midterm study guide

PATHO STUDY GUIDE TEST 1

WEEK 2

1) Process of inflammation and importance Protective response, rids organism of:

o Initial cause of injury (microbes, toxins, hypoxia)o Consequences of injury (necrotic or damaged cells/tissues)

Without ito Infections uncheckedo Wounds never healo Permanent festering sores

Cardinal signso Heato Rednesso Swellingo Paino Loss of function

Complex reactiono Inflammatory stimulus o Soluble factors triggered (inflammatory mediators) o Circulating cells and proteins rapidly recruited to site of injury o Coordinated reaction of blood vessels, leukocytes, and plasma proteins o Inflammatory response

Importance for ARNPso Inflammation can be harmful

Can be inappropriately triggered or poorly controlled Can become cause of injury and disease

o Underlying pathogenesis of many chronic diseases is damaging inflammation RA, atherosclerosis, lung fibrosis Life-threatening hypersensitivity reactions

o Anti-inflammatory drugs Control harmful sequelae without interfering with beneficial effects

2) Acute vs. Chronic Inflammation Acute inflammation

o Exudation of fluid and plasma proteins into extracellular tissues (SG > 1.020)o Migration of leukocytes

Predominanatly neutrophils (polymorphonuclear leukocytes = POLYS)o Patterns of inflammation

Serous thin serous fluid FIbrinous abundant Fibrin exudate fibrosis Suppurative or purulent purulent exudate (consists of neutrophils,

necrotic cells, and edema fluid) Ulcers tissue necrosis and inflammation near surface surface

excavation

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Chronic inflammationo Infiltration with mononuclear leukocytes (MONOS)

Macrophages Liver: Kupffer cells Spleen & lymph nodes: sinus histocytes Lungs: alveolar macrophages

Lymphocytes Plasma cells Eosinophils Mast cells NK cells

o Tissue destructiono Angiogenesiso Fibrosiso Patterns of inflammation: granulomatous inflammation

Focal accumulation of activated macrophages, develop epithelial-like appearance

Types Foreign body granuloma giant cells and epithelial cells form Immune granuloma epithelioid cells and multinucleate giant

cells form

3) Primary inflammatory disease: Extrinsic Asthma Etiology

o Genetic predisposition to atopic reactionso Triggered by environmental allergens (dust, pollen, dander, foods, etc.)o Type I hypersensitivity (Immediate, IgE mediated)

Exaggerated immune response to exogenous antigens Patho

o Initial allergen sensitization in airways o T helper 2 cells activated o Cytokines secreted that promote allergic inflammation o B cells stimulated to produce IgE and other antibodies o IgE coats submucosal mast cell surfaces o Further exposure to same allergen cross-links surface bound IgE o Mast cell degranulation o Leukotrines, histamine, prostaglandins, and acetylcholine are released o Lymphocytes recruited in late phase reaction

Morphologyo HIstology

Thickening of airway wall Sub-basement membrane fibrosis Increased vascularity Increased size of submucosal glands

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Hypertrophy and hyperplasia of bronchial wall muscle Thing mucous plugs containing shed epithelium

o Skin test with offending antigen Immediate wheal and flare reaction

o Key players Lymphocytes Eos Polys Monos Epithelial cells

Elevated during asthma attacko Sputum

Curschmann spirals Charcot-Leyden crystals

Clinical manifestationso Wheezing, coughing, chest tightness, SOB, dyspneao Difficulty with exhalationo Acute attack lasts up to a few hours

4) Acute inflammatory disease: Acute Salpingitis Etiology

o Polymicrobial infection, which ascends reproductive tract d/t: Surgical procedure that breaks cervical barrier Altered microenvironment of vagnia and cervix (antibiotic treatment,

ovulation, menstruation, STD) that allows infectious microbe to proliferate and ascend

Sexual intercourse that facilitates spread from vagina to fallopian tubeo Common microorganisms

Neisseria gonorrheae, Chlamydia trichomatis, mycoplasma, staphylococcus, and streptococcus

Pathoo Vaginal infection o Infective agent climbs endometrial wall, damaging cells and tissue as it makes its

way to upper reproductive organs o Endometrium vulnerable to other infectious microbes as a result of cellular

damage o Widespread inflammation o Inflammation reaches fallopial tubes o Degeneration and deciliation of epithelial cells o Intraluminal agglutination o Clubbing of involved fallopian tube(s)

Morphologyo Laproscopy: tubal wall edema, visible hyperemia of tubal surface, presence of

exudate on tubal surfaces and fimbriae

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Standard for diagnosiso Transvaginal u/s or MRI: thickened, fluid-filled tubeso Endometrial biopsy: endometritiso Abundant WBCs on saline microscopy of vaginal secretionso High ESRo High CRPo DNA probe or culture: cervical infection with N gonorrhoeae or C trachomatis

Clinical manifestationso Abnormal cervical mucopurulent discharge, bleeding, or odoro Fever (oral temp > 38.8C)o Urinary frequencyo Low back pain, lower abdominal pain

Pelvic organ, adnexal, and cervical motion tendernesso N&V

5) Chronic inflammatory disease: Chronic Granulomatous disease Etiology

o Primary immunodeficiency of innate immune systemo Caused by defect in one of 4 genes that encode for NADPH oxidase

Enzyme responsible for microbicidal respiratory burst of phagocytes and generation of superoxide

o X-linked (more common) or autosomal recessive X-linked

Mutation in gp91phox Autosomal recessive

Mutation in p22, p47, or p67 Patho

o Mutation in gp91phox, p22, p47, or p67 o Defective NADPH oxidase function o Inability of phagocytes to kill ingested microbes o Susceptibility to severe and recurrent bacterial and fungal infections by catalase-

positive organisms and organisms resistant to nonoxidative killingo Tissue necrosis, slow inflammatory resolution o Granuloma formation

Morphologyo NBT dye test: neutrophils in patients with CGD are unable to reduce oxidized

NBT to insoluble blue formazan Diagnostic for gene carriers and prenatal diagnosis

o DHR test: Same as NBT test but fluorescent dye used Diagnostic Can detect x-linked carrier status

o CBC: leukocytosis, microcytic hypochromic anemiao C&S: catalase positive bacteria isolated from lesionso Quantitative immunoglobulin tests: High IgG, IgM, and IgA (IgE high or normal)

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Clinical manifestationso Disease usually becomes apparent during first 2 years of life o Recurrent bacterial and fungal infections occurring at epithelial surfaces and in

organs with a large number of reticuloendothelial cells (lung, skin, lymph nodes, liver)

o Earliest manifestations often involve skin: dermatitis, reuccrent pyodermas appear as perianal, axillary, or scalp abscesses

o Systemic findings: osteomyelitis, gingivitis, pulmonary abscesses and granulomas (recurrent pneumomonia), spleen and/or liver abscesses, or hepatosplenomegaly

o Mucosal infllammatory disorders (colitis, enteritis, gastric outlet obstruction) diarrhea may occur

o Fever may occur

6) Cellular regeneration vs. repair Regeneration

o Proliferation of cells and tissues to completely replace lost or damaged tissueo Mammals do not regenerate spontaneouslyo Parenchymal cell death (with intact tissue framework), superficial wounds, some

inflammatory processes Repair

o May restore some original structures (regeneration) but involves collagen deposition and scar formation

o Physiologic adaption of an organ after injury in an effort to re-establish continuity without regards to exact replacement of lost/damaged tissue

o Parenchymal cell death (with damaged tissue framework), deep wounds, scar formation

Growth factorso Epidermal growth factor (EGF) & transforming GF alpha (TGF)

Involved in epithelial cell, hepatocyte, and fibroblast proliferation o Hepatocyte growth factor (HGF)

Mitogenic effects on hepatocytes and most epithelial cells Promotes cell scattering and migration

o Platelet-derived growth factor (PDGF) Causes migration and proliferation of fibroblasts, smooth muscle cells, and

monocytes to areas of inflammation and healing skin woundso Vascular endothelial growth factor (VEGF)

Potent inducer of blood vessel formation in early development Central role in angiogenesis in adults

o Fibroblast growth factor (FGF) Contributes to angiongenesis, meatopoises, and wound repair

o TGF beta Growth inhibitor of epithelial cells and leukocytes Stimulates production of fibrobalasts and smooth muscle cells

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7) Stem Cells Undifferentiated biological cells

o Can differentiate into specialized cells and can divide to produce more stem cells Two types in mammals

o Embryonic stem cells Found in inner mass of blastocysts Pluripotent

Can generate all the different types of cells in the body Give rise to multipotent stem cells and eventually differentiated,

specialized cells that make up the entire body Can be grown and expanded indefinitely in undifferentiated state

o Adult stem cells Found in various tissues (skin, gut lining, cornea, hematopoietic tissue) =

tissue-specific With progenitor cells, act as a repair system for the body, replenishing

adult tissues Multipotent

Already somewhat specialized and can produce some or all of the mature cell types found within the particular tissue or organ in which they reside

Importanceo ES cells may be used in the future to repopulate damaged organs

ES have already been used to produce insulin-producing pancreatic cells, nerve cells, myocardial cells, or hepatocytes in animals with experimentally produced diabetes, neurologic deficits, myocardial infarctions, and liver damage respectively

o Induced pluripotent stem cells (iPS cells) are adult cells that are engineered, or reprogrammed to become pluripotent (behave like an ES cell)

Good way to make pluripotent stem cell lines that are specific to a disease or even to an individual patient

o Future developments Use of disease-specific stem cells

Study the cause of a particular disease Test drugs Discovering new approaches to cure or treat disease

Use of patient-specific stem cells Cell therapy Cells lines are from the patient themselves May minimize some serious complications of rejection and

immunosuppression that can occur following transplants from unrelated donors

o Current therapies Hematopoietic stem cells

Most frequently used stem cells for therapyo Often collected from umbilical cord blood, bone marrow, or

peripheral blood of ppl receiving cytokines that mobilize HSC

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Bone marrow transplants used to transfer blood stem cells to patients with hematologic diseases

o To reconstitute bone marrow after depletion caused by disease or irradiation

Collecting blood stem cells as treatment for leukemia, lymphoma, and several inherited blood disorders

Tissue grafts Some bone, skin, and corneal diseases or injuries can be treated by

grafting tissues that are derived from or maintained by stem cells

8) Angiogenesis Important bc it affects:

o Phsyiologic reactions Wound healing, regeneration, vascularization of ischemic tissues,

menstruationo Pathologic processes

Tumor development and metastasis, diabetic retinopathy, chronic inflammation

o Use of agents with pro or anti-angiogenic activity Blood vessel formation in adults Mechanism

o Branching or extension of preexisting vessels Vasodilation Increased permeability of existing vessels Degradation of ECM Migration, proliferation, and maturation of endothelial cells Recruitment of periendothelial cells to form mature vessel

o Recruitment of endothelial progenitor cells from bone marrow EPCs are mobilized from bone marrow EPCs migrate to site of injury or tumor growth At these sites, EPCs differentiate and form a mature network by linking to

existing vessels Motility and directed migration of endothelial cells, controlle by:

o Integrinso Matricellular proteinso Proteinases

Cleave extracellular proteins that release VEGF and FGF-2 Stimulate angiogenesis

9) Repair, scar formation, fibrosis Repair

o Inflammation Fibrin clot formation Wound exudation

o Proliferative phase

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Angiogenesis, fibroblast and endothelial cell proliferation Granulation tissue

Collagen synthesis Wound matrix formation and epithelialization

o Maturation phase ECM deposition Collagen cross-linked Wound contraction Tensile strength development

Scar formationo Eventually, granulation tissue evolves into a scar composed of largely inactive,

spindle-shaped fibroblasts, dense collagen, fragments of elastic tissue, and other ECM components

Fibrosiso Excessive deposition of collageno Often in chronic inflammatory diseases

Activates macrophages and lymphocytes Production of growth factors and cytokines Increase collagen synthesis

10) Influences on wound healing Local factors

o Infection persistent tissue injury and inflammationo Mechanical factors delay healing by compressing blood vessels and separating

wound edgeso Foreign bodieso Size and type small incisional injuries (not large excisional, or blunt trauma)

heal faster and with less scar formationo Location Face is highly vascularized, heals faster

Systemico Nutrition Protein and vit c deficiency inhibit collagen synthesis and retard

healingo Metabolic status DM is associated with delayed healing d/t microangiopathyo Hormones Glucocorticoids (anti-inflammatory effects) inhibit collagen

synthesis

11) Types of dysfunctional wound healing Deficient scar formation

o Dehiscenceo D/t: infection, increased abdominal pressure, comiting, coughing, ileus

Excessive formation of repair componentso Excess collagen hypertrophic scaro Scar tissue beyond boundary of original wound without regression keloido Excess granulation tissue, blocks re-epithelialization exuberant granulation

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o Exuberant proliferation of fibroblasts and other connective tissue after excision desmoids, or aggressive fibromatoses

Formation of contractureso Exaggeration of normal contracture processo Prone to develop on palms, soles, ant. Thoraxo Commonly seen after serious burnso Can compromise joint movement

WEEK 3

1) Starling’s Law: Burns Injured tissue Inflammatory reaction Release of inflammatory mediators Increased capillary permeability Loss of water and plasma proteins from vascular compartment into interstitial

o Intravascular hypovolemiao Decreased capillary osmotic pressure

Edemao Increased interstitial osmotic pressure

Edema Decreased transport of capillary filtered protein Lymph obstruction Decreased absorption of interstitial fluid Edema

Decreased cell membrane potential Intracellular shift of Na+ and H20 Cellular swelling Resuscitation

o During the period of increased edema formation (the first 24 hours after burn), maintenance of normovolemia with aggressive fluid resuscitation and fluid boluses only exacerbates the severity of edema formation.

o Maintenance of end organ perfusion - not the rapid achievement of normovolemia - is the goal of burn resuscitation.

o The end organ monitored during resuscitation is the kidney, with urine output guiding fluid rates.

o By 24 hours after burn, the endothelial leak has sealed and albumin infusions can safely be started.

o Insensible fluid losses through the burn wound begin in the second 24 hours following burn and continue to be significant until the burn wound is closed.

2) Virchow’s Triad: Trauma Virchow’s Triad – predisposing factors to thrombosis

o Endothelial injury HTN

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Hyperlipidemia Cigarettes smoking Turbulent blood flow over scarred valves Radiation Metabolic abnormalities Bacterial endotoxin

o Abnormalities of blood flow Turbulence

Valvular dysfunction Septal defects Aneurysms

Stasis Atriba fibrillation Aneurysms

o Hypercoagulability of blood Primary

Factor V muitatuion Prothrombin mutation Protein C & S deficiencies Hyperhomocysteinemia

Secondary Prolonged bed rest or immobilization MI, A fib, prosthetic cardiac valves Cancer Tissue injury (surgery, frx, burn) OCR HRT Pregnancy Obesity

3) Septic shock Etiology

o Spread and expansion of initially localized infection (abscess, peritonitis, pneumonia) into bloodstream

o Most frequently triggered by Gram + bacteriao Next most common: Gram – bacteria and fungi

Pathoo Macrophages, neutrophils, and other immune cells express receptors that

respond to a variety of substances derived from microorganismso Activated cells release inflammatory mediators and immunosuppressive factors

that modify host response o Inflammatory mediators

Systemic vasodilation pooling of blood in periphery hypoperfusion Coagulation Complement activation

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o Immune suppression Shift from pro to anti-inflammatory cytokine production Lymphocyte apoptosis

o Endothelial cell activation and injury Thrombosis Increased vascular permeability Systemic vasodilation Vasodilation DIC in ~50% of septic pts

o Metabolic abnormalities Suppress cellular function Insulin resistance and hyperglycemia

o Organ dysfunction MODS = Heart, kidneys, ARDS, liver Culminates in death

Morphology and clinical manifestationso Early, nonprogressive phase

Reflex compensatory (neurohumoral) mechanisms (adrenergic response) activated to maintain CO and BP (perfusion of vital organs is maintained)

Baroreceptor reflexes Catecholamine release RAA activation ADH release Generalized sympathetic stimulation

S/Sx Tachycardia Weak, rapid pulse Tachypnea Peripheral vasodilation hypotension Cutaneous vasodilation warm, flushed skin Renal conservation of fluid

o Progressive phase Tissue hypoperfusion

Onset of worsening circulatory and metabolic imbalances (acidosis)

Widespread tissue hypoxia lactic acidosis lowers tissue pH blunts vasomotor response

Arterioles dilate blood pools in microcirculation worsens CO S/Sx

Decrease in UOP Confusion

o Irreversible phase Widespread cell injury lysosomal leakage NO synthesis worsened myocardial contractile function Vasoconstriction acute tubular necrosis renal failure Ischemia hypoxia cellular injury

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o MODS S/Sx Brain – ischemic encephalopathy Heart – coagulation necrosis, subendocardial hemorrhage, contraction

band necrosis Kidneys – acute tubular necrosis, oliguria, anuria, electrolyte disturbances Lungs – diffuse alveolar damage (shock lung) Adrenal – corticol cell lipid depletion, conversion of inactivated vacuolated

cells to metabolically active cells that store lipids GI – hemorrhagic enteropathy (mucosal hemorrhages and necroses) Liver – fatty change, central hemorrhage necrosis

4) DIC Etiology

o Secondary to constant stimulation of homeostasis (always a secondary disorder) Release of tissue factor and/or thromboplastic substances activation of

extrinsic pathway of coagulation Sepsis Severe tissue destruction (trauma, burns) Pancreatitis Neoplasms Obstetric complications Snakebites

Injury to endothelial cells exposing subendothelial collagen Activation of intrinsic and extrinsic pathways of coagulation

Pathoo Sudden insidious onset of widespread fibrin thrombi in microcirculation o Vascular occusion tissue ischemia

Brain Lungs Heart Kidneys Gut Peripheral vasculature

o Excessive activation of plasmin and fibrinolysis, proteolysis of clotting factors Ultimately hemostatic components consumed (consumptive

coagulopathy) o Bleeding diathesis

Morphologyo Thrombi in organs

In glomeruli renal cortical necrosis In alveolar capillaries pulmonary edema

o Microinfarcts in CNSo Increased FSPs and D-Dimero Increased aPTT and PTo Decreased platelets and clotting factors

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Clinical manifestationso Acute or insidious and chronico Bleedingo Convulsionso Comao Cyanosiso Dyspneao Hypotensiono Microangiopathic hemolytic anemiao Oliguria and ARFo Respiratory failureo Shocko Thrombotic complications

5) HIT Etiology

o Immune-mediated syndrome following heparin administration Patho

o Initiation Heparin-dependen antibodies (IgG) recognize PF4/heparin complexes on

platelet surfaces and vascular walls IgG binds to complexes on platelets Antibody activates platelets via Fc receptor Positive feedback for platelet activation Activated platelets release microparticles with prothrombotic activity

o Development of hypercoagulable state Platelet microparticles, endothelial cell injury, and monocyte activation

promote thrombin generation PF4 release neutralizes heparin and leads to formation of more

PF4/heparin complexes, exposing more antigens Platelet activation further amplified

Morphologyo Thrombocytopenia (>50% decrease)o Recovery of platelet count after cessation of therapyo Prolonged aPTTo Platelet activation test: detect heparin dependent antibodes to PF4/heparin

complex (positive)o Other cause not apparent

Clinical manifestationso Timing 5-14 days after administration of heparin

Sooner with previous heparin exposureo Thrombotic complication

Unusual thromboembolism, skin lesions, or anaphylaxis Hemorrhage

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Sudden MI Peripheral arterial thrombosis PE DIC

6) Antiphospholipid antibody syndrome (APLS) Etiology

o Autoimmune phenomenono Abnormal antibodies directed against phospholipidso Can occur by itself (primary)

1/3 with primary APLS have heart valve abnormalitieso Can be caused by an underlying condition (secondary)

SLE Patho

o Antiphospholipid antibodies reduce levels of a protein that binds phospholipids and has potent procoagulant activity

o Increased tendency of blood to cot Morphology

o Thrombocytopenia in 20-40%o Abnormal antiphospholipid antibodies in blood

Clinical manifestationso Increased tendency of blood to cloto Migraine h/ao Recurrent pregnancy losses (repeat spontaneous abortions)o Recurrent arterial or venous thrombi

PE CVA

o Cardiac valve vegetations

7) TTP Etiology

o Rare blood condition caused by defective breakdown of vWF by vWF cleaving protease

o In newborns and children, often inherited conditiono Triggers for adult-onset, most often develops spontaneously

Drugs Antiplatelet drugs, OCPs, quinine

Pregnancy Infections

HIV SLE Malignancy

Pathoo Antibody affects vWF cleaving protease

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o Ultra-large vWF in circulation o Stimulates homeostasis

Morphologyo Homeostasis o Thrombi in brain and kidneys thrombocytopenia

HTN, High Creat,o Fragmentation of RBCs o Microangiopathic hemolysis develops if RBC destruction is greater than

replacement Clinical manifestations

o Thrombi in brain: h/a, confusion, aphasia, transiet paralysis, numbness, seizures, fever

o Consumption of platelets bruising, rarely bleeding (from nose or gomes)o RBC destruction anemia, pallor, fatigue, DOE, jaundice, red or brown urine

8) HUS Etiology

o Most likely autoimmune Patho

o Commonly, infection in GI system by E.coli (found on contamined food like meat, dairy products, juice)

o Endothelial damage (specifically, in renal vasculature) o Progressive renal failureo Bacterial originally lodged in GI system make toxins that enter bloodstream o Toxins destroy RBCs

Morphologyo Cardinal lesions composed of arteriolar and capillary microthrombi and RBC

fragmentationo Occlusive lesions of arterioles and small arteries develop microinfarctionso Obliterative arteriolar lesions HTN, progressive loss of functiono Glomerular thrombotic microangiopathic lesions and cortical necrosiso Consumptive coagulopathy

Thrombocytopeniao Microangiopathic hemolytic anemia

Clinical manifestationso Venous thrombosis

Local congestion and edema in vasculatiure distal to thrombus Local inflammation with classic signs

Homan’s sign Embolus to lungs PE Majority

Superficial leg veins Deep leg veins

o Arterial and cardiac thrombosis

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Embolize to tissues nourished by that involved artery Cardiac thrombosis

Mural thrombio After acute MIo Afibo Rheumatic heart disease

9) NCI Website Tumor markers

o More than 20 in clinical useo Some associated with 1 type of cancer, others with 2+o No universal tumor markero Uses

Dx of cancer Predict therapy response Monitor response to treatment Determine whether cancer has returned

o Made by cancer cells and noncancerous cells Much higher number in cancer cells

Tobacco is the leading cause of preventable illness and death in the USo 443,000 deaths/yro 49,000 deaths/yr due to second hand exposure

The most common cancerso Men: skin, prostate, lung, colorectalo Women: skin, breast, lung, colorectal

10) Cancer genetics Inherited mutations play a major role in the development of 5-10% of all cancers The genetic mutations associated with more than 50 hereditary cancer syndromes have

been identified, and genetic tests can help tell whether a person from a family with such a syndrome has one of these mutations

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WEEK 4

1) Type I Hypersensitivity: Extrinsic Asthma See pg. 2

2) Type II Hypersensitivity: ITP Etiology

o Tissue specifico Antibody-mediatedo Autoantibody stimulation

Chronic GPs on surface of platelets become immunogenic Productin of autoantibodies stimulated

Acute Unknown – may be infection

Pathoo Platelets coated with autoantibodies to platelet membrane antigens o Splenic sequestration and phagocytosis by mononuclear macrophages o Shortened life span of platelets, incomplete compensation by platelet

production from bone marrow megakaryocytes o Decreased platelet count

Morphologyo Thrombocytopeniao Splenomegaly

Clinical manifestationso Bleeding tendency

Purpura Petechiae

3) Type III Hypersensitivity: SLE Etiology

o Immune complex mediated Antigen-antibody complexes are formed in the circulation and later

deposited in vessel walls or extravascular tissues Not organ specific

o Chronic, multisystem inflammatory diseaseo More common in females

Pathoo Autoantibodis against: nuclear acids, RBCs, coagulation proteins,

phospholipids, lymphocytes, platelets, etc.o Diverse deposition of circulating immune complexes containing antibody

against host DNA Morphology

o + ANA

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o LE prep: + Lupus Erythematous antibodyo Increased ESR

Clinical manifestations (4/11 = diagnosis)o Serositis

Pleuritis Pericarditis Peritonitis

o Oral uclerso Arthritiso Photosensitivityo Blood changeso Renal involvement (proteinuria or casts)o ANAo Immunological changeso Neuro signs (seizures, frank psychosis)o Malar rasho Discoid rash

4) Type IV Hypersensitivity: Graft vs Host Disease Etiology

o Associated with allogeneic hematopoietic cell transplantation (HCT), transplantation of solid organs containing lymphoid tissue, and transfusion of unirradiated blood products

o Immune-mediated disease resulting from interaction between donor and recipient adaptive immunity

Graft is more immunocompetent than host Patho

o Hyperacute Immediate and rare response to preexisting antibodies

o Acute T cell-mediated response weeks after transplant

o Chronic Slow progressive organ failure despite immunosuppressive drug

therapy after months or years of normal fxno T cells in graft perceive host tissue as antigenically foreign o Produce excess pro-inflammatory cytokines o Host tissues are attacked o Host incapable of mounting effecting immunologic rxn against graft o Immune reaction causes disease in transplant recipient

Morphologyo Biopsy of grafted tissue shows inflammatory damageo Transplanted tissue/organ dysfunction

High bilirubin, ALT, AST Clinical manifestation

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o Signs of dysfunction/failure of transplanted tissue/organo Inflammatory lesions

Skin Pruritic or painful rash

GI tract membranes Diarrhea, GI bleed, abdominal pain, ileus

Liver Jaundice, pruritius

5) Immunodeficiency disorder: DiGeorge Syndrome Etiology

o Majority d/t spontaneous deletion of chromosome 22q11.2o Mutation causes abnormal cell and tissue development during fetal growth

Defective development of pharyngeal pouches that give rise to thymus, thyroid, parathyoids, maxilla, mandible, aortic arch, cardiac outflow tract, and external/middle ear

Pathoo Primary immunodeficiency diseaseo Abnormalities in thymus gland (where T cells develop) o Poor T cell production and function o Immunosuppression o Susceptibility to infection

Morphologyo Lymphopeniao Hypoplast/aplastic thymuso Characteristic clinical findings

Congenital cardiac anomalies Hypocalcemia (d/t abnormalities in parathyroids) Severe combined immunodeficiency (SCID)

o Deletion in chromosome 22q.12 Clinical manifestations

o Facial features Palatal abnormalities nasal-sounding speech Low set ears Underdeveloped chin Short philtrum Bulbous nose tipe Heavy eyelids Small mouth

o Developmental delayo Recurrent infectionso Psychiatric abnormalitieso Chronic inflammatory diseaseo Hypocalcemia seizures

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6) Infections Viral

o Examples Herpes virus (HSV, VZV, CMV, EBV), Hep B, Measles

o Infectious Mononucleosis Etiology

EBVo Portal - Epithelial cells of oropharynx

Patho Transmission via intimate contact with body secretions

(primarily saliva) EBV binds to CD21 receptors in tonsils Infects B cells

o Productive infection: lysis of infected cells, release of virions, infection of other B cells

o Latent infection: memory B lymphocytes serve as lifelong reservoirs

Circulating B cells spread the infection throughout the entire reticular endothelial system (liver, spleen, peripheral lymph nodes)

o Humoral response EBV-infected B cells induce B cell proliferation IgM antibodies formed against viral capsid

antigen later, IgG antibodies formed and persist for life

o Cellular response NK cells cells and predominantly CD8+ cytotoxic

T cells control proliferating B lymphocytes infected with EBV

Morphology Throat swab and rapid antigen testing or culture

o Negative for strep CBC

o Absolute lymphocytosis >50% WBC = lymphocytes

>10% atypical (express CD8+, histologically atypical)

o Leukocytosiso Thrombocytopenia commono Elevated ESR

LFTo High ALT, AST, lactic acid dehydrogenase

Histology

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o Lymphoproliferative response or infiltration in oropharyngeal epithelium, lymph, and spleen

Heterophile antibody test (Monospot test)o Pos = humoral immune response to EBV

EBV-specific antibodies if Monospot negativeo Viral capsid antigen (VCA)

Pos IgG antibodies against VCA = past infection, exists for life

Pos IgM = current, acute infectiono EBV nuclear antigen (EBVNA) – expressed when latent

infection Pos IgG in early infection = not acute EBV

infection Neg IgG = acute EBV infection, given pos IgM VCA

o Early antigen (EA) – IgG antibodies to EA present at onset of illness

Anti-D Pos IgG = recent infection Neg IgG = does not exclude acute illness

Anti-R Pos IgG = may be infectious mono

PCR assayso EBV DNA quantification

Clinical manifestations Lymphadenopathy

o Symmetric, moderately tender, discreteo Mostly in posterior cervical, axillary, and groin

Splenomegalyo Vulnerable to rupture

Fever, malaise, h/a, severe fatigue Pharyngitis and/or pharyngitis

o Pharyngeal inflammation, tonsillar exudates (white, grey green, or necrotic)

o Palatal petechiae with streaky hemorrhages and blotchy red macules

Maculopapular, urticarial, or petechial rasho Often occurs following ampicillin or amoxicillino Most prominent over trunk

Tx Supportive therapy

o Acet or NSAIDS for fever, sore throat, malaiseo Adequate fluid and nutritiono Rest

Avoid splenic rupture (no physical activity for 3 weeks, s/sx: abd pain, LUQ pain, L shoulder pain)

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Corticosteroids considered for complications Bacterial

o Examples Staph aureus, strep pneumonia, neisseria gonorrhea, Escherichia coli,

chlamydia tracomatiso Acute salpingits

See pg. 3 Tx

At least 2 broad-spectrum antibiotics to treat gonorrhea and chlamydia, gram-negative organisms, anaerobes, and strep

o Ceftriaxone 250mg IM once PLUSo Doxycycline 100mg PO bid for 14 days

Aspirin, advil, or acetaminophen for pain Re-evaluation by HCP 3 days after starting antibiotics Tx of sexual partners (even if no symptoms)

o No sex until tx complete and tests indicate no infection Hospitlization if:

o N&V, high fevero Pregnanto Needs IV antibiotics (not responding or can’t take PO

meds)o Abscess in fallopian tube or ovary

Surgery to prevent rupture and infection spreado Comorbid condition that might require immediate

surgery Fungal

o Examples Cadidiasis albicans, Cryptococcus neoformas, aspergillus fumigatus

o Cryptococcosis Etiology

Cryptococcus neoformaso Encapsulated yeasto Causes meningoencephilitis in health pplo Causes opportunistic infections in immunosuppressed

ppl Patho

Inhalation of yeast infection Virulence factors enable evasion of host defenses in

immunocompromisedo Polysaccharide capsule

Inhibits phagocytosis and leukocyte migration Can undergo phenotypic switching changes in

strx and size of capsule to evade immune response

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o Melanin production by laccase Laccase catalyzes formation of melanin-like

pigment antioxidant properties, increased virulence

o Serine proteinase Cleaves basement membrane proteins to aid in

tissue invastion Can establish latent infection and granuloma

formation that can reactivate in immunosuppressed hosts

Morphology Smears of body fluids, secretions, exudates

o Yeast but no pseudohyphal or hyphal formso Thick gelatinous capsule

Fixed tissue specimeno Capsular polysach strains intense red with periodic acid-

Schiff and mucicarmineo Agglutination assay with antibody-coated beads detect

stains Culture

o Definitive diagnosiso CSF, sputum, urine, sometimes blood

CSFo High proteino Lymphocytosiso Monocytosiso Neutrophiliao Low glucoseo India ink prep: thick, encapsulated yeast forming

narrow-based budso May be normal in ppl with AIDS (except for india ink)

Latex test for cryptococcal capsular antigeno Positive in CSF or blood specimens or both = meningitis

Chest xrayo Primary lung lesions, pneumonia

Clinical manifestations Indolent infection in immunocompetent pts More severe, progressive infection in immunocompromised pts Primary lung lesions

o May be asymptomatic or s/sx of pneumonia CNS lesions (meninges, cortical gray, basal nuclei) Variable host response

o Immunosuppressed Lung Brain and meninges

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Meningitis with minimal, nonspecific sx d/t cerebral edema (h/a, blurred vision, confusion, depression, agitation, behavior change)

Virtually no inflam rxn Involved tissues contain cystic gelatinous masses

of yeast = soap-bubble lesionso Severely immunosuppressed

Spread to skin, liver, spleen, adrenals, bones, kidneys, joints, prostate

Few sx except for skin lesions Pustular, popular, nodular, or ulcerated

lesionso Immunocompetent

Chronic granulomatous rxn (macrophages, lymphocytes, foreign-body type giant cells)

Tx Localized pulmonary involvement

o May need no treatmento Fluconazole maybe to prevent dissemination and

shorten course of illness Involvement of other organs/tissues

o Systemic antifungal: Fluconazole; Amphotericin w Flucystosine for more severe disease

Parasitico Examples

Trichomonas vaginalis, giardia lamblia, strongyloides stercoraliso Stronyloidiasis

Etiology Strongyloides stercoralis (roundworm) Humans infected when larvae penetrate skin Hyperinfection may result in immunosuppressed pts

Patho Skin Travel circulation to lungs Break thru pulmonary capillaries Ascend respiratory tract where they are swallowed, reaching

intestine Female worms live in mucosae of small intestine Asexual reproduction Eggs hatch in bowel lumen Rhabditiform larvae liberated

o Most passed in stool continuing cycle of infection Some rhabditiform larvae covert to infectious filariform larvae

within intestine o Some immediately reenter bowel well (internal

autoinfection)

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o Others pass in stool and reenter thru skin of buttocks and thighs (external autoinfection)

Morphology Microscopic exam of stool

o Detects larvae Endoscopy sample of proximal small bowel lumen via

aspirationo Larvae present

Biopsy of suspicious intestinal lesionso Mild infection: larvae only in duodenal crypts,

eosinophil-rich infiltrate in lamina propria, mucosal edema

o Hyperinfection: many adult warms, larvae, and eggs in duodenal crypts and ileum

Hyperinfectiono Invasion of larvae into colonic submucosa, lymphatics,

blood vessels – with mononuclear infiltrateo Worms of all stages in other organs (skin, lungs, sputum,

CNS, liver, heart)o Chest xray: diffuse interstitial infiltrates, consolidation,

or abscesseso Serologic testing (EIA): IgG antibodies detected

Clinical manifestations Maybe asymptomatic Lava currens

o Cutaneous larvae autoinfection o Eruption in perianal region that rapidly spreadso Causes intense pruritis

Most prominent symptomso Pulmonary symptoms

Loffler’s syndrome (pulmonary infiltrate with eos) – cough, wheezing

Dyspnea, hemoptysis, respiratory failureo GI symptoms

Anorexia, epigastric pain/tenderness, diarrhea, N & V, weight loss, malabsorption

CNS involvemento Parasitic meningitis, brain abscesses, diffuse brain

invasion Secondary gram-neg meningitis and bacteremia Liver involvement

o Cholestatic and graunulomatous hepatitis Tx

Ivermectin

25


WEEK 5

1) Smoking Effects

o 1/5 deaths/yr in the USo Narrows vasculature Reduces circulation Cardiovascular disease

Coronary heart disease Peripheral vascular disease Stroke AAA

o Damages airways and alveoli Respiratory disease Lung cancer Lung disease (COPD)

o Cancer AML Bladder Cervical Esophageal Renal Laryngeal Lung Oral Pancreatic Pharyngeal Stomach

o Lower bone density in postmenopausal women Risks

o Infertilityo Preterm deliveryo Stillbirtho Low birth weighto SIDSo Hip fracture

2) Alcohol Immediate health risks (commonly d/t binge drinking)

o Unintentional injuries: traffic injuries, falls, drownings, burns, firearm injurieso Violence: IPV, childhood maltreatmento Risky sexual behaviors: unprotected sex, sex with multiple ppl, inc risk of sexual

assault unintended pregnancy, STDso Miscarriage and stillbirth among pregnant womeno Physical and mental birth defects among childreno Alcohol poisoning CNS suppression: LOC, low BP, low temp, coma, resp

depression, death

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Long-term health riskso Neuro problems: dementia, stroke, neuropathyo Cardiovascular problems: MI, cardiomyopathy, afib, HTNo Psych problems: depression, anxiety, suicideo Social problems: unemployment, lost productivity, family problemso Cancer: mouth, throat, esophagus, liver, colon, breasto Liver disease: alcoholic hepatitis, cirrhosis, worsening of liver fxn and

interference with meds in those with Hep Co Gi problems: pancreatitis, gastritis

3) Adverse effects of therapeutic drugs OCPs

o Derm: oily skin, acne, hirsutismo Psych: h/a, migraines, depression, nervousness, dec libido, dec moodo GI: nausea, hepatic adenoma, pancreatitis, wt gain, bloating (d/t fluid retention)o Repro: abnormal bleeding, breast tenderness, inc vag d/c, congenital

abnormalities when given in early pregnancyo Cardio: atherosclerosis, VT, CVA, MI, inc BP, inc triglycerideso Malignancy: breast ca., gallbladder disease, cervical ca.o Endo: mild insulin resistance, inc T3, T4, cortisol, estradiol, and testosterone

Anabolic steroidso Hepatic: inc LFT (hepatotoxicity), liver ca.o Cardio: dec HDL, inc LDL, inc cholesterol, inc BP, cardiac hypertrophyo Endo/Repro: dec thyroid fxn, dec LH, dec FSHo Men: dec spermatogenesis, abn sperm, feminization, dec testes sizeo Women: hirsutism, voice deepening, clitoral hypertrophy, dec breast mass,

amenorrhea, male-patterned baldnesso Derm: oily hair and skin, alopecia, sebaceous cysts, inc acneo Psych: mood changes, aggression, hostility, dependence, addiction

4) Adverse effects of nontherapeutic drugs Cocaine

o CNS: inc risk of CVA, vertigo, seizures, tremor, twitcheso Immune: fever, eosinophiliao HEENT: rhinorrhea, nasal perforation, sore throat, hoarse voice, tooth abrasion,

dilated pupilso Derm: pruritiso Cardio: inc risk of MI, vasoconstriction, inc BP, inc HR, arrhythmiao Pulm: inc risk of respiratory arrest, hemoptysis, bronchospasm, dyspnea,

infiltrates, chest pain, asthma, lung damageo Psych: bizarre or violent behavior, dec attention, insomnia, inc alertness, elevated

mood, irritability, paranoia, restlessness, anxiety, excited speech, dec sex fxno GI: ulcers, perforationo Renal: rhabdomyolysis sudden, overwhelming kidney failure

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Marijuanao Cardio: inc risk of heart failure, inc HR, inc BP, poor circulationo HEENT: blood shot eyes, dilate pupils, dec IOP, dry moutho GI: inc risk of pancreatic ca., inc appetite, tender lining (bleeding, ulcers)o Pulm: inc risk of lung, mouth , and throat ca., inc risk of infection, cough,

hoarseness, asthma-like sx, chronic bronchitis, emphysemao Psych: disturbances, short term memory loss, slower rxn, sleep disturbance,

impaired ability to learn new things, can’t do complex tasks, poor concentration, loss of motivation

o Repro: dec sperm count and motility, dec libido, egg damage, irregular mensturation, altered hormone levels, impaired fertility

o Pregnancy: low birth wight; fetus: small head, irritability, poor growth/development

5) Vitamins Vit A

o Source: animal derived foods (liver, fish, eggs, milk, butter)o Fxn: normal vision, cell prolif and diff of specialized epithelia, resistance to

infection, photoprotection, antioxidanto Deficiency: night blindness, xerophthalmia, blindness, squamous metaplasia,

infection vulnerability (esp measles) Vit D

o Source: endogenous synthesis in skin by photoconversion of a precursor via solar/artificial UV energy; dietary: deep sea fish, plants, grains

o Fxn: maintenance of Ca and PO4 in plasma bone mineralization, neuromuscular transmission, metabolic function

o Deficiency: osteomalacia in adults, rickets in kids, hypocalcemia tetany Vit C

o Source: milk, liver, fish, fruits, vegetableso Fxn: antioxidant, hydroxylation of collageno Deficiency: scurvy (poor vessel support bleeding tendency, inadequate osteoid

synthesis, impaired woundhealing) Vit B9

o Source: green leafy veg, folate-fortified breads/cereals, legumes, seedso Fxn: AA, protein, DNA, and heme synthesiso Deficiency: megaloblast anemia, LBW, NTD, glossitis, freq infection, inc

hemocysteine

6) Periodontal disease Etiology

o Independent from bacterial infection Commonly Gram neg anaerobic

o Dependent, associated with: AIDS, leukemia, Crohn’s, DM, Down syndrome, sarcoidosis

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o Risks: smoking, hormonal changes in women, medications, genes, poor oral hygiene, increasing age, men have more plaque, low socioeconomic, stress, alcohol and drug use, vit c or Ca deficiency, immune deficiency

Pathoo Bacterial challenge o Host immune and inflammatory response o Gingival inflammation o Gums pull away from teeth leaving deep pockets where bacteria grows o Connective tissue and bone metabolism (periodontitis)o Link to CVD (atherosclerosis, MI, CVA)

Common susceptibility model Genetically determined phenotype Inc risk of atherosclerosis and infection

Systemic inflammation model Periodontal infection Inflammation Inc systemic levels of cytokines, CRP, IL-1, IL-6, TNFa,

prostaglandin E2 Damage to vascular endothelium Ahterosclerosiss

Infection model Oral, bacterial pathogens get into bloodstream Invade endothelium Endothelial dysfunction, inflammation, atherosclerosis

Cross-reactivity/molecular mimicry model Bacterial LPS, cytokines, and mechanical stress Host induced to express host-protective HSP on endothelial cells Host immune system may not differentiate between homologous

self-HSP and bacterial HSP Antibodies cross-react with bacterial HSP and self-HSP on

endothelial cells Endothelial dysfunction Atherosclerosis

Morphologyo Swab or needle aspiration of lesions or abscess

C&S Gram stain and acid fast stain for bacteria KOH for fungi

o Tissue biopsy Evidence of acute or chronic inflammation and infection

o PCR Can sometimes detect specific microbial genes

o Xray, CT, MRI Visualize periodontal bone loss Abscesses

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o Indicators of inflammation Inc CRP Inc fibrinogen Inc WBC

o Dental exam >3mm periodontal pockets between teeth and gums Buildup of plaque and tartar above and below the gums Loss of attachment d/t complete destruction of periodontal ligament and

alveolar bone (in periodontitis) Tooth mobility

o Clinical manifestations Gingiva inflammation (bleeding, redness, edema) Receding gums – teeth look longer Loose teeth Foul breath Exposed roots at base of teeth Painful chewing Sensitive teeth Periodontitis can cause: infective endocarditis, pulmonary and brain

abscesses, and adverse pregnancies

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WEEK 6

1) Anemia Hemolytic anemias

o Ex: G6PD deficiency, thalassemias, sickle cell disease, lead poisoning, Rh diseaseo Morphology

CBC Low h/h Low RBC Normal or high MCV, MCH High retic Intravascular hemolysis

o Low haptoglobino Presence of free hgb

Urine – intravascular hemolysis Hemoglobinuria (PNH) Hemosiderinuria (chronic intravascular hemolysis)

CMP High LDH High unconjugated bilirubin

Bone marrow Erythroid hyperplasia High normoblasts High erythropoietin

Liver MRI, serum ferritin, liver biopsy Hemosiderosis in liver, spleen, BM

Peripheral smear Spherocytes (hereditary spherocytosis, warm-antibody hemolytic

anemia) Schistocytes (microangiopathic hemolytic anemia) RBC agglutination (cold-antibody hemolytic anemia) Heinz bodies and blister cells (G6PD deficiency) Sickle cells (SCD)

Xray Frontal bossing in kids and infants

Positive direct coomb’s test (Autoimmune hemolytic anemia)

Donath-Landsteiner antibody (Paroxysmal cold hemoglobinuria)

Flow cytometry for CD55 and CD59 (PNH)

o Clinical manifestations Signs of anemia (pallor, fatigue, dyspnea, potential for HF) Acute onset Hepatosplenomegaly

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Gallstones with chronic hemolysis Continuous release of free hgb pulmonary HTN syncope, chest pain,

progressive breathlessness RVF peripheral edema, ascites Jaundice with dark urine Chronic leg ulcers and pain (SCD)

Anemias of decreased erythropoiesis o Ex: iron deficiency anemia, anemic of chronic disease, megaoblastic anemia

(pernicious and folate deficiency)o Morphology

Iron deficiency anemia Microcytic hypochromic Low retic Low ferritin Low Fe Low transferrin saturation High TIBC High erythropoietin High RDW

Anemia of chronic disease Microcytic or normocytic Low Fe Low TIBC Low erythropoietin Normal or high ferritin

Megaloblastic anemia (folate, pernicious) Macrocytic RBCs Hypercellular bone marrow

o Megaloblast, macrocytes, metamyelocytes, megakaryocytes Pancytopenia Hypersegmented neutrophils

Aplastic anemia Normocytic Low retic Fatty liver Hypocellular bone marrow

o Clinical manfestations All have classic signs of anemia plus: Iron deficiency anemia

PICA Impaired work and cognitive performance Fingernail abnormalities: thinning, spooning, flattening Reduced immunocompetence

Folate deficiency anemia GI symptoms

o Glossitis

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o Chelitiso Dermatitis

Pernicious anemia Beefy tongue CNS abnormalities: symmetric numbness, tingling, burning in feet

or hands, unsteady gain and loss of position sense Aplastic anemia

Petechiae, ecchymoses Persistent minor infections

2) Thalassemia Etiology

o Inherited (autosomal recessive) hypochromic, microcytic anemia with varying degrees of severity

Low hgb, low MCV, normal RDWo Genetic defects result in absent of decreased production of mRNA an globin chain

synthesiso Alpha globins are coded on chromosome 16

Two genes on each chromosome Four genes in each diploid cell Gene deletions alpha thalassemias Zeta globin genes = Gowery’ hemoglobin (embryonic) also on

chromosome 16o Beta globins are coded on chromosome 11

One gene on each chromosome 2 genes in each diploid cell Point mutations beta thalassemias

Severity depends on where the mutations lie Delta (Hgb A2), Gamma (HgbF), and Epsilon (embryonic) also on

chromosome 11 Patho and Clinical manifestations

o Beta thalasemiia 3-6 months of age, synthesis switches from gamma to beta synthesis Reduced or nonexistent production of beta globin

Poor oxygen carrying capacity of RBCs Failure to thrive, poor brain development, fatigue, lethargy

Increased alpha globin production and precipitation Excess alpha globin chains precipitate in cells RBC precursors destroyed in bone marrow

Increased splenic destruction of dysfunctional RBCs Anemia, jaundice, splenomegaly, gall stones, leg ulcers

Hyperplastic bone marrow Ineffective erythropoiesis

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Thalassemic facies: poor bone growth, frontal bossing, bone pain, mandibular malocclusion, prominent malar eminence, pathological frx

Increase in extramedullary erythropoiesis Iron overload Hemosiderosis Increased absorption and transfusions DM, growth retardation, hypogonadic hypoogonadism (pituitary

glands, testes, ovaries), hypocalcemia, osteoporosis, arrhythmias, myocarditis, heart failure, liver fibrosis and cirrhosis, pathologic fractures

o Alpha thalassemia Silent carrier

Deletion of one alpha globin gene No clinical significance

Alpha thal trait Deletion of 2 alpha globin genes Mild microcytic anemia

Hgb H disease Deletion of 3 alpha globin genes Severe microcytic anemia

o Splenomegalyo Jaundiceo Bony abnormalities, particularly involving cheeks and

foreheado Small, appear malnourishedo Tissue hypoxia

Severe imbalance between alpha and beta chain production Accumulation of beta cahins inside RBCs Beta chains begin to associate in groups of four (instead of pairing

with alpha chains) Abnormal hemoglobin produced = hemoglobin H Hb H does not carry O2 properly functionally useless to cell Hb H protein damages membrane that surrounds RBC

accelerating cell destruction Bart’s Hb

Deletion of four alpha globin genes Incompatible with life

o Hydrops fetaliso In utero or early neonatal death

Gamma chains produced during fetal life associate in groups of four

Form abnormal hemoglobin = Barts Hb Morphology

o Beta Thal Homozygous beta thal (beta thal major or cooley’s anemia)

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Hb electrophoresiso Increased Hb A2 productiono Increased Hb F production

Severe anemia Few retic Numerous nucleated RBC Inc unconjugated bilirubin Inc serum ferritin Inc transferrin saturation Radiograph

o Bone marrow hyperplasia Liver biopsy

o Iron overload Thalassemia intermediate

Microcytic anemia Growth failure Hepatosplenomegaly Hyperbilirubinemia Thalasemic facies at 2-5 years of age

Thalassemia minima and minor More severe than thalassemia trait but less severe than

thalassemia intermedia Thalassemia trait

Minimal or no anemia MIcrocytosis Inc RBC count Hb-electrophoresis

o Inc HbFo Inc HbA2

o Alpha thal PCR

Missing alpha genes Inc production of Bart’s Hb during fetal life (present at birth) Marrow is filled with red cell precursors Low h/t, low MCV, and normal RDW in all types except carrier state

(normal labs)

3) Thrombocytopenia vs. Bleeding problem ITP

o See pg. 17 Hemophilia A

o Eiology Inherited (x-linked) or spontaneous disorder Deficiency in activity of

clotting factor VIII

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Decreased amount of FVIII protein Functionally abnormal FVIII Combo of both

o Patho Normal coagulation cascade (intrinsic pathway)

FVIII is proteolytically activated Serves as cofactor for FIXa to activate FX FX acts with FV and a phospholipid surface to generate thrombin

from prothrombin Thrombin then converts Fibrinogen to Fibrin Developing clot is stabilized

Deficiency in FVII Insufficient generation of thrombin Clot formation delayed Clot formed is friable and easily dislodged

o Morphology CBC

Normal or Low hgb/hct (if active bleeding) Coag studies

Prolonged aPTT Fibrinogen test

Evaluate risk of forming blood clot when clotting times are abnormal (FSP will be high)

FVIII assay Shows type of hemophilia and severity, guides tx

To monitor complications: CT scan, MRI (acute head bleeds), MRI (joints), u/s (joint effusion)

o Clinical manifestations Tendency to bleed easily Prlonged bleeding Frequent bruising General: weakness, orthostasis Musculoskeletal (mainly joints – elbows, knees, ankles): hmerthroses,

swelling, reduced mobility, tingling, crackling, warmth, pain, stiffness, refusal to use joint

CNS: h/a, stiff neck, vomiting, lethargy, irritbiliay, spinal cord syndromes GI: hematemesis, melena, abdominal pain GU: hematuria, renal colic Other: epistaxis, oral mucosal hemorrhage, hemoptysis, dyspnea,

compartment syndrome, contusions

4) Hematology tests CBC

o Purpose

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Screen for: Anemia, infection, leukemia, risk of bleeding, asthma, allergies, cause of bruising, cause of fatigue, polycythemia, blood loss

o RBC NORM: 4.5-6 million/cu mm blood

High RBCHypoxiaAlcoholismPVSmokingDehydration

Low RBC = anemia BM suppressionHemorrhageLack of substances to make RBCDestruction of RBC

o Erythrocyte indices Mean corpuscle volume (MCV)

The volume (size) of the average RBC NORM: 80-100

Mean

corpuscular hemoglobin (MCH) Weight of hemoglobin in each cell NORM: 27-31 pg

Mean corpuscular hemoglobin concentration (MCHC) The concentration of hemoglobin in the average RBC cell NORM: 32-36 g/dL

Red cell distribution width (RDW) Shows different sizes of RBC cells, high means presence of cells of

widely differing sizes NORM: 11-14.5%

o Hct Percentage, by volume, of packed RBC in a whole blood sample NORM: 40-50%

Low HctShockHemorrhageDehydrationExcessive IV fluid administration

o Hgb Amount of hemoglobin in blood (part of RBC that carries O2) NORM: 12-17 g/dL Purpose

Screen for anemia

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HighFolate deficiencyVit B12 deficiency

LowFe defiencyThalassemia deficiency


Identify severity of anemia Evaluate response to anemia tx

Low HgbLow RBC

BM problemsHemoglobinopathies (Thal, SC)

Normal RBCFe deficiency anemia

High HgbPVSevere burnsCOPDCHF

o Thrombocyte (platelet) count Ability to form blood clots NORM: 150-400,000 mm3

High plateletsActive bleedingCancerBM problems

Low plateletsBleeding riskITPPregnancySplenomegaly

o WBC NORM: 5-10,000 mcL3

High WBCInflammationInfectionLeukemiaTissue damageStressSurgery

Low WBCAlcoholismAutoimmune d/oImmune suppression (AIDS, steroids, chemo)Aplastic anemia

o WBC with differential Gives quantity of each WBC cell type, providing important info in

diagnosing the patient’s condition Neutrophils

NORM: 60%

High NeutBacterial infectionStress responseInflammation or necrosisPregnancySteroid therapy

Low NeutBM problemsViral infectionsAutoimmune diseaseMegaloblastic anemia

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Lymphocytes NORM: 30%

High LymphViral infectionsTBLymphoma or leukemia

Monocytes NORM: 6%

High MonosBacterial infectionsRecovery from acute infectionsProtozoan infectionsChronic steroid therapyGranulomatous diseases

Eosinophils NORM: 3%

High EosAllergyParasitic infectionSkin diseasesNeoplastic diseases

Basophils NORM: 1%

High BasosHypothyroidismMyeloproliferative diseasesChicken pox

Band neutrophils NORM: 1%

Reticulocyte counto Purpose

To determine ability of bone marrow to produce RBCso Percentage of reticulocytes in blood (immature RBC released by BM) o NORM: 0.5-2.5%

High ReticHemolytic anemias

Low ReticCirrhosis

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Anemia treatmentHigh altitudeBlood lossThalassemia

Anemia of decreased erythropoiesisRadiation exposureBM failure

Hgb A-1co Purpose

To monitor and evaluate diabetic control over the past 3 monthso Glyocsylated hgb reflects average blood glucose over a 3 month periodo NORM/effective disease control: 2.5-6%

Hgb electrophoresiso Purpose

To determine presence of abnormal hgb, and measure how much of it there is

o Hb A = normalo Hb A2 = b-thalassemiao Hb F = b-thalassemia, hereditary persistence of fetal Hb (HPFH)o Hb S = sickle cello Hv C = Hb trait or disease

ESRo Purpose

To evaluate systemic presence of inflammation – frequently, the earliest indicator of disease (TB, autoimmume, malignancies)

o Time required for RBCs from a whole blood sample to settle to the bottom of a vertical tube

Coomb’s testso Purpose

To determine whether someone with hemolytic anemia has autoimmune hemolytic anemia

o Positive = AIHA

40


WEEK 7

1) Importance of ANPs knowing about skin conditions To teach prevention strategies for skin cancer To recognize malignant and non malignant problems promptly and treat/refer them

accordingly To decrease patient anxiety by performing a methodical workup and taking all patient

skin complaints seriously To detect systemic diseases that might have dermatologic manifestations To provide counseling about skin condition affecting patient

Seborrheic keratosis (derm problem, nonmalignant, most common problem) Etiology

o Risks: increasing age, Caucasian, exposure to UV light, genetic predisposition, papillomaviruses

o Most common benign tumor in older ppl Patho

o FGFR3 = membrane-bound receptor TK Older age, exposure to UV radiation Gene mutation Constitutive activation of FGFR3 Constant transmission of signals to cell without ligand binding

o Polymorphisms in other genes might increase susceptibility to FGFR3 mutations in the skin

Morphologyo Subtypes based on predominant histology

Acanthosis Papillomatosis Hyperkeratosis Horn pseudocysts

o Three most common subtypes Acanthotic (most common) Hyperkeratotic (verrucous) Adenoid

o Dermatoscopy Horn cysts or pseudocysts Pseudofollicular openings Gyrus sulcus pattern Opaque yellow-brown or gray-brown color Poorly defined streak-like densities Superficial serpiginous vascular structures

Clinical manifestationso Benign epithelial skin tumoro Generally asymptomatic

41


o If irritation or trauma occurs to lesions: itching, pain, bleeding, redness, crustingo Lesion characteristics

Sharply demarcated Round or oval-shaped “Stuck on” appearance Appear anywhere on body except palms or soles Sun exposed areas (chest, back, head, neck) most commonly affected

o Varying characteristics Grouping: solitary or disseminated in large numbers Diameter: 0.5-1cm Pigment: skin color/yellowish, gray-brown, or black Thickness: elevated or flat Surface texture: velvety, greasy, horned

Impetigo (derm problem, acute inflammatory, nonmalignant) Etiology

o Acute, highly contagious gram-positive bacterial infection of superficial layers of epidermis – bacteria introduced from environment and transiently colonize cutaneous surface

Most commonly from infection by GABHS or S aureus S aureus is only cause of bullous impetigo

o Risks: young age, hot/humid climates, recent antibiotic treatment, preexisting cutaneous disease, immunosuppression, systemic disease, IV drug abuse, dialysis

o Spread by direct contact with lesions or with nasal carriers Patho

o Skin disruption facilitates bacterial colonization or infection Scratching, herpes virus, pediculosis, burns, surgery, trauma, radiation

therapy, biteso Fibronectin receptors revealed, which are required by teichoic acid adhesions for

GABHS and S aureus to colonize o GABHS or S aureus invades disrupted surface and colonizes

Morphologyo Gram stain and C & S of exudate under scab, pus, or bullae fluid

Gram-positive cocci in chains on gram stain Strep Gram-positive cocci in clusters on gram stain S aureus

o If acute poststreptococcal glomerulonephritis (APSGN) is suspected Serologic testing for strep antibodies (Anti-Dnase B and AH titers) Urinalysis: hematuria, proteinuria, clylindruria

o Bacterial culture of nares to determine if pt is S aureus carrier If neg culture and persistent episodes of impetigo, bacterial culture of

axillae, pharynx, and perineum obtainedo Serum IgM levels obtained in cases of recurrent impetigo in pts with neg S aureus

carrier status and no predisoposing factors to rule out other immunodeficiencies Clinical manifestations

o Variants

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Non-bullous impetigo Most common form Papules vesicles surrounded by erythema pustules

pustules enlarge and break down thick, adherent crusts formed with characteristic golden appearance

Lesions commonly on face and extremities Well-localized Regional lymphadenitis may occur

Bullous impetigo Most common skin infection in kids Vesicles enlarge to form flaccid bullae with clear yellow fluid

fluid becomes darker and more turbid bullae rupture thin brown crust remains

Lesions commonly on trunk Ecthyma

Ulcerative form Lesins extend through epidermis and deep into dermis “Punched-out” ulcers covered with yellow crust, surrounded by

raised violaceous marginso Complications

PSGN Rheumatic fever

Psoriasis (derm problem, chronic inflammatory, nonmalignant) Etiology

o Chronic, multifactorial inflammatory disease Keritnocytes in epidermis hyperproliferate (loss of control) Epidermal cell turnover rate increases

o Environmental factors Stress, cold, trauma, infections (strep, staph, HIV), alcohol, drugs

o Genetic factors Obesity Human leukocyte antigen (HLA) alleles

o Immunologic factors Excess T cell activity

Pathoo Antigenic stimuli o Innate immune cells in skin activated

Produce proinflammatory cytokines (IFN-alpha) o Myeloid dendritic cells in skin activated

Produce cytokines (IL-23 and IL-12) o T cells attracted, activated, and differentiated

Produce cytokines o Stimulate keratinocytes to proliferate and produce proinflammatory

antimicrobial peptides and cytokines

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Cytokines and keratinocytes participate in positive feedback loops Inflammatory response perpetuated

Morphologyo Five subcategories – differ in severity and location

Chronic plaque psoriasis Intertriginous psoriasis Pustular psoriasis Erythrodermic psoriasis Nail psoriasis Plaque psoriasis (most common) Guttate psoriasis

o Punch biopsy of skin Basal cell hyperplasia Proliferation of subepidermal vasculature Absence of normal cell maturation Keratinization Large number of activated T cells present in epidermis

o Auspitz sign When scales are removed, small droplets of blood appear within a few

secondso Xrays

To determine joint or bone involvemento Classification

Psoriasis area and severity index (PASI) Physicians global assessment (PGA)

Clinical manifestationso Cutaneous inflammation

Raised, itchy, pink plaques with a silver-white scale Burning and soreness

o Most common locations Joints (often distal, elbows, knees)

Stiff, swollen, throbbing, swollen, tender Scalp Lower back Intergluteal cleft Glans of penis

o Nail changes Thickening, Crumbling, Pitting, Discoloration

o Ocular manifestations Extropian, Trichiasis, Conjunctivitis, Conjunctivial hyperemia, Corneal

dryness, Blepharitiso Complications

Bacterial infection Depression and social isolation Thickened skin

44


Dehydration (fluid and electrolyte imbalances)

Malignant Melanoma (derm problem, malignant) Etiology

o Environmental risks r/t UV light Sun exposure Burns early in life Tanning bed use Living close to equator Living at high elevation

o Genetic factors Fair skin Having more than 50 moles or dysplastic nevi Family history of melanoma Tumor suppressor genes (p16 and p19), RB1, PTEN/MMAC1, and ras

o Immunologic factors Weakened immune system (HIV, organ transplants)

Pathoo Unrepaired DNA damage to cells o Mutations triggered o Genes responsible for proliferation, differentiation, and apoptosis are affected o Cutaneous melanocytes in basal layer of epidermis (benign melanocytic nevi)

change from physiologic to pathologic o Melanocytic nevi with architectural and cytologic atypia (dysplastic nevi) o Melanocytes become rapidly producing cancer cells o Angiogenesis o Radial growth phase: malignant cells grow in radial fashion on epidermis o Vertical growth phase: malignant cells invade dermis o Metastases

Morphologyo To determine metastases

Chest xray, brain MRI, and CT of chest/abdomen/pelvis Lungs are first place of metastases Common sites of metastases: brain, liver, lungs

High LFT metastastic disease to liver High LDH Distant metastases

Considered in staging systemo Biopsy of suspicious lesion, characteristic histologic features

Cytologic atypia Enlarged cells with large, pleomorphic, hyperchromic nuclei with

prominent nucleoli Numerous mitotic figures Pagetoid growth pattern with upward growth of melanocytes, so they are

no longer confined to basal layero Immunochemical stains

45


S-100 and homatropine methylbromid (HMB45) are positive o Fluorescence in situ hybridization

Cytogenic analysis of melanocytic neoplasms through the detection of chromosomal aberrations

o Dermatoscopy of lesion Pigment network – increased variability in lines, color, distribution, hole

sizes Globules/dots – multiple of different size, shape, and color, not associated

with pigmented network Streaks – radial projections at periphery of lesion Blue white veil over papular areas – diffuse throughout lesion, different

hues Regression structures (scar-like areas) – asymmetric, >50% of lesion Hyperpigemented areas – structureless light brown area at periphery Blotch – peripheral hyperpigmentation Vascular structures – dotted, serpentine, polymorphous, corkscrew Crystalline structures present

o Major subtypes based on growth patterns Lentigo maligna melanoma Superficial spreading melanoma Arcal lentiginous melanoma Nodular melanoma

Clinical manifestationso Arise anywhere on bodyo Most commonly appear on sun-exposed areas (arms, neck, face, back, back of

calves) Except in darker skinned people (between toes, fingers)

o May cause itching or paino ABCDE

Melanoma more likely to be ASYMMETRIC Melanoma more likely to have BORDER irregularity (jagged, notched,

scalloped) Melanoma more likely to be very dark black, brown, or blue in COLOR and

have uneven distribution of COLOR Melanomas are more likely to be >6 mm in DIAMETER Melanomas are more likely to EVOLVE (change in growth, color, shape,

itchiness, or bleeding)o Ugly duckling rule

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midterm study guide

Documents

necrotic cells

allergic inflammation

inflammation ra

arnps inflammation

process of inflammation

multinucleate giant

inflammatory mediators

site of injury