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E n d o c r i n o l o g y

American Manualof Examination

in Medicine(2CK)

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E n d o c r i n o l o g y

American Manualof Examination

in Medicine(2CK)

AuthorJuan Simón Chacín

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Amer ican Manual of Examinat ion in Medic ine (2CK)

01. Hypothalamic-Pituitary Pathology .................................1

1.1. Cushing’s Syndrome .........................................................................................................1

1.2. Acromegaly ....................................................................................................................................2

1.3. Hyperprolactinemia ..........................................................................................................2

1.4. Diabetes Insipidus................................................................................................................3

1.5. Syndrome of Inadequa teSecretion of Vasopressin SIAD H ..........................................4

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

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

2.2. Hyperthyroidism ....................................................................................................................5

2.3. Hypothyroidism ......................................................................................................................6

2.4. Thyroiditis .........................................................................................................................................6

2.5. Thyroid Nodule and Thyroid Cancer .........................................................7

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

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

3.2. Pheochromocytoma .........................................................................................................8

3.3. Primary Hyperaldosteronism PHA ..........................................................9

3.4. Congenital Adrenal Hyperplasia CAH ...........................................10

04. Alteration in Hydrocarbonate Metabolism ....10

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

4.2. Type 2 Diabetes Mellitus ........................................................................................11

4.3. Treatment of Diabetes Mellitus ....................................................................12

4.4. Metabolic Syndrome ....................................................................................................14

05. Bone Pathology and Phosphocalcic

Metabolism .........................................................................................................14

5.1. Osteoporosis ............................................................................................................................14

5.2. Paget’s Disease ....................................................................................................................15

5.3. Hyperparathyroidism ..................................................................................................15

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

Index

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Endocrinology

Chapter 01

Hypothalamic-

Pituitary Pathology

1.1. Cushing’s Syndrome

• Cushing’s syndrome (CS) is a set of diverse symptoms, due to an

excess in corsol producon by the adrenal cortex (endogenous

Cushing’s) or by sustained administraton of glucocortcoids (exog-

enous and facttous Cushing’s).

• The most frequent cause is iatrogenic administraon of steroids due

to another reason; the most frequent endogenous cause is Cushing’s

diseases (overproducon of ACTH due to a pituitary adenoma) in 65%

to 70% of the cases, autonomous producon of corsol as a result of

adrenal pathology (adrenal CS because of adenomas, adrenal hyper-

plasia and adrenal carcinoma) in about 15% to 20% and the ectopic CSas a result of paraneoplasc producon of ACTH (bronchial carcinoma

of small cells is the most frequent; carcinoid tumors, CMT and pheo-

chromocytoma) in 15%.

Clinical presentation (Figure 1)

Moon face

Acne

Central obesity

Muscle weakness

Capillary fragility

Hirsutism

Wine-red stretch marks

Figure 1. Clinical presentation of Cushing’s syndrome

• Characteristc features of Cushing’s Syndrome include (from the

most frequent to the least)

Symptoms: weight gain, menstrual cycle irregularity, hirsutsm,

psychiatric alteratons, muscle weakness.

Signs: central obesity, facial plethora, moon facies, hemato-

mas and capillary fragility, vinous red stretch marks, edemas

in lower extremites, proximal myopathy and hyperpigmenta-

ton.

The most specific are facial plethora, capillary fragility, muscle

weakness or proximal myopathy, wine-red stretch marks and,

weight gain with growth rate delay.

• Patents present in half of the cases, alteratons of carbohydrate

metabolism (DM and carbohydrate intolerance), high blood

pressure (HBP) and osteoporosis; and less frequently, nephro-

lithiasis.

• In ectopic CS cases, symptoms and signs typical of CS may appear

and cardinal manifestatons consist of glucose intolerance, hypopo-

tassemic alkalosis, proximal myopathy and cutaneous hyperpigmen-

taton.

Diagnosis

• Whatever the cause of excess cortsol producton, there will always

be an increased cortsol excreton, aboliton of its circadian rhythm

and absence of cortsol secreton inhibiton with a low dose of glu-

cocortcoids.

• Biochemical diagnosis of hypercortsolism requires two positve

tests of the following (they are regarded as “first line test”): high

corsoluria 24 h, high nocturnal salivary corsol (measured be-

tween 11 p.m. and midnight) and/or lack of suppression of basal

plasma cortsol afer administraton of low doses of dexametha-

sone: 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 patents who

have had misleading results on a prior test and when there is a

high clinical suspicion of Cushing’s syndrome: high late-night se-

rum corsol (measured between 11 p.m. and midnight) and com-

bined suppression test with 2 mg of DXM + CRH smulus: useful

to diff erentate people suff ering from pseudo Cushing’s (it remains

suppressed afer CRH) from those with CS (they experience a high

plasma concentraton of cortsol and ACTH afer CRH administra-

ton).

• For eologic diagnosis or diagnosis for localizaton, the first step

will always be determining baseline ACTH to diff erentate between

ACTH-dependent CS (central or ectopic) and ACTH-independent CS

(adrenal). If ACTH is < 5 pg/mL (low or suppressed), it is ACTH inde-pendent, so the next step is to perform an adrenal imaging test (adre-

nal 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 relatvely intact). Therefore,

afer CRH administraton, there is an increase in ACTH and cortsol

at baseline in most patents with hypothalamic dysfuncton or an

ACTH-secretng pituitary tumor (macroadenoma and microadeno-

ma).

• The 8 mg DXM Liddle’s test with a high dose (long high-dose

dexamethasone suppression test) is a useful test to discrimi-

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cal diabetes mellitus); hypercalciuria and nephrolithiasis. Hyperpro-

lactnemia is present in a third of the cases. Sleep apnea. Increase

in the frequency of nasal polyps and intracranial aneurysm. Three

to ten tmes higher risk of having premalignant polyps and colon

cancer.

Diagnosis

• Random determinatons 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 afer oral

glucose overload (OGO).

• Imaging studies (adrenal NMR) afer hormonal diagnosis, which

will reveal a selar lesion in most cases (macroadenoma is more fre-

quent).

• A complete assessment of pituitary funcon is necessary to rule out

the existence of panhypopituitarism.

• Every acromegaly suff erer must have a colonoscopy performed at

the tme of diagnosis and steps towards early detecon of pos-

sible complica

ons (i.e., sleep apnea, diabetes mellitus amongothers).

Treatment

• Transsphenoidal surgery is the choice in microadenomas and

macroadenomas that are potentally resectable. In macroad-

enomas with wide extraselar extension although surgery is not

curatve, it can improve response to medical treatment (“deb-

ulking”).

• The medical treatment of choice in acromegaly is the somatostan

analogs (octreotde, slow-release octreotde and lanreotde) which

suppress GH secreton. These drugs can be used as a therapeutc

first choice, when the surgical risk is unacceptable, the patents re-

ject surgery or a macroadenoma is present with scarce possibilitesof being completely resected with or without debulking. Pegviso-

mant, a GH receptor antagonist is another alternave. It is the sec-

ond treatment of choice afer somatostan analogs, in the event cu-

rave criteria is not met or because of the appearance of severe side

eff ects.

• Radiotherapy is utlized in diseased people who did not reach cure

afer surgery or when surgery is contraindicated or the patent re-

jects it. At present, radiotherapy is a second or third choice treat-

ment.

1.3.Hyperprolactinemia

• Increase in prolactn levels. The most frequent cause of hyperp-

rolactnemia is pregnancy and the most frequent pathologic pri-

mary source is drugs intake.

• The most common functoning pituitary tumor is prolactnoma.

Other tumors can cause hyperprolactnemia, because of com-

pression of the pituitary stalk (and loss of dopamine inhibitory

tone on lactotroph) cells, like nonfunctoning adenomas and

other selar masses. Hypothyroidism, chronic renal disease and

hepatc cirrhosis are also causes of hyperprolactnemia (Table

1).

nate patents with ACTH-secretng pituitary microadenoma. A

positve response occurs when cortsol in urine or plasma is re-

duced (> 90% of baseline) afer DXM administraton, while mac-

roadenomas and most ectopic ACTH-secretng 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 Cushing’s) a bilateral

catheterizaton of inferior petrosal sinuses must be performed. The

demonstraon afer CRH smulaon of an ACTH peripheral gradient

(higher level in petrosal sinus than in peripheral vein) enables locat-

ing the site of ACTH hypersecreon 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

• Eologic treatment of choice is surgery in adrenal pathology (ad-

enomas and carcinoma) and in Cushing’s disease (via transsphe-

noidal approach). Also in ectopic tumors in which resecton is pos-sible.

• Pituitary radiotherapy is used in cases in which cure is not achieved

afer transsphenoidal surgery of Cushing’s disease.

• When etologic treatment is not possible or it did not turn out eff ec-

tve, it is necessary to resort to medical adrenalectomy (mitotane)

or to inhibitors of cortsol synthesis (ketokonazole, aminoglutethi-

mide or metopirone).

• Occasionally, bilateral surgical adrenalectomy is needed when de-

finitve treatments (surgery or radiotherapy) fail or side eff ects to

drug treatment develop. Then, a substtuton treatment is required

with glucocortcoids and mineral or cortcoids.

1.2. Acromegaly

• Debilitatng chronic disease because of an increased producton of

growth hormone (GH), habitually because of GH-secretng pituitary

adenomas. A total of 75% of them are macroadenomas (greater

than 1 cm).

• When GH excess develops before epiphyseal plate closure in chil-

dren, the linear growth increases and results in gigantsm.

Clinical presentation

• Symptoms: progressive growth and enlargement of hands, feet andperimeter, prognathism, exaggerated development of the tongue and

coarsening facial features. Weakness and tredness, profuse sweat-

ing, headache, carpal tunnel syndrome, muscle weakness and ar-

thralgia. Amenorrhea, hirsutsm.

• 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

optcal chiasm. HBP. Myocardiopathy (ventricular hypertrophy) and

heart failure because of diastolic dysfuncton, goiter, hepatomegaly

and splenomegaly.

• People suff ering from this disorder may be insulin-resistant with

abnormal hydrocarbon metabolism (glucose intolerance and clini-

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PHYSIOLOGIC

HYPERSECRETION

· Pregnancy

· Lactancy · Stimulation of thorax wall

· Sleep

· Stress

LESION OF THE

HYPOTHALAMUS

OR PITUITARY

STALK

Tumors · Craniopharyngioma · Meningioma

· Dysgerminoma · Metastasis

· Empty Turkish saddle · Lymphocitary hypophysis

· Adenoma with stalk compression

· Granulomas

· Rathke’s cysts · Radiation

Traumatisms · Section of the

pituitary stalk· Suprasellar surgery

HYPOPHESEAL

HYPERSECRETION

· Prolactinoma · Acromegaly

SYSTEMIC

DISORDERS

· Chronic renal failure · Hypothyroidism

· Cirrhosis

· Comitial crisis

DRUGS

Dopamine receptor

antagonists

· Phenothiazines:

chlorpromazine· Butyrophenones:

haloperidol

· Thioxanthenes

· Metoclopramide

Dopamine synthesis

inhibitors

Methyldopa

Cathecolaminesdepletion

Reserpine

Opiates

H2 antagonists · Cimetidine

· Ranitidine

Imipramines Amitriptyline

Serotonin reuptake inhibitors

Calcium antagonists Verapamil

Estrogens and anti-androgens

Table 1. Etiology of hyperprolactinemia

Clinical presentation • Hyperprolactemia generates inhibion of hypothalamic release

of GnRH, with a decrease in LH and FSH (hypogonadotropic hypo-

gonadism), manifestng through sexual and reproductve functon

disorders.

• In premenopausal women: galactorrhea, anomalies in the men-

strual cycle, like oligomenorrhea, infertlity because of anovula-

tory cycles or menorrhea.

• In men: a decrease in libido, impotence and infertlity, as well as the

possible appearance of alteratons in the visual field (by chiasmatc

compression of a macroprolactnoma). In postmenopausal women

compressive symptoms are also predominant.

Diagnosis

• High prolactn baseline values.

Prolactn levels < 100 μg/L may be owing to microadenomas,

as well as lesions in the stalk and in the hypothalamus, and

to the remaining reasons for nonneoplastc hyperprolac-

tnemia.

Prolactn levels > 100 μg/L in the absence of pregnancy are very

likely to result from microprolactnoma.

Prolactn levels > 250 μg/L are virtually diagnostc of a PRL-pro-

ducing pituitary adenoma, usually a macroadenoma.

• Pituitary MRN to assess the existence of a lesion at that level.

Prolactnomas (much in the same way as other pituitary adeno-

mas) are classified into microadenomas (lesser than 1 cm) and

macroadenomas (greater than 1 cm).

Treatment

• Treatment indicatons for prolactnomas are stated in Table 2.

• Pharmacologic treatment is the treatment of choice: dopaminer-gic agonists (the most utlized are cabergoline, bromocriptne).

• Surgical treatment is reserved for patents with persistent visual

defects despite dopaminergic agonist treatment and for those

patents who do not tolerate dopaminergic agonists. Decompres-

sive surgery may also be necessary in tumors with a significant

cystc or hemorrhagic component to relieve visual symptoms and

headache.

PROLACTINOMAS: TREATMENT INDICATIONS

· Microprolactinomas. In the following cases:

- Women: desire for pregnancy, severe hypogonadism with highrisk of osteoporosis, bothersome galactorrhea, decrease in libido

- Men: decrease in libido or sexual potency, sterility

· Macroprolactinomas. They are always treated

Table 2. Indications for treatment of prolactinomas

1.4. Diabetes Insipidus

• Inability to generate concentrated urine because of the absence of

(partal or complete antdiuretc hormone secreton) or a defect in

its acton 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, infiltratve illnesses, cranio-cephalic traumatsms,

posterior to surgery or pituitary radiotherapy. Also necrosis

of vascular origin, infectons, alcohol, chlorpromazine and

phenytoin.

Nephrogenic ID: lack of ADH renal response. The most usual

reasons are hypercalciuria, lithium administraton, hypopotas-

semia and tubulointersttal nephropathy. Other related drugs

are demeclocycline, methoxyflurane, foscarnet, cidofovir, am-

photericin B, didanosine, ifosfamide, ofloxacin, orlistat and V2

receptor antagonists (vaptans).

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• Symptoms: Persistent polyuria (> 3 L/day in adults, > 2 L/day in

children) of hypotonic urine (low density < 1.010, generally di-

minished osmolality < 300 mOsm/kg) and polydipsia contnual

thirst.

• Sudden onset of symptoms, above all, in central DI.

• Normal functon of the thirst center enables polydipsia to adjust

to polyuria and avoid dehydraton, so most cases are normona-

tremic.

• When water access is not available (i.e., seniors, the insttutonal-

ized), significant dehydraton and hypernatremia, with alteraton of

the level of consciousness, comital crisis and even coma.

Diagnosis

• Dehydraon test or thirst test (Miller test): simple and reliable form

for the diagnosis of diabetes insipidus and distnguish ADH defi-

ciency from other polyuric syndromes. The test involves comparing

urine osmolarity afer deprivaton of water and the osmolarity ob-

tained afer DDAVP (ADH synthetc analog). In ID (both central and nephrogenic) hypotonic polyuria persists

afer dehydraton, while in primary polydipsia urine becomes

concentrated.

• Response to DDAVP administraon:

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 patent presents analytc alteratons compatble with dehy-

draton (elevated plasma osmolarity > 295 mOsm/L, hypernatre-

mia) the dehydraton test is not necessary (it can even be danger-

ous). The next step will be direct administraton of DDAVP.

• Brain MRN in central ID to rule out hypothalamic or pituitary le-sions.

Treatment

• Central ID: hormonal substtuton with DDAVP. If certain ADH re-

serve is conserved (partal CID) the response may involve carbam-

azepine, clofibrate and chlorpropamide.

• Nephrogenic ID: salt and water restricton, administraton of diuret-

ics that increase natriuresis, (thiazides). NSAIDs can be adminis-

tered as coadjuvant (indomethacin).

1.5. Syndrome of InadequateSecretion of Vasopressin

SIADH

• Hyponatremia secondary to free water retenton due to inappro-

priately high ADH secreton, in relaton to plasma osmolarity and

independent, at least partally, of osmotc control.

• The origin of this ADH can be the neurohypophysis, neoplas-

tc tssues or inflammatory tssues. SIADH causes are listed in

Table 3.

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, clobrate,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 presentaton depends, in general, on how fast plasma so-

dium levels go down.

• If hyponatremia is severe (< 125 mEq/L) or of an acute onset, thefollowing symptoms become predominant: brain edema cerebral,

like agitaton, irritability, confusion, coma and convulsions, together

with unspecific changes in EEG.

• If hyponatremia is mild (130-135 mEq/L) or of progressive devel-

opment, symptoms are more unspecific, for example, anorexia,

nausea and vomitng, headache, sensaton of instability.

Diagnosis

• Suspicion must be maintained on every patent with hyponatre-

mia (< 135 mmol/L), plasma hypoosmolality (< 275 mOsm/kg) and

without maximum urine diluon (> 100 mOsm/kg), but without

edemas, orthostatc hypotension, dehydraton signs, or thyroid or

adrenal hypofuncon (Table 4).• Other findings are detecton of low levels of ureic nitrogen, creat-

nine, ureic acid (< 4 mg/dL) and albumin in the presence of normal

renal functon 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

Identfy and correctly treat the triggering underlying cause whenever

possible.

• If there is acute hyponatremia with CNS alteraton, comital cri-

sis, subarachnoid hemorrhage or severe hyponatremia (< 125

mEq/L):

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Careful and progressive correcton with hypertonic saline serum

(correct Na+ 1-2 mEq/L/h in symptomatc patents 0.3 mmol/L/h

in asymptomatc suff erers 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 pontne myelinolysis (locked-in

syndrome).

• If there is chronic hyponatremia, the patent is asymptomac and

sodium levels are over 125 mEq/L:

Hydric restricton.

Salt contributon and low doses of furosemide.

Lithium or demeclocycline.

Vasopressin receptor antagonists (vaptans). Indicated in case of

SIADH of any etology refractory to other therapies.

Chapter 02

Thyroid Pathology

2.1. Thyroid Function Test

• Determinaon of thyroid smulang hormone (TSH): the best test

for the screening of thyroid pathology and assessment of its func-

ton. 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).

• Determinaon of total T4: it is not useful for the study of thyroid

pathology, as T4 circulates in plasma and it is almost completelybound to its carrier protein (TBG). T4 values can be altered by this

protein variaton.

• Determinaon of free T4: of choice afer TSH determinaton, for the

screening of thyroid pathology. See Table 5 for interpretaton.

• 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 etologic diff erental diagnosis of hyperthyroidism.

PRIMARY

hypothyroidism

CENTRAL

hypothyroidism

PRIMARY

hyperthyroidism

CENTRAL

hyperthyroidism

TSH N or

T4L

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

2.2. Hyperthyroidism

• Hyperthyroidism is the clinical and analytc situaton that results

from the eff ect of excessive amounts of thyroid hormones circulat-

ing throughout body tssues and it is present with high values of T3

and T4.

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

adults. It has an autoimmune origin (presence of thyroid stmulat-

ing antbodies or TSI or TSH-R-Ab) that exists in associaton with:

hyperthyroidism, diff use goiter and extrathyroidal signs (ophthalmic

and derma signs). Not all characteristcs are necessary for diagnosis.

In a gammagraphy, Graves disease reveals a generalized increased

uptake.

• Toxic mulnodular goiter (TMG) or hyperfunctoning is the most

usual reason for hyperthyroidism in the elderly. Thyroid gammag-

raphy reveals a multnodular gland with several hyperfunctoning

nodules that alternate with other normofunctoning or hypofunc-

toning nodules.

• The toxic adenoma is observed in the gammagraphy as a single nod-

ule, which intensely concentrates the radiotracer and with almost

total suppression of the rest of the gland.

• (Postpartum, subacute) thyroidis may appear with an inital phase

of hyperthyroidism as a result of inflammaton and release of the

preformed hormone. Thyroid gammagraphy shows an abolished or

“white” gland.

Clinical presentation • Symptoms: plethoric aspect with nervousness, weakness, emoton-

al lability, decreases in performance, excessive sweatng and heat

intolerance. There are also increased intestnal transit, increased

appette with paradoxic weight loss, pruritus and alteratons in the

menstrual cycle (oligomenorrhea).

• Signs: wet skin, goiter that is diff use and spongy in GD (it is irregular

with a nodular surface in the SMB), arrhythmias (sinusoidal tachy-

cardia, atrial fibrillaton), distal tremor, acropachy, alopecia, palpe-

bral retracton, proximal myopathy, myoclonias and hyperreflexia.

Exophthalmoses, pretbial myxedema and thyroidal murmur can be

appreciated in Graves disease.

• “Apathec hyperthyroidism”: in advanced age, it can manifest

through weight loss, muscular weakness, depression, mental slow-ness, apathy and arrhythmias or heart failure.

Diagnosis

• Determinaon of TSH: it is the most useful isolated inital determi-

naton for diagnosis. TSH may be diminished or suppressed in pri-

mary hyperthyroidism.

• Determinaon of free T4: it is high in clinical hypothyroidism. It may

be normal in subclinical hyperthyroidism (with low TSH).

• Determinaon of free T3: it is indicated if TSH is low and T4 is nor-

mal.

• For the eologic diagnosis, elaboratng a detailed clinical record

and determining -according to clinical suspicion- of antthyroid an-tbodies (including TSI) +/- thyroid gammagraphy enables classifica-

ton of most cases of hyperthyroidism.

Treatment

• Symptomac: propranolol for the control of adrenergic symptoms.

• Anthyroid drugs (methimazole or propylthiouracil) in GD. They can

also be utlized in MTG.

• Definite treatment: radioactve iodine (I-131) is of choice in the USA

for the treatment of GD. Thyroidectomy can also be performed, es-

pecially in the presence of large goiters, failure or intolerance to

prior treatments.

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Complications

• Thyroid storm: emergency situaton and of increased mortality

(20% to 30%) characterized by irritability, delirium or coma, fever,

tachycardia, hypotension, vomitng and diarrhea. It requires emer-

gency treatment with i.v. propranolol, propylthiouracil and cort-

coids. Iodine or iodine contrasts can also be used.

2.3. Hypothyroidism

• Situaton that results from the lack of thyroid hormone eff ect on

body ssues and presents with low levels of free T3 and T4. Pri-

mary thyroid causes consttute 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 etology (Hashimoto’s thyroidis) is the most com-

mon reason in developed countries. Hashimoto’s thyroidits pres-

ents with positve antthyroglobulin and antmycrosomal (antTPO)which precipitate thyroid destructon.

• There is also another important factor: postablave hypothyroid-

ism (radioiodine or surgery) or afer administraton of I-131 as a

treatment for hyperthyroidism.

• Other types of thyroidis -subacute and postpartum) usually ap-

pear with a hypothyroidism phase afer an inital phase of hypothy-

roidism. Hypothyroidism can be permanent.

• Other less frequent causes are external cervical irradiaton, drugs

like lithium, amiodarone or tyrosine kinase inhibitors (that work

as an oncologic treatment), infiltratve diseases, granulomatous

or metastatc thyroidits, and congenital alteratons in thyroid hor-

mone synthesis and thyroid agenesis.

Clinical Presentation

(Figure 2)

• Unspecific inital symptoms with progressive appearance: fatgue,

lethargy, constpaton, cold intolerance, rigidity and muscle con-

tracture, carpal tunnel syndrome and menstrual cycle disorders.

Progressive deterioraton of intellectual and motor actvites, for

example, dementa and abnormal involuntary movements, loss of

appette 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 relaxaton

phase of osteotendinous reflexes. Bradichardia and pericardial fluid

accumulaton (even obstructon of pericardial drainage). Adynamic

ileum, megacolon and intestnal obstructon.• Determining TSH: it is the most useful isolated inital determinaton

for diagnosis. THS is increased in primary hypothyroidism and it is

low or inappropriately normal in central hypothyroidism.

• Determinaon of free T4: it is low in clinical hypothyroidism. It may

be normal in subclinical hypothyroidism with a high TSH).

• For the eologic diagnosis, drawing up a detailed clinical record and

determining antthyroid antbodies enables classificaton of most

cases of hypothyroidism.

Treatment

• Hormonal replacement with levothyroxine (L-T4).

Alopecia

Macroglossia

Intolerance

to cold temperatures

Carpal

tunnel syndrome

Metrorrhagia

Coarse, dryand yellow skin

BradypsychiaMemory loss

Palpebral edema

CardiomegalyPericardial effusion

Constipation

Weakness,spasticity

Slowed Achillesreex

Weight gain

Figure 2. Clinical presentation of hypothyroidism

Complications

• Myxedematous coma: severe complicaton 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 patent with untreated -or poorly treated-hypothyroidism. It can also appear in a hypothyroid suff erer under

treatment, who abruptly suspends medicaton. Mortality ranges

from 30% to 60%. It requires immediate treatment with intravenous

L-T4 together with hydrocortsone administraton -so that an adre-

nal crisis will not be triggered- untl a normal pituitary-adrenal axis

actvity is achieved.

2.4. Thyroiditis

• A set of heterogeneous eology processes and several clinical charac-teriscs that appear with thyroid inflammaton. The most common

types of thyroidis are (granulomatous subacute and viral thyroidis or

Quervain’s) thyroidis; autoimmune or Hashimoto’s thyroidis; post-

partum thyroidis postradiaon and amiodarone-induced thyroidis.


• Viral subacute (Quervain’s) thyroidits presents with a painful goiter,

general discomfort and concomitant -or recent- upper respiratory

tract infecton.

• The remaining types of thyroidits appear together with a painful

goiter.

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Endocrinology

Diagnosis

• Thyroidits usually comprises two phases: 1) thyrotoxicosis followed

by 2) hypothyroidism, hence, the thyroid functon test varies ac-

cording to the phase in which diagnosis is made.

• Thyroid gammagraphy: presents with generalized hypocapta-

ton of the gland, by inflammaton during the hyperthyroidism

phase.

Treatment

• Symptomac: β-blockers in the hyperthyroidism phase. In milder

cases of Quervain’s thyroidits, symptoms are usually controlled

with ASA. More severe cases require cortcosteroids.

• If hypothyroidism: levothyroxine should be given, although this

phase may be temporary and not permanent.

• The use of anthyroid drugs is not indicated.

2.5.Thyroid Noduleand Thyroid Cancer

• The incidence of thyroid carcinoma in the populaton represents

only a fracton of patents that have thyroid nodules. In single nod-

ules, thyroid carcinoma incidence is approximately 5%; multnodular

goiters, thyroid cancer incidence are also 5% per individual nodule.


• They are usually asymptomac at the tme of diagnosis. They are in-

cidentally found through imaging tests, i.e., a CTA scan of the cervical-

thoracic region, a carotd Doppler ultrasound test) or thyroid palpaton.

• Hyperfunconing nodules are present with signs and symptoms of

hyperthyroidism.

• Large nodules and, especially, those adjacent to the trachea/esopha-

gus, can produce compressive symptoms (dysphagia, dyspnea and

cough).

• Clinical findings that suggest malignancy are: rapid growth of the le-

sion, fixaon to adjacent structures, vocal cords paralysis, Horner’s

syndrome, present adenopathies, and a history of radiaon in child-

hood, size > 4 cm, and family record of medullary thyroid cancer (MTC).

• Cervical examinaton will enable nodule localizaton and a descripton

of the nodule’s characteristcs: stony consistency, painless, aached

to superficial and/or deep planes, as well as the presence of cervical

anterior lymphoadenopathies, all signs suggestve of malignancy).

Diagnosis (Table 6)

• TSH determinaon: to rule out thyroid hyper or hypofuncton. Hy-

perfunctoning nodules are seldom malignant (< 1%).

• Thyroid ultrasound study: it makes it possible to assess the nod-

ule features as well as the remainder of the gland and the pres-

ence or absence of pathologic cervical ganglia. The presence of

microcalcificatons, hypoechogenicity, and the presence of an irregu-

lar rim and an increased intranodal vascularizaton are all ultrasound

signs of malignancy.

PAPILLARY FOLLICULAR MEDULLARY ANAPLASTIC LYMPHOMA

Epidemiology · Bimodal distribution:

2.nd and 3.rd decade/

middle age

· 70% follicularepithelium tumors

· Relation

to radiationin childhood

· Advanced age

· 15% to 20%

tumors of follicular

epithelium

Four ways:

· Sporadic (80%)

· MEN 2A

· MEN 2B · Familial no MEN

6.th, 7.th decades

· 5% follicular

epithelium tumors

· Women 55-75 years

of age

· 5% of all thyroid

tumors · Relation

to Hashimoto’s

thyroiditisand positive

antiperoxidase

antibodies

Derived from

follicular epithelium

Yes Yes No Yes No

Pathologic

anatomy

· Papillae with follicular

elements and cells

· “Sand-grain sized”calcications or

psammoma bodies

(typical, but rare)

Capsular and/or

capsule invasion is

what differentiates itfrom benign follicular

adenoma

· Cell C accumulation

with amyloid

substance · Multicentric

in familial forms

· Gigantic

and fusiform cells

· Hard to differentiatefrom lymphomas

or sarcomas

Diffuse β lymphoma

with large cells

Growth,

dissemination

and metastasis

Slow growth with

neighboring structures

invasion and lymphaticdissemination

Slow growth, but early

hematic dissemination,

with lung, bone andCNS metastasis

Calcied adenopathies

and metastasis to CNS

and bone

Rapid growth with

huge local invasion

ulcerating skin

-

Marker Thyroglobulin Thyroglobulin Calcitonin/ACE - -

I-131 Yes Yes No No No

Prognosis The best Hürthle subtype: worse

clinical course

Bad The worst (months

survival)

Variable

Table 6. Malignant tumors of the thyroid

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• These tumors are commonly associated with multple endocrine

neoplasias (MEN) 2A and 2B.


• Hypertension is the most frequent manifestaton. It is usually kept

in 60% of the cases. Hypertension is sometmes malignant and it is

resistant to conventonal treatment in almost every case.

• Paroxysms or hypertensive crises are characterized by a significant

increase in blood pressure accompanied by headache, profuse sweat-

ing, palpitaons, anguish, and imminent sensaon of death, paleness,

thoracic and abdominal pain, accompanied by nausea and voming.

• Paroxysms are triggered by postural changes, psychological stress,

physical exercises, Valsalva’s maneuver, some food and drugs; anes-

thesia and surgery. However, the triggering factor cannot be idenfied

on some occasions.

Diagnosis

• An increase in free catecholamines and/or metabolites (meta-

nephrines) in 24-hour urine or plasma. • CT and abdominal MRl are the imaging techniques most commonly

utlized to localize the tumor.

• Gammagraphy with MIBG (meta-iodobenzylguanidin), is the most

effi cient method to detect extra-adrenal pheochromocytoma (either

primary or metastac). Cytology of pheochromocytomas is contra-

indicated.

Treatment

• The treatment of choice is laparoscopic pheochromocytoma re-

secton. Surgery should be conducted in a specialized center, once

proper preoperave preparaon has taken place. Pre-op treatment

consists of:

α blockade with phenoxybenzamine at least 10-14 days beforesurgery.

β blockade if necessary with propranolol (to prevent tachycardias).

Preoperave volume load with salt, to prevent rebound hypo-

tension in the immediate postoperatve period.

• It is very important to be reminded that β-blockers are never to be

administered untl α blockade has been established, as a hyperten-

sive crisis would be triggered.

• In the event of a hypertensive crisis before the patent is fully estab-

lished on an α blockade therapy, i.v. phentolamine or nitroprussiate.

• When a pheochromocytoma is malignant and unresectable, medi-

cal treatment with α blockers is carried out. There is also chemo-

therapy administraton with the use of cyclophosphamide, vincris-tne and dacarbazine. MIBG administraton can be used if there is

positve tumor uptake, in repettve doses.

3.3. Primary

Hyperaldosteronism PHA

PHA occurs because of autonomous secreon of aldosterone through the

glomerulus zone of the adrenal gland. A 60% originates in an aldosterone-

secreng adrenal adenoma (Conn’s syndrome). PHA can also result from

adrenal bilateral micronodular or macronodular hyperplasia, unilateral

adrenal hyperplasia or familial etology, like glucocortcoid-remediable

PHA. An aldosterone-secretng adrenal carcinoma is very rare.


• HBP is the predominant and universal finding, with diastolic values

over 110 mmHg. There is greater prevalence of aff ectaton of target

organs (hypertensive retnopathy, cardiopathy and nephropathy) in

these kinds of patents.

• Because of increased renal excreton of potassium, hypopotasse-

mia occurs, which if marked, is present along with muscle weak-

ness, fatgue, 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 patents who have their

debut with HBP without risk factors or a family history (see Table 7

for screening indicatons for PHA).

PHA: INDICATIONS FOR EARLY DETECTION

· Moderate/severe HBP (SBP ≥ 160 and/or DBP ≥ 100 mmHg)

· Hypertension resistant to pharmacologic treatment (SBP > 140or 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 analycs: hypopotassemia, mild hypernatremia, metabolic

alkalosis, hypomagnesaemia.

• PHA screening: determinaton of baseline aldosterone (it must be

increased, > 15 ng/dL) and aldosterone/acvity quoent 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 inhibiton causes -in

healthy people- a decrease in aldosterone, which does not occur in

primary hyperaldosteronism).

• Etologic diagnostc takes place afer biochemical diagnosis: abdom-

inal CT. Catheterism of adrenal veins is reserved (as it is invasive)

for lesions < 1 cm (or with a negatve CT) in individuals > 40 years ofage, in which the prevalence of nonfunctoning adrenal adenomas

is very high.

Treatment

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

laparoscopic extrpaton.

• PHA by bilateral hyperplasia is addressed with spironolactone (aldo-

sterone- receptor antagonist) or other potassium-sparing diuretcs,

like, triamterene or amiloride.

• PHA sensitve to glucocortcoids can be treated with small doses of

cortcosteroids or with potassium-sparing diuretcs.

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0

3.4. Congenital AdrenalHyperplasia CAH

• It consists of a group of adrenal steroidogenesis disorders stemming

from a hereditary deficiency of one of the enzymes of steroid bio-

synthesis, with subsequent “accumulaton” of cortsol precursors

prior to enzyme deficiency.

• Congenital Adrenal Hyperplasia (CHA) is the most frequent adrenal

disorder in childhood and it can be accompanied by severe deficien-

cies that endangers the life of a newborn, while partal defects are

manifested afer adolescence by hirsutsm and virilizaton in wom-

en.

• The most common form of CHA is 21-hydroxylase deficiency

(autosomal recessive heritage in 95% of cases), whose clinical

presentaton, diagnosis and treatment will be discussed below:


• Classic form: it presents with ambiguous genitalia in girls and

precocious puberty in children. In 80% of the cases it is associ-ated with a salt-wastng syndrome due to mineralocortcoids and

cortsol.

• Nonclassic form: hyperandrogenism, oligomenorrhea and subfertl-

ity in adolescents and grown women. It is very similar to polycystc

ovary syndrome.

Diagnosis

• Diagnosis is confirmed by an increase in baseline 17-hydroxiproges-

terone baseline and afer ACTH smulaon.

Treatment

• In the case of salt-wastng syndrome: repositon of salt and vol-ume; glucocortcoid administraton. If later, 21-hidroxilase syn-

drome becomes severe, mineralocortcoid replacement must be

administered.

• Surgical correcton of ambiguous genitalia in girls.

• The treatment and management of CAH will be discussed further on

in the Gynecology secton.

Chapter 04

Alteration in

Hydrocarbonate

Metabolism (Table 8)

Diabetes mellitus (DM) is a set of heterogeneous syndromes of mult-

factorial etopathogenesis, whose common nexus is chronic hyperglyce-

mia. Chronic macrovascular and microvascular complicatons develop

along the course of the disease.

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 nding

Treatment Always insulin Diet, oral antidiabeticdrugs or insulin

Tendency to

ketosis

Yes No

Heritage Predisposition to HLA Concordance > 90%

of identical twins

Autoimmunity

against β cell

Yes No

Insulin resistance No Yes

Table 8. Differences between DM type 1 and 2

4.1. Type 1 Diabetes Mellitus

• It consttutes 5% to 10% of the total cases of DM.

• Result of the deficiency (usually absolute) in insulin secreton be-

cause of cell β cell destructon of the pancreas.


• Type 1 DM typically aff ects children and adolescents with normal

weight.

• Cardinal manifestaons: polyuria, polydipsia, polyphagia and weight

loss, whose appearance is usually rapid and of short evoluton.

• These patents need insulin administraton to prevent the appear-ance of ketoacidosis. Type 1 DB is subdivided into 1A (positve auto-

immunity) and 1B or idiopathic.

• Genetc predispositon associated with HLA-DR3 and DR-4.

Diagnosis

• Diagnostc 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 + compatble symptoms with DM >

200 mg/dL.

• Presence of anbodies pancreatc ant-islets, ant-IA2 (associated

protein with insulinoma 2), ant-GAD (descarboxylase of glutamic

acid) and ant-ZnT8 (zinc channel): The first three are more fre-

quently positve in people with DM1.

Treatment

• Insulin therapy in intensive paern (subcutaneous, bolus-baseline

paern or pump subcutaneous insulin infusion), simulatng physi-

ologic secreton of the pancreas: baseline insulin and insulin before

each meal (Figure 3).

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2

• Type 2 DM suff erers may develop hyperosmolar nonketoc hyper-

glycemia in cases of metabolic control, infectons or severe intercur-

rent pathology. Some patents may have their debut with this disease.

Diagnosis

• The same criteria as for diagnosis of DM1.

• Negave anbodies (although they are routnely requested).

• DM2 screening in the general populaton:

Every three years, asymptomatc people aged ≥ 45, and regard-

less of age in case of patents with overweight or obesity (BMI

≥ 25 kg/m2) and some other risk factor for DM type 2 develop-

ment (see Table 11).

1. Age ≥ 45

2. Regardless of age in individual with BMI ≥ 25 kg/m2 and someadditional 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 Pacic 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 mellitusin asymptomatic adult patients (ADA, 2010)

Treatment

• Monitoring goals are the same as for Type 1 DM patents (see Table

11); given that the hypoglycemia risk factor is not high, especially in

elderly patents.

• Blood pressure should be controlled (objectve: < 140/ < 80 mmHg),

renal functon, lipid profile and early detecon of comorbilies

(microalbuminuria for diabetc nephropathy, examinaton of the

patent’s retna, by means of fundoscopy or nonmydriatc retnogra-

phy, complete neurologic examinaton , etc).

• Met ormin treatment may be commenced in a preventve man-

ner in paents with prediabetes (glycemia on an empty stom-

ach > 100 mg/dL, but < 126 mg/dL and/or afer 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, hypertriglycer-idemia, a history of DM in first degree relaves 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.

• Weight loss:

Goal: lose 5% to 10% of inital 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

• An-aggregaon:

Primary preventon: men > 50 years of age or women > 10 years

afer menopause (in general > 60) with some major cardiovas-

cular risk factor (family history of cardiovascular disease, hyper-

tension, dysplemia, smoking or albuminuria) or those patents

at risk of having a cardiovascular event, in ten years is higherthan 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)

• Diabec Ketoacidosis:

Typical, although not exclusive of DM type 1. It occurs because

of insulin deficiency and an increase in contrainsular hormones,

mainly glucagon. First manifestaton of DM type 1 in 25% to 30%

of cases. In known diabetc patents, precipitatng reasons are

usually abandonment of insulin treatment, dietary transgres-sions, infectons (30% to 40% of the cases), traumas, surgery,

gestaton, and endocrinopathies, like Cushing’s syndrome or

Graves-Basedow disease among others.

Clinical presentaton: nausea, vomitng and abdominal pain,

together with diabetc cardinal symptomatology. If not treat-

ed precociously, obnubilaton and coma will develop. During

physical examinaton, outstanding manifestatons are tachy-

pnea, Kussmaul respiraton and dehydraton signs, like dry

mucosa, hypotension and a decrease in ocular globe pres-

sure. Prerenal and renal failure may occur because of dehy-

draton.

Diagnosis: Hyperglycemia + metabolic acidosis with increased

anion gap, presence of increased ketonic bodies in blood andurine.

Treatment with intravenous insulinotherapy, serum therapy, in-

travenous potassium administraton, bicarbonate (if pH < 7) and

treatment of triggering cause.

• Hyperosmolar nonketoc hyperglycemia:

Typical, but not exclusive of DM type 2.

Insuffi cient response of insulin acton because of insulin resis-

tance, unable to counteract the increase in contrarregulatory

hormones caused by triggering stressing factors. Residual insulin

secreton is capable of minimizing or impedes ketosis, but not

preventng hyperglycemia.

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SULPHONYLUREAS MEGLITINIDES BIGUANIDESGLUCOSIDASE

INHIBITORSTIAZOLIDINEDIONES

IV-DPP

INHIBITORS

ANALOGOUS

OF GLP-1

Active

substance

· Glibenclamide

· Glipizide · Gliclazide

· Gliquidone

· Glimepiride

· Repaglinide

· Nateglinide

Metformin · Acarbose

· Miglitol

· Pioglitazone

· Rosiglitazone

· Sitagliptin

· Vildagliptin · Saxagliptin

· Exenatide

· Liraglutide

Mechanism

of action

Insulin secretion

stimulus insustained way

through bond to β

cell receptor

Insulin

secretionstimulus in

acute way

throughbond to β cell

receptor

Liver

resistanceto insulin

decreases

Transient

inhibitionof intestinal

α-glucosidase

They decrease

peripheral resistance(muscle and adipose

tissue) to insulin by

means of bond toPPAR-γ

They increase

endogenousGLP-1 half like

dipeptidyl

peptidase IV

Similar effect

to endogenousGLP-1

(increase in

insulin secretionmediated through

intake , slowing

gastric emptying)resistant to DPP IV

Side effects Severe and

sustained

hypoglycemia

Hypoglycemia

(infrequent)

· GI

discomfort

(the mostfrequent)

· Lactic

acidosis

(the mostsevere, but

rare)

GI discomfort · Hepatotoxicity

· Hydric retention

· Heart failure · Osteoporosis

in women

· Increase in

transaminase

(vildagliptin) · Discrete

increase in

respiratory

and urinarytract

infections

· Nausea

and vomiting

(frequent) · Pancreatitis

(very rare)

· Deterioration of

renal function

Contraindications · Pregnancy · Hepatopathy · RI

· Pregnancy · Liver disease · Severe RI

Situationspredisposingto lacticacidosis

Pregnantwomen andchildren

· Hepatopathy · Heart failure · Rosiglitazone

withdrawn inEurope due toan increase incoronary events

Pregnantwomenand children

Use not approvedalong with insulin

Use Secondtherapeutic stepin type 2 DM withpancreatic reserve

· Postprandialglycemiacontrol

· Elderlypeople with

some degreeof declinein renalfunction

First choicein type 2 DM

· Scarcelyeffective

· Control ofpospandrialhyperglycemia

Associated withmetformin orin case of itscontraindicationmild-moderate RI

· 2.nd therapeuticstep in type2 DM

· Sitagliptin

approved inmonotherapyand incombinationwith insulin

· Obesitytogether with

metformin

· Its use alsoapproved with

sulfonylureas

(increased risk

of hypoglycemiaand less weight

loss)

Table 12. Characteristics of oral antidiabetic drugs and noninsulin therapies in type 2 diabetes mellitus

PREVENTION (early phases) SYMPTOMATIC TREATMENT (advanced phases)

Diabetic retinopathy Strict glycemic control Photocoagulation

Diabetic

nephropathy

· 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

Dialysis or kidney transplant

Neuropathy

and diabetic foot

· Strict glycemic control and foot care

· Smoking cessation

NEUROPATHY

· Pain: opiates, tricyclics, anticonvulsants, duloxetine and capsaicin · Orthostatic hypotension: postural measures, fludrocortisone

· Diarrhea: loperamide

· Gastroparesis: prokinetics and erythromycin

ULCERS

Debridement, rest, antibiotics and revascularization

Macroangiopathy · Strict HBC control

· Smoking cessation

· Antiplatelet therapy

· Lipid-lowering therapy

Arterial revascularization techniques

Table 13. Prevention and treatment of chronic complications in DM

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4

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

cases; underlying infecton process and general deterioraton of

the patent are also contributng factors.

Triggering factors: infecton (in approximately 60% of the cases),

leaving therapy or inadequate treatment. A 20% of the individu-

als suff ering from Hyperosmolar hyperglycemic state (HHS) have

not been previously diagnosed with DM.

Clinical presentaon: severe dehydraon. Alteraon of the level of

consciousness, from stupor up to coma (hyperosmolar coma). Neuro-

logic manifestaons (as convulsions or transient hemiplegia), as well

as microthrombosis and disseminated vascular coagulaon may oc-

cur.

Diagnosis: glycemia > 600 mg/dL, negave –or mildly posive- keton-

ic bodies can be traced in urine or serum, BP > 7.30, eff ecve serum

osmolality > 320 mOsm/kg and plasma bicarbonate (> 18 mEq/L).

Treatment: aggressive serum therapy, electrolytc replacement

and insulin therapy, as well as treatment of the triggering factor.

Complications of Insulin Treatment

• Somogyi phenomena: an increase in fastng glycemia because of anincrease in contrarregulatory cell in response to nocturnal hypogly-

cemia. Treatment involves reducing insulin dose to prevent noctur-

nal hypoglycemia.

• Dawn phenomenon. An increase in plasma glucose. Plasma glucose

increase in the first hours in the morning, in relaon to GH nocturnal

or circadian rhythm of corsol. Disncon from Somogyi phenom-

enon 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

• Associaon of several cardiovascular risk factors, including abdom-

inal obesity, dyslipemia, hypertension and glucose alteraton, which

can coexist in the same aff ected person.

• Also called X syndrome, it has as a main pathophysiologic substrate

insulin resistance. There are many definitons of the metabolic syn-

drome (MS).

Diagnosis

Diagnosis criteria of ATP-III (2004) are as follow:

• Abdominal circumference: > 102 cm (> 40 inches) in men and > 88cm (> 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 anthypertensive med-

icaton.

• Fastng 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 comorbilites (HBP and dyslipidemia).

• For patents at high risk of developing DM type 2, start with met or-

min can be assessed.

Chapter 05

Bone Pathology

and Phosphocalcic

Metabolism

5.1. Osteoporosis

• Loss of bone mass equal to or higher than 2.5 SD (standard devia-ton) 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, hypercorsolism and hypogonadism. Other accom-

panying illnesses are also rheumatoid arthris, systemic mastocytosis,

mulple myeloma and chronic treatment with corcoids among others.


• It is an asymptomac disease untl fracture appears; backbone frac-

ture is the most common.

• Fractures in vertebral bodies and forearm distal radius (de Collesfracture) are frequent complicaton.

• Vertebral bone fracture causes back pain, of acute onset with fre-

quent irradiaton toward the abdomen and backbone deformity. It

usually occurs afer sudden flexions, but sometmes there is a trig-

gering 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 (30-

35 years of age) of the same sex.

• Rule out secondary causes: full biochemical lab test that includesCa, P, TSH, PTH, 25(OH) vitamin D, 24-hour excreted calciuria, tes-

tosterone (men), serum proteinogram and screening of Cushing’s

syndrome if clinical presentaton is suggestve.

• Convenonal bone x-ray: it is lile sensitve for osteopenia diagno-

sis, as a loss greater than 30% of bone mass is needed to be radio-

logically detected.

Treatment

• Change in life style: do exercise. Abstnence of smoking habit.

• Calcium and vitamin D: this recommendaton applies for all patents

diagnosed with osteoporosis, regardless they receive additonal

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Endocrinology

pharmacological treatment or not. Calcium and vitamin D favor a

reducton of fracture rates, hip fracture included.

• Biphosphonates: alendronate, risedronate, zoledronate, ibandro-

nate are all potent inhibitors of bone resorpton. They decrease ver-

tebral fractures and femur neck fracture.

• Selecve estrogen response modifiers or SERMs -raloxifene and

tamoxifen. They reduce replacement and loss of bone mass; dimin-

ishing the incidence of vertebral fractures, without having proven

their eff ect on the preventon of femoral neck fractures.

• Denosumab, monoclonal antbody with a high affi nity for RANKL. In

postmenopausic women, significantly reduce the risk for vertebral,

nonvertebral and hip fracture.

5.2. Paget’s Disease

The second most frequent osteopathy in developed countries.

• Characterized by an increase in bone resorpton, followed by a com-

pensatory increase in synthesis (bone replacement can be up to 20tmes 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 infecon could be the origin of Pag-

et’s disease in genetcally predisposed individuals.

• Primary bone pain is the more habitual clinical manifestaton.

• Other manifestatons are the gradual appearance of deformaons

or swelling in the limbs, problems with gait because of the diff er-

ence in limb length, headache and facial pain, backbone lower

extremites pain, hearing loss owing to direct aff ectaton 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 complicatons occur because of bonegrowth in the base of the cranium, which can compress the medulla

and can cause tetraplegia.

Diagnosis

• Biochemical: alkaline phosphatase is a good test choice for early

detecton and treatment response. Other parameters also help es-

tablish a diagnosis, i.e., an increase in other parameters of bone

formaton (osteocalcin, procollagene) and bone resorpton (hy-

droxyproline, acid phosphatase, pyridinoline, deoxypyridinoline and

peptde).

• Convenonal bone x-ray: characteristc radiologic alteratons, like

an increase in bone size, cortcal thickening and alteratons in thetrabecular paern, coexistence of lytc and blastc areas, fractures,

“vertebras with rim-like appearance” and circumscribed osteopo-

rosis.

• Bone gammagraphy: this enables checking the extent of the disease.

Treatment

• Asymptomac: they do not need treatment.

• Symptomac: (persistent pain, nerve compression, bone deformity

of rapid progression that results in gait diffi cultes, heart failure, hy-

percalcemia and hypercalciuria, bone fractures and reparaton for

orthopedic surgery). Biphosphonates is the treatment of choice.

Complications

• Increase in cardiac output: an increased blood flow in bone, with an

increase in the venous return network in aff ected areas, which may

give rise to heart failure in patents 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 hypercal-

cemia. There is also a greater incidence of hyperuricemia and gout.

• Sarcoma. Shown in 1% of the patents. Sarcoma is the most severe

complicaton 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 calciumand phosphorous metabolism. Hyperparathyroidism is defined as

elevated values of PTH in plasma, with diff erent eff ects on calcium

and phosphorous depending on the specific cause.

• Primary hyperparathyroidism: in 85% of cases, primary hyperthy-

roidism is caused by autonomous secreton by a single or multple

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.

• Terary hyperparathyroidism: the secondary increase in PTH over

tme in patents with chronic renal failure. In theory, it can lead to

hyperplasia of the parathyroid glands. Tertary hyperparathyroidismoccurs when one gland -or more- becomes autonomous (even re-

maining afer renal transplantaton).

PRIMARY

Hyperpara-

thyroidism

SECONDARY

Hyperpara-

thyroidism

TERTIARY

Hyperpara-

thyroidism

PTHi

Calcemia N or N or

Phosphatemia

Table 14. Differential diagnosis of hyperparathyroidism. Lab parameters(N: normal)

We will mainly discuss primary hyperparathyroidism:


• Most cases diagnosed are asymptomac and hypercalcemia is

found by chance.

• HBP is present in 50% to 70% of the patents. Peptc ulcer and gastri-

ts, acute pancreatts and cholelitasis are also present.

• Other manifestatons are: headache, asthenia, depression, anemia,

band keratopathy, constpaton, proximal muscle weakness, poly-

uria, gout, chondrocalcinosis, osteoporosis and increased cardio-

vascular risk, fatgue, depression and anxiety.

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

tumors” (accumulaton of multnuclear giant osteoclasts). Other

changes are generalized or circumscribed osteopenia (salt and pep-

per skull) and subperiosteal resorpton phenomena (radial zone of

the middle phalanx of fingers) or generalized (clavicle). Bone dis-

ease may be silent or cause local pain and even pathologic fractures.

• Renal aff ectaon. Nephrolithiasis and nephrocalcinosis.

Diagnosis

• General analycs: hypercalcemia, hypophosphatemia, metabolic

acidosis, hypercalciuria and diminished phosphate tubular resorp-

ton.

• High values of intact PTH (PTHi) in relaton to plasma calcemia. Some

patents show inappropriately normal values, but never low or sup-

pressed.

• Localizaon diagnosis: they should only be requested if surgical

treatment is indicated, but not forced.

Cervical ultrasound and gammagraphy with Tc-sestamibi: current-

ly, the combinaon of both techniques off er greater diagnosc

yield and enables the performance of a minimally invasive surgery.

• Complicaons of diagnosis: bone densitometry (DEXA scan) to rule

out osteopenia or osteoporosis, in lumbar spine, hip and distal ra-

dius. Renal ultrasound test.

Treatment

• Parathyroidectomy if the patent meets surgical criteria (Table

15). If there is a parathyroid adenoma, an adenomatous gland

is removed. If any of the following occurs: parathyroid hyper-

plasia, total parathyroidectomy with implant in forearm muscles

or sternocleidomastoid muscle or subtotal parathyroidectomy

(leave a porton of the last gland).

• In severe, symptomatc acute hypercalcemia, treatment involvesabundant hydraton, loop diuretcs and i.v. Biphosphonates.

• In asymptomac paents, secure effi cient hydraton.

• Cinacalcet, a calcimimetc, increases circulatng calcium affi nity

by its receptor resultng in a significant decrease in calcium and

PTH levels. Therefore, it is indicated in secondary hyperparathy-

roidism in CRD and in primary hyperparathyroidism suff erers un-

suitable for surgery because of accompanying comorbilites or in

those aff ected by the disease who refuse surgery.

• To prevent secondary hyperparathyroidism development in CRD

patents, oral phosphorus chelants must be administered, but

the patent’s diet intake needs to be restricted.

· 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 radiusand/or any prior fracture because of fragility

Any primary hyperparathyroidism that presents signs or symptoms

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

Table 15. Indications for surgery in asymptomatic primaryhyperparathyroidism (Workshop, 2008)

Chapter 06

Multiple Endocrine

Neoplasia (MEN)

• Neoplastc syndromes that aff ect multple endocrine organs and

that have hereditary etology (autosomal dominant).

• MEN 1 (Wermer’s syndrome) associaon of hyperparathyroidism (the

most frequent manifestaon, because of parathyroid hyperplasia), pi-

tuitary adenoma and cell tumors of pancreac islets. “The 3 Ps”: para-

thyroid, pancreas and pituitary. Mulple Endocrine Neoplasia (MEN)

(Table 16).

• MEN type 2A (Sipple’s syndrome) confluence of medullary thyroid

cancer (or MTC, the most common manifestaton), pheochromocy-

toma (bilaterality is more frequent than sporadic pheochromocy-

toma) and hyperparathyroidism (the most frequent form is hyper-

plasia as in MEN 1) (Table 17).

• MEN type 2B consists of (aggressive) MTC with the presence of mu-cosa neuromas (tp of the tongue, eyelids and digestve tract).

• When MTC and pheochromocytoma converge, pheochromocytoma

should be surgically treated first.

ENDOCRINE MANIFESTATIONSNONENDOCRINE

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)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

1. Facial angiobromas

(85%)2. Collagenomas (70%)

3. Lipomas (30%)

Table 16. Associations in MEN 1

SYNDROME CHARACTERISTICS

MEN 2A · Medullary thyroid carcinoma

· Pheochromocytoma (50%) · Hyperparathyroidism (10%)

· Lichenoid cutaneous amyloidosis

· Hirschprung’s disease

Familial medullary

thyroid carcinoma

· Medullary thyroid carcinoma

· It can be associated with Hirschprung’s disease

MEN 2B · Medullary thyroid carcinoma (more precociousand 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

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