Endocrinology Flashcards
srif(somatostatin from hypothalamus)
Negative to prolactin and TSH
GH on liver
Chondrocytes-linear and organ growth
IGF-1 negative on hypothalamus
Prolactin
Increase breast
TSH on thyroid
T4/T3
Pituitary adenoma
Benign monoclonal tumors that arise from one of five pituitary cell types
Nonfunctional pituitary adenoma
1/3 no clinical symptoms
Most common functional pituitary tumor
PRL
Genetics pituitary adenoma
MEN1, carney, mutant Arya hydrocarbon receptor inhibitor protein (AIP).
Mass effect symptoms
HA, visual loss through compression of the optic chiasm superiorly (bitemporal hemianopia)
Pituitary stalk compression
HyperPRL
Pituitary apoplexy
Hemorrhage into a preexisting adenoma or post partum as sheehans syndrome
HA< bitemporal changes, ophthalmoplegia, cardiovascular collapse, hypotension,
Hypotension, hypoglycemia, can hemorrhage, death
Treat pituitary apoplexy
Glucocorticoids, surgical decompression though when visual or neurologic symptoms are present
Diagnose pituitary adenomas
Sagittarius and coronal T1 weighted MRI before and after gadolinium
Visual field assessment if close to chiasm
How see pituitary apoplexy
CT or mRI of the pituitary may reveal signs of stellar hemorrhage with deviation of the pituitary stalk and compression of pituitary tissue
Treat pituitary tumor with surgery
Surgery if mass lesion that impinge on structures or correct hypersecretion BUT DOENST WORK IN HYPER PRL
Goal of surgery for pituitary
Resection without damage to normal pituitary tissue to decrease chance of hypopituitarism,
Post op risk of pituitary adenoma
DI, hypopit, CSF rhinorrhea, vision loss, oculomotor palsy
Radiation
Adjunct to surgery , but efficacy delayed and 50% get hormonal defiencies within 10 years
PRL tumor treat
Drugs
Prolactin function
Induce and maintain lactation and decrease reproductive function and drive (via suppression of gonadotropin releasing hormone, gonadotroph is, and gaonadal , steroidogenesis)
Physiologic elevation prolactin
Pregnancy and lactation
Most common non physiologic cause of prolactin >100 microg/L
Pituitary adenoma
Meds (risperidone, chlorpromazine, perphenazine, haloperidol, metoclopramide, opiates, H2 antagonists, amitriptyline, SSRI, verampamil, estrogens), pituitary stalk damage, renal failure
Nipple stimulation
Women hyperprolactinemia
Amenorrhea, glactorrhea, infertility
Men hyperprolactinemia
Hypogonadism, mass effects and rarely galactorrhea
Diagnose hyperprolactinemia
Fasting, morning PRL levels should be measured;
No neoplastic causes should be excluded-pregnancy test, hypothyroidism, medications
Treat hyperprolactinemia
Stop drugs that may be causing it
Pituitary MRI
Surgery for sellar or hypothalamic mass lesions
Dopamine agonist -shrinkage and reduction of PRL levels and adenoma shrinking
9FOR MICROPROLACTINOMAS)
Estrogen replacement
Cabergoline and bromocriptine
GH hypersecretion
Somatotroph adenomas
MEN1, carney, mcCune albright, familial AIP mutations
Rare for extrapituitary causes
Clincial features acromegaly
40-45
Delayed diagnosis of a decade
Facial features, widened teeth spacing, deepening of the voice, snoring, increased shoe or glove size, ring tightening, hyperhidrosis, oily skin, arthropathy, carpal tunnel syndrome.
Cardiomyopathy, left ventricular hypertrophy, diastolic dysfunction, sleep apnea, glucose intolerance, DM, colon polyps, colonic malignancy
Gigantism
Before epiphysis closes
Diagnose hyperGH
IGF-1 levels are useful screening , elevation suggests acromegaly
Need more than 1 time
Confirmed with oral glucose load test,
RI usually macroadenomas-delayed onset
Treat acromegaly
Transsphenoidal surgery*
Somatostatin analogues (ocreotide,)
Dopamine agonists in adjunct
GH receptor antagonist (pegvisomant)
Pituitary irradiation)
Gonadotropin producing adenoma
FSH intact and LHb and FSHb subunits, which are uncombined a subunits
Treat gonadotropin producing adenoma
Surgery for mass effects or hypopituitarism
If small follow with regular MR and visual field test
Diagnose Gonadotropin adenomas
Immunohistochemical analyisis of resected tumor tissue
TSH adenoma
Rare, large and locally invasive
Hyperthyroidism and/or sella mass effect
Diagnosis TSH adenomas
Elevated T4 levels in the setting of inappropriately normal or high TSH secretion and MRI evidence of a pituitary adenoma.
Surgery is indicated and is usually followed by somatostatin analogue therapy to treat residual tumor
Somatostatin analogue therapy
Thyroid ablation or antithyroid drugs can be used to reduce thyroid hormone levels
Most common cause of hypopituitarism
Neoplastic (macroadenomatous destruction,or following hypophysectomy or radiaiton therapy)
Sequential pattern that pituitary hormone failure follows
GH>FSH>LH>TSH>ACTH
Hypopituitarism following cranial irradiation develops
Over 5-15 years
Hypo GH
growth disorders in children; increased intraabdominal fat, reduced lean body mass, hyperlipidemia, reduced bone mineral density, decreased stamina, and social isolation in adults
Hyp FSH LH
Menstrual disorders and infertility in women; hypogonadism in men
ACTH
Features of hypocortisolism without mineralocorticoid defiency
hypo TSH
Growth retardation in children; features of hypothyroidism in children and adults
Hypo PRL
Failure to lactate postpartum
Diagnose hypopituitarism
Low levels of hormones in setting of low target hormone levels
8 am cortisol level, TSH< free T4, IGF-I, testosterone in men, associated menstrual cycles in women, and PRL level
Provocative tests for definitive diagnosis of GH and ACTH defiency**
Insulin tolerance test for GH
Insulin tolerance, metyrapone test, or CRH stimulation test for ACTH
Treat hypopituitarism
Hormonal replacement
GH therapy
Fluid retention, joint pain, carpal tunnel
Glucorticoid replacement
Always precede I-thyroxine therapy to avoid precipitation of adrenal crisis.
What else is posterior pituitary called
Neurohypophysis
ADH
Acts on renal tubules to induce water retention, leading to concentration of the urine.
Oxytocin
Stimulates postpartum milk letdown in response to sucking
Diabetes insipidus
Insufficient ADP production prom hypothalamus or impaired action in kidney
Central DI
Insufficient release
-head trauma,neoplastic, inflammatory, congenital, genetic, MOST IDIOPATHIC
Gestational DI
Increased metabolism of plasma ADH by an aminopeptidase produced by the placenta leads to a relative defiency of AVP during pregnancy
Primary polydipsia
Results in secondary insuffiency of ADH due to physiologic inhibiton of ADH secretion by excessive fluid intake
Nephrogenic DI
ADH resistance at the level of the kidney; it can be genetic or acquired from drug exposure (lithium, demeclocyline, amphotericin B), metabolic conditions (hypercalcemia, hypokalemia) or renal damage
Clincial features DI
Polyuria, excessive thirst, polydipsia with 24 hour urineoutput of >50 ml/kg per day and urine osmolarity that is less than that of serum (<300, specific gravity<1.01)
Clinical or laboratory signs of dehydration
Hypernatremia, occur only of the pt simultaneously has a thirst defect (not uncommon in patients with CNS disease) or does not have access to water.
Diagnose DI
Must be differentiated from other causes of polyuria
Fluid deprivationt est.
-morning
Measure body weight, plasma osmolarity, serum sodium, and urine volume and osmolality every hour)
-stop tes with body weight decreases 5% or plasma osmolality/sodium exceeds the upper limit of normal.
If the urine osmolality is <300 mosmol/kg with serum hyperosmolality, desmopressin (0.03 μg/kg SC) should be administered with repeat measurement of urine osmolality 1–2 h later. An increase of >50% indicates severe pituitary DI, whereas a smaller or absent response suggests nephrogenic DI. Measurement of AVP levels before and after fluid deprivation may be helfpul to distinguish central and nephrogenic DI. Occasionally, hypertonic saline infusion may be required if fluid deprivation does not achieve the requisite level of hypertonic dehydration, but this should be administered with caution
Treat DI
Desmopressin subcutaneousl, nasal spray, or oral
Thiazide diuretic and/or amiloride with low na diet or prostagladin synthesis
SIADH
Hyponatremia, reflecting water retention
Cause of SIADH
Neoplasma, lung infections, CNS disorders, drugs
Clincial features SIADH
If hyponatremia develops gradually, it may be asymptomatic until it reaches a severe stage. However, if it develops acutely, symptoms of water intoxication may include mild headache, confusion, anorexia, nausea, vomiting, coma, and convulsions. Laboratory findings include low BUN, creatinine, uric acid, and albumin; serum Na <130 meq/L and plasma osmolality <270 mosmol/kg; urine is not maximally diluted and frequently hypertonic to plasma, and urinary Na+ is usually >20 mmol
Treat SIADH
TREATMENT: SIADH
Fluid intake should be restricted to 500 mL less than urinary output. In pts with severe symptoms or signs, hypertonic (3%) saline can be infused at ≤0.05 mL/kg body weight IV per minute, with hourly sodium levels measured until Na increases by 12 meq/L or to 130 meq/L, whichever occurs first. However, if the hyponatremia has been present for >24–48 h and is corrected too rapidly, saline infusion has the potential to produce central pontine myelinolysis, a serious, potentially fatal neurologic complication caused by osmotic fluid shifts. Vasopressin antagonists (conivaptan, tolvaptan) are now available, but experience with these agents in SIADH treatment is limited. Oral vaptan (tolvaptan), a selective V2 antagonist increases urinary water excretion by blocking the antidiuretic effect of AVP. It should be initiated in the hospital (typically 15 mg PO qd) to evaluate the clinical response and avoid excessive diuresis. Other options include demeclocycline, 150–300 mg PO tid or qid, or fludrocortisone, 0.05–0.2 mg PO bid. The effect of the demeclocycline manifests in 7–14 days and is due to induction of a reversible form of nephrogenic DI. The effect of fludrocortisone also requires 1–2 weeks and is partly due to increased retention of sodium and possibly inhibition of thirst. It also increases urinary potassium excretion, which may require replacement through dietary adjustments or supplements and may induce hypertension
Thyroid
Thyroidal production of the hormones thyroxine (T4) and triiodothyronine (T3) is controlled via a classic endocrine feedback loop (see Fig. 168-1). Some T3 is secreted by the thyroid, but most is produced by deiodination of T4 in peripheral tissues. Both T4 and T3 are bound to carrier proteins (thyroid-binding globulin [TBG], transthyretin [binds T4], and albumin) in the circulation. Increased levels of total T4 and T3 with normal free levels are seen in states of increased carrier proteins (pregnancy, estrogens, cirrhosis, hepatitis, and inherited disorders). Conversely, decreased total T4 and T3 levels with normal free levels are seen in severe systemic illness, chronic liver disease, and nephrosis
Deficient thyroid hormone
Thyroid failure
Pituitary or hypothalamic disease
Congenital
Lab hypothyroidism
TSH high, low T4
Iodine suffiency and hypothyroidism
autoimmune disease and iatrogenic causes are the most common etiologies of hypothyroidism
Age hypothyroidism
The peak age of occurrence is around 60 years, and prevalence increases with age
Symptoms hypothyroidism
Lethargy, dry hair an skin, cold intolerance, hair loss, diffficulty concentrating, poor memory, constipation, mild weight gain with poor appetite, dyspnea, hoarse voice, muscle cramping, and menorrhagia
Bradycardia, mild diastolic HTN, prolongation of relaxation phase of DTR, cool peripheral extremities
GOITER
Carpal tunnel, cardiomegaly,
Patient with hypothyroidism
Dull expressionless face, sparse hair, periorbital puffiness, large tongue pale, doughy cool skin
Hypothermic stupendous state from hypothyroidism
Myxedema coma
Factors that predispose to myxedema coma
Cold exposure, trauma, infection, and administration of narcotics
Diagnosis hypothyroidism
Decreased serum free T4 is common to all varieties of hypothyroidism. An elevated serum TSH is a sensitive marker of primary hypothyroidism but is not found in secondary hypothyroidism. A summary of the investigations used to determine the existence and cause of hypothyroidism is provided in Fig. 170-1. Thyroid peroxidase (TPO) antibodies are increased in >90% of pts with autoimmune-mediated hypothyroidism. Elevated cholesterol, increased creatine phosphokinase, and anemia may be present; bradycardia, low-amplitude QRS complexes, and flattened or inverted T waves may be present on ECG
Treat hypothyroidism
Adult pts <60 years without evidence of heart disease may be started on 50–100 μg of levothyroxine (T4) daily. In the elderly or in pts with known coronary artery disease, the starting dose of levothyroxine is 12.5–25 μg/d. The dose should be adjusted in 12.5- to 25-μg increments every 6–8 weeks on the basis of TSH levels, until a normal TSH level is achieved. The average daily replacement dose is 1.6 μg/kg per day, but dosing should be individualized and guided by TSH measurement. In secondary hypothyroidism, TSH levels cannot be used, and therapy needs to be guided by free T4 measurement. Women on levothyroxine replacement should have a TSH level checked as soon as pregnancy is diagnosed, as the replacement dose typically increases by 30–50% during pregnancy. Failure to recognize and treat maternal hypothyroidism may adversely affect fetal neural development. Therapy for myxedema coma should include levothyroxine (500 μg) as a single IV bolus followed by daily treatment with levothyroxine (50–100 μg/d), along with hydrocortisone (50 mg every 6 h) for impaired adrenal reserve, ventilatory support, space blankets, and treatment of precipitating factors
Thyrotoxicosis
Causes of thyroid hormone excess include primary hyperthyroidism (Graves’ disease, toxic multinodular goiter [MNG], toxic adenoma, iodine excess); thyroid destruction (subacute thyroiditis, silent thyroiditis, amiodarone, radiation); extrathyroidal sources of thyroid hormone (thyrotoxicosis factitia, struma ovarii, functioning follicular carcinoma); and secondary hyperthyroidism (TSH-secreting pituitary adenoma, thyroid hormone resistance syndrome, human chorionic gonadotropin [hCG]-secreting tumors, gestational thyrotoxicosis). Graves’ disease, caused by activating TSH-receptor antibodies, is the most common cause of thyrotoxicosis and accounts for 60–80% of cases. Its prevalence in women is 10-fold higher than in men; its peak occurrence is at age 20–50 years
Clincila thyrotoxicosis
Symptoms include nervousness, irritability, heat intolerance, excessive sweating, palpitations, fatigue and weakness, weight loss with increased appetite, frequent bowel movements, and oligomenorrhea. Pts are anxious, restless, and fidgety. Skin is warm and moist, and fingernails may separate from the nail bed (Plummer’s nails). Eyelid retraction and lid lag may be present. Cardiovascular findings include tachycardia, systolic hypertension, systolic murmur, and atrial fibrillation. A fine tremor, hyperreflexia, and proximal muscle weakness also may be present. Long-standing thyrotoxicosis may lead to osteopenia. In the elderly, the classic signs of thyrotoxicosis may not be apparent, the main manifestations being weight loss and fatigue (“apathetic thyrotoxicosis
Graves
In Graves’ disease, the thyroid is usually diffusely enlarged to two to three times its normal size, and a bruit or thrill may be present. Infiltrative ophthalmopathy (with variable degrees of proptosis, periorbital swelling, and ophthalmoplegia) and dermopathy (pretibial myxedema) also may be found; these are extrathyroidal manifestations of the autoimmune process. In subacute thyroiditis, the thyroid is exquisitely tender and enlarged with referred pain to the jaw or ear, and sometimes accompanied by fever and preceded by an upper respiratory tract infection. Solitary or multiple nodules may be present in toxic adenoma or toxic MNG
Thyrotoxic crisis
Thyrotoxic crisis, or thyroid storm, is rare, presents as a life-threatening exacerbation of hyperthyroidism, and can be accompanied by fever, delirium, seizures, arrhythmias, coma, vomiting, diarrhea, and jaundice.
Diagnose thyrotoxicosis
Investigations used to determine the existence and causes of thyrotoxicosis are summarized in Fig. 170-2. Serum TSH is a sensitive marker of thyrotoxicosis caused by Graves’ disease, autonomous thyroid nodules, thyroiditis, and exogenous levothyroxine treatment. Associated laboratory abnormalities include elevation of bilirubin, liver enzymes, and ferritin. Thyroid radioiodine uptake may be required to distinguish the various etiologies: high uptake in Graves’ disease and nodular disease versus low uptake in thyroid destruction, iodine excess, and extrathyroidal sources of thyroid hormone. (Note: Radioiodine is the nuclide required for quantitative thyroid uptake, whereas technetium is sufficient for imaging purposes.) The ESR is elevated in subacute thyroiditis
Treat thyrotoxicosis
Graves’ disease may be treated with antithyroid drugs or radioiodine; subtotal thyroidectomy is rarely indicated. The main antithyroid drugs are methimazole or carbimazole (10–20 mg two to three times a day initially, titrated to 2.5–10 mg/d) and propylthiouracil (PTU) (100–200 mg every 8 h initially, titrated to 50 mg once or twice a day). Methimazole is preferred in most pts because of easier dosing. Thyroid function tests should be checked 3–4 weeks after initiation of treatment, with adjustments to maintain a normal free T4 level. Since TSH recovery from suppression is delayed, serum TSH levels should not be used for dose adjustment in the first few months. The common side effects are rash, urticaria, fever, and arthralgia (1–5% of pts). Uncommon but major side effects include hepatitis, an SLE-like syndrome, and, rarely, agranulocytosis (<1%). All pts should be given written instructions regarding the symptoms of possible agranulocytosis (sore throat, fever, mouth ulcers) and the need to stop treatment pending a complete blood count to confirm that agranulocytosis is not present. Propranolol (20–40 mg every 6 h) or longer-acting beta blockers such as atenolol (50 mg/d) may be useful at the start of treatment to control adrenergic symptoms until euthyroidism is reached. Anticoagulation with warfarin should be considered in pts with atrial fibrillation. Radioiodine can also be used as initial treatment or in pts who do not undergo remission after a 1- to 2-year trial of antithyroid drugs. Antecedent treatment with antithyroid drugs should be considered in elderly pts and those with cardiac problems, with cessation of antithyroid drugs 3–5 days prior to radioiodine administration. Radioiodine treatment is contraindicated in pregnancy; instead, symptoms should be controlled with the lowest effective dose of PTU. (Methimazole is not recommended in pregnancy because of reports of fetal agenesis cutis.) Corneal drying may be relieved with artificial tears and taping the eyelids shut during sleep. Progressive exophthalmos with chemosis, ophthalmoplegia, or vision loss is treated with large doses of prednisone (40–80 mg/d) and ophthalmologic referral; orbital decompression may be required
Treat thyroid storm
In thyroid storm, large doses of PTU (600-mg loading dose) should be administered orally, per nasogastric tube, or per rectum, followed 1 h later by five drops saturated solution of KI (SSKI) q6h. PTU (200–300 mg every 6 h) should be continued, along with propranolol (40–60 mg PO q4h or 2 mg IV every 4 h) and dexamethasone (2 mg every 6 h). Any underlying precipitating cause should be identified and treated
Toxic nodule treatment
Radioiodine is the treatment of choice for toxic nodules. Subacute thyroiditis in its thyrotoxic phase should be treated with NSAIDs and beta blockade to control symptoms, with monitoring of the TSH and free T4 levels every 4 weeks. Antithyroid drugs are not effective in thyroiditis. The clinical course of subacute thyroiditis is summarized in Fig. 170-3. Transient levothyroxine replacement (50–100 μg/d) may be required if the hypothyroid phase is prolonged. Silent thyroiditis (or postpartum thyroiditis if within 3–6 months of delivery) should be treated with beta blockade during the thyrotoxic phase and levothyroxine in the hypothyroid phase, with withdrawal after 6–9 months to assess recovery
Clincila course subacute thyroiditis
Clinical course of subacute thyroiditis. The release of thyroid hormones is initially associated with a thyrotoxic phase and suppressed TSH levels. A hypothyroid phase then ensues, with T4 and TSH levels that are initially low but gradually increase. During the recovery phase, increased TSH levels combined with resolution of thyroid follicular injury leads to normalization of thyroid function, often several months after the beginning of the illness. ESR, erythrocyte sedimentation rate; TSH, thyroid-stimulating hormone; UT4, unbound T4.
Sick euthyroid syndrome
Any acute, severe illness can cause abnormalities of circulating thyroid hormone levels or TSH, even in the absence of underlying thyroid disease. Therefore, the routine testing of thyroid function should be avoided in acutely ill pts unless a thyroid disorder is strongly suspected. The most common pattern in sick euthyroid syndrome is a decrease in total and free T3 levels, with normal levels of TSH and T4. This is considered an adaptive response to a catabolic state. More ill pts may additionally have a fall in total T4 levels, with normal free T4 levels. TSH levels may range from <0.1 to >20 mU/L, with normalization after recovery from illness. The pathogenesis of this condition is not fully understood but may involve altered binding of T4 to TBG and effects of high glucocorticoid and cytokine levels. Unless there is historic or unequivocal clinical evidence of hypothyroidism, thyroid hormone should not be administered and thyroid function tests should be repeated after recovery
Amiodarone
Amiodarone is a type III antiarrhythmic agent that has some structural similarity to thyroid hormone and has a high iodine content. Amiodarone treatment leads to substantial iodine overload and is associated with (1) acute, transient suppression of thyroid function, (2) hypothyroidism, or (3) thyrotoxicosis. These effects are only partially attributable to iodine overload. Hypothyroidism can occur in pts with preexisting thyroid disease, with an inability to escape from the suppressive effect of excess iodine. Pts with hypothyroidism can be easily managed with levothyroxine replacement therapy, without a need to stop amiodarone
There are two major forms of amiodarone-induced thyrotoxicosis (AIT).
Type 1 AIT is associated with an underlying thyroid abnormality (preclinical Graves’ disease or nodular goiter). Thyroid hormone synthesis becomes excessive as a result of increased iodine exposure. Type 2 AIT occurs in pts with no intrinsic thyroid abnormalities and is the result of destructive thyroiditis. Differentiation between type 1 and type 2 AIT may be difficult as the high iodine load interferes with thyroid scans. The drug should be stopped, if possible, although this is often difficult to achieve without compromising the arrhythmia management.
Goiter
Goiter refers to an enlarged thyroid gland (>20–25 g), which can be diffuse or nodular. Goiter is more common in women than men.
Causes goiter
Biosynthetic defects, iodine deficiency, autoimmune disease, dietary goitrogens (cabbage, cassava root), and nodular diseases can lead to goiter. Worldwide, iodine deficiency is the most common etiology of goiter. Nontoxic MNG is common in both iodine-deficient and iodine-replete populations, with a prevalence of up to 12%. The etiology, other than iodine deficiency, is usually not known and may be multifactorial
Substernal goiter
Substernal goiter may obstruct the thoracic inlet and should be evaluated with respiratory flow measurements and CT or MRI in pts with obstructive signs or symptoms (difficulty swallowing, tracheal compression, or plethora
When do thyroid function test
Thyroid function tests should be performed in all pts with goiter to exclude thyrotoxicosis or hypothyroidism.
US for goiter
U ltrasound is not generally indicated in the evaluation of diffuse goiter, unless a nodule is palpable on physical examination.
Treat goiter
Iodine or thyroid hormone replacement induces variable regression of goiter in iodine deficiency. Thyroid hormone replacement is rarely effective in significantly shrinking a nontoxic goiter that is not due to iodine deficiency or a biosynthetic defect. Radioiodine reduces goiter size by about 50% in the majority of pts. Surgery is rarely indicated for diffuse goiter but may be required to alleviate compression in pts with nontoxic MNG
Toxic multinodular goiter
In addition to features of goiter, the clinical presentation of toxic MNG includes subclinical hyperthyroidism or mild thyrotoxicosis. The pt is usually elderly and may present with atrial fibrillation or palpitations, tachycardia, nervousness, tremor, or weight loss
Cause toxic multinodular goiter
Recent exposure to iodine, from contrast dyes or other sources, may precipitate or exacerbate thyrotoxicosis; this may be prevented by prior administration of an antithyroid drug.
Labs toxic multinodular goiter
The TSH level is low. T4 may be normal or minimally increased; T3 is often elevated to a greater degree than T4. Thyroid scan shows heterogeneous uptake with multiple regions of increased and decreased uptake; 24-h uptake of radioiodine may not be increased. . Cold nodules in a MNG should be evaluated in the same way as solitary nodules (see below)
Treat toxic multinodular goiter
Antithyroid drugs, often in combination with beta blockers, can normalize thyroid function and improve clinical features of thyrotoxicosis but do not induce remission. A trial of radioiodine should be considered before subjecting pts, many of whom are elderly, to surgery. Subtotal thyroidectomy provides definitive treatment of goiter and thyrotoxicosis. Pts should be rendered euthyroid with antithyroid drugs before surgical intervention
Toxic adenoma
A solitary, autonomously functioning thyroid nodule is referred to as toxic adenoma. Most cases are cause by somatic activating mutations of the TSH receptor. Thyrotoxicosis is typically mild. A thyroid scan provides a definitive diagnostic test, demonstrating focal uptake in the hyperfunctioning nodule and diminished uptake in the remainder of the gland, as activity of the normal thyroid is suppressed. Radioiodine ablation with relatively large doses (e.g., 10–29.9 mCi 131I) is usually the treatment of choice
Thyroid neoplasm
Adenoma (benign )
Carcinoma (malignant)
Carcinoma thyroid
Carcinomas of the follicular epithelium include papillary, follicular, and anaplastic thyroid cancer
Epidemiology thyroid cancer
Thyroid cancer incidence is ~12/100,000 per year and increases with age. Papillary thyroid cancer is the most common type of thyroid cancer (70–90%). It tends to be multifocal and to invade locally
Follicular thyroid cancer diagnose
Follicular thyroid cancer is difficult to diagnose via fine-needle aspiration (FNA) because the distinction between benign and malignant follicular neoplasms rests largely on evidence of invasion into vessels, nerves, or adjacent structures. It tends to spread hematogenously, leading to bone, lung, and CNS metastases
Anaplastic carcinoma
Anaplastic carcinoma is rare, highly malignant, and rapidly fatal
Thyroid lymphoma
Thyroid lymphoma may arise in the background of Hashimoto’s thyroiditis and occurs in the setting of a rapidly expanding thyroid mass.
Medullary thyroid. Carcinoma
Medullary thyroid carcinoma arises from parafollicular (C) cells producing calcitonin and may occur sporadically or as a familial disorder, sometimes in association with multiple endocrine neoplasia type 2.
Clincila thyroid carcinoma
Features suggesting carcinoma include recent or rapid growth of a nodule or mass, history of neck irradiation, lymph node involvement, hoarseness, and fixation to surrounding tissues. Glandular enlargement may result in compression and displacement of the trachea or esophagus and obstructive symptoms. Age <20 or >45, male sex, and larger nodule size are associated with a worse prognosis
Diagnose thyroid cancer
Approach to the patient with a thyroid nodule. FNA, fine-needle aspiration; LN, lymph node; PTC, papillary thyroid cancer; TSH, thyroid-stimulating hormone; US, ultrasound
Treat thyroid cancer benign
Benign nodules should be monitored via serial examination. TSH suppression with levothyroxine results in decreased nodule size in about 30% of pts. Suppressive therapy should not exceed 6–12 months if unsuccessful
Treat thyroid cancer: follicular adenoma
Follicular adenomas cannot be distinguished from follicular carcinomas on the basis of cytologic analysis of FNA specimens. The extent of surgical resection (lobectomy vs. near-total thyroidectomy) should be discussed prior to surgery
Near total thyroidectomy
Near-total thyroidectomy is required for papillary and follicular carcinoma and should be performed by a surgeon who is highly experienced in the procedure
Radioiodine treatment thyroid cancer
risk factors and pathologic features indicate the need for radioiodine treatment, the pt should be treated for several weeks postoperatively with liothyronine (T3, 25 μg two to three times a day), followed by withdrawal for an additional 2 weeks, in preparation for postsurgical radioablation of remnant tissue. A therapeutic dose of 131I is administered when the TSH level is >25 IU/L. Alternatively, recombinant TSH (0.9 mg) is administered as two daily consecutive injections followed by 131I 24 h after the second injection. This appears to be equally effective as thyroid hormone withdrawal for radioablation therapy.
Treat medullary thyroid carcinoma
The management of medullary thyroid carcinoma is surgical, as these tumors do not take up radioiodine. Testing for RET mutations should be performed to assess for the presence of MEN 2, and the family should be screened if testing is positive. Following surgery, serum calcitonin provides a marker of residual or recurrent disease
Adrenal cortex
The adrenal cortex produces three major classes of steroids: (1) glucocorticoids, (2) mineralocorticoids, and (3) adrenal androgens. Clinical syndromes may result from deficiency or excess of these hormones. The adrenal medulla produces catecholamines, with excess being caused by a pheochromocytoma
Cushing
most common cause of Cushing’s syndrome is iatrogenic, due to administration of glucocorticoids for therapeutic reasons. Endogenous Cushing’s syndrome results from production of excess cortisol (and other steroid hormones) by the adrenal cortex. The major cause is bilateral adrenal hyperplasia secondary to hypersecretion of adrenocorticotropic hormone (ACTH) by the pituitary (Cushing’s disease) or from ectopic sources such as small cell carcinoma of the lung; carcinoids of the bronchus, thymus, gut and ovary, medullary carcinoma of the thyroid; or pheochromocytoma. Adenomas or carcinoma of the adrenal gland account for about 15–20% of endogenous Cushing’s syndrome cases. There is a female preponderance in endogenous Cushing’s syndrome except for the ectopic ACTH syndrome
Clincial cushing
Some common manifestations (central obesity, hypertension, osteoporosis, psychological disturbances, acne, hirsutism, amenorrhea, and diabetes mellitus) are relatively nonspecific. More specific findings include easy bruising, purple striae, proximal myopathy, fat deposition in the face and nuchal areas (moon facies and buffalo hump), and rarely virilization. Thin, fragile skin and plethoric moon facies also may be found. Hypokalemia and metabolic alkalosis are prominent, particularly with ectopic production of ACTH
Diagnose cushing
The diagnosis of Cushing’s syndrome requires demonstration of increased cortisol production and abnormal cortisol suppression in response to dexamethasone. For initial screening, measurement of 24-h urinary free cortisol, the 1-mg overnight dexamethasone test [8:00 a.m. plasma cortisol <1.8 μg/dL (50 nmol/L)], or late-night salivary cortisol measurement is appropriate. Repeat testing or performance of more than one screening test may be required. Definitive diagnosis is established in equivocal cases by inadequate suppression of urinary cortisol [<10 μg/d (25 nmol/d)] or plasma cortisol [<5 μg/dL (140 nmol/L)] after 0.5 mg dexamethasone every 6 h for 48
Localize source of cushing
This evaluation is best performed by an experienced endocrinologist. Low levels of plasma ACTH levels suggest an adrenal adenoma or carcinoma; inappropriately normal or high plasma ACTH levels suggest a pituitary or ectopic source. In 95% of ACTH-producing pituitary microadenomas, cortisol production is suppressed by high-dose dexamethasone (2 mg every 6 h for 48 h). MRI of the pituitary should be obtained but may not reveal a microadenoma because these tumors are typically very small. Furthermore, because up to 10% of ectopic sources of ACTH may also suppress after high-dose dexamethasone testing, inferior petrosal sinus sampling may be required to distinguish pituitary from peripheral sources of ACTH. Testing with corticotropin-releasing hormone (CRH) also may be helpful in determining the source of ACTH. Imaging of the chest and abdomen is required to localize the source of ectopic ACTH production; small bronchial carcinoids may escape detection by conventional CT. Pts with chronic alcoholism, depression, or obesity may have false-positive results in testing for Cushing’s syndrome—a condition named pseudo-Cushing’s syndrome. Similarly, pts with acute illness may have abnormal laboratory test results, since major stress alters the normal regulation of ACTH secretion. The management of Cushing’s syndrome is summarized in Fig. 171-1.
Treat cushing
Uncontrolled hypercorticism carries a poor prognosis, and treatment of Cushing’s syndrome is therefore necessary. Transsphenoidal surgery for pituitary ACTH-secreting microadenomas is curative in 70–80% when performed by a highly experienced surgeon, but long-term follow-up is required because these tumors may recur. Radiation therapy may be used when a surgical cure is not achieved (Chap. 168). Therapy of adrenal adenoma or carcinoma requires surgical excision; stress doses of glucocorticoids must be given pre- and postoperatively. Metastatic and unresectable adrenal carcinomas are treated with mitotane in doses gradually increased to 6 g/d in three or four divided doses. On occasion, debulking of lung carcinoma or resection of carcinoid tumors can result in remission of ectopic Cushing’s syndrome. If the source of ACTH cannot be resected, medical management with ketoconazole (600–1200 mg/d), metyrapone (2–3 g/d), or mitotane (2–3 mg/d) may relieve manifestations of cortisol excess. In some cases, bilateral total adrenalectomy is required to control hypercorticism. Pts with unresectable pituitary adenomas who have had bilateral adrenalectomy are at risk for Nelson’s syndrome (aggressive pituitary adenoma enlargement
Hyperaldosteronism
Aldosteronism is caused by hypersecretion of the adrenal mineralocorticoid aldosterone. Primary hyperaldosteronism refers to an adrenal cause and can be due to either an adrenal adenoma or bilateral adrenal hyperplasia. Rare causes include glucocorticoid-remediable hyperaldosteronism, some forms of congenital adrenal hyperplasia, and other disorders of true or apparent mineralocorticoid excess (see Table 406-3, HPIM-19). The term secondary hyperaldosteronism is used when an extraadrenal stimulus for renin secretion is present, as in renal artery stenosis, decompensated liver cirrhosis, or diuretic therapy
Clincial hyperaldosteronism
Most pts with primary hyperaldosteronism have difficult to control hypertension (especially diastolic) and hypokalemia. Headaches are common. Edema is characteristically absent, unless congestive heart failure or renal disease is present. Hypokalemia, caused by urinary potassium losses, may cause muscle weakness, fatigue, and polyuria, although potassium levels may be normal in mild primary hyperaldosteronism. Metabolic alkalosis is a typical feature
Diagnose hyperaldosteronism
The diagnosis is suggested by treatment-resistant hypertension that is associated with persistent hypokalemia in a nonedematous pt who is not receiving potassium-wasting diuretics. In pts receiving potassium-wasting diuretics, the diuretic should be discontinued and potassium supplements should be administered for 1–2 weeks. If hypokalemia persists after supplementation, screening using a serum aldosterone and plasma renin activity should be performed
More
. If hypokalemia persists after supplementation, screening using a serum aldosterone and plasma renin activity should be performed. Ideally, antihypertensives should be stopped before testing, but that is often impractical. Aldosterone receptor antagonists, beta-adrenergic blockers, ACE inhibitors, and angiotensin receptor blockers interfere with testing and should be substituted with other antihypertensives if possible. A ratio of serum aldosterone (in ng/dL) to plasma renin activity (in ng/mL per hour) >30 and an absolute level of aldosterone >15 ng/dL suggest primary aldosteronism. Failure to suppress plasma aldosterone (to <5 ng/dL after 500 mL/h of normal saline × 4 h) or urinary aldosterone after saline or sodium loading (to <10 μg/d on day 3 of 200 mmol/d oral NaCl + fludrocortisone 0.2 mg twice daily × 3 days) confirms primary hyperaldosteronism. Caution should be used with sodium loading in a hypertensive pt. Localization should then be undertaken with a high-resolution CT scan of the adrenal glands. If the CT scan is negative, bilateral adrenal vein sampling may be required to diagnose a unilateral aldosterone-producing adenoma. Secondary hyperaldosteronism is associated with elevated plasma renin activity
Treat hyperaldosteronism
Surgery can be curative in pts with adrenal adenoma but is not effective for adrenal hyperplasia, which is managed with sodium restriction and spironolactone (25–100 mg twice daily) or eplerenone (25–50 mg twice daily). The sodium channel blocker amiloride (5–10 mg twice a day) also can be used. Secondary hyperaldosteronism is treated with salt restriction and correction of the underlying cause
Addison
Addison’s disease occurs when >90% of adrenal tissue is destroyed. The most common cause is autoimmune destruction (alone, or as part of type I or type II polyglandular autoimmune syndromes). Tuberculosis used to be the leading etiology. Other granulomatous diseases (histoplasmosis, coccidioidomycosis, cryptococcosis, sarcoidosis), bilateral adrenalectomy, bilateral tumor metastases, bilateral hemorrhage, CMV, HIV, amyloidosis, and congenital diseases (some types of congenital adrenal hypoplasia, adrenal hypoplasia congenita, and adrenoleukodystrophy) are additional etiologies
Clincial Addison
Manifestations include fatigue, weakness, anorexia, nausea and vomiting, weight loss, abdominal pain, cutaneous and mucosal pigmentation, salt craving, hypotension (especially orthostatic), and, occasionally, hypoglycemia. Routine laboratory parameters may be normal, but typically serum Na is reduced and serum K increased. Extracellular fluid depletion accentuates hypotension. In secondary adrenal insufficiency, pigmentation is diminished and serum potassium is not elevated. Serum Na tends to be low because of hemodilution stemming from excess vasopressin secreted in the setting of cortisol deficiency
Diagnose Addison
The best screening test is the cortisol response 60 min after 250 μg ACTH (cosyntropin) IV or IM. Cortisol levels should exceed 18 μg/dL 30–60 min after the ACTH. If the response is abnormal, then primary and secondary deficiency may be distinguished by measurement of aldosterone from the same blood samples. In secondary, but not primary, adrenal insufficiency, the aldosterone increment from baseline will be normal (≥5 ng/dL). Furthermore, in primary adrenal insufficiency, plasma ACTH is elevated, whereas in secondary adrenal insufficiency, plasma ACTH values are low or inappropriately normal. Pts with recent onset or partial pituitary insufficiency may have a normal response to the rapid ACTH stimulation test. In these pts, alternative testing (metyrapone test or insulin tolerance testing) can be used for diagnosis
Treat Addison
Hydrocortisone, at 15–25 mg/d divided into 2/3 in the morning and 1/3 in the afternoon, is the mainstay of glucocorticoid replacement. Some pts benefit from doses administered three times daily, and other glucocorticoids may be given at equivalent doses. Mineralocorticoid supplementation is usually needed for primary adrenal insufficiency, with administration of 0.05–0.1 mg fludrocortisone PO qd and maintenance of adequate Na intake. Doses should be titrated to normalize Na and K levels and to maintain normal blood pressure without postural changes. Measurement of plasma renin levels may also be useful in titrating the dose. Mineralocorticoid replacement is not needed in pts with secondary adrenal insufficiency. All pts with adrenal insufficiency should be instructed in the parenteral self-administration of steroids and should be registered with a medical alert system. During periods of intercurrent illness, the dose of hydrocortisone should be doubled. During adrenal crisis, high-dose hydrocortisone (10 mg/h continuous IV or 100-mg bolus IV three times a day) should be administered along with normal saline. Thereafter, if the pt is improving and is afebrile, the dose can be tapered by 20–30% daily to usual replacement doses
Hypoaldosteronism
Isolated aldosterone deficiency accompanied by normal cortisol production occurs with hyporeninism, as an inherited aldosterone synthase deficiency, postoperatively following removal of aldosterone-secreting adenomas (transient), and during protracted heparin therapy. Hyporeninemic hypoaldosteronism is seen most commonly in adults with diabetes mellitus and mild renal failure; it is characterized by mild to moderate hyperkalemia. This is usually a benign condition that can be managed by observation. If needed, oral fludrocortisone (0.05–0.15 mg/d PO) restores electrolyte balance if salt intake is adequate. In pts with hypertension, mild renal insufficiency, or congestive heart failure, an alternative approach is to reduce salt intake and to administer furosemide
Incidental adrenal mass
). The majority (70–80%) of such “incidentalomas” are clinically nonfunctional, and the probability of an adrenal carcinoma is low (<0.01%).
Genetic incidental adrenal mass
Genetic syndromes such as MEN 1, MEN 2, Carney syndrome, and McCune-Albright syndrome are all associated with adrenal masses.
Diagnose incidental adrenal mass
first step in evaluation is to determine the functional status by measurement of plasma free metanephrines to screen for pheochromocytoma (Fig. 171-2). In a pt with a known extraadrenal malignancy, there is a 30–50% chance that the incidentaloma is a metastasis. Additional hormonal evaluation should include 24-h urine for urinary free cortisol or overnight 1-mg dexamethasone suppression testing, plasma renin activity/aldosterone ratio in hypertensives, DHEAS in women with signs of androgen excess, and estradiol in males with feminization. Fine-needle aspiration is rarely indicated and absolutely contraindicated if a pheochromocytoma is suspected. Adrenocortical cancer is suggested by large size (>4–6 cm), irregular margins, tumor inhomogeneity, soft tissue calcifications, and high unenhanced CT attenuation values (>10 HU).
Obesity
prevalence of obesity has increased dramatically over the past 3 decades. In the United States, about 34% of adults age >20 are obese (BMI >30), and another 34% are overweight (BMI 25–30). Most alarming is a similar trend among children, where about 16% of adolescents are obese. This has led to an epidemic of type 2 diabetes in children, a condition almost never seen until recently. These trends to increased obesity are not limited to Western societies but are occurring worldwide.
Genetic obesity
Among monogenic causes, mutations in the melanocortin receptor 4 are most common and account for ~1% of obesity in the general population and ~6% in severe, early-onset obesity. Syndromic obesity forms include Prader-Willi syndrome and Laurence-Moon-Biedl syndrome. Other monogenetic or syndromic causes are extremely rare.
Secondary causes obesity
ondary causes of obesity include hypothalamic injury, hypothyroidism, Cushing’s syndrome, and hypogonadism. Drug-induced weight gain is also common in those who use antidiabetes agents (insulin, sulfonylureas, thiazolidinediones), glucocorticoids, psychotropic agents, mood stabilizers (lithium), antidepressants (tricyclics, monoamine oxidase inhibitors, paroxetine, mirtazapine), or antiepileptic drugs (valproate, gabapentin, carbamazepine). Insulin-secreting tumors can cause overeating and weight gain
Clinical obesity
Obesity has major adverse effects on health. Increased mortality from obesity is primarily due to cardiovascular disease, hypertension, gall bladder disease, diabetes mellitus, and several types of cancer, such as cancer of the esophagus, colon, rectum, pancreas, liver, and prostate, and gallbladder, bile ducts, breasts, endometrium, cervix, and ovaries in women. Sleep apnea in severely obese individuals poses serious health risks. Obesity is also associated with an increased incidence of steatohepatitis, gastroesophageal reflux, osteoarthritis, gout, back pain, skin infections, and depression. Hypogonadism in men and infertility in both sexes are prevalent in obesity; in women this may be associated with hyperandrogenism (polycystic ovarian syndrome
Treat obesity
High rate relapse
Life style
Pharm
Bariatric surgery
Bariatric surgery
Bariatric surgery should be considered for pts with severe obesity (BMI ≥40 kg/m2) or moderate obesity (BMI ≥35 kg/m2) associated with a serious medical condition, with repeated failures of other therapeutic approaches, at eligible weight for >3 years, capable of tolerating surgery, and without addictions or major psychopathology. Weight-loss surgeries are either restrictive (limiting the amount of food the stomach can hold and slowing gastric emptying), such as laparoscopic adjustable silicone gastric banding, or restrictive-malabsorptive, such as Roux-en-Y gastric bypass (Fig. 172-1). These procedures generally produce a 30–35% weight loss that is maintained in about 40% of pts at 4 years. In many patients, there is significant improvement in co-morbid conditions including type 2 diabetes mellitus, hypertension, sleep apnea, hyperlipidemia, and cardiovascular events. The metabolic benefits appear to be the combined result of weight loss and physiologic responses of gut hormones and adipose tissue metabolism. Complications include stomal stenosis, marginal ulcers, and dumping syndrome. Procedures with a malabsorptive component require lifelong supplementation of micronutrients (iron, folate, calcium, vitamins B12 and D) and are associated with a risk of islet cell hyperplasia and hypoglycemia
DM prevelance
The prevalence of DM is increasing rapidly; type 2 DM frequency in particular is rising in parallel with the epidemic of obesity (Chap. 172). Between 1985 and 2013, the worldwide prevalence of DM has risen more than 10-fold, from 30 million to 382 million cases. In the United States, DM prevalence at greater than 8% of the population, increasing with age. A significant portion of persons with DM are undiagnosed
Diagnose DM
-confirm with repeat testing on a different day
Fasting plasma glucose ≥7.0 mmol/L (≥126 mg/dL)
Symptoms of diabetes plus a random blood glucose concentration ≥11.1 mmol/L (≥200 mg/dL)
2-h plasma glucose ≥11.1 mmol/L (≥200 mg/dL) during a 75-g oral glucose tolerance test.
Hemoglobin A1c >6.5%
Two intermediate categories
Impaired fasting glucose (IFG) for a fasting plasma glucose level of 5.6–6.9 mmol/L (100–125 mg/dL)
Impaired glucose tolerance (IGT) for plasma glucose levels of 7.8–11.1 mmol/L (140–199 mg/dL) 2 h after a 75-g oral glucose load
Individuals with IFG or IGT who do not have DM
High risk of getting type 2 DM
Screening DM
Screening with a fasting plasma glucose level is recommended every 3 years for individuals over the age of 45, as well as for younger individuals who are overweight (body mass index ≥25 kg/m2) and have one or more additional risk factors (Table 173-1).
Metabolic syndrome
The metabolic syndrome (also known as insulin resistance syndrome or syndrome X) is a term used to describe a commonly found constellation of metabolic derangements that includes insulin resistance (with or without diabetes), hypertension, dyslipidemia, central or visceral obesity, and endothelial dysfunction and is associated with accelerated cardiovascular disease
Clinical features DM
Common presenting symptoms of DM include polyuria, polydipsia, weight loss, fatigue, weakness, blurred vision, frequent superficial infections, and poor wound healing
Chronic complications DM
Ophthalmologic: nonproliferative or proliferative diabetic retinopathy, macular edema, rubeosis of iris, glaucoma, cataracts
Renal: proteinuria, end-stage renal disease (ESRD), type IV renal tubular acidosis
Neurologic: distal symmetric polyneuropathy, polyradiculopathy, mononeuropathy, autonomic neuropathy
Gastrointestinal: gastroparesis, diarrhea, constipation
Genitourinary: cystopathy, erectile dysfunction, female sexual dysfunction, vaginal candidiasis
Cardiovascular: coronary artery disease, congestive heart failure, peripheral vascular disease, stroke
Lower extremity: foot deformity (hammer toe, claw toe, Charcot foot), ulceration, amputation
Dermatologic: Infections (folliculitis, furunculosis, cellulitis), necrobiosis, poor healing, ulcers, gangrene
Dental: Periodontal disease
Treat DM
Optimal treatment of DM requires more than plasma glucose management. Comprehensive diabetes care should also detect and manage DM-specific complications and modify risk factors for DM-associated diseases. The pt with type 1 or type 2 DM should receive education about nutrition, exercise, care of diabetes during illness, and medications to lower the plasma glucose. In general, the target HbA1c level should be <7.0%, although individual considerations (age, ability to implement a complex treatment regimen, and presence of other medical conditions) should also be taken into account. Intensive therapy reduces long-term complications but is associated with more frequent and more severe hypoglycemic episodes. Goal preprandial capillary plasma glucose levels should be 3.9–7.2 mmol/L (70–130 mg/dL) and postprandial levels should be <10.0 mmol/L (<180 mg/dL) 1–2 h after a meal
Type 1 treat
In general, pts with type 1 DM require 0.5–1.0 U/kg per day of insulin divided into multiple doses. Combinations of insulin preparations with different times of onset and duration of action should be used (Table 173-2). Preferred regimens include injection of glargine at bedtime with preprandial lispro, glulisine, or insulin aspart or continuous SC insulin using an infusion device. Pramlintide, an injectable amylin analogue, can be used as adjunct therapy to control postprandial glucose excursions.
Type 2 treat
Pts with type 2 DM may be managed with diet and exercise alone or in conjunction with oral glucose-lowering agents, insulin, or a combination of oral agents and insulin. The classes of oral glucose-lowering agents and dosing regimens are listed in Table 173-3. In addition, exenatide and liraglutide are injectable glucagon-like peptide 1 (GLP-1, an incretin) analogues that may be used in combination with metformin or sulfonylureas. A reasonable treatment algorithm for initial therapy proposes metformin as initial therapy because of its efficacy (1–2% decrease in HbA1c), known side-effect profile, and relatively low cost (Fig. 173-1). Metformin has the advantage that it promotes mild weight loss, lowers insulin levels, improves the lipid profile slightly, lowers cancer risk, and does not cause hypoglycemia when used as monotherapy, although it is contraindicated in renal insufficiency, congestive heart failure, any form of acidosis, liver disease, or severe hypoxia, and should be temporarily discontinued in pts who are seriously ill or receiving radiographic contrast material. Metformin therapy can be followed by addition of a second oral agent (insulin secretagogue, DPP-IV inhibitor, thiazolidinedione, α-glucosidase inhibitor, or SLGT2 inhibitor). Combinations of two oral agents may be used with additive effects, with stepwise addition of bedtime insulin or a third oral agent if adequate control is not achieved. As endogenous insulin production falls, multiple injections of long-acting and short-acting insulin may be required, as in type 1 DM. Individuals who require >1 U/kg per day of long-acting insulin should be considered for combination therapy with an insulin-sensitizing agent such as metformin or a thiazolidinedione. Insulin-requiring type 2 DM pts may also benefit from addition of pramlintide.
Manage hospitalized diabetic
The goals of diabetes management during hospitalization are near-normal glycemic control, avoidance of hypoglycemia, and transition back to the outpatient diabetes treatment regimen. Pts with type 1 DM undergoing general anesthesia and surgery, or with serious illness, should receive continuous insulin, either through an IV insulin infusion or by SC administration of a reduced dose of long-acting insulin. Short-acting insulin alone is insufficient to prevent the onset of diabetic ketoacidosis. Oral hypoglycemic agents should be discontinued in pts with type 2 DM at the time of hospitalization. Either regular insulin infusion (0.05–0.15 U/kg per hour) or a reduced dose (by 30–50%) of long-acting insulin and short-acting insulin (held, or reduced by 30–50%), with infusion of a solution of 5% dextrose, should be administered when pts are NPO for a procedure. A regimen of long- and short-acting SC insulin should be used in type 2 pts who are eating. The glycemic goal for hospitalized pts with DM should be a preprandial glucose of <7.8 mmol/L (<140 mg/dL) and <10 mmol/L (<180 mg/dL) at post-meal times. For critically ill pts, glucose levels of 7.8–10.0 mmol/L (140–180 mg/dL) are recommended. Those with DM undergoing radiographic procedures with contrast dye should be well hydrated before and after dye exposure, and the serum creatinine should be monitored after the procedure
Amenorrhea
Amenorrhea refers to the absence of menstrual periods. It is classified as primary, if menstrual bleeding has never occurred by age 15 in the absence of hormonal treatment, or secondary, if menstrual periods are absent for >3 months in a woman with previous periodic menses. Pregnancy should be excluded in women of childbearing age with amenorrhea, even when history and physical examination are not suggestive. Oligomenorrhea is defined as a cycle length of >35 days or <10 menses per year. Both the frequency and amount of bleeding are irregular in oligomenorrhea. Frequent or heavy irregular bleeding is termed dysfunctional uterine bleeding if anatomic uterine lesions or a bleeding diathesis has been excluded
Amenorrhea and low FSH and LH
Women with amenorrhea and low FSH and LH levels have hypogonadotropic hypogonadism due to disease of either the hypothalamus or the pituitary. Hypothalamic causes include congenital idiopathic hypogonadotropic hypogonadism, hypothalamic lesions (craniopharyngiomas and other tumors, tuberculosis, sarcoidosis, metastatic tumors), hypothalamic trauma or irradiation, vigorous exercise, eating disorders, stress, and chronic debilitating diseases (end-stage renal disease, malignancy, malabsorption). The most common form of hypothalamic amenorrhea is functional, reversible gonadotropin-releasing hormone (GnRH) deficiency due to psychological or physical stress, including excess exercise and anorexia nervosa. Disorders of the pituitary include rare developmental defects, pituitary adenomas, granulomas, postradiation hypopituitarism, and Sheehan’s syndrome. They can lead to amenorrhea by two mechanisms: direct interference with gonadotropin production, or inhibition of GnRH secretion via excess prolactin production
Amenorrhea with high FSH and ovarian failure
Women with amenorrhea and high FSH levels have ovarian failure, which may be due to Turner’s syndrome, pure gonadal dysgenesis, premature ovarian failure, the resistant-ovary syndrome, and chemotherapy or radiation therapy for malignancy. The diagnosis of premature ovarian failure is applied to women who cease menstruating before age 40.
PCOS
Polycystic ovarian syndrome (PCOS) is characterized by the presence of clinical or biochemical hyperandrogenism (hirsutism, acne, male pattern baldness) in association with amenorrhea or oligomenorrhea. The metabolic syndrome and infertility are often present; these features are worsened with coexistent obesity. Additional disorders with a similar presentation include excess androgen production from adrenal or ovarian tumors and adult-onset congenital adrenal hyperplasia. Hyperthyroidism may be associated with oligo- or amenorrhea; hypothyroidism more typically with metrorrhagia
Diagnose amenorrhea
The initial evaluation involves careful physical examination including assessment of hyperandrogenism, serum or urine human chorionic gonadotropin (hCG), and serum FSH levels (Fig. 175-1). Anatomic defects are usually diagnosed by physical examination, though hysterosalpingography or direct visual examination by hysteroscopy may be required. A karyotype should be performed when gonadal dysgenesis is suspected. The diagnosis of PCOS is based on the coexistence of chronic anovulation and androgen excess, after ruling out other etiologies for these features. The evaluation of pituitary function and hyperprolactinemia is described in Chap. 168. In the absence of a known etiology for hypogonadotropic hypogonadism, MRI of the pituitary-hypothalamic region should be performed when gonadotropins are low or inappropriately normal
Treat amenorrhea
Disorders of the outflow tract are managed surgically. Decreased estrogen production, whether from ovarian failure or hypothalamic/pituitary disease, should be treated with cyclic estrogens, either in the form of oral contraceptives or conjugated estrogens (0.625–1.25 mg/d PO) and medroxyprogesterone acetate (2.5 mg/d PO or 5–10 mg during the last 5 days of the month). PCOS may be treated with medications to induce periodic withdrawal menses (medroxyprogesterone acetate 5–10 mg or progesterone 200 mg daily for 10–14 days of each month, or oral contraceptive agents) and weight reduction, along with treatment of hirsutism and, if desired, ovulation induction (see below). Individuals with PCOS may benefit from insulin-sensitizing drugs, such as metformin, and should be screened for diabetes mellitus
Pelvic pain
Pelvic pain may be associated with normal or abnormal menstrual cycles and may originate in the pelvis or be referred from another region of the body. A high index of suspicion must be entertained for extrapelvic disorders that refer to the pelvis, such as appendicitis, diverticulitis, cholecystitis, intestinal obstruction, and urinary tract infections. A thorough history including the type, location, radiation, and status with respect to increasing or decreasing severity can help to identify the cause of acute pelvic pain. Associations with vaginal bleeding, sexual activity, defecation, urination, movement, or eating should be sought. Determination of whether the pain is acute versus chronic, constant versus spasmodic, and cyclic versus noncyclic will direct further investigation
Acute pelvic pain
Pelvic inflammatory disease most commonly presents with bilateral lower abdominal pain. Unilateral pain suggests adnexal pathology from rupture, bleeding, or torsion of ovarian cysts, or, less commonly, neoplasms of the ovary, fallopian tubes, or paraovarian areas. Ectopic pregnancy is associated with right- or left-sided lower abdominal pain, vaginal bleeding, and menstrual cycle abnormalities, with clinical signs appearing 6–8 weeks after the last normal menstrual period. Orthostatic signs and fever may be present. Uterine pathology includes endometritis and degenerating leiomyomas
Chronic pelvic pain
Many women experience lower abdominal discomfort with ovulation (mittelschmerz), characterized as a dull, aching pain at midcycle that lasts minutes to hours. In addition, ovulatory women may experience somatic symptoms during the few days prior to menses, including edema, breast engorgement, and abdominal bloating or discomfort. A symptom complex of cyclic irritability, depression, and lethargy is known as premenstrual syndrome (PMS). Severe or incapacitating cramping with ovulatory menses in the absence of demonstrable disorders of the pelvis is termed primary dysmenorrhea. Secondary dysmenorrhea is caused by underlying pelvic pathology such as endometriosis, adenomyosis, or cervical stenosis
Diagnose pelvic pain
Evaluation includes a history, pelvic examination, hCG measurement, tests for chlamydial and gonococcal infections, and pelvic ultrasound. Laparoscopy or laparotomy is indicated in some cases of pelvic pain of undetermined cause
Treat pelvic pain
Primary dysmenorrhea is best treated with NSAIDs or oral contraceptive agents. Secondary dysmenorrhea not responding to NSAIDs suggests pelvic pathology, such as endometriosis. Infections should be treated with the appropriate antibiotics. Symptoms from PMS may improve with selective serotonin reuptake inhibitor (SSRI) therapy. The majority of unruptured ectopic pregnancies are treated with methotrexate, which has 85–95% success rate. Surgery may be required for structural abnormalities
Hirsutism
Hirsutism, defined as excessive male-pattern hair growth, affects ~10% of women. It may be familial or caused by PCOS, ovarian or adrenal neoplasms, congenital adrenal hyperplasia, Cushing’s syndrome, pregnancy, and drugs (androgens, oral contraceptives containing androgenic progestins). Other drugs, such as minoxidil, phenytoin, diazoxide, and cyclosporine, can cause excessive growth of non-androgen-dependent vellus hair, leading to hypertrichosis
Clincial hirtusiam
An objective clinical assessment of hair distribution and quantity is central to the evaluation. A commonly used method to grade hair growth is the Ferriman-Gallwey score (see Fig. 68-1, p. 333, in HPIM-19). Associated manifestations of androgen excess include acne and male-pattern balding (androgenic alopecia). Virilization, on the other hand, refers to the state in which androgen levels are sufficiently high to cause deepening of the voice, breast atrophy, increased muscle bulk, clitoromegaly, and increased libido. Historic elements include menstrual history and the age of onset, rate of progression, and distribution of hair growth. Sudden development of hirsutism, rapid progression, and virilization suggests an ovarian or adrenal neoplasm
Diagnose hirtuism
An approach to testing for androgen excess is depicted in Fig. 175-2. PCOS is a relatively common cause of hirsutism. The dexamethasone androgen-suppression test (0.5 mg PO every 6 h × 4 days, with free testosterone levels obtained before and after administration of dexamethasone) may distinguish ovarian from adrenal overproduction. Incomplete suppression suggests ovarian androgen excess. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency can be excluded by a 17-hydroxyprogesterone level that is <6 nmol/L (<2 μg/L) either in the morning during the follicular phase or 1 h after administration of 250 μg of cosyntropin. CT may localize an adrenal mass, and ultrasound may identify an ovarian mass, if evaluation suggests these possibilities
Treat hirsutism
Treatment of a remediable underlying cause (e.g., Cushing’s syndrome, adrenal or ovarian tumor) also improves hirsutism. In idiopathic hirsutism or PCOS, symptomatic physical or pharmacologic treatment is indicated. Nonpharmacologic treatments include (1) bleaching; (2) depilatory such as shaving and chemical treatments; and (3) epilatory such as plucking, waxing, electrolysis, and laser therapy. Pharmacologic therapy includes oral contraceptives with a low androgenic progestin and spironolactone (100–200 mg/d PO), often in combination. Flutamide is also effective as an antiandrogen, but its use is limited by hepatotoxicity. Glucocorticoids (dexamethasone, 0.25–0.5 mg at bedtime, or prednisone, 5–10 mg at bedtime) are the mainstay of treatment in pts with congenital adrenal hyperplasia. Attenuation of hair growth with pharmacologic therapy is typically not evident until 6 months after initiation of medical treatment and therefore should be used in conjunction with nonpharmacologic treatments
Menopause
Menopause is defined as the final episode of menstrual bleeding and occurs at a median age of 51 years. It is the consequence of depletion of ovarian follicles or of oophorectomy. The onset of perimenopause, when fertility wanes and menstrual irregularity increases, precedes the final menses by 2–8 years
Clinical menopause
The most common menopausal symptoms are vasomotor instability (hot flashes and night sweats), mood changes (nervousness, anxiety, irritability, and depression), insomnia, and atrophy of the urogenital epithelium and skin. FSH levels are elevated to ≥40 IU/L with estradiol levels that are <30 pg/mL
Treat menopause
During perimenopause, low-dose combined oral contraceptives may be of benefit. The rational use of postmenopausal hormone therapy requires balancing the potential benefits and risks. Concerns include increased risks of endometrial cancer, breast cancer, thromboembolic disease, and gallbladder disease, as well as probably increased risks of stroke, cardiovascular events, and ovarian cancer. Benefits include a delay in postmenopausal bone loss and probably decreased risks of colorectal cancer and diabetes mellitus
Contraception
Oral contraceptive agents are widely used for both prevention of pregnancy and control of dysmenorrhea and anovulatory bleeding. Combination oral contraceptive agents contain synthetic estrogen (ethinyl estradiol or mestranol) and synthetic progestins. Some progestins possess an inherent androgenic action. Low-dose norgestimate and third-generation progestins (desogestrel, gestodene, drospirenone) have a less androgenic profile; levonorgestrel appears to be the most androgenic of the progestins and should be avoided in pts with hyperandrogenic symptoms. The three major formulation types include fixed-dose estrogen-progestin, phasic estrogen-progestin, and progestin only
Risk oral contraception
Despite overall safety, oral contraceptive users are at risk for venous thromboembolism, hypertension, and cholelithiasis. Risks for myocardial infarction and stroke are increased with smoking and aging. Side effects, including breakthrough bleeding, amenorrhea, breast tenderness, and weight gain, are often responsive to a change in formulation
Absolute contraindications oral contraceptions
Absolute contraindications to the use of oral contraceptives include previous thromboembolic disorders, cerebrovascular or coronary artery disease, carcinoma of the breasts or other estrogen-dependent neoplasia, liver disease, hypertriglyceridemia, heavy smoking with age over 35, undiagnosed uterine bleeding, or known or suspected pregnancy. Relative contraindications include hypertension and anticonvulsant drug therapy
Emergency contraception
Emergency contraceptive pills, containing progestin only, can be used within 72 h of unprotected intercourse for prevention of pregnancy. Plan B is an emergency contraceptive kit specifically designed for postcoital contraception. Mifepristone (RU486) also may be used but is not available in most countries.
Infertility
Infertility is defined as the inability to conceive after 12 months of unprotected sexual intercourse. The causes of infertility are outlined in Fig. 175-3. Male infertility is discussed in
Clincial infertility
he initial evaluation includes discussion of the appropriate timing of intercourse, semen analysis in the male, confirmation of ovulation in the female, and, in the majority of situations, documentation of tubal patency in the female. Abnormalities in menstrual function constitute the most common cause of female infertility (Fig. 175-1). A history of regular, cyclic, predictable, spontaneous menses usually indicates ovulatory cycles, which may be confirmed by urinary ovulation predictor kits, basal body temperature graphs, or plasma progesterone measurements during the luteal phase of the cycle. An FSH level <10 IU/mL on day 3 of the cycle predicts adequate ovarian oocyte reserve. Tubal disease can be evaluated by obtaining a hysterosalpingogram or by diagnostic laparoscopy. Endometriosis may be suggested by history and examination, but is often clinically silent and can only be excluded definitively by laparoscopy
Treat infertility
The treatment of infertility should be tailored to the problems unique to each couple. Treatment options include expectant management, clomiphene citrate with or without intrauterine insemination (IUI), gonadotropins with or without IUI, and in vitro fertilization (IVF). In specific situations, surgery, gonadotropin therapy, intracytoplasmic sperm injection (ICSI), or assisted reproductive technologies with donor egg or sperm may be required
Breast cancer
The most common tumor in women; 234,190 women in the United States were diagnosed in 2015 and 40,730 died with breast cancer. Men also get breast cancer; F:M is 150:1. Breast cancer is hormone dependent. Women with late menarche, early menopause, and first full-term pregnancy by age 18 years have a significantly reduced risk. The average American woman has about a one in nine lifetime risk of developing breast cancer. Dietary fat is a controversial risk factor. Oral contraceptives have little, if any, effect on risk and lower the risk of endometrial and ovarian cancer. Voluntary interruption of pregnancy does not increase risk. Estrogen replacement therapy may slightly increase the risk, but the beneficial effects of estrogen on quality of life, bone mineral density, and decreased risk of colorectal cancer appear to be somewhat outnumbered by increases in cardiovascular and thrombotic diseases. Women who received therapeutic radiation before age 30 years are at increased risk. Breast cancer risk is increased when a sister and mother also had the disease
Genetics breast cancer
Perhaps 8–10% of breast cancer is familial. BRCA-1 mutations account for about 5%. BRCA-1 maps to chromosome 17q21 and appears to be involved in transcription-coupled DNA repair. Ashkenazi Jewish women have a 1% chance of having a common mutation (deletion of adenine and guanine at position 185). The BRCA-1 syndrome includes an increased risk of ovarian cancer in women and prostate cancer in men. BRCA-2 on chromosome 11 may account for 2–3% of breast cancer. Mutations are associated with an increased risk of breast cancer in men and women. Germ-line mutations in p53 (Li-Fraumeni syndrome) are very rare, but breast cancer, sarcomas, and other malignancies occur in such families. Germ-line mutations in PALB2, hCHK2, and PTEN may account for some familial breast cancer. Sporadic breast cancers show many genetic alterations, including overexpression of HER2/neu in 25% of cases, p53 mutations in 40%, and loss of heterozygosity at other loci
Diagnose breast cancer
Breast cancer is usually diagnosed by biopsy of a nodule detected by mammogram or by palpation. Women should be strongly encouraged to examine their breasts monthly. In premenopausal women, questionable or nonsuspicious (small) masses should be reexamined in 2–4 weeks (Fig. 70-1). A mass in a premenopausal woman that persists throughout her cycle and any mass in a postmenopausal woman should be aspirated. If the mass is a cyst filled with nonbloody fluid that goes away with aspiration, the pt is returned to routine screening. If the cyst aspiration leaves a residual mass or reveals bloody fluid, the pt should have a mammogram and excisional biopsy. If the mass is solid, the pt should undergo a mammogram and excisional biopsy. Screening mammograms performed every other year beginning at age 50 years have been shown to save lives. The controversy regarding screening mammograms beginning at age 40 years relates to the following facts: (1) the disease is much less common in the 40- to 49-year age group, and screening is generally less successful for less common problems; (2) workup of mammographic abnormalities in the 40- to 49-year age group less commonly diagnoses cancer; and (3) about 50% of women who are screened annually during their forties have an abnormality at some point that requires a diagnostic procedure (usually a biopsy), yet very few evaluations reveal cancer. However, many believe in the value of screening mammography beginning at age 40 years. After 13–15 years of follow-up, women who start screening at age 40 years have a small survival benefit. Women with familial breast cancer more often have false-negative mammograms. MRI is a better screening tool in these women. Women with dense breasts (>50% fibroglandular tissue) are said to be at increased risk (1.2- to 2-fold), but it is not clear that they require increased surveillance
Staging breast cancer
herapy and prognosis are dictated by stage of disease (Table 70-1). Unless the breast mass is large or fixed to the chest wall, staging of the ipsilateral axilla is performed at the time of lumpectomy (see below). Within pts of a given stage, individual characteristics of the tumor may influence prognosis: expression of estrogen receptor improves prognosis, while overexpression of HER2/neu, mutations in p53, high growth fraction, and aneuploidy worsen the prognosis. Molecular profiling has identified genetically distinct subsets including luminal A and B (estrogen receptor positive), normal breast-like, HER2-amplified, and basal (or triple-negative based on no expression of hormone receptors or overexpression of HER2. These subsets differ in prognosis. Breast cancer can spread almost anywhere but commonly goes to bone, lungs, liver, soft tissue, and brain
Treat breast cancer for ductal carcinoma in situ
Ductal carcinoma in situ is noninvasive tumor present in the breast ducts. Treatment of choice is wide excision with breast radiation therapy. In one study, adjuvant tamoxifen further reduced the risk of recurrence
Invasive breast cancer treat
Invasive breast cancer can be classified as operable, locally advanced, and metastatic. In operable breast cancer, the outcome of primary therapy is the same with modified radical mastectomy or lumpectomy followed by breast radiation therapy. Axillary dissection may be replaced with sentinel node biopsy to evaluate node involvement. The sentinel node is identified by injecting a dye in the tumor site at surgery; the first node in which dye appears is the sentinel node. Women with tumors <1 cm and negative axillary nodes require no additional therapy beyond their primary lumpectomy and breast radiation. Adjuvant combination chemotherapy for 6 months appears to benefit premenopausal women with positive lymph nodes, pre- and postmenopausal women with negative lymph nodes but with large tumors or poor prognostic features, and postmenopausal women with positive lymph nodes whose tumors do not express estrogen receptors. Estrogen receptor–positive tumors >1 cm with or without involvement of lymph nodes are treated with aromatase inhibitors. Women who began treatment with tamoxifen before aromatase inhibitors were approved should switch to an aromatase inhibitor after 5 years of tamoxifen and continue for another 5 years
Adjuvant chemo
Adjuvant chemotherapy is added to hormonal therapy in estrogen receptor–positive, node-positive women and is used without hormonal therapy in estrogen receptor–negative node-positive women, whether they are pre- or postmenopausal. Various regimens have been used. The most effective regimen appears to be four cycles of doxorubicin, 60 mg/m2, plus cyclophosphamide, 600 mg/m2, IV on day 1 of each 3-week cycle followed by four cycles of paclitaxel, 175 mg/m2, by 3-h infusion on day 1 of each 3-week cycle. In women with HER2+ tumors, trastuzumab augments the ability of chemotherapy to prevent recurrence. The activity of other combinations is being explored. In premenopausal women, ovarian ablation (e.g., with the luteinizing hormone–releasing hormone [LHRH] inhibitor goserelin) may be as effective as adjuvant chemotherapy
Postmenopausal treatment
Tamoxifen adjuvant therapy (20 mg/d for 5 years) or an aromatase inhibitor (anastrozole, letrozole, exemestane) is used for postmenopausal women with tumors expressing estrogen receptors whose nodes are positive or whose nodes are negative but with large tumors or poor prognostic features. Breast cancer will recur in about half of pts with localized disease. High-dose adjuvant therapy with marrow support does not appear to benefit even women with high risk of recurrence
Locally advanced breast cancer treatment
Pts with locally advanced breast cancer benefit from neoadjuvant combination chemotherapy (e.g., CAF: cyclophosphamide 500 mg/m2, doxorubicin 50 mg/m2, and 5-fluorouracil 500 mg/m2 all given IV on days 1 and 8 of a monthly cycle for 6 cycles) followed by surgery plus breast radiation therapy
Treat metastatic breast cancer
Treatment for metastatic disease depends on estrogen receptor status and treatment philosophy. No therapy is known to cure pts with metastatic disease. Randomized trials do not show that the use of high-dose therapy with hematopoietic stem cell support improves survival. Median survival is about 22 months with conventional treatment: aromatase inhibitors for estrogen receptor–positive tumors and combination chemotherapy for receptor-negative tumors. Pts whose tumors express HER2/neu have higher response rates by adding trastuzumab (anti-HER2/neu) to chemotherapy. Trastuzumab emtansine is a drug conjugate that targets HER2-expressing cells and has antitumor activity. Some advocate sequential use of active single agents in the setting of metastatic disease. Active agents in anthracycline- and taxane-resistant disease include capecitabine, vinorelbine, gemcitabine, irinotecan, and platinum agents. Pts progressing on adjuvant tamoxifen may benefit from an aromatase inhibitor such as letrozole or anastrozole. Half of pts who respond to one endocrine therapy will respond to another. Bisphosphonates reduce skeletal complications and may promote antitumor effects of other therapy. Radiation therapy is useful for palliation of symptoms
Prevent breast cancer
Women with breast cancer have a 0.5% per year risk of developing a second breast cancer. Women at increased risk of breast cancer can reduce their risk by 49% by taking tamoxifen or an aromatase inhibitor for 5 years. Women with BRCA-1 mutations can reduce the risk by 90% with simple mastectomy
