Pathoma Notes - Ch 1: Growth Adaptations, Cell Death, and Injury

**PATHOMA NOTES** Ch 1 -- Growth Adaptations, Cell Death and Injury ================================================= GROWTH ADAPTATIONS ------------------ Atrophy = decrease in cell size or number (apoptosis) - A diagram of cell division Description automatically generated with medium con...

**PATHOMA NOTES** Ch 1 -- Growth Adaptations, Cell Death and Injury ================================================= GROWTH ADAPTATIONS ------------------ Atrophy = decrease in cell size or number (apoptosis) - A diagram of cell division Description automatically generated with medium confidence - Autophagy involves making vacuoles of cellular components that are then consumed by lysosomes Metaplasia - Occurs via reprogramming of stem cells - Reversible with removal of the driving stressor (ex. treatment of GERD) - Can progress to cancer - Exception: apocrine metaplasia (associated with fibrocystic change of breast) - Vit A deficiency associated with metaplasia of specialized epithelia (ex. conjunctiva of eye is squamous epithelium) - Keratomalasia = thickened conjunctiva - Mesenchymal tissue - Myositis ossificans - Inflammation of skeletal muscle (trauma) -\> converted to bone Dysplasia (ex. CIN) - Reversible (unlike cancer) Aplasia (ex. unilateral renal agenesis) - Failure of cellular production during embryogenesis Hypoplasia (ex. streak ovary in Turner syndrome) - Decrease in cell production during embryogenesis CELL INJURY (stress \> ability to adapt) ---------------------------------------- Hypoxia - Ischemia -- dec blood flow thru organ (block in artery for delivery or vein for drainage, shock/overall) - Ex. Budd-Chiari syndrome (hepatic vein) -- mcc polycythemia vera - Hypoxemia -- decreased O2 content of blood (PaO2 \< 60 mmHg, SaO2 \ Fe2+) Reversible vs. irreversible injury - Reversible = cellular swelling - Loss of microvilli, membrane blebbing (pulls away from cytoskeleton), swelling of RER (which results in ribosome dissociation -\> decreased protein synthesis) - Due to failure of Na/K w/o ATP -\> Na builds up -\> water follows - Irreversible = membrane damage - Plasma membrane loss -\> intracellular enzyme leaks out, Ca rushes in - Mitochondrial membrane -\> ETC on inner membrane, cyto-C release causes apoptosis - Lysosome -\> lysosomal enz leak into cytosol -\> breaks down cell contents CELL DEATH ---------- Hallmark = loss of nucleus: (1) pyknosis (shrinks); (2) karyorrhexis (breaks up into big pieces); (3) karyolysis (broken down to building blocks) Mechanisms - Necrosis -- large group of cells, [followed by acute inflammation] - Coagulative --retain cell shape/architecture and organ structure - Ex. ischemic infarction (except brain) - Red infarction -- blood reenters tissue, tissue is loosely organized (ex. hemorrhage after infarction) - Liquefactive -- enzymatic lysis of cells - Ex. brain infarction, abscess, pancreatitis - Gangrenous -- coagulative but resembles mummified tissue - Ex. ischemia of lower limb - If superinfected -\> liquefactive, wet gangrene - Caseous -- "cottage-cheese like" - Between liquefactive and coagulative - Granulomatous inflammation due to TB or fungal infection - Fat -- chalky white due to Ca+ deposition (saponification) - Ex. breast, peripancreatic - Can be associated with a giant cell response - Fibrinoid -- blood vessel specific - Leaking of proteins into vessel wall -\> bright pink staining - Ex. malignant HTN, vasculitis - Apoptosis -- single/small groups of cells, not followed by inflammation - As cell shrinks, cytoplasm becomes concentrated -\> increased pink (eosinophilic) - Apoptotic bodies are removed by macrophages - Caspases -- mediated by: - Intrinsic mitochondrial pathway inactivates BCL-2 - Cytochrome C - Extrinsic receptor-ligand pathway - FAS ligand binds FAS death receptor (CD95) on target cell - Ex. negative selection of T cells in thymus - TNF binds TNF receptor on target cell - Cytotoxic CD8+ T cell pathway - Perforins creates pores in membrane - Granzyme enters pores and activates caspases FREE RADIAL INJURY ------------------ \*\*O2 -\> superoxide -\> hydrogen peroxide -\> hydroxyl -\> water\*\* Most damaging = OH (hydroxyl (O2 received 3 H electrons) Examples - O2-dependent (superoxide burst!) - O2 \-\-\-\-- (NADPH oxidase) \-- superoxide (O2-) \--\> H2O2 - Copper and Iron (Wilson's disease, hemochromatosis) - Acetaminophen injury - CCl4 - Dry cleaning exposure - CCl4 \-\-\-\-\--(P450)\-\--\> CCl3 -- that causes cellular swelling/reversible injury in liver [fatty change in liver] b/c can't remove fat from liver b/c can't make apo-lipoproteins - Reperfusion injury Mechanism - Peroxidation of lipids - Oxidation of DNA and proteins -\> oncogenesis Elimination - Antioxidants (vits) - Enzymes: SQD, Glutathione peroxidase, Catalase - Metal carrier proteins (for copper and iron) AMYLOID ------- Misfolded protein that deposits in extracellular space -\> damage tissue Characteristics - B-pleated sheet configuration - Congo red staining and apple-green birefringent under polarized light (after Congo) - Tends to develop around blood vessels Systemic - Primary: AL amyloid due to Ig light chain, associated with MM - Secondary: AA amyloid protein derived from SAA - SAA = acute phase reactant increased in chronic inflam, malignancy, familial mediterranean fever - Familial Mediterranean fever -- dysfunctional neutrophils -\> episodes of fever + serosal inflammation that causes AA depositions - Findings - \*\*kidney = \#1 involved - Nephrotic syndrome, restrictive cardiomyopathy/arrhythmia, tongue enlargement, malabsorption, hepatosplenomegaly - Dx = tissue biopsy Localized - Senile cardiac amyloidosis - Non-mutated [serum transthyretin deposits] in heart - Usually asx elderly - Familial amyloid cardiomyopathy - Mutated serum transthyretin - Restrictive cardiomyopathy - NIDDM (Type 2 DM) - Amylin deposits in islets of pancreas 2/2 high insulin production (amylin derived from insulin) - Alzheimer - AB amyloid (derived from B-amyloid precursor protein on chrom 21) - Dialysis associated - B2-microglobulin (provides structural support to MHC cells) deposits in joints - Not filtered well via dialysis so builds up in blood - Medullary carcinoma of thyroid - Calcitonin deposits in tumor (tumor cells w/amyloid background) Ch 2 -- Inflammation ==================== ACUTE INFLAMMATION ------------------ Two components = edema/fluid + neutrophils in tissue - [Vasodilation of arteriole] - [Increased vascular permeability at post-capillary venule] - [Factors that attract neutrophils = LTB4, C5A, IL-8, bacterial products] - Pain due to bradykinin and PGE2 which sensitize the sensory nerve endings - [Fever due to macrophages that release IL-1 and TNF -\> increase COX in perivascular cells of hypothal -\> increase PGE2 to raise temp setpoint] Response to infection *or tissue necrosis* Immediate response with limited specificity b/c innate immunity Mediators - TLRs -\> upregulation of NF-kB -\> activates multiple immune response genes - On macrophages, dendritic cells - Recognize PAMPs (molecules that are common on pathogens) - Ex. CD14 on macrophages that recognizes LPS (gram negative bacteria) - Arachidonic acid - Released from cell membrane by phospholipase A2 -\> acted on by COX and 5-lipooxygenase -\> - PGI2, PGD2, PGE2 -\> vasodilation of arteriole + vascular permeability of postcapillary venule - PGE2 -\> fever, pain - 5-lipo -\> leukotriene - LTB4 -\> activates neutrophils - LTC4, D4, E4 -\> smooth muscle contraction -\> vasoconstriction, bronchospasm, increased vascular permeability - Mast cells - In connective tissue - Activated by: - Tissue trauma - Complement proteins C3a and C5a - Cross-linking of cell-surface IgE antigen - Immediate response -\> dump preformed **[histamine granules -\> vasodilation, vascular permeability]** - Delayed response -\> production of AA metabolites, including leukotrienes - Complement - Activation - Classical: C1 binds IgG or IgM that is bound to antigen - "GM makes classic cars" - Alternative pathway: microbial products -\> directly activate complement - Mannose-binding lectin pathway: MBL binds mannose on microorganisms -\> activates complement - Result: C3 convertase (C3a, C3b) -\> C5 convertase (C5a, C5b) -\> MAC formation (C5b-9) - C3a, C5a -\> mass cell degranulation - C5a -\> chemotaxis of neutrophils - C3b -\> opsonin for phagocytosis - MAC -- lyses microbes by creating holes in cell membrane - Hageman factor - Produced in liver - Activated in response to subendothelial or tissue collagen - Significant role in DIC in severe GN sepsis - Activates - Coagulation and fibrinolytic system - Complement - Kinin system -- cleaves HMWK to bradykinin -\> vasodilation, increased vascular permeability, pain Neutrophil arrival and function - Vasodilation (slows blood flow in post-cap venule) -\> margination (move to side) -\> rolling (slowed down by [selection upregulation and expression on endothelial cell surface]) -\> adhesion (via [cellular adhesion molecules + integrins)] -\> transmigration and chemotaxis -\> phagocytosis that is enhanced by opsonins (IgG and C3b) - Selectins bind sialyl Lewis X on leukocytes -\> interaction causes rolling - P-selection (from Weibel-Palade bodies) mediated by histamine - E-selection induced by TNF, IL-1 - Adhesion - CAM upregulated in endothelium by TNF and IL-1 - Integrin upregulated on leukocytes by C5a and LTB4 - **Leukocyte Adhesion Deficiency**: autosomal recessive, deficient IL-18 subunit if integrin - Delayed separation of umbilical cord, lack pus, increased circulating neutrophils - Phagocytosis - **Chediak-Higashi Syndrome** - Protein trafficking defect (autosomal recessive, microtubule) - Can't move things around in neutrophils - Characterized by impaired phagolysosome formation - Increased risk of pyogenic infection, neutropenia, giant leukocyte granules (b/c can't move granules from Golgi), **albinism** Destruction of phagocytosed material - O2-dependent killing - O2 -\> O2- by NADPH oxide -\> H2O2 by SOD -\> HOCL by MPO - **Chronic granulomatous disease** - NADPH oxidase (X-linked or autosomal recessive - \*Skin abscesses w/[catalase-positive organisms] - S. aureus - Pseudomonas cepacian - S. marcescens - Nocardia, aspergillus - Most bacteria produce H2O2 and can still produce HOCl but those that produce catalase don't!! - Nitrobue tetrazolium test -- stays colorless if NADPH oxidase defect - **MPO deficiency** -- increased Candida infection risk - O2 independent killing - Lysosome, major basic protein Resolution - All neutrophils undergo apoptosis within 24 hours Macrophages - Peak \@2-3 days - Enz in secondary granules -- lysozyme especially - Manage the next step: - Resolution and healing via IL-10, TGF-beta - Anti-inflammatory - Continued acute inflammation via IL-8 - Abscess - Chronic inflammation -\> digest and express microbe particles on MHC class II on cell surface CHRONIC INFLAMMATION -------------------- T cell development - Bone marrow as T cell progenitors - Thymus -\> TCR rearrangement -\> CD4 vs. CD8 - TCR recognizes antigen presented on MHC - MHC II = CD4 (2 x 4 = 8) - MHC I = CD8 (1 x 8 = 8) - Activation requires binding antigen/MHC complex [and additional second signal] - CD4 -\> secrete cytokines - Extracellular antigen that is phagocytosed and presented via MHC II (APCs) - B7 on APC binds **[CD28]** on CD4 (7 x 4 = 28) - Or CD80 on epidermal dendritic cells - Subsets - Th1 -\> help CD8 T cell - IL-2 (T-cell growth factor, CD8 T cell activator) - IFN-gamma (macrophage activator) - Th2 -\> help B cells - IL-4 - class switch to IgG and IgE - IL-5 -- eosinophil chemotaxis and activation, maturation of B cells to plasma cells, class switch to IgA - IL-10 -- inhibits Th1 phenotype - CD8 -\> kill via secretion of perforins and granzyme -\> apoptosis or via FasL that binds Fas and activates apoptosis - Intracellular antigen processed and presented on MHC I - IL-2 from CD4 B lymphocytes - Immature B cells -\> Ig rearrangement -\> naïve B cells with IgM and IgD - Activation - Antigen binding surface IgM or IgD -\> plasma cell secreting IgM - T-cell dependent - B cell consumes and presents antigen to CD4 via MHC II [and] CD40R on B cell binds CD40L on CD4 to provide 2^nd^ activation signal -\> Th2 pathway -\> IL-4, IL-5 -\> isotype switching, hypermutation, maturation to plasma cells Granulomatous inflammation - [Defining feature = epithelioid histiocyte] (macrophages w/abundant pink cytoplasm) - Usually surrounded by giant cells + rim of lymphocytes - Caseating vs. noncaseating - Noncaseating lacks central necrosis - Reaction to foreign material - Sarcoidosis - Beryllium exposure - Chron disease - Cat scratch disease (stellate shape granuloma) - Caseating has central necrosis -- TB and fungus - AFB stain for TB - Silver stain (GMS) for fungus - Steps of formation - Macrophages present MHCII/antigen to CD4 and secrete IL-12 -\> activate CD4 -\> Th1 subtype -\> IFN-gamma released -\> converts macrophages into epithelioid histiocytes and giant cells - Occurs for both types of granulomas PRIMARY IMMUNODEFICIENCY ------------------------ DiGeorge Syndrome -- CATCH-22 - 3^rd^/4^th^ pharyngeal pouch - 22q11 microdeletion - Lack thymus -\> T cell deficiency SCID -- no T or B cells - Cytokine receptor defects - **[Adenosine deaminase deficiency]** -- toxic buildup of adenosine and deoxyaminase b/c can't break down in purine salvage pathway - MHC class II deficiency (CD4) X-linked agammaglobulinemia - Complete lack Ig due to disordered B-cell maturation so can't make plasma cells - Due to **[Bruton tyrosine kinase mutation]** - Presents after 6mo of life with recurrent [bacterial, enterovirus, and Giardia] infections; live vaccines avoided CVID -- low Ig, similar to X-linked agammaglobulinemia, same infections, but present older, higher risk for autoimmune disease and lymphoma IgA deficiency -- mucosal infections, esp viral; associated with celiac disease Hyper-IgM Syndrome - Due to mutated CD40L or CD40 receptor - Second signal cannot be delivered to helper T cells in B cell activation - Can only make IgM with the basic pathway - Cytokines necessary for Ig class switching not produced - Low IgA, IgG, and IgE -\> pyogenic infections esp at mucosal sites Wiskott-Aldrich Syndrome - Thrombocytopenia - Eczema - Recurrent infections (wide range) - WAS protein, X-linked Complement deficiency - C5-9 -\> increased Neisseria infection - C1 inhibitor deficiency -- hereditary angioedema, esp periorbital edema AUTOIMMUNE DISORDERS -------------------- Tolerance - Central tolerance in thymus - AIRE mutation -- autoimmune polyendocrine syndrome - AIRE needed for MEC to express subset of self-antigens - Hypoparathyroidism - Adrenal failure - Candida - SC -\> DP (Cd4, CD8, T cell receptor \-\-\-- positive selection (confirm bind MHC/antigen complex) \-\-\--\> Single positive \-\-\-\-\--negative selection (confirm don't bind too strongly to self-antigen, in medulla, dendritic cells and medullary epithelial cells (MEC) present antigen) \-\--\> naïve mature T cells - Central tolerance in bone marrow - SC \-\--(Ig express)\-\--\> immature \-\-\--(negative selection of Ig when presented with antigens by dendritic cells) \-\-\--\> naïve mature B cell - If too tight binding: - RAG genes -- allow for editing of light change in response to negative selection - Apoptosis - Peripheral tolerance - TCR-MHC II on dendritic cell [but no second signal anergy] - If repeatedly binds single signal [apoptosis] - CD95 (FAS)/death receptor - **Fas apoptosis pathway mutations (ALPS) -- can't do this, causes cytopenias but lots of lymphocytes proliferating** - If repeated bind to single signal FASL expressed apoptosis - Regulatory T cells (CD4+ CD25+ FoxP3+) - CD4 cells that suppress immune responses - Block T cell activiation - CTLA4 competes with CD28 for B7 decreases probability of second signal - Cytokines -- IL-10, TGF-b - Blocks primary signal and second signal - CD25 = IL-2R (requires IL-2 for growth and survival) - Diseases - CD25 polymorphisms associated with autoimmunity - FOXP3 mutations -- IPEX syndrome WOUND HEALING ------------- Regenerative capacity of tissues - Labile tissues - Constantly cycling b/c stem cells - Bowel (mucosal crypts), skin (basal cell layer), bone marrow (hematopoietic stem cell -- marker = CD34+) - Stable tissues - Quiescent but can reenter cell cycle - Liver, PCT - Permanent tissue - Lack significant regenerative potential instead repair with fibrous scar - Also repair if regenerative stem cells lost - Myocardium, skeletal muscle, neurons Repair - Granulation tissue = initial phase - Fibroblasts: deposit type III collagen - Capillaries: provide nutrients - Myofibroblasts: contract wound - Eventually forms scar - Type III collagen replaced with type I collagen by collagenase - **Requires zinc as cofactor** - Mediators - A close-up of a text Description automatically generated - Delayed wound healing - Infection - Vitamin C deficiency (hydroxylation of procollagen so that it can be crosslinked) - Copper (lysyl oxidase needed for cross linking collagen) - Zinc (collagenase needs this) - Foreign bodies, ischemia, diabetes malnutrition Ch 3 -- Neoplasm ================ NEOPLASIA --------- G6PD isoforms (or androgen receptor isoforms) can be used to prove monoclonality in XX individuals - X-linked - Hyperplasia maintains the ratio of the maternal and paternal allele in females - Neoplasia does not maintain this ratio due to monoclonality B cell clonality -- look at light chain phenotype (normal = 3 kappa : 1 lambda) Most common - By incidence -- breast/prostate, lung, colorectal - By mortality -- lung, breast/prostate, colorectal Basic principles - 30 divisions occur before the earliest symptoms arise - Each division results in increased mutations -\> late sx in divisions means more mutations before can detect so poor prognosis CARCINOGENESIS -------------- Carcinogens - Chemicals - Aflatoxin (derived from Aspergillus, grains) -\> HCC - Alkylating agents (chemo) -\> leukemia, lymphoma - Alcohol -\> SCC or oropharynx, pancreatic carcinoma, HCC - Arsenic (smoking) -\> SCC of skin, lung cancer, angiosarcoma of liver - Asbestos -\> lung carcinoma \> mesothelioma - Cigarette smoke (esp polycyclic hydrocarbons) -\> carcinoma of oropharynx, esophagus, lung, kidney, bladder - Nitrosamines (smoked foods, esp in Japan) -\> stomach carcinoma - Naphthylamine (smoke) -\> urothelial carcinoma or bladder - **Vinyl chloride (occupational hazard, PVC pipe) -\> angiosarcoma of liver** - Nickel, chromium, beryllium, silica (occupational hazards) -\> lung carcinoma - Viruses - EBV -\> nasopharyngeal (Chinese male, African individual, neck mass), Burkitt, CNS lymphoma in AIDS - HHV-8 -\> Kaposi sarcoma (endothelial cell sarcoma, purple raised lesions) - Eastern European older males (excise) - AIDS (tx HIV) - Transplant pt (decreased immunosuppression) - HBC, HCV -\> HCC - HTLV-1 -\> adult T cell leukemia/lymphoma - High-risk HPV (16, 18, 31, 33) -\> SCC vagina, vulva, anus, cervix, adenocarcinoma of cervix - Radiation - Ionizing (nuclear reactor accidents, radiotherapy) -\> AML, CML, papillary carcinoma of thyroid - Generates hydroxyl free radicals - Nonionizing (UVB sunlight) -\> basal cell carcinoma, SCC, melanoma - Forms pyrimidine dimers in DNA that are excised by restriction endonuclease [Regulatory Systems] Protooncogenes - Enable cell growth and differentiation - - Types - Growth factors - PDGFB (platelet-derived growth factor) - Overexpression -\> autocrine regulation -\> astrocytoma - Growth factor receptors - ERBB2 (HER2/neu) (epidermal growth factor receptor) - Amplification -\> breast cancer - RET (neural growth factor receptor) - Point mutation -\> MEN2A and B, sporadic medullary carcinoma of thyroid - KIT (stem cell growth factor receptor) - Point mutation -\> GI stromal tumor - Signal transducers - RAS gene family (GTP-binding protein) - RAS-GDP \-\--GF binds receptor \--\> RAS-GTP \-\-\--GAP dephosphorylates RAS-GTP \-\--\> RAS-GDP - Point mutation -\> carcinoma, melanoma, lymphoma - ABL (tyrosine kinase) - t(9,22) with BCR -\> CML and some types of ALL - Nuclear regulators (transcription factors) - C-MYC - T(8;14) involving IgH -\> Burkitt lymphoma - **N**-MYC amplification -\> **n**euroblastoma - **L**-MYC amplification -\> **l**ung carcinoma (small cell) - Cell cycle regulators - Cell cycle regulation - G1-\>S is most regulated - Cyclin D1 - RB - P53 - CCND1 (cyclin D1) - T(11:14) involving IgH -\> mantle cell lymphoma - CDK4 (cyclin dependent kinase) - Amplification -\> melanoma Tumor suppressor genes -- require 2 hits - Regulate cell growth - G1 -\> S - P53 - Function: checks for DNA mutations -\> repair or apoptosis - Apoptosis: p53 -\> BAX knockouts BCL-2 - Requires 2-hit - Germline mutation = Li-Fraumeni syndrome (associated with increased cancer risk) - RB - Function: binds E2F until Rb is phosphorylated by cyclin D/CDK4 complex - If mutated with 2 hits -\> E2F is free to allow G1 to S phase - Sporadic mutation -\> unilateral retinoblastoma - Germline mutation (familial) -\> b/l retinoblastoma, osteosarcoma Regulators of apoptosis - Bcl2 - Stabilizes mitochondrial membrane so cytochrome c not released - Overexpressed in follicular lymphoma (14:18 translocation) - Want a lot of apoptosis in the follicle normally b/c undergoing somatic hypermutation b/c if mutations fail want those cells to die Telomerase is necessary for cell immortality -- upregulated in cancers Angiogenesis - FGF, VEGF Immune surveillance of tumor cells - Downregulate **MHC class I** so that don't express the abnormal proteins that the cells are making - Immunodeficiency increases risk of cancer b/c not doing this well TUMOR PROGRESSION ----------------- Process of invasion - Downregulation of e-cadherin -\> enables cancer cells to detach from neighbor cells - Attach to BM laminin - Produce collagenase IV -\> destroy BM - Attach to fibronectin in extracellular space - Enter vascular or lymphatic space - Carcinoma -\> regional lymphatic spread - Sarcoma -\> hematogenous spread, esp to lungs - Exception carcinomas: - Renal cell carcinoma -\> renal vein - Hepatocellular carcinoma -\> hepatic vein - Follicular carcinoma of thyroid - Choriocarcinoma - Seeding -\> ovarian carcinoma ("omental caking") CLINICAL CHARACTERISTICS ------------------------ Immunohistochemistry (brown stain = + response to marker) - Intermediate filaments - Keratin -\> epithelium - Vimentin -\> mesenchyme - Desmin -\> muscle - GFAP -\> neuroglia - Neurofilament -\> neurons - Others - PSA -\> prostate epithelium - ER -\> breast epithelium - Thyroglobulin -\> thyroid follicular cells - Chromogranin -\> neuroendocrine cells (ex. small cell carcinoma of lung (worst), carcinoid tumors (most well-differentiated)) - S-100 -\> melanoma Serum tumor markers - PSA - AFP Ch 3 -- Heme ============ PRIMARY HEMOSTASIS ------------------ 1. Transient vasoconstriction a. Mediated by neural reflex b. Endothelium releases endothelin 2. vWF binds to collagen in BM c. vWF in endothelial cells (Wiebel-P bodies) and in platelets (alpha granules) 3. Platelet binds vWF via GP1b 4. Platelet activation, shape change, dump mediators -\> ADP and TXA2 d. ADP induce platelets to exposure Gp2b3 receptors enables platelet aggregation e. TXA2 further platelet aggregation signal 5. Fibrinogen = linker molecule between platelets when aggregate (link between Gp2b3 receptors) **Primary hemostasis issue = mucosal and skin bleeding** **Intracranial bleeding = risk of severe** **Petechiae are generally not from qualitative disorders** Disorders - ITP - IgG Ab against platelet (ex. GPII/bIII) made in spleen - Ab-bound platelet are consumed by splenic macrophages - IVIG tx works because then macrophages consume these instead and leave the platelets - Two forms - Acute -\> children, post-viral infection, self-limited - Chronic -\> primary or secondary (ex. SLE), women of childbearing - Will have high megakaryocytes on BM bx - Microangiopathic hemolytic anemia - Platelet microthrombi in small vessels - Causes - TTP -- ADAMTS-13 deficiency (can't degrade vWF multimers) - Genetic or autoAb - FAT RN - HUS -- drugs or E. coli infection (verotoxin) causes endothelial damage - schistocyte (two points, helmet cell) - **Bernard-Soulier syndrome** - Genetic GP1b deficiency - Platelet adhesion is impaired - Enlarged platelets (b/c more immature platelets produced) in smear with mild thrombocytopenia - Glanzmann thrombasthenia - GIIb/IIIa deficiency - Platelet aggregation impaired - Aspirin irreversibility inactivates COX -\> lack TXA2 -\> impairs platelet aggregation - Uremia -\> both adhesion and aggregation are impaired SECONDARY HEMOSTASIS -------------------- Coagulation factor activation requires - Ca (in platelet granules) - Phospholipid surface (platelet membrane) - Exposure to activating substance Coagulation factor inhibitor vs. Hemophilia A - Mixing study (mix patient's plasma with normal plasma) - If PTT corrects -\> Hemophilia A - If PTT doesn't correct -\> inhibitor vWF Disease - Autosomal dominant -\> decreased vWF factor - Platelet adhesion issues - PTT prolonged b/c need for stabilize VIII (but doesn't cause clinical problems consistent with this) - Abnormal ristocetin test (normal would aggregate but don't in this test) - Tx = desmopressin -- causes release of vWF from WP bodies of endothelial cells Vit K deficiency - 2, 7, 9, 10 - **B/c produced by bacteria in gut, people at risk are:** - Newborns - Long-term abx therapy - Malabsorption Liver failure - Decreased coagulation factor production - Decreased activation of Vit K by epoxide reductase - **Follow w/PT** OTHER DISORDERS OF HEMOSTASIS ----------------------------- Fibrinolysis via tPA - Plasminogen -\> plasmin - Plasmin - \(1) cleaves fibrin and serum fibrinogen (stops future clots) - \(2) destroys coagulation factors - \(3) blocks platelet aggregation - Alpha 2 anti-plasmin inactivates Causes of overactive fibrinolysis - Radical prostatectomy - Release of urokinase -\> activates plasmin - Cirrhosis -\> reduced production of alpha 2 anti-plasmin Lab findings and presentation is similar to DIC [but] - **Normal platelet count** - **No D-dimer** Tx: aminocaproic acid to block the formation of plasmin from plasminogen THROMBOSIS ---------- Thrombus is characterized by: 1. Lines of Zahn (don't see if postmortem clot) -- RBC then fibrin then RBCA purple and red paint on a surface Description automatically generated with medium confidence 2. Attachment to the vessel wall Endothelial protection against thrombosis - Barrier blocks subendothelial collagen from vWF - Prostaglandin I2 blocks thrombosis - NO -\> vasodilation - Heparin-like molecules produce anti-thrombin III - tPA to cause fibrinolysis - Thrombomodulin -\> thrombin can't convert fibrinogen -\> fibrin and instead it activates Protein C to block coagulation cascade High levels of homocysteine cause endothelial damage -\> increased risk of thrombosis EMBOLUS ------- Cholesterol emboli  - Cholesterol clefts in atherosclerotic embolus Fat embolus A close up of a cell Description automatically generated - Petechiae, dyspnea Gas embolus - Decompression sickness, lap surgery - Joint and muscle pain - Respiratory symptoms Amniotic fluid embolus  - SOB, neuro sx, DIC - Characterized by squamous cells, keratin debris from fetal skin in embolus Ch 5 -- Red Blood Cell Disorders ================================ MICROCYTIC ANEMIA ----------------- Core principles - Due to an "extra" division in RBC development - Problem of decreased production of Hb to maintain \[Hb\] makes smaller cells - Causes - Low heme - Low Fe IDA - **Free erythrocyte protoporphyrin = high in IDA** - Can't use the Fe anemia of chronic disease - Low protoporphorin **sideroblastic anemia** - Low globin thalassemia - RDW = spectrum of size of RBCs - High in - IDA b/c makes normal cells first and then small cells so have both sizes Iron basics - **Absorbed in duodenum** by enterocytes via **ferroportin (**enterocyte -\> BV) - [Can regulate this step] (b/c can't get rid of iron very well so don't want to take up too much) - **Transferrin** transports iron and delivers it to liver and BM macrophages for storage - Storaged intracellularly bound to **ferritin** - **When ferritin drops, transferrin (TIBC) increases b/c the liver makes more of it in response** - Labs - Serum iron (on transferrin) - TIBC- how many transferrin molecules are in the blood - \% saturation - Usually 1/3 transferrin molecules are bound to iron - Serum ferritin - Gastrectomy can cause IDA - B/c Fe2+ = absorbed - Acid maintains the Fe2+ state - Stages of deficiency - Storage depleted (decreased ferritin, increase TIBC) -\> serum depleted (decreased % saturation) -\> normocytic anemia -\> microcytic, hypochromic anemia Anemia of chronic disease - Hepcidin is an acute phase reactant -\> - Sequesters iron in storage site - Suppresses EPO production - Labs - High ferritin, low TIBC - Low serum iron, low saturation - High FEP Sideroblastic anemia - Low protoporphyrin - Final reaction attaches it to iron to make heme (in mito) - Proto synthesis requires B6 (for ALAS = rls) - Final step: iron enters mito to combine - If no proto iron trapped in mito creates ring around nucleus - Associations - Alcoholism - Lead poisoning -\> denatures enz including ALAD, FEMD - Vit B6 deficiency due to isoniazid tx Thalassemia - Alpha - 4 copies of alpha hemoglobin (2 mom, 2 dad) -- on same chromosome - Caused by gene **[deletion]** - 3 genes deleted -\> B chains for tetramers (HbH) that damage RBCs - 4 genes deleted -\> hydrops fetalis b/c can't make fetal Hb - Hb Barts = tetramer of gamma chains - Beta - Caused by gene **[mutation]** - Can cause absent or diminished production of B chains - Minor (B/B+) - Slight reduction in production - Target cells - Decrease cytoplasm - Increase membrane - Major (Bo/Bo) - Spleen consumes any RBCs that get out of BM - Massive erythroid hyperplasia - Expansion of hematopoiesis into marrow of skull + facial bones crew cut appearance on x-ray + chipmunk-like faceA x-ray of a skull Description automatically generated - Extramedullary hematopoiesis -\> hepatosplenomegaly - Risk of aplastic crisis with parvovirus B19 - Infects erythroid precursors - Don't have the reserve to manage lack of RBC development for a period of time - Chronic transfusions secondary hemochromatosis - Nucleated RBCs in smear from extramedullary hematopoiesis - No HbA b/c no beta MACROCYTIC ANEMIA ----------------- Megaloblastic anemia - Can't do all the divisions b/c don't have all the DNA precursors - Will see megaloblastic change of all rapidly dividing cells (ex. intestine) - Folate deficiency - Absorbed in jejunum - Develops in months b/c minimal stores - Normal MMA - B12 - B12-animal protein -\> B12-R binder -\> B12 cleaved from R binder in the small bowel by proteases -\> B12 binds IF -\> absorbed in ileum - R binder made in salivary gland - Proteases produced by pancreas - IF made by parietal cells of stomach - **Pink in histology** - **Protein pump (make acid)** - **Pernicious anemia** - Causes - \#1 pernicious anemia - Pancreatic insufficiency - Terminal ileum damage (ex. Chron's) - [Rare] dietary deficiency (vegan) - Buildup of MMA in myelin of spinal cord -\> subacute combined degeneration of spinal cord Other causes - Alcoholism - Liver disease - Drugs (5-FU) NORMOCYTIC ANEMIA ----------------- Underproduction Peripheral destruction - Extravascular -- liver, spleen, etc - Reticuloendothelial cells - Macrophages of spleen, liver, LN - Consume - Globin -\> AA - Heme -\> iron + proto - Proto -\> unconjugated bili - Hereditary spherocytosis - Membrane bleds lost b/c don't have cytoskeleton tethering -\> sphere - Range in size of cells high RDW - Can't maneuver in spleen consumed - Dx: osmotic fragility test -\> increased fragility in hypotonic solution - Howell-Jolly bodies - Spleen is supposed to remove fragments of DNA (blue/purple dot) - Post-splenectomy!! - Sickle Cell Anemia - Sickling is due to increased polymerization of HgS - Sickling causes RBC membrane damage less flexible RBCs - spleen removes them - intravascular hemolysis - Target cells b/c cells dehydrate so decreased cytoplasm - Intravascular - Hb spills out of cells into blood -\> binds haptoglobin -\> send to spleen - Paroxysmal Nocturnal Hematuria - MIRL and DAF inactivate complement that comes near RBC - GPI = anchoring protein on surface of RBC - **Acquired defect in myeloid stem cell not all cells have GP1** - **Issue for RBC, WBC, plt** - Intravascular hemolysis that occurs episodically, often at night - Testing - Acidify serum -\> activate complement - CD55 uses GPI for linker molecule -\> don't have - **Main cause of death = thrombosis of hepatic, portal, or cerebral veins due to destroyed platelets releasing cytoplasmic contents** - G6PD Deficiency - Need G6PD to make NADPH to regenerate GSH to protect against oxidative stress - **Reduced half-life of G6PD = problem for old RBCs during oxidative stress** - Oxidative stress causes older RBCs to lysis - Oxidative stress precipitates Hb as Heinz bodies - Heinz bodies removed by splenic macrophages -\> bite cells - Immune hemolytic anemia - IgG extravascular - "warm" - Membrane of Ab-coated RBC consumed by splenic macrophages results in **spherocytes** - Associated with SLE, CLL, certain drugs - IgM intravascular - "Cold" - Binds RBCs in extremities fixes complement MAC complex intravascular hemolysis - Coombs test - Direct does patient have RBCs already bound by IgG? - Indirect does patient have Ab in serum? - Microangiopathic hemolytic anemia - Thrombus forms in small vessel -\> shearing -\> spherocytes - TTP, HUS - Malaria (b/c life cycle requires RBC lysis) Correct reticulocyte count by Rt x Hct/45 - Micro or macrocytic anemia - Renal failure (low EPO) - Damage to BM precursor cells - Parvovirus B19 infects progenitor red cells and halts erythropoiesis - Aplastic anemia - Meylophthisic process: process that replaces BM Ch 6 -- White Blood Cell Disorders ================================== LEUKOPENIA, LEUKOCYTOSIS ------------------------ High cortisol state apoptosis of lymphocytes; increased neutrophils due to disrupted adhesion of marginated neutrophil pool The most sensitive cell to radiation = lymphocytes!! EBV - Infects oropharynx, B cells, liver (causes hepatitis) - Causes a CD8+ T cell response - Generalized LAD (paracortex) - Splenomegaly (periarterial lymphatic sheath) - Atypical lymphocytes - Screening: monospot test uses [IgM] heterophile Abs - Negative tested too early or due to CMV - Dx = EBV viral capsid antigen ACUTE LEUKEMIA -------------- - Blast proliferation crowd out normal hematopoiesis - \>20% blasts in BM - Acute sx - Blasts = large immature (v little cytoplasm) cells, often with punched out nucleoli on smear - AML vs. ALL - AML -- MPO+ - MPO causes Auer bodies - Average age 50-60 - Subclassification - **Cytogenic abnormalities** - Lineage of myeloblasts (ex. erythroblastic, megaryoblastic, monoblastic, myeloblastic) - **Acute monocytic leukemia** - Proliferation of monoblasts - Infiltrate gums - Don't have Auer rods - **Acute megakaryoblastic leukemia** - Lack MPO - Associated with Down Syndrome before age 5 - Surface markers - Acute promyelocytic leukemia - T(15;17) disrupts retinoic acid receptor promyelocytes accumulate numerous Auer rods - **Medical emergency b/c Auer rods increase risk of DIC** - Tx = ATRA b/c allows maturation - Increased risk with exposure to alkylating agent, radiotherapy myelodysplastic syndrome - Cytopenias with hypercellular bone marrow (\ rash, plaques, nodules - Pautrier microabscesses - When spread to blood -\> Sezary syndrome - Cerebriform nuclei on smear MYELOPROLIFERATIVE DISORDERS ---------------------------- All myeloid cells will be increased but named for predominant lineage - Late adulthood - High WBC w/hypercellular marrow - Common complications - Hyperuricemia, gout - Progression to marrow fibrosis - Transformation to acute leukemia CML - Granulocytes [especially basophils] - T(9;22) -\> BCR-ABL -\> increased tyrosine kinase - Tx: imatinib - Mutation is in HSC!!! therefore can transform to AML [or ALL] - Splenomegaly = common - Enlarging spleen = marker for accelerated disease phase transformation to AML (2/3) or ALL (1/3) is likely and soon - Distinguishing from leukemoid reaction - LAP negative -- used for inflammation - Increased basophils - T(9;22) Polycythemia Vera - Associated with JAK2 kinase mutation - Presentation = hyperviscosity + itching after bathing - \#1 cause of Budd Chiari syndrome - Mast cells increased too itching after bathing - Distinguishing from reactive polycythemia - Normal SaO2 - Decreased EPO Essential Thrombocythemia - JAK2 kinase mutation - Rarely progresses to marrow fibrosis or acute leukemia - No significant risk for hyperuricemia or gout Myelofibrosis - Megakaryocytes produce PDGF results in marrow fibrosis - Splenomegaly - Leucoerythroblastic smear - Tear drop cells LYMPHADENOPATHY AND LYMPHOMA ---------------------------- In inflammation -- hyperplasia of LN regions - Rheumatoid arthritis + early HIV follicles - Paracortex viral infection - LN draining tissue with cancer sinus histiocytes NHL - Small more normal, grow in normal LN patterns - Follicle - B cells - CD20 - Painless LAD - T(14;18) -- BCL-2 stabilizes mitochondrial membrane so avoid apoptosis - Usually asx, only treat if sx - Can progress to DLBCL (enlarging LN) - Distinguish from follicular hyperplasia by: - Disruption of normal architecture (not only in the cortex) - Lack of tingible bodies (macrophages eating in apoptosis) - BCL2, monoclonal - Mantle - Small B cells (CD20) that expand the mantle zone - T(11;14) -- cyclin D overexpression promotes G1/S transition in cell cycle via phosphorylation - Margin - Small B cells (CD20) - Associated with chronic inflammatory states (Hashimoto's, Sjogren, H pylori) b/c formed by post-germinal center B cells - MALToma = marginal zone lymphoma of stomach - Intermediate size - Burkitt - CD20+ - Associated with EBV - T(8:14) -- c-myc oncogene that promotes cell growth via transcription - High mitotic rate, starry sky appearance (sky = cells, star = macrophages that are eating the cells that are dividing so fast that they are dying) - Large - DLBCL - CD20+ - Most common form of NHL - Clinically aggressive -- not normal architecture or cells Hodgkin Lymphoma - Mass is predominantly inflammatory cells [not neoplastic cells] - Reed-Sternberg cells secrete cytokines that attract reactive cells to make a mass - CD15 CD30+ - Multilobed nuclei w/prominent nucleoli - Secretion of cytokines - Can cause B symptoms - Attract lymphocytes, plasma cells, macrophages, eosinophils - May lead to fibrosis - Classified based on the reactive cells - Nodular sclerosis = most common PLASMA CELL DISORDERS --------------------- Multiple myeloma - IL-6 is often elevated - GF for plasma cells - Sx due to substances produced by cells - Bone pain w/hypercalcemia - Osteoclast-activating factor (IL-1) activate RANK receptor on osteoclasts - Loss of antigenic diversity increased infection risk - Rouleaux formation b/c decreased charge distribution between RBC - Primary AL amyloidosis b/c overproduce light chain \> heavy free light chain deposits in tissue - Can deposits in kidney renal failure - M spike: IgG \> IgA \> other Ig MGUS - M spike but no other MM findings - Common in eldery Waldenstrom macroglobulinemia - B cell lymphoma with Monoclonal IgM - Generalized LAD but no lytic lesions - Increased viscosity due to IgM size - Bleeding b/c defective platelet aggregation LANGERHANS CELL HISTOCYTOSIS ---------------------------- Langerhans cells - Dendritic cells found predominantly in skin - Derived from BM monocytes - Present antigen to naïve T-cells LCH - Birbeck (tennis racket) granules on EM - Cells = CD1a+ and S100+ by immunohistochemistry **Subtypes -- if names in disease then malignant and usually involves skin; if 2 people's names = children \ increased vagal stimulation -\> increased Ach -\> increased acid - Shock -\> hypovolemia/decreased blood flow Chronic gastritis - Autoimmune - Autoimmune destruction of parietal cells - T-cell mediated - Atrophy of mucosa of [fundus and body] - Achlorhydria w/increased gastrin levels, antral G-cell hyperplasia - Megaloblastic anemia due to lack of IF - Increased risk for gastric adenocarcinoma due to intestinal metaplasia - H pylori - Ureases, proteases -\> inflammation -\> weaken mucosal defenses - Does not invade - Most common in antrum Gastric adenocarcinoma - Intestinal type - Large irregular ulcer with heaped up margins - Lesser curvature of antrum - Risks: intestinal metaplasia (both chronic gastritis causes), nitrosamines, blood type A - Diffuse type - Signet ring cells that diffusely infiltrate gastric wall - Desmoplasia results in thickening of stomach wall (linitis plastica) - Not associated with with H pylori, intestinal metaplasia, nitrosamines Random Notes ============ ALCOHOL ------- Intoxication - Due to cerebellar neuron toxicity - Mechanism - GABA agonism - NMDA (glutamate) inhibition Associations - Dilated cardiomyopathy - Wernicke-Korsakoff Syndrome - CAN of beer (INO) - Mamillary bodies - **Thiamine before glucose** - Cirrhosis - Pancreatitis - Esophageal varices - Gout (alcohol decreases uric acid metabolism b/c competes for lactic acid and BHB and can acutely worsen gout) - Aspiration PNA Withdrawal - Chronic alcohol use - Downregulation of GABA receptors - If remove the stimulus fewer GABA available loss of balance overexcitation - Alcohol hallucinosis = hallucinations but AOx4 !!!! - Vs. delirium tremens = disoriented, psychosis, death - Use OLT benzos LYSOSOMAL STORAGE DISEASES -------------------------- Fabry - Enz: alpha-galactosidase A - Buildup: ceramide trihexoside - Mnemonic: my Fabrite activity is to make a Ceramic Galaxy. Sorry to keep HARPing on it. - X-linked - Hypohidrosis, angiokeratomas, renal failure, peripheral neuropathy Gaucher - Enz: glucocerebrosidase - Buildup: glucocerebroside - Mnemonic: (in crying voice) OMGauch, he's such a Bro" - Tissue paper cytoplasm, lipid laden - Osteoporosis - Gross femoral head (AVN) Tay Sach - Enz: Hexosaminidase A - Buildup: GM2 ganglioside - Mnemonic: A Gang of 6 small Jews - Small = no hepatosplenomegaly - Cherry red spot - Onion skin lysosomes Niemann Pick - Enz: sphingomyelinase - Buildup: sphingomyelin - Mnemonic: pick your nose with a big foamy sphinger - Big = hepatosplenomegaly - Cherry red spot - "Foam cells" or "lipid laden macrophages" Krabbe's Disease - Enz: beta galactocerebrosidase - Buildup: galactocerebrosidase - Mnemonic: the Glob of GOO-ey Krabbe is out of the world - Glob of crab meat -\> globoid cells - Oligodendrocyte destruction - Optic atrophy Hunter's Disease - Enz: Iduronate sulfatase - Buildup: dermatan sulfate, heparan sulfate - Mnemonic: X marks the spot for the Hunter - No corneal clouding - \+ behavioral aggression - Gargoyles - Airway obstruction Hurler's Disease - Enz: alpha-2-iduronitase - Buildup: dermatan sulfate, heparan sulfate - Mnemonic: - \+ corneal clouding Metachromatic leukodystrophy - Enz: arylsulfatase A - Buildup: cerebroside sulfate - Mnemonic: Metapod is aryl broken pokemon - Central and peripheral demyelination - Ataxia - Dementia SIGNAL TRANSDUCTION ------------------- G-Protein Coupled Receptors 1. Signal binds 2. Conformational change to gamma-beta-alpha-GDP G proteins 3. Alpha subunit dissociates 4. Alpha-GDP alpha-GTP = active a. Gs i. Stimulates adenyl cyclase 1. ATP cAMP a. cAMP activates Protein Kinase A b. Gi ii. Inhibits adenyl cyclase c. Gq iii. Stimulates phospholipase C 2. PIP2 IP3 + DAG b. IP3 Ca released from ER c. DAG activates Protein Kinase C (PKC) - Examples - Gs and Gi control FLAT Cream Pop And HHealthy GGrapes - Basophilic pituitary hormones: FSH, LH, ACTH, TSH - CRH - hCG - ADH (V2) - MSH - PTH - Calcitonin - GHRH - Glucagon - Histamine (H2) - Gq controls - GnRH - Oxytocin - ADH (V1) - Histamine (H1) - Angiotensin II - Gastrin Receptor Tyrosine Kinase 1. GF or local signal binds 2. Dimerization of RTKs 3. Cross phosphorylation (phosphorylate each other) SH2 domain = binding site for internal enzymes a. RAS-GDP binds activates as RAS-GTP i. RAS-GTP RAF MEK ERK 1. Controlled by MAP-kinases (activators) 2. Amplifies signal b/c each activates more than 1 3. Affects transcription ii. Controls 4. Insulin 5. IGF1 6. FGF 7. PDGF 8. EGF cGMP Pathway 1. NO enters the cell 2. Activates guanylate cyclase 3. GC convert GTP cGMP a. cGMP Protein Kinase G - Controls - BNP - ANP - EDRF Bacterial Virulence Factors =========================== **INVASION** IgA Protease - Secreted -\> cleaves IgA Ab -\> adhere to mucosal surfaces - Organisms - S. pneumoniae - H. flu type B - N. meningitidis - N. gonorrhea **AVOID IMMUNE DEFENSES** M protein - Prevents opsonization and phagocytosis -\> allows organize to avoid immune defenses - Similar to antigens in heart -\> rheumatic fever - Organisms - Strep pyogenes Protein A - Binds Fc portion of IgG -\> only Fab portion exposed -\> prevents opsonization and phagocytosis - Organisms - S. aureus (on cell surface) **TOXIC TO HOST** Type III Secretion System (Injectisome) - Protein structure that inserts into host cells -\> injects exotoxins - Organisms - **Gram negatives** - Salmonella - Shigella - E. coli - Pseudomonas - In the envelope Endotoxins - LPS on [surface] of **gram negative** bacteria - Lipid A = toxic component of LPS - Source of endotoxin genes = bacterial chromosome - Bacterial cell death -\> release of **[Lipid A]** -\> host releases cytokines (TNF, IL1, IL6) -\> sepsis -\> septic shock - Shock is due to dysregulated immune response to virulence factor Exotoxins - Secreted proteins that inflict disease - Used by most gram positive and some gram negative bacteria - Source of exotoxin genes - Bacterial chromosome - Plasmids - Lysogenic bacteriophages following lysogenic conversion (phage DNA can produce protein products) - **Block protein synthesis** - Block elongation factor (EF-2) - Diphtheria - Pseudomonas - Ribosomal inhibition (60S) - EHEC - Shigella - **Increase fluid secretion** - Stimulate Gs [-\> increase cAMP] -\> increase Cl and water in lumen of gut -\> watery diarrhea - ETEC (heat-labile and stable toxin) -- ligand for the Gs pathway GPCR - Cholera - Mimics adenylate cyclase -\> increased cAMP -\> Cl and H2O movement -\> edema surrounding black eschar in cutaneous anthrax - Anthrax (edema toxin) - **Inhibit phagocytosis** - Inhibit Gi \-\--\> increase adenylate cyclase -\> increased cAMP -\> decreased neutrophil recruitment -\> decreased phagocytosis - Pertussis toxin - **Activate host immune system** - Recruit and activate neutrophils -\> cytokines -\> mucosal inflammation, fluid loss, diarrhea - C. diff (Toxin A) - **Disrupt cytoskeleton** - Induce actin depolymerization -\> mucosal cell death -\> bowel wall necrosis, pseudomembrane formation - C. diff (Toxin B) - **Block neurotransmission** - Block SNARE proteins in Renshaw cell -\> block NT vesicle release -\> no GABA/glycine released -\> no inhibition of motor neuron - Tetanoid toxin - Block SNARE protein -\> no Ach relased - Botox - **Cell membrane lysis** - Phospholipase degrades cell membrane, hydrolyzes lecithin - C. perfringens (alpha toxin) - Streptolysin O degrades cell membrane - S. pyogenes - **Superantigens** - Crosslink MHC II and T Cell Receptor -\> massive cytokine release from T cells -\> toxic shock syndrome (or like syndrome) - S. aureus (TSST) - Can also have a reaction to an exfoliative toxin at the same time - S. pyogenes (erythrogenic toxin A) - Also causes scarlet fever A screenshot of a computer Description automatically generated Familial Dyslipidemia ===================== **Familial Hypercholesterolemia** LDL receptor gene mutations - Class 1 = decreased quantity - Class 2 = decreased intracellular transport of LDL receptors back to surface after dropping LDL off with lysosome - Class 3 = binding LDL-LDL receptor issues - Class 4 = no coated pits so can't internalize LDL receptors - Class 5 = issue with recycling of LDL receptors -\> decreased total number Presentation - Autosomal dominant - Symptoms - Xanthomas (hands, tendons, knees) -- esp achilles tendon - Xanthelasma palpebrarum -- eyelids - Premature atherosclerosis A table of type i and ii Description automatically generated 1 LP 2 LD b adds V 3 is E 4 gets more - Type 1 = LPL deficiency - TG accumulation - **Pancreatitis** (b/c high TG) - Type 2a = LDL deficiency - Ten**D**on xanthomas - Type 2b = Type 2a + **V**LDL buildup - Type 3 = ApoE deficiency - Remnant buildup (chylo + VLDL) - **Palmar xanthoma** (hand giving \#3) - Type 4 = VLDL **[overproduction]** - Pancreatitis - High TG -\> pancreatitis - VLDL has more letters - Type 5 = type 1 + 4 Abetalipoproteinemia - Deficiency of ApoB48 and ApoB100 - No VLDL, LDL, chylomicrons -\> can't absorb fats steatorrhea, decreased fat soluble vitamins (A and E especially) - Autosomal recessive - Acanthocytes - Tx: vit E, restrict TGs