Learning Objectives
- Apply high-yield biochemistry (enzyme deficiencies, metabolic pathways, molecular biology) to clinical vignettes
- Identify key microorganisms by their virulence factors, clinical presentations, and treatment
- Understand immunology: B/T cell development, hypersensitivity, immunodeficiencies, autoimmune diseases
- Master pharmacology drug classes, mechanisms, and toxicities using Sketchy Medical mnemonics
- Use Pathoma and First Aid to integrate pathophysiology with clinical manifestations
1. High-yield Biochemistry
1.1 Enzyme deficiency diseases
| Disease | Deficient enzyme | Substrate ↑ | Clinical features |
|---|
| PKU | Phenylalanine hydroxylase | Phenylalanine | Intellectual disability, musty odour, fair skin |
| Albinism (oculocutaneous) | Tyrosinase | Tyrosine | Depigmentation, ↑ skin cancer risk |
| Homocystinuria | Cystathionine β-synthase | Homocysteine | Marfanoid, DVT, intellectual disability |
| Maple syrup urine disease | Branched-chain α-ketoacid dehydrogenase | Leu, Ile, Val | Sweet urine, encephalopathy |
| Gaucher | β-glucocerebrosidase | Glucocerebroside | Hepatosplenomegaly, bone pain, Gaucher cells |
| Tay-Sachs | Hexosaminidase A | GM2 ganglioside | Cherry-red spot, progressive neurodegeneration (no HSM) |
| Niemann-Pick | Sphingomyelinase | Sphingomyelin | Cherry-red spot + foam cells + HSM |
| Fabry | α-galactosidase A | Ceramide trihexoside | X-linked, angiokeratomas, renal failure |
1.2 Molecular biology — high-yield Step 1
- DNA replication: leading strand continuous (primase → DNA pol δ/ε); lagging strand Okazaki fragments (DNA pol α → DNA ligase).
- Transcription factors: NF-κB (inflammation), p53 (cell cycle arrest/apoptosis), Rb (G1/S checkpoint tumour suppressor).
- Oncogenes: Ras (point mutation — colorectal, pancreatic), c-Myc (Burkitt lymphoma t(8;14)), HER2/neu (breast).
- Tumour suppressors: BRCA1/2 (breast/ovarian), APC (FAP colorectal), VHL (renal clear cell), NF1/NF2.
1.3 Vitamins — clinical vignettes
| Vitamin | Deficiency | Toxicity |
|---|
| A | Night blindness, Bitot spots, xerophthalmia | Teratogen, pseudotumour cerebri, hepatotoxicity |
| B1 (thiamine) | Wernicke (confusion+ataxia+ophthalmoplegia), Korsakoff, beriberi | None significant |
| B3 (niacin) | Pellagra (4D: diarrhea, dermatitis, dementia, death) | Flushing (prostaglandin-mediated) |
| B6 (pyridoxine) | Peripheral neuropathy (isoniazid use), sideroblastic anemia | Peripheral neuropathy |
| B12 | Megaloblastic anemia + subacute combined degeneration (posterior + lateral cord) | None |
| C | Scurvy (perifollicular hemorrhage, bleeding gums, poor wound healing) | Kidney stones (oxalate) |
| D | Rickets (children), osteomalacia (adults) | Hypercalcemia |
| K | Bleeding (↑ PT/INR, ↑ aPTT), neonatal hemorrhagic disease | None (K1); hemolytic anemia (K3 synthetic) |
2. High-yield Microbiology
2.1 Gram-positive bacteria — key pathogens
- S. aureus: catalase+, coagulase+; MRSA (mecA gene); toxins: TSST-1, exfoliative toxin (scalded skin), enterotoxin. Treat MRSA: vancomycin.
- S. pneumoniae: optochin-sensitive, bile-soluble, encapsulated; #1 cause of meningitis, pneumonia, otitis media in adults.
- S. pyogenes (GAS): bacitracin-sensitive; M protein (anti-phagocytic); complications: rheumatic fever, PSGN.
- Listeria: tumbling motility at 4°C; food-borne; meningitis in neonates + immunocompromised.
- C. difficile: pseudomembranous colitis after antibiotics (clindamycin, FQ); treat: oral vancomycin or fidaxomicin.
2.2 Gram-negative bacteria
- N. meningitidis: oxidase+, ferments maltose; Waterhouse-Friderichsen (adrenal hemorrhage + DIC).
- H. influenzae: chocolate agar + XV factors; unencapsulated = non-typeable = #1 cause otitis media.
- E. coli: ETEC (traveller's diarrhea — heat-labile + heat-stable toxins); EHEC O157:H7 (HUS — shiga-like toxin).
- Pseudomonas: blue-green pigment (pyocyanin), grape odour; CF, burn patients; treat: pip-tazo, cefepime, meropenem.
2.3 Viruses — Step 1 must-know
| Virus | Genome | Key disease | Vaccine |
|---|
| HIV | +ss RNA (retrovirus) | AIDS — CD4 destruction | No (research) |
| HBV | Partially ds DNA | Hepatitis B, HCC | Yes (HepB series) |
| EBV | ds DNA (herpesvirus) | Mono, Burkitt lymphoma, NPC | No |
| CMV | ds DNA (herpesvirus) | Congenital (periventricular calcif.), retinitis in AIDS | No |
| Parvovirus B19 | ss DNA | Fifth disease, aplastic crisis in sickle cell | No |
| Measles (Rubeola) | -ss RNA | Koplik spots, SSPE, giant cell pneumonia | Yes (MMR) |
3. High-yield Immunology
3.1 Hypersensitivity reactions
| Type | Mechanism | Example |
|---|
| I — Immediate | IgE + mast cells | Anaphylaxis, allergic asthma, urticaria |
| II — Cytotoxic | IgG/IgM vs cell surface | ABO mismatch, Goodpasture, autoimmune hemolytic anemia |
| III — Immune complex | IgG/IgM complex deposition | SLE, PSGN, serum sickness, Arthus reaction |
| IV — Delayed | T-cell mediated (CD4 or CD8) | PPD test, contact dermatitis, transplant rejection |
3.2 Primary immunodeficiencies
- Bruton's (XLA): absent B cells (Bruton's tyrosine kinase mutation); recurrent bacterial infections after 6 months.
- SCID: absent T and B cells (ADA deficiency most common); opportunistic infections; treat: HSCT.
- DiGeorge: 22q11 deletion; absent thymus; T-cell deficiency; conotruncal heart defects, hypocalcemia.
- CGD: NADPH oxidase defect; catalase+ infections (S. aureus, Aspergillus); nitroblue tetrazolium test.
- Hyper-IgM: CD40L defect; low IgA/IgG/IgE; Pneumocystis jirovecii pneumonia.
4. High-yield Pharmacology
4.1 Beta-blockers — differences
| Drug | Selectivity | Special property |
|---|
| Metoprolol, atenolol | β1 selective | Safer in COPD/asthma |
| Carvedilol | Non-selective β + α1 | Use in heart failure (HFrEF) |
| Propranolol | Non-selective | Prophylaxis migraine, essential tremor, thyroid storm |
| Labetalol | Non-selective β + α1 | HTN in pregnancy, hypertensive emergency |
4.2 Antibiotics — key mechanisms and toxicities
- Aminoglycosides: irreversible 30S binding; nephrotoxicity + ototoxicity (co-toxicity with furosemide).
- Tetracyclines: reversible 30S; teratogen (avoid in pregnancy, children < 8 yr); photosensitivity; chelated by milk/antacids.
- Vancomycin: cell wall (peptidoglycan terminal D-Ala-D-Ala); Red man syndrome (infuse slowly); VRE resistant via D-Ala-D-Lac.
- Fluoroquinolones: DNA gyrase (bacteria); tendinopathy; QTc prolongation; avoid in pregnancy.
- Metronidazole: DNA strand breaks (anaerobes, protozoa); disulfiram-like reaction with alcohol.
4.3 Autonomic pharmacology — high-yield
- Atropine: muscarinic antagonist; dry mouth, urinary retention, cycloplegia, tachycardia; antidote organophosphate poisoning with pralidoxime.
- Phenylephrine: pure α1 agonist; reflex bradycardia (baroreceptor); used for nasal decongestion and hypotension without tachycardia.
- Neostigmine: reversible AChE inhibitor; reversal of NMJ blockade; cannot cross BBB (quaternary amine).
Practical Case — Step 1 vignette
"A 3-month-old has recurrent Staphylococcal skin infections. Neutrophil count normal. Dihydrorhodamine flow cytometry test is abnormal."
Diagnosis: Chronic Granulomatous Disease (CGD) — NADPH oxidase deficiency → neutrophils cannot generate reactive oxygen species to kill catalase+ organisms.
Why DHR test?: Replaces nitroblue tetrazolium test; measures H2O2 production in neutrophils.
Sketchy tip: Use the Sketchy Micro visual library for bacteria/fungi/viruses — each scene encodes morphology, toxins, and treatment. Studies show 20-30% better retention vs text-only. Pair with Anki cards for 90-day spaced repetition.
Step 1 traps: Tay-Sachs has NO hepatosplenomegaly (unlike Niemann-Pick and Gaucher). This distinction appears nearly every exam. Sketchy encodes this: "Tay's restaurant has no enlarged kitchen."
5. Key takeaways
- Lysosomal storage diseases: match substrate → enzyme → clinical phenotype.
- Gram stain + special tests (catalase, coagulase, optochin) identify bacteria.
- Hypersensitivity type I-IV: mechanism determines clinical syndrome.
- Immunodeficiencies: age of onset + type of infection guides diagnosis.
- Beta-blocker selectivity and antibiotic toxicities = perennial Step 1 questions.
Further reading
