Pathophysiology and Disease Processes

Inflammation is the body's response to injury, infection, or irritation. Acute inflammation (hours to days): immediate response to tissue damage. Characteristics: redness (rubor, vasodilation), heat (calor, increased blood flow), swelling (tumor, edema from fluid leakage), pain (dolor, due to cytokine release), and loss of function (functio laesa). Mechanism: cytokines (TNF, IL-1, IL-6) and complement activate immune cells. Neutrophils arrive first, ingest bacteria and debris, then die, releasing pus. If infection is controlled, acute inflammation resolves. If not controlled or injury persists, it becomes chronic. Chronic inflammation (weeks to years): ongoing response. Characteristics: lymphocytes and macrophages accumulate; tissue destruction and fibrosis occur. Damage accumulates over time, causing organ dysfunction. Causes: chronic infection (TB, chronic hepatitis), autoimmune disease (lupus, rheumatoid arthritis), chronic irritation (smoking, asbestos), or failure of acute inflammation resolution. Pathology: granulomas form (collections of macrophages containing the irritant). Example: TB causes chronic granulomatous inflammation in lungs. Fibrosis results as collagen replaces damaged tissue, causing scarring and loss of organ function. Distinguishing acute from chronic guides treatment: acute inflammation often resolves with antibiotics (if infected) or time; chronic inflammation may require immunosuppression or removal of the irritant.

Atherosclerosis is the progressive buildup of lipid-laden plaques inside arteries, narrowing blood flow and increasing risk of blood clots. Mechanism: (1) Endothelial injury: high cholesterol, high blood pressure, smoking, or inflammation damages the inner lining (endothelium) of arteries. (2) Lipid deposition: LDL cholesterol oxidizes and enters the vessel wall; macrophages engulf it, becoming foam cells. A fatty streak forms. (3) Plaque formation: smooth muscle cells migrate into the wall, collagen is deposited, and a fibrous cap forms over lipid core. (4) Narrowing and turbulence: plaque narrows the lumen, increasing blood flow velocity and creating turbulence. (5) Thrombosis: if the cap ruptures, the lipid core is exposed; platelets adhere and a thrombus (clot) forms acutely, occluding blood flow. Consequences: (1) Stable atherosclerosis (asymptomatic): plaques present but don't obstruct much. (2) Unstable atherosclerosis (symptomatic): angina (chest pain from partial obstruction) occurs with exertion. (3) Acute coronary syndrome: cap ruptures, thrombus forms, myocardial infarction (MI, heart attack) occurs due to lack of blood flow to heart muscle. (4) Stroke: same process in carotid or cerebral arteries causes ischemic stroke. Reversal is difficult, so prevention is paramount: control cholesterol, blood pressure, smoking, and inflammation.

Diabetes is chronic elevation of blood glucose (hyperglycemia) resulting from inadequate insulin production (type 1) or insulin resistance (type 2). Diagnosis: fasting glucose ≥126 mg/dL, random glucose ≥200 with symptoms, or A1C ≥6.5%. Mechanism of damage: high glucose damages organs through multiple pathways. (1) Glycation (non-enzymatic attachment of glucose to proteins): high glucose causes glucose to stick to hemoglobin (forming A1C), to collagen in blood vessel walls (making them stiff), to lens proteins (causing cataracts). (2) Osmotic stress: high glucose in blood draws fluid into cells (causing blurred vision from lens swelling), then out of cells (causing dehydration). (3) Oxidative stress: high glucose generates reactive oxygen species (ROS), damaging cells. (4) Inflammatory cascade: hyperglycemia activates inflammation, damaging vessels and tissues. Organ-specific damage: (1) Retinopathy: damage to retinal blood vessels causes vision loss (leading cause of blindness in working-age adults). (2) Nephropathy: glomerular damage from glucose and high blood pressure causes protein loss in urine (albuminuria), progressing to kidney failure requiring dialysis. (3) Neuropathy: peripheral nerve damage from oxidative stress causes numbness, pain, and foot ulcers (leading cause of amputation in working-age adults). (4) Cardiovascular disease: accelerated atherosclerosis causes MI and stroke. (5) Infection susceptibility: high glucose impairs immune function. Prevention/management: control glucose (A1C <7%), blood pressure, and cholesterol; exercise; diet; and screening for complications.

Cancer is uncontrolled growth of abnormal cells that invade and damage surrounding tissue and spread (metastasize) to distant sites. Normal cells vs. cancer cells: normal cells divide a limited number of times (~50–70), respond to growth signals, respect tissue boundaries (adhesion), die when damaged (apoptosis), and require oxygen and nutrients. Cancer cells: divide indefinitely (immortalization), ignore growth stop signals (loss of tumor suppressors like p53), lose adhesion (epithelial-mesenchymal transition), resist apoptosis, and metastasize. Hallmarks of malignant transformation: (1) Oncogenes (accelerator broken) — mutations activate growth signals (RAS, HER2, MYC), driving constant division. (2) Tumor suppressors (brake broken) — mutations inactivate growth brakes (p53, RB, APC), allowing uncontrolled division. (3) Epigenetic changes: DNA methylation and histone modifications silence tumor suppressors or activate oncogenes. (4) Angiogenesis: tumors induce new blood vessel growth to feed themselves. (5) Invasion and metastasis: cells lose adhesion, invade surrounding tissue, intravasate (enter blood vessels), circulate, extravasate (exit vessels), and colonize distant organs. (6) Immune evasion: tumors hide from immune system by downregulating tumor antigens or expressing checkpoint inhibitors (PD-L1). Pathology: histology shows high mitotic rate, large irregular nuclei, loss of normal architecture. Lab markers: elevated tumor markers (CEA, PSA, hCG) may track disease. Treatment: surgery (remove tumor), chemotherapy (poison fast-dividing cells), radiation (damage DNA), immunotherapy (unleash immune system), or targeted therapy (block specific mutations).

Sepsis is life-threatening organ dysfunction caused by dysregulated host response to infection. Progression: (1) Infection: bacteria (usually), virus, or fungi invade; local inflammatory response (fever, redness, pus). (2) Bacteremia: bacteria enter bloodstream; systemic inflammatory response syndrome (SIRS) develops: fever >38°C or <36°C, heart rate >90, respiratory rate >20, WBC >12k or <4k. (3) Sepsis: SIRS + infection (infection confirmed by culture or clinical evidence). Symptoms: fever, confusion, rapid breathing, low blood pressure. (4) Severe sepsis: sepsis + organ dysfunction (low urine output = kidney failure, low oxygen = respiratory failure, low platelets = bleeding risk, elevated lactate = tissue hypoxia). (5) Septic shock: severe sepsis + refractory hypotension (blood pressure won't respond to fluids alone; vasopressors required). Pathophysiology: (1) Cytokine storm: TNF, IL-1, IL-6 are released in excess, causing systemic inflammation. (2) Endothelial dysfunction: vessels leak, causing edema and fluid loss. (3) Coagulopathy: disseminated intravascular coagulation (DIC) develops, consuming clotting factors and platelets, causing bleeding and thrombosis simultaneously. (4) Organ failure: kidneys (acute kidney injury), liver (hepatic failure), lungs (acute respiratory distress syndrome/ARDS), heart (cardiogenic shock). Mortality: severe sepsis ~25%, septic shock ~40–50%. Treatment: (1) Recognize early (SIRS + suspected infection). (2) Blood cultures before antibiotics. (3) Broad-spectrum antibiotics within 1 hour. (4) Aggressive fluid resuscitation. (5) Vasopressors if hypotensive despite fluids. (6) Source control (drain abscess, remove infected line). (7) Glucose control (keep <180). Speed matters: each hour of delay increases mortality.

Acute kidney injury (AKI) is rapid loss of kidney function (hours to days), causing retention of creatinine, urea, and potassium, and inability to concentrate urine. Diagnosis: increase in serum creatinine by ≥0.3 mg/dL within 48 hours or ≥50% from baseline, or urine output <0.5 mL/kg/hr for ≥6 hours. Classification by cause (prerenal, intrinsic renal, postrenal): (1) Prerenal AKI (≈55% of cases): inadequate blood flow to kidneys. Causes: hypotension (sepsis, hemorrhage, cardiogenic shock), dehydration, or renal artery stenosis. Labs: high BUN/creatinine ratio (>20), low urine sodium (<20 mEq/L), concentrated urine (high osmolality). Reversible if blood flow restored. (2) Intrinsic renal AKI (≈35%): direct kidney tissue damage. Causes: acute tubular necrosis (ATN) from ischemia or nephrotoxins (drugs like aminoglycosides, contrast dye, rhabdomyolysis from crush injury releasing myoglobin), glomerulonephritis (immune attack on glomeruli), or interstitial nephritis (allergic reaction). Labs: muddy brown urine (myoglobin), RBC casts (glomerulonephritis). Slower to reverse. (3) Postrenal AKI (≈10%): obstruction of urinary flow. Causes: kidney stones, enlarged prostate, tumors, or strictures. Bilateral obstruction required for AKI. Rapidly reversible if obstruction removed. Stages: Stage 1 (mild): creatinine 1–1.5× baseline, urine <0.5 mL/kg/hr; Stage 2 (moderate): 1.5–2× baseline, <0.5 mL/kg/hr ×12 hours; Stage 3 (severe): >3× baseline or creatinine >4 mg/dL, anuria (no urine output) for >12 hours. Treatment: identify cause, restore blood flow (fluids, pressors), remove nephrotoxins, monitor potassium and fluid balance. Dialysis if creatinine >10 or potassium >6.5. Prognosis: depends on cause (prerenal = 95% recover; intrinsic = 50% recover without chronic kidney disease).

Chronic kidney disease (CKD) is long-standing reduction in kidney function (GFR <60 mL/min/1.73 m² or persistent kidney damage for ≥3 months). Stages: Stage 1 (normal): GFR ≥90 (kidney damage present but function preserved); Stage 2 (mild): GFR 60–89; Stage 3a (moderate): GFR 45–59; Stage 3b (moderate): GFR 30–44; Stage 4 (severe): GFR 15–29; Stage 5 (ESRD): GFR <15 (requires dialysis or transplant). Causes: (1) Diabetes (35% of CKD; high glucose damages glomeruli) and hypertension (30%; high pressure damages vessels); (2) glomerulonephritis (immune attack); (3) polycystic kidney disease (inherited cysts destroy kidney); (4) chronic obstruction or reflux. Pathophysiology of progression: (1) Injury → nephron loss. (2) Remaining nephrons hypertrophy (enlarge) to compensate; this causes intraglomerular hypertension. (3) Chronic hyperfiltration damages the hypertrophied nephrons. (4) Proteinuria (protein loss in urine) indicates ongoing glomerular damage. (5) Progressive fibrosis → more nephrons lost. Intervention slows progression: (1) Tight glucose control (A1C <7) slows diabetic CKD. (2) Tight blood pressure control (<130/80) slows all CKD. (3) ACE inhibitors and ARBs reduce proteinuria and intraglomerular pressure. (4) Avoid nephrotoxins (NSAIDs, contrast dye). (5) Monitor electrolytes and fluid. Consequences of CKD: (1) Anemia (kidneys make erythropoietin). (2) Hypertension (kidneys regulate blood pressure). (3) Bone disease (kidneys activate vitamin D). (4) Cardiovascular disease (inflammation, accelerated atherosclerosis). ESRD requires dialysis (artificial kidney to filter blood) 3 times/week or peritoneal dialysis daily, or kidney transplant (gold standard; one transplant kidney can function 10–20 years).