Inflammation• Squamous cell carcinoma can arise after 3rd degree burns• Acute inflammation - neutrophils and IgM• Chronic inflammation - monocytes, macrophages, and IgG• Granulomas are type 4 hypersensitivity reaction - macrophage takes Tb

around lymph and vessels while it processes it, then presents it via class II MHC to CD4 T cells

◦ CD4 T cells release IFN-gamma and macrophage inhibitory factor▪ IFN-gamma tells macrophage to kill organism▪ macrophage inhibitory factor keeps macrophages in situ▪ macrophage makes IL-12, presenting antigen to Th1 cells to

make them into memory T cells◦ However, Tb stays alive in the granuloma and can reactivate◦ In TB test, CD1 Langerhans cells with Burbeck granules (tennis

racquets) present purified antigen to Th1 memory T cells. The memory T cells release inflammatory cytokines ---> postive test▪ HIV patient would always be neg b/c no helper T cells. In fact,

cant make granulomas so Tb goes all over body.• Renal medulla most susceptible to ischemia. Proximal tubule is most active in

reabsorption, so that is most susceptible area.• Lung repaired by type II pneumocyte• Astrocyte repairs brain.

◦ Schwannoma is tumor of Schwann cells. Assoc w/ neurofibromatosis and acoustic neuromas if in auditory canal.

• ESR - measures agglutination of RBCs by IgM◦ IgM is a cold-agglutination antibody (explains Raynaud’s

phenomenon)• Oxygen-dependent myeloperoxidase located in lysosomes in neutrophils.

Neutrophils do toxic granulation to make more lysosmes and myeloperoxidase.

Fluid and hemodynamics• Non pitting edema is either from exudate (inflammatory) or lymphedema

◦ most common lymphedema is after breast mastectomy. can cause lymphangiosarcoma.

• Pitting edema is transudate◦ Transudate in pulmonary edema from LH failure. Fluid backup causes

increased hydrostatic pressure.◦ In RH failure, increased hydrostatic pressure in veins causes edema◦ In cirrhosis, decreased oncotic pressure causes edema

• Albumin resonsible for oncotic pressure that keeps fluid in vessels◦ Can see loss in cirrhosis, 3rd degree burn, malabsorption,

Kwashiorkor, nephrotic syndrome• Histamine is Type 1 hypersensitivity • Bee sting, treat with airway management and 1:1000 epinephrine

• ⅔ of ECF is interstitial fluid, ⅓ is vascular• ⅔ of all fluid is ICF. ⅓ of is ECF.• Na and glucose limited to ECF, urea can move between ICF and ECF• Hyponatremia - water moves from ECF to ICF

◦ cerebral edema ---> mental status abnormalities◦ diliutional hyponatremia from hyperglycemia

• Hypernatremia - water moves from ICF to ECF◦ cerebral contraction ---> mental status abnormalities

• Isotonic• Hypertonic• Hypotonic

NEOPLASIA• Hamartomas - non-malignant overgrowth of tissue (i.e. bronchial hamartoma

of cartilage growth and Peutz-Jeghers syndrome)• Choristoma - normal tissue in an abnormal location• malignant cells usu. longer cell cycle• 30 doubling times = clinically detectable tumor• metastasis

◦ carcinomas (i.e. breast) - lymphatic first, then hematogenous◦ sarcoma - hematogenous

• seeding - tumor throws off pieces of itself  (ovarian --> Pouch of Douglas, peripheral lung --> pleura, glioblastoma --> spinal fluid)

• most common cancers in:◦ lung - met from breast◦ bone - met from breast (Batson’s plexus)

▪ osteolytic - multiple myeloma (plasma cells make IL1 aka osteoclast activating factor)

▪ osteoblastic - prostate ca. making alkaline phosphatase◦ liver - met from lung◦ left superclavicular LN - met from stomach◦ brain - met from lung◦ liver - met from lung◦ adrenal - met from lung

• stains◦ desmin - for muscle like embryonal rhabdomyosarcoma◦ keratin - for carcinomas◦ S100 - for neural crest tumors (small cells in lung, melanocytes)

• electron microscopy ◦ neurosecretory granules in neural crest tumor◦ Burbeck granules in histiocytosis X◦ actin and myosin in muscle

• proto-oncogenes◦ make growth factors that bind to receptors (i.e Erb2 in breast, Ret in

MEN, sis)

◦ messenger systems to nucleus, usu tyrosine kinase (i.e. Ras, Abl)◦ stimulate transcription of message (i.e. myc)

• suppressor genes - p53 and Rb keep cells in G1 phase• oncogenesis - 1) mutation, 2) replication, 3) specialization

◦ 1) mutation▪ point mutations - Ras and p53▪ amplification - Erb2▪ translocation

▪ Abl from 9 --> 22 causes Philadelphia chromosome in CML

▪ Epstein Barr virus translocates myc from 8 --> 14 in Burkitt’s lymphoma▪ virus binding to CD21 to B cells stimulates them

to divide into plasma cells --> more errors▪ t(14:18) in B cell lymphoma▪ t(15:17) in acute promyelocytic leukemia. cure with

vitamin A. • causes of cancer - chemical > viral > radiation

◦ cyclophosphamide causes transitional cell carcinoma of bladder◦ polycyclic hydrocarbons causes squamous and small cell lung cancer◦ HSV 8 causes Kaposi’s sarcoma◦ EBV causes Burkitt’s lymphoma, nasopharyngeal ca ◦ HBV + aflatoxin in rice mold causes hepatic carcinoma◦ HIV causes primary CNS lymphoma◦ HPV causes squamous carcinoma of cervix, vagina, or anus

▪ E6 inhibits p53 and E7 inhibits Rb◦ radiation causes CML, thryoid adenoma, osteogenic sarcoma◦ UVB light causes basal cell carcinoma by making thymidine dimers◦ Rb mutation from chromosome 13. see “white eyed” reflex◦ helicobacter pylori causes adenocarcinoma and malignant lymphoma◦ xeroderma pigmentosum - defective DNA repair

• CD8 cytotoxic T cells recognize altered Class I MHC and stimulate apoptosis• cachexia due to TNF-alpha• malignancies lead to hypercoaguable state; can observe migratory

thrombophlebitis• malignancies can elevate platelet count• paraneoplastic syndromes

◦ hypercalcemia - tumor makes PTHrp◦ acanthosis nigricans - assoc w/ gastric adenocarcinoma◦ clubbing (hypertrophic osteoarthropathy) - assoc w/ primary lung

cancer◦ heliotrope rash + elevated serum CK - dermatomyositis from leukemia◦ mitral valve vegetations (marantic endocarditis) - assoc w/ colon

cancers◦ hyponatremia or Cushing’s - small cell carcinoma of lung (SIADH or

ACTH)

◦ hypercalcemia or 2* polycythemia  - renal adenocarcinoma (PTHrp or EPO)

◦ hypoglycemia or 2* polycythemia - HCC (insulin or EPO)◦ hypocalcemia or Cushing’s - medullary thyroid carcinoma (calcitonin

or ACTH)• tumor markers

◦ alpha fetoproten▪ high - yolk sac tumor, hepatocellular carcinoma, open neural

tube defects▪ low - Down syndrome

◦ Ig-light chain is high in multiple myeloma◦ CA125 high for ovarian cancer◦ CEA high for colon cancer, making immune complex and causing

nephrosis◦ beta HCG for hyatidiform mole

• childhood cancers◦ cerebellar cystic astrocytoma most common primary brain tumor◦ medulloblastoma most common brain malignancy◦ ALL most common malignancy◦ Ewing’s sarcoma, embryonal rhabdomyosarcoma

• adult cancers◦ most common in women - breast > lung > colon◦ most common in men - prostate > lung > colon◦ most common GYN cancer - endometrial > ovarian > cervical◦ GYN killers - ovarian > cervical > endometrial◦ HCC is only cancer preventable with vaccine (HBV)

HEMATOLOGY• microcytic anemia (avg MCV < 80) - iron def causing GI bleed (abs in

duodenum) thalassemias, sideroblastic anemia, anemia of chronic disease• macrocytic anemias (avg MCV > 100) - B12 (ileum) and folate (jejunum) def• normocytic anemias

◦ low corrected retic count - aplastic anemia, renal dz◦ high corrected retic count - hemolytic anemias (spherocytosis, sickle

cell, G6PD deficiency, AI)• corrected retic count aka reticulocyte production index = retic count (%) x

Hct/45◦ 45 is normal Hct◦ then divide by 2 if there is polychromasia:

• 3 x Hgb should = Hct• every unit of packed RBCs should increase Hgb by 1 and Hct by 3. if not --> GI

bleed from iron def• Complete blood count

◦ MCV◦ RDW (red cell distribution width) ◦ WBC count◦ PLT count

• spherocytes (too little membrane) • target cells (too much membrane) present in alcoholism and

hemoglobinopathies• hypochromic cells in microcytic anemia b/c not enough hemoglobin• B12 or folate deficiency - can’t make dNTP or DNA. nucleus can’t condense --

> megaloblastic anemia

◦ B12/cobalamin removes methyl from methyltetrahydrofolate and adds it to homocysteine. Homocysteine is now methionine, a 1-carbon donor.

◦ Homocysteine high in folate or B12 def◦ Homocysteine causes thromboses◦ B12/Cobalamin also removes 1 C from propionyl coA -->

methylmalonyl coA --> succinyl coA

▪ methylmalonate high in B12 deficiency▪ propioinyl coA block myelin synthesis --> DEMENTIA, dorsal

column, and lat CST problems.▪ treating B12 def with folate cures anemia but NOT neuro Sx▪ B12 bound by R factor in mouth, cleaved off in duodenum by

panc enzymes. Then B12 binds intrisinsic factor in duodenum. Reabs by terminal ileum (where Crohn’s hits)

◦ pernicious anemia - AI destroys parietal cells and surrounding area --> atrophic gastritis, achlorhydria, B12 deficiency

◦ B12 deficiency seen in vegans, alcoholics (can’t cleave off R factor), bacterial overgrowth (eat B12), Crohn’s (hits terminal ileum)

◦ Folate converted to monoglutamate form by intestinal conjugase (phenytoin blocks conjugase). Abs in jejunum. Absorption blocked by OCPs and alcoholism.▪ Hypersegmented neutrophils in B12 or folate def

◦ Schilling’s test localizes B12 def▪ 1. Give radio-B12 orally. None comes out in urine --> not

reabsorbing B12▪ 2. Give radio-B12 + IF. If B12 in urine --> pernicious anemia▪ 3. Give 10 days of ABX. Repeat radio-B12. If B12 in urine -->

bac overgrowth▪ 4. Give radio-B12 + pancreas factor. If B12 in urine -->

pancreatitis• Normocytic anemia + corrected retic count < 2% = early iron def, anemia of

chronic disease, mild blood loss, aplastic anemia (worry about Hep C causing pancytopenia), only anemia (parvovirus), renal failure (no EPO)

• Normocytic anemia + corrected retic count > 3%◦ Intravascular hemolysis - IgM binds, activates complement-mediated

killing of RBC. Hemoglobin released in blood ---> hemoglobinuria + dec. haptoglobin▪ G6PD-def - X-linked recessive. G6PD in PPP makes NADPH and

GSH▪ primaquine and dapsone cause oxidative stress,

reducing GSH levels --> hemolytic anemia

▪ infxn causes cells to use NADPH i+ NADPH oxidase in oxygen-dependent MPO system ---> ppt hemolytic anemia

▪ to diagnose during hemolytic episode --> Heinz stain ▪ to diagnose after hemolytic episode --> G6PD assay

▪ microangiopathic anemia - RBCs hit calcified aortic valve or fibrin (in DIC), become fragmented schistocytes▪ can then cause iron def anemia

◦ Extravascular hemolysis - Mps in spleen or liver destroy IgG or C3b bound RBCs, and altered shape RBCs (shperocytes, Sickle cells). Mp breaks RBC down into unconjugated bilirubin, spits it out into blood, bound by albumin, then carried to liver and conjugated ---> jaundice, but not in urine b/c bilirubin is lipid soluble▪ spherocytosis - autosomal dom def of spectrin. tx with

splenectomy▪ Sickle cell dz - auto recessive. anemia + vaso-occlusive disease

when sickle cells occlude small vessels▪ spleens die (Howell-Jolly bodies not removed), then

Strep. pneumoniae sepsis occurs

▪ b/c no splenic Mps, Salmonella osteomyelitis occurs▪ hydroxyurea increases HgbF

◦ Most common cause of autoimmune hemolytic anemia▪ 1) lupus - IgG and C3b on RBCs

▪ test with direct Coomb’s to test for Ab on RBC▪ not indirect Coomb’s (detects Abs in serum)

▪ 2) drugs▪ penicillin - attaches to RBC and IgG antibody can attack

it (Type II)▪ methyldopa - alters Rh antigens, IgGs can attack Rh

antigens (Type II)▪ hydralazine - causes drug-induced lupus

▪ quinidine - IgM binds drug and makes immune complex (Type III). IgM can then bind RBC and activate complement

◦ decay accelerating factor deficiency - complement deposits on blood cells --> paroxysmal nocturnal hemoglobinuria

• Infectious mononucleosis - causes activated atypical T cells attacking EBV-infected B cells

◦ Heterophile antibodies in serum specific for mono• Causes of eosinophilia: Type I hypersenstivity, neoplasia, asthma, collagen

vascular dz, invasive helminths• Polycythemia - increased RBC count (not mass), Hgb and Hct

Relative – decreased plasma volume concentrates RBCs inc RBC count Absolute - actual increase in RBC number Approriate – compensating for tissue hypoxia from altitude, lung dz, or

COPD Inappropriate – not compensating;

o polycythemia rubrovera are neoplastic stem cells. “Four Hs” hyperviscosity – increased TPR and thromboses (cause of

death) hypervolemia – only myelodyspastic syndrome with

hypervolemia histaminemia – from increased mast cells. Manifests as

generalized itching. Hyperuricemia – increased cell turnover produces more

purines more uric acido ectopic EPO synthesis from kidney tumor

Leukemia – tumor of HSCs. Hepatosplenomegaly. Blasts in blood. Always anemia b/c HSCs crowd out normal RBCs. If blasts <30% of bone marrow chronic. If blasts > 30% of bone marrow acute 0-14 yrs = ALL (CD10+ B cell leukemias) 15-39 yrs = AML (myeloblast with Auer rod)

40-59 yrs = AML and CMLo CML has Philadelphia chromosome - t(9:22) making Bcr-abl gene

60 + = CLL (most common cause of generalized lymphadenopathy in 60+ patient)

o B cell leukemia, so no plasma cells (hypogammaglobulinemia)o Die of infxn

Hairy cell leukemia – dx with tartrate resistant acid phosphatase

Acute progranulocytic leukemia – A LOT of Auer rods, even outside of cell:

o Always have DICo T(15:17)o Treat with retinoic acid, which forces blasts to mature

Extramedullary hematopoesis in agnogenic myeloid metaplasia – hematopoesis shifts to spleen. Meanwhile, Mp cause fibrosis in bone marrow.

o Tear drop cells are RBCs that travel through fibrosed bone marrow on way to blood:

Lymphadenopathyo Brutons agammaglobulinemia – no germinal follicleso DiGeorge syndrome – no paracortexo Follicular B cell lymphoma – monotonous cells in lymph node;

t(14:18). Most common primary cancer of LN. Most common cancer is metastasis.

o Burkitt’s lymphoma – t(8:14) of c-myc oncogeneo Histiocytosis X – gen LAD, HSM. Langerhans cell shows Burbeck

granules on EM:

o Hodgkin’s disease – MC form is ‘nodular sclerosing’o Typically woman with mediastinal LN + 1 more above diaphragmo Reed-Sternberg cell is malignant cell:

Polyclonal gammopathy – IgG is antibody assoc w/ chronic inflammation. Made by benign plasma cells.

Monoclonal gammopathy – 1 malignant IgG plasma clone suppresses other plasma cells. See an “M-spike”. Multiple myeloma. Cells make IL-1 (osteoclast-activating factor) lytic lesions. Plasma cells with bright blue cytoplasm and eccentric nuclei.

Amyloidosis – Trisomy 21 pts make more beta amyloid (toxic senile placques to neurons), getting Alzheimer’s ~ 40 y/o.

Gaucher’s disease – Mp lysosomes fill with glucocerebroside because deficient in glucocerebrosidase. Cytoplasm looks wrinkly.

Niemann Pick disease – pt with severe MR and sphingolipid in lysosomes. Mp looks “bubbly”:

Why don’t we form clots?o Glysoaminoglycans (i.e. heparin) enhance anti-thrombin 3

Anti-thrombin 3 inactivates serine proteaseso PGI2 is vasodilator made by endothelial cellso Protein C and S – Vit K dependent, inactivate V and VIIIo Tissue plasminogen activator – activates plasmin

Estrogen antagonizes anti-thrombin 3 thrombi! How do we stop bleeding?

o Bleeding time test – measures platelet function 1. Cut skin activates tissue thromboplastin, exposes collagen

(activates XII) and Von Willebrand’s factor in endothelial cell. Platelets adhere to VWF.

2. Platelets release ADP after sticking 3. Platelets then make thromboxane A2, which:

o vasoconstrictso bronchoconstrictso aggregates platelets and fibrinogen, completing platelet

plug. Abnl bleeding time – thrombocytopenia, von Willebrand’s dz, aspirin

(irreversibly) and NSAIDs (reversible)