pathopharm/phys exam 1

pathophysiology

intersection between physiology and pathology, studying abnormalities in physiologic functioning in living beings

pathology

study/diagnosis of disease/abnormalities through examination of organs, tissues, cells, and bodily fluids

physiology

study of mechanical, physical, and biochemical function of organisms

pathogenesis

development and evolution of disease —> from initial stage —> ultimate expression of the manifestations of disease

Concept of Normality in Health

• Normal = within expected range

• based upon references (i.e. patients BP normally ~120/80) that’s influenced by individual characteristics (i.e. age, lifestyle, business)

• abnormality does not meanillness

• disease disrupts normal functioning

• context is critical to assess

Stages and Clinical Course

• Latent period

  • Prodromal symptoms

• Acute phase

  • Chronic Disease

• silent/latent period

• subclinical stage

Latent Stage

Interval between initial contact with injurious agent and first appearance of signs and symptoms

• infectious disease have incubation period

Prodromal Symptoms

• non-specific symptoms

  • headaches

  • malaise

  • severity

Acute phase

disease reaches full intensity —> signs and symptoms gain the greatest severity

• acute conditions: severe manifestations but short course

Chronic disease

Processes can have acute phase but be prolonged when the body’s defenses cannot overcome the causative agent or stressor

• cases can develop insidiously (gradual and silent —> causes harm before noticing) and not have an acute phase

Silent/Latent period

signs and symptoms become mild or disappear

• Ex: Syphilis has two latent periods between primary and secondary clinical stages and the other occurring between secondary and tertiary stages

Subclinical Stage

Patient functions normally although diseases process is established

• structure and function of organs provide a large reserve or safety margin for function impairment can only become evident when the damage is completely destroyed

  • ex. chronic renal disease capability of destroying kidneys before manifestation

Exacerbation

Sudden increase in severity of signs and symptoms

remission

abatement/decline in severity of signs and symptoms

• if longer than 5 years considered permanent/cured

convalesence

stage of recovery post disease, injury, or surgical operation

• sequela: disease produces subsequent pathologic conditions

  • i.e. sequel of inflammatory process being scarring

• complication: separate process that arises secondarily bc of change produced by original problem

  • bacterial pneumonia is a complication of a viral infection

Levels of prevention

• primary: reduce causative risk for susceptible individuals

  • encouraging exercise and healthy eating to avoid becoming overweight

• secondary: early indentification/detection, screening, and management of disease before being symptomatic

  • i.e. checking bmi at every wellness to identify individuals who are overweight

• tertiary: rehabilitation, supportive care, reducing disability, and restoring effective functioning when disease already established

  • i.e. helping obese individuals lose weight to prevent more severe consequences

homeostasis

maintaining internal conditions in a stable state by keeping parameters the same

• tendency to stabilize organisms normal function despite changes internally and externally

• negative feedback loops = sense and correct deviations from set-points to support survival of individuals

Allostasis

• ability to successfully adapt to challenges → body has to vary internal parameters and match to environmental demands

  • Example: respiratory rate increase when exercise or when ill w/ pneumonia for more oxygen

  • Useful changes in one body system may be detrimental to another if prolonged → changes are needed to support survival at point of time

    • I.e. when in shock, blood flow is essential to organs and is maintained by the perfusion to kidney, skin, and gastrointestinal tract, so body is not concerned about digesting dinner or making urine when diverting resources to brain and heart

Stress

•  tension in the body or mind → can be physical and/or mental state → threat to homeostasis

  • Stressor: any variable that throws body out of allostatic balance

  • Stress response: body response to try and restore balance → can become damaging when repeatedly activated 

General Adaptation Syndrome

model of how the body responds to any stressor - physical or emotional either good or bad

• alarm —> resistance —> exhaustion

Alarm

fight or flight response” – two hormonal cascades happen at the same time

• Fast Pathway (SNS) → hypothalamus → release cryptocopropin-releasing hormone (CRH) → activate sympathetic nervous system → adrenal medulla release epinephrine and norepinephrine (catecholamines)

  • Immediate jolt response (racing heart, alertness)

• Slower pathway (HPA Axis) → hypothalamus → CRH → anterior pituitary gland → adrenocorticotropic hormone (ACTH) → adrenal cortex release cortisol

  • Follow up hormone surge → sustains response (cortisol)

• ***hypothalamus → pituitary gland → adrenal = HPA axis. CRH starts. ACTH continues as cortisol is end product

Resistance

prolonged alarm stage = body damage = shifts to managing to stress-long term 

• Cortisol + catecholamines (i.e. epinephrine and norepinephrine) mobilize glucose, free fatty acids, and amino acids as fuel for metabolically active organs 

• Amino acids also acts building blocks for repair for stressors

• If stressor resolves → body returns to allostatic balance 

  • New normal does not have to match old normal, COPD patient will not have same oxygen saturation as normal individual

Exhaustion

• body no longer able to return to homeostasis after prolonged exposure to noxious agents 

  • Selye’s idea: finite amount of “adaptation energy” → death occurs once over

  • Stress response itself is damaging over time

Hypoxia

body tissues and organs fail to retrieve oxygen to function properly

Reversible Cell Injury

Mild, short-lived — withstand assault and completely return to baseline/normal

Hydropic swelling

Cellular swelling to accumulation of water - reversible

• result of malfunction sodium-potassium pump maintaining ionic equilibrium —> osmotic gradient for water entry due to accumulation of sodium ion

Intracellular Accumulations

Excessive accumulation of substances in cells

• can be normal intracellular substances like fat or abnormal substances produced by cells due to faulty metabolism/synthesis

• accumulation of pigment + particles that cells cannot degrade

Cellular adaptation

persistent sublethal injury —> cause adaptation via structure or function, reversible

atrophy

cells shrink and reduce their differentiated functions in response to variety of normal or injurous factors

disuse

atrophy —→ reduction in functional demand

• i.e. immobilization via bed rest = shrinkage of skeletal muscle cells

denervation

atrophy —> decrease in muscle size due to loss of nervous stimulation

ischemia

atrophy —> inadequate blood supply to tissue, if blood supply cut all cells with die

• sublethal ischemia = cell atrophy

• heart, brain, kidneys, and lower legs

nutrient starvation

atrophy —> result of poor intake, absorption, or distribution of tissues

interruption of endocrine signals

atrophy - glandular tissues throughout body depend on growth-stimulating (trophic) signals to maintain size and function

• adrenal cortex, thyroid, and gonads will atrophy w/o trophic signals

persistent cell injury

atropy —> result from persistent cell injury, chronic inflammation and infection

hypertrophy

increase in cell mass/bigger accompanied by augmented functional capacity —> affected by physiological or pathophysiologic demands —> cell enlargement results from net increase in cellular protein content

• reversible —> structural tissue unchanged

• organ enlargement from hypertrophy and hyperplasia

• notable —> increase in skeletal muscle mass + muscle stem cells dividing

• physiologic hypertrophy

  • trophic hormones

  • i.e. sex hormone cause breast and uterus to change

• pathophysiologic hypertrophy

  • abnormal stress, enlargement as a maladaptive response

  • i.e. liver enlargement due to bodily toxins, cardiac muscle enlargement to high blood pressure

• hypertrophic adaptation is particularly important for cells that are unable to undergo mitotic division

hyperplasia

cells capable of mitotic division increase functional capacity by increasing # of cells

• result from increased physiologic demand or hormonal stimulation

  • estrogen —> increase in number of endometrial and uterine stomal cells

• persistent cell injury = hyperplasia

  • epithelial cell irritation, chronic frictional injury —> callouses

  • epithelium of bladder becomes hyperplastic in response to chronic inflammation of cystitis

metaplasia

replacement of one differentiated cell type with another —> adapting to persistent injury w/ replacement cell types better able to tolerate injurous stimulation

• reversible when injurious stimulus removed

• ex. chronic irritation of bronchial mucosa via smoke converts ciliated columnar epithelium to stratified squamous epithelium

• metaplastic cells are well differentiated but cancerous transformations may occur

dysplasia

disorganized appearance of cells due to abnormal variations in size, shape, and arrangement

• risk for cancerous cells —> i.e. preneoplastic legions

• common in hyperplastic squamous epithelium

• reversible if cause is removed

irreversible cell injury

too severe or prolonged to allow adaptation or repair

necrosis

cell death from external injury —> pathologic and associated with significant tissue dmg

• Consequence of ischemia or toxic injury → cell rupture → contents in ETC → inflammation

• Shrunken (pyknotic) nucleus that is subsequently degraded (karyolysis), a swollen cell volume, dispersed ribosomes and disrupted plasma and organelle membranes

Coagulative necrosis

•  ischemia → loss of plasma membrane to maintain electrochemical gradients → influx of calcium ions and mitochondrial dysfunction → ends w/ degradation

dry gangrene

•  coagulative necrosis characterized by blackened, dry, wrinkled tissue separated from adjacent healthy tissue by an obvious line of demarcation

liquefactive

• dissolution of dead cells. Liquefied area of lysosomal enzymes result in abscesses or cysts form dissolved dead tissue

  • Rich in degradative enzymes + supportive of connective tissue

  • Bacterial infection triggers localized collection of WBCS 

  • Wet gangrene: appears cold and black in internal organs, foul-smleling bc of invasion of bacteria → can spread tissue dmg + release toxins into bloodstream

fat necrosis

• death of adipose tissues

  • Trauma or pancreatitis → release of activated digestive enzymes from pancreas or injured tissue 

caseous

lung damage due to tuberculosis —> clumpy cheese

apoptosis

• intracellular cascades that result in regulated cell death → ingested by neighboring cells w/ minimal disruption of tissue. 

  • Non-inflammatory, normal physiologic process in some and pathologic in others

tissue hypoxia

•  lack of oxygen to organs

  •  caused by ischemia (lack of blood supply to area)

ischemia

• Interruption of blood flow to area

• Common cause of cell injury

• Cellular damage occurs after blood supply is restored (reperfusion injury)

ischemia-reperfusion injury

• Calcium overload

• Formation of reactive oxygen molecules (free radicals)

• Subsequent inflammation

bacteria

• Most dmg cells from outside

• Single-celled, rigid wall organisms w/o internal organelles

• Characterized by 

  • Shape (cocci, rods, spirals)

  • Reaction to stain (gram negative, gram positive, acid fast)

  • Oxygen requirements (aerobic, anaerobic)

Viruses

• Dmg cells from inside

• Small genetic material (DNA, RNA) associated w/ proteins and lipids

• Intracellular pathogens use host energy and enzymes to replicate

• Viral replicate can/cannot destroy cell

• DNA virus may incorporate into host genome

• RNA virus serve as template for production of viral RNA and proteins

neoplasia

abnormal cell growth = tumor

• Two categories: Malignant and Benign

• Malignant neoplasm is cancer

• Cancer = altered cellular genes

• Malignant = months of intensive treatment with u

benign tumors

• No potential to kill host → can be in life-threatening location

• Resembles original tissue type

• Does not invade adjacent tissue or spread

• Grows slowly

• Little vascularity

• Rarely necrotic

• Often retain function

• Encapsulated

malignant tumors

• Can kill the host if untreated → benign tumors cannot

• Grows rapidly

• Vessel growth in tumor 

• Necrotic areas

• Dysfunctional

• Tissue-specific differentiation

  • Greater degree of anaplasia indicates aggressive malignancy

  • (anaplasia → lack of differentiated cancer cells)

• Confirmed by invasive or metastasizing nature

patterns of spread

metastasis: cancer cell leaves original (primary) tumor —→ travels to another part of body to form new tumor

• spread through blood (hematogenous spread)

  • primary tumor —> blood stream —> distant organ —> new tumor

  • cancer cells that enter blood do not survive

    • immune cells destroys them

    • undergo apoptosis’

    • need to attach to suitable tissue/matrix to survive

  • how do they travel to organs?

    • travel along normal circulation - i.e. colon cancer spreading to liver bc blood from intestines travel thru portal vein of liver

    • homing - cancer cells attracted to certain organs via chemostatic signals

      • integrins and cell adhesion molecules

• spread through lymphatic system

  • primary tumor —> nearby lymph node —> next lymph node —> next lymph node

  • predictable

  • cancer cells enter lymphatic vessels near original tumor (spreads to lymph node that drains lymph node where tumor is located)

  • Hodgkin’s lymphoma

leukopenia

deficiency in circulating white blood cells —> reduces ability to fight infection

• primary cause: malignant invasion of bone marrow

• contributing factors

  • malnutrition

  • chemotherapy

• opportunistic organisms only infect immunocompromised host

neutropenia

lower-than-normal levels of neutrophils in blood

• neutrophil = WBC that help fights infections

• increased risk of infection

• causes

  • chemotherapy —> damages bone marrow where neutrophils are made

  • radiation therapy

  • certain medications

  • bone marrow disorders

thrombocytopenia

• deficiency in circulating platelets

  • important mediator in blood clotting

  • predispose to life-threatening hemorrhage, esp if count is below 20,000/mm3

• anemia, leukopenia, thrombocytopenia all managed by blood replacement therapy

Cancer Therapy

early detection is best prognosis for cure

• mainstays of therapy

  • surgery

  • radiation therapy

  • chemotherapy

• emerging therapies

  • immunotherapy

  • molecular/targeted therapy

  • gene therapy

  • stem cell transplantation

Infectious process

• pathogen: disease causing microorganism —> body multiply, spread —> tissue damage

Infection

• subclinical (no symptoms) or clinicals (symptomatic)

• can remain localized (wound infection) or become systemic (sepsis)

• requires presence of pathogen + host response

Infectious disease

• symptomatic and clinically apparent

• communicable disease spread person-to-person

• example: tuberculosis, influenza, COVID-19, sexually infections (STIs)

Hospital Acquired Infections (HAIS)

• occurs in healthcare facilities —> hospitals, nursing homes, doctor’s offices, and dental offices

• result of contact by healthcare personnel —> bacterial, viral, or fungal pathogens

• safety issue by joint commission

• rising costs and public awareness increase importance of prevention

• patients are at risk

• 3 key vulnerability

  • lower resistance to pathogens (compromised immune systems)

  • increased exposure to pathogens (some antibiotic-resistance)

  • invasive procedures (break natural defense barriers)

transmission of infection

routes: direct and indirect

direct transmission

• exchange of bodily fluids —> kissing or sexual intercourse

• bite from animal/contaminated soil

• placenta (vertical transmission)

  • ex. HIV transmitted through feces

indirect transmission

• vehicle-borne transfer: infectious agent transported to host

  • vehicles = food, water, clothing, plasma, or tissues

• airborne transmission: occurs due to aerosols which can be carried greater distances from source of transmission

  • measles, COVID-19, and Legionnare’s disease

• Vector-borne transmission: mechanical transfer occurs when insect carries infectious agent on its feet or proboscis

  • not required multiplication or development before transfer

  • biological vector borne transport = agent propagates and there is cyclic development before arthropod can transmit disease

Emerging infectious diseases

• Pathogens spread faster in greater numbers bc of global transport networks

• Ex. coronavirus, ebola, zika

Weapons of Bioterrorism

• Bioterrorism fortification

• Reducing risk of exposure

• Improving public health surveillance

Chains of transmission

• reservoir (humans, animals, insects, soil) —> portal of exit (nasal or oral mucosa) —> mode of transmission (insect bites, nasal droplets, semen) —> portral of entry (nasal mucosa, oral mucosa, skin abrasion, skin puncture) —> susceptible victim (malnourished, unimmunized, immune compromised)

Breaking the chain

• Destroy reservoir →  mosquito eradication, garbage disposal, sewage treatment

• Blocking portal of exit → PPE, condom usage

• blocking mode of transmission → PPE, isolation, hand wash, cooking

• Blocking portal of entry → PPE, condom usage

• Reduce susceptibility → vaccination, optimal rest, optimal nutrition

anaerobic vs aerobic

• Aerobic: needs oxygen to grow/survive

• Anaerobic: doesn’t need oxygen

active immunity

body makes antibodies

• natural active: infection —> body fights infection —> body makes own antibodies

• artificial active: receive vaccine —> immune system responds —> body develops antibodies and memory cells

passive immunity

body receives antibodies

• natural passive: mother t baby

  • antibodies crossed through placenta

  • antibodies can be passed through breast milk

• artificial passive: receive performed antibodies

• passive immunity does not create lasing immune memory

Hypersensitivity

• normal immune response that is either

  • Inappropriately triggered, excessive, and produces undesirable effects on body

  • Four types:

    • Types I, II, and III mediated by antibodies

    • Type IV is T cell-mediated

  • Reactions specific to particular antigen

Type 1 Hypersensitivity

Allergic reaction

• etiology: strong genetic or hereditary linkage regarding IgE response to antigens

• pathogenesis: immediate hypersensitivity —> reaction is immediate

• clinical manifestations

  • mild → hives, seasonal allergic rhinitis, eczema

  • More problematic → throat constriction, localized edema, wheezing, tachycardia

  • Anaphylaxis → life-threatening reaction, occurs in small number of highly allergic individuals

  • Treatment

    • Antihistamines: block effect of histamine

    • Beta-adrenergics: decrease bronchoconstrictions and bronchospasms

    • Corticosteroids: decrease inflammatory response

    • Anticholinergics: block parasympathetic system

    • Anti-IgE therapy: inhibits binding of IgE to mast ccells

    • Epinephrine: adrenergic agent given to IM, subQ, or IV during acute allergic reactions. Highly allergic individuals carry an EpiPen

Type II Hypersensitivity

tissue-specific, cytotoxic, or cytolytic hypersensitivity

• immediate reaction, can occur over some time

• antibodies attack antigens on surface of specific cells causing lysis

• Cell lysis mediated by activated complement fragments (membrane attack complex)

• transfusion reaction

  • individuals receiving blood from someone with different blood group type

  • recipient antibodies attach to the donor’s red blood cell antigens

Type III Hypersensitivity

immune complex reaction

• immune and phagocytic systems fail to remove antigen-antibody immune complexes

• not tissue specific and not an immediate reaction

• possible etiologies

  • recent infection or persistent low-grade infections

  • extrinsic environmental antigen from molds, plants, or animals

  • autoimmune process

• Mechanisms of injury

  • tissue injury = inflammatory rection

  • activation of complement —> mediator

  • phagocytic cells —> attracted to tissue

• Pathogenesis

  • antigen form antigen-antibody complex —> precipitate out of blood or body fluid to tissues

  • immune complex not removed —> inflammatory process

  • activation of classic complement cascade → release C3a, C5a → cause tissue destruction, scarring, and further reaction

  • Antigen-antibody complex → out of blood and to tissue → cause inflammatory process → activate classic complement cascade → tissue destruction

Type IV Hypersensitivity

delayed hypersensitivity → damage resulting from delayed cellular reaction to an antigen

• no primary antibody involvement

• principle mediators → lymhocytes

  • Examples:

    • Type Iva - granulomatous hypersensitivity

    • Type IVa - tuberculin-type hypersensitivity

    • Type IVa - Allergic contact dermatitis

    • Type IVb - persistent asthma

    • Type IVc - stevens johnson syndrome and toxic epidermal necrolysis

    • Type IVd - Pustular Psoriasis

Hodgkin’s Lymphoma

malignant disorder of lymph nodes caused by Reed-Sternberg cells

• Reed-sternberg cells: originate from B cells in germinal center of lymph nodes

  • grow and spread predictably

• B cell → undergo mutation → malignant Reed-Sternberg cells → clonal growth

  • all malignant cells come from one abnormal cell

• Begin in one lymph node and metastasizes along continuous lymphatic pathways → predictable from one lymph node to nearby nodes to distant lymphatic tissue

• late disease → invade blood vessels → hematogenous dissemination → widespread

• Clinical Manifestations

  • early = asymptomatic

  • classic presentation = painless lymphadenopathy = enlarge, painless, lymph nodes

    • common above diaphragm → cervical, supraclavicular, axillary, mediastinal

    • possible systemic symptoms: fever, night sweats, itching, weight loss, malaise

    • cannot involve spleen and bone marrow

• diagnosis:

  • painless lymphadenopathy (painless enlarged lymph nodes) → lymph node biopsy → histologic examination → Reed-Sternberg cells identified →staging test to determine reach of cancer

Multiple Myeloma

malignant disorder of mature, antibody-secreting B lymphomas (plasma cells)

• B lymphocytes → plasma cells → instead of produce antibodies, multiply uncontrollably → cancer

• malignant plasma cell invades bone and multiple tumor sites

• occurs in older pop — older than 40 years

• Men > women

• cancerous plasma cell = one original abnormal cell→ clones

  • all copy same cancerous cell = same antibody

• Problem 1 - Premalignant stage: excess production of monoclonal antibodies → no evidence of bone lesions or Bence Jones protein

  • Affected individuals remain asymptomatic until disease is advanced → subclinical

  • Diagnosis occurs during asymptomatic phase bc protein in urine or high serum calcium levels

  • First symptom: bone pain

• Problem 2 - Bence Jones Protein: light chains from antibodies of cancerous plasma cells

  • accumulate in kidneys and cause damage

• Problem 3 - increased osteoclast activity: cancerous plasma cell accumulate in bone marrow/bone → increase activity of osteoclast

  • osteoclast break down bone = bone lesions/destruction

  • bone = weaker = bone pain, pathologic fracture, compression fracture

• problem 4 - hypercalcemia: osteoclast activity → bone destruction → calcium released fromb one into blood

  • kidney problem

• problem 5 - anemia

  • bone marrow produce RBCs, platelets, WBCs

  • if cancerous plasma cell takes up space → normal blood cell production is crowded out

  • Less RBCs = Anemia

  • Less WBCs = increased risk of infection risk

  • Less platelets = incresaed bleeding risk

HIV and AIDS

acquired immunodeficiency disorders

• hallmark is the decrease in CD4+ and helper T cells

  • help mediate antigen presenting cells and other cells

  • therefore = weakening of immune system

AIDS

• Chronic disease caused by the diseases and disorders that decrease T-helper cells —> loss of immune

• leaves host susceptible to secondary infections

• develops over period of time —> continuous destruction of immune system

transmission

• Sexual

• Parenteral: transmission through blood or direct entry into bloodstream

  • Contaminated needles

• Perinatal: mother to infant

  • In utero

  • During delivery (intrapartum)

  • breastfeeding

epidemiology

retroviruses HIV type 1 and HIV type 2 

- HIV-1  

- HIV-2 

- longer clinical latency period 

- from onset of infection to development of symptoms 

- slower progression rate 

- Higher CD4 counts 

- lower plasma HIV-2 RNA viral load 

- dunno what that is 

- lower mortality rates 

- can progress to AIDS 

- ppl can be infected with both types 

etiology

- virus moves across the body 

- targets CD4+ T cells 

- Replicate itself 

- at time of exposure => infection occurs when virus moves across epithelium or mucosal membrane of the body => thats when virus occurs 

- RNA retro virus 

- triggers a defect in the cell mediated immune system 

- causes infection that may progress to AIDS 

pathogenesis

• Entry & Attachment

  • HIV cross epithelial/mucosal membrane to target cell

  • Surface protein gp120 binds to CD4 receptor on CD4+ T cells

• Coreceptor binding (required - gp120 alone isn’t enough)

  • CCR5 = early infection = macrophage, memory T cell

  • CXCR4 = later infection = T cells

• Fusion & Entry

  • Gp120 attaches to CD4 and chemoreceptors → gp41 inserts into host cell

  • Viral and host membranes fuse → viral core enters cytoplasm

• Replication

  • Viral RNA → converted + embedded as viral DNA into host nucleus

  • Host cell machinery produces

    • New viral RNA

    • Viral proteins

    • Viral enzymes

• Assembly & Mutation

  • New viral components assemble at cell membrane, bud off as immature particles

  • Protease enzymes cut precursor proteins into smaller, active pieces → virion is now active

• Consequences CD4+ Cell Damage

  • Infected CD4+ cells die through several mechanisms

  • Drives progressive immune damage

    • CD4+ cells → immune function → opportunistic infections → malignancies → AIDS

• ONE LINE → HIV attaches (Gp120 → CD4 → coreceptors) → fuse and enters (gp41) → hijacks cells to replicate → assemble + mature (protease) → kills CD4+ cells → progressive immune collapse → AIDS
   systemic effects 

  - HIV affects multiple organ systems 

  - brain 

  - heart 

  - kidneys 

  - complications 

  - arise from both virus and opportunistic infections 

  - without treatment => progresses from initial HIV infection => AIDS - takes like 10 yrs for this to happen 

  - cannot cure but can slow progression 

  
  
  

progression of HIV

• Phase 1: initial infection in 3-6 weeks, mild, nonspecific “flu-like” symptoms

  • Self limiting → initial immune response limits infection

  • Seroconversion: antibodies form in 2-10 weeks (blood test) → person tests HIV positive 

• Phase 2: latent = asymptomatic or lymphadenopathy present

  • HIV replicates in lymph nodes, destroys lymph tissue over time

  • Helper T4 cell count decrease → weaker immune response

  • Move into active infection

• Phase 3: acute

  • AIDS =immunodeficiency

  • Low T4 cell count

  • Severe opportunistic infections

  • Cancers

  • Wasting syndrome

  • CNS involvement

HIV infection from Seroconversion to AIDS

• - acute infection (2-4 weeks after exposure) 

  • - rapid HIV replication 

  • - no detected antibodies yet 

  • - infectious but asymptomatic 

    • - can spread ez 

    • - cld have flu symptoms tho 

• - Seroconversion (3 weeks to 6 months after exposure) - when antiB become detectable in blood 

  • - flu-like symptoms 

  • - CD4 T cell count is above 400 

• - clinical latency period (3-12 years) 

  • - HIV replicates in the lymph nodes 

  • - gradual destruction of lymph nodes 

  • - mild symptoms 

    • - fatigue 

    • - weight loss 

    • - fever 

  • - CD4 T cell count slowly declines 

• - early symptomatic HIV infection

  • - more opportunistic infections more frequently 

  • - further decline in CD4 T cell count 

• - late-stage HIV infection (AIDS) 

  • - CD4 T cell count is below 200!!! 

  • - can be diagnosed with cancer 

  • - survival is 1-3 years without treatment 

• - why wld ppl go without treatment 

  • - compliance 

  • - some ppl don’t have enough money 

  • - but early diagnoses and treatment improves outcome

diagnostic tests

• Rapid HIV assays, home test kits

• ELISA:

  • Positive for HIV antibodies if blood or oral mucosal transudate of an infected person reacts with the** surface antigen of killed HIV virus

    • Means the body already started making antibodies to defend itself because body has HIV

  • Must be performed with both HIV-1 and HIV-2 viral antigens

• Western blot test: used when ELISA test is positive and to confirm the presence of HIV

• Neonates: culture virus from blood and peripheral tissue

monitor progression of HIV

• - CD4+ T lymphocyte cell count (CD4+) 

• - HIV RNA viral load 

  • - measured b4 and during treatment 

  • - goal is to suppress undetectable levels 

  • - monitored every 3-6 months 

  • - or 6 months if they r stable for 2+ years! 

• - CD4+ lymphocyte percentage 

  • - indicates overall immune function 

  • - marker of disease progression from HIV to AIDS . 

  • - monitored every 3-6 months during treatment 

  • - mores stable 

• - Genotypic resistance testing 

  • - initial evaluation and routine management 

  • - identifies viral mutations to guide drug selection 

• - HLA-B*-5701 testing 

  • - baseline test before starting specific treatments 

• - after initial diagnosis => lab test => needs to be performed to stage disease and assist in monitoring and treatment 

• - anti retroviral will slow down progression

clinical manifestations

• - course of HIV infection 

  • - parallels function of immune system 

  • - as immune system decreases 

• - number of opportunistic infections and malignancies increase 

  • - normal functioning of organs decline 

  • - Systemic Manifestations 

    • - malnutrition/wasting syndrome 

    • - greater than 10% body weight due to HIV infection 

    • - major muscle wasting 

      • - due to a few things 

• - malnutrition from elevated metabolic rates 

  • - chronic inflammation 

  • - anorexia 

  • - decrease in food intake 

  • - multiple opportunistic results

  • - malnutrition 

    • - LCD among AIDS patients 

    • - NOT HIV 

  • - Gastrointestinal Manifestations 

    • - nearly universal in HIV-Infected people ; GI tract - major target organ - Major GI complication—chronic diarrhea 

    • - watery or bloody stool 

    • - malabsorption 

    • - severe weight loss => muscle wasting 

    • - increased morbidity and death 

    • - major target organ 

    • - abdominal pain 

    • - drugs 

      • - antimedic 

      • - antidiarrhea 

  • - Pulmonary manifestations 

    • - opportunistic pneumonias 

    • - Parenchymal lung disease 

    • - adult respiratory distress syndrome 

    • - Pneumocystis jiroveci (PCP) 

      • - most common opportunistic infection 

      • - activates pneumocytis pneumonia 

    • - may have nonspecific flu-like symptoms 

      • - fever 

      • - fatigue 

      • - weight loss 

      • - cld seem like anything tbh 

    • - severe hypoxemia 

    • - falls below 200 

  • - Mucocutaneous manifestations 

    • - may be allergic, infectious, or neoplastic in origin 

    • - viral exanthem — usually 1st symptom 

      • - assoc w seroconversion 

• - erythematous rash found on face, trunk, and arm 

  • - self-limiting 

• - occurs in 40-60% of all HIV infected persons 

  • - occurs in both early and late stages of HIV infection 

  • - 

  • - neurological manifestatons 

    • - often why ppl w HIV seek treatment 

      • - once it gets into neurological system => it invades the CNS => occurs early in course of infection during primary systemic attack on body (spreading to lymph nodes) 

    • - symptoms

      • - inattentiveness 

      • - confusion 

      • - forgetfulness 

      • - loss of concentration 

      • - slow verbal responses 

      • - headaches 

• - inability to complete or perform complex tasks 

  • - peripheral neuropathy 

  • - encephalopathy with dementia 

    • HIV-associated dementia = shrinking basal ganglia, widened sulci, and ventricular enlargemetn

  • - headache 

  • - focal deficits 

  • - cardiovascular manifestations 

    • - weakness 

    • - dyspnea 

    • - fatigue to acute chest pain 

    • - creatine kinase (CK) elevations and pulmonary edema 

    • - ventricular dysfunction 

    • - higher in HIV patients if not treated 

      • - and renal too 

    • - HIV therapy may protect the pt from HiV induced cardiovascular disease - manifestations in other systems 

    • - renal impairment 

    • - hematologic impairment 

    • - liver dysfunction 

    • - endocrine dysfunction 

    • - rheumatologic manifestations

treatment

• Treatment: Primarily Antiretroviral therapy (ART), used to be highly active antiretroviral therapy (HAART).

  • Mainly aims to:

    • Suppress HIV viral load

    •  Preserve/restore immune function

    • Increase or maintain CD4 count

    • Delay disease progression

    •  Reduce opportunistic infections

    • Reduce morbidity

    • Prolong survival

    • Reduce HIV transmission

    • Prevent/reduce clinical manifestations

  • Multiple drugs must be used

    • If only one medication is used: resistant virus → continues replicating

    • Combination therapy attacks HIV at multiple points.

    • Therefore: Multiple medications → greater viral suppression → less resistance

• CD4 < 200cells /μL = AIDS stage, and major increase in opportunistic infection risk

• CD4 percentage < 14% = increased risk of AIDS defining illnesses

• Drug Classes 

  • WAYS TO MEMORIZE!!! → name + side effects 

    • Zidovudine (AZT, Retrovir): AZT makes the RBCs ZZZ (zero blood). Zaps bone marrow= anemia, neutropenia.

    • Lamivudine (3TC, Epivir): L for Liver. Active against Hep B

    • Emtricitabine (FTC, Emtriva): E=Easy

    • Abacavir (ABC, Ziagen): A=Allergy. Causes hypersensitivity reaction

    • (nucleoTide reverse Transcriptase) Tenofovir: Ten toes in your kidneys and bones!!!

      • TRIPLE T

    • Efavirenze: E=eerie dreams. Gives you vivid dreams, dizziness, insomnia

    • Nevirapine: N=Nasty rash, rash fever, mucosal involvement

    • Rilpivirine: R=real food. Should be taken with a high-fat meal

    • Delavirdine: D=Drug interactions with CYP450

    • Doravirine: D= Dora is Drowsy

    • Etravirine: E=Everything NNRTI, CNS, rash, liver, GI

• Protease inhibitors: Works during the viral maturation phase.

  • Binds to and inhibits HIV enzyme protease. Normally, protease cuts viral protein precursors into the correct sizes needed to make mature HIV particles. When it is blocked, immature viral particles are produced; they are defective and noninfectious, thus HIV replication reduced. 

  • Examples: *brand name in parenthesis REALLY FAT ANTS TAKE DONUTS!!!

    • Ritonavir (Norvir)

    • Fosamprenavir (Lexiva)

    • Atazanavir (Reyataz)

    • Tipranavir (Aptivus) — ritonavir-boosted

    • Darunavir (Prezista) — ritonavir-boosted

  • Ritonavir boosters: slows down how quickly liver breaks down primary HIV meds. This allows the drug to stay in the body longer.

• Fusion Inhibitors: Extracellular and blocks the fusion of HIV viral membrane with the target cell membrane. Prevents HIV from entering cell.

  • EX: Enfuvirtide (Fuzeon), only FDA approved fusion inhibitor

    • Never used alone (monotherapy).

    • Always used with other HIV medications.

    • Used to decrease viral load.

    • Can increase the effects of protease inhibitors.

    • Given only by subcutaneous injection.

• CCR5 Inhibitors: Blocks CCRV coreceptor. Prevents HIV from binding to cell membrane and is useful during earlier HIV infection when CCR5-tropic virus predominates.

  • EX: Maraviroc (Celsentri) MARA blocks the CCR5 door! Celsentri sounds like cell entry.

    • Rarely used as first-line therapy.

    • Tropism testing is required before treatment.

      • Determines which coreceptor HIV uses to enter cells

    • Always used with other antiretroviral medications.

    • Interacts with the cytochrome P450 system.

    • Rarely used in the U.S. because special testing is required.

• Cytochrome P450 3A (CYP3A) Inhibitors: Inhibit liver enzyme system responsible for metabolizing many meds.

  • EX: Cobicistat (Tybost) and Ritonavir (Norvir) COB and RIT STOP THE CYP

    • Always given with other antiretroviral medications.

    • Frequently used as pharmacokinetic boosters.

    • Makes primary HIV meds last longer

•  Integrase Strand Transfer Inhibitors (INSTIs): Blocks HIV enzyme integrase. REALLY BIG DOGS EAT!!! All end in tegravir -TEGR- inTEGRase

  • HIV RNA -> DNA -> Integrase inserts viral DNA into human chromosome. INSTIs prevent this.

  • Integrase blocked → viral DNA cannot be inserted into human DNA → viral replication decreases

  • Examples:

    • Raltegravir (Isentress)

    • Bictegravir (Biktarvy)

    • Dolutegravir (Tivicay)

    • Elvitegravir (Genvoya)

  • Concerns about neurotoxicity

  • CNS safety

  • More frequent neuropsychiatric adverse events

• Post Attachment Inhibitors: Prevents HIV virion from attaching to certain immune cells. They act after initial attachment in HIV entry process.

  • EX: Ibalizumab (Trogarzo) = I-BLOCK after attachment

    • Always given with other HIV meds

• Other treatments

  • Filgrastim (Neupogen): Human granulocyte colony stimulating factor (G-CSF)

    • Increases neutrophils and improves innate immunity in people with neutropenia

    • Helpful for medication-induced neutropenia.

    • Given daily via subQ route

  • Epoetin Alfa (or erythropoietin)

    • Used to manage medication-induced anemia.

    • Adverse effect is hypertension

  • Intravenous Immunoglobulin (IVIG)

    • Used in HIV infected children with T-cell count greater than 200/μL

    • May decrease the incidence of: Serious bacterial infections, Minor bacterial infections, Viral infections, Opportunistic infections

  • Interferon Alfa-2b (also called Intron A)

    • Treats AIDS-related Kaposi sarcoma in adults

anemia

• Reduction of oxygen-carrying capacity

• Tissue hypoxia

• Compensatory mechanisms to restore tissue oxygenation

causes of anemia

• Decreased RBC production (oxygen carriers)

  • Decrease in intake of certain nutrients → iron, folic acid, and cobalamin

  • Decrease in production of erythropoietin → necessary for formation of RBCS by bone marrow

• Blood loss

  • Liver disease

  • Bleeding duodenal ulcer

  • Colorectal cancer

  • Acute trauma

  • Gastrointestinal bleeding

  • Ruptured aortic aneurysm

• Increased RBC production (more than necessary)

  • Sickle cell disease

  • Side effect of medications (methyldopa/aldomet)

  • Administration of incompatible blood

  • Trauma (cardiopulmonary bypass)

types of anemia

Microcytic-hypochromic anemia: small size, pale color, contains abnormally low amount of hemoglobin → UNIVERSAL FOR THESE ANEMIA TYPES

• Iron deficiency anemia

• Sideroblastic anemia

• Thalassemia

Normocytic-normochromic anemia: normal size, normal color; normal hemoglobin content → erythrocytes decreased in number → all anemias are different and don’t share common factors 

• Aplastic Anemia

• Hemolytic anemia

• Sickle Cell Anemia

• Anemia of Chronic Renal Failure

Macrocytic-normochromic anemia: large size, normal color; normal concentration of hemoglobin

• Folate-deficiency anemia

• Pernicious anemia

• Secondary Polycythemia

• 
  

Iron deficiency anemia

• most common - microcytic-hypochromic anemia

  • Decreased intake of iron → poor absorption

  • Growth spurts, pregnancy, or breastfeeding

  • Chronic blood loss

  • Severe liver disease

  • Infections and cancers

  • Signs and symptoms

    • Pale skin and mucous membranes from vasoconstriction

    • Fatigue and intolerance to cold

    • Irritability → response from CNS from decreased oxygen supply

    • Degenerative changes: brittle hair, concave nails, inflammation of oral mucosa and tongue, angular stomatitis, difficulty swallowing

    • Irregular menstrual cycles

    • Slow healing

    • Cardiac effects: tachycardia, palpitations, dyspnea, fainting

Sideroblastic anemia

• Two types - microcytic-hypochromic anemia

  • Acquired: Primary disorder, which is idiopathic, and is associated with myeloproliferative or myeloplastic disorders

  • Hereditary: This is rare

• Seen mostly in males and associated with recessive X-linked transmission  

• Linked to genetic, chromosomal, or enzyme issues  

• Present in infancy/childhood but remains hidden  

• In adults, other conditions (diabetes/cardiac failure) that lead to clinical manifestations  

• Caused by impaired synthesis of heme in bone marrow associated with alcoholism and folate deficiency  

• Signs/Symptoms  

  • Enlarged li ver and spleen  

  • Normal or mild decrease in liver function  

  • Cardiac rhythm problems (occur late)

Thalassemia

• Most common genetic disorder worldwide. microcytic-hypochroomic anemia 

  • Results in abnormal hemoglobin synthesis. Two forms: -

    • Beta

      • Most common

      • Often seen in Mediterranean countries

    • Alpha

      • Seen in Indian, Chinese, or Southwest Asian populations

      • Leads to multiple potential gene mutations

      • Has varied effects on hemoglobin