Tell me about all the important clinical case studies in biochemistry I am preparing for a viva at least 20 of them

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Here are 25 important clinical case studies in biochemistry for your viva preparation, organized by category, drawn from Lippincott Illustrated Reviews: Biochemistry (8th ed), Harper's Illustrated Biochemistry (32nd ed), and Basic Medical Biochemistry (6th ed).

25 Important Clinical Case Studies in Biochemistry - Viva Preparation

SECTION A: LIPID METABOLISM & CARDIOVASCULAR

Case 1 - Familial Hypercholesterolemia (FH) with Acute MI

Presentation: 35-year-old male, severe substernal chest pain for 2 hours, dyspnea, diaphoresis, nausea. Family history: father died of heart disease at 45, paternal aunt at 39. Smoker (2-3 packs/day). Physical exam: corneal arcus, xanthelasmas on eyelids.

Key Lab Results:

Parameter	Patient	Normal
Troponin	0.5 ng/mL (H)	<0.04
Total cholesterol	365 mg/dL (H)	<200
LDL cholesterol	304 mg/dL (H)	<130
HDL cholesterol	38 mg/dL (L)	>45
Triglycerides	115 mg/dL	<150

Diagnosis: Acute MI + Heterozygous Familial Hypercholesterolemia (Type IIa hyperlipoproteinemia)

Biochemistry Viva Points:

FH is caused by a loss-of-function mutation in the LDL receptor (LDLR gene) - autosomal dominant
LDL receptors are found on hepatocytes and most body cells; they bind apolipoprotein B-100 on LDL
Without functional LDL receptors, plasma LDL cannot be internalized and cleared - it accumulates
Heterozygotes have ~50% receptor activity - LDL is 2-3x normal. Homozygotes (1 in 1 million) have cholesterol >600 mg/dL and MI before age 20
Cholesterol deposits form: xanthelasmas (eyelids), corneal arcus, tendon xanthomas (absent here - only seen in more severe cases)
Troponin is the gold-standard cardiac biomarker for MI (rises 3-6 hours, peaks 24h, persists 10-14 days)
Treatment: Statins - inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Statins reduce hepatic cholesterol production, upregulating LDLR expression, increasing LDL clearance

Case 2 - Lipoprotein Lipase Deficiency (Type I Hyperlipoproteinemia)

Presentation: Recurrent episodes of severe abdominal pain (pancreatitis) since childhood; eruptive xanthomas on skin; creamy plasma (lipemia retinalis).

Diagnosis: Lipoprotein lipase (LPL) deficiency

Biochemistry Viva Points:

LPL is anchored to capillary endothelium, especially in adipose and muscle. It hydrolyzes triacylglycerols (TAG) in chylomicrons and VLDL
Deficiency causes massive hypertriglyceridemia - plasma looks creamy/milky
No increased risk of atherosclerosis (LDL is normal)
LPL requires apolipoprotein C-II (apoC-II) as a cofactor - apoC-II deficiency gives the same phenotype
Eruptive xanthomas = deposits of TAG-rich lipoproteins in skin macrophages

SECTION B: CARBOHYDRATE METABOLISM

Case 3 - Glycogen Storage Disease Type Ia (Von Gierke Disease)

Presentation: 4-month-old male with "twitching" movements before feedings (hypoglycemic seizures). Protuberant, firm abdomen; hepatomegaly (liver palpable 4 cm below costal margin). Sleepy and clammy.

Key Lab Results:

Parameter	Patient	Normal
Glucose	50 mg/dL (L)	60-105
Lactate	3.4 mmol/L (H)	0.6-3.2
Uric acid	5.6 mg/dL (H)	2.4-5.4
Triglycerides	280 mg/dL (H)	<90
pH	7.30 (L)	7.35-7.45

Liver biopsy: Enlarged hepatocytes loaded with lipid (TAG) and carbohydrate. Liver glycogen elevated, normal structure. Glucose 6-phosphatase activity <10% of normal.

Glucagon test: No rise in blood glucose (confirming inability to release glucose from glycogen), but blood lactate increases.

Diagnosis: Glucose 6-phosphatase deficiency - GSD Type Ia (von Gierke disease)

Biochemistry Viva Points:

Glucose 6-phosphatase is located in the endoplasmic reticulum membrane of liver and kidney
It is the final step of BOTH gluconeogenesis and glycogenolysis - its deficiency blocks free glucose release
Why does glucagon raise lactate but not glucose? Glycogen is broken down to glucose 6-phosphate (G6P), but G6P cannot be converted to free glucose. G6P is shunted to glycolysis - producing lactate
Hypoglycemia - because glucose cannot be released from the liver
Hyperlipidemia and hyperuricemia - secondary consequences of impaired G6P metabolism
Treatment: Cornstarch therapy (uncooked cornstarch releases glucose slowly), nocturnal continuous glucose feeds, avoidance of fructose and galactose
Long-term complications: hepatic adenomas, risk of hepatocellular carcinoma, renal disease, gout

Case 4 - Diabetic Ketoacidosis (DKA)

Presentation: 40-year-old female with Type 1 diabetes (24 years), brought to ED in confused, disoriented state. Signs of dehydration (dry mucous membranes, poor skin turgor). Kussmaul respiration (deep, rapid breathing). Faintly fruity breath odor. UTI confirmed on urinalysis.

Key Lab Results:

Parameter	Patient	Normal
Glucose	414 mg/dL (H)	70-99
3-Hydroxybutyrate	350 mg/dL (H)	0-3
HCO3-	12 mmol/L (L)	22-28
pH	7.1 (L)	7.35-7.45
K+	5.3 mmol/L (H)	3.5-5.0

Diagnosis: Diabetic ketoacidosis (DKA) precipitated by urinary tract infection

Biochemistry Viva Points:

DKA occurs in Type 1 DM (absolute insulin deficiency) - uncontrolled lipolysis floods liver with free fatty acids
Liver converts FFAs to acetyl-CoA via beta-oxidation; excess acetyl-CoA overwhelms TCA cycle, diverted to ketogenesis (acetoacetate, 3-hydroxybutyrate, acetone)
Acetone = fruity breath odor
Kussmaul respiration = compensatory hyperventilation to blow off CO2 and correct metabolic acidosis
Why is K+ elevated despite total body K+ depletion? Acidosis causes H+ to enter cells, K+ exits cells to maintain electroneutrality
3-Hydroxybutyrate is the predominant ketone body in DKA (ratio 3-OHB : acetoacetate = ~3:1)
UTI triggers DKA by raising counter-regulatory hormones (glucagon, cortisol, epinephrine)
Treatment: Insulin (turns off ketogenesis), IV fluids (saline), careful K+ replacement as pH corrects

Case 5 - Type 2 Diabetes Mellitus / Insulin Resistance

Presentation (Harper's Case): 5-year-old boy with drowsiness, coma-like episodes, "chemical, alcohol-like" odor on breath and urine. Glucose tolerance test (GTT) shows impaired glucose clearance but high plasma glucose. Biological insulin assay shows normal/low activity, but radioimmunoassay shows normal insulin levels - suggesting the patient produces normal amounts of immunoreactive insulin but it has low biologic activity.

Diagnosis: Mutant insulin with impaired biologic activity (a rare cause of insulin resistance)

Biochemistry Viva Points:

Insulin is synthesized as preproinsulin → proinsulin (after signal peptide cleavage) → insulin + C-peptide (by prohormone convertase in secretory granules)
Radioimmunoassay (RIA) detects antibody-antigen binding (structure-dependent) - detects even structurally abnormal insulin
Biological assay measures function (glucose uptake) - detects only active insulin
This case helped establish the structure-function distinction of insulin
C-peptide is used clinically to assess endogenous insulin production (not affected by exogenous insulin)

SECTION C: AMINO ACID METABOLISM & INBORN ERRORS

Case 6 - Phenylketonuria (PKU)

Presentation: Neonate found to have elevated phenylalanine on newborn screening (Guthrie test). If untreated: severe intellectual disability, fair skin and hair (lack of melanin), musty/mousy urine odor, seizures, eczema.

Diagnosis: Phenylalanine hydroxylase (PAH) deficiency - autosomal recessive

Biochemistry Viva Points:

PAH converts phenylalanine → tyrosine (requires cofactor tetrahydrobiopterin, BH4)
Deficiency leads to accumulation of Phe and its transamination product phenylpyruvate (detected in urine = phenylketonuria)
Tyrosine becomes an essential amino acid in PKU patients (cannot be synthesized)
Neurotoxicity: high Phe competes with other large neutral amino acids for brain transport, disrupting neurotransmitter synthesis
Treatment: Phenylalanine-restricted diet (protein substitute formulas) lifelong; Sapropterin (BH4 analog) for BH4-responsive mutations (~25% of patients)
Neonatal screening: heel-prick blood on Guthrie card - phenylalanine >120 μmol/L is positive

Case 7 - Maple Syrup Urine Disease (MSUD)

Presentation: Neonate develops poor feeding, vomiting, lethargy, hypotonia, and seizures within first week of life. Urine and cerumen have a distinctive sweet, maple syrup or burnt sugar odor.

Diagnosis: Branched-chain alpha-keto acid decarboxylase complex deficiency - autosomal recessive

Biochemistry Viva Points:

Branched-chain amino acids (BCAAs): leucine, isoleucine, valine
Deficient enzyme: branched-chain alpha-keto acid (BCKA) dehydrogenase complex - analogous to pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase (all use TPP, lipoate, CoA, FAD, NAD+)
Keto acids of leucine (alpha-ketoisocaproate), isoleucine, and valine accumulate in blood and urine
Leucine is especially neurotoxic - inhibits glutamate decarboxylase, impairs myelin synthesis
Treatment: BCAA-restricted diet, thiamine supplementation (some patients are thiamine/TPP-responsive), liver transplant
Neonatal screening by tandem mass spectrometry

Case 8 - Urea Cycle Defect (Argininosuccinate Synthetase Deficiency - Citrullinemia)

Presentation: 40-hour-old neonate with irritability, lethargy, hypothermia, vomiting, tachypnea, and seizure. Laboratory: elevated ammonia, low BUN, elevated argininosuccinate (>60x normal), elevated citrulline (4x normal), elevated glutamine, decreased arginine. Respiratory alkalosis.

Diagnosis: Urea cycle enzyme defect - most likely argininosuccinate synthetase deficiency (Citrullinemia Type I)

Biochemistry Viva Points:

Argininosuccinate synthetase condenses citrulline + aspartate → argininosuccinate (consumes 2 ATP)
Deficiency: citrulline and ammonia accumulate; argininosuccinate accumulates proportionally
Hyperammonemia is toxic to the brain - NH3 depletes alpha-ketoglutarate (via glutamate dehydrogenase), impairing TCA cycle in neurons
Glutamine elevation reflects the brain's attempt to detoxify ammonia (glutamine synthetase: glutamate + NH3 → glutamine) - paradoxically causes cerebral edema
Respiratory alkalosis = ammonia directly stimulates the respiratory center
Why is arginine supplemented? When the cycle is blocked, arginine becomes conditionally essential. Arginine also supports alternative nitrogen excretion as citrulline
Treatment: Hemodialysis (acute), sodium benzoate (conjugates glycine), sodium phenylacetate (conjugates glutamine) - alternative nitrogen excretion. Low-protein diet long-term.

Case 9 - Alkaptonuria

Presentation: Middle-aged adult with dark discoloration of urine (turns black on standing or exposure to air), arthritis of large joints, and bluish-black pigmentation of ear cartilage and sclera (ochronosis). Joint X-rays show calcification of intervertebral discs.

Diagnosis: Homogentisate oxidase deficiency - autosomal recessive

Biochemistry Viva Points:

Deficient enzyme: homogentisate 1,2-dioxygenase in tyrosine degradation pathway
Homogentisic acid accumulates, is oxidized to benzoquinone acetate which polymerizes to form a melanin-like pigment - deposits in connective tissue (ochronosis)
The pathway: Phenylalanine → Tyrosine → 4-Hydroxyphenylpyruvate → Homogentisate → (blocked here) → Maleylacetoacetate → Fumarylacetoacetate → Fumarate + Acetoacetate
Homogentisic acid is excreted in urine; oxidizes to dark color
Benedict's test: positive (reducing substance); but glucose oxidase test: negative (confirms it is not glucose)
No effective treatment currently; high-dose ascorbic acid may slow ochronosis

Case 10 - Homocystinuria

Presentation: Tall, thin teenager with dislocated lens (ectopia lentis - downward), intellectual disability, long fingers (Marfanoid habitus), premature atherosclerosis, thromboembolism. Elevated homocysteine in urine and blood.

Diagnosis: Cystathionine beta-synthase (CBS) deficiency - most common cause of homocystinuria

Biochemistry Viva Points:

CBS condenses homocysteine + serine → cystathionine (requires pyridoxal phosphate/B6 as cofactor)
Homocysteine accumulates → oxidative damage to vessel walls → premature atherosclerosis and thrombosis
Homocysteine interferes with cross-linking of collagen and fibrillin - hence Marfanoid features and ectopia lentis (downward displacement, unlike Marfan where displacement is upward)
~50% of patients respond to high-dose pyridoxine (B6)
Non-B6 responsive: treated with methionine restriction, cystine supplementation, betaine (remethylates homocysteine back to methionine), folate + B12 (support remethylation)
Mild hyperhomocysteinemia: linked to cardiovascular disease in general population

SECTION D: HEME METABOLISM & HEMOGLOBIN

Case 11 - G6PD Deficiency (Hemolytic Anemia)

Presentation: 63-year-old male started a sulfonamide antibiotic 4 days ago for UTI. Now presents with: dark/brownish urine, fatigue, scleral icterus (jaundice), tachycardia, pale appearance, mild splenomegaly. Peripheral blood smear: Heinz bodies (precipitated hemoglobin), reticulocytosis. Urine positive for hemoglobin (hemoglobinuria).

Diagnosis: Glucose 6-phosphate dehydrogenase (G6PD) deficiency - X-linked recessive

Biochemistry Viva Points:

G6PD is the first enzyme of the pentose phosphate pathway (HMP shunt) - produces NADPH
NADPH is required to keep glutathione in its reduced form (GSH) via glutathione reductase
GSH protects RBCs from oxidative damage; without it, Hb oxidizes to methemoglobin and precipitates as Heinz bodies → RBC membrane damaged → hemolysis
RBCs have no mitochondria - the HMP shunt is their ONLY source of NADPH
Triggers: oxidative drugs (sulfonamides, primaquine, dapsone), fava beans, infection
Jaundice = unconjugated hyperbilirubinemia from excess heme breakdown
Bilirubin pathway: Heme → Biliverdin → Unconjugated bilirubin (water insoluble, transported bound to albumin) → Liver conjugates with glucuronic acid → Conjugated bilirubin (water soluble) → bile → stercobilin (feces) / urobilinogen → urobilin (urine)
Treatment: Remove offending drug; supportive care. Most recover without transfusion.

Case 12 - Beta-Thalassemia Minor (Microcytic Anemia)

Presentation: 24-year-old asymptomatic male, flagged at pre-employment medical. Normal physical exam. Hemoglobin: 9.6 g/dL (L), MCV: 70 μm3 (L), serum iron: normal.

Hb Electrophoresis:

	Patient	Normal
HbA	90% (L)	96-98%
HbA2	6% (H)	<3%
HbF	4% (H)	<2%

Diagnosis: Beta-thalassemia trait (beta-thalassemia minor)

Biochemistry Viva Points:

Beta-thalassemia = reduced or absent synthesis of beta-globin chains (mutations usually affect transcription or mRNA processing, not coding sequence)
With fewer beta chains, alpha chains accumulate and precipitate in developing RBCs, causing ineffective erythropoiesis
HbA2 (alpha2delta2) elevation is the hallmark of beta-thal trait - delta chains compensate for absent beta chains
HbF (alpha2gamma2) elevation - fetal hemoglobin reactivation
Normal serum iron distinguishes from iron-deficiency anemia (which is the main differential for microcytic anemia)
Iron supplements will NOT help in thalassemia trait - viva trap
Autosomal recessive; two trait carriers have 25% chance of Cooley anemia (beta-thalassemia major) in offspring
Cooley anemia (homozygous): severe hemolytic anemia, extramedullary hematopoiesis, iron overload, requires regular transfusions + deferoxamine (iron chelator)

Case 13 - Sickle Cell Disease

Presentation: Child with recurrent painful crises, dactylitis (swollen hands/feet), acute chest syndrome, splenic sequestration, increased susceptibility to encapsulated bacteria (functional asplenia).

Diagnosis: Sickle cell disease (HbSS)

Biochemistry Viva Points:

Point mutation: glutamic acid → valine at position 6 of beta-globin (GAG → GTG at codon 6)
Single amino acid change converts hydrophilic glutamate to hydrophobic valine
In deoxygenated state, HbS polymerizes into rigid fibers, distorting RBCs into sickle shapes
Vaso-occlusion from sickled cells causes ischemic pain crises
HbS has reduced oxygen affinity - right-shifted oxygen-dissociation curve (beneficial for O2 release to tissues)
HbAS (sickle trait): protective against Plasmodium falciparum malaria - explains high frequency in malaria-endemic regions (balanced polymorphism)
Newborn screening: hemoglobin electrophoresis (FS pattern = fetal + sickle)
Treatment: Hydroxyurea (increases HbF, reduces sickling), regular transfusions, bone marrow transplant

Case 14 - Methemoglobinemia

Presentation: Infant with cyanosis unresponsive to oxygen therapy, chocolate-brown blood. History of well-water feeding or exposure to nitrates/nitrites or dapsone.

Diagnosis: Methemoglobinemia

Biochemistry Viva Points:

Methemoglobin = iron oxidized from Fe2+ (ferrous) → Fe3+ (ferric) - cannot bind O2
Nitrites (from contaminated well water), dapsone, benzocaine cause oxidative stress converting Hb to MetHb
Normal RBCs have methemoglobin reductase (NADH-cytochrome b5 reductase) to convert MetHb back to Hb
Blood is chocolate-brown; pulse oximetry unreliable (reads falsely ~85%)
Treatment: Methylene blue - reduces MetHb via NADPH-dependent pathway; requires G6PD (hence contraindicated in G6PD deficiency)

SECTION E: DNA & MOLECULAR BIOLOGY

Case 15 - Xeroderma Pigmentosum (XP)

Presentation: 6-year-old male with extreme sun sensitivity; freckle-like hyperpigmentation on sun-exposed skin; actinic keratosis; telangiectasia; photophobia. Two biopsied skin lesions are squamous cell carcinomas.

Diagnosis: Xeroderma pigmentosum - defect in nucleotide excision repair (NER)

Biochemistry Viva Points:

NER removes bulky DNA lesions caused by UV radiation: pyrimidine (TT) dimers (cyclobutane dimers) and (6-4) photoproducts
NER mechanism: damage recognition → dual incision ~25-30 nucleotides around the lesion → gap filling by DNA pol → ligation
XP mutations affect XP proteins (XPA through XPG) involved in this recognition-incision process
Without NER, UV-induced dimers accumulate → mutations in proto-oncogenes/tumor suppressor genes → cancer
XP cells also show defective transcription-coupled repair (TCR) - repair of actively transcribed genes
Cockayne syndrome = defect in TCR only (no skin cancer, but premature aging, neurodegeneration)
Treatment: Total UV avoidance. Regular surveillance for skin cancers. Xeroderma patients often have >1000-fold increased risk of skin cancer.

Case 16 - Lyme Disease / Doxycycline and Ribosome Biochemistry

Presentation: 34-year-old female returns from camping trip; develops expanding circular rash on left thigh (~11 cm), with central clearing (erythema migrans - bullseye rash), myalgia, arthralgia, headache, low-grade fever over 2 weeks.

Diagnosis: Lyme disease - Borrelia burgdorferi (tick-borne, Ixodes genus)

Biochemistry Viva Points:

Doxycycline (tetracycline class) - binds the 30S ribosomal subunit of prokaryotes, blocks aminoacyl-tRNA from entering the A site
Tetracyclines are bacteriostatic
Prokaryotic ribosomes: 70S (30S + 50S); Eukaryotic: 80S (40S + 60S) - basis of antibiotic selectivity
Peptidyltransferase (on the large subunit - 23S rRNA) is a ribozyme - catalyzes peptide bond formation
Shine-Dalgarno sequence (purine-rich in mRNA, near AUG) aligns with 16S rRNA of the 30S subunit to initiate prokaryotic translation
Lab diagnosis: two-tier testing - ELISA (screening) → if positive → Western blot (confirmation). Both detect antibodies against B. burgdorferi proteins.

SECTION F: NUCLEOTIDE METABOLISM

Case 17 - Gout (Purine Metabolism Disorder)

Presentation: 22-year-old obese male (BMI 31) presents with severe inflammatory pain at base of thumb (1st carpometacarpal joint). Joint aspirate: needle-shaped monosodium urate (MSU) crystals (negatively birefringent under polarized light). Blood urate: 8.5 mg/dL (normal: <8.0 mg/dL). Unusually young age suggests an underlying enzymopathy.

Diagnosis: Gout - MSU crystal deposition disease. Young age suggests partial HGPRT deficiency (Kelley-Seegmiller syndrome) or PRPP synthetase overactivity.

Biochemistry Viva Points:

Uric acid is the final product of purine degradation in humans (xanthine → uric acid via xanthine oxidase)
Primates (including humans) lack uricase (urate oxidase) - hence uric acid accumulates (not further broken down to more soluble allantoin)
HGPRT (hypoxanthine-guanine phosphoribosyl transferase) - key salvage enzyme. Deficiency shunts purines to degradation instead of recycling → more uric acid
Complete HGPRT deficiency = Lesch-Nyhan syndrome (X-linked): gout + severe neurologic disorder + self-mutilation
Allopurinol is converted to oxypurinol which is a suicide inhibitor of xanthine oxidase (mechanism-based inhibition) - reduces uric acid production
Colchicine inhibits microtubule polymerization in neutrophils - prevents neutrophil migration into joint (anti-inflammatory in gout, does not lower uric acid)
Risk factors: obesity, high purine diet (red meat, shellfish), alcohol (beer especially), diuretics, dehydration

Case 18 - Lesch-Nyhan Syndrome

Presentation: Young male infant with developmental delay, choreoathetosis, spasticity, intellectual disability, compulsive self-mutilation (biting fingers and lips), severe gout with kidney stones.

Diagnosis: Complete HGPRT deficiency - Lesch-Nyhan syndrome (X-linked recessive)

Biochemistry Viva Points:

HGPRT salvages hypoxanthine and guanine → IMP and GMP respectively, reusing preformed purine bases
Complete absence: all hypoxanthine and guanine are degraded to uric acid → severe hyperuricemia and gout
The neurologic features are due to dopamine neuron dysfunction (HGPRT is especially important in basal ganglia dopaminergic neurons)
De novo purine synthesis is upregulated because salvage pathway is absent (no feedback inhibition of PRPP amidotransferase by IMP/GMP)
Allopurinol manages gout but does NOT improve neurologic symptoms

SECTION G: VITAMINS & COFACTORS

Case 19 - Vitamin B12 Deficiency (Pernicious Anemia)

Presentation: 58-year-old female with fatigue, glossitis (smooth, beefy-red tongue), subacute combined degeneration of the spinal cord (paresthesias, ataxia, positive Romberg), macrocytic anemia (elevated MCV), hypersegmented neutrophils.

Diagnosis: Pernicious anemia - autoimmune destruction of gastric parietal cells → loss of intrinsic factor → B12 malabsorption

Biochemistry Viva Points:

Vitamin B12 (cobalamin) acts as cofactor for two enzymes:
1. Methylmalonyl-CoA mutase (mitochondria) - converts methylmalonyl-CoA → succinyl-CoA (odd-chain FA and branched-chain AA metabolism)
2. Methionine synthase (cytoplasm) - converts homocysteine + methyltetrahydrofolate → methionine + THF
B12 deficiency causes methylmalonic acidemia/aciduria (diagnostic marker) and hyperhomocysteinemia
Folate trap: B12 is required to regenerate THF from methylTHF; without B12, folate is "trapped" as methylTHF, unavailable for DNA synthesis → megaloblastic anemia
Serum methylmalonic acid distinguishes B12 deficiency from folate deficiency (elevated only in B12 deficiency)
Schilling test: was used to distinguish dietary B12 deficiency from pernicious anemia
Treatment: IM hydroxocobalamin or cyanocobalamin (bypasses intrinsic factor)

Case 20 - Vitamin D Deficiency (Rickets / Osteomalacia)

Presentation: 3-year-old child with bowing of legs (genu varum), rachitic rosary (costochondral beading), craniotabes (soft skull bones), widened wrists. Laboratory: low calcium, low phosphate, elevated ALP, elevated PTH, low 25-hydroxyvitamin D.

Diagnosis: Nutritional rickets - vitamin D deficiency

Biochemistry Viva Points:

Vitamin D metabolism pathway:
- Skin: 7-dehydrocholesterol + UV → cholecalciferol (D3)
- Liver: D3 → 25-hydroxyvitamin D3 (calcidiol) - via 25-hydroxylase (principal storage form, measured clinically)
- Kidney: 25-OH D3 → 1,25-dihydroxyvitamin D3 (calcitriol) - via 1-alpha-hydroxylase (active hormone; stimulated by PTH, low phosphate)
Calcitriol acts as a steroid hormone - nuclear receptor - promotes intestinal Ca2+ and phosphate absorption
Deficiency → low serum Ca2+ → secondary hyperparathyroidism → PTH mobilizes Ca2+ from bone (osteoclast activation), increases renal phosphate wasting → undermineralized bone matrix (osteoid accumulation) → rickets in children, osteomalacia in adults

SECTION H: COAGULATION & THROMBOSIS

Case 21 - Deep Venous Thrombosis (DVT) with Factor V Leiden

Presentation: 19-year-old female, 10 days post-splenectomy following bicycle accident; right knee immobilized; still on oral contraceptive pills (OCP). Now has right calf pain, swelling, erythema, warmth. Ultrasound confirms DVT.

Diagnosis: Deep venous thrombosis - precipitated by Virchow's triad (stasis + hypercoagulable state from OCP + vascular injury from surgery)

Biochemistry Viva Points:

Factor V Leiden: point mutation (Arg506Gln in Factor V) makes Factor Va resistant to inactivation by Protein C
Protein C (activated by thrombomodulin-thrombin complex) inactivates Factors Va and VIIIa - normally limits clotting
Factor V Leiden = most common inherited thrombophilia in Caucasians
OCP increases risk of DVT by raising levels of clotting factors (Factor VII, VIII, X, fibrinogen) and reducing Protein S
Heparin mechanism: activates antithrombin III → inhibits thrombin (IIa) and Factor Xa
Warfarin mechanism: inhibits vitamin K epoxide reductase → impairs gamma-carboxylation of Factors II, VII, IX, X and Proteins C and S (vitamin K-dependent factors)
Heparin works immediately; warfarin takes 3-5 days to achieve full effect (long half-life of existing clotting factors)

SECTION I: GENETIC & TRANSPORT DEFECTS

Case 22 - Cystic Fibrosis (CF)

Presentation: 2-day-old female neonate has NOT had a first bowel movement (failure to pass meconium). Distended abdomen, bilious vomiting. Abdominal X-ray confirms meconium ileus (obstruction of ileum by thick meconium). Chloride sweat test: Cl- >60 mEq/L (diagnostic). Genetic analysis confirms CF.

Diagnosis: Cystic fibrosis - CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene mutation

Biochemistry Viva Points:

CFTR = ATP-gated chloride channel in apical membrane of epithelial cells (lung, pancreas, sweat glands, intestine)
Most common mutation: ΔF508 (deletion of phenylalanine at position 508) - codon deletion (in-frame, NOT frameshift). The mutant protein misfolds and is retained in the ER and degraded by the ubiquitin-proteasome system
Without CFTR: Cl- cannot exit the cell → Na+ and water follow Cl- back → dehydrated, thick, viscous mucus
Sweat glands: Opposite effect - CFTR reabsorbs Cl- in sweat duct; without CFTR, Cl- (and Na+) lost in sweat → salty sweat (diagnostic >60 mEq/L)
Steatorrhea: Thick mucus blocks pancreatic ducts → pancreatic exocrine insufficiency → malabsorption of fats and fat-soluble vitamins (A, D, E, K)
Most common lethal autosomal recessive in Caucasians (~1/3,300 live births)
CFTR modulators (ivacaftor/lumacaftor/tezacaftor-elexacaftor) are now approved for specific mutations

Case 23 - Wilson's Disease (Copper Metabolism)

Presentation: 20-year-old with hepatitis, neuropsychiatric symptoms (tremor, dysarthria, personality change), and Kayser-Fleischer rings (golden-brown rings at periphery of cornea). Low serum ceruloplasmin, elevated urinary copper.

Diagnosis: Wilson's disease - ATP7B gene mutation (autosomal recessive)

Biochemistry Viva Points:

ATP7B is a copper-transporting P-type ATPase in hepatocytes - responsible for:
1. Incorporating copper into ceruloplasmin (the major copper-carrying protein)
2. Excreting copper into bile
Deficiency: copper accumulates in liver → spills into blood → deposits in brain, cornea (K-F rings), kidneys, joints
Low serum ceruloplasmin (paradoxically, copper is elevated in tissues but ceruloplasmin cannot be assembled properly)
24-hour urine copper: elevated
Liver copper on biopsy: >250 μg/g dry weight
Treatment: D-penicillamine (copper chelator), trientine, zinc (induces metallothionein in enterocytes, blocks copper absorption)

Case 24 - Hemochromatosis (Iron Overload)

Presentation: Middle-aged male with fatigue, arthralgia, liver cirrhosis, diabetes mellitus ("bronze diabetes"), bronze/grey skin pigmentation, hypogonadism, cardiomyopathy. Markedly elevated serum ferritin and transferrin saturation (>45%).

Diagnosis: Hereditary hemochromatosis - HFE gene mutation (C282Y most common) - autosomal recessive

Biochemistry Viva Points:

HFE protein normally upregulates hepcidin (a peptide hormone from liver) which binds ferroportin on enterocytes and macrophages, blocking iron export into plasma
Defective HFE → low hepcidin → ferroportin stays active → uncontrolled iron absorption from gut
Iron saturates transferrin → deposits as hemosiderin and ferritin in liver, pancreas, heart, skin, gonads
Prussian blue stain (Perls' stain) of liver biopsy: blue iron deposits in hepatocytes
Liver: cirrhosis + increased risk of HCC
Pancreas: destruction of islet cells → secondary diabetes
Skin: iron + melanin = bronze pigmentation
Treatment: Phlebotomy (1 unit/week until ferritin <50 ng/mL) - most effective; deferoxamine for patients who cannot tolerate phlebotomy

Case 25 - Acute Intermittent Porphyria (AIP)

Presentation: Young woman with recurrent attacks of severe colicky abdominal pain, vomiting, constipation, neuropsychiatric symptoms (anxiety, psychosis, seizures), and peripheral neuropathy. Dark (reddish-brown) urine on standing. Attacks precipitated by fasting, drugs (barbiturates, sulfonamides), or hormonal changes.

Diagnosis: Acute intermittent porphyria - porphobilinogen (PBG) deaminase deficiency

Biochemistry Viva Points:

Heme synthesis pathway (key steps):
- ALA synthase (rate-limiting; mitochondria) → ALA → porphobilinogen (PBG) → hydroxymethylbilane → uroporphyrinogen III → coproporphyrinogen III → protoporphyrin IX → Heme
AIP = deficiency of HMB synthase (porphobilinogen deaminase) - causes ALA and PBG accumulation
ALA and PBG are neurotoxic - explain abdominal pain and neuropsychiatric symptoms
Drug/fasting precipitants work by increasing demand for heme (via inducing ALA synthase) → more toxic precursors accumulate
Diagnostic tests: Elevated urine PBG (Watson-Schwartz test = positive, turns red with Ehrlich's reagent), elevated ALA
No skin photosensitivity in AIP (unlike porphyria cutanea tarda where porphyrins accumulate in skin)
Treatment: IV glucose (suppresses ALA synthase via glucose-mediated repression), IV hemin (heme arginate - provides feedback suppression of ALA synthase), avoid precipitants

Quick Viva Summary Table

Case	Condition	Key Enzyme/Defect	Classic Hallmark
1	Familial Hypercholesterolemia	LDL receptor loss	Xanthelasma, corneal arcus, early MI
2	LPL Deficiency	Lipoprotein lipase	Creamy plasma, pancreatitis, eruptive xanthomas
3	Von Gierke (GSD Ia)	Glucose 6-phosphatase	Hypoglycemia + lactic acidosis + hepatomegaly
4	Diabetic Ketoacidosis	Insulin deficiency	Kussmaul breathing, fruity breath, high ketones
5	Mutant Insulin	Proinsulin processing	RIA vs biological assay discordance
6	Phenylketonuria	Phenylalanine hydroxylase	Musty urine, intellectual disability, fair skin
7	MSUD	BCKA dehydrogenase complex	Maple syrup urine, neonatal encephalopathy
8	Citrullinemia/Urea Cycle	Argininosuccinate synthetase	Hyperammonemia, respiratory alkalosis, neonate
9	Alkaptonuria	Homogentisate oxidase	Black urine, ochronosis, arthritis
10	Homocystinuria	Cystathionine beta-synthase	Downward lens dislocation, thrombosis, Marfanoid
11	G6PD Deficiency	G6PD/HMP shunt	Heinz bodies, drug-triggered hemolysis
12	Beta-Thalassemia Trait	Beta-globin reduction	Elevated HbA2, microcytic anemia, normal iron
13	Sickle Cell Disease	HbS (Glu→Val mutation)	Vaso-occlusive crises, functional asplenia
14	Methemoglobinemia	MetHb reductase/oxidant	Cyanosis + chocolate blood + no response to O2
15	Xeroderma Pigmentosum	Nucleotide excision repair	Sun sensitivity, skin cancers in childhood
16	Lyme Disease	Ribosome/translation	Bullseye rash, doxycycline blocks 30S ribosome
17	Gout (young onset)	Xanthine oxidase/HGPRT	MSU crystals, young age = enzymopathy
18	Lesch-Nyhan Syndrome	Complete HGPRT loss	Self-mutilation + severe gout + X-linked
19	Pernicious Anemia	Intrinsic factor/B12	Macrocytic anemia + SACD + methylmalonic acid
20	Rickets	Vitamin D/1-alpha-hydroxylase	Bowing, rachitic rosary, low Ca, high PTH
21	DVT/Factor V Leiden	Protein C resistance	Post-surgery + OCP + immobilization
22	Cystic Fibrosis	CFTR (ΔF508)	Meconium ileus, salty sweat, steatorrhea
23	Wilson's Disease	ATP7B copper pump	K-F rings, low ceruloplasmin, neuropsychiatric
24	Hemochromatosis	HFE/hepcidin/ferroportin	Bronze diabetes, cirrhosis, high transferrin sat
25	Acute Intermittent Porphyria	PBG deaminase	Abdominal pain + dark urine + NO skin signs

Sources: Lippincott Illustrated Reviews: Biochemistry 8th Ed; Harper's Illustrated Biochemistry 32nd Ed; Basic Medical Biochemistry: A Clinical Approach 6th Ed.

Viva tip: For each case, be prepared to discuss: (1) the specific enzyme/protein defect, (2) the metabolic pathway disrupted, (3) why the clinical features arise biochemically, (4) the diagnostic test result that is pathognomonic, and (5) the biochemical basis of treatment.

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