Syndrome of Inappropriate Antidiuretic Hormone (SIADH) - Nursing Study Guide PDF

**CHAPTER 22 -- Alterations of Hormonal Regulation** **Know the pathophysiology, etiology, clinical manifestations, treatment and complications of syndrome of inappropriate antidiuretic hormone (SIADH)?** Define: characterized by high levels of anti-diuretic hormone in the absence of normal physio...

**CHAPTER 22 -- Alterations of Hormonal Regulation** **Know the pathophysiology, etiology, clinical manifestations, treatment and complications of syndrome of inappropriate antidiuretic hormone (SIADH)?** Define: characterized by high levels of anti-diuretic hormone in the absence of normal physiologic stimuli for its release. +-----------------------+-----------------------+-----------------------+ | **Causes of SIADH** | | | +=======================+=======================+=======================+ | Common | ectopic production of | | | | ADH by tumors (small | | | | cell carcinoma of the | | | | duodenum, stomach, | | | | and pancreas) | | | | | | | | cancers of the | | | | bladder, prostate, | | | | and endometrium | | | | | | | | lymphomas | | | | | | | | sarcomas | | +-----------------------+-----------------------+-----------------------+ | Pulmonary Disorders | Pneumonia | | | | | | | | asthma | | | | | | | | cystic fibrosis | | | | | | | | respiratory failure | | | | requiring mechanical | | | | ventilation | | +-----------------------+-----------------------+-----------------------+ | CNS Disorders | Encephalitis | Tumors | | | | | | | Meningitis | Trauma including | | | | neuro surgery | | | Intracranial | | | | hemorrhage | | +-----------------------+-----------------------+-----------------------+ | **Medications | Hypoglycemic | General anesthetics | | (especially in the | medications | | | elderly)** | | Chemotherapeutic | | | Antidepressants | agents | | \*Stimulate ADH | | | | release, enhance | Antipsychotics | NSAIDs | | physiologic effects | | | | of ADH or have | Narcotics | Synthetic ADH | | biologic action | | | | similar to ADH | | | +-----------------------+-----------------------+-----------------------+ **Pathophysiology: features of SIADH are the result of enhanced renal water retention** ADH increases renal collecting duct permeability to water inducing the insertion of aquaporin-2 (water channel protein) the tubular luminal membrane (increases water reabsorption by the kidneys) expansion of extracellular fluid volume dilutional hyponatremia (low serum sodium concentration), hypoosmolarity, and urine (inappropriately concentrated serum osmolarity) = water is reabsorbed that normal would be excreted **Clinical Manifestations:** result from hypotonic hyponatremia hypervolemia and weight gain; severity and rapidity of onset determine the extent of the symptoms; symptoms resolve with correction of hyponatremia +-----------------------+-----------------------+-----------------------+ | Serum sodium level | Thirst | Dyspnea on exertion | | decreases rabidly | | | | from 140-130 mEq/L | Impaired Taste | Fatigue | | | | | | | Anorexia | Dulled sensorium | | | | | | | | \*Weight gain usually | | | | absent | +=======================+=======================+=======================+ | Serum sodium levels | Vomiting Abdominal | \*weight gain from | | decrease from 130 to | cramps | water retention | | 120 mEq/L | | | +-----------------------+-----------------------+-----------------------+ | Serum sodium levels | Confusion Lethargy | Seizures Severe, | | less than 110 to 115 | Muscle twitching | sometimes | | mEq/L \*even when | | irreversible | | hyponatremia develops | | neurologic damage may | | slowly | | occur | +-----------------------+-----------------------+-----------------------+ **Diagnosis** includes the following: 1. Serum hypoosmolality (\ | aren't effective); new chemo | | | and targeted molecular | | - Men erectile dysfunction, | therapy options | | infertility, osteopenia | | | Increasing tumor size | **Goal of Treatment:** restore | | headache and visual | normal gonadal function and | | impairment | fertility; reduce tumor size | +-----------------------------------+-----------------------------------+ +-----------------------------------+-----------------------------------+ | **PRIMARY AUTONOMOUS GH-SECRETING | | | PITUITARY ADENOMA** | | +===================================+===================================+ | | **Clinical Manifestations** | +-----------------------------------+-----------------------------------+ | Most common cause of | - - - | | **acromegaly** continuous | | | exposure to high levels of GH and | | | IGF-1 (slowly progressive | | | disease; left untreated decrease | - - - | | life expectancy) | | | | | | **Patho:** GH baseline secretion | | | pattern and sleep-related GH | - Pegvisomant supplement | | peaks are lost [unpredictable | somatostatin analogs; | | secretory pattern] | effective drug that induces | | | tissue insensitivity to GH | | - **\*Acromegalics** GH never | (blocks GH receptor) | | completely suppressed (only | | | slight elevation of GH & | **GOAL:** normalize GH and IGF-1 | | IGF-1 can stimulate growth) | serum levels (age range), | | | restoring normal pituitary | | - **Children/Adolescents** | function, relieving or preventing | | (whose epiphyseal plates | complications from tumor | | aren't closed) | expansion | | | | | | | | | | | - **Adults** (epiphyseal is | | | closed) increase levels of GH | | | and | | | | | | **Hormonal effects of too much GH | | | on Pancreas:** | | | | | | - Inhibition of peripheral | | | glucose uptake and increased | | | hepatic glucose production | | | compensatory hyperinsulinism | | | | | | - Adipose tissue inflammation | | | and impaired adipogenesis | | | insulin resistance | | | | | | - Diabetes Mellitus pancreas | | | cannot secrete enough insulin | | | to offset effects of GH | | | | | | **Hormonal effects of too much GH | | | and IGF-1 on Heart:** | | | | | | - Progressive myocardial growth | | | Cardiomyopathy | | | | | | - Hypertension and left-sided | | | heart failure (1/2 of | | | acromegalics) | | | | | | o Valvular heart disease and | | | arrhythmias | | | | | | **Hormonal effects of too much GH | | | on renal tubules:** | | | | | | - Increase phosphate | | | reabsorption mild | | | hyperphosphatemia | | | | | | As tumor grows (occupying more | | | space) compression of surrounding | | | hormone-secreting cells | | | [hypopituitarism can | | | occur] | | | | | | **Diagnosis (**physical and | | | laboratory evaluation): | | | | | | - Appearance of clinical | | | features | | | | | | - Visual field testing | | | | | | - MRI or CT | | | | | | - Elevated levels of IGF-1 | | | | | | - GH level elevated and not | | | suppression with oral glucose | | | tolerance testing | | +-----------------------------------+-----------------------------------+ **What is acromegaly?** **Etiology:** 1. Continuous exposure to high levels of GH and IGF-1 2. Almost always caused by GH-secreting pituitary adenoma (rarely caused by ectopic production of GHRH) 3. Occurs in adults in the 40-59-year-old age group; present years before diagnosis (insidious nature of disease) **Complications**: 1. Increased mortality and death 2. Hypertension heart disease CAD, stroke, DM, or malignancy (colon or lung) Death **Patho:** 1. **GH Secreting Pituitary Tumor** a. GH baseline secretion pattern and sleep-related GH peaks are lost i. [unpredictable secretory pattern] b. **\*Acromegalics** ii. GH never completely suppressed (only slight elevation of GH & IGF-1 can stimulate growth) iii. **Children/Adolescents** (whose epiphyseal plates aren't closed) 1. increased GHexcessive skeletal growth (grow to be 8-9ft tall) [GIGANTISM] iv. **Adults** (epiphyseal is closed) increase levels of GH and IGF-1 connective tissue proliferation, increase cytoplasmic matrix, and bony proliferation (body appearance resembling acromegaly) 2. **Hormonal effects of too much GH on Pancreas:** c. Inhibition of peripheral glucose uptake and increased hepatic glucose production compensatory hyperinsulinism d. Adipose tissue inflammation and impaired adipogenesis insulin resistance e. Diabetes Mellitus pancreas cannot secrete enough insulin to offset effects of GH 3. **Hormonal effects of too much GH and IGF-1 on Heart:** f. Progressive myocardial growth Cardiomyopathy g. Hypertension and left-sided heart failure (1/2 of acromegalics) h. Valvular heart disease and arrhythmias 4. **Hormonal effects of too much GH on renal tubules:** i. Increase phosphate reabsorption mild hyperphosphatemia 5. As tumor grows **(space-occupying lesion**) compression of surrounding hormone-secreting cells [hypopituitarism can occur] **Clinical Manifestations:** 1. [Connective tissue proliferation] a. **Enlarged tongue** b. **Interstitial edema** c. Enlarged/overactive sebaceous and sweat glands **(body odor)** d. **Course skin/body hair** 2. [Bony proliferation] e. Large joint arthropathy f. Periosteal vertebral growth g. Enlargement of bones of the face, hands, feet h. **Decrease ROM, kyphosis, lower jaw/forehead protrusion** 3. [IGF-1] i. Cartilaginous growth i. ribs elongate at bony-cartilage junction ii. barrel-chest appearance j. Increased proliferation of cartilage spine/joints iii. backaches/arthralgias 4. [Continued bony/soft tissue overgrowth] k. Entrapment of nerves iv. Causing peripheral damage weakness, muscular atrophy, footdrop, sensory changes in hands (carpal tunnel) l. Sleep disordered breathing exacerbate issues of the heart 5. [Diabetes Mellitus symptoms] polyuria and polydipsia 6. [CNS symptoms] (growing tumor size) m. Headache n. Seizure activity o. Visual field disturbances p. Papilledema q. [Complete compression hypopituitarism] v. gonadotropin secretion affected amenorrhea (women) / sexual dysfunction (men) 7. [Acromegaly Hypertension:] r. asymptomatic until heart-failure symptoms develop 8. [Hyperprolactinemia] (30-40% occurrence) **Evaluation and Treatment** - Diagnosis is confirmed by the appearance of clinical features of the disease, visual field testing, MRI scans, and elevated levels of IGF-1 (GH level is typically elevated and no suppressed with oral glucose tolerance testing) **GOAL:** Normalize GH and IGF-1 serum levels to age range, restoring normal pituitary function, and relieving or preventing complications related to tumor expansion. **Treatment of choice Acromegaly**: transsphenoidal surgery to remove GH-secreting adenoma - Stereotactic radiation therapy if rapid control of GH levels is not essential, individual is not a good candidate for surgery, hyperfunction persists after subtotal resection **Somatostatin analogs** (octreotide, octreotide acetate, and lanreotide) normalize IGF-1 levels and lower GH levels - Pegvisomant supplement somatostatin analogs; effective drug that induces tissue insensitivity to GH (blocks GH receptor) ***Dopaminergic agonists** (carbergoline)* if tumor is secreting prolactin **What is Graves disease? Signs and symptoms? Labs?** **Etiology:** underlying cause of 50% to 80% of cases of hyperthyroidism and has a prevalence 3.0% of women and 0.5% of men in the U.S **Cause:** unknown; genetic factors interacting with environmental triggers play an important role in the pathogenesis **Classification:** autoimmune (from form of type II hypersensitivity) 1. Infiltration of lymphocytes and Thyroid-stimulating immunoglobulins (TSI) autoantibodies (directed against TSH receptor) stimulate thyroid override normal feedback mechanisms hyperplasia of the gland (Goiter) and increased synthesis of TH (especially T3) 1. Increased levels of TH affect all systems -- classic s/s of hyperthyroidism a. Thin hair, exophthalmos b. normal of enlarged nodular thyroid c. tachycardia, weight loss d. warm skin with heat intolerance **TSI** (thyroid stimulating immunoglobulin) contribute to two major distinguishing manifestations of Graves' disease: **ophthalmopathy** and **dermopathy** (pretibial myxedema and acropachy). Two categories of ophthalmopathy are: 1. [Functional abnormalities]: a. Hyperactivity of the sympathetic division of the autonomic system b. Von Graefe\'s sign: Lag of the globe on upward gaze and lag of the upper lid on downward gaze i. Upper eyelid lags behind the movement of the eye when looking downwards causing a noticeably delay in eyelid movement compared the eyeball itself 2. [Infiltrative changes] c. orbital contents with enlargement of the ocular muscles d. TSH receptor autoantibodies reacting with receptors on orbital fibroblasts e. Increased secretion of hyaluronic acid, adipogenesis, inflammation and edema of the orbital contents: ii. exophthalmos (protrusion of the eyeball) iii. periorbital edema iv. extraocular muscle weakness strabismus and diplopia (double vision) v. irritation, pain, lacrimation, photophobia, blurred vision, decreased visual acuity, papilledema, visual field impairment, exposure keratosis, corneal ulceration 3. Very high levels of TSI pretibial myxedema (Graces dermopathy) subcutaneous swelling on the anterior portions of the legs (indurated and erythematous skin) **Evaluation**: 1. Elevated TH (T3) 2. Suppressed TSH 3. Normal of elevated radioactive iodine uptake scan **Treatment:** antithyroid drugs, radioactive iodine ablation (caution in Graves ophthalmopathy can worsen condition), or surgery 1. Smoking exacerbates the disease and cessation is necessary 2. Exophthalmos or pretibial myxedema no treatment 3. Progressive ophthalmopathy orbital decompression and glucocorticoids 4. Immunosuppressive drugs (rituximab) are being evaluated **What is hypoparathyroidism?** +-----------------------------------+-----------------------------------+ | **Define:** abnormally low PTH | **Clinical Manifestations**: | | levels | (primarily those of hypocalcemia) | | |  lowered threshold for nerve and | | **Most common cause:** damage to | muscle excitation (only requires | | or removal of the parathyroid | mild stimulus to elicit a | | glands during thyroid surgery | response) | | \[occurs because of the anatomic | | | proximity of the parathyroid | 1. Perioral numbness, | | glands to the thyroid\] | paresthesia, tingling, and | | | tetany (caused by muscle | | **Other causes:** | spasms, hyperreflexia, | | | tonic-clonic convulsions, | | 1. Genetic syndromes | laryngeal spasms, death from | | | asphyxiation) | | a. Familial | | | hypoparathyroidism | 2. Dry skin, loss of body and | | | scalp hair, hypoplasia of | | b. DiGeorge syndrome | developing teeth, horizontal | | (velocardiofacial | ridges on the nails, basal | | syndrome | ganglia calcifications, bone | | | deformities (brachydactyly | | c. Idiopathic or autoimmune | and bowing of long bones) | | form of the disease | | | | Chvostek and Trousseau signs = | | 2. Hypomagnesemia  decrease in | used to evaluate for | | PTH secretion and function | neuromuscular irritability | | | | | 3. Pseudohypoparathyroidism | 1. Tapping cheek  twitching of | | (inherited condition)  | upper lip | | resistance to PTH in the | | | proximal renal tubule and | 2. Sustained inflation of a BP | | cannot produce cAMP  | cuff on upper arm to a | | hypocalcemia with normal or | level \SBP  painful carpal | | elevated PTH | spasm | | | | | **Patho:** a lack of circulating | Phosphate retention (from | | PTH  depressed serum calcium | increase renal absorption of | | levels and increased serum | phosphate)  hypoparathyroidism | | phosphate. | | | | PTH deficiency  | | - Absence of PTH  impaired | hyperphosphatemia  inhibits | | resorption calcium from the | activation of vitamin D  further | | bone and dysregulation of | decrease of calcium lowers GI | | calcium reabsorption by the | absorption of calcium | | renal tubules  increased | | | phosphate reabsorption  | **Evaluation:** a low serum | | decreases renal phosphate | calcium level and a high | | excretion  hyperphosphatemia | phosphorus level  absence of | | | renal failure, intestinal | | - Hypomagnesemia (inhibits PTH | disorders, nutrient deficiencies, | | secretion) caused by: chronic | or in the individuals who have | | alcoholism, malnutrition, | had thyroidectomy suggests | | malabsorption, increased | hypoparathyroidism. | | renal clearance of Mg | | | (aminoglycoside antibiotics, | 1. PTH levels are low  serum | | certain chemo drugs, | magnesium and urinary calcium | | prolonged mag-deficient | excretion can help diagnosis | | parenteral nutritional | | | therapy) = correct magnesium | **Treatment:** is directed toward | | to return PTH to normal | alleviation of hypocalcemia | | | (acute  parenteral | | | administration of calcium; | | | maintenance  oral doses active | | | form of vitamin D and calcium) | +-----------------------------------+-----------------------------------+ **Understand hypo/hyperglycemia** +-----------------------------------------------------------------------+ | **HYPERGLYCEMIA** | +=======================================================================+ | **Define:** excessive glucose in the blood cause by excessive | | carbohydrate intake. | | | | A diagram of the cause of chronic hyperglycemia AI-generated content | | may be incorrect. | | | | **Typical presentation:** overweight, dyslipidemia, hyperinsulinemia, | | and hypertensive. | | | | **Hallmark Clinical Manifestations**: polyuria and polydipsia, | | fatigue, pruritus, recurrent infections, visual changes, and | | neuropathy. | | | | **Treatment:** | | | | 1. diet, exercise | | | | 2. Oral hypoglycemics Metformin is considered primary pharmogenic | | | | 3. Insulin later stage Type 2 DM | +-----------------------------------------------------------------------+ | **HYPOGLYCEMIA** | +-----------------------------------------------------------------------+ | **Define:** "insulin shock or insulin reaction" | | | | Neonates: blood glucose levels are \< 47 mg/dl Children/ Adults: \< | | 70 mg/dl | | | | **Causes:** | | | | - **Exogenous**: medications, exercise, or alcohol | | | | - **Endogenous**: tumors on the pancreas or inherited disorders | | | | - **Functional**: hyperalimentation, spontaneous, or liver disease | | | | **Patho:** Type 2 diabetics (lower risk for hypoglycemia)  retain | | relatively intact glucose counter regulatory mechanisms. | | | | - Activation of the sympathetic nervous system (neurogenic | | adrenergic symptoms) **[OR]** | | | | - Abrupt cessation of glucose delivery to the brain | | (neuroglycopenic symptoms), **[OR]** both | | | | **Clinical Manifestations:** | | | | Rapid decrease in blood glucose level with tachycardia, palpitations, | | diaphoresis, tremors, pallor, and arousal anxiety  Neurogenic | | symptoms | | | | - Neuroglycopenia  including headache, dizziness, irritability, | | fatigue, poor judgment, confusion, visual changes, hunger, | | seizures, and coma. | | | | **Treatment:** immediate replacement of glucose either *orally* or | | *intravenously*. | | | | [Glucagon] for home use can be prescribed for individuals | | with high risk. | | | | **Prevention:** medication and diet management, monitoring glucose | | levels, and education | +-----------------------------------------------------------------------+ **Know the pathophysiology, etiology, clinical manifestations, treatment and complications of DM I and DM II.** **Diabetes Mellitus:** **Define:** characterized by hyperglycemia caused by defects in insulin secretion, insulin action, or both; affects metabolism of fat, protein, and carbohydrates. Etiology: dysfunction of the pancreas **Classification Types:** - Type 1: beta cell destruction leading to absolute insulin deficiency - Type 2: insulin resistance with relative insulin deficiency OR insulin secretory defect with insulin resistance **Diagnosis based on:** - glycosylated hemoglobin (HgA1C) levels - fasting plasma glucose (FPG) levels - 2-hour plasma glucose level during oral glucose tolerance testing (OTT) using a 75-g oral glucose load or random glucose levels for individuals with symptoms - HgA1C permanent attachment of glucose to hemoglobin molecules - Reflects average glucose exposure over life of a red blood cell (RBC) (approximately 120 days) **Diagnostic Criteria for Diabetes Mellitus** 1. HgA1C (as measure in a DCCT-referenced assay) ≥ 6.5% OR 2. FPG ≥126 mgdL (7.0 mmol/L); fasting is defined as no caloric intake for at least 8 hrs OR 3. 2-hr plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an OGTT OR 4. In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose \200 mg/dL (11.1 mmol/L) **Categories of increased risk for diabetes (Prediabetes)** 1. FPG 100 to 125 mg/dL 2. 2 hr PG in the range of 140-199 mg/dL during an OGTT 3. HbA1C 5.7 to 6.4 **Diabetes Mellitus Type I** **Cause:** - Pancreatic atrophy and loss of beta cells-Beta cell destruction leading to absolute insulin deficiency - Immune mediated diabetes is most common form (90%) and idiopathic (10%) **Secondary to other diseases** - Pancreatitis or idiopathic diabetes (type 1B; fulminant disorder) - Type 1B diabetes mostly in people of Asian or African decent; varying degrees of insulin deficiency **Genetic Susceptibility** - 10% - 30% of individuals with newly diagnosed Type 1 DM first-degree relative (parent or sibling) with Type 1 DM (50% concordance rate in twins) **Environmental Factors** (significant contribution to the development of Type 1 DM) - Several types of viral infection (especially enteroviruses) autoimmune damage to beta cells - Exposure to other infectious microorganisms (such as Helicobacter pylori), exposure to cow's milk proteins and a relative lack of vitamin D **Immunologically Mediated Destruction of Beta Cells**: - Autoimmune Type 1 DM is a slowly progressive autoimmune T cell-mediated disease that occurs in genetically susceptible individuals - The destruction of beta cells progresses through the following stages: 1. Lymphocyte and macrophage infiltrate islets inflammation (insulinitis) and islet beta cell death 2. Production of autoantibodies against islet cells, insulin, glutamic acid decarboxylase (GAD), and other cytoplasmic proteins 3. Relative inactivity of T regulatory cells that contribute to a decrease in beta-cell mass and insulin production (normally serve to inhibit the immune response and maintain self-tolerance) - Insulin synthesis declines enough for hyperglycemia when destruction of 80-90% insulin secreting beta cells of the islet of Langerhans [hypoinsulinemia ] - [Increase of glucagon secretion] (produced by alpha cells of the islets; acts on liver to increase blood glucose level via glycogenolysis and gluconeogenesis) - Decrease secretion of amylin (beta-cell hormone; suppresses glucagon release from alpha cells) Alpha & Beta cells abnormal lack of insulin relative excess of glucagon = hyperglycemia in Type 1 DM **Clinical Manifestations & Rationale for Type 1 Diabetes Mellitus:** **Manifestations** **Rationale** -------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Polydipsia Because of elevated blood glucose levels, water is osmotically attracted from body cells, resulting in intracellular dehydration and hypothalamic stimulation of thirst Polyuria Hyperglycemia acts as an osmotic diuretic; the amount of glucose filtered by the glomeruli of the kidneys exceeds the amount that can be reabsorbed by the renal tubules; glycosuria results, accompanied by large amounts of water lost in the urine Polyphagia Depletion of cellular stores of carbohydrates, fats, and protein results in cellular starvation and corresponding increase in hunger Weight loss Weight loss occurs because of fluid loss in osmotic diuresis and the loss of body tissue as fat and proteins are used for energy as a result of the effects of insulin deficiency Fatigue Metabolic changes results in poor use of food products, contributing to lethargy and fatigue; sleep loss from severe nocturia also contributes to fatigue **Onset of Type I Diabetes:** long preclinical period with gradual destruction of beta cells insulin deficiency and hyperglycemia **Effects**: metabolism of fat, protein, and carbohydrates - Glucose accumulates in blood and urine (as renal threshold is exceeded) osmotic diuresis (polyuria and thirst) - Wide fluctuations in blood glucose levels occur. - Lack of insulin protein and fat breakdown weight loss - Increased hepatic metabolism of fat high levels of circulating ketones **DKA** **Common presentations:** - Obese - Metabolic syndrome (dyslipidemia and hypertension) = synergistic effects from intensive insulin therapy (promoting weight gain) - Lifestyle factors (lack of exercise/poor nutrition) - High risk of chronic complications = heart disease and stroke **Diagnosis:** - polydipsia, polyuria, polyphagia - weight loss - hyperglycemia present in fasting and postprandial states - C-peptide (component of proinsulin released during insulin production) serum measurement as a surrogate for insulin levels = indicative of residual beta-cell mass and function - **ZnT8Ab Autoantibody Test** remains THE BEST WAY to identify diabetes and to distinguish Type 1 from Type 2 - \*\*Nearly half of children aged 4 years or younger, are first diagnosed when they present with signs and symptoms of DKA. - In DKA, acetone (a volatile form of ketones) is exhaled by hyperventilation and gives the breath a sweet or "fruity" odor. - Occasionally, diabetic coma is the initial symptom of the disease. **Evaluation:** - Assess for evidence of the chronic complications of type 1 diabetes (renal, nervous system, cardiac, peripheral vascular, retinal, and bony tissue damage) **Prevention of autoimmune destruction of beta cells:** - Avoidance of cow's milk - Utilization of a gluten-free diet - Increased intake of omega-3 fatty acids, and vitamin D **Treatment:** - Combination of insulin, meal planning, exercise, and self-monitoring of blood glucose - Islet cell/stem cell transplant and whole pancreas transplantation (successful in selected individuals) **Diabetes Mellitus Type 2** **Etiology:** - More common than Type 1 DM - Prevalence highest in African American woman and greatly increased in children (especially Native American and obese children) **Genetic-environmental Risk factors:** - age, obesity, hypertension, physical inactivity, family history **Metabolic syndrome** (HIGH RISK OF TYPE 2 DM): - Central obesity, dyslipidemia, prehypertension, and elevated fasting blood glucose level - Develops during childhood; highly prevalent among overweight children and adolescents - Early recognition and treatment (vigorous lifestyle changes) reduce cardiovascular events **Pathophysiology**: genetic, epigenetic, and environmental interactions - Insulin resistance suboptimal response of insulin-secretive tissues (especially liver, muscle, and adipose tissue) - Mechanisms: abnormality of insulin molecule, high amounts of insulin antagonists, downregulation of insulin receptor, decreased/abnormal activation of post receptor kinases, alteration of glucose transporter (GLUT) proteins - Obesity most important contributors to insulin resistance - Adipokines (leptin and adiponectin) - Elevated levels of serum fatty acids (FFAs) and intracellular deposits of triglycerides and cholesterol - Release of inflammatory cytokines - Alterations in oxidative phosphorylation - Hyperinsulinemia and impaired insulin receptor signaling - Compensatory hyperinsulinemia prevents clinical appearance of diabetes for years; beta-cell dysfunction relative deficiency of insulin activity - Glucagon increased (produced by alpha cells of pancreas; acts in liver to increase blood glucose levels) - Less responsive pancreatic alpha cells to glucose inhibition increase of glucagon secretion - High levels of glucagon High levels of blood glucose (associated with amylin) - Amylin (islet amyloid polypeptide; beta cell hormone decreased in Type 1 & 2 DM) - Amylin increases satiety and suppresses glucagon release from the alpha cells - Deposition of abnormal (misfolded) amyloid polypeptide in the pancreas - Pramlintide (synthetic analog of amylin) treatment in both Type 1&2 diabetes - The incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulintropic polypeptide (GIP) class of peptides released from the GI tract in response of food intake. - Increase the sensitivity of beta cells to circulating glucose levels improving insulin response to meals; peptides are important in maintaining glycemic control. Hormones from GI tract insulin resistance - Ghrelin (peptide produced in the stomach and pancreatic islets) - Regulates food intake, energy balance, and hormone secretion - Decreased levels increased insulin resistance and increased fasting insulin levels **Clinical manifestations:** **Classic symptoms**: Overweight, dyslipidemia, hyperinsulinemia, and hypertensive - Nonspecific symptoms: fatigue, pruritus, recurrent infections, visual changes, or symptoms of neuropathy (paresthesia or weakness) - Progressed WITH NO TREATMENT coronary artery, peripheral artery, and cerebrovascular disease may develop. **Prevention:** diet and exercise; diabetic medications in high-risk individuals **Goal:** restoration of near-euglycemia (normal blood glucose level) and correction of related metabolic disorders **Treatment:** - The first step in management is to establish an appropriate glycemic goal - Dietary measures, including restriction of the total caloric intake - Weight loss improved insulin sensitivity and glucose tolerance, preserves beta-cell function, inhibitory effect on progression of Type 2 DM - diets should match activity levels and include more complex carbs -- rather than simple sugars, foods low in fat, adequate protein, and fiber - Exercise reduces postprandial blood glucose levels, diminishes insulin requirements, lowers triglyceride and cholesterol levels and increases the level of HDL cholesterol (\*\*hypoglycemia exercising while receiving sulfonylurea or insulin) - Bariatric surgery morbid obesity who don't respond to diet and exercise - For most individuals, medications are needed for optimal management - Insulin injections - Oral hypoglycemic agents Metformin is primary choice of treatment AND - Second oral agent (GLP-1 receptor agonist) OR - Basal insulin (if the HbA1c target is not maintained over 3 months) +-----------------------+-----------------------+-----------------------+ | | Type 1 Diabetes: | Type 2 Diabetes: | | | Primary β-Cell Defect | Insulin Resistance | | | or Failure | with Inadequate | | | | Insulin Secretion | +=======================+=======================+=======================+ | Incidence | | | +-----------------------+-----------------------+-----------------------+ | Frequency | 5%--10% of all cases | Accounts for most | | | of diabetes mellitus | cases (≈90%--95%) | | | Prevalence rate is | Prevalence rate for | | | 0.17% | adults is 10.9% | +-----------------------+-----------------------+-----------------------+ | Change in incidences | Incidence is | Incidence in adults | | | increasing | more than tripled in | | | | the past 3 decades | +-----------------------+-----------------------+-----------------------+ | Characteristics | | | +-----------------------+-----------------------+-----------------------+ | Age at onset | Peak onset at age | Risk of developing | | | 11--13 years | diabetes increases | | | (slightly earlier for | after age 40 years | | | girls than for boys); | | | | rare in children | | | | younger than 9 months | | | | and adults older than | | | | 30 years | | +-----------------------+-----------------------+-----------------------+ | Sex | Similar in males and | Similar in males and | | | females | females | +-----------------------+-----------------------+-----------------------+ | Racial distribution | Rates for whites | Risk is highest for | | | 1.5--2 times higher | African Americans and | | | than for other ethnic | Native Americans | | | groups | | +-----------------------+-----------------------+-----------------------+ | Weight | Generally normal or | Obesity is common and | | | underweight | is a frequent | | | | contributing factor | | | | to precipitate type 2 | | | | diabetes among those | | | | susceptible | +-----------------------+-----------------------+-----------------------+ | Etiology | | | +-----------------------+-----------------------+-----------------------+ | Common theory | Autoimmune: genetic | Genetic | | | and environmental | susceptibility | | | factors, resulting in | (polygenic) combined | | | gradual process of | with environmental | | | autoimmune | determinants; defects | | | destruction in | in β-cell function | | | genetically | combined with insulin | | | susceptible | resistance | | | individuals | | | | | Associated with | | | Nonautoimmune: | long-duration obesity | | | Unknown | | +-----------------------+-----------------------+-----------------------+ | Presence of antibody | Autoantibodies to | Autoantibodies not | | | insulin and to | present | | | glutamic acid | | | | decarboxylase (GAD65) | | +-----------------------+-----------------------+-----------------------+ | Insulin resistance | Insulin resistance at | Insulin resistance is | | | diagnosis is unusual, | virtually universal | | | but may occur as | and multifactorial in | | | individual ages and | origin | | | gains weight | | +-----------------------+-----------------------+-----------------------+ | Insulin secretion | Severe insulin | Typically increased | | | deficiency or no | at time of diagnosis, | | | insulin secretion at | but progressively | | | all | declines over course | | | | of illness | +-----------------------+-----------------------+-----------------------+ **Why do diabetic pts usually develop hyperlipidemia?** Intra-abdominal adipocytes or adipocyte-associated mononuclear cells (from activated macrophages in other tissues)  release of inflammatory cytokines  induce insulin resistance through a post-receptor mechanism  **play and important role in the genesis of fatty liver, atherosclerosis, and dyslipidemia** **Why does polyuria and polydipsia and weight loss occur with the onset of diabetes?** Type I DM affects the metabolism of fat, protein, and carbohydrates. Increased glucose accumulates in the blood and appears in the urine (renal threshold for glucose is exceeded) osmotic diuresis manifested as polyuria and thirst (polydipsia) Lack of insulin protein and fat breakdown resulting in weight loss **Know hyperosmolar hyperglycemic nonketotic syndrome (HHNKS)? Know diabetic ketoacidosis (DKA)? What's the difference?** +-----------------------+-----------------------+-----------------------+ | Common Acute | | | | Complications of | | | | Diabetes Mellitus | | | +=======================+=======================+=======================+ | Hypoglycemia in | Diabetic Ketoacidosis | Hyperglycemic | | Persons with Diabetes | | Nonketotic Syndromes | | Mellitus | | | +-----------------------+-----------------------+-----------------------+ | Synonyms | | | +-----------------------+-----------------------+-----------------------+ | Insulin shock, | Diabetic coma | Hyperosmolar | | insulin reaction | syndrome | hyperglycemia | | | | nonketotic coma | +-----------------------+-----------------------+-----------------------+ | Persons at Risk | | | +-----------------------+-----------------------+-----------------------+ | Individuals taking | Individuals with type | Older adults with | | insulin | 1 diabetes | type 2 diabetes, | | | | nondiabetic persons | | Individuals with | Individuals with | with predisposing | | rapidly fluctuating | undiagnosed diabetes | factors, such as | | blood glucose levels | | pancreatitis; | | | | individuals with | | Individuals with type | | undiagnosed diabetes | | 2 diabetes taking | | | | non-insulin | | | | antidiabetic | | | | medications | | | +-----------------------+-----------------------+-----------------------+ | Predisposing Factors | | | +-----------------------+-----------------------+-----------------------+ | Excessive insulin or | Stressful situation | Infection, | | non-insulin | such as infection, | medications that | | antidiabetic agents, | accident, trauma, | antagonize insulin, | | lack of sufficient | emotional stress; | comorbid condition | | food intake, | omission of insulin; | | | excessive physical | medications that | | | exercise, abrupt | antagonize insulin | | | decline in insulin | | | | needs (e.g., renal | | | | failure, immediately | | | | postpartum), | | | | simultaneous use of | | | | insulin-potentiating | | | | agents or β-blocking | | | | agents that mask | | | | symptoms | | | +-----------------------+-----------------------+-----------------------+ | Typical Onset | | | +-----------------------+-----------------------+-----------------------+ | Rapid | Slow | Slowest | +-----------------------+-----------------------+-----------------------+ | Adrenergic reaction: | Malaise, dry mouth, | Polyuria, polydipsia, | | pallor, sweating, | headache, polyuria, | hypovolemia, | | tachycardia, | polydipsia, weight | dehydration (parched | | palpitations, hunger, | loss, nausea, | lips, poor skin | | restlessness, | vomiting, pruritus, | turgor), hypotension, | | anxiety, tremors | abdominal pain, | tachycardia, | | | lethargy, shortness | hypoperfusion, weight | | Neurogenic reaction: | of breath, Kussmaul | loss, weakness, | | fatigue, | respirations, fruity | nausea, vomiting, | | irritability, | or acetone odor to | abdominal pain, | | headache, loss of | breath | hypothermia, stupor, | | concentration, visual | | coma, seizures | | disturbances, | | | | dizziness, hunger, | | | | confusion, transient | | | | sensory or motor | | | | defects, convulsions, | | | | coma, death | | | +-----------------------+-----------------------+-----------------------+ | Laboratory Analysis | | | +-----------------------+-----------------------+-----------------------+ | Serum glucose | Glucose levels | Glucose levels | | \250 mg/dL, | \>600 mg/dL, lack of | | (first 2--3 days) and | reduction in | ketosis, serum | | \320 mOsm/L, | | | increased anion gap, | elevated blood urea | | | increased plasma | nitrogen and | | | levels of | creatinine levels | | | β-hydroxybutyrate, | | | | acetoacetate, and | | | | acetone | | +-----------------------+-----------------------+-----------------------+ **[Diabetic ketoacidosis (DKA) ]** - insulin deficiency and an increase in counter- regulatory hormones (catecholamines, cortisol, glucagon, and GH) decrease glucose uptake, increased fat mobilization (released fatty acids from adipocytes) - ketogenesis (increases ketone bodies --acetoacetate, hydroxybutyrate, and acetone drop in pH triggers buffering system --metabolic acidosis) **Etiology:** Common in Type 1 DM - Most common precipitating factor for DKA is intercurrent illness (infection, trauma, surgery, or MI) - Interruption of insulin administration may result in DKA - Symptoms include Kussmaul respirations, CNS depression, and ketonuria (insulin deficiency more profound than HHS) **Diagnosis:** - serum glucose \> 250 mg/dl, bicarb \< 18 mg/dl, pH \< 7.30, anion gap and urine and serum ketones. **Treatment:** - give insulin, increase fluid volume (replace that which was lost), replace electrolytes, and monitor closely. **[Hyperglycemic hyperosmolar syndrome (HHS)]** - life-threatening emergency - Most often precipitated by infections, medications, nonadherence to DM treatment, or coexisting disease - Common in DM II, as well as chronic pancreatitis **Clinical Manifestations:** - Extreme serum glucose level elevation glycosuria and polyuria - As much as 19 grams of glucose/hr lost in diuresis severe volume depletion, increased serum osmolarity, intracellular dehydration and loss of electrolytes including k+ - Neuro changes such as stupor correlate with the degree of hyperosmolarity and are common (a.k.a. "hyperosmolar hyperglycemic coma") **Evaluation:** - Glucose more than 600 mg/dl - Near normal serum bicarb level and ph - Serum osmolarity greater than 320mosm/L - Absent or low levels of ketones in urine and in serum **Treatment:** - Give insulin and fluid infusion over 24 hours. - Fluid replacement with both crystalloids and colloids is more rapid then DKA - Electrolyte infusion may take several days, especially k. - Differs from DKA in lack of ketosis. - Glucose levels are higher in HHS than DKA because of volume depletion. Higher degree of fluid loss in HHS than DKA, which leads to severe dehydration in HHS. Fluid replacement with both crystalloids and colloids is more rapid. HHS is a significant risk for infection, sepsis, and venous thrombosis. **Complications:** - sepsis, infection, and venous thrombosis **Why do diabetics develop retinopathy? Know microvascular complications of DM.** 1. Cause: a. Damage to retinal blood vessels and RBC's b. Platelet aggregation c. Relative hypoxemia d. Hypertension 2. Leading cause of blindness in the world 3. Develops more rapidly with Type 2 DM likelihood of longstanding hyperglycemia before diagnosis 4. Macular edema (fluids accumulation and retinal thickening near center of the macula) leading cause of visual impairment among persons with diabetes. 5. Blurring of vision consequence of hyperglycemia and sorbitol accumulation in the lens. 6. Reduced visual acuity dehydration of the lens, aqueous humor, and vitreous humor **Why do diabetic pts have CVD?** Cardiovascular disease: - Ultimate cause of death in up to 68% of people with DM (higher risk in women) - Hypertension (Type 1 microalbuminuria; Type 2 metabolic syndrome) increases risk for coronary artery disease and stroke - Coronary artery disease = most common cause of morbidity and mortality in individuals with DM Insulin resistance or deficit, chronic hyperglycemia, accumulation of advanced glycation end products activation of metabolic pathways that cause tissue damage result in the chronic complications of DM. The incidence of CHF is higher in individuals with DM (even without myocardial infarction) - Oxidative stress, proinflammatory factors myocardial remodeling and cardiomyopathy with increased amounts of collagen in the ventricular wall, and ventricular hypertrophy Unlike microangiopathy, atherosclerotic disease is unrelated to the severity of diabetes and is often present in those with insulin resistance and impaired glucose tolerance. The premature atherosclerosis of diabetes has many contributing factors: - Hyperinsulinemia (insulin resistance) - Hyperglycemia - Hypertriglyceridemia - Low levels of high-density lipoprotein (hdl) - High levels of low-density lipoprotein (ldl) - Lipoprotein oxidation - Platelet abnormalities **Patho:** Hyperglycemia induces mitochondrial overproduction of oxygen free radicals (key pathologic mechanism for the activation of the metabolic pathways associated with atherogenesis and damage to large and small vessels) - Advanced glycosylated end products attach to their receptor (RAGE) in the walls of blood vessels promoting oxidative stress, inflammation, endothelial and vascular smooth muscle dysfunction, and thrombosis. - More severe and accelerated with the presence of other risk factors: - hyperlipidemia, hypertension, and smoking **Know the pathophysiology, etiology, clinical manifestations, treatment and complications of Cushing disease**. Define **Cushing Disease:** excess endogenous secretion of ACTH (corticotropin). - Cushing syndrome (clinical manifestations) resulting from exposure to excess endogenous cortisol; more common in women. **Etiology:** 1. ACTH-dependent hypercortisolism (about 80%); more common in adults a. Pituitary adenoma or ectopic secreting non-pituitary tumor (small carcinoma of the lung) overproduction of pituitary ACTH 2. ACTH-independent hypercortisolism (20%); more common in children b. Rare benign or malignant tumor of one or both adrenal glands cortisol secretion 3. Cushing-like syndrome (long-term pharmacologic administration of glucocorticoids) **Pathophysiology:** 1. ACTH-dependent hypercortisolism excess ACTH excess production of cortisol loss of feedback control of ACTH secretion increased cortisol and adrenal 2. Androgens and inhibited corticotropin releasing hormone (CRH) a. Lack diurnal or circadian secretion patterns of ACTH and cortisol b. Do not increase ACTH and cortisol secretion in response to a stressor 3. ACTH-independent secreting tumors of the adrenal cortex secrete only cortisol. 4. Elevated cortisol levels suppress CRH and ACTH secretion from the hypothalamus and anterior pituitary low levels of ACTH atrophy of the remaining normal portions of the adrenal cortex (over time) alter the cortisol-secreting activity of normal cells 5. Secretion of cortisol by the tumor exceeds normal cortisol levels symptoms of hypercortisolism develop. **Clinical Manifestations:** 1. Weight gain (most common feature) accumulation of adipose tissue in the trunk, facial, and cervical areas a. Characteristic patterns of fat deposition = "truncal obesity", "moon face", and "buffalo hump" b. Transient weight gain (sodium and water retention) mineralcorticoid effects of cortisol (present in high levels) 2. Glucose intolerance cortisol-induced insulin resistance, glucogenesis, and glycogen storage by the liver 3. Protein wasting catabolic effects of cortisol on peripheral tissues muscle weakness 4. Renal stones hypercalciuria 5. Purple striae of truncal area loss of collagen thin, weakened integumentary tissues (capillaries are more visible, tissues easily stretched by adipose deposits) 6. Alterations in their mental status (50% of individuals) effects of cortisol on hippocampal neurons subsequent implications on learning, memory, and other neurologic functions (irritability, depression severe psychiatric disturbances i.e. schizophrenia) 7. Bronze/brownish hyperpigmentation very high levels of ACTH increased levels of melanocyte-stimulating hormones 8. Hypertension (vasoconstriction) elevated cortisol 9. Females increased adrenal androgen levels (increased hair growth, especially facial hair, acne, and oligomenorrhea); infertility is more common among women **Complications:** 1. Metabolic syndrome (abdominal obesity, hypertension, glucose intolerance, and dyslipidemias (common) 2. Hypercortisolism increased risk for cardiovascular complications (CAD, heart failure, and stroke) 3. Chronically elevated cortisol suppression of immune system, increased risk of infection, and poor wound healing **Evaluation:** 1. variety of laboratory tests to diagnose hypercortisolism (determine underlying disorder and differentiate ACTH-dependent (measurable) from ACTH-independent (non-measurable) Urine and serum cortisol and serum ACTH concentration 2. Other tests include: Dexamethasone suppression test, bilateral inferior petrosal sinus sampling; late night salivary cortisol levels (screening test and to document alterations in diurnal variation of cortisol level) 3. Routine labs: hyperglycemia, glycosuria, hypokalemia, and metabolic alkalosis 4. Diagnostic imaging: tumors **Treatment:** 1. Specific for cause of hypercorticoadrenalism medication, radiation, and surgery 2. Differentiation among pituitary, ectopic, and adrenal causes essential for effective treatment 3. Without treatment 50% Cushing syndrome die within 5 years of onset infection, suicide, complications from arteriosclerosis, and hypertensive disease