05 Endocrine

HPA

The hypothalamic-pituitary axis (HPA) regulates the synthesis, storage, and secretion of most major hormones in the human body through direct or feedback pathways that modulate hypothalamus and pituitary gland function.

The pituitary gland has two functionally and morphologically distinct sections, known as the anterior and posterior lobes.

The hypothalamus communicates with the:

• Anterior pituitary via the portal vascular system

• Posterior pituitary via direct neuronal extension

The hormones secreted from the anterior pituitary lobe are normally controlled by positive feed-forward releasing factors from the hypothalamus via the portal vascular system. This means that the production of a hormone in the hypothalamus generally stimulates production of the corresponding hormone in the pituitary.

NOTE: The exception is prolactin, which is inhibited by hypothalamic dopamine production. Somatostatin also has a small inhibitory effect on growth hormone.

The posterior pituitary is essentially a continuation of the hypothalamus, which again, is a CNS structure. Therefore, the posterior pituitary lobe is sometimes referred to as the neurohypophysis. Unlike the anterior lobe, hormones are not made in the posterior lobe, but they are simply stored after being made in the hypothalamus.

The hypothalamus produces the following hormones:

• Thyrotropin-releasing hormone (TRH)

• Corticotropin-releasing hormone (CRH)

• Growth hormone-releasing hormone (GHRH)

• Gonadotropin-releasing hormone (GnRH)

• Somatostatin

• Dopamine

NOTE: It also producesantidiuretic hormone (ADH, vasopressin) and oxytocin, which are discussed in the posterior pituitary section.

Hypothalamic "releasing hormones" travel to the anterior pituitary via the hypophyseal portal (venous) system to exert their stimulatory effects, causing the anterior pituitary to secrete:

• TRH - Thyroid stimulating hormone (TSH)

• CRH - Adrenocorticotropic hormone (ACTH)

• GHRH - Growth hormone (GH)

• GnRH - Follicle stimulating hormone (FSH)andluteinizing hormone (LH)

Hypothalamic "non-releasing hormones" generally have an inhibitory effect on the anterior pituitary:

• Somatostatin inhibits growth hormone (GH)

• Dopamine inhibits prolactin (PRL)

The anterior pituitary is responsible for the secretion of seven major hormones. The endocrine targets of these hormones are:

1. TSH acts on thyroid gland epithelium.

2. Prolactin has no direct endocrine target, but is important in lactation, menorrhea, libido, and fertility.

3. ACTH stimulates the adrenal cortex, primarily zona fasiculata and zona reticularis.

4. GH acts on receptors in the liver.

5. FSH stimulates testicular Sertoli cells and ovarian granulosa cells.

6. LH stimulates testiscular Leydig cells and ovarian theca cells.

7. MSH acts on melanocytes in the skin and hair.

End-organ effects generally have inhibitory effects on the hypothalamus, known as a "negative-feedback loop". For example,__excess free T4 produced by the thyroid will inhibit TRH production in the hypothalamus, which inhibits TSH production by the anterior pituitary, which decreases T4.

The posterior pituitary or neurohypophysis is a continuation of modified CNS cells from the hypothalamus.

Its main function is to store and secrete ADH (vasopressin) and oxytocin, which were synthesized in the hypothalamus. When stimulated, these pre-formed hormones are directly released into the venous circulation.

The primary stimulus for antidiuretic hormone (ADH) secretion is anincrease in serum osmolarity. ADH secretion can also be stimulated by volume contraction.

ADH's function is to conserve water by increasing the reabsorption of water from the collecting tubule of the nephron.

Oxytocin is released primarily in response to cervical dilation during pregnancy. This leads to uterine smooth muscle contractions and labor.

Oxytocin is also released during nipple stimulation in a lactating woman and serves to stimulate the smooth muscle around the lactiferous ducts to excrete breast milk.

Acromegaly

Acromegaly is generalized body enlargement due to excessive growth hormone production after the growth plates have fused.

Acromegaly is caused by excessive growth hormone production from the pituitary gland. The most common cause is a pituitary somatotroph adenoma.

One key is to differentiate between acromegaly and gigantism. Gigantism occurs before fusion of the epiphyseal plates. Acromegaly occurs after the epiphyseal growth plates have fused.

A great way to remember this is Acromegaly → After (Both start with "A").

Symptoms

Acromegaly is an insidious process, often presenting after many years. Patients will experience subtle changes such as coarsening of features, changes in glove or hat size, or musculoskeletal complaints such as arthralgias due to tissue overgrowth.

As with any pituitary tumor, bitemporal hemianopsia may occur due to compression of the optic chiasm. This mass effect may also cause headaches.

The hands, skull, and jaw (macrognathia) are the most affected.

Patients with acromegaly may have hyperhidrosis (excessive sweating).

Diagnosis

Measurement of serum IGF-1 is the best initial screening test for patients with suspected acromegaly. The finding of normal IGF-1 levels is sufficient to rule out acromegaly.

Note: Since serum GH levels fluctuate throughout the day, it is not used as an initial screening test because it is not as sensitive as serum IGF-1.

Oral glucose tolerance test (OGTT) is used to confirm a diagnosis of acromegaly in patients with elevated IGF-1 due to its high level of specificity.

An OGTT is considered positive when serum GH concentrations remain > 2ng/mL (inappropriately elevated) within two hours after ingestion of 75 g of glucose (normal value is <1.ng/ml).

Patients with both elevated IGF-1 levels AND positive oral glucose tolerance test should receive a MRI of the brain to look for a pituitary tumor.

Complications

Metabolic complications of acromegaly include:

• Diabetes mellitus due to increased insulin resistance caused by the excess GH

• Hyperlipidemia

Growth hormone can cause macroglossia (enlarged tongue), resulting in obstructive sleep apnea.

Heart failure is the most common cause of death in patients with acromegaly.

Treatment

Transsphenoidal resection of the pituitary adenoma is the treatment of choice.

Radiation therapy may be used if IGF-1 elevations persist after surgery.

Three classes of agents that can be used to treat acromegaly are:

• Somatostatin analogs (e.g. octreotide)

• Dopamine agonists (e.g. cabergoline)

• GH receptor antagonist (e.g. pegvisomant)

CAH

Congenital adrenal hyperplasia (aka CAH or adrenogenital syndrome) is an autosomal recessive disorder caused by deficiencies in adrenal steroid synthesis due to enzymatic defects.

The three main enzymatic deficiencies are:

• 21-OH

• 11-OH

• 17-OH

The most common cause of CAH is 21-hydroxylase deficiency.

There is no negative feedback due to the deficient adrenal steroid synthesis. Therefore, there will be increased ACTH production, which leads to adrenal hyperplasia (including androgen excess)

A unifying feature between 21, 11, and 17-OH deficiencies is that a deficiency in one pathway causes precursor shunting to the remaining functional pathways

So, an enzyme deficiency in one pathway may lead to overproduction of a different enzyme in another pathway.

21-OH

21-OH deficiency: This enzyme is responsible for the synthesis of aldosterone and cortisol.

Deficiency leads to:

• ↓ Aldosterone

• ↓ Cortisol

• ↑ Androgens

Clinically, this presents as salt wasting with hypotension and ambiguous female genitalia, or male precocious puberty.

Labs:

• Hyponatremia

• Hyperkalemia

• Excess androgen

11-OH

11-OH deficiency:

This enzyme is one step down the cortisol/aldosterone synthesis pathway. As such, it presents similarly to 21-OH deficiency, with one key difference:

The aldosterone precursor that accumulated in a 21-OH deficiency didn’t have any hormonal activity, but a deficiency in 11-hydroxyase allows for production of 11-deoxycorticosterone, which has a weak mineralocorticoid effect. This causes salt and water retention.

Therefore, clinically, it presents with hypertension and ambiguous female genitalia or precocious male puberty (from excess androgens).

21 and 11 are similar numbers, so remember that they are in the same pathway and cause similar effects. Additionally, 11-OH deficiency can be remembered with the mnemonic “↑↑-OH deficiency” with up arrows representing the hypertension and masculinized genitalia.

17-OH

17-OH deficiency:

Deficiency in this enzyme prevents androgens and cortisol production. This results in high aldosterone levels and dysfunctional sexual development.

Males will be born with either feminized or completely female external genitalia and hypertension (from salt and water retention)

Since female genitalia is the default pathway, females will appear sexually normal at birth. However, since androgens are essential to puberty, the females will present with a lack of secondary sexual development and amenorrhea. Like males, they will also have hypertension.

Labs:

• Hypernatremia --> HTN

• Hypokalemia

• Decreased androgens

Diagnostic Workup:

• Thorough History and Physical exam including genitalia

• Blood pressure

• Basic Metabolic Panel (Na, K)

Imaging studies may also help with the diagnosis

• Abdominal ultrasound to evaluate the adrenal glands

• Ultrasound can also be used to diagnose testicular adrenal rest tumors (benign testicular tumors found in both classic and non-classic CAH) and should be done beginning in adolescence

Classic CAH

Classic CAH (impaired cortisol and aldosterone) may cause adrenal crisis in the newborn, if severe. In the salt-wasting form, newborn infants develop symptoms shortly after birth that include:

• Vomiting

• Dehydration

• Electrolyte imbalances

• Cardiac arrhythmia

Newborn screening for 21-hydroxylase deficiency is now a part of many screening programs. The initial evaluation would consist of blood chemistry to look at the kidney function and potassium level as well as renin and aldosterone levels.

Further evaluation of CAH involves the measurement of specific hormonal levels.

• For 21-OH deficiency, measuring 17-hydroxyprogesterone levels is important for diagnosis. The levels are elevated in this condition.

• In 11-OH deficiency, there are elevated levels of 11-deoxycortisol (or 11 DOC for short).

• An ACTH stimulation test is used to confirm the diagnosis and the type of CAH.

Treatment

The mainstay of treatment for patients with congenital adrenal hyperplasia is exogenous glucocorticoids and mineralocorticoids (e.g. fludrocortisone).

The first-line glucocorticoid depends on the age of the patient; in children, hydrocortisone is used due to its short half life, which decreases the risk of iatrogenic short stature. In adults, dexamethasone is used.

Stress doses of glucocorticoids should be used in patients with congenital adrenal hyperplasia that are experiencing physical stress or illness to avoid an adrenal crisis.

DI

Diabetes insipidus (DI) is the inability of the body to retain water, which is normally done by reabsorbing it from the urine. There are two types: central and nephrogenic.

Causes

Central diabetes insipidus is caused by decreased ADH synthesis from the hypothalamus or decreased release from the posterior pituitary. Causes of central DI include:

• Idiopathic: destruction of the ADH-secreting cells in the hypothalamus

• Trauma

• Tumors

• Anorexia nervosa

Nephrogenic diabetes insipidus is caused by renal resistance to antidiuretic hormone. Causes include:

• Hereditary renal diseases

• Drugs

• Hypokalemia

• Hypercalcemia

Drugs that cause nephrogenic diabetes insipidus include:

• Lithium

• Demeclocycline (tetracycline antibiotic)

• Cidofovir (antiviral)

• Foscarnet (antiviral)

• Amphotericin (antifungal)

Symptoms

Patients classically present with polyuria, polydipsia, and new-onset nocturia.

In adults, onset of symptoms is usually abrupt in central DI, but more gradual in nephrogenic DI.

Diagnosis

The first step of workup of diabetes insipidus is urinalysis and serum metabolic panel. Findings include:

• Inappropriately dilute urine, meaning the urine osmolality will be < serum osmolality.

• Urine specific gravity <1.006 (or urine osmolality < 200 osmol/kg), with serum osmolality >290 osmol/kg.

Note: Low urine and serum osmolality is characteristic of psychogenic polydipsia, not diabetes insipidus.

If urine osmolality is low and serum osmolality is high, the next step is a water deprivation test.

• In normal physiology, decreased water intake leads to higher serum osmolality, provoking release of ADH and consequent water resorption from the urine, resulting in increased urine osmolality.

• No change in urine osmolality after water deprivation is diagnostic of diabetes insipidus.

Once the diagnosis of diabetes insipidus is established with the water deprivation test, the next step is a DDAVP test to distinguish central DI from nephrogenic DI. DDAVP (a.k.a. desmopressin) is a synthetic form of ADH/vasopressin.

• In central DI, administration of DDAVP will result in increased urine osmolality, because the absent vasopressin is replaced by a synthetic analogue.

• In nephrogenic DI, there will be no change in urine osmolality with administration of DDAVP, since the problem is renal resistance to ADH.

Treatment

The key treatment in central DI is desmopressin, which can be administered IV, SQ, PO, or intranasally. Surgery may be appropriate if the condition is caused by a pituitary or hypothalamic tumor.

For nephrogenic DI, the key is to treat the underlying disorder, if present. The following are helpful in symptomatic management:

• Hydrochlorothiazide, due to sodium excretion in the distal convoluted tubule, mild hypovolemia, and compensatory increased sodium and water reabsorption in the proximal tubule

• indomethacin, an NSAID that functions by similar mechanism as hydrochlorothiazide

• Amiloride in lithium-induced DI. Amiloride is a potassium-sparing diuretic that blocks lithium entry through the epithelial sodium channels in principal cells

DKA

Diabetic ketoacidosis is a hyperglycemic crisis characterized by the presence of ketones and metabolic acidosis.

DKA is a complication of diabetes mellitus (most commonly type 1).

Physiologic stress (e.g., infection, intoxication, lack of medication) leads to increased blood glucose and therefore increased insulin demand. In the setting of severe insulin deficiency, as seen in type 1 diabetes, the increased glucose cannot be used as energy. As a result, lipolysis occurs, leading to increased circulating free fatty acids that eventually breakdown to ketones.

In the setting of insulin deficiency, the free fatty acids undergo hepatic conversion into ketones (β-hydroxybutyrate, acetoacetate), which causes the ketonuria seen in DKA. The ketones are converted into ketoacids (β-hydroxybutyric acid, acetoacetic acid), which contributes to the metabolic acidosis seen in DKA.

Symptoms

Patients classically present with abdominal pain, vomiting, fruity breath odor, and profound dehydration (even though they may not look like it).

Note that while DKA is a complication of diabetes, it can be an initial presentation of type 1 diabetes, so the patient may not be a known diabetic at the time of evaluation. DKA can also be seen in type 2 diabetics.

The conversion of acetoacetic acid to acetone causes the fruity odor on the patient’s breath.

Hyperglycemia leads to glucosuria, which causes osmotic diuresis and subsequent dehydration. Patients may even have mental status changes secondary to dehydration.

Kussmaul respirations are a respiratory compensation for the metabolic acidosis in DKA. Carbonic acid in blood is converted to CO2. Increased blood CO2 levels cause deep, rapid breathing in an attempt to expel the excess CO2. This breathing pattern is called Kussmaul respirations and is a notable characteristic of severe DKA.

Diagnosis

Diagnosis of DKA is based on:

• Elevated glucose (>300 mg/dL)

• Anion gapped metabolic acidosis (bicarbonate < 15mEq/L, pH < 7.30, AG > 17)

• Urine strongly positive for glucose and ketones

Initial electrolyte panel commonly shows normal or high potassium and low sodium.

Glucose and ketones in the blood pass into the urine, causing osmotic diuresis, (loss of water and electrolytes in the urine). Potassium moves from intracellular fluid to extracellular fluid to compensate for electrolyte loss, so patients with DKA, who actually have low total-body potassium stores, generally have normal or high serum potassium on labs.

When potassium moves from intracellular fluid to extracellular fluid, water follows. Sodium gets diluted out by the increased water, so patients with DKA, who actually have normal total-body sodium stores, generally havelow sodium on labs.

Treatment

Treatment of DKA includes:

• Normal saline

• Potassium

• Insulin and glucose

• Treatment of the precipitating event as appropriate

Potassium levels should be checked BEFORE starting insulin therapy because insulin can worsen preexisting hypokalemia leading to fatal cardiac arrhythmias.

Fluid repletion should take place slowly, over 1-2 days, to prevent cerebral and pulmonary edema. Cerebral edema alone accounts for 60-90% of deaths from DKA in children, so careful monitoring for neurologic changes is recommended throughout the course of treatment. Normal saline is used to restore the depleted extra-cellular fluid volume as well as augment counterregulatory hormones.

Contrary to popular belief, insulin is NOT given solely to bring down the blood sugar. It is used mainly to prevent further ketogenesis and lipolysis. In fact, when glucose comes down to 200 mg/dL glucose or dextrose is given along with the insulin to prevent hypoglycemia.

• The optimal rate of glucose decline is 100 mg/dL per hour.

• Glucose should not fall below 200 mg/dL during the first 4-5 hours of treatment, due to risks of rebound ketosis and cerebral edema.

• Insulin infusion is given until the ketosis is corrected, rather than until the glucose level is normal. The patient can then be transitioned to subcutaneous insulin.

Insulin repletion causes potassium to move back into cells, which provokes hypokalemia in DKA patients with low total-body potassium stores. So, potassium is administered with insulin even if the initial lab results show normal potassium levels to prevent hypokalemia.

Diagnosis of the precipitating event is important in DKA. Treat it if applicable (e.g., give antibiotics for infection), and plan management to prevent future episodes (e.g., change insulin regimen).

Complications of DKA include hypoglycemia, hypokalemia, and cerebral and pulmonary edema. The first two complications are much less common now than they used to be, because of the current preventive measures we take in DKA treatment. See above for treatment of DKA

The best way to monitor for resolution of DKA is diappearance of the elevated anion gap.

HHNK

Hyperglycemic hyperosmolar non-ketosis (HHNK) is a hyperglycemic crisis characterized by hyperosmolality and dehydration without ketosis. It is also known as hyperglycemic hyperosmolar state (HHS), nonketotic hyperglycemia, and hyperosmolar non-ketotic coma (HONK).

HHNK is usually a complication of type 2 diabetes mellitus. It is not usually seen in type 1 diabetes mellitus.

Dehydration in HHNK occurs via:

• Physiologic stress (e.g., infection, intoxication, lack of medication) leads to increased blood glucose and therefore increased insulin demand.

• In the setting of insulin resistance (type 2 diabetes mellitus), glucose cannot be cleared, leading to increased plasma osmolality.

• The increased plasma osmolality leads to osmotic diuresis, which causes the significant dehydration seen in HHNK.

Type 1 diabetics typically have little to no circulating insulin, which causes lipolysis during a hyperglycemic crisis, leading to diabetic ketoacidosis (DKA).

In contrast, type 2 diabetics typically have some circulating insulin, which is sufficient to prevent lipolysis and therefore prevent development of ketosis and acidosis.

Symptoms

The classic presentation of hyperglycemic hyperosmotic non-ketosis (HHNK) is:

• Several weeks history of polydipsia, polyuria, and altered mental status

• Clinical signs of significant dehydration, causing anorexia and weight loss

• Known or unknown type 2 diabetes.

Symptoms usually develop gradually. The fluid deficit in HHNK can be up to 10L.

HHNK is typically seen in elderly patients who have multiple comorbid conditions.

Mental status changes, such as confusion and coma, are often present due to the change in volume and osmolar status.

Diagnosis

Diagnosis of HHNK is based on:

• Elevated glucose (>600 mg/dL)

• Elevated plasma osmolality (>350 mOsm/L)

• Absence of ketones in the blood or urine

Arterial blood gases (ABG) typically shows normal pH (>7.3) and normal bicarbonate (>15), unlike in DKA.

Initial electrolyte panel commonly shows normal potassium despite low total-body potassium stores.

• Glucose in the blood passes into the urine, causing osmotic diuresis (loss of water and electrolytes in the urine).

• Potassium moves from the intracellular fluid to the extracellular fluid to compensate for electrolyte loss

• So patients with HHNK, who actually have low total-body potassium stores, generally have normal potassium levels on labs.

Dehydration causes prerenal azotemia, resulting in elevation in creatinine.

Seeking a precipitating event is crucial in HHNK, because:

• The precipitating event is often severe

• Comorbid conditions are common

• Mortality can be up to 15% even with optimal treatment

Acute febrile illness is often the precipitating event, with pneumonia and urinary tract infections among the most common causes.

In contrast, DKA often occurs due to absolute insulin deficiency or non-compliance with insulin regimen.

The initial step in the treatment of HHNK is isotonic saline infusion. Additional components of treatment include insulin, glucose, and potassium in addition to treating the precipitating event (treat underlying ACS, sepsis, etc.).

Complications of HHNK treatment include hypoglycemia, hypokalemia, and cerebral and pulmonary edema.

Treatment

Fluid repletion should take place slowly, over 1-2 days, to prevent cerebral and pulmonary edema.

Insulin is given to prevent ketogenesis and lipolysis (precipitating factors in DKA) and to reduce the blood sugar. When glucose decreases to 250-300 mg/dL, 5% dextrose solution should be co-administered with insulin to prevent iatrogenic hypoglycemia.

Insulin therapy causes potassium to move into cells, inducing hypokalemia in HHNK patients with low total-body potassium stores.

Therefore, potassium is administered with insulin even if the initial lab results show normal potassium levels.

The largest prognostic factor in recovery from HHNK is the degree of hemodynamic instability at presentation. Therefore, aggressive volume resuscitation and correcting the underlying cause is important.

Prolactinoma

Prolactinoma is a benign hyperfunctioning adenoma of the anterior pituitary that secretes the hormone prolactin.

To remember the hormones secreted by the anterior pituitary, use the mnemonic "My FLAT PiG" = MSH, FSH, LH, ACTH, TSH, Prolactin, GH

• MSH (Melanocyte-Stimulating Hormone) – Corticotroph

• FSH (Follice-Stimulating Hormone) – Gonadotroph

• LH (Luteinizing Hormone) – Gonadotroph

• ACTH (Adreno-corticotropic Hormone) – Corticotroph

• TSH (Thyroid Stimulating Hormone) – Thyrotroph

• Prolactin – Lactotroph

• GH (Growth Hormone) – Somatotroph

Also, to be complete, remember that the anterior pituitary secretes Endorphins, Lipotropin, and POMC (pro-opiomelanocortin), but this is not high yield for Step 2

A prolactinoma is the most common pituitary tumor, accounting for approximately 30% of all hyperfunctioning pituitary adenomas.

Other Causes

A prolactinoma is NOT the only cause of hyperprolactinemia (elevated prolactin levels). Other causes include:

• Pregnancy (reaches peak at delivery)

• Drugs that block dopamine synthesis (methyldopa, verapamil, haloperidol)

• Dopamine depleting drugs

• Renal failure

• Hypothyroidism

• Hypothalamic damage (head trauma)

Remember: Dopamine normally INHIBITS Prolactin.

Symptoms

Signs/Symptoms: Female: Galactorrhea and Amenorrhea Male: Loss of libido, Erectile Dysfunction, and Gynecomastia

Enlargement of the pituitary gland → compression of optic chiasm → bitemporal hemianopsia (loss of peripheral vision).

Diagnosis and Treatment

Increased Prolactin (>200ng/mL) on labs suggests prolactinoma, but this varies depending on size of tumor

MRI of the hypothalamic-pituitary region is the imaging modality of choice in the workup of suspected prolactinoma.

Treatment for prolactinoma includes:

• Dopamine agonists bromocriptine or cabergoline. Dopamine inhibits Prolactin release. This also explains why dopamine antagonists (ex: antipsychotics) cause galactorrhea (low dopamine leads to high prolactin).

• Transsphenoidal surgical resection for large tumors.

• Radiation therapy in refractory cases.

SIADH

The syndrome of inappropriate anti-diuretic hormone (SIADH) is a condition of excess anti-diuretic hormone (ADH) leading to impaired water excretion and excessive water retention.

Causes

Causes include:

• Ectopic production of ADH, most commonly from small-cell lung carcinoma

• CNS disorder or trauma, such as stroke, hemorrhage, infection, or psychosis

• Pulmonary disease, particularly pneumonia

• Surgery, especially transsphenoidal pituitary surgery

• Drugs: cyclophosphamide, carbamazepine, SSRIs

Symptoms

SIADH should be suspected in any patient with hyponatremia, serum hypoosmolality, and urine osmolality > 100 mOsmol/kg.

Patients may experience the following symptoms:

• Cognitive slowing and confusion

• Anorexia

• Ataxia with muscle weakness causing falls

• Generalized seizures

• Coma

Note: these symptoms are typically only seen with severe or acute-onset hyponatremia.

Physical exam is most often normal, with no evidence of fluid overload or volume depletion (normal blood pressure, skin turgor, etc.).

Diagnosis

Diagnosis is made using both the clinical appearance of euvolemia and the laboratory results described below.

When SIADH is suspected, the following labs should be ordered, and these results are consistent with SIADH:

• Serum electrolytes (sodium, potassium, bicarbonate): low sodium, normal potassium and bicarbonate

• Serum osmolality: low

• Urine osmolality: submaximally dilute (> 100 mOsmol/kg)

• Urinary sodium excretion: normal or high, not reduced like other causes of hyponatremia

• Anion gap: reduced

• Serum blood urea nitrogen (BUN): low (< 10 mg/dL)

• Serum uric acid: low (< 4 mg/dL)

• Blood glucose: normal value rules out hyperglycemia as cause of hyponatremia

• Serum cortisol: normal value rules out adrenal insufficiency as cause of hyponatremia

• Thyroid-stimulating hormone: normal value rules out hypothyroidism as cause of hyponatremia

Correction of hyponatremia after fluid restriction is indicative of SIADH.

Imaging is used to find the cause of the SIADH, rather than to come to the initial diagnosis of SIADH.

• Chest x-ray may show small-cell lung carcinoma producing exogenous ADH.

• Head CT or MRI may show a brain tumor or other CNS disorder causing excessive ADH production. It may also show cerebral edema, a complication of SIADH.

Complications of SIADH are typically neurologic issues such as seizure or coma, due to hyponatremia.

Treatment

Treatment focuses on correcting the hyponatremia.

First-line therapy in emergent situations is infusion of 3% hypertonic saline. Do not correct sodium levels too quickly, as rapid normalization of sodium levels can lead to central pontine myelinolysis!

• The goal is to raise serum sodium levels by 0.5-1 mEq/hour.

• Sodium levels should not be raised more than 10-12 mEq in the first 24 hours.

• Maximum sodium level is 125-130 mEq/L.

In non-emergent situations, use fluid restriction and/or V2 receptor antagonists.

• Fluid restriction limits water intake, forcing the kidneys to excrete free water from plasma to maintain the fixed osmolality dictated by ADH secretion.

• V2 (vasopressin) receptor antagonists, the –vaptans, reduce aquaporin channels in the renal collecting ducts, thereby decreasing permeability of the duct to water and reducing the amount of water reabsorbed into the body in the collecting duct.

• Furosemide and other loop diuretics can also be used to increase free water excretion, but should be used in conjuction with infusion of hypertonic saline to avoid net sodium loss.

• Demeclocycline, an older tetracycline, can induce diabetes insipidus by interfering with the action of ADH on the collecting duct. This drug is no longer commonly used, because its onset of action can take over a week, it can be nephrotoxic in patients with liver disease, and it is no longer available in most countries.

Aside from correcting the hyponatremia, further care centers on finding and treating the cause of the SIADH. This may involve:

• Surgery or chemotherapy for small-cell lung carcinoma

• Antibiotics for pneumonia

• Neurology or cardiology intervention for CNS disorder

• Medication management for drug-induced SIADH

DM I

Type I diabetes mellitus is caused by autoimmune destruction of the insulin-producing beta cells of the pancreas. It usually presents in childhood or adolescence.

There is a weak genetic association with HLA-DR3 and HLA-DR4.

Clinical Presentation: Remember the three P’s:

The three P’s are symptoms of uncontrolled hyperglycemia:

• Polyphagia

• Polydipsia

• Polyuria

A complication of Type I DM is diabetic ketoacidosis (or DKA). For more info, please see the topic on DKA.

Diagnosis

The preferred screening test for the diagnosis of diabetes mellitus is a fasting serum glucose ≥126 mg/dL measured on two separate days. Fasting is defined as 8 hours without caloric intake.

In addition to a fasting plasma glucose of ≥126 mg/dL, the diagnosis of diabetes mellitus can also be established with:

• HbA1c ≥ 6.5%

• Random blood glucose ≥ 200 mg/dL on one occasion in a patient with symptoms of hyperglycemia(e.g. polyuria, polydipsia)

Previous standards included 2 hr plasma glucose ≥ 200 mg/dl (11.1 mmol/l) during oral glucose tolerance testing with 75g oral glucose challenge. However, this is more expensive and less reliable than the other methods and is no longer recommended by the CDC.

When it is difficult to distinguish T1DM from T2DM, the following lab findings suggest a diagnosis of T1DM:

• Presence of autoantibodies directed against components of the pancreatic islets [e.g. glutamic acid decarboxylase (GAD65), tyrosine phosphatases, insulin, zinc transporter 8 (ZnT8)]

• Low or inappropriately normal fasting C-peptide and insulin levels in a patient with hyperglycemia

Insulin medications vary according to their duration of action. Regimens are often developed using meal-time rapid acting insulin superimposed over a background of a long-acting insulin. This serves to most closely mirror normal physiological levels.

Since insulin is degraded in the GI tract, it must be administered subcutaneously, whether by a pump, needle, or pen. Glucose levels must be checked frequently.

Complications of hyperglycemia are nephropathy, neuropathy, and vascular damage. Acutely, diabetic ketoacidosis is a potentially fatal complication that occurs in Type 1 diabetes mellitus.

Insulin

Rapid acting: Insulin glulisine, insulin aspart, and insulin lispro (GAL).

• Onset: 15-20 min

• Duration: 2-5 hr

Short acting: regular and semilente

• Onset: Both → 15 min

• Duration: Regular → 2-5 hr, Semilente → 12 hr

Intermediate acting: lente, isophane (NPH)

• Onset: 2 hr

• Duration: 24 hr

Long acting: ultralente (insulin glargine, insulin detemir, protamine-zinc)

• Onset: 4 hr

• Duration: 36 hr

Note: Insulin glargine (Lantus insulin) has no peak

Treatment

A common insulin regimen that tries to mimic the insulin physiologically is to administer a long acting insulin (Lantus) to provide background insulin, and rapid acting insulin (e.g. Lispro) with meals. (Note: Recall that insulin is secreted continuously; however, the level of insulin secretion rises in response to a glucose/carbohydrate load).

An insulin pump can also be prescribed for patients. They are implanted and provide a basal rate of insulin as well as increased doses with a meal. They allow for excellent glucose control.

Treatment: Since DM type I results from an absolute deficiency of insulin production from beta islet cells, the classic drugs used in DM type II can’t be used. Instead, type I is managed through administration of different forms of insulin.

Screening Recommendations for Diabetes (both Type I and Type II):

• Albumin/creatinine ratio minimum yearly

• Hemoglobin A1c every 3 months

• Annual eye and foot exams

DM II

Type II diabetes is most likely a result of both genetic and environmental factors. There is no association with HLA system. The interaction between genes and the environment has been demonstrated by twin concordance rates that approach 100%, but with a wide range of disease onset and course.

The following are risk factors for type II diabetes:

• Obesity

• Sedentary lifestyle and physical inactivity

• History of gestational diabetes

• Family history of diabetes

• Coexisting hypertension and dyslipidemia

• Increasing age

• Certain ethnic groups (African-Americans, Native Americans, Asian Americans, Pacific Islanders)

Type II Diabetes Mellitus is characterized by both insulin resistance and pancreatic beta-cell dysfunction. As insulin resistance develops, the beta cells must secrete more and more insulin to compensate. Over time, the beta cells “wear out” and are no longer able to compensate. By the time hyperglycemia is detected, all type II diabetics exhibit both decreased insulin secretion and increased insulin resistance.

Clinical Manifestations of Type II DM: The individual with Type II DM can present with the three P’s of polyphagia, polydipsia and polyuria, however many people are asymptomatic and the initial diagnosis is found on routine lab work (asymptomatic hyperglycemia).

Type I DM usually presents in children and adolescents, whereas type II DM is usually adult onset, often with a strong family history and association with morbid obesity.

Since insulin is available, ketoacidosis is unlikely to occur — indeed, true DKA (diabetic ketoacidosis) is an uncommon (though not impossible) complication of uncontrolled type 2 diabetes. However, uncontrolled type 2 diabetics are at risk of developing hyperosmolar hyperglycemic nonketotic syndrome, a conditions which results in hyperosmolar intravascular dehydration and can lead to coma. (Please see separate topic on HHNK for more details).

Antidiabetic

There are 5 major oral antidiabetic agents, which can be remembered with the mnemonic STαB Mellitus: Sulfonylureas, Thiazolidinediones, α-glucosidase inhibitors, Biguanides, Meglitinides. GLP agonists and DPP-4 inhibitors are newer medications.

Sulfonylureas: Commonly used medications include glyburide, glipizide, chlorpropamide, and tolbutamide.

• Mechanism: ↑ Insulin secretion by closure of ATP-gated K+ channel in pancreatic β cell membrane.

• Remember that the GLUT2 transporters bring glucose into beta cells where it is metabolized to produce ATP via aerobic respiration. The rise in ATP is the trigger for the beta cell to release insulin.

• When the K channel closes, the cell is depolarized (because it’s an inward rectifying channel) causing voltage-gated Ca2+ channels to open, which triggers the release of insulin.

• Special notes: Glyburide dose must be decreased with renal failure. Glipizide must be reduced with hepatic failure. Also, care must be taken to prevent overadministration and subsequent hypoglycemia.

Thiazolidinediones: Commonly used medications include Troglitazone, rosiglitazone, and pioglitazone

• Mechanism: Binds to PPAR-γ (peroxisome proliferator activating receptor-gamma), causing increased insulin receptor number and sensitivity, as well as decreased hepatic gluconeogenesis.

• Side effects include hepatotoxicity and cardiovascular toxicity. Absolute contraindication in pts with liver failure or CHF.

α-glucosidase inhibitors: The 2 commonly used medications include acarbose and miglitol.

• Mechanism: Prevent disaccharides in the gut from their final degradation into monosaccharides by brush border enzymes prior to absorption.

• In other words, it simulates disaccharidase deficiency (e.g. lactose intolerance), causing osmotic diarrhea and presenting more sugars to the colonic flora, which digests them, releasing gas and causing flatulence and is thus poorly tolerated by patients.

Biguanides: Metformin is the most important biguanide and the first line agent for DM type II.

• Mechanism: Metformin activates AMPK (AMP-activated protein kinase) → ↑ expression of orphan nuclear receptor SHP (small heterodimer partner) → inhibits expression of liver PEPCK and glucose-6-phosphatase, thus repressing hepatic gluconeogenesis.

• Side effects:

  • GI distress (e.g., diarrhea)

  • Weight loss

  • Lactic acidosis (rare, but 50% mortality when it occurs), especially in patients with underlying renal disease.

Meglitinides (e.g. nateglinide, repaglinide) have a similar mechanism of action as sulfonylureas; they close ATP-dependent potassium channels in the β-cell membrane, thus inducing insulin release.​

The most common adverse effect of meglitinides (e.g. nateglinide) is hypoglycemia. This is especially common in patients with renal failure.

Glucagon-like peptide-1 (GLP-1) agonists include exenatide and liraglutide. They have multiple mechanisms of action, including the stimulation of pancreatic beta cells. These agents also inhibit glucagon secretion and have a role in the digestion of carbohydrates by delaying gastric emptying.

Adverse effects of GLP-1 agonists (e.g. exenatide, liraglutide) include:

• Weight loss

• Nausea, vomiting, diarrhea

• Acute pancreatitis

Sitagliptin is a dipeptidyl peptidase (IV) inhibitor (DPP-4). By inhibiting this enzyme, it increases the levels of glucagon like peptide. This stimulates the secretion of insulin by the beta cells.

• It can be used with other medications in the treatment of type II diabetes

• It can cause diarrhea and increased liver function tests in some people

• There has been an association with pancreatitis and even pancreatic cancer with this medication

Diagnosis

Diagnosis is most often made due to fasting serum glucose ≥126 mg/dL (7.0 mmol/l), measured on two separate occasions. Fasting is defined as 8 hours without caloric intake. Other diagnostic options include:

• HbA1c ≥ 6.5%

• Random blood glucose ≥ 200 mg/dl on two occasions

• Random blood glucose ≥ 200 mg/dl on one occasion in a patient with symptoms of hyperglycemia (polyuria, polydipsia, etc)

• Previous standards included 2hr plasma glucose ≥ 200 mg/dl (11.1 mmol/l) during oral glucose tolerance testing with 75g oral glucose challenge. However, this is more expensive and less reliable than the other methods and is no longer recommended by the CDC.

Treatment

Lifestyle modifications for DM type II related morbidities include:

• Smoking cessation

• Healthy eating and active lifestyle

ACE inhibitors are used prophylactically in diabetes. ACE inhibitors dilate the nephron’s efferent arterioles, decreasing filtration pressure and preventing the progression of diabetic nephropathy.

Statins are used for all patients with any history of CAD, in patients with LDL > 100mg/dL who are under 40 years, and in patients with a cardiovascular risk factor over 40 years. Note: The goal LDL is < 100mg/dL and ideal is LDL < 70mg/dL.

Diabetic patients age 40-75 with an estimated risk >7.5% should be given high-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily). Those with a 10-year risk <7.5% may be considered for moderate-intensity therapy (eg, atorvastatin 10-20 mg, simvastatin 20-40 mg). This patient's estimated risk is >7.5% (risk calculator) and he therefore needs high-intensity statin therapy.

Pneumovax and yearly influenza shots are indicated because of the immunosuppressive effect of diabetes.

Screening Recommendations for diabetes (both Type I and Type II) are:

• Albumin/creatinine ratio checked yearly at minimum

• Hemoglobin A1c checked every 3 months

• Annual ophthalmic and podiatry examinations

Myxedema Coma

Myxedema coma is a state of severe hypothyroidism characterized by decreased mental status, hypothermia, hyponatremia, and respiratory depression.

Myxedema coma most commonly occurs in elderly patients.

Myxedema coma can be the result of longstanding uncontrolled hypothyroidism, most commonly primary hypothyroidism such as chronic autoimmune thyroiditis, or post-surgical or post-radioablative hypothyroidism.

Less often the hypothyroid state is secondary to pituitary or hypothalamic dysfunction. In these cases, the hypothyroidism would be accompanied by adrenal insufficiency.

Myxedema coma can also be precipitated by factors that include:

• Infection

• Cold exposure

• Myocardial infarction

• Opioids and other sedatives

Other symptoms are due to slowing of function in multiple organ systems, such as bradycardia with decreased cardiac output or hypoventilation leading to hypercapnia.

Myxedema coma should be suspected in any patient with:

• Depressed mental status

• Hypothermia

• Bradycardia

• Hypoventilation (with resulting hypercapnia)

• Hypoglycemia

• Hyponatremia

Particularly suspect this in a patient with post-thyroidectomy scar or known history of long-standing hypothyroidism.

Patients may have nonpitting edema due to abnormal mucin deposits—hence the name “myxedema”—resulting in puffy hands and face, swollen lips, enlarged tongue, and edematous pharynx. This can make airway management challenging.

Myxedema coma is an endocrine emergency with a 50-75% mortality rate. If laboratory results are delayed, treatment should begin upon clinical suspicion.

Diagnosis

Initial diagnosis and initiation of treatment is based on history and physical exam. Before treatment begins, however, blood should be drawn for serum:

• TSH (thyrotropin)

• Free T4

• Cortisol

Cortisol should be drawn before and after administration of glucocorticoids to monitor for adrenal insufficiency secondary to hypopituitarism.

Since most patients with myxedema coma have primary hypothyroidism, labs most commonly reveal low free T4 and high TSH.

Cardiac complications of myxedema coma include bradycardia and decreased myocardial contractility, with resultant low cardiac output and hypotension. Congestive heart failure can be seen in patients with preexisting cardiac disease. These abnormalities are fully reversible with correction of thyroid hormones.

Lipid abnormalities include elevated LDL and triglycerides.

Normocytic anemia may be present.

Treatment

Treatment for myxedema coma consists of:

• Thyroid hormone replacement

• Stress doses of glucocorticoids

• Supportive care

As with any patient who is critically ill and comatose, empiric antibiotics should also be considered until negative cultures prove absence of infection.

Thyroid hormone replacement is given, most often using IV levothyroxine (LT4). T3 can also be used, as can a combination of T3 and LT4.

Glucocorticoids (e.g. hydrocortisone) are given in stress doses as cortisol replacement until the possibility of coexisting adrenal insufficiency is excluded.

Supportive measures can mean the difference between survival and death in myxedema coma, particularly in the first 24 hours.

• Intubation with mechanical ventilation counters the hypoventilation and resultant hypercapnia with acidosis

• Passive rewarming counters the hypothermia

• Non-dilute fluids with electrolytes and glucose counter hypotension, hypoglycemia, and hyponatremia.

Control of hypothyroidism using levothyroxine or other thyroid hormone replacement is key to preventing another episode of myxedema coma.

Hirsutism

Causes of hirsutism in women
Etiology	Clinical features
PCOS	Oligomenorrhea, hyperandrogenism, obesity Associated with type 2 diabetes, dyslipidemia, hypertension
Idiopathic hirsutism	Normal menstruation Normal serum androgens
Nonclassic 21-hydroxylase deficiency	Similar to PCOS Elevated serum 17-hydroxyprogesterone
Androgen-secreting ovarian tumors, ovarian hyperthecosis	More common in postmenopausal women Rapidly progressive hirsutism with virilization Very high serum androgens
Cushing syndrome	Obesity (usually face, neck, trunk, abdomen) Increased libido, virilization, irregular menses
PCOS = polycystic ovary syndrome.

	LH	DHEAS	T
PCOS	High	High or normal	High
Adrenal Mass	Low	High	High
Ovarian Tumor	Low	Normal	High
Idiopathic	Normal	Normal	Normal

Women normally produce a number of androgens, including testosterone (T), androstenedione (AS), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS). AS, DHEA, and T are produced by both the ovaries and the adrenals. In contrast, DHEAS is produced predominantly in the adrenal glands.

This patient has an adrenal mass with rapidly progressive (ie, over weeks) hirsutism (excess terminal hair growth) and virilization (eg, clitoromegaly), suggesting very high androgen levels due to an androgen-producing neoplasm. Most androgen-producing adrenal tumors overproduce DHEAS. Although DHEA and DHEAS are used as diagnostic markers, they have negligible androgenic activity, and the clinical features are due to the conversion of DHEA and DHEAS to more potent androgens (ie, AS and T). Therefore, this patient would most likely have elevated DHEAS and T levels. LH would be low due to negative feedback by T.

MEN

Multiple endocrine neoplasias (MEN) are a group of genetically inherited diseases that result in proliferative lesions of multiple endocrine organs. All three MEN syndromes are associated with autosomal dominant inheritance.

MEN 1

MEN-1, aka Wermer syndrome, can be remembered as the "3 Ps" or the mnemonic “Para-Pan-Pit”:

• Parathyroid hyperplasia

• Pancreatic endocrine tumors

• Pituitary adenomas

Multiple endocrine neoplasia type 1
Manifestation	Clinical features
Pituitary adenomas (10%-20%)	Secretion of prolactin, growth hormone, ACTH (or “nonfunctioning” tumors) Mass effects (eg, headache, visual field defects)
Primary hyperparathyroidism (>90%)	Multiple parathyroid adenomas or parathyroid hyperplasia Hypercalcemia (eg, polyuria, kidney stones, decreased bone density)
Pancreatic/gastrointestinal neuroendocrine tumors (60%-70%)	Gastrinoma - recurrent peptic ulcersInsulinoma - hypoglycemia VIPoma - secretory diarrhea, hypokalemia, hypochlorhydria Glucagonoma - weight loss, necrolytic migratory erythema, hyperglycemia

The most common manifestation of MEN-1 is primary hyperparathyroidism. Parathyroid abnormalities include hyperplasia (monoclonal) and adenomas.

Pancreatic endocrine tumors in MEN-1 include:

• Gastrinomas associated with Zollinger-Ellison syndrome is most common

• Insulinomas

• Glucagonomas

• Nonfunctioning pancreatic tumors

Pituitary adenomas are most frequently prolactinomas, although some patients develop somatotrophin-secreting tumors (leading to acromegaly).

MEN-1 syndrome is caused by mutations in the MEN1 tumor suppressor gene, which encodes a poorly-understood product called menin,involved in transcription regulation.

MEN 2

MEN-2 is subclassified into three distinct syndromes. These are:

1. MEN-2A

2. MEN-2B

3. Familial medullary thyroid cancer

Familial medullary thyroid cancer is a variant of MEN-2A that presents with only medullary thyroid cancer without the increased risk of pheochromocytoma and hyperparathyroidism.

2A

MEN-2A, or Sipple syndrome, can be remembered using the mnemonic “MPH”:

• Medullary thyroid carcinoma

• Pheochromocytoma

• Hyperplasia of the parathyroid glands

2B

MEN-2B includes medullary thyroid cancer and pheochromocytoma like MEN-2A with mucosal neuromas and marfanoid body habitus. It can be remembered with the mnemonic “MMMP”:

• Mucosal neuromas of the skin and mucosa (oral and intestinal ganglioneuromatosis)

• Marfanoid body habitus describes the long, axial skeletal features and hyperextensible joints seen in MEN-2B

• Medullary thyroid cancer

• Pheochromocytoma

Medullary thyroid carcinomas are seen in 100% of patients with MEN-2A and MEN-2B provided the patient lives long enough.

Genetic testing for mutations in the RET proto-oncogene is the most sensitive test for patients with suspected MEN-2A and MEN-2B.

Screening of family members is warranted only for patients with MEN-2A and MEN-2B. Screening relatives of patients with MEN-1 has not been proven to decrease morbidity and mortality in these individuals.

Treatment

Patients who are determined to have the RET proto-oncogene should undergo prophylactic total thyroidectomy to prevent the development of medullary thyroid cancer.

Myopathy

Common causes of myopathy
Connective tissue diseases	Polymyositis/dermatomyositis Inclusion body myositis Vasculitis Overlap syndrome (mixed connective tissue disease)
Endocrine/metabolic	Hypothyroidism, thyrotoxicosis Cushing syndrome Electrolytes (↓ potassium, calcium, phosphorus)
Drugs/toxins	Corticosteroids, statins Zidovudine, colchicine Alcohol, cocaine, heroin
Miscellaneous	Infections, trauma, hyperthermia

This patient has myalgias and proximal muscle weakness with an elevated serum creatine kinase (CK) level. In a relatively young, otherwise healthy woman with fatigue and delayed deep tendon reflexes, this presentation is most consistent with hypothyroid myopathy. Myopathy occurs in over one third of patients with hypothyroidism, and can range from an asymptomatic elevation in CK to myalgias, muscle hypertrophy, proximal myopathy, and rhabdomyolysis. Serum CK can be elevated for years before a patient develops clinical symptoms of hypothyroidism, and there is no clear correlation between the degree of CK elevation and severity of muscle disease. Inflammatory markers (eg, erythrocyte sedimentation rate, C-reactive protein) may be normal or mildly elevated.

Polymyositis is characterized by symmetric proximal muscle weakness. Sedimentation rate and CK are elevated in approximately half of patients, and the diagnosis can be confirmed with muscle biopsy. However, myalgias are typically absent or mild and deep tendon reflexes are normal.

Thyroid storm vs pheo

Thyroid storm can be precipitated by surgery in patients with preexisting thyrotoxicosis, but the presentation is usually less acute, and almost all patients will have pyrexia. Severely elevated blood pressure and pallor (from catecholamine-induced vasoconstriction) are more likely due to catecholamine surge from pheochromocytoma.

Hypoglycemia

	IGF2	C peptide	Insulin	Pro insulin
Exogenous	Low	Low	High
Sulfonurea	low	high	high	Low
Insulinoma	low	high	high	High
Non beta-oma	high	Low	low

Non-beta cell tumors, typically large mesenchymal tumors, can lead to hypoglycemia independent of insulin. Such tumors produce insulin-like growth factor II (IGF II), which has an insulinomimetic action after binding to insulin receptors. In patients with suspected non-beta cell tumors, the serum IGF II level can be measured. Patients with this condition characteristically have suppressed insulin and c-peptide levels.