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Portage Pathophysiology Module 9
Hormones - ☑️ Chemical messengers that regulate metabolism, growth, sexual drive, and sleep regulation.
They come from glands (pituitary, thyroid, parathyroid, adrenal) and organs (pancreas, gonads.
Hormone functions - ☑️ open and close ion channels (membrane potential)
stimulate gene expression to influence protein synthesis
activate or inhibit enzyme systems
induce secretory activity
stimulate mitosis
Endocrine - ☑️ Hormones are released to circulation to act on a target organ (i.e. TSH, ADH)
Paracrine - ☑️ Hormones act locally on cells close to where they are released (i.e. estrogen and testosterone)
Autocrine - ☑️ Hormones produce a biologic action on the cell that released them (i.e. insulin)
Homeostasis - ☑️ keeping hormone levels within a specific range that the body needs for optimal function
What are the different structural types of hormones? - ☑️ 1) amines and amino acids
- peptides and proteins
- steroids (cholesterol)
What is the function of the hypothalamus? - ☑️ The hypothalamus serves to link the nervous system to the endocrine system. It regulates homeostasis, body temperature, hunger, behavior, emotion, and pain. The hypothalamus produces releasing hormones, which stimulate the pituitary to release stimulating hormones.
What hormones does the hypothalamus release? - ☑️ GHRH, somatostatin, dopamine, TRH, CRH, GnRH
GHRH → GH
TRH → TSH
CRH → ACTH
GnRH → LH & FSH
What is the role of the pituitary gland? - ☑️ The pituitary gland is known as the "master gland," since it stimulates target organs to secrete their hormones.
What hormones does the anterior pituitary gland secrete? - ☑️ GH, ACTH, TSH, FSH, LH, & prolactin
What hormones does the posterior pituitary gland secrete? - ☑️ ADH and oxytocin
Explain the concept of negative feedback and give an example: - ☑️ Negative feedback is how the body maintains homeostasis, or equilibrium. The brain is constantly monitoring hormone levels to keep levels within its certain range or set-point. Negative feedback prevents over-secretion of any hormone. The action of ADH, which dilutes the blood, is one example. Once the blood is dilute, the hypothalamus detects the dilute levels and stops releasing ADH.
Explain the concept of positive feedback and give an example: - ☑️ Positive feedback enhances or increases the amount of the hormone that is released. One example is oxytocin, a hormone that causes the uterus to contract. The action of the uterus contracting causes more oxytocin to be released.
Be familiar with Table 9.2 Source and Major Actions of Selected Hormones - ☑️
Explain the ways in which hormones can be over-secreted: - ☑️ 1) the target gland over-secretes due to pathology
the pituitary or hypothalamus over-stimulates the target gland
hormones are being produced from a different site (i.e. hormone producing tumor)
hyperactive genetic mutation of the target hormone receptors.
How does decreased hormone secretion occur? - ☑️ 1) a congenital or acquired disorder of the target gland
the pituitary does not secrete enough stimulating hormone
the hypothalamus does not secrete enough releasing hormone
the hormone is defective
the receptors of the target organ do not respond.
Adrenal insufficiency can be caused by what ways? - ☑️ (1) Primary adrenal insufficiency, or Addison's disease, due to dysfunction in the adrenal glands.
(2) Decreased ACTH stimulation from the pituitary, or secondary adrenal insufficiency.
(3) Decreased CRH from the hypothalamus, or tertiary adrenal insufficiency.
The synthetic T4 thyroid hormone, thyroxine, is used to treat hypothyroidism. When the serum TSH levels are normalized, the correct dosage of thyroxine is found and maintained.
What lab values will be altered in primary and secondary hyperthyroidism? - ☑️ With primary hyperthyroidism, TSH will be low, since the thyroid is secreting a lot of the hormone without being told by the pituitary.
With secondary hyperthyroidism, the TSH will be high, since the pituitary is over-secreting it. In both cases, T4 and T3 will be elevated, since this is what differentiates hyper- from hypo- thyroidism.
Primary hyperthyroidism - ☑️ occurs when the thyroid over-secretes thyroid hormone, as seen in Graves' disease (autoimmune disorder discussed in module 3) or a toxic nodule (thyroid nodule that secretes excess thyroid hormone, not triggered by the pituitary).
Secondary hyperthyroidism - ☑️ occurs when the pituitary over-stimulates the thyroid to secrete thyroid hormone, as with a pituitary tumor. Sometimes an ectopic source of thyroid hormone occurs, as seen with an ovarian tumor.
Hyperthyroidism clinical presentation - ☑️ Signs and symptoms of hyperthyroidism (also called thyrotoxicosis) include weight loss and increased appetite (high metabolism), tachycardia (sometimes a-fib), dyspnea, heat intolerance, tremor, and nervousness. With Graves' disease, ophthalmopathy, exopthalmos, pretibial myxedema, diffuse goiter, and/or thyroid bruit - which is a rushing sound over the thyroid on auscultation.
Hyperthyroidism diagnosis - ☑️ The pathogenesis of hyperthyroidism differs by type, and different hormones will be elevated or decreased. With primary hyperthyroidism, TSH will be low, since the thyroid is secreting a lot of the hormone without being signaled by the pituitary. With secondary hyperthyroidism, the TSH will be high, since the pituitary is over-secreting it. In both cases, T4 and T3 will be elevated, since this is what differentiates hyper- from hypo- thyroidism. With Graves' disease, anti-TSH receptor antibodies may also be present.
The radioiodine uptake test and thyroid scans can detect thyroid function and nodules. Ultrasound can differentiate between cystic and solid lesions. To differentiate benign versus malignant thyroid disease, fine-needle aspiration biopsy is the gold standard.
Hyperthyroidism treatment - ☑️ Beta-blockers can be used for the treatment of tachycardia and anxiety. To reduce the amount of circulating thyroid hormone, both methimazole and propylthiouricil decrease thyroid hormone synthesis. For long-term treatment, the thyroid can be removed surgically or destroyed by radioactive iodine. However, these treatments can lead to hypothyroidism.
Medulla of the adrenal gland - ☑️ secretes epinephrine and norepinephrine
cortex of the adrenal gland - ☑️ Zona glomerulosa secretes aldosterone
Zona fasciculata secretes glucocorticoids
Zona reticularis secretes sex hormones
Glucocorticoids (cortisol) - ☑️ reducing inflammation, increasing blood pressure, gluconeogensis (↑ blood sugar), and it plays a role in the stress response and metabolism.
Remember, ACTH stimulates cortisol secretion from the adrenal glands, and CRH stimulates the release of ACTH.
Aldosterone - ☑️ triggers reabsorption of sodium (which raises blood pressure) and secretion of potassium in the kidneys. Aldosterone secretion can be caused by the renin-angiotensin-aldosterone system or hyperkalemia, as a way to decrease potassium.
What causes aldosterone deficiency? - ☑️ (1) a lack or failure of the renin-angiotensin stimulus (from kidney disease or drugs)
(2) ACE inhibitors
(3) the adrenal cortex is not secreting aldosterone (adrenal insufficiency)
Adrenal insufficiency can be caused by: - ☑️ Primary adrenal insufficiency, or Addison's disease, due to dysfunction in the adrenal glands.
Decreased ACTH stimulation from the pituitary, or secondary adrenal insufficiency.
Decreased CRH from the hypothalamus, or tertiary adrenal insufficiency.
With Addison's disease, what hormones and lab values will be altered? - ☑️ With Addison's disease, both cortisol and aldosterone secretion are decreased and ACTH levels are elevated. With low aldosterone, there will be low sodium, and increased potassium. Low sodium will also cause hypotension.
Addison disease pathology - ☑️ The result of insufficient cortisol and aldosterone secretion, accompanied by elevated ACTH levels. With low aldosterone, there will be low sodium, and increased potassium. Low sodium will also cause hypotension. The most common cause of Addison's disease is due to autoimmune destruction. Other causes include adrenal hemorrhage. infection, or tumor metastases.
Addison's disease clinical presentation - ☑️ A decrease in the mineralocorticoids will lead to hyponatremia, water loss, and hyperkalemia. This loss of fluid will cause dehydration, orthostatic hypotension, decreased cardiac output, fatigue, weakness, and salt craving.
A decrease in the glucocorticoids will lead to lethargy, hypoglycemia, nausea, vomiting, lack of appetite, and weight loss.
High levels of ACTH, and subsequently high levels of melanocyte-stimulating hormone causes hyperpigmentation of the skin, where the skin appears bronzed or tanned.
purple striae (stretch marks)
osteoporosis and/or osteonecrosis
acne
hirsutism (male-pattern
hair growth in women)
virilization (women develop masculine physical traits)
immunosuppression
diabetes
cognitive changes
Cushing syndrome diagnosis - ☑️ To determine an elevated cortisol secretion, one can either check a 24-hour urinary collection for free cortisol, check the level of cortisol in the saliva in the late evening, or check if cortisol levels are suppressed (which is normally what happens) when exogenous glucocorticoids are given. The latter is called the dexamethasone suppression test.
ACTH will be low if the adrenal glands are hyper-secreting on their own, increasing the negative feedback on the pituitary. If ACTH is high, something is over-secreting it, such as a tumor.
Hypokalemia (increased K excretion) and hypertension (retaining sodium) are commonly seen. There may also be a decreased immune and inflammatory response.
Cushing syndrome treatment - ☑️ Iatrogenic disease is treated by tapering off the glucocorticoid therapy. The other types of disease are treated by surgical removal or radiation of the offending tumor.
Pancreas - ☑️ The endocrine portion contains the islets of Langerhans, which secrete insulin and glucagon into the blood to regulate blood glucose levels.
Insulin - ☑️ Insulin moves glucose into cells to reduce blood sugar levels.
Glucagon - ☑️ release of glucose into the blood when levels are low. These hormones work together to maintain normal blood sugar.
Glycogenesis - ☑️ when insulin is released from the beta cells of the pancreas to promote glucose uptake into the cells and store it as glycogen, fat, and protein.
Glycolysis -
☑️ when glucose is broken down for energy (also by insulin).
Glycogenolysis - ☑️ Glucagon is produced by the alpha cells. It decreases glycolysis and increases gluconeogenesis, which is glucose formation and glycogenolysis, which is the breakdown of glycogen to release glucose.
What is insulin resistance? - ☑️ Insulin resistance is when insulin does not work effectively, whereby the hormone (insulin) fails to stimulate glucose uptake into the cell.
Obesity leads to a decreased number of insulin receptors. This is seen in type 2 diabetes.
Be familiar with Table 9.3 Comparison of type 1 and type 2 diabetes. - ☑️
Type 1 Diabetes - ☑️ usually diagnosed at a younger age. Individuals are usually of a normal weight or have had a recent weight loss. Symptoms may come on abruptly and be severe, as seen with diabetic ketoacidosis. Type 1 diabetics produce no insulin and therefore require insulin for life.
Type 2 diabetes - ☑️ typically diagnosed later in life. However, with the rising prevalence of obesity in the child and adolescent population, it is now being diagnosed at a younger age. Symptoms are more gradual, and patients are often asymptomatic. Screening for the disease is frequently done, especially in high-risk populations.
Pathogenesis of type 2 DM - ☑️
What is metabolic syndrome? - ☑️ Metabolic syndrome is a myriad of conditions that increases one's risk of heart disease, stroke, and type 2 diabetes. These include elevated blood sugar, high cholesterol, hypertension, and obesity, particularly increased body fat around the waist.
polydipsia - ☑️ increased thirst
polyuria - ☑️ increased urination
polyphagia - ☑️ increased appetite
Ketosis - ☑️ can occur in type 1 diabetes. When the body breaks down fat, as if it were starving, and forms ketones, or ketoacids.
diabetic ketoacidosis (DKA) - ☑️ a metabolic acidosis
heart attack
stroke
Be familiar with Figure 9.12 Chronic complications - ☑️
Table 9.4 Criteria for diagnosing diabetes. - ☑️
DM treatment - ☑️ normalize glucose levels as much as possible to prevent acute and chronic complications
All people with type 1 diabetes require insulin replacement. Dietary management and exercise are important in order to adjust insulin therapy to meet one's needs.
People with type 2 diabetes are usually overweight. As such, diet, exercise, and weight loss may be all that they need to control blood glucose levels. Even a moderate weight loss of 5-10% of total body weight has been shown to improve glucose control. A heart healthy diet is important, since many are at risk for or already have cardiovascular disease. Regular exercise is not only important for weight loss, but also improving the muscle-fat ratio that increases peripheral insulin receptivity. Aggressive management of hyperglycemia, hypertension, hyperlipidemia, and antiplatelets should be done.
insulin secretagogues - ☑️ the sulfonylureas, such as glipizide and glyburide. They act by stimulating the release of insulin from beta cells in the pancreas. They are known to cause hypoglycemia, so should be avoided in the elderly and patients with impaired hepatic or renal function. Two other insulin secretagogues (nonsulfonylurea) are repaglinide and nateglinide. They have a similar mechanism of action and side effects. They must be taken shortly before meals.
biguanides - ☑️ metformin. It decreases hepatic glucose production and intestinal glucose absorption and increases insulin sensitivity. Since it does not release insulin secretion, it does not cause hypoglycemia. Other beneficial side effects include weight loss and lower blood lipids, making this a popular choice for treatment. It should, however, be avoided when dehydrated, or with liver disease and elevated creatinine levels.
α-glucosidase inhibitors - ☑️ include acarbose and miglitol. These inhibit pancreatic alpha-amylase and intestinal alpha-glucoside hydrolase, which delay carbohydrate absorption. This helps decrease postprandial (occurring after a meal) hyperglycemia.
thiazolidinediones - ☑️ comprised of pioglitazone and rosiglitazone and work by increasing insulin sensitivity of the fat, skeletal muscle, and liver. These drugs have been under scrutiny, and rosiglitazone is currently restricted due to increased risk of cardiac events. These drugs are contraindicated in heart failure patients due to exacerbation of CHF by fluid accumulation.
Dipeptidyl peptidase-4 enzyme inhibitors - ☑️ nclude sitagliptin, saxagliptin, alogliptin, and linagliptin, which are a type of incretin therapy. Incretins are released by the GI tract after a high carbohydrate meal and stimulate insulin
secretion from the beta cells. GLP-1 and GIP (see module 7) are the main incretins secreted, of which the enzyme DPP-4 rapidly breaks down. Therefore, DPP-4 inhibitors inhibit the enzyme DPP-4, which increases GLP-1 and GIP, which increases insulin release and decreases glucagon levels.
Glucagon-like peptide-1 (GLP-1) agonists - ☑️ exenatide and liraglutide, among others. They activate glucagon-like-peptide-1 (GLP-1) receptor, increasing insulin secretion, decreasing glucagon secretion, and delaying gastric emptying (incretin imitator). These drugs are taken by injection, instead of orally, and their main side effects include nausea and weight loss.
Insulin - ☑️ can be rapid-acting, short-acting, intermediate-acting, or long-acting. They each have a different onset, peak, and duration of action, so must be administered accordingly in regard to eating. Insulin is always administered by a subcutaneous injection, since insulin is destroyed in the GI tract. Available now are multiple daily injections (MDI), which mimics the normal pattern of insulin secreted in the body and continuous subcutaneous insulin infusion (CSII) which uses an insulin pump. They act by giving a continuous basal injection in addition to bolus doses around mealtimes.
Hypoglycemia - ☑️ a serious side effect of insulin therapy, and some oral hypoglycemic drugs. It is defined as a blood glucose of < 60 mg/dL, with associated cognitive impairments. It can be caused by a change in medication or dosage, lack of drug adherence, not eating, or increased exercise. Symptoms often include headache, confusion, anxiety, tachycardia, and cool/clammy skin. It can sometimes cause seizures or coma. It is treated with 15-20 g of glucose, since it works quickly. Complex carbohydrates can be given once glucose levels are controlled. IV, IM, or subcutaneous glucose can be given in life-threatening emergencies.
