulbous enlargements on a capillary plexus that

drains into the superior vena cava. Some of these neurons produce

arginine vasopressin (AVP), also known as antidiuretic hormone;

others produce oxytocin. AVP acts on the renal tubules to reduce

water loss by concentrating the urine. Oxytocin stimulates postpartum

milk letdown in response to suckling. A deficiency of AVP secretion

or action causes a syndrome characterized by the production of large

amounts of dilute urine. Excessive or inappropriate AVP production

impairs urinary water excretion and predisposes to hyponatremia if

water intake is not reduced in parallel with urine output.

VASOPRESSIN

■ SYNTHESIS AND SECRETION

AVP is a nonapeptide composed of a six-member disulfide ring and

a tripeptide tail (Fig. 381-1). It is synthesized via a polypeptide precursor that includes AVP, neurophysin, and copeptin, all encoded by

a single gene on chromosome 20. After preliminary processing and

folding, the precursor is packaged in neurosecretory vesicles, where it

is transported down the axon; further processed to AVP, neurophysin,

and copeptin; and stored in neurosecretory vesicles until released by

exocytosis into peripheral blood.

In healthy individuals, AVP secretion is regulated primarily by the

“effective” osmotic pressure, which is determined largely by the plasma

concentration of sodium and its anions. This regulation is mediated by

specialized cells in the anteromedial hypothalamus, known as osmoreceptors. The osmoreceptors receive blood from small perforating

branches of the anterior communicating artery. They are extremely

sensitive to small changes in the plasma concentration of sodium and

its anions but normally are insensitive to other naturally occurring

plasma solutes such as urea and glucose. This osmoregulatory system

includes inhibitory as well as stimulatory components that function in

concert to form a threshold, or set point, control system. Below this

threshold, plasma AVP is suppressed to levels that permit the development of a maximum water diuresis. Above it, plasma AVP rises steeply

in direct proportion to plasma osmolarity, quickly reaching levels sufficient to produce maximum antidiuresis. The absolute levels of plasma

osmolarity/sodium at which minimally and maximally effective levels

of plasma AVP occur differ from person to person, apparently due to

genetic influences on the set and sensitivity of the system. However,

the average threshold, or set point, for AVP release corresponds to a

plasma osmolarity and sodium of ~275 mosmol/L and 135 meq/L,

respectively; levels only 2–4% higher normally result in maximum

antidiuresis.

The set point of the osmostat decreases ~1% during the luteal phase

of the menstrual cycle and ~3% during pregnancy. It is also reduced

381 Disorders of the

Neurohypophysis

Gary L. Robertson, Daniel G. Bichet

DDAVP –Cys–Tyr–Phe–Gln–Asp–Cys–Pro–D–Arg–Gly–NH2

S S

AVP NH2–Cys–Tyr–Phe–Gln–Asp–Cys–Pro–L–Arg–Gly–NH2

S S

Oxytocin NH2–Cys–Tyr–Ile–Gln–Asp–Cys–Pro–L–Leu–Gly–NH2

S S

FIGURE 381-1 Primary structures of arginine vasopressin (AVP), oxytocin, and

desmopressin (DDAVP).

2919 Disorders of the Neurohypophysis CHAPTER 381

by a decrease in blood pressure or by volume loss of >10–20%. These

hemodynamic influences are mediated by neuronal afferents that originate in transmural pressure receptors of the heart and large arteries

and project via the vagus and glossopharyngeal nerves to the brainstem, which sends postsynaptic projections to the hypothalamus. AVP

secretion also can be stimulated by nausea, acute hypoglycemia, glucocorticoid deficiency, smoking, and, possibly, hyperangiotensinemia.

Emetic stimuli are extremely potent since they typically elicit immediate, 50- to 100-fold increases in plasma AVP even when the nausea is

transient and is not associated with vomiting or other symptoms. They

appear to act via the emetic center in the medulla and can be blocked

completely by treatment with antiemetics such as fluphenazine. There

is no evidence that pain or other noxious stresses have any effect on

AVP unless they elicit a vasovagal reaction with its associated nausea

and hypotension.

■ ACTION

The most important, if not the only, physiologic action of AVP is to

reduce water excretion by promoting concentration of urine. This

antidiuretic effect is achieved primarily by increasing the hydroosmotic

permeability of principal cells that line the distal tubule and medullary

collecting ducts of the kidney (Fig. 381-2). In the absence of AVP,

these cells are impermeable to water and reabsorb little, if any, of the

relatively large volume of dilute filtrate that enters from the proximal

nephron. In this condition, the rate of urine output can be as high as

0.2 mL/kg per min and the specific gravity and osmolarity as low as

~1.000 and 50 mosmol/L, respectively. When AVP is secreted, it binds

to V2

 receptors on the basal surface of principal cells causing water

channels composed of aquaporin-2 to be inserted into the apical surface

of the cell. These channels allow water to flow passively from the lumen

through the cell down the osmotic gradient created by the hypertonicity of the

renal medulla. The magnitude of this

antidiuretic effect varies in direct proportion to plasma AVP, the rate of solute

excretion, and the level of hypertonicity

in the renal medulla. The maximum antidiuresis achievable in healthy humans

occurs at plasma AVP levels in the range

of 1 to 3 pg/mL and results in a urine

osmolarity as high as 1200 mosmol/L

and a rate of output as low as 0.35 mL/

min. However, maximum concentrating

capacity varies considerably depending

on the level of hypertonicity in the renal

medulla and that, in turn, is a function

of the level and duration of AVP receptor 2 (AVPR2)–stimulated readsorption

of urea in the distal nephron. Hence, if

basal AVP stimulation of AVPR2 is low

for any reason (e.g., a high basal fluid

intake), the rise in urine osmolarity that

occurs immediately after an increase

in hormone levels may be so blunted

as to suggest a defect in antidiuretic

function. This probably accounts for the

shortcomings of the traditional indirect

methods for the differential diagnosis of

diabetes insipidus (see below).

At high concentrations, AVP also

causes contraction of smooth muscle

in blood vessels in the skin and gastrointestinal tract, induces glycogenolysis

in the liver, and potentiates adrenocorticotropic hormone (ACTH) release

by corticotropin-releasing factor. These

effects are mediated by V1a or V1b receptors that are coupled to phospholipase

C. They may also affect the sensitivity of

Glomerulus

Henle’s loop

Collecting

tubule

Collecting duct

principal cells

180 L/d

(290)

Na + H2O

Na

H2O

H2O

H2O H2O

AQP 2

Vesicle

AQP3

AQP4

V2 receptor

Apical Basal

AVP

cAMP

36 L/d

(290)

24 L/d

(60)

1 L/d

Tight junctions

FIGURE 381-2 Antidiuretic effect of arginine vasopressin (AVP) in the regulation of urine volume. In a typical 70-kg

adult, the kidney filters ~180 L/d of plasma. Of this, ~144 L (80%) is reabsorbed isosmotically in the proximal tubule and

another 8 L (4–5%) is reabsorbed without solute in the descending limb of Henle’s loop. The remainder is diluted to an

osmolarity of ~60 mmol/kg by selective reabsorption of sodium and chloride in the ascending limb. In the absence of AVP,

the urine issuing from the loop passes largely unmodified through the distal tubules and collecting ducts, resulting in a

maximum water diuresis. In the presence of AVP, solute-free water is reabsorbed osmotically through the principal cells

of the collecting ducts, resulting in the excretion of a much smaller volume of concentrated urine. This antidiuretic effect

is mediated via a G protein–coupled V2

 receptor that increases intracellular cyclic AMP, thereby inducing translocation

of aquaporin 2 (AQP 2) water channels into the apical membrane. The resultant increase in permeability permits an

influx of water that diffuses out of the cell through AQP 3 and AQP 4 water channels on the basal-lateral surface. The net

rate of flux across the cell is determined by the number of AQP 2 water channels in the apical membrane and the

strength of the osmotic gradient between tubular fluid and the renal medulla. Tight junctions on the lateral surface of

the cells serve to prevent unregulated water flow. The V2

 receptors and AQP 2 are encoded by genes on chromosome

Xq28 and 12q13, respectively.

the baroreceptor and influence sympathetic and parasympathetic outflows to a variety of target organs, including the heart, the peripheral

vasculature, and the kidneys. Their role, if any, in human physiology/

pathophysiology remains to be determined.

■ METABOLISM

AVP distributes rapidly into a space roughly equal to the extracellular

fluid volume. It is cleared irreversibly with a half-life (t

1/2) of 10–30 min.

Most AVP clearance is due to degradation in the liver and kidneys.

During pregnancy, the metabolic clearance of AVP is increased threeto fourfold due to placental production of an N-terminal peptidase.

THIRST

Because AVP cannot reduce water loss below a certain minimum level

obligated by urinary solute load and evaporation from skin and lungs,

a mechanism for ensuring adequate intake is essential for preventing

dehydration. This vital function is performed by the thirst mechanism.

Like AVP, thirst and fluid intake are regulated primarily by an osmostat

that is situated in the anteromedial hypothalamus and is able to detect

very small changes in the plasma concentration of sodium and its

anions. The thirst osmostat appears to be “set” about 3% higher than

the AVP osmostat. This arrangement ensures that thirst, polydipsia,

and dilution of body fluids do not occur until plasma osmolarity/

sodium exceeds the defensive capacity of the antidiuretic mechanism.

Defects in this mechanism result in hypodipsia, diverse abnormalities

in AVP secretion, and a variety of clinical disorders of water balance

(see below). The gastrointestinal tract also has a mechanism that

detects fluid intake and inhibits thirst and AVP secretion before water

is absorbed sufficiently to lower plasma osmolarity/sodium. However,

the resultant inhibition of thirst and AVP is transient unless plasma

2920 PART 12 Endocrinology and Metabolism

osmolarity/sodium is reduced, and the role of this system in clinical

disorders of water balance has not been determined.

OXYTOCIN

Oxytocin is also a nonapeptide that differs from AVP only at positions

3 and 8 (Fig. 381-1). However, it has relatively little antidiuretic effect

and seems to act mainly on mammary ducts to facilitate milk letdown

during nursing. It also may help initiate or facilitate labor by stimulating contraction of uterine smooth muscle, but it is not clear if this

action is physiologic or necessary for normal delivery.

DEFICIENCIES OF AVP SECRETION AND

ACTION

■ DIABETES INSIPIDUS

Clinical Characteristics Diabetes insipidus (DI) is a syndrome characterized by the excretion of abnormally large volumes of dilute urine. The 24-h urine volume exceeds 40 mL/

kg body weight, and the 24-h urine osmolarity is <280 mosm/L.

The polyuria produces symptoms of urinary frequency, enuresis, and/

or nocturia. It also results in a slight rise in plasma osmolarity/sodium

that stimulates thirst and a commensurate increase in fluid intake

(polydipsia). Hence, clinical symptoms and signs of dehydration are

uncommon unless thirst and/or water intake are also impaired.

Etiology DI is divided into four different types based on the

etiology. The most common is due to a primary deficiency of AVP

secretion. It is referred to variously as neurohypophyseal, neurogenic, pituitary, cranial, or central DI. It can be caused by a variety

of congenital, acquired, or genetic disorders but is often idiopathic

(Table 381-1). Six genetic forms of pituitary DI are now known. By far,

the most common is transmitted in an autosomal dominant mode and

is caused by diverse mutations in the coding region of one allele of the

AVP–neurophysin II (or AVP-NPII) gene. All the mutations alter one

or more amino acids known to be critical for correct processing and/or

folding of the prohormone, thus interfering with its trafficking through

the endoplasmic reticulum. Presumably, the misfolded mutant precursor accumulates and interferes with the production of AVP by the normal allele. Eventually, it destroys the magnocellular neurons in which

it is produced since histologic studies in a few patients show fibrosis

and a lack of AVP-containing neurons in the posterior pituitary. The

AVP deficiency usually is not present at birth but develops gradually

over a period of months to years, progressing from partial to severe at

different rates depending on the mutation and other unknown variables. Once established, the deficiency of AVP is permanent, but for

unknown reasons, the DI occasionally improves or remits completely

in late middle age. The parvocellular neurons that make AVP and the

magnocellular neurons that make oxytocin appear to be unaffected.

There are also rare autosomal recessive forms of pituitary DI. One is

due to an inactivating mutation in the AVP portion of the gene that

results in production of a biologically inactive form of AVP. Another

is due to a large deletion that involves the majority of the AVP gene

and regulatory sequences in the intergenic region. A third is caused by

mutations of the WFS1 gene responsible for Wolfram’s syndrome (DI,

diabetes mellitus, optic atrophy, and neural deafness [DIDMOAD]).

An X-linked recessive form pituitary DI linked to Xq28 also has been

reported, but the causative gene has not yet been identified. Finally,

mutations in the PCSK1 gene have been associated with severe early

malabsorptive diarrhea and an undefined polyuria-polydipsia syndrome developing before 5 years of age.

The second type of DI is due to a suppression of AVP secretion

by excessive intake of fluids. It is commonly referred to as primary

polydipsia and can be subdivided into three subcategories. In one,

called dipsogenic DI, the excessive fluid intake appears to be caused

by inappropriate thirst. It can occur following head trauma or in

association with multifocal diseases of the brain such as neurosarcoid,

tuberculous meningitis, and multiple sclerosis, but like pituitary DI,

it is often idiopathic. The second subcategory, psychogenic polydipsia,

is not associated with thirst, and the polydipsia seems to be a feature

of psychosis or obsessive-compulsive disorder. The third subcategory,

iatrogenic polydipsia, is due to an increase in water intake motivated by

a belief in its health benefits.

The third type of DI is also due to a deficiency of AVP caused by

an increased rate of degradation by an N-terminal aminopeptidase

produced in the placenta. It is referred to as gestational DI because

the signs and symptoms manifest during pregnancy and usually remit

several weeks after delivery. The fourth type of DI is caused by renal

insensitivity to the antidiuretic action of AVP. It is called nephrogenic

DI and can be caused by a drug such as lithium, a disorder such as

TABLE 381-1 Causes of Diabetes Insipidus

Pituitary diabetes insipidus

Acquired

 Head trauma (closed and

penetrating) including pituitary

surgery

Neoplasms

 Primary

 Craniopharyngioma

 Pituitary adenoma (suprasellar)

 Dysgerminoma

 Meningioma

 Metastatic (lung, breast)

 Hematologic (lymphoma,

leukemia)

Granulomas

 Sarcoidosis

 Histiocytosis

 Xanthoma disseminatum

Infectious

 Chronic meningitis

 Viral encephalitis

 Toxoplasmosis

Inflammatory

 Lymphocytic

infundibuloneurohypophysitis

 Granulomatosis with polyangiitis

(Wegener’s)

 Lupus erythematosus

 Scleroderma

Chemical toxins

 Tetrodotoxin

 Snake venom

Vascular

 Sheehan’s syndrome

 Aneurysm (internal carotid)

 Aortocoronary bypass

 Hypoxic encephalopathy

Idiopathic

Congenital malformations

Septo-optic dysplasia

Midline craniofacial defects

Holoprosencephaly

Hypogenesis, ectopia of pituitary

Genetic

Autosomal dominant

(AVP-neurophysin gene)

Autosomal recessive

Type A (AVP-neurophysin gene)

Type B (AVP-neurophysin gene)

Type C (Wolfram’s [4p-WFS1] gene)

X-linked recessive (Xq28)

Gestational diabetes insipidus

Pregnancy (second and third

trimesters)

Nephrogenic diabetes insipidus

Acquired

Drugs

 Lithium

 Demeclocycline

 Methoxyflurane

 Amphotericin B

 Aminoglycosides

 Cisplatin

 Rifampin

 Foscarnet

Metabolic

 Hypercalcemia, hypercalciuria

 Hypokalemia

Obstruction (ureter or urethra)

Vascular

 Sickle cell disease and trait

 Ischemia (acute tubular necrosis)

Granulomas

 Sarcoidosis

Neoplasms

 Sarcoma

Infiltration

 Amyloidosis

Idiopathic

Genetic

 X-linked recessive (AVP receptor-2

gene)

Autosomal recessive (AQP2 gene)

Autosomal dominant (AQP2 gene)

Primary polydipsia

Acquired

Psychogenic

 Schizophrenia

 Obsessive compulsive disorder

Dipsogenic (abnormal thirst)

 Granulomas (sarcoidosis)

 Infectious (tuberculous

meningitis)

 Head trauma (closed and

penetrating)

 Demyelination (multiple sclerosis)

 Drugs

 Idiopathic

 Iatrogenic

Abbreviation: AVP, arginine vasopressin.

2921 Disorders of the Neurohypophysis CHAPTER 381

1000

800

600

400

200

0

Urine osmolarity, mosmol/L

0.1 0.5 1 3

Plasma vasopressin, pg/mL

A B

10 30 60

60

40

20

15

10

5

0

270 280 290 300 310

Plasma vasopressin, pg/mL

Plasma osmolarity, mosmol/L

FIGURE 381-3 Relationship of plasma arginine vasopressin (AVP) to urine osmolarity (A) and plasma osmolarity

(B) before and during fluid deprivation–hypertonic saline infusion test in patients who are normal or have primary

polydipsia (blue zones), pituitary diabetes insipidus (green zones), or nephrogenic diabetes insipidus (pink zones).

hypokalemia, or a genetic mutation (Table

381-1). The most common genetic form

is transmitted in a semirecessive X-linked

manner and is due to mutations in the gene

on chromosome Xq28 that encodes the V2

receptor. There are also autosomal recessive or dominant forms of nephrogenic

DI. They are caused by mutations of the

gene on chromosome 20 that encodes the

aquaporin-2 water channels necessary for

readsorption of water from dilute urine in

the renal collecting ducts.

Pathophysiology In pituitary and

nephrogenic DI, the defect in urine concentration results in a rise in the rate of

water excretion, a small (1–2%) decrease in

body water, and a commensurate increase

in plasma osmolarity/sodium, which stimulates thirst and a compensatory increase

in water intake. The severity of the defect

in antidiuretic function varies significantly from patient to patient. In

some, it is nearly complete and cannot be overcome by even an intense

stimulus such as nausea or severe dehydration. In others, the defect

in AVP secretion or action is incomplete, and a modest stimulus such

as a few hours of fluid deprivation, smoking, or a vasovagal reaction

is sufficient to concentrate the urine. However, even in patients with

a partial defect, the maximum level of urine osmolarity produced

by these stimuli is usually less than normal partly because the prior

deficiency in basal AVP stimulation temporarily diminishes renal

concentrating capacity. Nevertheless, the underlying cause of the DI

can be determined by analyzing the relationship of urine osmolarity to

plasma AVP (Fig. 381-3A) and of plasma AVP to plasma osmolarity/

sodium (Fig. 381-3B).

The pathophysiology of primary polydipsia is the reverse of that

in pituitary and nephrogenic DI. The increase in fluid intake reduces

plasma osmolarity/sodium and AVP secretion. The resultant urinary

dilution produces a compensatory increase in urinary free-water

excretion that usually offsets the increase in intake and stabilizes

plasma osmolarity/sodium at a level below basal. Thus, hyponatremia

is uncommon unless the polydipsia is very severe or the compensatory

water diuresis is impaired. Fluid deprivation or hypertonic saline infusion produces a normal rise in plasma AVP, but the resultant increase

in urine concentration is usually subnormal because the capacity of the

kidney to concentrate the urine is temporarily diminished by the prior

lack of AVP stimulation. Thus, the maximum level of urine osmolarity

achieved is often indistinguishable from that produced by fluid deprivation and/or administration of antidiuretic hormone in partial pituitary or partial nephrogenic DI. However, unlike the other two types of

DI, the relationships of the rise in plasma AVP to the rise in plasma and

urine osmolarity are both normal in primary polydipsia (Fig. 381-3).

Differential Diagnosis If symptoms of urinary frequency, enuresis, nocturia, and/or persistent thirst are present in the absence of glucosuria, the possibility of DI should be evaluated by collecting a 24-h

urine on unrestricted fluid intake. If the osmolarity is <280 mosm/L

and the volume >50 mL/kg per day, the patient has DI and should be

evaluated further to determine the type. Sometimes the type can be

inferred from the clinical setting. Often, however, this information

is lacking, ambiguous, or even misleading, and other approaches to

differential diagnosis are needed. In the few patients in whom basal

plasma osmolarity and/or sodium are above the normal range, a fluid

deprivation test is unnecessary and potentially hazardous because primary polydipsia can be excluded. Therefore, an injection of AVP (0.5

IU) or desmopressin (2 μg) followed by a repeat measurement of urine

osmolarity will suffice to determine if the DI is due to a severe defect

in the secretion or action of AVP. However, if basal plasma osmolarity and sodium are within normal limits, as they usually are, some

other method is needed to determine the type of DI. The traditional

approach is to stop all fluid intake for 4–6 h and closely monitor the

changes in body weight, plasma osmolarity/sodium, and urine osmolarity. If plasma osmolarity and sodium rise above the normal range

without concentrating the urine, primary polydipsia is excluded, and

the effect on urine osmolarity of injecting AVP or desmopressin will

determine if the patient has severe pituitary or severe nephrogenic DI.

If, however, fluid deprivation results in concentration of the urine, the

effect on urine osmolarity of injecting AVP or desmopressin does not

distinguish reliably between partial pituitary DI, partial nephrogenic

DI, and primary polydipsia because all three disorders temporarily

diminish renal concentrating capacity to a variable extent depending

on the severity of the basal polyuria.

The ambiguities inherent in the indirect method of differential

diagnosis usually can be avoided by measuring plasma AVP before and

during 4–6 h of complete fluid deprivation and relating these values to

the concurrent level of plasma and urine osmolarity (Fig. 381-3). This

approach distinguishes reliably between pituitary and nephrogenic

DI even when the defect in AVP secretion or action is partial. It also

differentiates partial pituitary DI from primary polydipsia if plasma

osmolarity and sodium rise above the normal range. However, this

level of dehydration is difficult to achieve by fluid deprivation alone

when urinary concentration occurs. Therefore, it is usually necessary to add a short infusion of 3% saline (0.1 mL/kg body weight per

minute for 60–90 min) and repeat the measurements of plasma AVP

when plasma osmolarity and sodium rise above the normal range.

This approach differentiates reliably between partial pituitary DI and

primary polydipsia as evidenced by other findings, including MRI of

the posterior pituitary and a properly dosed and closely monitored trial

of antidiuretic therapy.

A simpler and less stressful but equally reliable way to differentiate

among pituitary DI, nephrogenic DI, and primary polydipsia is to start

by measuring basal plasma AVP and urine osmolarity under conditions

of unrestricted fluid intake (Fig. 381-4). If AVP is normal or elevated

(>1 pg/mL) and the concurrent urine osmolarity is low (<280 mosm/L),

the patient has nephrogenic DI and the only additional evaluation

required is to determine the cause. If, however, basal plasma AVP

is low or undetectable (<1 pg/mL), nephrogenic DI is very unlikely,

and a brain MRI can be performed to determine if the hyperintense

signal normally emitted by the posterior pituitary on T1-weighted

images is present. Because this “bright spot” is a function of pituitary

stores of AVP, it is almost always present in primary polydipsia but is

abnormally small or absent in pituitary DI even when the deficiency

in AVP is partial or due to production of a biologically inactive form

of the hormone. The bright spot is also faint or absent in nephrogenic

DI presumably because the chronic stimulus to AVP secretion depletes

pituitary stores of the hormone. Therefore, MRI does not differentiate

between pituitary and nephrogenic DI unless it reveals other pathology

involving the gland. The other caveat is that the pituitary bright spot is

2922 PART 12 Endocrinology and Metabolism

Brain MRI

Urinary frequency, nocturia, enuresis

24-h urine volume and osmolarity on unrestricted fluid intake

Volume >40 mL/kg

Osmolarity <300 mosm/L

Basal plasma AVP

>1 pg/mL <1 pg/mL

Nephrogenic

DI

Pituitary bright spot

Present Absent

Anatomy

Pathology?

Primary polydipsia Pituitary DI

GU evaluation

Volume <40 mL/kg

Osmolarity >300 mosm/L

FIGURE 381-4 Simplified approach to the differential diagnosis of diabetes

insipidus. When symptoms suggest diabetes insipidus (DI), the syndrome should

be differentiated from a genitourinary (GU) abnormality by measuring the 24-h

urine volume and osmolarity on unrestricted fluid intake. If DI is confirmed, basal

plasma arginine vasopressin (AVP) should be measured on unrestricted fluid intake.

If AVP is normal or elevated (>1 pg/mL), the patient probably has nephrogenic DI.

However, if plasma AVP is low or undetectable, the patient has either pituitary DI

or primary polydipsia. In that case, magnetic resonance imaging (MRI) of the brain

can be performed to differentiate between these two conditions by determining

whether or not the normal posterior pituitary bright spot is visible on T1-weighted

midsagittal images. In addition, the MRI anatomy of the pituitary hypothalamic area

can be examined to look for evidence of pathology that sometimes causes pituitary

DI or the dipsogenic form of primary polydipsia. MRI is not reliable for differential

diagnosis unless nephrogenic DI has been excluded because the bright spot is also

absent, small, or faint in this condition.

also absent in patients with empty sella even in the absence of any type

of DI and is sometimes present in infants in the early stages of familial

pituitary DI.

If MRI and/or AVP assays with the requisite sensitivity and specificity are unavailable and a fluid deprivation test is impractical or

undesirable, a third way to differentiate among pituitary DI, nephrogenic DI, and primary polydipsia is a properly dosed and closely

monitored trial of desmopressin therapy (see below). In nephrogenic

DI, this treatment has no effect on urine output, fluid intake, or plasma

osmolarity/sodium. In pituitary DI, it abolishes the polyuria and polydipsia and reduces plasma osmolarity/sodium by 1–2%. However, in

primary polydipsia, antidiuretic therapy eliminates the polyuria but

not the polydipsia and, as a consequence, produces moderate to severe

hyponatremia within 8–24 h.

The measurement of plasma copeptin has also been advocated for

the differential diagnosis of DI since it is synthesized and co-secreted

with AVP. However, because copeptin is cleared from plasma more

slowly than AVP, its relationship to plasma and urine osmolarity is

not diagnostic, and another approach based on the change in plasma

copeptin after an infusion of hypertonic saline has been reported.

However, unlike the measurement of plasma AVP, the diagnoses

obtained by the copeptin method do not correlate well with the MRI

findings or the response to antidiuretic therapy. The reason for these

disparities remains to be determined.

TREATMENT

Diabetes Insipidus

The signs and symptoms of uncomplicated pituitary DI can be

eliminated by treatment with desmopressin (DDAVP), a synthetic analogue of AVP (Fig. 381-1). DDAVP acts selectively at V2

receptors to increase urine concentration and decrease urine flow

in a dose-dependent manner. It is also more resistant to degradation than is AVP and has a three- to fourfold longer duration of

action. DDAVP can be given by IV or SC injection, nasal inhalation, or orally by means of a tablet or melt. The doses required to

control pituitary DI vary depending on the patient and the route of

administration. However, among adults, they usually range from

1–2 μg qd or bid by injection, 10–20 μg bid or tid by nasal spray,

or 100–400 μg bid or tid orally. The onset of antidiuresis is rapid,

ranging from as little as 15 min after injection to 60 min after oral

administration. When given in a dose that normalizes 24-h urinary

osmolarity (400–800 mosmol/L) and volume (15–30 mL/kg body

weight), DDAVP produces a slight increase in total body water and

a (1–2%) decrease in plasma osmolarity/sodium that rapidly eliminates thirst and polydipsia (Fig. 381-5). Consequently, water balance is maintained within the normal range. Hyponatremia rarely

develops unless urine volume is reduced to <10 mL/kg per day or

fluid intake is excessive due to an associated abnormality in thirst

or cognition. Fortunately, thirst abnormalities are rare, and if the

patient learns to drink only when truly thirsty, DDAVP can be given

safely in doses sufficient to normalize urine output without the

need for allowing intermittent escape to prevent water intoxication.

Primary polydipsia cannot be treated safely with DDAVP or

any other antidiuretic drug because eliminating the polyuria does

not eliminate the urge to drink. Therefore, it invariably produces

hyponatremia and/or other signs of water intoxication, usually

within 8–24 h if urine output is normalized completely. There is

no consistently effective way to correct dipsogenic or psychogenic

polydipsia, but the iatrogenic form may respond to patient education. To minimize the risk of water intoxication, all patients should

be warned about the use of other drugs such as thiazide diuretics or

carbamazepine (Tegretol) that can impair urinary free-water excretion directly or indirectly.

The polyuria and polydipsia of nephrogenic DI are not affected

by treatment with standard doses of DDAVP. If resistance is partial,

it may be overcome by tenfold higher doses, but this treatment is too

expensive and inconvenient for long-term use. However, treatment

with conventional doses of a thiazide diuretic and/or amiloride in

conjunction with a low-sodium diet and a prostaglandin synthesis

inhibitor (e.g., indomethacin) usually reduces the polyuria and

polydipsia by 30–70% and may eliminate them completely. Side

effects such as hypokalemia and gastric irritation can be minimized

by the use of amiloride or potassium supplements and by taking

medications with meals.

Days of treatment

0

225

250

275

300

325

01234

Fluid intake and urine output L/d

Plasma osmolarity mosmol/L

0

6

12

18

24

Desmopressin 200 mcg

po q8h

Intake

Output

Pos

FIGURE 381-5 Effect of desmopressin therapy on fluid intake (blue bars),

urine output (orange bars), and plasma osmolarity (red line) in a patient with

uncomplicated pituitary diabetes insipidus. Note that treatment rapidly reduces

fluid intake and urine output to normal, with only a slight increase in body water as

evidenced by the slight decrease in plasma osmolarity.

2923 Disorders of the Neurohypophysis CHAPTER 381

Plasma vasopressin, pg/mL

20

18

16

14

12

10

8

6

4

2

0

240 260 280 300 320

Plasma osmolarity, mosmol/L

340 360 380

P

Partial AH

Normal range

Total AH

a

c

b

d

T

FIGURE 381-6 Heterogeneity of osmoregulatory dysfunction in adipsic hypernatremia

(AH) and the syndrome of inappropriate antidiuresis (SIAD). Each line depicts

schematically the relationship of plasma arginine vasopressin (AVP) to plasma

osmolarity during water loading and/or infusion of 3% saline in a patient with either

AH (open symbols) or SIAD (closed symbols). The shaded area indicates the normal

range of the relationship. The horizontal broken line indicates the plasma AVP

level below which the hormone is undetectable and urinary concentration usually

does not occur. Lines P and T represent patients with a selective deficiency in the

osmoregulation of thirst and AVP that is either partial ( ) or total ( ). In the latter,

plasma AVP does not change in response to increases or decreases in plasma

osmolarity but remains within a range sufficient to concentrate the urine even if

overhydration produces hypotonic hyponatremia. In contrast, if the osmoregulatory

deficiency is partial ( ), rehydration of the patient suppresses plasma AVP to levels

that result in urinary dilution and polyuria before plasma osmolarity and sodium are

reduced to normal. Lines a–d represent different defects in the osmoregulation

of plasma AVP observed in patients with SIADH or SIAD. In a ( ), plasma AVP is

markedly elevated and fluctuates widely without relation to changes in plasma

osmolarity, indicating complete loss of osmoregulation. In b ( ), plasma AVP

remains fixed at a slightly elevated level until plasma osmolarity reaches the normal

range, at which point it begins to rise appropriately, indicating a selective defect

in the inhibitory component of the osmoregulatory mechanism. In c ( ), plasma

AVP rises in close correlation with plasma osmolarity before the latter reaches

the normal range, indicating downward resetting of the osmostat. In d ( ), plasma

AVP appears to be osmoregulated normally, suggesting that the inappropriate

antidiuresis is caused by some other abnormality.

■ HYPODIPSIC HYPERNATREMIA

An increase in plasma osmolarity/sodium above the normal range

(hypertonic hypernatremia) can be due to a decrease in total body

water or an increase in total body sodium. The former results from a

failure to drink enough water to replace normal or increased urinary

and insensible loss due either to water deprivation or a lack of thirst

(hypodipsia). This chapter focuses on hypodipsic hypernatremia, the

form of hypernatremia due to a primary defect in the thirst mechanism. Hypernatremia caused by an increase in total body sodium is

described elsewhere (Chap. 386).

Clinical Characteristics Hypodipsic hypernatremia is a syndrome characterized by chronic or recurrent hypertonic dehydration.

The hypernatremia varies widely in severity and is often associated

with signs of hypovolemia such as tachycardia, postural hypotension,

azotemia, hyperuricemia, and hypokalemia due to secondary hyperaldosteronism. Muscle weakness, pain, rhabdomyolysis, hyperglycemia,

hyperlipidemia, and acute renal failure may also occur. Obtundation

or coma may be present. At presentation, plasma AVP is usually but

not always subnormal relative to the concurrent hypernatremia/

hyperosmolemia. DI is usually absent but may develop during rehydration as blood volume, blood pressure, and plasma osmolarity/sodium

return toward normal.

Etiology Hypodipsia is usually due to hypogenesis or destruction

of the osmoreceptors in the anterior hypothalamus that regulate thirst.

The defect can result from various congenital malformations of midline brain structures or may be acquired due to diseases such as surgery or aneurysms of the anterior communicating artery, primary or

metastatic tumors in the hypothalamus, head trauma, granulomatous

diseases such as sarcoidosis and histiocytosis, AIDS, and cytomegalovirus encephalitis. Adipsic hypernatremia without demonstrable hypothalamic lesions has also been associated with autoantibodies directed

against the subfornical organ. Episodes of transient hypodipsic hypernatremia have also been reported in association with depression or

other psychological disorders, suggesting that reversible neurochemical defects in the osmoregulation of thirst can also occur.

Pathophysiology A deficiency in osmotically induced thirst

results in a failure to drink enough water to replenish obligatory renal

and extrarenal losses. Consequently, plasma osmolarity and sodium

rise often to extremely high levels before the disorder is recognized. In

most cases, plasma AVP is subnormal relative to the hyperosmolarity/

hypernatremia, but it is still adequate to prevent DI. However, during

rehydration, plasma AVP sometimes falls to levels that result in DI

before the dehydration is fully corrected (Fig. 381-6). In other cases,

plasma AVP does not decline even when the patient is overhydrated

and a hyponatremic syndrome indistinguishable from inappropriate

antidiuresis develops. This suggests that the AVP osmoreceptors

normally provide inhibitory as well as stimulatory input to the neurohypophysis. In both situations, AVP secretion responds normally

to nonosmotic stimuli such as nausea, hypovolemia, or hypotension,

indicating that the neurohypophysis is intact. In a few patients, however, the neurohypophysis is also destroyed, resulting in a combination

of chronic pituitary DI and hypodipsia, a life-threatening disorder

that can be very difficult to manage. Rarely, the regulation of AVP

secretion is completely normal, suggesting that the lack of thirst is due

to a defect in post-osmoreceptor neural pathways to higher cognitive

centers.

Differential Diagnosis Hypodipsic hypernatremia usually can be

distinguished from other causes of inadequate fluid intake (e.g., coma,

paralysis, restraints, absence of fresh water) by the clinical history and

setting. Previous episodes and/or denial of thirst and failure to drink

spontaneously when the patient is conscious, unrestrained, and hypernatremic are virtually diagnostic. The hypernatremia caused by excessive retention or intake of sodium can be distinguished by the presence

of thirst as well as the physical and laboratory signs of hypervolemia

rather than hypovolemia.

TREATMENT

Hypodipsic Hypernatremia

Hypodipsic hypernatremia can be corrected by administering water

orally if the patient is alert and cooperative or by infusing hypotonic

fluids (0.45% saline or 5% dextrose and water) if the patient is not.

The amount of free water in liters required to correct the deficit

(ΔFW) can be estimated from body weight in kg (BW) and the

serum sodium concentration in mmol/L (SNa) by the formula ΔFW =

0.5BW × ([SNa – 140]/140). If serum glucose (SGlu) is elevated, the

measured SNa should be corrected (SNa

*

) by the formula SNa

*

 = SNa +

([SGlu – 90]/36). This amount plus an allowance for continuing

insensible and urinary losses should be given over a 24- to 48-h

period. Close monitoring of serum sodium as well as fluid intake

and urinary output is essential because, depending on the extent of

osmoreceptor deficiency, some patients will develop AVP-deficient

DI, requiring DDAVP therapy to complete rehydration; others will

develop hyponatremia and a syndrome of inappropriate antidiuresis (SIAD)-like picture if overhydrated. If hyperglycemia and/or

hypokalemia are present, insulin and/or potassium supplements

should be given with the expectation that both can be discontinued

when rehydration is complete. Plasma urea/creatinine should be

monitored closely for signs of acute renal failure caused by rhabdomyolysis, hypovolemia, and hypotension.

Once the patient has been rehydrated, an MRI of the brain and

tests of anterior pituitary function should be performed to look for

2924 PART 12 Endocrinology and Metabolism

TABLE 381-2 Causes of Syndrome of Inappropriate Antidiuresis

Neoplasms

Carcinomas

Lung

Duodenum

Pancreas

Ovary

Bladder, ureter

Other neoplasms

Thymoma

Mesothelioma

Bronchial adenoma

Carcinoid

Gangliocytoma

Ewing’s sarcoma

Genetic

AVP receptor-2

Head trauma (closed and penetrating)

Infections

Pneumonia, bacterial or viral

Abscess, lung or brain

Cavitation (aspergillosis)

Tuberculosis, lung or brain

Meningitis, bacterial or viral

Encephalitis

AIDS

Vascular

 Cerebrovascular occlusions,

hemorrhage

Cavernous sinus thrombosis

Neurologic

Guillain-Barré syndrome

Multiple sclerosis

Delirium tremens

Amyotrophic lateral sclerosis

Hydrocephalus

Psychosis

Peripheral neuropathy

Congenital malformations

Agenesis corpus callosum

Cleft lip/palate

Other midline defects

Metabolic

Acute intermittent porphyria

Pulmonary

Asthma

Pneumothorax

Positive-pressure respiration

Drugs

Vasopressin or desmopressin

Serotonin reuptake inhibitors

Oxytocin, high dose

Vincristine

Carbamazepine

Nicotine

Phenothiazines

Cyclophosphamide

Tricyclic antidepressants

Monoamine oxidase inhibitors

Abbreviation: AVP, arginine vasopressin.

the cause and collateral defects in other hypothalamic functions.

A long-term management plan to prevent or minimize recurrence

of the fluid and electrolyte imbalance also should be developed.

This should include a practical method to regulate fluid intake in

accordance with variations in water balance as indicated by changes

in body weight or serum sodium determined by home monitoring

analyzers. Prescribing a fixed fluid intake is often problematic and

potentially dangerous because insensible as well as urinary loss varies significantly over time due to changes in ambient temperature

and physical activity as well as diet and antidiuresis.

■ INAPPROPRIATE ANTIDIURESIS

(SEE ALSO CHAP. 53)

Clinical Characteristics SIAD is characterized by hypoosmolemic hyponatremia and impaired urinary dilution in the absence

of hypovolemia, hypotension, or other nonosmotic stimuli to AVP

secretion. If the hyponatremia develops gradually or exists for more

than a few days, it may be largely asymptomatic. However, if the

hyponatremia is severe or develops acutely, it can cause a variety of

adverse symptoms and signs ranging from headache, confusion, and

anorexia to nausea, vomiting, coma, and convulsions. SIAD occurs in

many diverse clinical settings (Table 381-2).

Etiology The cause of SIAD is a failure to maximally dilute the

urine and mount a water diuresis when total water intake exceeds

urinary and insensible water loss. In most cases, the defect in urinary

dilution is due to an abnormality in AVP secretion and is commonly

referred to as the syndrome of inappropriate antidiuretic hormone

(SIADH). The defect in the osmoregulation of AVP secretion can take

any of several different forms (Fig. 381-6). The most common is one

in which the AVP secretion responds normally to osmotic stimulation

and suppression but the threshold or set point of the system is lower

than normal. These patients are able to dilute their urine if plasma

osmolarity/sodium is reduced below the abnormal set point. In others,

the secretion of AVP appears to be fixed or totally erratic. In ~10% of

cases, there is no demonstrable defect in the osmoregulation of AVP

secretion, and the failure to maximally dilute the urine may be due to

an abnormality in the kidney. This form may be referred to as nephrogenic SIAD (NSIAD). In some of these patients, the inappropriate

antidiuresis has been traced to a constitutive activating mutation of the

V2

 receptor gene or the stimulatory G alpha protein GNAS. This form

of inappropriate antidiuresis may be referred to as familial NSIAD.

Pathophysiology In SIADH and NSIAD, the failure to mount a

water diuresis when intake exceeds urinary and insensible loss results

in a slight expansion of total body water followed by a modest increase

in urinary sodium excretion due at least in part to suppression of

plasma renin activity and aldosterone secretion. As a result, expansion

of extracellular volume is minimal, and clinically detectable edema

does not develop. However, intracellular volume increases in proportion to the severity and rapidity of the change in plasma sodium. In the

brain, this cellular swelling causes an increase in pressure that triggers

a variety of symptoms. After several days, the swelling and symptoms

may subside due to inactivation of some intracellular solutes and resultant decrease in cellular volume.

Differential Diagnosis SIADH and NSIAD must be differentiated

from other types of hypo-osmolemic hyponatremia associated with

impaired urinary dilution. This is usually possible from the history,

physical examination, and basic laboratory findings (Table 381-3).

Hypervolemic hyponatremia (type I) typically occurs in patients

with generalized edema due to severe congestive heart failure or

cirrhosis. Plasma renin activity (PRA) and aldosterone are elevated.

Hypovolemic hyponatremia (type II) occurs in patients with loss

of sodium and water due to severe vomiting, diarrhea, or primary

adrenal insufficiency. It is usually associated with hypotension in the

recumbent or upright position and an elevation in PRA. Euvolemic

hyponatremia (type III) is divisible into two groups, which need to

be managed differently. In one group, the cause is a severe deficiency

in cortisol or thyroxine and should be treated accordingly. The other

group is composed of patients with SIADH and NSIAD. In both, edema

and a history or signs of sodium and water loss are absent, urinary

sodium may be slightly elevated, and PRA is often low. Measurement

of plasma AVP is usually of little diagnostic value except to differentiate SIADH from NSIAD in children or families with two or more

affected members. If it is undetectable, sequencing of the AVPR2 gene

is indicated.

TREATMENT

Inappropriate Antidiuresis

The management of hyponatremia differs depending on the type

as well as the severity and duration of symptoms. In hypervolemic

hyponatremia, the objective should be to reduce total body sodium

and water. If the hyponatremia is mild and symptomatic, restricting

daily fluid intake to less than total urinary and insensible water

loss usually suffices to prevent progression and gradually correct the defect. However, if basal urine output is very low or the

hyponatremia is severe and/or symptomatic, an AVP antagonist

such as tolvaptan or conivaptan can be given to increase the rate of

urinary water excretion (see below). Their use should be limited to

30 days at a time because longer periods may cause or worsen

abnormal liver chemistries. Infusion of hypertonic saline is absolutely contraindicated in hypervolemic hyponatremia because it

further increases total body sodium and water, worsens the edema,

and may precipitate cardiovascular decompensation.

In hypovolemic hyponatremia, fluid restriction and inhibitors of

AVP action are absolutely contraindicated because they aggravate

the hypovolemia and could precipitate hemodynamic collapse.

Instead, an effort should be made to stop the loss of sodium

and water and replace the deficits by mouth or infusion of isotonic or hypertonic saline. As in the treatment of other forms of

2925 Disorders of the Neurohypophysis CHAPTER 381

TABLE 381-3 Differential Diagnosis of Hyponatremia Based on Clinical Assessment of Extracellular Fluid Volume (ECFV)

CLINICAL FINDINGS TYPE I, HYPERVOLEMIC TYPE II, HYPOVOLEMIC TYPE III, EUVOLEMIC SIADH AND SIAD EUVOLEMIC

History

CHF, cirrhosis, or nephrosis

Salt and water loss

ACTH-cortisol deficiency and/or nausea and

vomiting

Yes

No

No

No

Yes

No

No

No

Yes

No

No

No

Physical examination

Generalized edema, ascites

Postural hypotension

Yes

Maybe

No

Maybe

No

Maybea

No

No

Laboratory

BUN, creatinine

Uric acid

Serum potassium

Serum urate

Serum albumin

Serum cortisol

Plasma renin activity

 Urinary sodium (meq per unit of time)g

High-normal

High-normal

Low-normal

High

Low-normal

Normal-high

High

Low

High-normal

High-normal

Low-normalb

High

High-normal

Normal-highd

High

Lowh

Low-normal

Low-normal

Normalc

Low

Normal

Lowe

Lowf

Highi

Low-normal

Low-normal

Normal

Low

Normal

Normal

Low

Highi

a

Postural hypotension may occur in secondary (ACTH-dependent) adrenal insufficiency even though extracellular fluid volume and aldosterone are usually normal. b

Serum

potassium may be high if hypovolemia is due to aldosterone deficiency. c

Serum potassium may be low if vomiting causes alkalosis. d

Serum cortisol is low if hypovolemia

is due to primary adrenal insufficiency (Addison’s disease). e

Serum cortisol will be normal or high if the cause is nausea and vomiting rather than secondary (ACTHdependent) adrenal insufficiency. f

Plasma renin activity may be high if the cause is secondary (ACTH) adrenal insufficiency. g

Urinary sodium should be expressed as the

rate of excretion rather than the concentration. In a hyponatremic adult, an excretion rate >25 meq/d (or 25 μeq/mg of creatinine) could be considered high. h

The rate

of urinary sodium excretion may be high if the hypovolemia is due to diuretic abuse, primary adrenal insufficiency, or other causes of renal sodium wasting. i

The rate of

urinary sodium excretion may be low if intake is curtailed by symptoms or treatment.

Abbreviations: ACTH, adrenocorticotropic hormone; BUN, blood urea nitrogen; CHF, congestive heart failure; SIAD, syndrome of inappropriate antidiuresis; SIADH,

syndrome of inappropriate antidiuretic hormone.

hyponatremia, care must be taken to ensure that plasma sodium

does not increase too rapidly or too far since doing so may produce

osmotic demyelination in the brain.

In euvolemic hyponatremia, the treatment of choice depends

on the cause. If it is a deficiency in cortisol or thyroxine, gradual

replacement usually suffices to eliminate all signs and symptoms,

including the hyponatremia. In SIADH, the excess body water

should be eliminated. If the hyponatremia is mild and largely

asymptomatic, restricting total water intake to ~30 mL/kg per day

less than urine output for several days or until the syndrome remits

spontaneously will usually suffice. If, however, the hyponatremia

is severe and symptomatic, the goal should be to partially correct

it by intravenous infusion of hypertonic (3%) saline or administration of an AVP antagonist such as tolvaptan or conivaptan

(Fig. 381-7). Infusion of 3% saline at a rate of ~0.05 mL/kg body

weight per min raises serum sodium at a rate of ~1–2 meq/L per h,

not only by replacing the slight sodium deficit but also by promoting a solute diuresis, which reduces total body water. Alternatively,

a vaptan can be used to reduce body water by increasing urine

output. Tolvaptan should be started at a dose of 15 mg PO qd and

increased to 30 mg and 60 mg as needed to produce a brisk water

diuresis. Conivaptan can be given intravenously starting with a

loading dose of 20 mg over 30 min followed by another 20 mg IV

over 24 h. With either vaptan, fluid intake should be monitored

and restricted so as to underreplace urine output by ~5 mL/kg

body weight per h. With hypertonic saline or vaptan therapy,

plasma osmolarity and/or sodium should be checked every 1–2 h,

and water intake or the treatment should be adjusted to keep the

rate of rise at ~1% an hour until the values reach ~270 mosm/L or

130 meq/L, at which point the treatment should be discontinued.

Raising the plasma sodium faster or farther may increase the risk

of central pontine myelinolysis, an acute, potentially fatal neurologic syndrome characterized by quadriparesis, ataxia, and abnormal extraocular movements.

In SIAD due to an activating mutation of the V2

 receptor, the

V2

 antagonists may not block the antidiuresis or raise plasma

osmolarity/sodium. In that condition, use of an osmotic diuretic

such as urea is reported to be effective in long-term prevention or

correction of hyponatremia. However, some vaptans may be effective in patients with a different type of activating mutation of the V2

receptor, so the response to this therapy may be neither predictable

nor diagnostic.

■ GLOBAL PERSPECTIVES

The incidence, clinical characteristics, etiology, pathophysiology, differential diagnosis, and treatments of fluid and electrolyte disorders in

tropical and nonindustrialized countries differ in some respects from

those in the United States and other industrialized parts of the world.

0

–2 –1123

Day

4567

110

115

120

125

130

V V

135

140

145

500

1000

Fluid intake and urine output mL/d

Serum Na meq/L

1500

2000

2500

3000

3500

4000

Fluid intake

Urine output

Serum Na

FIGURE 381-7 The effect of vaptan therapy on water balance in a patient with

chronic syndrome of inappropriate antidiuretic hormone (SIADH). The periods of

vaptan (V) therapy are indicated by the green shaded boxes at the top. Urine output

is indicated by orange bars. Fluid intake is shown by the open bars. Intake was

restricted to 1 L/d throughout. Serum sodium is indicated by the black line. Note that

sodium increased progressively when vaptan increased urine output to levels that

clearly exceeded fluid intake.

2926 PART 12 Endocrinology and Metabolism

Hyponatremia, for example, appears to be more common and is more

likely to be due to infectious diseases such as cholera, shigellosis, and

other diarrheal disorders. In these circumstances, hyponatremia is

probably due to gastrointestinal losses of salt and water (hypovolemia

type II), but other abnormalities, including undefined infectious toxins, also may contribute. The causes of DI are similar worldwide except

that malaria and venoms from snake or insect bites are much more

common in some tropical climates.

■ FURTHER READING

Bichet DG: Regulation of thirst and vasopressin release. Annu Rev

Physiol 81:359, 2019.

Bichet DG et al: GNAS: A new nephrogenic cause of inappropriate

antidiuresis. J Am Soc Nephrol 30:722, 2019.

Fenske W et al: A copeptin based approach in the diagnosis of diabetes

insipidus. N Engl J Med 379:428, 2018.

Oiso Y et al: Clinical review: Treatment of neurohypophyseal diabetes

insipidus. J Clin Endocrinol Metab 98:3958, 2013.

Robertson GL: Vaptans for the treatment of hyponatremia. Nat Rev

Endocrinol 7:151, 2011.

Robertson GL: Diabetes insipidus: Differential diagnosis and management. Best Pract Res Clin Endocrinol Metab 30:205, 2016.

The thyroid gland produces two related hormones, thyroxine (T4

) and

triiodothyronine (T3

) (Fig. 382-1). Acting through thyroid hormone

receptors (TR) α and β, these hormones play a critical role in cell differentiation and organogenesis during development and help maintain

thermogenic and metabolic homeostasis in the adult. Autoimmune

disorders of the thyroid gland can stimulate overproduction of thyroid

hormones (thyrotoxicosis) or cause glandular destruction and hormone

deficiency (hypothyroidism). Benign nodules and various forms of

thyroid cancer are relatively common and amenable to detection by

physical examination, ultrasound, and other imaging techniques.

382 Thyroid Gland

Physiology and Testing

J. Larry Jameson, Susan J. Mandel,

Anthony P. Weetman

Thyroxine (T4)

3,5,3',5'-Tetraiodothyronine

Triiodothyronine (T3)

3,5,3'-Triiodothyronine

Deiodinase 1 or 2

(5'-Deiodination)

Deiodinase 3>2

(5-Deiodination)

Reverse T3 (rT3)

3,3',5'-Triiodothyronine

O CH2

NH2

3

5

3' HO 5' CH

I

I

I

I

COOH

O CH2

NH2

HO CH

I I

I

COOH O CH2

NH2

HO CH

I I

I

COOH

FIGURE 382-1 Structures of thyroid hormones. Thyroxine (T4

) contains four iodine atoms.

Deiodination leads to production of the potent hormone triiodothyronine (T3

) or the inactive

hormone reverse T3

.

ANATOMY AND DEVELOPMENT

The thyroid (Greek thyreos, shield, plus eidos, form) consists of two lobes

connected by an isthmus. It is located anterior to the trachea between

the cricoid cartilage and the suprasternal notch. The normal thyroid is

12–20 g in size, highly vascular, and soft in consistency. Four parathyroid

glands, which produce parathyroid hormone (Chap. 410), are located

posterior to each pole of the thyroid. The recurrent laryngeal nerves

traverse the lateral borders of the thyroid gland and must be identified

during thyroid surgery to avoid injury and vocal cord paralysis.

The thyroid gland develops from the floor of the primitive pharynx

during the third week of gestation. The developing gland migrates

along the thyroglossal duct to reach its final location in the neck. This

feature accounts for the rare ectopic location of thyroid tissue at the

base of the tongue (lingual thyroid) as well as the occurrence of thyroglossal duct cysts along this developmental tract. Thyroid hormone

synthesis begins at about 11 weeks’ gestation.

Neural crest derivatives from the ultimobranchial body give rise to

thyroid medullary C cells that produce calcitonin, a calcium-lowering

hormone. The C cells are interspersed throughout the thyroid gland,

although their density is greatest in the juncture of the upper one-third

and lower two-thirds of the gland. Calcitonin plays a minimal role in

calcium homeostasis in humans, but the C cells are important because

of their involvement in medullary thyroid cancer.

Thyroid gland development is orchestrated by the coordinated expression of several developmental transcription factors. Thyroid transcription factor (TTF)-1, TTF-2, NKX2-1, and paired homeobox-8 (PAX-8)

are expressed selectively, but not exclusively, in the thyroid gland. In

combination, they dictate thyroid cell development and the induction

of thyroid-specific genes such as thyroglobulin (Tg), thyroid peroxidase

(TPO), the sodium iodide symporter (Na+

/I–

, NIS), and the thyroid-stimulating hormone (TSH) receptor (TSH-R). Mutations in these developmental transcription factors or their downstream target genes are rare

causes of thyroid agenesis or dyshormonogenesis, although the causes of

most forms of congenital hypothyroidism remain unknown (see Chap.

383, Table 383-1). Because congenital hypothyroidism occurs in ~1 in

4000 newborns, neonatal screening is now performed in most industrialized countries. Transplacental passage of maternal thyroid hormone

occurs before the fetal thyroid gland begins to function and provides

significant hormone support to a fetus with congenital hypothyroidism.

Early thyroid hormone replacement in newborns with congenital hypothyroidism prevents potentially severe developmental abnormalities.

The thyroid gland consists of numerous spherical follicles composed

of thyroid follicular cells that surround secreted colloid, a proteinaceous fluid containing large amounts of thyroglobulin, the protein

precursor of thyroid hormones (Fig. 382-2). The thyroid follicular cells

are polarized—the basolateral surface is apposed to the bloodstream

and an apical surface faces the follicular lumen. Increased demand for

thyroid hormone is regulated by TSH, which binds to its receptor on

the basolateral surface of the follicular cells. This binding

leads to Tg reabsorption from the follicular lumen and

proteolysis within the cytoplasm, yielding thyroid hormones for secretion into the bloodstream.

REGULATION OF THE THYROID

AXIS

TSH, secreted by the thyrotrope cells of the anterior pituitary, plays a pivotal role in control of the thyroid axis and

serves as the most useful physiologic marker of thyroid

hormone action. TSH is a 31-kDa hormone composed of

α and β subunits; the α subunit is common to the other

glycoprotein hormones (luteinizing hormone, folliclestimulating hormone, human chorionic gonadotropin

[hCG]), whereas the TSH β subunit is unique to TSH.

The extent and nature of carbohydrate modification are

modulated by thyrotropin-releasing hormone (TRH) and

influence the biologic activity of the hormone.

The thyroid axis is a classic example of an endocrine

feedback loop (Chap. 377). Hypothalamic TRH stimulates

pituitary production of TSH, which, in turn, stimulates

2927Thyroid Gland Physiology and Testing CHAPTER 382

of Tg into the thyroid follicular cell allows proteolysis and the release

of newly synthesized T4

 and T3

.

Iodine Metabolism and Transport Iodide uptake is a critical

first step in thyroid hormone synthesis. Ingested iodine is bound to

serum proteins, particularly albumin. Unbound iodine is excreted in

the urine. The thyroid gland extracts iodine from the circulation in

a highly efficient manner. For example, 10–25% of radioactive tracer

(e.g., 123I) is taken up by the normal thyroid gland over 24 h in an

iodine-replete state; this value can rise to 70–90% in Graves’ disease.

Iodide uptake is mediated by NIS, which is expressed at the basolateral

membrane of thyroid follicular cells. NIS is most highly expressed in

the thyroid gland, but low levels are present in the salivary glands, lactating breast, and placenta. The iodide transport mechanism is highly

regulated, allowing adaptation to variations in dietary supply. Low

iodine levels increase the amount of NIS and stimulate uptake, whereas

high iodine levels suppress NIS expression and uptake. The selective

expression of NIS in the thyroid allows isotopic scanning, treatment

of hyperthyroidism, and ablation of thyroid cancer with radioisotopes

of iodine, without significant effects on other organs. Mutation of the

NIS gene is a rare cause of congenital hypothyroidism, underscoring its

importance in thyroid hormone synthesis. Another iodine transporter,

pendrin, is located on the apical surface of thyroid cells and mediates

iodine efflux into the lumen. Mutation of the pendrin gene causes Pendred syndrome, a disorder characterized by defective organification of

iodine, goiter, and sensorineural deafness.

Iodine deficiency is prevalent in many mountainous regions and in

central Africa, central South America, and northern Asia (Fig. 382-3).

Europe remains mildly iodine-deficient, and health surveys indicate

that iodine intake has been falling in the United States and Australia.

The World Health Organization (WHO) estimates that about 2 billion

people are iodine-deficient, based on urinary excretion data. In areas

of relative iodine deficiency, there is an increased prevalence of goiter

and, when deficiency is severe, hypothyroidism and cretinism. Cretinism is characterized by intellectual disability and growth retardation

and occurs when children who live in iodine-deficient regions are not

treated with iodine or thyroid hormone to restore normal thyroid hormone levels during early life. These children are often born to mothers

with iodine deficiency, and it is likely that maternal thyroid hormone

deficiency worsens the condition. Concomitant selenium deficiency

may also contribute to the neurologic manifestations of cretinism.

Iodine supplementation of salt, bread, and other food substances has

markedly reduced the prevalence of cretinism. Unfortunately, however,

iodine deficiency remains the most common cause of preventable intellectual disability, often because of societal resistance to food additives

or the cost of supplementation. In addition to overt cretinism, mild

iodine deficiency can lead to subtle reduction of IQ. Oversupply of

iodine, through supplements or foods enriched in iodine (e.g., shellfish, kelp), is associated with an increased incidence of autoimmune

thyroid disease. The Recommended Dietary Allowance (RDA) is

220 μg iodine per day for pregnant women and 290 μg iodine per day

for breastfeeding women. Because the effects of iodine deficiency are

most severe in pregnant women and their babies, the American Thyroid Association has recommended that all pregnant and breastfeeding

women in the United States and Canada take a prenatal multivitamin

containing 150 μg iodine per day. Urinary iodine is >100 μg/L in

iodine-sufficient populations.

Organification, Coupling, Storage, and Release After iodide

enters the thyroid, it is trapped and transported to the apical membrane of thyroid follicular cells, where it is oxidized in an organification reaction that involves TPO and hydrogen peroxide produced by

dual oxidase (DUOX) and DUOX maturation factor (DUOXA). The

reactive iodine atom is added to specific tyrosyl residues within Tg, a

large (660 kDa) dimeric protein that consists of 2769 amino acids. The

iodotyrosines in Tg are then coupled via an ether linkage in a reaction

that is also catalyzed by TPO. Either T4

 or T3

 can be produced by this

reaction, depending on the number of iodine atoms present in the

iodotyrosines. After coupling, Tg is taken back into the thyroid cell,

thyroid hormone synthesis and secretion. Thyroid hormones act via

negative feedback predominantly through thyroid hormone receptor

β2 (TRβ2) to inhibit TRH and TSH production (Fig. 382-2). The “set

point” in this axis is established by TSH. TRH is the major positive regulator of TSH synthesis and secretion. Peak TSH secretion occurs ~15

min after administration of exogenous TRH. Dopamine, glucocorticoids, and somatostatin suppress TSH but are not of major physiologic

importance except when these agents are administered in pharmacologic doses. Reduced levels of thyroid hormone increase basal TSH

production and enhance TRH-mediated stimulation of TSH. High thyroid hormone levels rapidly and directly suppress TSH gene expression

and inhibit TRH stimulation of TSH secretion, indicating that thyroid

hormones are the dominant regulator of TSH production. Like other

pituitary hormones, TSH is released in a pulsatile manner and exhibits a diurnal rhythm; its highest levels occur at night. However, these

TSH excursions are modest in comparison to those of other pituitary

hormones, in part, because TSH has a relatively long plasma half-life

(50 min). Consequently, single measurements of TSH are adequate for

assessing its circulating level. TSH is measured using immunoradiometric assays that are highly sensitive and specific. These assays readily

distinguish between normal and suppressed TSH values; thus, TSH can

be used for the diagnosis of primary hyperthyroidism (low TSH) or

primary hypothyroidism (high TSH).

THYROID HORMONE SYNTHESIS,

METABOLISM, AND ACTION

■ THYROID HORMONE SYNTHESIS

Thyroid hormones are derived from Tg, a large iodinated glycoprotein.

After secretion into the thyroid follicle, Tg is iodinated on tyrosine

residues that are subsequently coupled via an ether linkage. Reuptake

+

+

–

–

Hypothalamus

TRH

I

-

TSH

Pituitary

Thyroid

Peripheral

actions

Follicular

cell

Thyroid follicle

Iodination

Tg

Tg

Tg-MIT

DIT

+ II

-

cAMP

TSH-R

Basal

Apical

T3 T4

T4 T3

NIS

TPO

Coupling

FIGURE 382-2 Regulation of thyroid hormone synthesis. Left. Thyroid hormones

T4

 and T3

 feed back to inhibit hypothalamic production of thyrotropin-releasing

hormone (TRH) and pituitary production of thyroid-stimulating hormone (TSH).

TSH stimulates thyroid gland production of T4

 and T3

. Right. Thyroid follicles are

formed by thyroid epithelial cells surrounding proteinaceous colloid, which contains

thyroglobulin. Follicular cells, which are polarized, synthesize thyroglobulin and

carry out thyroid hormone biosynthesis (see text for details). DIT, diiodotyrosine;

MIT, monoiodotyrosine; NIS, sodium iodide symporter; Tg, thyroglobulin; TPO,

thyroid peroxidase; TSH-R, thyroid-stimulating hormone receptor.

2928 PART 12 Endocrinology and Metabolism

where it is processed in lysosomes to release T4

 and T3

. Uncoupled

mono- and diiodotyrosines (MIT, DIT) can be deiodinated by the

enzyme dehalogenase, thereby recycling any iodide that is not converted into thyroid hormones.

Disorders of thyroid hormone synthesis are rare causes of congenital

hypothyroidism (Chap. 383). The vast majority of these disorders are

due to recessive mutations in TPO or Tg, but defects have also been

identified in the TSH-R, NIS, pendrin, hydrogen peroxide generation,

and dehalogenase, as well as genes involved in thyroid gland development. In the case of biosynthetic defects, the gland is incapable of

synthesizing adequate amounts of hormone, leading to increased TSH

and a large goiter.

TSH Action TSH regulates thyroid gland function through the

TSH-R, a seven-transmembrane G protein–coupled receptor (GPCR).

The TSH-R is coupled to the α subunit of stimulatory G protein (GS

α),

which activates adenylyl cyclase, leading to increased production of

cyclic adenosine monophosphate (cAMP). TSH also stimulates phosphatidylinositol turnover by activating phospholipase C. Recessive

loss-of-function TSH-R mutations cause thyroid hypoplasia and congenital hypothyroidism. Dominant gain-of-function mutations cause

sporadic or familial hyperthyroidism that is characterized by goiter,

thyroid cell hyperplasia, and autonomous function (Chap. 384). Most

of these activating mutations occur in the transmembrane domain of

the receptor. They mimic the conformational changes induced by TSH

binding or the interactions of thyroid-stimulating immunoglobulins

(TSIs) in Graves’ disease. Activating TSH-R mutations also occur as

somatic events, leading to clonal selection and expansion of the affected

thyroid follicular cell and autonomously functioning thyroid nodules.

Other Factors That Influence Hormone Synthesis and

Release Although TSH is the dominant hormonal regulator of

thyroid gland growth and function, a variety of growth factors, most

produced locally in the thyroid gland, also influence thyroid hormone

synthesis. These include insulin-like growth factor 1 (IGF-1), epidermal growth factor, transforming growth factor β (TGF-β), endothelins,

and various cytokines. The quantitative roles of these factors are not

well understood, but they are important in selected disease states.

In acromegaly, for example, increased levels of growth hormone and

IGF-1 are associated with goiter and predisposition to multinodular

goiter (MNG). Certain cytokines and interleukins (ILs) produced in

association with autoimmune thyroid disease induce thyroid growth,

whereas others lead to apoptosis. Iodine deficiency increases thyroid

blood flow and upregulates the NIS, stimulating more efficient iodine

uptake. Excess iodide transiently inhibits thyroid iodide organification,

a phenomenon known as the Wolff-Chaikoff effect. In individuals with

a normal thyroid, the gland escapes from this inhibitory effect and

iodide organification resumes; the suppressive action of high iodide

No recent data

18

3

42

105

13

9

Sub-national data 4

National data

Global scorecard of iodine nutrition in 2021

Iodine intake in the general population assessed by median urinary iodine concentration (mUIC) in school-age children (SAC)

a

Studies conducted in 2005–2020

Iodine intake

Insufficient

mUIC

<100 µg/L

Adequateb

mUIC

100–299 µg/L

Excess

mUIC

≥300 µg/L

FIGURE 382-3 Worldwide iodine nutrition. a

In population monitoring of iodine status using urinary iodine concentration (UIC), school-age children (SAC) serve as a proxy

for the general population; therefore, preference has been given to studies carried out in SAC. The UIC data have been selected for each country in the following order of

priority: data from the most recent known nationally representative survey carried out between 2005 and 2020 in (i) SAC, (ii) SAC and adolescents, (iii) adolescents, (iv) women

of reproductive age, (v) other adults (excluding pregnant or lactating women), and (vi) other eligible populations. In the absence of recent national surveys, subnational data

were used in the same order of priority. Subnational UIC surveys are commonly carried out to provide a rapid assessment of population iodine status, but due to a lack of

sampling rigor, they may over- or underestimate the iodine status at the national level and should be interpreted with caution. b

Adequate iodine intake in school-age children

corresponds to median UIC values in the range 100-299 μg/L, and includes categories previously referred to as “Adequate” (100-199 μg/L) and “More than adequate”

(200-299 μg/L). (Reproduced with permission from The Iodine Global Network. Global scorecard of iodine nutrition in 2021 in the general population based on data in school-age

children (SAC). IGN: Ottawa, Canada. 2021.)