Endocrinology

American Manual
of Examination
in Medicine
(2CK)

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Endocrinology

American Manual
of Examination
in Medicine
(2CK)
Author

Juan Simn Chacn

A m e r i c a n Manua l o f Ex am i na ti o n i n Me di c ine (2CK)

Index
01. Hypothalamic-Pituitary Pathology ................................. 1
1.1.
1.2.
1.3.
1.4.
1.5.

Cushings Syndrome ......................................................................................................... 1

Acromegaly .................................................................................................................................... 2
Hyperprolactinemia .......................................................................................................... 2
Diabetes Insipidus................................................................................................................ 3
Syndrome of Inadequate
Secretion of Vasopressin (SIADH) .......................................... 4

02. Thyroid Pathology ................................................................................. 5

2.1.
2.2.
2.3.
2.4.
2.5.

Thyroid Function Test...................................................................................................... 5

Hyperthyroidism .................................................................................................................... 5
Hypothyroidism ...................................................................................................................... 6
Thyroiditis......................................................................................................................................... 6
Thyroid Nodule and Thyroid Cancer ......................................................... 7

03. Adrenal Pathology ................................................................................. 8

3.1.
3.2.
3.3.
3.4.

Adrenal Failure .......................................................................................................................... 8

Pheochromocytoma......................................................................................................... 8
Primary Hyperaldosteronism (PHA).......................................................... 9
Congenital Adrenal Hyperplasia (CAH) ........................................... 10

04. Alteration in Hydrocarbonate Metabolism.... 10

4.1.
4.2.
4.3.
4.4.

Type 1 Diabetes Mellitus ........................................................................................ 10

Type 2 Diabetes Mellitus ........................................................................................ 11
Treatment of Diabetes Mellitus .................................................................... 12
Metabolic Syndrome.................................................................................................... 14

05. Bone Pathology and Phosphocalcic

Metabolism ......................................................................................................... 14
5.1. Osteoporosis ............................................................................................................................ 14
5.2. Pagets Disease .................................................................................................................... 15
5.3. Hyperparathyroidism .................................................................................................. 15

06. Multiple Endocrine Neoplasia (MEN) .......................... 16

Endo c ri no l ogy

HypothalamicChapter 01

Pituitary Pathology

1.1. Cushings Syndrome

Cushings syndrome (CS) is a set of diverse symptoms, due to an

excess in cortisol production by the adrenal cortex (endogenous
Cushings) or by sustained administration of glucocorticoids (exogenous and factitious Cushings).
The most frequent cause is iatrogenic administration of steroids due
to another reason; the most frequent endogenous cause is Cushings
diseases (overproduction of ACTH due to a pituitary adenoma) in 65%
to 70% of the cases, autonomous production of cortisol as a result of
adrenal pathology (adrenal CS because of adenomas, adrenal hyperplasia and adrenal carcinoma) in about 15% to 20% and the ectopic CS
as a result of paraneoplastic production of ACTH (bronchial carcinoma
of small cells is the most frequent; carcinoid tumors, CMT and pheochromocytoma) in 15%.

Clinical presentation (Figure 1)

Moon face

Acne
Capillary fragility

Hirsutism
Central obesity

Wine-red stretch marks

Muscle weakness

Figure 1. Clinical presentation of Cushings syndrome

Characteristic features of Cushings Syndrome include (from the

most frequent to the least)
Symptoms: weight gain, menstrual cycle irregularity, hirsutism,
psychiatric alterations, muscle weakness.
Signs: central obesity, facial plethora, moon facies, hematomas and capillary fragility, vinous red stretch marks, edemas
in lower extremities, proximal myopathy and hyperpigmentation.
The most specific are facial plethora, capillary fragility, muscle
weakness or proximal myopathy, wine-red stretch marks and,
weight gain with growth rate delay.
Patients present in half of the cases, alterations of carbohydrate
metabolism (DM and carbohydrate intolerance), high blood
pressure (HBP) and osteoporosis; and less frequently, nephrolithiasis.
In ectopic CS cases, symptoms and signs typical of CS may appear
and cardinal manifestations consist of glucose intolerance, hypopotassemic alkalosis, proximal myopathy and cutaneous hyperpigmentation.

Diagnosis
Whatever the cause of excess cortisol production, there will always
be an increased cortisol excretion, abolition of its circadian rhythm
and absence of cortisol secretion inhibition with a low dose of glucocorticoids.
Biochemical diagnosis of hypercortisolism requires two positive
tests of the following (they are regarded as first line test): high
cortisoluria 24 h, high nocturnal salivary cortisol (measured between 11 p.m. and midnight) and/or lack of suppression of basal
plasma cortisol after administration of low doses of dexamethasone: nocturnal suppression with 1 mg of dexamethasone (Nugent
test) and/or low-dose dexamethasone suppression test (classic test
of 2 mg DXM or low-dose Liddle test).
There are second-line tests to be performed on patients who
have had misleading results on a prior test and when there is a
high clinical suspicion of Cushings syndrome: high late-night serum cortisol (measured between 11 p.m. and midnight) and combined suppression test with 2 mg of DXM + CRH stimulus: useful
to dierentiate people suering from pseudo Cushings (it remains
suppressed after CRH) from those with CS (they experience a high
plasma concentration of cortisol and ACTH after CRH administration).
For etiologic diagnosis or diagnosis for localization, the first step
will always be determining baseline ACTH to dierentiate between
ACTH-dependent CS (central or ectopic) and ACTH-independent CS
(adrenal). If ACTH is < 5 pg/mL (low or suppressed), it is ACTH independent, so the next step is to perform an adrenal imaging test (adrenal CT scan, MRN). If > 20 pg/mL, it is ACTH-dependent and the next
step is to perform a pituitary MRN.
Intermediate results (from 5 to 20 pg/mL) will probably reveal an
ACTH-dependent CS, so a CRH test will be taken (central CS keeps
a hypothalamic pituitary-adrenal axis relatively intact). Therefore,
after CRH administration, there is an increase in ACTH and cortisol
at baseline in most patients with hypothalamic dysfunction or an
ACTH-secreting pituitary tumor (macroadenoma and microadenoma).
The 8 mg DXM Liddles test with a high dose (long high-dose
dexamethasone suppression test) is a useful test to discrimi-

A m e r i c a n Manua l o f Ex am i na ti o n i n Me di c ine (2CK)

nate patients with ACTH-secreting pituitary microadenoma. A

positive response occurs when cortisol in urine or plasma is reduced (> 90% of baseline) after DXM administration, while macroadenomas and most ectopic ACTH-secreting tumors do not do
so.
When a CS is ACTH-dependent and there is no clear tumoral image
in the pituitary gland ( 6 mm) or there are hypopotassemia and/or
metabolic alkalosis (more frequent in ectopic Cushings) a bilateral
catheterization of inferior petrosal sinuses must be performed. The
demonstration after CRH stimulation of an ACTH peripheral gradient
(higher level in petrosal sinus than in peripheral vein) enables locating the site of ACTH hypersecretion in the pituitary gland. If there is
no gradient: there is an ectopic source producing ACTH, hence, the
tumor should be sought (thoracoabdominal CT scan, octreoscan test
or PET scan).

Treatment
Etiologic treatment of choice is surgery in adrenal pathology (adenomas and carcinoma) and in Cushings disease (via transsphenoidal approach). Also in ectopic tumors in which resection is possible.
Pituitary radiotherapy is used in cases in which cure is not achieved
after transsphenoidal surgery of Cushings disease.
When etiologic treatment is not possible or it did not turn out eective, it is necessary to resort to medical adrenalectomy (mitotane)
or to inhibitors of cortisol synthesis (ketokonazole, aminoglutethimide or metopirone).
Occasionally, bilateral surgical adrenalectomy is needed when definitive treatments (surgery or radiotherapy) fail or side eects to
drug treatment develop. Then, a substitution treatment is required
with glucocorticoids and mineral or corticoids.

1.2. Acromegaly
Debilitating chronic disease because of an increased production of
growth hormone (GH), habitually because of GH-secreting pituitary
adenomas. A total of 75% of them are macroadenomas (greater
than 1 cm).
When GH excess develops before epiphyseal plate closure in children, the linear growth increases and results in gigantism.

cal diabetes mellitus); hypercalciuria and nephrolithiasis. Hyperprolactinemia is present in a third of the cases. Sleep apnea. Increase
in the frequency of nasal polyps and intracranial aneurysm. Three
to ten times higher risk of having premalignant polyps and colon
cancer.

Diagnosis

Random determinations of GH should not be used for the diagnosis

of acromegaly.
Biochemical diagnosis is based on the presence of high IGF-I levels
for age and sex along with a GH that is not suppressed after oral
glucose overload (OGO).
Imaging studies (adrenal NMR) after hormonal diagnosis, which
will reveal a selar lesion in most cases (macroadenoma is more frequent).
A complete assessment of pituitary function is necessary to rule out
the existence of panhypopituitarism.
Every acromegaly suerer must have a colonoscopy performed at
the time of diagnosis and steps towards early detection of possible complications (i.e., sleep apnea, diabetes mellitus among
others).

Treatment
Transsphenoidal surgery is the choice in microadenomas and
macroadenomas that are potentially resectable. In macroadenomas with wide extraselar extension although surgery is not
curative, it can improve response to medical treatment (debulking).
The medical treatment of choice in acromegaly is the somatostatin
analogs (octreotide, slow-release octreotide and lanreotide) which
suppress GH secretion. These drugs can be used as a therapeutic
first choice, when the surgical risk is unacceptable, the patients reject surgery or a macroadenoma is present with scarce possibilities
of being completely resected with or without debulking. Pegvisomant, a GH receptor antagonist is another alternative. It is the second treatment of choice after somatostatin analogs, in the event curative criteria is not met or because of the appearance of severe side
eects.
Radiotherapy is utilized in diseased people who did not reach cure
after surgery or when surgery is contraindicated or the patient rejects it. At present, radiotherapy is a second or third choice treatment.

Clinical presentation
Symptoms: progressive growth and enlargement of hands, feet and
perimeter, prognathism, exaggerated development of the tongue and
coarsening facial features. Weakness and tiredness, profuse sweating, headache, carpal tunnel syndrome, muscle weakness and arthralgia. Amenorrhea, hirsutism.
Signs: cavernous voice as a result of laryngeal hypertrophy, wet and
doughy hands, deepening of skin crease, acanthosis nigricans and
oily skin. Bitemporal hemianopsia because of compression of the
optical chiasm. HBP. Myocardiopathy (ventricular hypertrophy) and
heart failure because of diastolic dysfunction, goiter, hepatomegaly
and splenomegaly.
People suering from this disorder may be insulin-resistant with
abnormal hydrocarbon metabolism (glucose intolerance and clini-

1.3. Hyperprolactinemia
Increase in prolactin levels. The most frequent cause of hyperprolactinemia is pregnancy and the most frequent pathologic primary source is drugs intake.
The most common functioning pituitary tumor is prolactinoma.
Other tumors can cause hyperprolactinemia, because of compression of the pituitary stalk (and loss of dopamine inhibitory
tone on lactotroph) cells, like nonfunctioning adenomas and
other selar masses. Hypothyroidism, chronic renal disease and
hepatic cirrhosis are also causes of hyperprolactinemia (Table
1).

Endo c ri no l ogy

PHYSIOLOGIC

HYPERSECRETION

Tumors

LESION OF THE
HYPOTHALAMUS
OR PITUITARY
STALK

Diagnosis

Pregnancy
Lactancy
Stimulation of thorax wall
Sleep
Stress

Craniopharyngioma
Meningioma
Dysgerminoma
Metastasis

Empty Turkish saddle

Lymphocitary hypophysis
Adenoma with stalk compression
Granulomas
Rathkes cysts
Radiation

Traumatisms

Section of the
pituitary stalk
Suprasellar surgery

Prolactinoma
HYPOPHESEAL
HYPERSECRETION Acromegaly
SYSTEMIC
DISORDERS

DRUGS

Chronic renal failure

Hypothyroidism
Cirrhosis
Comitial crisis

Dopamine receptor
antagonists

Phenothiazines:
chlorpromazine
Butyrophenones:
haloperidol
Thioxanthenes
Metoclopramide

Dopamine synthesis
inhibitors

Methyldopa

Cathecolamines
depletion

Reserpine

High prolactin baseline values.

Prolactin levels < 100 g/L may be owing to microadenomas,
as well as lesions in the stalk and in the hypothalamus, and
to the remaining reasons for nonneoplastic hyperprolactinemia.
Prolactin levels > 100 g/L in the absence of pregnancy are very
likely to result from microprolactinoma.
Prolactin levels > 250 g/L are virtually diagnostic of a PRL-producing pituitary adenoma, usually a macroadenoma.
Pituitary MRN to assess the existence of a lesion at that level.
Prolactinomas (much in the same way as other pituitary adenomas) are classified into microadenomas (lesser than 1 cm) and
macroadenomas (greater than 1 cm).

Treatment
Treatment indications for prolactinomas are stated in Table 2.
Pharmacologic treatment is the treatment of choice: dopaminergic agonists (the most utilized are cabergoline, bromocriptine).
Surgical treatment is reserved for patients with persistent visual
defects despite dopaminergic agonist treatment and for those
patients who do not tolerate dopaminergic agonists. Decompressive surgery may also be necessary in tumors with a significant
cystic or hemorrhagic component to relieve visual symptoms and
headache.

PROLACTINOMAS: TREATMENT INDICATIONS

Microprolactinomas. In the following cases:
- Women: desire for pregnancy, severe hypogonadism with high
risk of osteoporosis, bothersome galactorrhea, decrease in libido
- Men: decrease in libido or sexual potency, sterility

Opiates
H2 antagonists
Imipramines

Cimetidine
Ranitidine

Table 2. Indications for treatment of prolactinomas

Amitriptyline

Serotonin reuptake inhibitors

Calcium antagonists

Macroprolactinomas. They are always treated

Verapamil

1.4. Diabetes Insipidus

Estrogens and anti-androgens

Table 1. Etiology of hyperprolactinemia

Clinical presentation
Hyperprolactemia generates inhibition of hypothalamic release
of GnRH, with a decrease in LH and FSH (hypogonadotropic hypogonadism), manifesting through sexual and reproductive function
disorders.
In premenopausal women: galactorrhea, anomalies in the menstrual cycle, like oligomenorrhea, infertility because of anovulatory cycles or menorrhea.
In men: a decrease in libido, impotence and infertility, as well as the
possible appearance of alterations in the visual field (by chiasmatic
compression of a macroprolactinoma). In postmenopausal women
compressive symptoms are also predominant.

Inability to generate concentrated urine because of the absence of

(partial or complete antidiuretic hormone secretion) or a defect in
its action at renal level.
Diabetes insipidus is subdivided into:
Central ID: the neurohypophysis is incapable of releasing
ADH. Causes comprise idiopathic causes, brain or pituitary
tumors, infiltrative illnesses, cranio-cephalic traumatisms,
posterior to surgery or pituitary radiotherapy. Also necrosis
of vascular origin, infections, alcohol, chlorpromazine and
phenytoin.
Nephrogenic ID: lack of ADH renal response. The most usual
reasons are hypercalciuria, lithium administration, hypopotassemia and tubulointerstitial nephropathy. Other related drugs
are demeclocycline, methoxyflurane, foscarnet, cidofovir, amphotericin B, didanosine, ifosfamide, ofloxacin, orlistat and V2
receptor antagonists (vaptans).

A m e r i c a n Manua l o f Ex am i na ti o n i n Me di c ine (2CK)

Clinical presentation
Symptoms: Persistent polyuria (> 3 L/day in adults, > 2 L/day in
children) of hypotonic urine (low density < 1.010, generally diminished osmolality < 300 mOsm/kg) and polydipsia continual
thirst.
Sudden onset of symptoms, above all, in central DI.
Normal function of the thirst center enables polydipsia to adjust
to polyuria and avoid dehydration, so most cases are normonatremic.
When water access is not available (i.e., seniors, the institutionalized), significant dehydration and hypernatremia, with alteration of
the level of consciousness, comitial crisis and even coma.

Diagnosis
Dehydration test or thirst test (Miller test): simple and reliable form
for the diagnosis of diabetes insipidus and distinguish ADH deficiency from other polyuric syndromes. The test involves comparing
urine osmolarity after deprivation of water and the osmolarity obtained after DDAVP (ADH synthetic analog).
In ID (both central and nephrogenic) hypotonic polyuria persists
after dehydration, while in primary polydipsia urine becomes
concentrated.
Response to DDAVP administration:
If the response implies urinary osmolarity doubles and diuresis
decreases, it is a central ID. If that is not the response, then it is
a nephrogenic ID.
If the patient presents analytic alterations compatible with dehydration (elevated plasma osmolarity > 295 mOsm/L, hypernatremia) the dehydration test is not necessary (it can even be dangerous). The next step will be direct administration of DDAVP.
Brain MRN in central ID to rule out hypothalamic or pituitary lesions.

Treatment
Central ID: hormonal substitution with DDAVP. If certain ADH reserve is conserved (partial CID) the response may involve carbamazepine, clofibrate and chlorpropamide.
Nephrogenic ID: salt and water restriction, administration of diuretics that increase natriuresis, (thiazides). NSAIDs can be administered as coadjuvant (indomethacin).

1.5. Syndrome of Inadequate

Secretion of Vasopressin
SIADH

SIADH: ETIOLOGY
Neoplasias: lung microcytic, brain and neck tumors, duodenum and
pancreas neoplasias, neuroblastoma of olfactory nerve, thymoma
Nonmalignant lung diseases: pneumonia, asthma, atelectasis, acute
respiratory failure, neumothorax, mechanical ventilation
Alterations of CNS: infections, ictus, traumatisms, psychosis, thyroid
surgery
Drugs: chlorpropamide, carbamazepine and derivatives, clofibrate,
cyclophosphamide, tricyclics, MAOI, SSRI, vincristine, vinblastine,
oxytocin
Others: hypothyroidism, adrenal failure, major surgery of thorax and
abdomen, HIV, hereditary SIADH (constitutive activation of V2 receptor
and mutations of hypothalamic osmoreceptors, temporal arteritis

Table 3. Causes of inadequate secretion of AVP (SIADH)

Clinical presentation
Clinical presentation depends, in general, on how fast plasma sodium levels go down.
If hyponatremia is severe (< 125 mEq/L) or of an acute onset, the
following symptoms become predominant: brain edema cerebral,
like agitation, irritability, confusion, coma and convulsions, together
with unspecific changes in EEG.
If hyponatremia is mild (130-135 mEq/L) or of progressive development, symptoms are more unspecific, for example, anorexia,
nausea and vomiting, headache, sensation of instability.

Diagnosis
Suspicion must be maintained on every patient with hyponatremia (< 135 mmol/L), plasma hypoosmolality (< 275 mOsm/kg) and
without maximum urine dilution (> 100 mOsm/kg), but without
edemas, orthostatic hypotension, dehydration signs, or thyroid or
adrenal hypofunction (Table 4).
Other findings are detection of low levels of ureic nitrogen, creatinine, ureic acid (< 4 mg/dL) and albumin in the presence of normal
renal function and normal acid-base equilibrium and potassium.

MAJOR

MINOR

1. Hyponatremia
2. Plasma hypo-osmolality
3. No edemas
4. No volume depletion (normal BP)
5. Lack of maximum urine dilution
(urine osm > 100 mOsm/kg)
6. Exclusion of hypothyroidism and
adrenal failure

1. Pathologic hydric overload

2. High AVP levels in plasma and
urine

All major criteria are needed for diagnosis. Minor criteria are optional

Table 4. Diagnostic criteria for SIADH

Treatment
Hyponatremia secondary to free water retention due to inappropriately high ADH secretion, in relation to plasma osmolarity and
independent, at least partially, of osmotic control.
The origin of this ADH can be the neurohypophysis, neoplastic tissues or inflammatory tissues. SIADH causes are listed in
Table 3.

Identify and correctly treat the triggering underlying cause whenever

possible.
If there is acute hyponatremia with CNS alteration, comitial crisis, subarachnoid hemorrhage or severe hyponatremia (< 125
mEq/L):

Endo c ri no l ogy

Careful and progressive correction with hypertonic saline serum

(correct Na+ 1-2 mEq/L/h in symptomatic patients 0.3 mmol/L/h
in asymptomatic suerers with a maximum limit of 8 mEq/L/12
h, 12 mEq/L/24 h and 18 mEq/L in the first 48 hours). Do not
correct it faster to avoid central pontine myelinolysis (locked-in
syndrome).
If there is chronic hyponatremia, the patient is asymptomatic and
sodium levels are over 125 mEq/L:
Hydric restriction.
Salt contribution and low doses of furosemide.
Lithium or demeclocycline.
Vasopressin receptor antagonists (vaptans). Indicated in case of
SIADH of any etiology refractory to other therapies.

Thyroid Pathology

Graves disease (GD) is the most common cause in middle-aged

adults. It has an autoimmune origin (presence of thyroid stimulating antibodies or TSI or TSH-R-Ab) that exists in association with:
hyperthyroidism, diuse goiter and extrathyroidal signs (ophthalmic
and derma signs). Not all characteristics are necessary for diagnosis.
In a gammagraphy, Graves disease reveals a generalized increased
uptake.
Toxic multinodular goiter (TMG) or hyperfunctioning is the most
usual reason for hyperthyroidism in the elderly. Thyroid gammagraphy reveals a multinodular gland with several hyperfunctioning
nodules that alternate with other normofunctioning or hypofunctioning nodules.
The toxic adenoma is observed in the gammagraphy as a single nodule, which intensely concentrates the radiotracer and with almost
total suppression of the rest of the gland.
(Postpartum, subacute) thyroiditis may appear with an initial phase
of hyperthyroidism as a result of inflammation and release of the
preformed hormone. Thyroid gammagraphy shows an abolished or
white gland.

Clinical presentation

Chapter 02

2.1. Thyroid Function Test

Determination of thyroid stimulating hormone (TSH): the best test
for the screening of thyroid pathology and assessment of its function. Elevated values are usually related to primary hypothyroidism
(with low T3 and T4) and low or suppressed values, with primary
hyperthyroidism (with high T3 and T4).
Determination of total T4: it is not useful for the study of thyroid
pathology, as T4 circulates in plasma and it is almost completely
bound to its carrier protein (TBG). T4 values can be altered by this
protein variation.
Determination of free T4: of choice after TSH determination, for the
screening of thyroid pathology. See Table 5 for interpretation.
Thyroid gammagraphy: performed with iodine isotopes (I-131 and
I-123) or with Tc-99 in the form of pertechnetate. It is a useful test
for the etiologic dierential diagnosis of hyperthyroidism.

PRIMARY
CENTRAL
PRIMARY
CENTRAL
hypothyroidism hypothyroidism hyperthyroidism hyperthyroidism

TSH

N or

T4L

Table 5. Interpretation of thyroid function test (N: normal)

Symptoms: plethoric aspect with nervousness, weakness, emotional lability, decreases in performance, excessive sweating and heat
intolerance. There are also increased intestinal transit, increased
appetite with paradoxic weight loss, pruritus and alterations in the
menstrual cycle (oligomenorrhea).
Signs: wet skin, goiter that is diuse and spongy in GD (it is irregular
with a nodular surface in the SMB), arrhythmias (sinusoidal tachycardia, atrial fibrillation), distal tremor, acropachy, alopecia, palpebral retraction, proximal myopathy, myoclonias and hyperreflexia.
Exophthalmoses, pretibial myxedema and thyroidal murmur can be
appreciated in Graves disease.
Apathetic hyperthyroidism: in advanced age, it can manifest
through weight loss, muscular weakness, depression, mental slowness, apathy and arrhythmias or heart failure.

Diagnosis
Determination of TSH: it is the most useful isolated initial determination for diagnosis. TSH may be diminished or suppressed in primary hyperthyroidism.
Determination of free T4: it is high in clinical hypothyroidism. It may
be normal in subclinical hyperthyroidism (with low TSH).
Determination of free T3: it is indicated if TSH is low and T4 is normal.
For the etiologic diagnosis, elaborating a detailed clinical record
and determining -according to clinical suspicion- of antithyroid antibodies (including TSI) +/- thyroid gammagraphy enables classification of most cases of hyperthyroidism.

Treatment
2.2. Hyperthyroidism
Hyperthyroidism is the clinical and analytic situation that results
from the eect of excessive amounts of thyroid hormones circulating throughout body tissues and it is present with high values of T3
and T4.

Symptomatic: propranolol for the control of adrenergic symptoms.

Antithyroid drugs (methimazole or propylthiouracil) in GD. They can
also be utilized in MTG.
Definite treatment: radioactive iodine (I-131) is of choice in the USA
for the treatment of GD. Thyroidectomy can also be performed, especially in the presence of large goiters, failure or intolerance to
prior treatments.

A m e r i c a n Manua l o f Ex am i na ti o n i n Me di c ine (2CK)

Complications

Alopecia

Thyroid storm: emergency situation and of increased mortality

(20% to 30%) characterized by irritability, delirium or coma, fever,
tachycardia, hypotension, vomiting and diarrhea. It requires emergency treatment with i.v. propranolol, propylthiouracil and corticoids. Iodine or iodine contrasts can also be used.

Macroglossia

Intolerance
to cold temperatures

Bradypsychia
Memory loss
Palpebral edema
Cardiomegaly
Pericardial effusion

Metrorrhagia

2.3. Hypothyroidism
Situation that results from the lack of thyroid hormone eect on
body tissues and presents with low levels of free T3 and T4. Primary thyroid causes constitute more than 95% of the cases, but less
than 5% are of thyroid or hypothalamic origin. The most frequent
cause of hypothyroidism world-wide is iodine deficiency.
Autoimmune etiology (Hashimotos thyroiditis) is the most common reason in developed countries. Hashimotos thyroiditis presents with positive antithyroglobulin and antimycrosomal (antiTPO)
which precipitate thyroid destruction.
There is also another important factor: postablative hypothyroidism (radioiodine or surgery) or after administration of I-131 as a
treatment for hyperthyroidism.
Other types of thyroiditis -subacute and postpartum) usually appear with a hypothyroidism phase after an initial phase of hypothyroidism. Hypothyroidism can be permanent.
Other less frequent causes are external cervical irradiation, drugs
like lithium, amiodarone or tyrosine kinase inhibitors (that work
as an oncologic treatment), infiltrative diseases, granulomatous
or metastatic thyroiditis, and congenital alterations in thyroid hormone synthesis and thyroid agenesis.

Clinical Presentation (Figure 2)

Unspecific initial symptoms with progressive appearance: fatigue,
lethargy, constipation, cold intolerance, rigidity and muscle contracture, carpal tunnel syndrome and menstrual cycle disorders.
Progressive deterioration of intellectual and motor activities, for
example, dementia and abnormal involuntary movements, loss of
appetite and weight gain.
Signs: dry and coarse skin, loss of body hair, a deep voice and sleep
apnea may appear. Amimia, paleness, skin coldness, scarce body
hair, periorbitary edema and macroglossia. Prolonged relaxation
phase of osteotendinous reflexes. Bradichardia and pericardial fluid
accumulation (even obstruction of pericardial drainage). Adynamic
ileum, megacolon and intestinal obstruction.
Determining TSH: it is the most useful isolated initial determination
for diagnosis. THS is increased in primary hypothyroidism and it is
low or inappropriately normal in central hypothyroidism.
Determination of free T4: it is low in clinical hypothyroidism. It may
be normal in subclinical hypothyroidism with a high TSH).
For the etiologic diagnosis, drawing up a detailed clinical record and
determining antithyroid antibodies enables classification of most
cases of hypothyroidism.

Treatment
Hormonal replacement with levothyroxine (L-T4).

Constipation
Carpal
tunnel syndrome
Weakness,
spasticity

Coarse, dry
and yellow skin

Slowed Achilles
reflex

Weight gain

Figure 2. Clinical presentation of hypothyroidism

Complications
Myxedematous coma: severe complication of hypothyroidism with
stupor and hypothermia, likely to be mortal. The most frequent
cause of myxedematous coma is cold temperature exposure or
performing surgery on a patient with untreated -or poorly treatedhypothyroidism. It can also appear in a hypothyroid suerer under
treatment, who abruptly suspends medication. Mortality ranges
from 30% to 60%. It requires immediate treatment with intravenous
L-T4 together with hydrocortisone administration -so that an adrenal crisis will not be triggered- until a normal pituitary-adrenal axis
activity is achieved.

2.4. Thyroiditis

A set of heterogeneous etiology processes and several clinical characteristics that appear with thyroid inflammation. The most common
types of thyroiditis are (granulomatous subacute and viral thyroiditis or
Quervains) thyroiditis; autoimmune or Hashimotos thyroiditis; postpartum thyroiditis postradiation and amiodarone-induced thyroiditis.

Clinical presentation
Viral subacute (Quervains) thyroiditis presents with a painful goiter,
general discomfort and concomitant -or recent- upper respiratory
tract infection.
The remaining types of thyroiditis appear together with a painful
goiter.

Endo c ri no l ogy

Diagnosis

Clinical presentation

Thyroiditis usually comprises two phases: 1) thyrotoxicosis followed

by 2) hypothyroidism, hence, the thyroid function test varies according to the phase in which diagnosis is made.
Thyroid gammagraphy: presents with generalized hypocaptation of the gland, by inflammation during the hyperthyroidism
phase.

They are usually asymptomatic at the time of diagnosis. They are incidentally found through imaging tests, i.e., a CTA scan of the cervicalthoracic region, a carotid Doppler ultrasound test) or thyroid palpation.
Hyperfunctioning nodules are present with signs and symptoms of
hyperthyroidism.
Large nodules and, especially, those adjacent to the trachea/esophagus, can produce compressive symptoms (dysphagia, dyspnea and
cough).
Clinical findings that suggest malignancy are: rapid growth of the lesion, fixation to adjacent structures, vocal cords paralysis, Horners
syndrome, present adenopathies, and a history of radiation in childhood, size > 4 cm, and family record of medullary thyroid cancer (MTC).
Cervical examination will enable nodule localization and a description
of the nodules characteristics: stony consistency, painless, attached
to superficial and/or deep planes, as well as the presence of cervical
anterior lymphoadenopathies, all signs suggestive of malignancy).

Treatment
Symptomatic: -blockers in the hyperthyroidism phase. In milder
cases of Quervains thyroiditis, symptoms are usually controlled
with ASA. More severe cases require corticosteroids.
If hypothyroidism: levothyroxine should be given, although this
phase may be temporary and not permanent.
The use of antithyroid drugs is not indicated.

Diagnosis (Table 6)

2.5. Thyroid Nodule

and Thyroid Cancer

The incidence of thyroid carcinoma in the population represents
only a fraction of patients that have thyroid nodules. In single nodules, thyroid carcinoma incidence is approximately 5%; multinodular
goiters, thyroid cancer incidence are also 5% per individual nodule.

PAPILLARY
Epidemiology

Bimodal distribution:
2.nd and 3.rd decade/
middle age
70% follicular
epithelium tumors
Relation
to radiation
in childhood

TSH determination: to rule out thyroid hyper or hypofunction. Hyperfunctioning nodules are seldom malignant (< 1%).
Thyroid ultrasound study: it makes it possible to assess the nodule features as well as the remainder of the gland and the presence or absence of pathologic cervical ganglia. The presence of
microcalcifications, hypoechogenicity, and the presence of an irregular rim and an increased intranodal vascularization are all ultrasound
signs of malignancy.

FOLLICULAR

MEDULLARY

ANAPLASTIC
th

th

LYMPHOMA

Advanced age
15% to 20%
tumors of follicular
epithelium

Four ways:
Sporadic (80%)
MEN 2A
MEN 2B
Familial no MEN

6. , 7. decades
5% follicular
epithelium tumors

Women 55-75 years

of age
5% of all thyroid
tumors
Relation
to Hashimotos
thyroiditis
and positive
antiperoxidase
antibodies

Derived from
Yes
follicular epithelium

Yes

No

Yes

No

Pathologic
anatomy

Papillae with follicular

elements and cells
Sand-grain sized
calcifications or
psammoma bodies
(typical, but rare)

Capsular and/or
capsule invasion is
what differentiates it
from benign follicular
adenoma

Cell C accumulation
with amyloid
substance
Multicentric
in familial forms

Gigantic
and fusiform cells
Hard to differentiate
from lymphomas
or sarcomas

Diffuse lymphoma
with large cells

Growth,
dissemination
and metastasis

Slow growth with

neighboring structures
invasion and lymphatic
dissemination

Slow growth, but early Calcified adenopathies

hematic dissemination, and metastasis to CNS
with lung, bone and
and bone
CNS metastasis

Rapid growth with

huge local invasion
ulcerating skin

Marker

Thyroglobulin

Thyroglobulin

Calcitonin/ACE

I-131

Yes

Yes

No

No

No

Prognosis

The best

Hrthle subtype: worse Bad

clinical course

The worst (months

survival)

Variable

Table 6. Malignant tumors of the thyroid

A m e r i c a n Manua l o f Ex am i na ti o n i n Me di c ine (2CK)

Thyroid fine needle aspiration (FNA): test that offers the highest diagnostic yield. To differentiate malignant nodules from
benign nodules, except for lesions with abundant cellularity or
follicular lesions, in which case, vascular invasion needs to be
proven.
Determining calcitonin: if MTC is suspected.

Treatment
According to FNA results:
Benign cellularity: follow-up with palpation and ultrasound study
to evaluate the nodule size or the appearance of malignancy suggestive signs.
Malignant cellularity: thyroidectomy. Ablation of remaining thyroid
tissue with radioiodine in case of dierentiated (papillary and follicular) thyroid carcinoma.
Indeterminate cytology: repeat and assess FNA or perform
hemithyroidectomy according to risk factors and clinical suspicion
of malignancy.

Adrenal Pathology
Chapter 03

3.1. Adrenal Failure

Insucient production of adrenal hormones, especially glucocorticoids, even though according to etiology, there is also insucient
production of mineralocorticoids and adrenal androgens.
Adrenal insuciency (AI) can be:
Primary AI: a condition at adrenal level that destroys more
than 90% of the cortex (Addisons disease). In the United
States of America and the rest of the developed countries,
the most frequent factor is autoimmune adrenalitis. Also
tuberculosis and other infections (N. Neisseria meningitidis,
opportunist infections in AIDS patients, like CMV, deep mycoses).
Central AI secondary or tertiary: hypothalamic or pituitary illness that gives rise to ACTH or CRH deficiency (isolated or within
hypopituitarism).
Prolonged suppression of hypothalamic-pituitary-adrenal
axis activity because of exogenous steroid administration or
endogenous steroid production.

Clinical presentation
Clinical manifestations are nonspecific and of insidious onset.
Common symptoms of primary and secondary AI: asthenia and
progressive weakness, hypoglycemia, weight loss and gastrointestinal discomfort (abdominal pain, nausea and vomiting).
Exclusive symptoms of primary AI: mucocutaneous hyperpigmentation characteristic of compensatory increase in ACTH and its
peptides. Salt craving because of orthostatic hypotension. Loss of

ancillary and pubic hair in women as adrenal androgen secretion decreases. Calcifications of joint cartilage and pinna sometimes occur.

Diagnosis
General analytics: hyponatremia hypoglycemia, normocytic anemia, lymphocytosis and eosinophilia. Between a 15% to 20% of
patients present hypercalcemia of unclear origin. In primary AI, hyperpotassemia and metabolic acidosis (by mineralocorticoids deficiency, which are preserved in secondary AI) can be observed.
Baseline plasma cortisol at eight hours: values < 3 g/dL are diagnostic of AI. Values > 18 g/dL rule AI out. Intermediate values make
a ACTH stimulation test mandatory.
Stimulation test with 250 g of ACTH: it is a reference test or gold standard in primary AI. AI diagnosis is confirmed when after 30 or 60 minutes
of synthetic ACTH administration, cortisol is unable to go over 18 g/dL.
This test should be performed after four months of pituitary surgery or nine months of pituitary radiotherapy to assess possible
central AI. False negative results may be obtained because of absence of total atrophy of cranial nerves in the adrenal reticular
fascicular region as a result of lack of endogenous ACTH. In this
case, an insulin hypoglycemia test must take place.
Baseline plasma ACTH: ACTH concentration rises in primary AI and
it is reduced or inappropriately normal in secondary AI.

Treatment
Primary AI: hormone replacement with glucocorticoids and mineralocorticoids (hydrocortisone and fludrocortisone, respectively).
Central AI: only glucocorticoid replacement is needed.
In case of stress (i.e., major surgery, trauma or infection), regular
glucocorticoid dose should be doubled or tripled according to the
severity of the situation.
In case of an adrenal crisis (acute form of AI, characterized by high fever,
dehydration, nausea, vomiting and hypotension that can evolve into a
shock) i.v. corticosteroids must be administered at stress doses (at these
doses, there is already mineralocorticoid activity and it is not necessary
to administer fludrocortisone), aggressive volume replenishment with
physiologic saline solution and glucose to correct hypoglycemia. The
triggering cause must be researched and specifically addressed.
To prevent AI appearance in the case of chronic corticosteroid
treatment, a slow scheduled tapering of steroid dose should be carried out (i.e., descending pattern in alternate days).

3.2. Pheochromocytoma
Rare tumors that synthesize and release catecholamines, which produce chroman cells of the sympathetic nervous system (adrenal
medulla and sympathetic-parasympathetic ganglia).
Tumors localized in the thoracoabdominal cavity, outside the adrenal gland, are called extra-adrenal pheochromocytomas and tumors derived from cervical sympathetic-parasympathetic tissue are
denominated paragangliomas.
It is 10% tumor because 10% are bilateral, 10% are extra-adrenal,
10% appear in children and 10% are malignant owing to the presence of metastasis at a distance.

Endo c ri no l ogy

These tumors are commonly associated with multiple endocrine

neoplasias (MEN) 2A and 2B.

Clinical presentation
Hypertension is the most frequent manifestation. It is usually kept
in 60% of the cases. Hypertension is sometimes malignant and it is
resistant to conventional treatment in almost every case.
Paroxysms or hypertensive crises are characterized by a significant
increase in blood pressure accompanied by headache, profuse sweating, palpitations, anguish, and imminent sensation of death, paleness,
thoracic and abdominal pain, accompanied by nausea and vomiting.
Paroxysms are triggered by postural changes, psychological stress,
physical exercises, Valsalvas maneuver, some food and drugs; anesthesia and surgery. However, the triggering factor cannot be identified
on some occasions.

Diagnosis
An increase in free catecholamines and/or metabolites (metanephrines) in 24-hour urine or plasma.
CT and abdominal MRl are the imaging techniques most commonly
utilized to localize the tumor.
Gammagraphy with MIBG (meta-iodobenzylguanidin), is the most
ecient method to detect extra-adrenal pheochromocytoma (either
primary or metastatic). Cytology of pheochromocytomas is contraindicated.

Treatment
The treatment of choice is laparoscopic pheochromocytoma resection. Surgery should be conducted in a specialized center, once
proper preoperative preparation has taken place. Pre-op treatment
consists of:
blockade with phenoxybenzamine at least 10-14 days before
surgery.
blockade if necessary with propranolol (to prevent tachycardias).
Preoperative volume load with salt, to prevent rebound hypotension in the immediate postoperative period.
It is very important to be reminded that -blockers are never to be
administered until blockade has been established, as a hypertensive crisis would be triggered.
In the event of a hypertensive crisis before the patient is fully established on an blockade therapy, i.v. phentolamine or nitroprussiate.
When a pheochromocytoma is malignant and unresectable, medical treatment with blockers is carried out. There is also chemotherapy administration with the use of cyclophosphamide, vincristine and dacarbazine. MIBG administration can be used if there is
positive tumor uptake, in repetitive doses.

secreting adrenal adenoma (Conns syndrome). PHA can also result from
adrenal bilateral micronodular or macronodular hyperplasia, unilateral
adrenal hyperplasia or familial etiology, like glucocorticoid-remediable
PHA. An aldosterone-secreting adrenal carcinoma is very rare.

Clinical presentation
HBP is the predominant and universal finding, with diastolic values
over 110 mmHg. There is greater prevalence of aectation of target
organs (hypertensive retinopathy, cardiopathy and nephropathy) in
these kinds of patients.
Because of increased renal excretion of potassium, hypopotassemia occurs, which if marked, is present along with muscle weakness, fatigue, cramps and in severe cases, muscle palsy, as well as
electrocardiographic changes. Polyuria and polydipsia because of
nephrogenic ID.
PHA existence must be assessed in young patients who have their
debut with HBP without risk factors or a family history (see Table 7
for screening indications for PHA).

PHA: INDICATIONS FOR EARLY DETECTION

Moderate/severe HBP (SBP 160 and/or DBP 100 mmHg)
Hypertension resistant to pharmacologic treatment (SBP > 140
or DBP > 90 mmHg despite the use of three antihypertensive drugs
Patients with HBP and spontaneous or diuretic-induced
hypopotassemia
HBP and adrenal incidentalomas
Patients with HBP and family history of HPB of early onset or
cerebrovascular accidents in family members < 40 years of age
Hypertensive 1.st degree relatives of a patient diagnosed with PHA
HBP in children and young people (< 20 years of age)

Table 7. Indications for early detection of primary hyperaldosteronism

Diagnosis
General analytics: hypopotassemia, mild hypernatremia, metabolic
alkalosis, hypomagnesaemia.
PHA screening: determination of baseline aldosterone (it must be
increased, > 15 ng/dL) and aldosterone/activity quotient of plasma
renin > 30.
Confirm biochemical diagnosis using the suppression test: saline
physiologic serum infusion (the correct aldosterone suppression
excludes diagnosis) or captopril test (ACE inhibition causes -in
healthy people- a decrease in aldosterone, which does not occur in
primary hyperaldosteronism).
Etiologic diagnostic takes place after biochemical diagnosis: abdominal CT. Catheterism of adrenal veins is reserved (as it is invasive)
for lesions < 1 cm (or with a negative CT) in individuals > 40 years of
age, in which the prevalence of nonfunctioning adrenal adenomas
is very high.

Treatment
3.3. Primary

Hyperaldosteronism PHA
PHA occurs because of autonomous secretion of aldosterone through the
glomerulus zone of the adrenal gland. A 60% originates in an aldosterone-

In unilateral pathology, as an adenoma, the treatment of choice is

laparoscopic extirpation.
PHA by bilateral hyperplasia is addressed with spironolactone (aldosterone- receptor antagonist) or other potassium-sparing diuretics,
like, triamterene or amiloride.
PHA sensitive to glucocorticoids can be treated with small doses of
corticosteroids or with potassium-sparing diuretics.

A m e r i c a n Manua l o f Ex am i na ti o n i n Me di c ine (2CK)

3.4. Congenital Adrenal

Hyperplasia CAH
It consists of a group of adrenal steroidogenesis disorders stemming
from a hereditary deficiency of one of the enzymes of steroid biosynthesis, with subsequent accumulation of cortisol precursors
prior to enzyme deficiency.
Congenital Adrenal Hyperplasia (CHA) is the most frequent adrenal
disorder in childhood and it can be accompanied by severe deficiencies that endangers the life of a newborn, while partial defects are
manifested after adolescence by hirsutism and virilization in women.
The most common form of CHA is 21-hydroxylase deficiency
(autosomal recessive heritage in 95% of cases), whose clinical
presentation, diagnosis and treatment will be discussed below:

Clinical presentation

DIABETES MELLITUS
TYPE 1

DIABETES MELLITUS
TYPE 2

Age

< 40 years of age

(typically children
or adolescents)

> 40 years of age

Morphotype

Normal or low weight

Overweight or obesity

Onset

Abrupt, even with

ketoacidosis

Insidious, even
asymptomatic finding

Treatment

Always insulin

Diet, oral antidiabetic

drugs or insulin

Tendency to
ketosis

Yes

No

Heritage

Predisposition to HLA

Concordance > 90%

of identical twins

Autoimmunity
against cell

Yes

No

Insulin resistance

No

Yes

Table 8. Dierences between DM type 1 and 2

Classic form: it presents with ambiguous genitalia in girls and
precocious puberty in children. In 80% of the cases it is associated with a salt-wasting syndrome due to mineralocorticoids and
cortisol.
Nonclassic form: hyperandrogenism, oligomenorrhea and subfertility in adolescents and grown women. It is very similar to polycystic
ovary syndrome.

Diagnosis

It constitutes 5% to 10% of the total cases of DM.

Result of the deficiency (usually absolute) in insulin secretion because of cell cell destruction of the pancreas.

Clinical presentation

Diagnosis is confirmed by an increase in baseline 17-hydroxiprogesterone baseline and after ACTH stimulation.

Treatment
In the case of salt-wasting syndrome: reposition of salt and volume; glucocorticoid administration. If later, 21-hidroxilase syndrome becomes severe, mineralocorticoid replacement must be
administered.
Surgical correction of ambiguous genitalia in girls.
The treatment and management of CAH will be discussed further on
in the Gynecology section.

Alteration in
Chapter 04

4.1. Type 1 Diabetes Mellitus

Hydrocarbonate
Metabolism (Table 8)

Type 1 DM typically aects children and adolescents with normal

weight.
Cardinal manifestations: polyuria, polydipsia, polyphagia and weight
loss, whose appearance is usually rapid and of short evolution.
These patients need insulin administration to prevent the appearance of ketoacidosis. Type 1 DB is subdivided into 1A (positive autoimmunity) and 1B or idiopathic.
Genetic predisposition associated with HLA-DR3 and DR-4.

Diagnosis
Diagnostic criteria for diabetes mellitus:
Plasma glucose on an empty stomach > 126 mg/dL.
Plasma glucose two hours after oral glucose overload
(SOG) > 200 mg/dL.
Glycosylated hemoglobin (HbA1C) > 6.5%.
Plasma glycemia at random + compatible symptoms with DM >
200 mg/dL.
Presence of antibodies pancreatic anti-islets, anti-IA2 (associated
protein with insulinoma 2), anti-GAD (descarboxylase of glutamic
acid) and anti-ZnT8 (zinc channel): The first three are more frequently positive in people with DM1.

Treatment
Diabetes mellitus (DM) is a set of heterogeneous syndromes of multifactorial etiopathogenesis, whose common nexus is chronic hyperglycemia. Chronic macrovascular and microvascular complications develop
along the course of the disease.

10

Insulin therapy in intensive pattern (subcutaneous, bolus-baseline

pattern or pump subcutaneous insulin infusion), simulating physiologic secretion of the pancreas: baseline insulin and insulin before
each meal (Figure 3).

Endo c ri no l ogy

Insulin characteristics are listed in Table 9.

The control goal in most patients is an HbA1c < 7%. See Table 10.
The following manifestations must be monitored: blood pressure
(objective: < 140/ < 80 mmHg), renal function, lipid profile and
systematic early detection of comorbilities (microalbuminuria for
diabetic nephropathy, exploration of the patients retina through a
fundoscopy or nonmydriatic retinography, full neurologic examination, etc).

TYPE

ONSET

PEAK

Br

Lu

Di

Br

Br

Lu

Di

Br

DURATION

Prolonged or intermediate action insulins (control glycemia on an

empty stomach and preprandial)

Guidelines for intensified treatment

Intermediate action
NPH or NPL

Guidelines for conventional treatment

2 hours

4-6 hours

12 hours

Analogous of a prolonged action

Glargine

2 hours

It does not present 20-24 hours

Detemir

2 hours

It does not
present

12-24 hours

Br

Lu

Di

Br

Br

Lu

Di

Br

d.

Breakfast

Rapid action insulins (control postprandial glycemia although regular or

crystalline insulin can control preprandial glycemia of the following meal)
Human recombinant
insulin (rapid, regular
or crystalline)

30 minutes

2-3 hours

6-8 hours

Analogous with ultrarapid action

Aspartic, lispro
and glulisine

10 minutes

30-40 minutes

2-3 hours

PARAMETER

OBJECTIVE

HbA1c

< 7%*

Preprandial
Glycemia

70130 mg/dL*

Postprandial Glycemia

< 180 mg/dL*

* Goals should be individualized according to the duration of diabetes, age/

life expectancy, comorbility, known cardiovascular disease or advanced
microvascular disease, unnoticed hypoglycemias and individual aspects
of the patient. More or less tight glycemic objectives can be appropriate
according to different patients. Postprandial glycemia could be a target if
HbA1c is not controlled, despite achieving preprandial glycemia goals
Blood pressure

< 140/80 mmHg (individualize)

LDL Cholesterol

< 100 mg/dL

It is recommended
< 70 mg/dL in patients with
manifest cardiovascular disease

HDL Cholesterol

> 40 mg/dL in men

and > 50 mg/dL in women

Triglycerides

< 150 mg/dL

Suspension of smoking habit

HOSPITALIZED PATIENT
Critical patient

< 180 mg/dL (range 140-180 mg/dL)

Noncritical patient

Preprandial glycemia < 140 mg/dL

Any time blood glucose
< 180 mg/dL
Unclear evidence to make
a recommendation

Table 10. Objectives of metabolic control (ADA, 2014)

Insulinemia levels

Table 9. Types of insulin

Lunch

Lispro
or aspartic
or glulisine

Lispro
or aspartic
or glulisine

Dinner

Lispro
or aspartic
or glulisine

Glargine
Detemir

Detemir

Figure 3. Guidelines for insulin treatment

4.2. Type 2 Diabetes Mellitus

Type 2 DM makes up 80% to 90% of the total cases of DM.
It appear in subjects that present resistance to insulin and a relative
(rather than absolute) insulin deficiency.
Diabetic type 2 patients do not require insulin administration to prevent ketosis appearance. However, at some point in their lives they
could need it to control glycemia.

Clinical presentation
It is more frequent in adults and elderly people, especially in those
with a central distribution or abdominal obesity.
Cardinal manifestations: Polyuria, polydipsia, polyphagia and
weight loss, of insidious, progressive onset and of long duration in
many cases. At times, patients have their debut with chronic complications because of latent symptomatology.

11

A m e r i c a n Manua l o f Ex am i na ti o n i n Me di c ine (2CK)

Type 2 DM suerers may develop hyperosmolar nonketotic hyperglycemia in cases of metabolic control, infections or severe intercurrent pathology. Some patients may have their debut with this disease.

Diagnosis
The same criteria as for diagnosis of DM1.
Negative antibodies (although they are routinely requested).
DM2 screening in the general population:
Every three years, asymptomatic people aged 45, and regardless of age in case of patients with overweight or obesity (BMI
25 kg/m2) and some other risk factor for DM type 2 development (see Table 11).

1. Age 45
2. Regardless of age in individual with BMI 25 kg/m2 and some
additional risk factor:
Sedentarism
1.st degree relatives with a record of diabetes
Ethnic group at high risk (Afro-Americans, Hispano-Americans, native
Americans, Asian American and natives from the Pacific Islands)
People previously diagnosed with carbohydrate intolerance and
altered glucose in fastening or HbA1c 5.7%
Personal history of gestational diabetes or macrosomic fetus
Arterial hypertension
An increase in triglycerides or a decrease in HDL
Women with polycystic ovary syndrome
Clinical conditions associated with insulin resistance
(i.e., severe obesity or acanthosis nigricans)
Personal record of cardiovascular disease

Table 11. Screening indications for diabetes mellitus

in asymptomatic adult patients (ADA, 2010)

Treatment
Monitoring goals are the same as for Type 1 DM patients (see Table
11); given that the hypoglycemia risk factor is not high, especially in
elderly patients.
Blood pressure should be controlled (objective: < 140/ < 80 mmHg),
renal function, lipid profile and early detection of comorbilities
(microalbuminuria for diabetic nephropathy, examination of the
patients retina, by means of fundoscopy or nonmydriatic retinography, complete neurologic examination , etc).
Metformin treatment may be commenced in a preventive manner in patients with prediabetes (glycemia on an empty stomach > 100 mg/dL, but < 126 mg/dL and/or after two hours of OGO
> 140 and < 200 mg/dL) who are obese and who present another risk
factor of diabetes (HbA1c > 6%, HBP, a decrease in HDL, hypertriglyceridemia, a history of DM in first degree relatives under 60 years of age).

4.3. Treatment of Diabetes Mellitus

Lifestyle
Diet:
Low fat diet (< 30%), moderate in carbohydrates (< 55%) and
hypocaloric if there is overweight or obesity.

12

Weight loss:
Goal: lose 5% to 10% of initial weight through diet and exercise.
Exercise:
Exercise of moderate intensity, minimum 30 minutes a day, 5
days a week.
Quit smoking habit.

Pharmacotherapy
See Table 12, next page.

Control of Comorbilities
Anti-aggregation:
Primary prevention: men > 50 years of age or women > 10 years
after menopause (in general > 60) with some major cardiovascular risk factor (family history of cardiovascular disease, hypertension, dysplemia, smoking or albuminuria) or those patients
at risk of having a cardiovascular event, in ten years is higher
than 10%.
Blood pressure:
Target 140/< 80 mmHg. ACEIs are the treatment of choice, but
ARA-2 if the former are not tolerated.

Acute Complications (Table 13)

Diabetic Ketoacidosis:
Typical, although not exclusive of DM type 1. It occurs because
of insulin deficiency and an increase in contrainsular hormones,
mainly glucagon. First manifestation of DM type 1 in 25% to 30%
of cases. In known diabetic patients, precipitating reasons are
usually abandonment of insulin treatment, dietary transgressions, infections (30% to 40% of the cases), traumas, surgery,
gestation, and endocrinopathies, like Cushings syndrome or
Graves-Basedow disease among others.
Clinical presentation: nausea, vomiting and abdominal pain,
together with diabetic cardinal symptomatology. If not treated precociously, obnubilation and coma will develop. During
physical examination, outstanding manifestations are tachypnea, Kussmaul respiration and dehydration signs, like dry
mucosa, hypotension and a decrease in ocular globe pressure. Prerenal and renal failure may occur because of dehydration.
Diagnosis: Hyperglycemia + metabolic acidosis with increased
anion gap, presence of increased ketonic bodies in blood and
urine.
Treatment with intravenous insulinotherapy, serum therapy, intravenous potassium administration, bicarbonate (if pH < 7) and
treatment of triggering cause.
Hyperosmolar nonketotic hyperglycemia:
Typical, but not exclusive of DM type 2.
Insucient response of insulin action because of insulin resistance, unable to counteract the increase in contrarregulatory
hormones caused by triggering stressing factors. Residual insulin
secretion is capable of minimizing or impedes ketosis, but not
preventing hyperglycemia.

Endo c ri no l ogy

IV-DPP
INHIBITORS
Sitagliptin
Vildagliptin
Saxagliptin

ANALOGOUS
OF GLP-1
Exenatide
Liraglutide

They decrease
peripheral resistance
(muscle and adipose
tissue) to insulin by
means of bond to
PPAR-

They increase
endogenous
GLP-1 half like
dipeptidyl
peptidase IV

Similar effect
to endogenous
GLP-1
(increase in
insulin secretion
mediated through
intake , slowing
gastric emptying)
resistant to DPP IV

Hypoglycemia GI
GI discomfort
(infrequent)
discomfort
(the most
frequent)
Lactic
acidosis
(the most
severe, but
rare)

Increase in
Nausea
and vomiting
transaminase
(vildagliptin)
(frequent)
Pancreatitis
Discrete
increase in
(very rare)
respiratory
Deterioration of
and urinary
renal function
tract
infections

Pregnancy
Situations
Pregnant
Liver disease predisposing women and
Severe RI
to lactic
children
acidosis

Hepatopathy
Heart failure
Rosiglitazone
withdrawn in
Europe due to
an increase in
coronary events

Pregnant
women
and children

Associated with
metformin or
in case of its
contraindication
mild-moderate RI

2.nd
Obesity
therapeutic
together with
step in type
metformin
2 DM
Its use also
Sitagliptin
approved with
approved in
sulfonylureas
monotherapy
(increased risk
and in
of hypoglycemia
combination
and less weight
with insulin
loss)

SULPHONYLUREAS MEGLITINIDES BIGUANIDES

Active
substance

Mechanism
of action

Side effects

Glibenclamide
Glipizide
Gliclazide
Gliquidone
Glimepiride
Insulin secretion
stimulus in
sustained way
through bond to
cell receptor

Severe and
sustained
hypoglycemia

Contraindications Pregnancy
Hepatopathy
RI

Use

Repaglinide
Nateglinide

Metformin

Insulin
secretion
stimulus in
acute way
through
bond to cell
receptor

Liver
resistance
to insulin
decreases

GLUCOSIDASE
INHIBITORS
Acarbose
Miglitol

Transient
inhibition
of intestinal
-glucosidase

Scarcely
Second
Postprandial First choice
in type 2 DM
effective
therapeutic step
glycemia
Control of
in type 2 DM with
control
pospandrial
pancreatic reserve Elderly
hyperglycemia
people with
some degree
of decline
in renal
function

TIAZOLIDINEDIONES
Pioglitazone
Rosiglitazone

Hepatotoxicity
Hydric retention
Heart failure
Osteoporosis
in women

Use not approved

along with insulin

Table 12. Characteristics of oral antidiabetic drugs and noninsulin therapies in type 2 diabetes mellitus
PREVENTION (early phases)
Diabetic retinopathy
Diabetic
nephropathy

Neuropathy
and diabetic foot

Macroangiopathy

Strict glycemic control

Strict glycemic and HBC control
RAAS blockade (ACE inhibitors
or ARBs) if microalbuminuria or
macroalbuminuria or hypertension
Reduction of protein intake in chronic
kidney disease
Strict glycemic control and foot care
Smoking cessation

Strict HBC control

Smoking cessation
Antiplatelet therapy
Lipid-lowering therapy

SYMPTOMATIC TREATMENT (advanced phases)

Photocoagulation
Dialysis or kidney transplant

NEUROPATHY
Pain: opiates, tricyclics, anticonvulsants, duloxetine and capsaicin
Orthostatic hypotension: postural measures, udrocortisone
Diarrhea: loperamide
Gastroparesis: prokinetics and erythromycin
ULCERS
Debridement, rest, antibiotics and revascularization
Arterial revascularization techniques

Table 13. Prevention and treatment of chronic complications in DM

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A m e r i c a n Manua l o f Ex am i na ti o n i n Me di c ine (2CK)

Mortality, given this clinical profile, ranges from 5% to 20% of

cases; underlying infection process and general deterioration of
the patient are also contributing factors.
Triggering factors: infection (in approximately 60% of the cases),
leaving therapy or inadequate treatment. A 20% of the individuals suering from Hyperosmolar hyperglycemic state (HHS) have
not been previously diagnosed with DM.
Clinical presentation: severe dehydration. Alteration of the level of
consciousness, from stupor up to coma (hyperosmolar coma). Neurologic manifestations (as convulsions or transient hemiplegia), as well
as microthrombosis and disseminated vascular coagulation may occur.
Diagnosis: glycemia > 600 mg/dL, negative or mildly positive- ketonic bodies can be traced in urine or serum, BP > 7.30, eective serum
osmolality > 320 mOsm/kg and plasma bicarbonate (> 18 mEq/L).
Treatment: aggressive serum therapy, electrolytic replacement
and insulin therapy, as well as treatment of the triggering factor.

Complications of Insulin Treatment

Somogyi phenomena: an increase in fasting glycemia because of an
increase in contrarregulatory cell in response to nocturnal hypoglycemia. Treatment involves reducing insulin dose to prevent nocturnal hypoglycemia.
Dawn phenomenon. An increase in plasma glucose. Plasma glucose
increase in the first hours in the morning, in relation to GH nocturnal
or circadian rhythm of cortisol. Distinction from Somogyi phenomenon is made by determining glycemia at 3 a.m. Glucose will be low
if it is a Somogyi phenomenon and it will be normal if it is a dawn
phenomenon. Insulin should be increased if there is evidence of a
dawn phenomenon so normoglycemia levels are maintained.

4.4. Metabolic Syndrome

Association of several cardiovascular risk factors, including abdominal obesity, dyslipemia, hypertension and glucose alteration, which
can coexist in the same aected person.
Also called X syndrome, it has as a main pathophysiologic substrate
insulin resistance. There are many definitions of the metabolic syndrome (MS).

Diagnosis
Diagnosis criteria of ATP-III (2004) are as follow:
Abdominal circumference: > 102 cm (> 40 inches) in men and > 88
cm (> 35 inches) in women.
Triglycerides > 150 mg/dL.
HDL-cholesterol < 40 mg/dL in men and < 50 mg/dL in women.
Blood pressure > 135/ > 85 mmHg or request antihypertensive medication.
Fasting baseline insulin > 100 mg/dL.
At least three out of five criteria are needed for MS diagnosis.

Treatment
Weight loss should be encouraged, as well as specific treatment for
the remaining in comorbilities (HBP and dyslipidemia).

14

For patients at high risk of developing DM type 2, start with metformin can be assessed.

Bone Pathology
Chapter 05

and Phosphocalcic
Metabolism

5.1. Osteoporosis
Loss of bone mass equal to or higher than 2.5 SD (standard deviation) with respect to bone mass of young people of the same sex. It
is the more frequent metabolic bone disease.
Most of the cases belong to the primary osteoporosis or they are
not associated to other diseases.
Diseases present with secondary osteoporosis: hyperparathyroidism,
hyperthiroidism, hypercortisolism and hypogonadism. Other accompanying illnesses are also rheumatoid arthritis, systemic mastocytosis,
multiple myeloma and chronic treatment with corticoids among others.

Clinical presentation
It is an asymptomatic disease until fracture appears; backbone fracture is the most common.
Fractures in vertebral bodies and forearm distal radius (de Colles
fracture) are frequent complication.
Vertebral bone fracture causes back pain, of acute onset with frequent irradiation toward the abdomen and backbone deformity. It
usually occurs after sudden flexions, but sometimes there is a triggering factor. It happens more frequently in the middle and lower
dorsal vertebrae and in lumbar spine.

Diagnosis
Dual radiologic densitometry (DXA): loss of bone mass equal to or
higher than 2.5 SD with respect to bone mass of young people (3035 years of age) of the same sex.
Rule out secondary causes: full biochemical lab test that includes
Ca, P, TSH, PTH, 25(OH) vitamin D, 24-hour excreted calciuria, testosterone (men), serum proteinogram and screening of Cushings
syndrome if clinical presentation is suggestive.
Conventional bone x-ray: it is little sensitive for osteopenia diagnosis, as a loss greater than 30% of bone mass is needed to be radiologically detected.

Treatment
Change in life style: do exercise. Abstinence of smoking habit.
Calcium and vitamin D: this recommendation applies for all patients
diagnosed with osteoporosis, regardless they receive additional

Endo c ri no l ogy

pharmacological treatment or not. Calcium and vitamin D favor a

reduction of fracture rates, hip fracture included.
Biphosphonates: alendronate, risedronate, zoledronate, ibandronate are all potent inhibitors of bone resorption. They decrease vertebral fractures and femur neck fracture.
Selective estrogen response modifiers or SERMs -raloxifene and
tamoxifen. They reduce replacement and loss of bone mass; diminishing the incidence of vertebral fractures, without having proven
their eect on the prevention of femoral neck fractures.
Denosumab, monoclonal antibody with a high anity for RANKL. In
postmenopausic women, significantly reduce the risk for vertebral,
nonvertebral and hip fracture.

5.2. Pagets Disease

The second most frequent osteopathy in developed countries.
Characterized by an increase in bone resorption, followed by a compensatory increase in synthesis (bone replacement can be up to 20
times over normal values).
More frequent in men than in women and prevalence increases
with age, so the disease is usually present in the elderly.
The presence of viral inclusion bodies (paramixovirus) in osteoclasts
enables supposing that a viral infection could be the origin of Pagets disease in genetically predisposed individuals.
Primary bone pain is the more habitual clinical manifestation.
Other manifestations are the gradual appearance of deformations
or swelling in the limbs, problems with gait because of the dierence in limb length, headache and facial pain, backbone lower
extremities pain, hearing loss owing to direct aectation of small
internal bones in the inner ear or to compression of the 7.th cranial
nerve in the internal auditory orifice.
The most severe neurologic complications occur because of bone
growth in the base of the cranium, which can compress the medulla
and can cause tetraplegia.

Complications
Increase in cardiac output: an increased blood flow in bone, with an
increase in the venous return network in aected areas, which may
give rise to heart failure in patients with prior cardiopathy.
Pathologic fractures, arthropathy because of proximity (the most
frequent is the coxofemoral), compressive neurologic syndromes
and bucco-dental disorders.
Nephrolithiasis because of hypercalciuria. It rarely causes hypercalcemia. There is also a greater incidence of hyperuricemia and gout.
Sarcoma. Shown in 1% of the patients. Sarcoma is the most severe
complication and is usually located in the femur, the humerus, the
cranium, facial bones and pelvis.

5.3. Hyperparathyroidism

(Table 14)

Parathyroid glands produce parathyroid hormone (PTH), which,

together with vitamin D and calcitonin, is responsible for calcium
and phosphorous metabolism. Hyperparathyroidism is defined as
elevated values of PTH in plasma, with dierent eects on calcium
and phosphorous depending on the specific cause.
Primary hyperparathyroidism: in 85% of cases, primary hyperthyroidism is caused by autonomous secretion by a single or multiple
parathyroid adenomas, while hyperplasia is found in 15% of the
cases and parathyroid carcinoma in < 1%. Both forms of the disease
can appear in a sporadic way or as family disorders: MEN 1, MEN 2A,
familial hyperparathyroidism and jaw tumor syndromes.
Secondary hyperparathyroidism: a physiologic increase in PTH in renal
failure or vitamin D deficiency is considered to prevent hypocalcemia.
Tertiary hyperparathyroidism: the secondary increase in PTH over
time in patients with chronic renal failure. In theory, it can lead to
hyperplasia of the parathyroid glands. Tertiary hyperparathyroidism
occurs when one gland -or more- becomes autonomous (even remaining after renal transplantation).

Diagnosis
Biochemical: alkaline phosphatase is a good test choice for early
detection and treatment response. Other parameters also help establish a diagnosis, i.e., an increase in other parameters of bone
formation (osteocalcin, procollagene) and bone resorption (hydroxyproline, acid phosphatase, pyridinoline, deoxypyridinoline and
peptide).
Conventional bone x-ray: characteristic radiologic alterations, like
an increase in bone size, cortical thickening and alterations in the
trabecular pattern, coexistence of lytic and blastic areas, fractures,
vertebras with rim-like appearance and circumscribed osteoporosis.
Bone gammagraphy: this enables checking the extent of the disease.

Treatment
Asymptomatic: they do not need treatment.
Symptomatic: (persistent pain, nerve compression, bone deformity
of rapid progression that results in gait diculties, heart failure, hypercalcemia and hypercalciuria, bone fractures and reparation for
orthopedic surgery). Biphosphonates is the treatment of choice.

PRIMARY
Hyperparathyroidism

SECONDARY
Hyperparathyroidism

TERTIARY
Hyperparathyroidism

PTHi

Calcemia

N or

N or

Phosphatemia

Table 14. Dierential diagnosis of hyperparathyroidism. Lab parameters

(N: normal)

We will mainly discuss primary hyperparathyroidism:

Clinical presentation
Most cases diagnosed are asymptomatic and hypercalcemia is
found by chance.
HBP is present in 50% to 70% of the patients. Peptic ulcer and gastritis, acute pancreatitis and cholelitiasis are also present.
Other manifestations are: headache, asthenia, depression, anemia,
band keratopathy, constipation, proximal muscle weakness, polyuria, gout, chondrocalcinosis, osteoporosis and increased cardiovascular risk, fatigue, depression and anxiety.

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A m e r i c a n Manua l o f Ex am i na ti o n i n Me di c ine (2CK)

Bone disease. Appearance of bone cysts in long bones or brown

tumors (accumulation of multinuclear giant osteoclasts). Other
changes are generalized or circumscribed osteopenia (salt and pepper skull) and subperiosteal resorption phenomena (radial zone of
the middle phalanx of fingers) or generalized (clavicle). Bone disease may be silent or cause local pain and even pathologic fractures.
Renal aectation. Nephrolithiasis and nephrocalcinosis.

Diagnosis
General analytics: hypercalcemia, hypophosphatemia, metabolic
acidosis, hypercalciuria and diminished phosphate tubular resorption.
High values of intact PTH (PTHi) in relation to plasma calcemia. Some
patients show inappropriately normal values, but never low or suppressed.
Localization diagnosis: they should only be requested if surgical
treatment is indicated, but not forced.
Cervical ultrasound and gammagraphy with Tc-sestamibi: currently, the combination of both techniques oer greater diagnostic
yield and enables the performance of a minimally invasive surgery.
Complications of diagnosis: bone densitometry (DEXA scan) to rule
out osteopenia or osteoporosis, in lumbar spine, hip and distal radius. Renal ultrasound test.

Treatment
Parathyroidectomy if the patient meets surgical criteria (Table
15). If there is a parathyroid adenoma, an adenomatous gland
is removed. If any of the following occurs: parathyroid hyperplasia, total parathyroidectomy with implant in forearm muscles
or sternocleidomastoid muscle or subtotal parathyroidectomy
(leave a portion of the last gland).
In severe, symptomatic acute hypercalcemia, treatment involves
abundant hydration, loop diuretics and i.v. Biphosphonates.
In asymptomatic patients, secure ecient hydration.
Cinacalcet, a calcimimetic, increases circulating calcium anity
by its receptor resulting in a significant decrease in calcium and
PTH levels. Therefore, it is indicated in secondary hyperparathyroidism in CRD and in primary hyperparathyroidism suerers unsuitable for surgery because of accompanying comorbilities or in
those aected by the disease who refuse surgery.
To prevent secondary hyperparathyroidism development in CRD
patients, oral phosphorus chelants must be administered, but
the patients diet intake needs to be restricted.

Multiple Endocrine
Chapter 06

Neoplastic syndromes that aect multiple endocrine organs and

that have hereditary etiology (autosomal dominant).
MEN 1 (Wermers syndrome) association of hyperparathyroidism (the
most frequent manifestation, because of parathyroid hyperplasia), pituitary adenoma and cell tumors of pancreatic islets. The 3 Ps: parathyroid, pancreas and pituitary. Multiple Endocrine Neoplasia (MEN)
(Table 16).
MEN type 2A (Sipples syndrome) confluence of medullary thyroid
cancer (or MTC, the most common manifestation), pheochromocytoma (bilaterality is more frequent than sporadic pheochromocytoma) and hyperparathyroidism (the most frequent form is hyperplasia as in MEN 1) (Table 17).
MEN type 2B consists of (aggressive) MTC with the presence of mucosa neuromas (tip of the tongue, eyelids and digestive tract).
When MTC and pheochromocytoma converge, pheochromocytoma
should be surgically treated first.

ENDOCRINE MANIFESTATIONS
1. Parathyroid hyperplasia/adenoma (90%)
2. Enteropancreatic tumor (70%):
Gastrinomas (40%)
Pancreatic polypeptide (20%)
Insulinoma (10%)
Other more rare (i.e., vipoma and
glucagonoma)

Any primary hyperparathyroidism that presents signs or symptoms

related to hypercalcemia (i.e., nephrolithiasis) requires surgical
indication right from the start

Table 15. Indications for surgery in asymptomatic primary

hyperparathyroidism (Workshop, 2008)

16

NONENDOCRINE
MANIFESTATIONS
1. Facial angiofibromas
(85%)
2. Collagenomas (70%)
3. Lipomas (30%)

3. Pituitary tumors (40%):

Prolactin (20%)
Acromegaly (5%)
Combination of prolactin and GH (5%)
Nonsecretory (5%)
Others (TSH and so on)
4. Nonfunctioning adrenal adenomas

Table 16. Associations in MEN 1

SYNDROME
MEN 2A

Under 50 years of age

Age 50 with, at least, one of the following criteria:
- Serum calcium > 1 mg/dL over the upper limit of normality
- Decreased creatinine clearance (< 60 mL/min)
- Mineral bone density under 2.5 ED on T-score
in backbone, hip, femoral head or 1/3 distal of radius
and/or any prior fracture because of fragility

Neoplasia (MEN)

CHARACTERISTICS

Medullary thyroid carcinoma

Pheochromocytoma (50%)
Hyperparathyroidism (10%)
Lichenoid cutaneous amyloidosis
Hirschprungs disease

Familial medullary Medullary thyroid carcinoma

thyroid carcinoma It can be associated with Hirschprungs disease
MEN 2B

Medullary thyroid carcinoma (more precocious

and aggressive than in MEN 2A)
Pheochromocytoma (40% to 50%)
Mucocutaneous ganglioneuromatosis (95%)
Marfanoid habitus (without ectopia lentis or
aortic anomalies)

Table 17. Associations in MEN 2