Dr.

Ali’s Uworld Notes For Step 2 CK

Endocrinology
Diabetes Screening - According to the American Diabetes Association (ADA) guidelines,
diabetes mellitus (OM) screening should start at age 45 in patients with no DM risk factors.
However, patients with risk factors require screening at an earlier age. Plasma HbA 1 c is a
screening modality for diabetes mellitus.

Measurement of glycosylated hemoglobin is an excellent way to monitor chronic glycemic

control. It is reflective of the patient's average glucose levels over the preceding 1 00-120 days
(which correlates with RBC survival time).

Diabetes Drug Management in Obese Patients - Most patients who are initially controlled with
one antidiabetic medication eventually require the addition of more antidiabetic drugs to
achieve optimal glycemic control. Combining antidiabetic agents with different mechanisms of
action is typically done to achieve better glycemic control. Metformin is the only antidiabetic
drug that causes some weight loss. Sulfonylurea, TZDs and insulin lead to weight gain with
long-term use. Metformin is the only antidiabetic drug that causes some weight loss Hence it
is preferred in Overweight patients

Tight blood pressure control in diabetics has been shown to delay the development of
cardiovascular disease and renal failure. ACE inhibitors are the drug of choice for lowering
blood pressure to target levels ( < 130/80 mmHg) in diabetic patients..

Diabetic Nephropathy Screening - Development of nephropathy is preceded by development

of excessive protein excretion, the initial stages of which is termed microalbuminuria. Patients
with microalbuminuria typically have a urine albumin excretion value between 30-300 mg/24
hr. (Normal urine protein excretion is< 30 mg/24 hr). Spot urine collection and timed urine
collection for the measurement of urine microalbumin to creatinine ratio are generally
accepted as good screening methods for microalbuminuria. Although 24-hour urine collection
is slightly more accurate in screening for microalbuminuria, its inconvenience to patients makes
it less preferred by physicians. Routine dipstick testing is not recommended during the initial
stages of nephropathy. Dipsticks can only detect excessive urinary protein excretion when the
level is > 300 mg/24 hr (macroalbuminuria)

Several randomized controlled clinical trials have demonstrated the beneficial effects of ACE
inhibitors in slowing the progression of diabetic nephropathy. The use of ACE inhibitors reduces
urinary albumin excretion and the decline in creatinine clearance. Its use is recommended in
patients with microalbuminuria even if their blood pressure is normal, since microalbuminuria
is a sensitive marker of renal microvascular damage. The beneficial effect of ACE inhibitors is
due to the reduction in blood pressure as well as the direct effect on reducing intraglomerular
pressure.

Diabetic nephropathy begins with hyperfiltration (increased GFR) and microalbuminuria

(incipient nephropathy). If not treated, microalbuminuria progresses to macroproteinuria,
which is defined as urine protein excretion of more than 300 mg/d. This increase in the amount
of urinary protein is accompanied by the progressive decline in GFR and Edema development
Intensive blood pressure control is the only intervention which has been conclusively shown
to reduce the decline in GFR once azotemia develops. For diabetic patients, the goal blood
pressure is < 130/80 mm Hg (may be even lower). ACE inhibitors, and perhaps angiotensin
receptor blockers, are the preferred anti-hypertensive drugs for diabetics. Caution must be
exercised in using these agents in patients with renal insufficiency because of the increased
occurrence of hyperkalemia.

Intensive Glycemic Control is not useful once Azotemia has developed.

Diabetic Neuropathy - Symmetric distal sensory motor polyneuropathy is the most common
type of diabetic neuropathy, and is characterized by the classic "stocking glove" pattern of
sensory loss. Aside from symmetric distal sensorimotor polyneuropathy, diabetes can also
cause mononeuropathies of cranial and peripheral nerves.
Foot ulcerations are common in both type 1 and 2 OM patients, and diabetic foot complications
are the most common cause of nontraumatic lower limb amputations in the United States.
Multiple factors are responsible for diabetic foot ulcer. Diabetic neuropathy is present in
approximately 80% of diabetics who develop foot ulcers

Foot ulcers can be classified as follows:

 Grade 0: High-risk foot without an ulcer.

 Grade 1: Superficial ulcer with full skin thickness involvement, but no involvement of
underlying tissue.
 Grade 2: Deep ulcer penetrating to ligament or muscle. but no bone involvement or
abscess formation.
 Grade 3: Deep ulcer with cellulitis. abscess formation or osteomyelitis.
 Grade 4: Localized gangrene
 Grade 5: Extensive gangrene involving the whole foot

Lower extremity ulcers have multifactorial pathogenesis; therefore. its management needs
multidisciplinary expertise (i.e., orthopedics, vascular surgery, endocrinology, podiatry, and
infectious diseases). The following six interventions have been shown to be useful in the
management of diabetic foot ulcers:
1. Off-loading
2. Debridement
3. Wound dressings
4. Antibiotics
5. Revascularization
6. Amputation

The key steps in the management of grade 1 and 2 diabetic ulcers are proper wound care and
debridement.

Patients with grade 3 ulcers require a short period of hospitalization. surgical debridement,
culture of material obtained from deep in the ulcer, bone biopsy, and intravenous antibiotic
therapy. The infection is typically due to multiple organisms; therefore. antibiotics with
anaerobic and gram-negative coverage is usually used in patients with deep foot lacerations. In
this patient, antibiotics may be included as part of the management; however, prescribing an
antibiotic alone without proper wound care is insufficient and incorrect

Neuropathic pain is characteristically present at rest and worse at night. Generally, as diabetic
neuropathy progresses, the pain subsides and finally disappears. whereas the sensory deficit
persists. Tricyclic antidepressants are the drugs of choice for diabetic neuropathy. TCAs can
worsen urinary symptoms (due to cystopathy) and orthostatic hypotension (due to
cardiovascular autonomic neuropathy). Gabapentin is an alternative for these patients.

Diabetic Erectile Dysfunction - Erectile impotence in diabetic patients may be due to multiple
reasons, including autonomic neuropathy, medications, functional hypogonadism, and
problems with penile circulation. It is thus essential to have a broad differential diagnosis to
appropriately include all plausible causes of the patient's symptoms. Functional hypogonadism
is characterized by low testosterone and low gonadotropin (LH and FSH) levels in the presence
of a significant systemic illness (e.g., uncontrolled diabetes); the underlying pathology is
defective gonadotropin-releasing hormone (GnRH) secretion. In contrast, primary (testicular)
hypogonadism is characterized by elevated serum gonadotropin levels.

Diabetics have a high risk for erectile dysfunction, and this risk progressively increases with the
patient's age and duration of diabetes. Vascular complications, neuropathy and medications are
considered as the main causes of the increased prevalence of erectile dysfunction in these
patients, although psychological causes should not be overlooked. The first-line drugs of
treatment are the phosphodiesterase inhibitors (e.g ..sildenafil).

Remember the following when treatment with phosphodiesterase inhibitors is being

considered:

1. Sildenafil is contraindicated in patients being treated with nitrates. and in those who
are hypersensitive to sildenafil.

2. Sildenafil is used with precaution in conditions predisposing to priapism.

3. Concurrent use of drugs which interfere with the metabolism of sildenafil (e.g
erythromycin. cimetidine) may predispose to adverse reactions by prolonging its
plasma half life.

4. While combining with an alpha-blocker. it is important to give the drugs with at least
a 4-hour interval to reduce the risk of hypotension.

The nocturnal penile tumescence helps differentiate psychogenic from organic causes of male
erectile dysfunction. It is positive in psychogenic (i.e., marital discord); causes and negative in
organic causes.

Penile erections normally occur during REM sleep and on waking up. To achieve an erection,
intact nerves and blood supplies are essential. Failure to achieve a spontaneous erection during
the night and/or early morning is pathognomic of organic erectile dysfunction (ED). ED is a very
common complication in patients with a pelvic fracture and urethral injury. The incidence of
ED is as high as 30% in patients requiring catheter placement only, and can reach as high as 70%
in those undergoing open reduction.

Diabetic Gastroparesis - Diabetic gastroparesis (delayed gastric emptying) presents with

symptoms of anorexia, nausea, vomiting, early satiety, postprandial fullness, and impaired
glycemic control. Treatment of patients with diabetic gastroparesis includes a combination of
optimizing diabetes control; dietary modifications with increased fiber intake and small,
frequent meals; and medications to improve gastric emptying. Prokinetic agents (eg,
metoclopramide, erythromycin, cisapride) are useful in the management of symptoms.

If the patient's diabetes is well-controlled, as evidenced by his normal HbA 1 c level, At this
point, the most likely diagnosis is secondary (central) hypogonadism, which is characterized by
hypogonadism, low testosterone levels and inappropriately normal gonadotropin levels.
Measurement of serum prolactin levels is the most important biochemical test to perform in
patients with suspected central hypogonadism. Regardless of the cause, high serum prolactin
levels inhibit the release of GnRH, thereby resulting in hypogonadism.
Prolactin-secreting pituitary tumor is one of the most important causes of elevated prolactin
levels.

DKA - In patients with diabetes, infection can precipitate DKA(Look fro Inc WBC). This is
because infections cause systemic release of insulin counter regulatory hormones like
catecholamines and cortisol. The resultant relative excess of glucagon causes hyperglycemia,
ketonemia, and an osmotic diuresis. This diuresis is accompanied by a net renal loss of total
body potassium (K+) stores. Despite this reduction in K+ stores, however, the serum K+
concentration may actually be elevated, as acidemia and decreased insulin activity cause K + to
be redistributed to the extracellular fluid compartment. Thus, this patient most likely has a total
body K + deficit despite her hyperkalemia. The mild leukocytosis is consistent with infection
and/or DKA.

1st Check glucose level with Fingerstick Glucose test

Essential measures in the management of DKA include the following:

1. Restoration of intravascular volume: using 0.9% saline (normal saline)
2. Correction of hyperglycemia: using intravenous regular insulin
3. Correction of electrolyte abnormalities: Potassium correction is very crucial.
4. Treatment of precipitating factors such as infections: using antibiotics

Non Ketotic Hyperglycemic Hyperosmolar Coma- This condition is characterized by very high
blood glucose levels, hyperosmolality, normal anion gap and negative serum ketones.
Sometimes, patients get very dehydrated, and with poor tissue perfusion, lactic acidosis can
occur. HHNK is mostly seen in type 2 OM patients; such patients have circulating endogenous
insulin, which is able to suppress ketoacidosis, but not hyperglycemia.

Thiazide diuretics can precipitate HHS by reducing the intravascular volume, which decreases
glomerular filtration rate (GFR) and activates counter-regulatory hormones. The decreased
GFR leads to decreased renal glucose excretion, and the counter-regulatory hormones increase
glucose production and impair utilization. However, these patients have enough insulin (unlike
type 1 diabetics with complete insulin deficiency) to prevent ketosis but notthe hyperglycemia.
The glycosuria, decreased GFR, and hyperglycemia further worsen the osmotic diuresis and lead
to worsening hyperglycemia and increased serum osmolality. The increased osmolality
gradually leads to altered mentation, lethargy, and weakness. Diagnosis is established by serum
glucose (often >600 mg/dl), plasma osmolality > 320 mOsm/L, and absent ketonemia.

Look for a patient with Type II DM who recently got started on Thiazides & now presents with
confusion & Dehydration.

Fluid replacement is the most important step in the management of non-ketotic hyperglycemic
coma. When hypovolemia is present, normal saline should be started initially and then replaced
with 0 45% saline. Because of the large volumes of glucose induced osmotic diuresis, patients
may require up to 8 to 1 0 liters of normal saline to reach the euvolemic state. Regular insulin
should be administered in all cases of nonketotic hyperglycemic coma, but fluid replacement
alone can reduce hyperglycemia significantly Potassium should be administered in all cases of
nonketotic hyperglycemic coma once potassium level reaches to the normal level. This is due to
the movement of potassium into the cells under the influence of the administered insulin. 5%
dextrose is given once blood glucose level has been lowered to 250 mg/dl by insulin therapy. It
prevents the development of cerebral edema

Metabolic Syndrome - includes hypertension, impaired fasting glucose, and dyslipidemia.

Patients are also characteristically overweight (as seen in this case), with predominantly central
(abdominal) fat distribution that is reflected by an increased waist-to-hip ratio. Insulin
resistance plays a central role in the pathogenesis of metabolic syndrome. Metabolic syndrome
is diagnosed when at least 3 of the 5 following criteria are met

1. Abdominal obesity (Men: Waist circumference >40 inches; Women: Waist

circumference > 35 inches)

2. Fasting glucose > 100 - 110 mg/dl

3. Blood pressure > 130/80 mm Hg

4. Triglycerides > 150 mg/dl

5. HDL cholesterol (Men <40 mg/dl; Women <50 mg/dl)

Hypoglycemia In Non Diabetics - There are two important causes of hypoglycemia in non-
diabetic patients with elevated insulin levels:

1. Insulinoma (beta cell tumor)

2. Surreptitious use of insulin or sulfonylurea.

Helpful tests used in the evaluation of hypoglycemic patients are measurements of c-peptide,
proinsulin and sulfonylurea levels. Hypoglycemia secondary to insulinoma is associated with
elevated insulin, c-peptide and proinsulin levels.

Thyroid Disorders –

Sick Euthyroid Syndrome - Any patient with an acute, severe illness may have abnormal thyroid
function tests. This condition is called sick euthyroid syndrome, and the most common thyroid
hormone pattern in such patients is a fall in total and free T3 levels with normal T 4 and TSH
levels. (Remember the 'low T3 syndrome'.) Decreased levels of T3 occur due to the decreased
peripheral conversion of T 4 to T3.

Graves’s ophthalmopathy is the most common cause of exophthalmos in adults. This proptosis
occurs secondary to autoimmune lymphocytic infiltration of the extraocular muscles resulting
in fibroblast proliferation, hyaluronic acid deposition, edema and fibrosis

Management of Acute Thyrotoxicosis due to any cause of Hyperthroidism - Propranolol is

generally used for symptomatic relief until the cause of hyperthyroidism is identified and
definitively treated. Propranolol effectively relieves the tachycardia, tremor, sweating, and
anxiety that occur with hyperthyroidism due to any cause.

Hypothyroid Myopathy - Hypothyroidism is associated with a wide spectrum of muscle

involvement, ranging from asymptomatic elevation of serum CK concentrations to myalgias,
muscle hypertrophy, proximal myopathy, and rhabdomyolysis & sluggish bilateral ankle
reflexes. Serum CK can be elevated for years before a patient develops clinical symptoms of
hypothyroidism. There is no clear correlation between the degree of CK elevation and severity
of muscle disease. As a result, hypothyroidism should always be considered in patients with an
unexplained elevation of serum CK concentration.

Accumulation of matrix substances throughout the body causes a variety of the systemic
manifestations of hypothyroidism. Matrix accumulation in the median nerve and tendons of
the carpal tunnel may cause carpal tunnel syndrome.

Hyperlipidemia, unexplained hyponatremia and elevated serum muscle enzymes are

indications for thyroid function tests.

Serum thyroid-stimulating hormone (TSH) and T4 (if TSH is elevated) are the tests of choice to
diagnose hypothyroidism. Muscle biopsy usually is not needed for diagnosis and shows normal
or nonspecific changes in hypothyroid myopathy but inflammatory changes in polymyositis

Hypertension in Hyperthyroidism - Hypertension in patients with thyrotoxicosis is

predominantly systolic and caused by hyperdynamic circulation. The classic clinical
presentation of thyrotoxicosis includes weight loss, irritability, tachycardia, tremors, and lid
retraction. In addition, patients usually have systolic hypertension and an increase in pulse
pressure. It is important to know that the hyperdynamic state of hyperthyroidism causes the
secondary hypertension. The underlying pathology of these functional changes is most likely
the increased expression of myocardial sarcoplasmic reticulum calcium-dependent adenosine
triphosphatase, although a decrease in the expression of calcium-inhibiting protein and
phospholamban may play a role. Furthermore, excess thyroid hormone leads to increased
target organ sensitivity to endogenous catecholamines by increasing the expression of
adrenergic receptors. In extreme cases, high output heart failure may develop.
Thyroid Hormone Resistance - Patients with generalized resistance to thyroid hormones have
high serum T 4 and T3 levels with normal to mildly elevated TSH levels. Patients typically have
features of hypothyroidism despite having elevated free thyroid hormones.

Hyperthyroidism Management Problems - The antithyroid drugs propylthiouracil (PTU) and

methimazole (MMI) are associated with a number of minor, as well as potentially life-
threatening, side effects. Agranulocytosis is the most feared side effect, and is seen in
approximately 0.3% of patients treated with antithyroid drugs. It is caused by immune
destruction of granulocytes, and most cases occur within 90 days of treatment. Routine
monitoring of the granulocyte count is not cost effective and not advocated. Current
recommendations state that once the patient complains of fever and sore throat, the
antithyroid drug should be discontinued promptly and the WBC count measured.

Untreated hyperthyroid patients are at risk for rapid bone loss resulting from increased
osteoclastic activity in the bone cells. Untreated hyperthyroid patients are also at risk for
cardiac tachyarrhythmias, including atrial fibrillation.

Toxic Adenoma - Toxic adenoma presents as symptoms suggestive of thyroid toxicosis. There is
radioactive iodine uptake in the nodule, and suppression of uptake in the rest of the thyroid
gland. Patients with toxic nodule do not have infiltrative ophthalmopathy.

Thyrotoxicosis with low Iodine Uptake - The most important causes of thyrotoxicosis with low
radioactive iodine uptake include:

1. Subacute painless thyroiditis – swelling with no pain – Postpartum Thyroiditis.

2. Subacute granulomatous thyroiditis exqucitly painful
3. Iodine-induced thyroid toxicosis
4. Levothyroxine overdose
5. Struma ovarii

Thyroid Nodule - Although the prevalence of thyroid nodules in the adult population is high, the
majority are benign. Most thyroid nodules are benign colloid nodules. Thyroid stimulating
hormone (TSH) measurement and ultrasound are the first steps in evaluation. Radionuclide
scan is indicated for patients with low TSH. Hot nodules are almost always benign and can be
treated for hyperthyroidism. Fine-needle aspiration is indicated for patients with normal or high
TSH, cold nodules, thyroid cancer family history, or suspicious thyroid ultrasound findings.
Radioactive iodine ablative therapy is the preferred treatment for most patients with
hyperthyroidism, including Graves' disease, in North America. Contraindications of radioactive
iodine treatment are pregnancy and very severe ophthalmopathy.
Post Radioablative Thyrotoxicosis - radioactive iodine (the preferred treatment for
hyperthyroidism in the United States). Radioactive iodine (1-131) is taken up by thyroid
follicular cells and then destroys them by emitting beta radiation rays. While this effectively
treats hyperthyroidism in the longterm, dying thyroid cells release excess thyroid hormone into
the circulation. which can temporarily aggravate the hyperthyroid state. Thyrotoxicosis likely
explains the new-onset atrial fibrillation in this patient. In general, young patients free of
cardiovascular disease tolerate radioactive iodine ablative treatment without major problems.
However, in elderly patients and patients with significant cardiovascular disease, the temporary
increase in thyroid hormone levels can lead to complications. It is recommended that such
patients be pretreated with antithyroid medications like methimazole to deplete thyroid
hormone stores before beginning radioactive iodine therapy

Post Radioablative Hypothyroidism - In the United States, radioactive I131 is the most popular
treatment for hyperthyroidism in adult, non-pregnant patients. Fallowing such treatment,
patients become euthyroid in 2-6 months time. The major complication of therapy is
hypothyroidism which ultimately develops in more than 80% of adequately treated patients
with Graves' disease. Hypothyroidism results from the destruction of thyroid follicles by
radioactive iodine. Previous attempts to standardize the dosage of radioactive iodine (according
to the size of the thyroid gland) were generally unsuccessful in reducing the incidence of post-
radioablative hypothyroidism. Nevertheless, post-radioablative hypothyroidism can be easily
and effectively treated with levothyroxine administration; therefore. Radioiodine therapy
remains as the most preferred treatment of patients with Graves' disease.

Patients with toxic adenoma and multinodular goiter usually remain euthyroid after radioiodine
therapy. In such conditions, radioiodine accumulates and destroys only the autonomous areas
of the thyroid, and other parts of the gland (i.e., those whose function is suppressed due to the
hyperthyroid state) are spared from radioiodine accumulation.

Another relatively common side effect of radioiodine therapy is exacerbation of

ophthalmopathy, a rate as high as 10% has been reported. All patients should be informed
about this complication. This complication can be effectively prevented by high dose
corticosteroid treatment before and after the administration of radioactive iodine.

Factitious thyrotoxicosis results from ingestion of exogenous thyroid hormone. Patients

present with signs and symptoms of hyperthyroidism. but no goiter or exophthalmos. Thyroid
function tests demonstrate low TSH and elevated T3 and T 4. The diagnosis may be confirmed
by a 24-hour radioiodine uptake test showing diffusely decreased iodine uptake by the thyroid.
Biopsy of the thyroid demonstrates follicular atrophy.

Lymphoma in Hashimoto Thyroiditis - The risk of thyroid lymphoma is about 60 times higher in
patients with Hashimoto's thyroiditis compared to patients without thyroiditis. The typical
presentation is rapid enlargement of the thyroid gland in patients with preexisting Hashimoto's
thyroiditis. Compressive symptoms (e.g . dysphagia. voice change) are common. CT scan of the
neck shows enlargement of the thyroid gland around the trachea; this is also known as the
'doughnut sign.' Thyroid ultrasound shows a characteristic pseudocystic pattern. The
radioactive iodine uptake is reduced. Fine needle aspiration biopsy may miss the diagnosis;
therefore, core biopsy is often required for making a diagnosis.

Thyroid Cancer - The most common malignancy of the thyroid gland is papillary thyroid
cancer (70%), which also has the best prognosis. Papillary, follicular and anaplastic cancers arise
from thyroid follicular/epithelial cells. A history of head or neck irradiation during childhood
and a positive family history are important risk factors for epithelial thyroid carcinomas. There
is an increased frequency of thyroid carcinomas in females.

Histopathologically, demonstration of invasion of the capsule and blood vessels is required for
differentiating follicular cancers from follicular adenomas. Follicular thyroid cancers have the
propensity to invade blood vessels and metastasize to distal organs.

Prolactinoma - Lactotroph adenoma (prolactinoma) is the most common pituitary tumor. It

accounts for approximately 50% of primary pituitary tumors. F unctionallactotroph adenoma
produces prolactin, and patients present with hypogonadism and galactorrhea. Other less
common primary pituitary tumors include somatotroph adenoma, corticotroph adenoma,
thyrotroph adenoma, gonadotroph adenoma and craniopharyngioma. Due to a rich blood
supply, metastasis from cancer (particularly the lung and breast) can also involve the pituitary.

Prolactinoma treatment - A pituitary tumor less than 1 0 mm in diameter is called a

microadenoma. Microprolactinoma is a prolactin-secreting microadenoma, and is one of the
most common pituitary tumors encountered in clinical practice. Microprolactinoma classically
presents as amenorrhea and galactorrhea in females (as in this patient). and as hypogonadism
in males. Due to its small size. this microadenoma usually does not cause problems with other
pituitary hormones or a mass effect. The primary treatment for all prolactinomas (both micro-
as well as macroprolactinoma) is medical treatment with dopaminergic agents (e.g ..
bromocriptine and cabergoline). Medical treatment not only results in normalization of
prolactin levels. but leads to significant reduction in tumor size. Cabergoline is a new drug
which has fewer side effects. and has been shown to be more effective than bromocriptine.

Surgery is reserved only for those patients who do not respond to or do not tolerate treatment
with a dopamine agonist. Surgery is also indicated when impaired vision due to invasive
prolactinoma does not rapidly improve after drug treatment. Radiotherapy may be indicated
for aggressive tumors that do not respond to medical and surgical therapy. The response to
radiotherapy is generally delayed, and there is a risk of development of panhypopituitarism.

Acromegaly Management - Coarse facial features, arthralgias, uncontrolled hypertension,

increased ring size, skin tags, and carpal tunnel syndrome are consistent with untreated
acromegaly. Elevated growth hormone (GH) in acromegaly stimulates hepatic insulin-like
growth factor (IGF-1) secretion, which is responsible for most of the clinical features. IGF-1
levels are consistently elevated throughout the day (without fluctuations) in all patients with
acromegaly. In contrast, GH levels can fluctuate in a diurnal pattern and cannot be used alone
to diagnose acromegaly. As a result, measurement of IGF-1 level is the preferred single
screening test for acromegaly. However, IGF-1 levels can decrease with age and require
interpretation according to patient age. Serum IGF-1 level is also an excellent test for
monitoring the response to therapeutic intervention(s) in acromegaly.

The most common cause of death in patients with acromegaly is cardiovascular, accounting for
approximately 38-62% of deaths.

Patients with elevated IGF-1 levels should undergo confirmatory dynamic testing with 75 g
oral glucose suppression test. Following the administration of 75 g oral glucose, most normal
individuals will suppress serum GH levels to <1 ~g/dl. Patients with acromegaly, however, are
unable to suppress or sometimes paradoxically increase serum GH levels following an oral
glucose load.
Ovarian/Adrenal Androgen Secreting Tumor - Rapidly developing hyperandrogenism with
virilization is highly suggestive of an androgen-secreting neoplasm of the ovary or adrenal.
Serum testosterone and DHEAS levels are very helpful in delineating the site of excess
androgen production. Elevated testosterone levels with normal DHEAS levels indicate an
ovarian source, whereas elevated DHEAS levels with relatively normal testosterone levels
indicate an adrenal source. DHEA is secreted both from the ovaries and adrenals, whereas
DHEAS, a sulfated form of DHEA, is specifically secreted from the adrenals.

Parathyroidectomy Indications - The indications for parathyroidectomy in asymptomatic

patients with primary hyperparathyroidism are:

1. Serum calcium level at least 1 mg/dl above the upper limit of normal
2. Young age (<50 years old)
3. BMD less than T-2.5 at any site
4. Reduced renal function

Bone Histology Changes -

Osteomalacia (Adults Only) is characterized by defective mineralization of the bone.

Rickets (Children Only) is characterized by defective mineralization of both bone and growth
plate cartilage. Disordered skeletal remodeling in focal areas of the bone is the underlying
pathophysiology of Paget's disease of the bone.

Osteoporosis is characterized by low bone mass, but the bone that is present is normally
mineralized per unit volume.

Defective collagen formation is seen in patients with osteogenesis imperfecta.

Vitamin D Deficiency - low or low-normal serum calcium, low serum phosphate and increased
serum parathyroid hormone levels.

Serum Albumin & Calcium Connection - Albumin plays an important role in the homeostasis of
the three forms of plasma calcium, which are: ionized calcium (45%), albumin-bound calcium (
40%), and calcium bound to inorganic and organic anions (15%). Patients with
hypoalbuminemia can have a low level of total plasma calcium; however, they may not
manifest with clinical hypocalcemia because their levels of ionized calcium (the physiologically
active form) have remained normal. It is therefore very importantto calculate the corrected
serum calcium level, which helps determine the clinical significance of the low total plasma
calcium level.

Increased extracellular pH levels (e.g .. respiratory alkalosis) can cause an increase in the affinity
of serum albumin to calcium Thereby increasing the levels of albumin-bound calcium and
consequently decreasing the levels of ionized calcium. Ionized calcium is the only
physiologically active form which means that decreased levels of this form can result in clinical
manifestations of hypocalcemia.

The formula for corrected calcium level is:

Corrected calcium in mg/dl = measured total calcium + 0.8 (4.0 g/dl- measured serum albumin
in g/dl).

Another method is to roughly estimate the corrected calcium level:

With every 1 g/dl change in serum albumin level from 4 g/dl, there is a resultant change in total
plasma calcium level by 0.8 mg/dl. For instance, if the serum albumin level decreases from 4.0
g/dl to 3.0 gm/dl, the serum total calcium will decrease by 0.8 mg/dl.
Hypercalcemia of Immobilization - Immobilization of an individual with high bone turnover
results in increased osteoclastic activation that can lead to hypercalcemia. Bisphosphonate
therapy in immobilized patients is helpful in reducing hypercalcemia and preventing
osteopenia.

Hypercalcemia Of Malignancy - Malignancy is a common cause of hypercalcemia, usually

involving 1 of 4 mechanisms (Table). Metastatic breast cancer most commonly causes
hypercalcemia by producing parathyroid hormone-related peptide (PTHrP). PTHrP is not
produced by the primary tumor in many cases of breast cancer. Instead, it is produced locally
when the tumor metastasizes into the bone to induce bone resorption. Systemic PTHrP levels
are not elevated in these patients. Some cases of hypercalcemia in breast cancer are due to
both local and systemic PTHrP elevation. In some malignancies (eg, multiple myeloma,
lymphomas, leukemia), osteoclastic bone resorption is increased by cytokine production
including interleukin-6, interleukin-3, RANK-L, tumor necrosis factor-alpha, and macrophage
inflammatory factor 1-a.

The metastatic tumor cells do not directly cause bone resorption but instead secrete factors
that activate osteoclasts to indirectly cause bone resorption. This mechanism is responsible in
about 20% cases of breast cancer metastasis.

Pagets Disease of Bone aka Osteitis Deformans - The primary defect in Paget's disease is
abnormal bone remodeling. Initially, there is a localized excess of osteoclastic bone resorption,
in which there are usually increased numbers of larger than normal osteoclasis at the involved
sites. With progression of osteoclastic activity, activation of the osteoblasts and immature bone
deposition occurs. Activation of the osteoclasis and osteoblasts leads to transformation of
normal lamellar and woven bone into a chaotic "mosaic" pattern of irregularly juxtaposed
pieces of lamellar bone, interspersed with woven bone. In some cases, the disease eventually
gets burned out, in which the abnormal matrix persists, but cellular activity is nearly absent.

Patients are often asymptomatic; however, those with symptoms usually first note an increase
in hat size, which is indicative of asymmetric enlargement of the cranium. In patients with
cranial enlargement, hearing loss is a common complication. This hearing loss correlates with
loss of bone mineral density in the cochlear capsule. hearing loss, increased hat size, and
occasional headaches are common.

In general, the following tests accurately reflect the extent and activity of the disease:

1. Alkaline phosphatase - marker of bone formation; it is elevated in patients with Paget's

disease, and is most commonly used to assess the activity of disease, as well as response to
treatment.
2. Urinary n telopeptide - most commonly used as a marker of bone resorption.
Patients with Paget's disease should be evaluated carefully for bone pain, neurologic
compression syndrome, bone deformities, pseudo fractures, signs of increased metabolic
activity, and secondary osteoarthritis. Full-body bone scintigraphy followed by plain radiologic
confirmation in areas of increased tracer uptake can assess the full extent of the disease.
Nuclear bone scan is not very specific but is very sensitive for detecting the extent of skeletal
involvement. However, measurement of total serum alkaline phosphatase activity is an
effective and inexpensive test for determining Paget's disease activity in most patients.

Symptomatic individuals with metabolically active Paget's disease should receive treatment.
Bisphosphonates inhibit osteoclasis to suppress bone turnover and are the preferred therapy.
The clinical response (eg, decrease in bone pain) is often seen before alkaline phosphatase
normalizes.

Treatment of asymptomatic patients with minimal disease activity is usually not required as
studies have shown no significant benefit.

Hypercalcemia Diagnostic Approach – The first step in evaluating hypercalcemia is to

measure PTH. Hypercalcemia with low PTH is usually due to causes such as malignancy, Vitamin
D toxicity, or granulomatous diseases (eg, sarcoid). Hypercalcemia associated with
inappropriately normal or elevated PTH, as in this patient, is most commonly due to PHPT in the
ambulatory setting.

In normal individuals or those with PTH-independent hypercalcemia, the increased calcium

usually decreases serum PTH levels via the negative feedback mechanism. However,
hypercalcemia in PHPT does not significantly suppress PTH secretion from the autonomously
functioning adenomatous or hyperplastic parathyroid glands. Serum phosphorus may be low or
normal in patients with PH PT. Low phosphorus levels are more common in patients with
moderate to severe PHPT.
Vigorous hydration with intravenous normal saline is the first step in managing severe
symptomatic hypercalcemia. Asymptomatic or mild hypercalcemia ( < 12 mg/dL) usually does
not require immediate aggressive therapy. Bisphosphonates (eg, zoledronic acid) are the drugs
of choice for long-term management of hypercalcemia of malignancy.
Severe Hyponatremia Rx in SIADH - Severe hyponatremia (plasma sodium < 120
meq/L) with central nervous system symptoms (e.g., seizures or change in mental status)
requires aggressive management with intravenous 3% Hypertonic saline. Despite such
aggressive measures, rapid correction should be avoided because it can lead to central pontine
myelinosis. The rate of correction should therefore not exceed more than 0.5 to 1 mEq/Uhr.

Water restriction is the best treatment for mild asymptomatic hyponatremia.

Diabetes Incipidus Management - presents as polyuria and polydipsia due to anti-diuretic

hormone (AOH) deficiency or resistance. Patients are typically polydipsic and prefer cold
beverages. They characteristically excrete dilute urine in the presence of increased plasma
osmolality. Normal saline is the best initial intravenous fluid of choice for any patient with
gross intravascular fluid deficits and hypotension.

Once the intravascular volume improves, the water deficit can be corrected with hypotonic
fluids (0 .45% saline or 05%W). In patients without hypotension, hypotonic intravenous fluids
can be started as an initial therapy.
Conn’s Hyperaldosteronism - A young patient with hypertension, muscle weakness and
numbness should make you think of primary hyperaldosteronism. This condition is usually
caused by an aldosterone-secreting adrenal tumor. When there is an aldosterone excess in the
body, this causes anincreased renal sodium reabsorption with resultant hypertension.
Aldosterone also increases renal potassium loss with resultant muscle weakness and numbness.
The most specific laboratory value for this condition is increased aldosterone/renin ratio,
because an increased aldosterone level suppresses renin secretion.

Plasma aldosterone to plasma renin activity ratio (PA:PRA) is used as an initial screening test
for primary hyperaldosteronism;

Gluconeogenesis - In fasting, glycogen reserves drop dramatically in the first 12 hours, during
which gluconeogenesis starts to play an important role. After 24 hours, it represents the sole
source of glucose. The main substrates for gluconeogenesis are: gluconeogenic amino acids
(protein from muscle), lactate (from anaerobic glycolysis), and glycerol 3-phosphate (from TAG
in adipose). Alanine is the major gluconeogenic amino acid, and it is converted into pyruvate
in the liver by alanine aminotransferase (AL T). Pyruvate is eventually converted to glucose
though a series of reactions in the liver, and glucose is then released into the bloodstream.

Polyuria & Polydypsia - The major causes of polyuria and polydipsia in non-hospitalized
patients are diabetes mellitus, diabetes insipidus (01) and primary polydipsia (previously called
as psychogenic polydipsia).

Diabetes insipidus - Serum Hyperosmolarity + Urine Hypoosmolarity

SIADH - Serum Hypoosmolarity + Urine Hyperosmolarity

Primary Polydypsia is due to excessive water drinking; both plasma and urine are diluted.

Pheochromocytoma Rx - When treating patients with pheochromocytoma, do not give beta-

blockers without alpha-blockers. Always give an alpha-blocker first, followed by a beta-blocker;
doing this in the wrong order can precipitate a very danqerous increase in blood pressure.

MEN Syndrome - Multiple endocrine neoplasia type 2 is an autosomal dominant disorder. It is

further classified into MEN types 2a and 2b. Both subtypes are characterized by medullary
carcinoma of the thyroid and pheochromocytoma. The distinguishing feature for MEN type 2a
is primary hyperparathyroidism, while that of MEN type 2b are mucosal neuromas and
marfanoid habitus. Primary hyperparathyroidism in MEN type 2a is due to parathyroid
hyperplasia rather than parathyroid adenoma. Mucosal neuromas are the most distinctive
feature of MEN type 2b, and are present in more than 90% of cases; these are present on the
tongue, eyelids, lips and gastrointestinal tract.

MEN Screening - Genetic testing (RET proto-oncogene germ line mutation) is more sensitive
than biochemical measurement (serum calcitonin) and is the recommended screening test for
suspected multiple endocrine neoplasia type 2 syndromes. Total thyroidectomy is indicated for
patients with positive genetic testing; no further monitoring is required for patients with
negative testing.

Chronic Steroid Use - Chronic supraphysiologic doses of glucocorticoids suppress corticotropin-

releasing hormone release from the hypothalamus, causing central adrenal insufficiency.
Aldosterone secretion is relatively preserved in these patients because ACTH has a very modest
effect on its secretion. Laboratory studies typically show low ACTH and cortisol levels and
relatively normal aldosterone.

Testicular Tumor Markers - Leydig cell tumors are the most common type of testicular sex cord
stromal tumors, which may occur in all age groups, including young children. Leydig cells are
the principal source of testosterone and are capable of estrogen production, due to markedly
increased aromatase expression. The estrogen production is markedly increased in tumorous
growth of Leydig cells, with secondary inhibition of LH and FSH levels. Endocrine manifestations
are found in only 20 to 30 percent of adults, the most common being gynecomastia, however in
prepubertal cases, precocious puberty is common.
Choriocarcinoma is a germ cell tumor characterized by increased serum beta-HCG
Concentration.

In teratomas elevations in the serum concentration of AFP or beta-hCG can appear, which
cannot be attributed to teratomatous element, however they indicate the coexistence of other
germ cell tumor components.

In seminomas serum tumor markers are usually normal, although beta-hCG may be somewhat
elevated with seminomas that contain syncytiotrophoblastic giant cells.

Yolk sac tumor (endodermal sinus tumor) is a germ cell tumor accompanied by an increase in
serumAFP.

Panhypopituitarism - Pituitary tumors most commonly cause panhypopituitarism by exerting

pressure on pituitary cells to either temporarily or permanently impair cellular functions.
Anterior pituitary hormone deficiency can present with variable symptoms depending on the
rapidity of onset, severity of hormonal deficiencies ( eg, adrenocorticotropic hormone [ACTH],
thyroid), and types of hormonal involvement (single or multiple).

Glucocorticoid deficiency (weakness, fatigue, loss of appetite, eosinophilia) and hypothyroidism

(cold intolerance, constipation, bradycardia). Testing will show low thyroid-stimulating
hormone, low free T 4, and low cortisol. Hyperpigmentation is absent in central adrenal
insufficiency as ACTH and melanocyte-stimulating hormones levels are low. Aldosterone
secretion from the zona glomerulosa is ACTH-independent. As a result, secondary (central)
adrenal insufficiency does not cause hyperkalemia or salt wasting.

Bartter & Gitleman Syndrome –

The differential diagnoses of normotensive patients with hypokalemia and metabolic alkalosis
include:

1. Diuretic use
2. Surreptitious vomiting
3. Bartter syndrome
4. Gitelman syndrome

Classic Bartter syndrome usually presents early in life as Polyuria, Polydypsia and growth and
mental retardation. However, presentation can occur later in life, as in this patient. The
underlying pathology is defective sodium and chloride reabsorption in the thick ascending limb
of the Henle loop. resulting in hypovolemia and consequent activation of the renin-angiotensin
aldosterone system (RAAS). Gitelman syndrome is a subset of Bartter syndrome with a defect in
the distal convoluted tubule causing the same sequence of events. Activated RAAS causes an
increase in potassium and hydrogen ion secretion. leading to hypokalemia and metabolic
alkalosis.

Patients with Bartter syndrome have hypokalemia. Urinary chloride level > 20 mEq/L (most
often >40 mEq/L), metabolic alkalosis, and normal blood pressure.