USMLE Step 1 - Physiology & Pathology Essentials

• Reversible injury: Cellular swelling (blebs), ribosomal detachment (decreased protein synthesis), nuclear chromatin clumping, lipid accumulation.
• Irreversible injury: Plasma membrane damage, lysosomal rupture, mitochondrial permeability/vacuolation, nuclear pyknosis (condensation) $\to$ karyorrhexis (fragmentation) $\to$ karyolysis (dissolution).

• Apoptosis: ATP-dependent programmed cell death. No inflammation. Intrinsic pathway (mitochondrial release of cytochrome c controlled by $Bcl-2$/$Bax$) or extrinsic pathway (FasL/FasR or $TNF\text{-}\alpha$). Cleaved by caspases.
• Necrosis: Uncontrolled ATP-depleted cell death due to injury. Associated with enzymatic digestion, cell lysis, and local acute inflammation.

• Transudate: Hypocellular, low protein ($<3.0\text{ g/dL}$), normal LDH. Caused by increased hydrostatic pressure (e.g., Heart Failure) or decreased oncotic pressure (e.g., Cirrhosis, Nephrotic Syndrome).
• Exudate: Cellular, high protein ($>3.0\text{ g/dL}$), elevated LDH. Caused by increased vascular permeability due to inflammation, infection, or malignancy.

A pattern of chronic inflammation driven by Type IV hypersensitivity. Antigen-presenting cells secrete $IL\text{-}12$, activating $CD{4}^{+}$ T-helper cells into $Th1$ cells. $Th1$ cells secrete $\text{IFN-}\gamma$, which activates macrophages into epithelioid histiocytes and multinucleated giant cells. $TNF\text{-}\alpha$ maintains granuloma integrity.

Requires both alleles of a tumor suppressor gene to be inactivated for oncogenesis (loss of function).
• In sporadic cases: Two independent somatic mutations.
• In hereditary cases: One germline mutation inherited (first hit); second mutation acquired (second hit).
• Examples: $RB1$ (retinoblastoma), $TP53$ (Li-Fraumeni syndrome), $APC$ (FAP).

• $p53$: Induces $p21$ expression upon DNA damage, inhibiting CDKs and preventing ${\text{G}}_1\to \text{S}$ progression. Activates pro-apoptotic $Bax$ if DNA repair fails.
• $Rb$: Hypophosphorylated (active) $Rb$ binds and inhibits $E2F$, arresting the cell cycle in ${\text{G}}_1$. Hyperphosphorylation by CDK4/6-cyclin D complexes inactivates $Rb$, releasing $E2F$ to drive $\text{S}$-phase transition.

• Right Shift (Decreased $O_2$ affinity $\to$ increased tissue delivery): Elevated ${\text{pCO}}_2$, ${\text{H}}^{+}$ (decreased pH), $2,3\text{-BPG}$, and Temperature (Mnemonic: BAT21 drives to the Right).
• Left Shift (Increased $O_2$ affinity $\to$ decreased tissue delivery): Decreased ${\text{pCO}}_2$, elevated pH, decreased $2,3\text{-BPG}$, decreased Temperature, HbF, Carboxyhemoglobin, Methemoglobin.

• Obstructive (e.g., COPD, Asthma): Impaired expiration. ${\text{FEV}}_1/\text{FVC}<70\%$, increased Total Lung Capacity (TLC) and Residual Volume (RV).
• Restrictive (e.g., Pulmonary Fibrosis, ARDS): Impaired lung expansion. ${\text{FEV}}_1/\text{FVC}\ge 80\%$, reduced TLC, reduced $\text{FVC}$.