Ch 22- Alterations of Hormonal Regulation

• Syndrome of Inappropriate Antidiuretic Hormone (SIADH) is characterized by high levels of antidiuretic hormone without normal physiological stimuli.

Causes of SIADH

• Common causes include ectopic ADH production by tumors, such as small cell carcinoma of the duodenum, stomach, and pancreas.
• Other causes include cancers of the bladder, prostate, and endometrium, lymphomas, and sarcomas.
• Pulmonary disorders like pneumonia, asthma, cystic fibrosis, and respiratory failure may also cause SIADH.
• CNS disorders such as encephalitis, meningitis, tumors, trauma including neurosurgery and intracranial hemorrhage, and medications especially in the elderly can lead to SIADH.
• Medications such as hypoglycemic medications, general anesthetics, antidepressants, chemotherapeutic agents, antipsychotics, NSAIDs, narcotics, and synthetic ADH can also contribute to SIADH.

Pathophysiology of SIADH

• Features result from enhanced renal water retention.
• ADH increases renal collecting duct permeability to water, inducing the insertion of aquaporin-2 (water channel protein).
• This process increases water reabsorption by the kidneys.
• Expansion of extracellular fluid volume stems from this.
• Dilutional hyponatremia (low serum sodium concentration), hypo-osmolarity and inappropriately concentrated urine osmolarity occur. The water that is reabsorbed is water that would normally be excreted.

Clinical Manifestations of SIADH

• Clinical manifestations result from hypotonic hyponatremia, leading to hypervolemia and weight gain.
• The severity and rapidity of onset determine the extent of the symptoms.
• Symptoms resolve with correction of hyponatremia.
• Rapid decreases in serum sodium, from 140-130 mEq/L, may cause thirst, impaired taste, anorexia, dyspnea on exertion, fatigue, and dulled sensorium. Weight gain is usually absent, or instead, water retention.
• Serum sodium levels decreasing from 130 to 120 mEq/L can cause vomiting and abdominal cramps.
• Serum sodium levels less than 110 to 115 mEq/L, even with slow hyponatremia development, can cause confusion, lethargy, muscle twitching, seizures, and sometimes irreversible neurologic damage.

Diagnosis of SIADH

• Diagnosis includes serum hypo-osmolality (less than 280 mOsm/kg) and hyponatremia (serum sodium level less than 135 mEq/L).
• Urine hyperosmolarity (urine osmolality is always higher than concurrent serum osmolality) is also diagnostic.
• It also includes urine sodium excretion that matches sodium intake, normal renal, adrenal, and thyroid function, along with an absence of conditions that can alter volume status.
• Conditions include recent diuretic use, heart or liver failure, hypervolemia from any cause, or renal insufficiency.
• ADH is hard to measure in serum; copeptin (ADH precursor molecule) is used as a surrogate marker.
• Neurologic injury develops from hyponatremia.
• Cerebral salt wasting syndrome is characterized by hyponatremia, hypovolemia, weight loss, and elevated urine sodium levels.

Treatment of SIADH

• Address the underlying causal problems, restrict fluid intake, and carefully monitor sodium levels and neurological symptoms.
• Emergency correction of severe hyponatremia involves careful administration of hypertonic saline and restriction of fluid intake(800-1000mL/day).
• Resolution usually occurs within 3 days with 2-3kg weight loss from enhanced free water clearance, correcting hyponatremia and salt wasting.
• Rapid correction of hyponatremia can lead to a severe neurological syndrome, central pontine myelinolysis.
• Demeclocycline causes renal tubules to develop resistance to ADH and can treat resistant or chronic SIADH.
• Vasopressin receptor antagonists (vaptans) can also effectively treat SIADH.

Comparing Signs and Symptoms: DI vs SIADH

• Urine output is high in Diabetes Insipidus (DI) and low in SIADH.
• Urine osmolality is low (less than 100-200 mOsm/L) in DI and high (more than 800 mOsm/L) in SIADH.
• Urine specific gravity is low (less than 1.010) in DI and high (more than 1.020) in SIADH.
• Serum sodium is high (more than 145 mEq/L) in DI and low (less than 135) in SIADH.
• Serum osmolality is hyperosmolar (more than 300 200 mOsm/L) in DI and hypo-osmolar (less than 285 mOsm/L) in SIADH.
• Symptoms of DI include polyuria, thirst, high urine output, and signs of dehydration, while symptoms of SIADH include water retention, low urine output, nausea, vomiting, and mental changes.

Definition of Diabetes Insipidus (DI)

• Insufficiency of ADH leads to polyuria and polydipsia.
• An inability of the kidney to increase permeability to water that leads to excretion of large volumes of dilute urine and an increased plasma osmolality.
• Clinical manifestations include polyuria, nocturia, continuous thirst, and polydipsia.
• Long-standing DI can result in large bladder capacity and hydronephrosis in untreated individuals.

Causes of Neurogenic DI

• Any organic lesion affects the hypothalamus, pituitary stalk, or posterior pituitary, interfering with ADH synthesis, transport, release, and insufficient amounts of ADH.
• Causative lesions include primary or secondary brain tumors, aneurysms, thrombosis, infections, and immunologic disorders.
• DI can result as a complication of closed-head trauma or pituitary surgery, and surgery can be transient or permanent.

Causes of Nephrogenic DI

• Insensitivity of the renal collecting tubules to ADH caused is either generic or acquired (more common).
• Genetic form is often idiopathic, although genetic abnormalities that affect the vasopressin receptor have been noted.
• Acquired form relates to disorders and drugs that damage the renal tubule or inhibit the generation of cAMP in the tubules.
• Disorders causing irreversible DI include pyelonephritis, amyloidosis, destructive uropathies, polycystic disease, and intrinsic renal disease.
• Drugs causing reversible DI include lithium carbonate, colchicine, amphotericin B, loop diuretics, general anesthetics, and demeclocycline.

Treatment for Symptomatic DI Patients

• Treatment is based on the extent of the ADH deficiency and individual variables.
• Synthetic vasopressin analog desmopressin acetate (DDAVP) provides replacement therapy, administered intranasally or orally.
• The treatment for nephrogenic DI includes correction of any reversible underlying disorders, discontinuation of medications, and correction of associated electrolyte disorders.

Pituitary Adenoma Etiology

• Slow-growing benign tumors arise from cells of the anterior pituitary; they commonly secrete GH and prolactin.

• Pathophysiology involves hypothalamic and intra-pituitary factors such as altered expression of pituitary cell cycle genes, activation of pituitary selective oncoproteins, and loss of pituitary suppressor factors.

• Hormonal effects include hypersecretion from the adenoma itself and hyposecretion from surrounding pituitary cells.

• Adenomatous tissue secretes the hormone of the cell type from which it arose, without benefit of regulatory feedback mechanisms.

• Often associated with increased secretion of GH and prolactin.

• If the tumor exerts sufficient pressure, thyroid and adrenal hypofunction results, decreasing TSH and ACTH.

Types of Pituitary Adenomas

• Microadenomas are less than 10mm and often found incidentally on high-resolution MRI; they are hormonally silent and without significant hazards.
• Macroadenomas are greater than 10mm and more significant, causing alterations in hormone secretion or invasion of surrounding structures.
• Giant Adenomas are greater than 40mm, and often cause morbidity and mortality

Clinical Manifestations of Pituitary Adenoma

• Increase in tumor size causes headaches, fatigue, neck pain, stiffness, seizures, visual changes, temporary blindness, and neurologic function changes.
• The pressure produced by a pituitary adenoma decreases the function of neighboring anterior pituitary cells, causing hyposecretion of other anterior pituitary hormones.
• There is a decrease in gonadotropic secretion with menstrual irregularity, decreased libido, and receding secondary sex characteristics.
• If the tumor exerts sufficient pressure, thyroid and adrenal hypofunction result, decreasing TSH and ACTH, as well as hypothyroidism and hypocortisolism)
• Pressure exerted by the tumor may cause hyposecretion of GH, FSH, and LH

Prolactinoma Etiology and Hallmark Signs

• Prolactinoma is a tumor secreting prolactin, which means it is the most common of the hormonally active pituitary tumors.
• The hallmark sign is sustained prolactin concentration.
• Adenomas that continue growing occupy space, which then causes hypopituitarism.
• Microprolactinomas are less than 1cm, encapsulated, and non-invasive.
• Macroprolactinomas are greater than 1cm and can expand into the optic chiasm, invade local structures, and are difficult to treat.
• Clinical manifestations include hypogonadotropic hypogonadism in women and men.

Evaluation and Treatment of Prolactinoma

• Women experience amenorrhea, infertility, nonpuerperal milk production (galactorrhea), and hirsutism, and Undetection leads to estrogen deficiency, osteopenia or osteoporosis.
• Men experience erectile dysfunction, infertility, and osteopenia that cause increasing tumor size, headache, and visual impairment.
• Prolactinoma commonly restores fertility in anovulatory women.
• Can perform transsphenoidal surgery and radiotherapy when medications aren't effective, along with new chemo and targeted molecular therapy options.
• Goal: to restore normal gonadal function and fertility while reducing the tumor size.

Acromegaly

• Acromegaly stems from continuous exposure to high levels of GH and IGF-1, and if this progressive disease goes untreated, it can decrease life expectancy.
• GH baseline secretion pattern and sleep-related GH peaks are lost, and there is unpredictable pattern of secretion.
• GH never completely suppressed in acromegalics; growth even when slight elevation of GH with IGF-1.

Clinical Manifestations of Acromegaly

• Acromegaly connective tissue proliferation results in enlarged tongues, interstitial edema, enlarged/overactive sebaceous and sweat glands (body odor), and course skin/body hair.
• Asymptomatic until heart-failure symptoms develop, and there is a chance of hyperprolactinemia occur.
• Bone overgrowth leads to large joint arthropathy, vertebral growth, facial bone, hand, and feet enlargement, kyphosis, and protrusion of the lower jaw/forehead.
• IGF-1 can cause cartilaginous growth causing the ribs to elongate at bonycartilage junction resulting in barrel-chest and spinal cartilage proliferation causing spinal joint pain.
• Bony/soft tissue overgrowth with nerve entrapment may also occur causing peripheral damage (foot drop and muscular atrophy) and sensory changes (carpal tunnel).
• Endocrine effects are diabetes, compensatory hyperinsulinism, and insulin resistance from adipose tissue inflammation.

Symptoms of Tumors and CNS

• Sleep disordered breathing and exacerbates issues of the heart
• CNS symptoms occur from growing tumor mass -> headaches, seizures, visual field disturbances, and papilledema.

Acromegaly Evaluation and Treatment

• Diagnosis involves physical and lab testing as well as testing such as MRI to confirm elevated levels of certain growth hormones.

• The goal of treatment is to restore normal endocrine function and relieve complications.

• If not, the patient will experience hyperprolactinemia which leads to weight gain (due to increase adipose tissue).

• Normalize GH and IGF-1 serum levels and restore normal pituitary function. Goal is to prevent complications related to tumor expansion.

• Transsphenoidal surgery to remove GH-secreting adenoma is treatment of choice in acromegaly.

• For those who can't control the condition using medicines, new chemo and molecular therapies must be used

• For people with heart, skeletal, and CV issues, radiation will not work

• Somatostatin Analogs and pegvisomant can normalize certain growth level

Grave's Disease Etiology

• Underlying factor is hyperthyroidism (50-80%), more in women than men
• Cause is unknown, factors interact with environmental triggers which play role in the pathogenesis.
• Infiltration of lymphocytes and Thyroid-stimulating immunoglobulins (TSI) autoantibodies (directed against TSH receptor) stimulate thyroid hyperplasia and synthesis of TH.
• Increased levels of TH effect all systems creating hyperthyroidism
• Warm skin, intolerance to heat, tachycardia all result from high TH levels.

Graves Disease Manifestations

• Functional abnormalities in the eyes is hyperactivity of the sympathetic division of the autonomic system causing Von Graefe's sign (lag of the globe on upward gaze and lag of the upper lid on the downward gaze)
• Lack of eye downward movement can result in eyelid delay.
• Infiltrative changes are orbital contents, enlarged ocular muscles, receptor autoantibodies with receptors on orbital fibroblasts.
• Patient will have exophthalmos(protrusion of the eye)
• Swelling on the anterior portions of the legs (indurated and erythematous skin)(Graces dermopathy)can also occur

Graves Analysis and Treatment

• elevated TH (T3), suppressed TSH as well normal of elevated radioactive iodine uptake scan
• Surgery for antithyroid drug use has several benefits such as the minimization of condition worsening.
• Disease exacerbation may occur with the abuse of smoke, while exophthalmos can be cured with meds.

Hypoparathyroidism

• Results from abnormally low PTH levels, but mostly from the parathyroid glands getting damages such as during thyroid surgery.
• Reduced level in PTH creates reduces serum levels and increase serum phosphate.
• Genetic disease, low mag, inherited levels can lead to the condition/ or reduce the level of function.
• Lack of PTH impedes the resorption calcium from bones, calcium retention and excretion

Hypoparathyroidism Side Effects

• Neuromuscular activity can result as well tingling or tetany/cavitations.
• Used to evaluate signs in neuromuscular irritability.
• Can cause low serum calcium levels and high aphosphorus levels

Treatment of Hypothyroidism

• Caused by antibiotics, eating disorders and lack of magnesium
• Can prevent by avoiding renal failures and eating healthier
• Also maintain calcium balance

Hyperglycemia

• Excess glucose in the blood because of carbs
• Seen with the presence of high insulin, increased sugar release.
• Overweight, and high blood pressure can create it easier, as well several visual impairment and diabetic issues

Treatment for Hyperglycemia

• Incorporate exercise in diet
• Use metformin as medication
• Implement insulin

Hypoglycemia

• Insulin reaction
• Low blood sugar
• Treatment includes glucagon

Diabetes Mellitus Classification and Pathophysiology

• Hyperglycemia creates defects in insulin, but it is a dysfunction of fat,protein
• Dysfunction stems from pancreatic issues and types 1-2
• 1 is cell distraction
• 2 is resistance

Diabetes Mellitus Diagnosis

• Hemoglobin levels
• Fasting levels
• Glucose levels
• Involves cell attachment to hemoglobin molecules
• Genetic predispositions results from 10-30%
• Can come from viral infection and autoimmune damage

Diabetes Mellitus Symptoms and Diagnosis

• Polydipsia
• Weight loss
• Fatigue
• Glucose testing

Beta Cell abnormalities

• Lack of insulin results in abnormal glucose levels
• Auto antibody
• Test helps identify type 1 from 2
• Keto acidosis may be symptoms from the disease
• Lack of treatment includes coronary issues and heart diseases

Prevent and Help with Diabetes Mellitus

• Avoid cows milk.
• Avoid gluten
• Increase intake of omega-3

Diabetes Mellitus Type 2

• Prevalence in africa, especially in native tribes
• Age, obesity, are factors
• Central pressure and prehypertension

Insulin and Type 2

• Glucose is not taken as well
• Inflammatory can also do this.

Compensation Problems

• Hyperinsulinemia prevents symptoms of the body
• Glucagon increased from what is caused acts as lever to increase sugar
• Amylin is also beta cell that is decreased
• Weight loss and bad diet makes risk of death rise

Treatments and Goals

• Diet
• Surgery
• Most need more medications

Main Factors

• Basal treatment

Type 1 VS 2

• 1 has to do with autoimmune and factors. Insulin results usually are too less
• 2 results due to more resistance.

Complication Issues

• Results from low carbs, weight loss and onset of diabetes.

Know hyperosmolar hyperglycemic nonketotic syndrome (HHNKS)? Know diabetic ketoacidosis (DKA)? What's the difference?

• Glucose imbalance can causes these
• Dehydrate from ketoacdosis to prevent death.

Cause of diabetics developing retinopathy + other factors

• Damages caused by high blood sugar levels.

Also factors involve cardio diseases, due to the need of death, and increase in hypertension. Causes cardiac attacks. * Damage, tension and fats can also occur

• Oxidative stress, can also lead to infection
• Results from RAGE, and poor circulation or blood. The disease can occur with diabetes and cause death if not treated. With medication, cardio issues.