EXAM 2 PATHOLOGY 1

Hypersensitivity Reactions are…

An excessive immune response that leads to harmful host reactions rather than protection but requires a pre-sensitized state of the host!

Explain Type I Hypersensitivity

• IgE mediated: Pre-exposure to antigen causes production of IgE and binding to macrophages (sensitizing). When IgE encounters antigen again it produces massive degranulation of mast cells

  • Happens in atopic individuals

  • IL-4, IL-5, IL-10 and TNF release

  • Can cause local reactions or systemic reactions ( anaphylactic shock)

Explain Type II Hypersensitivity → examples

• IgG or IgM antibodies bind to intrinsic or extrinsic antigens

• Causes cytotoxic or non-cytotoxic reactions

• Activates complement, ADCC, Opsonization, Phagocytosis, Antibody Mediated Cellular destruction

• Examples:

  • Myasthenia gravis: antibodies bind to Ach receptors and prevent binding of Ach

  • Grave’s disease: antibodies bind to TSH receptors and cause excessive production of thyroid hormones

  • Erythroblastosis fetalis: rh- mom has rh+ fetus and produces IgG antibodies against it, then in second pregnancy it can cause the baby to have hemolytic anemia

Explain Type III Hypersensitivity → examples

• Antibody-Antigen complexes forms in circulation or at sites of antigen deposition and becomes stuck

• Causes complement activation and inflammation

• Examples:

  • Systemic lupus erythematosus

Explain Type IV Hypersensitivity → examples

• Not antibody mediated, it is T cell mediated by sensitized cells to environmental chemicals or persistent microbes

• Can be CD4+ mediated or CD8+ mediated

• Contact dermatitis, tuberculin test

• Type I diabetes: CD8+ cells kill pancreatic islet Beta cells

• Hashimoto thyroiditis: CD8+ cells kill thyroid epithelial cells

Types of grafts/transplants

• Autograft: tissue or organ is transferred from one part of the body to another in the same individual

• Isograft: tissue/organ transferred from one identical twin to the other

• Allograft: tissue/organ transferred from one individual to another on the same species with some differences in HLA

• Xenograft: tissue/organ is transferred between different species

Classification of Graft rejection

• Timeframe

• How does it happen

• Hyperacute rejections

  • Happens minutes to hours after transplantation

  • Pre-formed antibodies bind to alloantigen and activate complement as well as thrombus formation

  • Transplanted organ becomes necrotic and must be removed

• Acute rejections:

  • Happens in the first weeks or months

  • Can be mediated by T cells or antibodies

    • CD8 does direct killing while CD4+ T cells influence M and Neutrophils to kill

    • Antibodies are created after a while and activate complement

• Chronic rejection:

  • Happens months or years later

  • Mostly CD4+ mediated: find alloantigen and release cytokines that stimulate fibroblast proliferation (causes fibrosis) and vascular smooth muscle cells (causes vessel occlusion)

  • Antigens can be involved as well

How do we prevent and Treat Allograft rejection

Prior:

• Cross-Match Testing: confirm that ABO blood group of the donor and recipient are compatible

• Tissue typing: compares HLA allele matching between donor and recipient

After:

• Cyclosporine: suppresses T cell mediated immunity

• Azathioprine: antiproliferative agent

• Prednisone: anti-inflammatory steroid

Bone Marrow (BM) Transplantation

• Used for

• What must happen before BM grafting

• Used for patients with bone marrow failure syndromes, inherited blood disorders, immunodeficiencies or hematologic malignancies

  • CAN RESULT FROM DEFECTIVE BM, OR DAMAGED BM BY CHEMO OR RADIATION

• Before transplant, the host must be immunologically suppressed

Autologous vs Allogenic Transplant

• Autologous: BM is collected from host, processed, cryopreserved, host undergoes chemotherapy, then patient is infused with BM

• Allogenic: BM collected from donor, processed, host gets chemo, then BM is transplanted

Graft vs Host Disease (GVHD)

• When does it occur

• What cells cause it

• 2 types

• Occurs following allogenic BM transplants

• Caused by CD4 and CD8 cells in the graft that attack host tissues

• Types:

  • Acute affects liver skin and GI

  • Chronic causes fibrosis and atrophy in one of the previous organs AND the lungs

What are the factors associated with autoimmunity? Explain Infection

• Genetic susceptibility, Infections, Environmental insults such as UV radiation and smoking, gender (more frequent in women)

• Infections: cells that are supposed to not be activated are because the pathogen induced B7 expression on APC and activates T cell. Another way is that the pathogen can do molecular mimicry and cause a reaction to self

Systemic Lupus Erythematosus

• What kind of disease

• Pathogenesis

• What kind of antibodies have diagnostic value

• Higher incidence in

• Chronic systemic autoimmune disease

• The person will have susceptibility genes that may become activated due to encreased burden of nuclear antigens, which will cause formation of anti-nuclear antibody complexes, the b cells will detect them and create more antinuclear antibodies → BUT CAN ALSO BE ANTI PHOSPHOLIPID

  

• Anti dsDNA antibodies are associated with disease activity, prognosis and glomerulonephritis; Anti-smith antibodies are against RNP

• Higher incidence in females of childbearing age and in hispanics/african americans

Criteria for Diagnosis of Systemic Lupus Erythematosus

Skin: malar butterfly rash, discoid rash, photosensitivity

Mucosa: oral or nasopharyngeal ulcers

Serositis: pleuritis and pericarditis

Joints: arthritis is 2 or more joints

Kidney: REnal disorders (75% of cases

CNS: neurological disorder

Blood: hematologic disorders

Antibodies: high titers of anto-dsDNA or anti smith antibodies in serum

Skin and Renal Involvement of SLE

Skin

• Vacuolar degeneration of basal layer

• Edema and perivascular inflammation

• Vasculitis with fibrinoid necrosis

Renal

• Deposition of immune complexes in the kidney

Sjogren Syndrome (SS)

• What is it

• Higher incidence in

• Clinical Manifestations and what kind of hypers

• Pathogenesis

• Diagnostic criteria

• An autoimmune disease that destroys lacrimal and salivary glands

• 50-60 yo females

• Clinical Manifestations: Dry eyes, xerostomia, enlarged salivary glands, fibrosis and replacement by fat, hyperplasia obstructing ducts → Type IV hypersensitivity

• Pathogenesis:

  • CD4 T cells and B cells infiltrate lacrimal and salivary glands

  • Rheumatoid factor (anti IgG)

• Diagnostic criteria:

  • Schirmer Test: test tear production

  • Rheumatoid Factor

  • Lymphocytic infiltration in salivary glands

Systemic Sclerosis

• Incidence is higher in

• Pathogenesis

• Limited Systemic vs Diffuse

• Incidence is higher in females 25-50

• Pathogenesis: unknown etiology but it is believed genetic susceptibility and external stimuli may cause abnormal production of cytokines that increase synthesis of ECM and cause fibrosis due to excessive collagen production

• Limited : Skin involvement is confined to hands and face and visceral involvement doesn’t occur until late

  • CREST syndrome: calcinosis, raynaud phenomenon, esophageal dysfunction, sclerodactyly, telangiectasis

  • Anti centromere antibodies

    

• Diffuse: widespread skin involvement with early visceral involvement

  • antibodies against DNA topoisomerase

Bruton Disease (Agammaglobulinemia)

• Primary or secondary immunodeficiency

• Pathogenesis

• Clinical Features

• Primary

• X-linked chromosome has a mutation in Btk gene that makes B cells unable to mature, therefore you have complete lack of Ig other than IgM

• Recurrent infections due to lack of antibodies

DiGeorge Syndrome (Thymic Hypoplasia)

• Primary or secondary immunodeficiency

• Pathogenesis

• Clinical Features

• Primary

• Gene deletion causes defective embryologic development of 3rd and 4th pharyngeal pouch → thymus is underdeveloped and unavle to activate T cells

• Hypoparathyroidism, Facial abnormalities, cleft palate, heart defects, susceptible to viral and fungal infections

  

Severe Combined Immunodeficiency (SCID)

• Primary or secondary immunodeficiency

• X-linked vs Autosomal recessive Pathogenesis

• Treatment?

• Primary

• X linked: caused by mutation in IL2 receptor causes several IL to be absent, lack of IL-7 leads to absent expansion and proliferation of T AND B cells

• Autosomal Recessive: caused by mutations in adenosine deaminase gene, which then causes buildup of ATP metabolites and inhibits DNA synth, which is toxic to lymhocytes

  • This type shows the lowest counts of T cell, Nk, B cells in SCIF

• Treatment is Bone marrow transplant and sterile isolation because they are extremely susceptible to infections

Wiskott-Aldrich Syndrome (WAS)

• Primary or secondary immunodeficiency

• Pathogenesis

• Clinical Features

• Primary

• Mutation of WAS gene in X chromosome (recessive) (almost always males) cause progressive loss of T cells in blood but they are fine in BM

• Recurrent infections, thrombocytopenia, eczema, petechiae

  

HIV

• Primary or Secondary

• Transmission

• Important components of virus

• Two major targets of HIV

• Secondary

• Secual, parenteral (blood), vertical (mother to infant)

• Two copies of viral RNA, reverse transcriptase, gp120, gp41, integrase

• CD4 T cells and MAcrophages

Pathogenesis of HIV

1. gp120 of HIV binds CD4 cell through its CXCR4 receptor

2. Conformational change allows CXCR4-gp120 complex to bind CCR-5 on CD4 cell

3. gp41 is able to penetrate, HIV enters cell

4. Cytokine activation needed !!!!

5. HIV integrates into DNA and then replicates itself using the host machinery

   

• What happens to infected CD4 T cells?

• How do macrophages become reservoirs of infection?

• Infected CD4 T cells apoptose or are killed by CD8 T cells

• Macrophages become infected bt they are resistant to CD8 T cells so they accumulate in tissue

Describe Phases of HIV Infection

• Acute Phase: non-specific symptoms, viremia increases but CD8 cells attack and bring it down → 3-6 weeks after infection

• Chronic: asymptomatic phase but may have flu-like symptoms or lymphoadenopathy, virus production low because T cells are keeping it in check→ can last up to 10 years

• Crisis phase: CD$ T cell count drops below 200 and immune system severely compromised, serious risk of opportunistic infections, AIDS dementia, survival is only 3 years without treatment

  

What are some common infections AIDS patients acquire?

• Candidiasis, Pneumonia, CNS infections

• Burkitt Lymphoma

• Cervical and anal carcinomas

• Kaposi’s sarcoma (vascular tumors) → herpes

Diagnosis of HIV

• ELISA: colormetric immunosorbent assay thatputs HIV antigens with anti-HIV antibodies

  • Used as initial screening test

• Western Blot: used to detect major HIV proteins such as gp120, gp24, gp41

  • Confirmatory test

• Viral Load Test (RT-PCR): measures number of HIV RNA copies per mL of blood

  • Monitoring test to predict rate of decline of CD4 cells and progression of diseasd

• Hypoxia (decreased oxygen delivery) to specialized cells in the kidney results in increased expression and secretion of _________, which in turn increases ___ ____ ________

• Hypoxia (decreased oxygen delivery) to specialized cells in the kidney results in increased expression and secretion of erythropoietin, which in turn increases red cell production

• Anemia is a deficit in the mass of _____ ____, leading to reduced _______ delivery.

• Anemia is measured by _______ ______ or _______

• Oxygen saturation in anemia is ______ than normal, therefore the oxygen affinity ______ to help offset RBC mass deficiency

• Anemia is a deficit in the mass of circulating RBCs, leading to reduced oxygen delivery.

• Anemia is measured by hemoglobin concentration or hematocrit (RBC volume to total blood volume)

• Oxygen saturation in anemia is lower than normal, therefore the oxygen affinity decreases to help offset RBC mass deficiency

Clinical Manifestations of Anemia

• Mild to Moderate

• Severe Anemia

• Hemolytic Anemia

• Mild to Moderate: often asymptomatic but can have breathlessness (dyspnea) and fatigue upon exercise

• Severe Anemia: dyspnea and fatigue, pallor in nails, conjunctiva and buccal mucosa, tachycardia at rest

• Hemolytic Anemia: splenomegaly because too many defective RBC’s accumulate in the spleen, Jaundice

What test do you use to differentiate among anemia types such as hemolytic anemia, acute blood loss and decreased RBC production?

• Reticulocyte Count (young RBCs)

  • If reticulocytes high → hemolytic or acute blood loss

  • If reticulocyte count low → decreased RBC production

Anemia due to Blood Loss in Acute vs Chronic

• Acute: hematocrit and hemoglobin initially seem normal → THE ONLY normocytic monochromic anemia!!!

• Chronic: gradual onset until iron deficiency is developed → microcytic hypochromic

Microcytic vs. Macrocytic vs. Normocytic

• Microcytic: small red cell volume (MCV) and decreased mean red cell hemoglobin

  • Due to iron deficiency, thalassemia, Hb defect

• Macrocytic: RBCs larger than normal

  • Due to folate or B12 deficiency, hemolytic, BM failure, liver disease, alcoholism, hypothyroidism

  • Can be Megaloblastic

• Normocytic: RBCs are normal but there aren’t enough of them

  • Can be due to primary bone marrow problem such as aplasia or due to Bm replacement by leukemia, fibrosis or granulomas

Anemia due to Increased Red Cell Destruction (Hemolysis)

• Two types

• Examples

• Extravascular hemolysis

  • Increased phagocytosis of RBCs in SPLEEN

  • Causes hyperbilirubinemia, jaundice and splenomegaly

  • BETA THALASSEMIA IS EXTRAVASCULAR HEMOLYSIS!

• Intravascular hemolysis

  • Increased RBC destruction due to mechanical forces like turbulent flow OR due to biochemical agents such as immune response

  • Erythropoiesis remains efficient

Hereditary Spherocytosis (HS)

• What is it

• Clinical Manifestations

• Hemolysis is extravascular or intravascular?

• Autosomal dominant mutation of membrane SPECTRIN proteins affecting vertical connections between membrane skeleton and band3 → causes cells to lose ability to bend, they become spherical and get stuck, then macrophages eat them

• Moderate Anemia, Splenomegaly

• EXTRAVASCULAR HEMOLYSIS

Sickle Cell Anemia

• What is it

• Clinical Manifestations

• What test is required for definite Sickle Cell Anemia or Thalassemia diagnosis?

• A hereditary disease caused by a point mutation is the beta-globin gene and results in abnormal Hb (HbS(sickle))

  • Homozygous is severely affected

  • Cells undergo hemolysis or obstruct microcirculation

• Hemolytic anemia, jaundice, Ischemia

• Gel Electrophoresis

Alpha Thalassemia

• Causes

• Clinical Manifestations

• Caused by DELETIONS of one or more alpha globin genes → Severity depends on the number or genes

• Can be a silent carrier with only 1 mutation; can be all 4 genes = Hydrops Fetalis; or can be Alpha Thalassemia Trait with 3 alpha globin gene deletions and one hemoglobin BUT HAVE NO SYMPTOMS

Beta Thalassemia

• Cause

• Clinical Manifestations

• Cause

  • Beta Thalassemia MAJOR: very low or absent beta globin chains, causing the RBC to die in the bone marrow → ineffective erythropoiesis , which causes decreased hepcidin in the liver, leading to decreased intestinal iron absorption

    

• Clinical Manifestations

  • MAJOR: Hair-on-end appearance in skull, postnatal manifestation, growth retardation

    

  • INTERMEDIA: moderate severity, anemia

  • MINOR: asymptomatic

    

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

• Causes

• Clinical Manifestations

• X-linked mutation where G6PD is deficient therefore NADPH (ANTIOXIDANT) production is affected and cells undergo oxidative stress→ intravascular hemolysis → can be due to infection, fava beans, drugs

• Heinz bodies, Bite cells, intravascular hemolysis and extravascular hemolysis, anemia, splenomegaly, jaundice, hemoglobinemia, hemoglobinuria (

Iron Deficiency Anemia

• Leads to what kind of anemia

• Pathogenesis

• What is an indicator that iron storages status?

• Clinical Manifestations

• Leads to hypochromic microcytic anemia

• Pathogenesis: low iron levels cause inadequate hemoglobin production, erythroid activity increases, anemia appears once iron storage is completely depleted

• Ferritin is proportional to amount of iron

• Clinical Manifestations: Pallor, dyspnea, fatigue tachycardia, concave nail beds (spoon) (koilonychia)

  

Vitamin B12 Deficiency

• Why is it important

• Pathogenesis

• What type of anemia does it cause

• Clinical Manifestations

• Vitamin B12 comes from animal products and is required for synthesis of FH4, which is crucial for DNA synthesis

• Can be due to

  • Autoimmune attack on gastric mucosa → Pernicious anemia

  • Anti-parietal cell antibodies

  • Malabsorption

• MEGALOBLASTIC ANEMIA

• Anemia, Neurological symptoms such as demyelination of the spinal chord, malabsorption, low WBC and platelets, Pallor

Folate Deficiency

• Why is it important

• Pathogenesis

• What type of anemia does it cause

• Clinical Manifestations

• Folate is present in. fruits, vegetables, leafy greens,liver and meat, folate depletes quick because it has a small reserve, it is essential for DNA synthesis

• Pathogenesis: Suppressed DNA synthesis leads to decreased reticulocytes

• Megaloblastic Anemia

• Anemia, low WBC, low platelets, malabsorption, increased risk of neural defects during pregancy, NO NEUROLOGICAL SYMPTOMS!

Polycythemia

• What is it

• Causes

• Types

• Abnormally high number of circulating RBCs

• Types

  • Relative: due to hemoconcentration bc of loss of plasma volume → dehydration, vomiting, diarrhea, diuretic

  • Absolute: Increased total red cell mass

    • Primary: due to intrinsic abnormality of hematopoietic precursors, uncontrolled RBC proliferation independent of erythropoietin levels → often polycythemia vera aka myeloproliferative neoplasm

      

    • Secondary: due to elevated erythropoietin levels → high altitude, smoking, lung disease, cyanotic heart disease

Non-Neoplastic Disorders of WBCs

• Leukopenia: low WBC count

  • Neutropenia: low neutrophils, causes agranulocytosis

  • Lymphopenia

• Leukocytosis: elevated WBC count

  • Neutrophilic leukocytosis

  • Eosinophilic leukocytosis

  • Basophilic leukocytosis

  • Monocytosis

  • Lymphocytosis

Acute Lymphoblastic Lymphoma/Leukemia (ALL)

• What is it

• Causes

• Clinical Manifestations

• Markers for T vs B cells

• Neoplasms that cause uncontrolled proliferation of immature B and T cells (lymphocytes) → most are B cells (B-ALL) → most common cancer in children

• Caused by gene aberrations in transcription factors for B and T cell development

• Clinical Manifestations:

  • Hypercellular Bone Marrow packed with more than 20% lymphoblasts that have condensed chromatin, small nucleoli and are agranular

  • Fatigue, fever, Bleeding, Testicular enlargement, CNS manifestations, headache, vomiting, nerve palsies

• B cells have CD22, CD10 and CD19+ markers, while T cells have CD1, CD2, CD5 and CD7

Burkitt Lymphoma

• What is it

• Causes

• Types

• Histologic Patterns

• Clinical Manifestations

• Peripheral B Cell neoplasm that derives from mature peripheral cells with different degrees of maturation

• Cause: gene translocation activates oncogene and creates Philadelphia chromosome, increasing MYC protein levels

  • Can be associated with EBV

• Types: Sporadic, Endemic, Aggressive Lymphoma in individuals with HIV

• Histologic Patterns: Starry Sky

• Clinical Manifestations: Tumors in extra nodal sites → mandibular tumor or mass in ileocecum and peritoneum

Multiple Myeloma

• What is it

• Clinical Manifestations

• Plasma cell abnormality due to chromosomal abnormalities that increase their proliferation

  • Increased IL-6, IL-3 induces osteoclastic activity and increased DKK-1 suppresses osteoblast activity → leads to lytic bone lesions

    

• Clinical Manifestations: Multifocal destructive skeletal lesions such as in the vertebral column, ribs, skull, pelvis, femur, clavicle and scapula

  • Normocytic monochromic anemia

  • Renal failure: Bence Jones proteins in urine

Hodgkin Lymphoma

• What is it

• Clinical manifestation

• Neoplasm of the blood characterized by Reed-Sternberg (RS) cells → giant cells with mirror acidophilic nuclei and slightly basophilic cytoplasm

  • Usually found in a single lymph node, then it spreads

• Painless lymphadenopathy, fever, night sweats, weight loss

Acute Myeloid Leukemia (AML)

• What is it

• Histologic Pattern

• Clinical manifestations

• A Myeloproliferative neoplasm associated with radiation, chemotherapy and benzene exposure, cigarette smoking → drive by mutations that block myeloid cell differentiation (monoblasts, erythroblasts, megakaryocytes)

• Auer rods (need-like structures)

  

• Anemia, thrombocytopenia, neutropenia, gingival hyperplasia

Chronic Myeloid Leukemia (CML)

• What is it

• Clinical manifestations

• Phases

• Myeloproliferative disorder (mainly granulocytes) caused by the translocation and fusion of BCR-ABL leading to Philadelphia chromosome → leads to constitutive activity of tyrosine kinase that mimics growth factors

• Hypercellular bone marrow

• Phases

  • Chronic Phase → 3-5 years no symptoms other than elevated WBC

  • Accelerated Phase → fever, night sweats, splenomegaly, bone pain, chromosomal abnormalities

  • Blast crisis Phase → resembles AML

Define

• Ischemia

• Infarction

• Aneurysm

• Ischemic Heart Disease (IHD)

• Angina Pectoris

• Myocardial Infarction

• Ischemia: decrease in blood supply to tissues resulting in restriction and reduction of the availability o nutrients and the removal of metabolic wastes

• Infarction: area of ischemic necrosis within a tissue or organ produced by occlusion of either arterial supply or venous drainage

• Aneurysm: a localized abnormal dilation of a blood vessel of the heart

• Ischemic Heart Disease (IHD): group of syndromes caused by myocardial ischemia

• Angina Pectoris: one of the clinical syndromes of IHD, means chest pain where ischemia is not severe enough to cause infarction

• Myocardial Infarction: IHD clinical syndrome caused by ischemic necrosis of the myocardium

• 3 Types of arteries

• Constituents of the walls of blood vessels, layers

• Large elastic, Medium muscular, small

• Made of endothelium (intima), smooth muscle cells (media) and extracellular matrix (adventitia)

• Atherosclerosis

• Mockberg’s medial calcific sclerosis

• Arteriolosclerosis

• Atherosclerosis: hardening of arteries

• Mockberg’s medial calcific sclerosis; calcific deposits

• Arteriolosclerosis: hardening of arterioles

  • Hyaline

  • Hyperplastic: smooth muscle hyperplasia due to malignant hypertension → onion skin appearance

Atherosclerosis

• What is it characterized by

• Causes harm by

• Characterized by intimal lesions called atheromas, atheromatous or fibrofatty plaques which protrude and obstruct vascular lumens and weaken underlying media

• Causes harm by

  • Chronically decreasing blood supply

  • Occluding arteries suddenly by rupture of plaques

  • Weakening of walls tunica media causing atherosclerotic aneurysms

Atherosclerosis Non-Modifiable vs Controllable Factors

• Non-modifiable

  • Increasing age

  • Male sex

  • Family history

  • Genetic abnormalities

• Controllable

  • Hyperlipidemia

  • Hypertension

  • Smoking

  • Diabetes Mellitus

  • Inflammation

Hypercholesterolemia particularly due to ____ cholesterol is a major risk factor for Hyperlipidemia

______ cholesterol, in contrast, lowers the risk by mobilizing cholesterol fro, atheroma to the liver and excreting it through the bile

Hypercholesterolemia particularly due to LDL cholesterol is a major risk factor for Hyperlipidemia

HDL cholesterol, in contrast, lowers the risk by mobilizing cholesterol fro, atheroma to the liver and excreting it through the bile

Atherosclerosis Pathogenesis

1. Endothelial injury → endothelial dysfunction

2. Macrophage activation, migration of tunica media to intima

3. Fat is engulfed

4. Results in fatty core and fibrous cap

• Thin cap plaques are the most prone to plaque _____, generally leading to sudden _______ _____.

• Stable plaques can undergo surface _____ and _____, rapidly expanding the plaque size and leading to prominent _______. This event can lead to sudden ______ _____.

• Extensive narrowing of the luminal diameter drom large plaques generally results in ______ _____, reducing blood supply to the heart and resulting in _____.

• Atherosclerotic plaque develop primarily in

• The key process in atherosclerosis is ______ thickening and _____ accumulation

• Thin cap plaques are the most prone to plaque rupture, generally leading to sudden cardiac death.

• Stable plaques can undergo surface erosion and thrombosis, rapidly expanding the plaque size and leading to prominent calcifications. This event can lead to sudden cardiac death.

• Extensive narrowing of the luminal diameter from large plaques generally results in critical stenosis, reducing blood supply to the heart and resulting in angina.

• Atherosclerotic plaque develop primarily in elastic arteries and large/medium sized muscular arteries

• The key process in atherosclerosis is intimal thickening and lipid accumulation

  

• The fibrous cap is composed of

• The necrotic core consists of

• The fibrous cap is composed of macrophages, smooth muscle cells, lymphocytes

• The necrotic core consists of cellular debris, extracellular lipid with cholesterol crystals and foamy macrophages

• Ischemia not only limits tissue __________, but also reduces availability of _______ and the removal of ________ _______

• In more than 90% of cases, myocardial ischemia results from ______ _____ _____ due to obstructive atherosclerotic lesions in the epicardial coronary arteries

• In addition to coronary atherosclerosis, myocardial ischemia can be caused by:

• Ischemia not only limits tissue oxygenation, but also reduces availability of nutrients and the removal of metabolic wastes

• In more than 90% of cases, myocardial ischemia results from reduced blood flow due to obstructive atherosclerotic lesions in the epicardial coronary arteries

• In addition to coronary atherosclerosis, myocardial ischemia can be caused by: coronary emboli, myocardial vessel inflammation and vascular spasm

Angina Pectoris

• Define

• What is the pain due to

• 3 Types

• Angina Pectoris: characterized by paroxymal and usually recurrent attacks of substernal or sternal discomfort caused by transient (15 s to 15min) myocardial ischemia that is insufficient to induce myocyte necrosis

• Pain is likely a consequence of adenosine, bradykinin and other sympathetic and vagal stimulus

• 3 Types:

  • Stable/Typical: usually caused by stress, excitement, anxiety, and is due to a perfusion imbalance, improves with rest → EKG shows transient ST segment depression bc ischemia is subendocardial

  • Unstable or crescendo: increasingly frequent or severe caused by plaque → EKG shows depressed ST segment

  • Prinzmetal variant angina: episodic myocardial ischemia caused at rest by coronary artery spasm → EKG shows elevated ST segment (transmural ischemia)

What are some Causes of Myocardial Infarction?

• Coronary Artery Occlusion

• Vasospasm

• Emboli

• Due to the myocardial perfusion pattern from epicardium to endocardium, ischemia is most pronounced in the ____________, thus, irreversible injury of ischemic myocytes occurs first in the ___________ zone

• The MI is transmural when ___ than 50% of the myocardial wall is affected by the ischemic necrosis → shows ________ ST segment

• The Mi is subendocardial when ___ than 50% of the myocardial wall is affected by the ischemic necrosis → Shows _______ ST segment

• Due to the myocardial perfusion pattern from epicardium to endocardium, ischemia is most pronounced in the subendocardium, thus, irreversible injury of ischemic myocytes occurs first in thevsubendocardial zone

• The MI is transmural when more than 50% of the myocardial wall is affected by the ischemic necrosis → shows elevated ST segment

• The Mi is subendocardial when less than 50% of the myocardial wall is affected by the ischemic necrosis → Shows depressed ST segment

What are specific biomarkers used to detect myocardial damage? What is the timeline of when they are present

All present between 3-12 hours after event and continue to be elevated 7-10 days after

• Cardiac specific troponins T and I → cTnT and cTnI

• MB fraction of creatine kinase → CK-MB
  

• The most common congenital valve disorder is related to the _____ _______ valve, but it usually doe not result in _____ or ________ in early life, instead it is more prone to progressive degenerative _________ that gives rise to ______

• ________ stenosis of the aortic and mitral valves account for approximately 2/3rd of all valve disease

• The most common congenital valve disorder is related to the bicuspid aortic valve, but it usually doe not result in stenosis or incompetency in early life, instead it is more prone to progressive degenerative calcification that gives rise to stenosis

• ACQUIRED stenosis of the aortic and mitral valves account for approximately 2/3rd of all valve disease

Two Types of Degenerative Valve Disease

• Calcification/Fibrosis: cuspal or annular masses that obstruct valvular opening leading to stenosis

  • Inevitable with age

  • Most common cause of aortic stenosis

    

• Myxomatous: causes floppy valves that balloon back into left atrium

  • Uncommonly associated to Marfan syndrome (fibrilin1 mutation)

  • Midsystolic click and regurgitant murmur

Rheumatic Fever

• What causes it

• What can it progress to

• What cells and bodies are found in heart tissue affected by rheumatic fever?

• Commonly preceded by streptococcal group A pharyngitis, then CD4+ T cells attack Strep M proteins, but molecular mimicry causes T cells to confuse myocardial cells with M proteins and an autoimmune reaction occurs destroying the heart → results in pancarditis (all layers inflammed)

• Can progress to acute rheumatic carditis, where mitral valve will deform and can progress further to Rheumatic Heart Disease (leaflet thickening, fusion of tendinous chords, “fishmouth” stenosis)

• Aschoff bodies and Anitschkow cells:

Infective Endocarditis

• What is it

• Types

• A microbial infection (usually extracellular bacteria) Types of the heart valves or mural endocardium that leads to large vegetations and destruction of underlying tissue

• Types

  • Acute endocarditis: tumultuous destructive infections attacking previously normal valve

  • 10-20% caused by Strep. aureus, some because of IV drug use

  • Subacute endocarditis: slow, low virulence infections affecting previously abnormal heart valves

    • AKA pre-existing defect makes you prone to bacterial endocarditis

    • 50-60% caused by Strep Viridans

• Among the factors predisposing to endocarditis is seeding of the ______ with ________.

• The mechanism or portal of entry of the agent into the bloodstream may be an obvious _______ elsewhere, a ________ procedure that causes transient bacteremia, injection of contaminated bacteria directly to the bloodstream by _______ ___ ________.

• The most susceptible are the ____ and ____ valves although the ________ valve can be a frequent target as well for IV drug users

• Among the factors predisposing to endocarditis is seeding of the blood with microbes.

• The mechanism or portal of entry of the agent into the bloodstream may be an obvious infection elsewhere, a dental procedure that causes transient bacteremia, injection of contaminated bacteria directly to the bloodstream by intravenous drug use.

• The most susceptible are the aortic and mitral valves although the tricuspid valve can be a frequent target as well for IV drug users

Malignant Hypertension

• What is it

• Parameters

• What does it cause

• It is a rapidly rising and severe hypertension that can happen in normotensive persons but more often is superimposed on preexisting benign hypertensions

• Systolic pressure >180mmHg and diastolic pressure >120mmHg

• Renal failure, retinal hemorrhages and exudates

Essential Hypertension

• What is it

• Mechanisms/possible causes

• Consequences

• it is a hypertension that is idiopathic, that is it occurs by itself, not a consequence of another disease

• Genetic factors, environmental factors, reduced sodium excretion, vasoconstrictive influences

• Hyaline arteriosclerosis, hyperplastic arteriolosclerosis → but if left untreated it can have the same symptoms as malignant

Hyaline vs Hyperplastic arteriolosclerosis

• First damage seen in vasculature as a consequence of hypertension

• Hyaline: homogenous pink hyaline thickening, luminar narrowing → also seen in diabetics

• Hyperplastic: only in severe hypertension, the vessels become laminated with fibrinoid deposits/necrosis like an onion and the lumen narrows, mostly occurs in the kidney

Left-Sided Heart Failure

• What is it

• Most common causes

• Consequences

• Heart failure that can affect left side but eventually can lead to right side failure as well

• The most common causes are ischemic heart disease, systemic hypertension, mitral or aortic valve disease, primary myocardial disease

• The consequences are diminished systemic perfusion and elevated pulmonary circulation pressure → pulmonary congestion and edema produce heavy wet lungs, perivascular edema, edematous alveolar septa, accumulation of edema in alveolar space, cardiomegaly, NOT LOWER BODY EDEMA

Right-Sided Heart Failure and Cor Pulmonale

• Most common causes

• Consequences of Cor Pulmonale

• Most times is a consequence of left side failure but when isolated (Cor Pulmonale), it is due to disorders affecting the lungs

• Consequences include engorgement of systemic and portal venous systems, no pulmonary congestion, right ventricular hypertrophy/dilation, pulmonary embolism, lung disease of parenchyma

Aneurysm

• Define

• True vs. False aneurysm

• Due to what

• Aneurysm is a localized abnormal dilation of a blood vessel or the heart that may be congenital or acquire → weakening of underlying media

• True: the vascular wall is attenuated/weak, and it bulges out

• False: extravascular hematoma that freely communicates with intra-vascular space

• Can be due to CT abnormality like Marfan’s Syndrome or can be due to hypertension and atherosclerosis

Arterial dissection

• Define

• Causes

• Morphology

• Symptoms

• When blood enters a defect in the arterial wall and tunnels between layers

• Can be due to CT abnormality like Marfan’s Syndrome or can be due to hypertension and atherosclerosis → HYPERTENSION IS THE MAJOR RISK FACTOR!

• Double barrel appearance, absent inflammation

• Sudden excruciating pain on chest, radiating to the back and moving down

Takayasu Arteritis

• What is it

• Symptoms

• Autoimmune granulomatous inflammation of the aorta occurring in young Asian females

• Weak pulse, visual defects

Kawasaki Disease

• What is it

• It is an infectious triggered immune reaction that is delayed hypersensitivity that causes self-limited acute febrile disease in children, usually of Japanese descent

Pyogenic Granulomas

• Capillary hemangiomas present as rapidly growing red pedunculated lesions on the skin, gingival and oral mucosa

• Pregnant women

Pathological Responses of the Glomerulus to Injury

• Hypercellularity: proliferation of mesangial and endothelial cells and formation of crescents

• Basement Membrane Thickening: deposition of dense material and increased synthesis of protein

• Hyalinosis and Sclerosis: accumulation of hialine cartilage and deposition of extracellular collagenous matrix

Primary vs. Secondary Glomerular disease

• Primary: disorders in which the kidney is the only or predominant organ involved

• Primary: causes by another disease such as SLE

Nephrotic vs Nephritic Syndrome

Nephrotic: proteinuria >3.5, hypoalbuminemia <3, hyperlipidemia, edema

Nephritic: hematuria, mild proteinuria <3.5, renal failure, hypertension, smokey urine

Acute Proliferative Glomerulonephritis

• Immune complex containing streptococcal antigens form and deposit in BM

• Usually presents as nephritic syndrome with smoky urine/hematuria after strep throat

Rapidly Progressing Glomerulonephritis

• Rapid and progressive loss of renal function, severe oliguria (low urine output), poor prognosis

• Pathogenesis includes anti-GBM (glomerular basement membrane) antibodies with linear deposits of IgG and C3

• Can cause post-infection glomerulonephritis

Goodpasture Syndrome (Nephritic)

• Caused by anti-BM antibodies

• Clinical lung involvement including hemorrhage and hemoptysis precedes renal problems

Membranous Nephropathy

• Characterized by diffuse thickening of the glomerular capillary wall due to accumulation of IgG

• Chronic immune-complex mediated disease

Minimal Change Disease

• Effacement of podocytes only seen on EM

• Lipoid nephrosis or nil disease, most common nephrotic syndrome in children

Focal Segmental Glomerulosclerosis

• Epithelial damage of glomerulus characterized by hyalinosis and sclerosis

Berger Disease (IgA Nephropathy)

• IgA nephropathy caused by defective IgA (poorly glycosylated) and autoantibodies against this poorly formed IgA

• Mainly nephritic but can be nephrotic

Lesions seen in Diabetic Nephropathy

• Widespread thickening of the basement membrane

• Renal and vascular arteriolosclerosis

• Pyelonephritis (infection)

Urinary Tract Obstruction (Uropathy)

• also define hydronephrosis

• Lesions of the urinary tract cause obstruction and increase susceptibility to infection and stone formation

• Hydronephrosis is the dilation of renal pelvis and calyces due to obstruction

• In bilateral partial obstruction, what are the earliest manifestations?

• What about complete obstruction?

• Bilateral partial obstruction has inability to concentrate urine → Tubulointerstitial disorder

• Oliguria and anuria → incompatible with life

Urolithiasis (Renal Calculi)

• Form due to what

• Stones show on radiograph as…

• hypercalcemia and hypercalciuria, uric acid, cystine stones

• Radiopaque

Autosomal Dominant Polycystic Kidney Disease

• Mutations in PKD1 and 2 gene cause cysts that ultimately destroy both kidneys

• One mutation is inherited and the other one is acquired in the somatic cells of the kidney

• Small radially arranged cysts