N715 Exam 3 Pt 6 PDF

○ Genetic changes involve mutational and epigenetic mechanisms​ ○ Process of development similar to wound healing​ ○ - pro-inflammatory mediators, recruitment of T lymphocytes and macrophages, and fibroblasts to form stroma that surrounds and infiltrates the tumor ○ Note...

○ Genetic changes involve mutational and epigenetic mechanisms​ ○ Process of development similar to wound healing​ ○ - pro-inflammatory mediators, recruitment of T lymphocytes and macrophages, and fibroblasts to form stroma that surrounds and infiltrates the tumor ○ Notes Point mutations – protein development​ Chromosome translocations -- Gene amplification​ Driver mutations – drive progression of cancer; after critical # has occurred – become known as cancerous​ Selective advantage over neighboring cells via clonal proliferation or clonal expansion​ Epigenetic effects (e.g. carcinogen exposure) -- DNA methylation, histone acetylation or altered expression of non-coding RNA ○ Cancer Hallmarks  ○ Evading growth suppressors – inactivation of tumor suppression (antioncogenes)​ ○ Avoiding immune destruction​ ○ Enabling replicative immortality (when reach critical age, reactivate telomerase – to restore and maintain their telomeres – tricking cell to avoid shortening of telomeres over time)​ ○ Tumor-promoting inflammation – manipulate environment to promote progression (similar wound healing) - inflammatory system cells induce induction in damaged tissue -> neovascularization and local immune suppression ​ ○ Activating invasion and metastasis - driver mutations ​ ○ Inducing angiogenesis ​ ○ Genome instability and mutation – inc in alterations in life cycle ​ ○ Resisting cell death – apoptotic pathways disregulated dt mutation in p53 gene ​ ○ Deregulating cellular energetics – cancer produce ATP via glycolysis instead of oxidative phosphorylation ​ ○ Sustaining proliferative signaling Pathophysiology  ○ HYPOTHESIS: repeat exposure to carcinogens leads to dysplasia of lung epithelium ○ Genetic mutations that affect protein synthesis​ NSCLC: EGFR, KRAS, and p16​ SCLC: MYC, BCL2, and p53​ ○ Disrupt cell cycle, promote carcinogenesis​ ○ Uncontrolled proliferation​ ○ Complex: the development of lung cancer involves intricate interactions among genetic mutations, environmental factors, and cellular alterations. ○ Field of Injury/Field Carcinogenesis Effect in which the entire carcinogen-exposed epithelial field is primed for cancerization and tumor development​ Carcinogen exposure ---- widespread extensive histological changes in the bronchial epithelia of smokers​ Injured airway epithelium exhibits various molecular alterations (aberrant gene expression, LOH) – precede and inform the onset of primary lung cancer​ Inflammation and inflammatory-related damage ---- field of injury explained via tobacco injury as well as initiation of the inflammatory response​ Epigenetic alterations are also present in the airway field of injury ○ Air pollution, tobacco smoke, and other inhaled toxins contain numerous carcinogens​ ○ These carcinogens + genetic​predispositions, result in tumor development​ Driver mutations promote tumor development by altering the production and response to growth factors (EGFR, KRAS)— alter cell growth and differentiation by the production of inflammatory mediators.​ We then see immune evasion, angiogenesis, and invasive growth Bronchial mucosa suffers multiple carcinogenic ‘hits’ over time bc of repetitive exposure to toxins.​ Epithelial changes​ Metaplasia​ Carcinoma in situ​ preinvasive epithelial tumor (early sign of cancer, localized, usually in bronchus; can progress to metastatic cancer, stabilize, or regress and disappear; if a lot of proliferation and dysplasia – higher likelihood of malignancy Invasive carcinoma​ Further tumor progression includes invasion of surrounding tissues​  Metastasis to distant sites​ Brain​ Bone marrow​ Liver Clinical Manifestations ○ Vary depending on tumor type Squamous cell carcinoma: cough, hemoptysis, hypercalcemia​ Adenocarcinoma: pleural effusion​ Large cell carcinoma: chest wall pain, pleural effusion, cough, hemoptysis, pneumonia​ Small cell carcinoma: cough, chest pain, dyspnea, hemoptysis, wheezing​ Paraneoplastic Syndromes​ Hyponatremia​ Cushing’s Syndrome​ Hypocalcemia​  Gynecomastia​ Carcinoid Syndrome​ Lambert-Eaton Myasthenic Syndrome Patho Discussion rt Article ○ Within the article it is discussed how epithelial cells exposed to smoke carry alterations at the molecular level that can pinpoint the onset of several types of lung cancers.​ ○ ​The two major molecular pathways involved in lung adenocarcinoma are KRAS (Kirsten rat sarcoma viral oncogene) and EGFR (Epidermal growth factor receptors) pathways.​ ○ ​Premalignant lesions in the lung are significant indicators for the progression of lung cancer.​ NP Role ○ Smoking cessation support ○ Health education ○ Promoting regular screenings ○ Encouraging healthy lifestyle choices ○ Monitoring environmental risks ○ Vaccination advocacy APPLICATION HOUR Cancer in children: Myeloid (blood cells) v lymphoid (b- & t-cells) Non Hodgkin's: older adult population; night sweats, fever, lymphadenopathy (swollen lymph nodes); non-contiguous Hodgkins: typically older, but can see in 20-30s ○ same fatigue, fever, appetite loss, nonprod cough, painless lymphadenopathy; contiguous Lung cancer: typical dx at 65+ Cancer Hallmarks LYMPHOMAS ○ Cellular origins of these neoplasms? ○ Hodgkin’s B-cells “B” symptoms: night sweats, fever, fatigue, painless lymphadenopathy Contiguous -- line of enlarged lymph nodes Reed sternberg cells - large abnormal WBCs ○ Non-Hodgkin’s B & T-cells ○ Difference in clinical s/s? LUNG CANCER  ○ Clinical Presentation? *hemoptysis, weight loss, fatigue ○ Contributes to field of injury other than smoking: Radon, secondhand smoke, thirdhand smoke (wood burning in homes) air pollution, chemicals, genetics ○ How does epithelial-mesenchymal transformation affect cancer progression? Epithelial - rapid cell turnover - inc likelihood of malignancy/mutation Bronchogenic more inflammatory since sitting where air entering in and out, more sheer; hear wheezing (limitation of air passage), tissue friable - hemoptysis/bleeding We normally have protooncogenes; oncogenes cause cancer Malignant transformation - abnormal replication of cell, lack mechanism to keep things in check E.g. BRCA, tp53 - tumor suppressor genes - if not present and mutated, then not suppressing genes replicating abnormally -> cancer Epithelial cells transform into mesenchymal cells - further promote tumor synthesis and production ○ Small Cell v Nonsmall Cell v Large cell Small cell - neuroendocrine Neural activation and hormone release -- neurohormonal; lots of locations affected Cancer cells - nucleus is larger and not structured, take up more of the cell; can have multiple nuclei BREAST CANCER ○ 70% of breast cancers are adenocarcinomas. This means glandular tissue. ○ Sarcomas mean connective tissue; not typically seeing bleeding or discharge as opposed to adenocarcinoma (glandular) at the nipple ○ What codes for alpha-cadherin? - cell adhesion ○ How are receptors represented? ER PR HER2 Triple negative (- - -): terrible outcome; negative for these 3 receptors PROSTATE CANCER ○ “Pepe le pew”= the cancer  ○ Aromatizer bulb - aromatase or DHT; with age, risk inc with more forming into estrogen in peripheral tissue; testosterone produced in testes ○ Relate to tp53 and BRCA2 mutations Week 14: Musculoskeletal Symptoms Musculoskeletal Overview: Leading causes of musculoskeletal conditions in care is trauma broke, bone, sprain, strained ligament or tendon Arthritis: autoimmune and body attacks its own synovial fluid (rheumatoid arthritis) or osteoarthritis where athletes/farms been over using a joint and have broken down cartilage that pads the joints and it becomes bone to bone Bursitis: fluid filled sacs that align and protect articular surfaces of joints become inflamed Tendonitis: inflammation in the tendons that attach muscle to bone  Flat bones: smooth and flat on the inside (such as scapula) Long bones: epiphysis, shaft, and diaphysis Sesamoid bones: modular bones seen on feet or wrists Short bones: roughly equal dimensions in length, width, and thickness, giving them a cube-like or rounded shape. These bones are primarily designed to provide stability and support with limited movement. Irregular bones: vertebral body, transverse processes, lumen of spinal canal where cord runs ○ Important to note bones that contain hematopoietic stem cells and prone to more hemorrhage such as the long bones or pelvic fracture  Long bones contain epiphysis (ends of the long bone) is where you’ll see the epiphyseal birth plates until about age 18-19 before they seal. Ends of the bone are considered articular or movement surfaces and the bone itseld is a spongy on the inside Medullary cavity is where the bone marrow and stem cells are contained Compact bones that are hardened and mineralized on the outside full of hydroxyapatite (crystal like, gives it its solidity) as well as calcium and phosphate stores. Outer lining contains the periosteum which is very vascular and innervate- so when bone is broken, most pain comes from the nerve stimulation to the periosteum. Inside of bone is not highly innervated Osteon: Tubes and tunnels that comprise long bones. In the harder, outer portion that fits into those long bones is referred to as the cortical bone, inner part is trabecular bone (spongy bone) ○ Within osteons are long canals (conversion canals) which contain blood vessels, arterioles, and veins helping supply nutrition to the bone cells  Within osteons are osteocytes (functional units of bone) which transform from osteoblasts (anabolic cells that are going to lead to bone buildup and creation of osteocytes) ○ Osteoclasts: catabolic bone cells, breakdown bone cells leading to apoptosis ○ Bony structure: responsible for structure of the body and movement, coordination, and collaboration with muscle , ligaments, soft tendons, and tissues that align the bony skeleton and allow us to go where we please based on activation of muscle contraction. ○ Bony skeleton is also responsible for mechanoreception, so these receptors on the bones that detect movement and are going to detect impact. When dealing with pts that have osteoporosis, you need to emphasize weight bearing activity because the mechanoreception (bone making contact) is going to stimulate bone growth and prevent significant breakdown that comes with the disease ○ Bones are also responsible for mineral regulation: we store phosphate and calcium in the bones, magnesium  Constant anabolic and catabolic activity that goes on along the bony structures Regulated by 2 specific cytokines: rankl & OPG Osteoclast/catabolic→ Rankl: cytokine responsible for breakdown of bone and release of calcium from bony structures→ Bone resorption. ○ This is regulated by the presence of parathyroid hormone. Parathyroid hormone works with rankl to induce/activate the osteoclast for bone resorption/breakdown. Releases calcium to serum increasing amount of serum calcium. Osteoprotegerin (OPG) → cytokine responsible for anabolic function in bone, activates the osteoblasts to produce more bone cells which will differentiate to osteocytes through the release of cyclic AMP and also regulates maturity of collagen into bone tissue Break bone/replacing bone→ bone remodeling Activation ○ Stimulus: bone bruise/trauma ○ Apoptosis of osteocytes: wearing down of osteocytes when they’ve reached end of their own life cycle Resorption: Resorption→ cavity forms: ○ small cavity forms and ○ Podocytes attach to the rough surface of the bone and promote osteoclast activity and break down of the lysosomes in the cells to release digestive enzymes. There’s a small crater which then provides a template or substrate for new bone formation. Formation ○ The osteoblasts attach and there is synthesis of new bone cells which then undergo mineral deposition which is regulated by enzyme alkaline phosphatase. Alkaline phosphatase responsible of bone callus if bone is broken (you will see increase enzyme and osteoblast and see increased activity of bony callus) Soft tissues and MSK Terms Tendon: soft tissue; attaches muscle to bone Ligament: also soft tissue, fibrous and thick and attach bone to bone (knee; patellar ligament attaches knee cap to anterior tibia and fibula) Joint capsule: movement surface that allows for flexion and extension. If joint capsule itself gets infected, leakage, it can be problematic. Joint capsule is what is attacked in rheumatoid arthritis. Has a thick outer fibrous membrane, connective tissue. Inner synovial membrane which holds fluid and lubricates the large joint and allows it to move and not become bone on bone (osteoarthritis) Meniscus: gelatin-like structure/sac that serves as a shock absorber Bursa: fluid-filled sac around joint that also helps reduce friction of movement Osteoblasts: build bone, anabolic Osteoclasts: break down bone, catabolic Osteocyte: stabilizing bone cells which are simply metabolizing and composing the structure which will eventually become an osteoblast  For skeleton to move, you must have muscle contraction Sliding filament vs cross-bridge theory Requires ATP Begins with the motor end plate ○ To have a muscle contraction, you must have neuronal activation with acetylcholine across the synapse at the motor end plate. ○ This causes stimulation to release calcium which is stored in the sarcoplasmic reticulum of the muscle fibers. ○ When calcium is released, that allows for attachments of myosin to projections and the pulling interaction of myosin against the actin protein chain which is all coordinated by an enzyme called tropomyosin The sliding filament theory describes the overall process of muscle contraction, emphasizing the movement of filaments within a muscle fiber. 1. Key Components: ○ Actin (thin filament): A protein filament that is attached to the Z-lines of the sarcomere. ○ Myosin (thick filament): A protein filament with projections (myosin heads) that interact with actin. 2. Process: ○ During contraction, the actin filaments slide past the myosin filaments. ○ This causes the sarcomeres (the structural units of a muscle fiber) to shorten, leading to the contraction of the muscle.  ○ Importantly, the length of the filaments does not change; they simply slide over one another. 3. Outcome: ○ The sliding of filaments pulls the Z-lines closer together, shortening the muscle The cross-bridge theory explains the molecular mechanism by which the sliding filament process is achieved. It focuses on the interaction between myosin heads and actin filaments. 1. Key Components: ○ Myosin Heads: Part of the thick filament, these projections attach to binding sites on actin. ○ Actin Binding Sites: Located on the thin filament, these are exposed when calcium ions (Ca²⁺) bind to troponin and move tropomyosin out of the way. 2. Process: ○ Attachment: Myosin heads attach to the exposed binding sites on actin, forming a "cross-bridge." ○ Power Stroke: The myosin heads pivot, pulling the actin filament toward the center of the sarcomere. This step releases ADP and phosphate (Pᵢ). ○ Detachment: A new ATP molecule binds to the myosin head, causing it to release actin. ○ Resetting: The ATP is hydrolyzed into ADP and Pᵢ, re-energizing the myosin head for another cycle. 3. Outcome: ○ Repeated cycles of cross-bridge formation and detachment result in the sliding of actin past myosin, driving the contraction. Steps in Muscle Contraction Excitation: release of acetylcholine, it binds to the receptor sites on the postsynaptic part of cell and leads to release of calcium from sarcoplasmic reticulum. Once this occurs, the calcium binds to actin and allows myosin cross bridges to contain and pull myosin and active chains against one another (coupling) which leads to the sliding filaments and muscle contraction. Once that is accomplished the calcium is released and goes back up into the sarcoplasmic reticulum and the process repeats  In order for contraction, significant amount of ATP is needed Skeletal muscle contains highest amount of glycogen stores in the body because of constant movement (even if breathing, if not we would be in anaerobic metabolism and will cause kidney failure and death Glycogen is broken down quickly in the muscle which is regulated by enzyme glycogen phosphorylase Types of Fractures Transverse fracture: a break straight across the diaphysis (horizontal break) Lineal: vertical break Oblique non-displaced fractures: diagonal break Oblique displaced: bone is fractured and broken at an angle Spiral fracture: line itself has a twist to it Greenstick fracture: typically only in children since they have large amounts of cartilage, bones are soft and they don’t break all the way across. Disruption of the cortex (outer portion of the bone) but it doesn’t go all the way through Comminuted fracture: splintered into tiny pieces.  Important to think most bones especially long bones are straight Note if someone has a fracture, if its displaced, and follow the outer cortical lines of the bones which are smooth where you see an opacity or are pulled out of place that the margins/the bones don’t quite fit or line up smoothly. Or is there angulation, is the bone off at an angle and it doesn’t go straight up or down. You want to know if bone is broken at the proximal or distal portion and what direction that angle is. Know that bones can be displaced, non-displaced, or angulated Severe fractures particularly bones producing blood cells can hemorrhage Another risk, if bone breaks in certain places, can be an unstable injury.  ○ For example, in the image of the ankle, there's a possible crack in the fibula, but the person can walk on it and joint space is fairly equal meaning this is a stable injury. ○ On the right, fracture is very unstable and person won't be able to walk without bones shifting out of place--> highly unstable injury--> these can lead to neurovascular injury where it can push/compress blood vessels and nerves causing more complications There is blood vessel supply: arterial and venous to the bone tissue itself supplying nutrition So initially in a fracture, there will be a blood clot or hematoma that forms around that fracture. Once hematoma forms, fracture will form new blood vessels and bone cells to develop that callus formation and eventually develop new bone  Spine has discs that cushion and provide shock absorption between each vertebra in the spinal canal. If discs slip out of place or if they are bulging, putting pressure on the spinal cord or nerve roots where nerves come out of the spine, that can cause radiating pain of extremities, cause numbness or weakness and over time, if something is out of place and pressing on tissue it can cause ischemia and cause permanent loss of function Spinal fractures: ○ Compression: if vertebral body is weakened, it can collapse on itself ○ Wedge: usually from degeneration of bone and form a wedge and can lead to compression ○ Burst: someone who jumps from a long height and lands on feet (can cause compression) or burst/rupture the vertebral body and just break into little pieces  Increase bone resorption: break down of bones, as we age bones get more brittle. Osteoclast activity exceeds osteoblast activity Slower and decreased osteoblast activity: less build up of new bone and fewer functional osteocytes which are metabolizing Loss of collagen: causes wrinkles but also collagen is the basis of bone formation. We mineralize collagen, but no collagen means no bony structure. Increased calcification: very hardened bones but also brittle, can be “nody” and Cartilage becomes brittle (no longer smooth and flexible): leading to easier fractures and limited mobility Malnutrition: we don’t absorb nutrients leading to mineral deficiencies further leading to bone breakdown  Strain: injury to muscle or tendon. So if a tendon or muscle is pulled, it is injured but not completely ruptured (torn apart). Strain inflammation and irritation. Sprain: injury to ligament. Swelling, increased warmth, arrival of cytokines to the area. Activation of inflammatory response. If ligament is pulled all the way out, the bones slip out of place causing dislocation Hip dysplasia: abnormal growth along the bone and its stiff causing limited movement because of abnormal production of cells. New cells, not the same cells that should be produced in the synovial lining. ○ Characteristics:  Can range from mild (underdeveloped socket) to severe (nearly absent socket). Often congenital (present at birth) but can worsen over time. Leads to instability and increases the risk of subluxation or dislocation. ○ Causes: Genetic predisposition. Positioning in the womb (e.g., breech births). Environmental factors like swaddling tightly with legs extended. Subluxation: Subluxation is a partial or incomplete displacement of the femoral head from the acetabulum. The joint surfaces remain partially in contact, but the fit is abnormal. Head of femur pulled out a bit but still in the joint (not popped out) ○ Characteristics: A step beyond dysplasia but not a full dislocation. May be transient, occurring with certain movements or postures. ○ Causes: Developmental hip dysplasia. Trauma or injury (e.g., a fall or car accident). Underlying conditions like ligamentous laxity (e.g., Ehlers-Danlos syndrome) Dislocation: A hip dislocation occurs when the femoral head is completely displaced out of the acetabulum, ligaments pulled completely ○ Characteristics A severe and emergent condition. Can be congenital (as part of developmental dysplasia) or acquired (due to trauma). ○ Causes: Congenital: Hip dysplasia or birth trauma. Trauma: High-impact injuries, such as car accidents or sports injuries. Prosthetic Dislocation: Occurs in individuals with hip replacements CALCIUM DISORDERS → Calcium: Tightly regulated (homeostasis) under normal circumstances: ○ Exists in an ionized form in the bloodstream and its tightly regulated because it is needed for normal bone structure (have ability to contract muscles including heart) and conduct nerve impulses Maintained in Serum lvl of 8.4-10.2 mg/dL ~50% of Calcium is protein bound (albumin)  ~50% ionized/free form used for cellular metabolism ○ Of the 50% that is ionized and free, 10% of that is traveling around in complexes with citrate or phosphate Small circulating amounts complexed with citrate, phosphate (10%) Free calcium ↓ as pH ↑ ○ Patients develop hypocalcemia when given a lot of blood products. Blood is prepared with sodium citrate, so calcium is binding to sodium citrate in blood product which is decreasing amount of ionized/free calcium Calcium is very pH dependent. The amount that is free and ionized is going to be altered by the environment and if the patient is very alkalotic, the there will be less available free calcium for use by the cells If acidotic, then patient becomes hypercalcemic Significance of Calcium Dysregulation Hypercalcemia (> 10.2 mg/dL) ○ 1% of hospitalized patients ○ Poor prognosis in patients with malignancy Patients with malignancy/ with cancers that develop hypercalcemia tend to have poor prognosis Hypercalcemia is related to a primary dysfunction of the parathyroid gland. Parathyroid gland produces parathyroid hormone that helps in regulation of calcium ○ 90% cases due to primary hyperparathyroidism (PTH) First step in evaluating a patient with a calcium disorder is to order a parathyroid hormone level  Hypocalcemia (< 7.5-8.0 mg/dL) ○ With HYPOcalceima (low serum calcium): patients will typically be asymptomatic unless they develop clinical signs (if they do, its very concerning, need quick follow up and definitive treatment). ○ Typically asymptomatic; clinical signs concerning ○ Consider primary hypoparathyroidism vs renal/liver failure Want to consider if it is an issue with the parathyroid gland or does the patient have renal/liver failure where they are unable to reabsorb calcium or unable to process and obtain it from the stomach. ○ May be rapidly life threatening (laryngospasm, seizures, arrhythmias) ○ Complications range from subtle (depression) to life-threatening (arrhythmias) Calcium disorders in general can be rapidly life threatening and make sure to order EKG Hypocalcemia: Chvostek's sign and Trousseau's sign but also consider tetany, seizures, laryngeal spasm ○ Levels increase in acidotic states/decrease in alkalotic states Negative feedback loop Parathyroid gland releases parathyroid hormone and that is going to increase/elevate serum level of available calcium in the system. Parathyroid hormone is going to increase calcium levels and that is balanced and regulated by the thyroid gland, which produces calcitonin. People with osteoporosis take calcitonin because it drives calcium back into the bone and strengthens it but it is going to decrease the serum calcium levels available to the cells. Another aspect is thyroid hormone is going to decrease reabsorption from the kidneys, decrease absorption from calcium that we take through nutrition. Level of calcium in the blood is regulated by the two glands (parathyroid and thyroid) and three areas they work on is on the Bone- calcium will increase deposition. Parathyroid hormone is going to promote release of calcium from the bone Gut: Thyroid hormone, calcitonin is going to decrease the amount we absorb from foodstuff as it travels through the gut and the parathyroid hormone is going to increase it.  Kidneys: The thyroid hormone, calcitonin, is going to decrease calcium reabsorption from the nephrons in the kidneys while the parathyroid hormone is going to increase it. Vitamin D: Sources Two sources: ○ Sunlight – cholecalciferol ○ Nutrition- ergocalciferol (mainly from vegetables) Hydroxylated in the liver, converted to active Vitamin D3 in kidneys ○ Vitamin D needs to be hydroxylated in the liver to be converted to the active vitamin that works in the kidneys but also helps with increasing GI absorption of calcium, renal reabsorption, and promotes with parathyroid hormone the activity of osteoclasts. Function: Raise serum calcium levels Increase GI absorption Increase renal reabsorption Promote activity of osteoclasts  Anywhere along the way, the parathyroid gland can lead to issues with calcium, with thyroid (if we’re not producing or we’re producing too much calcitonin) and can lead to pathology if there’s vitamin D deficiency. PTH Sensitive to free/ extracellular calcium levels ○ Determines secretion of PTH Short half-life (3-5 minutes) ○ Parathyroid hormone has a very short half-life so if you don’t produce the correct amount of parathyroid hormone, you’re going to see the effects fairly quickly. ○ Someone can become highly hypocalcemia after surgical removal of thyroid gland and if the parathyroid gland is accidentally removed as well--> leading to clinical manifestations of hypocalcemia First step in the evaluation for etiology of calcium disorders Most likely cause of hypercalcemia →Hypercalcemia Mild (10.3-11.0 mg/dL) ○ Fatigue ○ Subtle cognitive changes, depression ○ Constipation Moderate (12-14 mg/dL) ○ Anorexia, nausea, generalized weakness ○ Altered mentation Severe (>14 mg/dL) ○ Severe dehydration ○ Lethargy progressing to coma, CNS changes ○ Renal dysfunction, diabetes insipidus →Clinical Presentation Generalized- weakness, anorexia, fatigue ○ Unintentional weight loss Drowsiness/lethargy, mild AMS progressing to coma Band keratopathy Shortened QT Interval ○ Clinically, you can see the shortening of the QT interval and when that happens you being to see tachyarrhythmias and life threatening complications ○ You want to order an EKG if you have a patient with hypercalcemia and ask questions about history (unintentional weight loss, night sweats, paraneoplastic syndromes) it may be that they have a cancer that has not been diagnosed yet. Constipation, pancreatitis Polyuria/diabetes insipidus, AKI, nephrocalcinosis/stones Algorithm is more for acute care Step 1: get a parathyroid hormone level along with an ionized calcium Lower part of algorithm is going to be for the acute care environment →Familial Hypocalciuric Hypercalcemia Inactivating mutation for CaSR ○ Familial Hypocalciuric Hypercalcemia is a condition with a genetic mutation or variant for the calcium SR (CaSR) gene which makes the parathyroid much more sensitive to serum calcium levels. Decrease sensitivity to serum Ca levels, increasing synthesis of PTH ○ What happens is the parathyroid is so sensitive that is recognizes even a mild decrease in calcium levels and it produces too much parathyroid hormone. So these individuals become hypercalcemic because of familial disorder. Combined with low renal excretion (24 hour urine calcium useful) Evaluation: ○ Family members