Index

BIOCHEMISTRY – MRCOG Part 1 Deep-Dive Study Document

Purpose: Comprehensive revision resource for the MRCOG Part 1 examination. Scope: Core biochemical principles with emphasis on reproductive, placental, fetal, and pregnancy-related biochemistry. Estimated reading time: Deep coverage — 20,000+ words.

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Table of Contents

1. Carbohydrate Metabolism
2. Lipid Metabolism
3. Amino Acid & Protein Metabolism
4. Nucleotide Metabolism
5. Vitamins & Coenzymes
6. Hormone Biochemistry
7. Enzymology
8. Acid-Base & Body Fluids
9. Placental & Fetal Biochemistry

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1. Carbohydrate Metabolism

1.1 Overview of Carbohydrates in Pregnancy

Carbohydrates are the primary energy source for both the mother and the developing fetus. In pregnancy, maternal metabolism shifts to ensure a continuous glucose supply to the fetus. The fetus consumes approximately 4–6 mg/kg/min of glucose, placing significant demands on maternal carbohydrate metabolism. Pregnancy is characterised by accelerated starvation — after an overnight fast, pregnant women show lower blood glucose and higher ketone body levels compared to non-pregnant women. This reflects increased placental consumption of glucose and altered hormonal milieu (high oestrogen, progesterone, human placental lactogen — hPL).

1.2 Glycolysis

Location: Cytosol of all cells. Pathway: Glucose → 2 Pyruvate (under aerobic conditions) or 2 Lactate (under anaerobic conditions).

• 10 enzymatic steps divided into two phases:
• Energy investment phase (steps 1–5): 2 ATP consumed.
• Energy payoff phase (steps 6–10): 4 ATP + 2 NADH produced.
• Net yield: 2 ATP, 2 NADH, and 2 pyruvate per molecule of glucose.
• Key regulatory enzymes:
• Hexokinase / Glucokinase: Glucose → Glucose-6-phosphate. Hexokinase (most tissues) is inhibited by G6P; glucokinase (liver, pancreas) is induced by insulin and has a higher Km (acts as glucose sensor).
• Phosphofructokinase-1 (PFK-1): Fructose-6-phosphate → Fructose-1,6-bisphosphate. Rate-limiting step. Activated by AMP, ADP, fructose-2,6-bisphosphate; inhibited by ATP and citrate.
• Pyruvate kinase: Phosphoenolpyruvate → Pyruvate. Activated by fructose-1,6-bisphosphate; inhibited by ATP and alanine.

Aerobic vs Anaerobic Fate of Pyruvate: - Aerobic: Pyruvate enters mitochondria, converted to acetyl-CoA by pyruvate dehydrogenase (PDH complex), then enters TCA cycle. - Anaerobic: Pyruvate reduced to lactate by lactate dehydrogenase (LDH), regenerating NAD+ to allow glycolysis to continue. This occurs in RBCs (no mitochondria), exercising muscle, and in the fetus during labour (fetal anaerobic metabolism → lactic acidosis).

Clinical relevance in obstetrics: - Fetal hypoxia → anaerobic glycolysis predominates → lactate accumulation → metabolic acidosis → abnormal fetal heart rate patterns, low cord pH. - Lactate measurement in fetal scalp blood sampling or cord blood. - Lactic acidosis can also complicate pregnancy in conditions like severe pre-eclampsia, placental abruption, and maternal sepsis.

Key Points for MRCOG: - Glycolysis occurs in cytosol — no mitochondria required. - Net 2 ATP per glucose (4 produced, 2 consumed). - 2 NADH per glucose — shuttle systems (glycerol-3-phosphate shuttle or malate-aspartate shuttle) transfer electrons into mitochondria for oxidative phosphorylation. - In RBCs, glycolysis is the sole energy source; they lack mitochondria.

1.3 The Citric Acid Cycle (TCA Cycle / Krebs Cycle)

Location: Mitochondrial matrix. Function: Complete oxidation of acetyl-CoA to CO₂, generating NADH, FADH₂, and GTP.

Steps in brief: 1. Acetyl-CoA (2C) + Oxaloacetate (4C) → Citrate (6C) — citrate synthase. 2. Citrate → Isocitrate — aconitase. 3. Isocitrate → α-Ketoglutarate (5C) + CO₂ — isocitrate dehydrogenase (NADH produced). 4. α-Ketoglutarate → Succinyl-CoA (4C) + CO₂ — α-ketoglutarate dehydrogenase (NADH produced). 5. Succinyl-CoA → Succinate — succinyl-CoA synthetase (GTP produced — substrate-level phosphorylation). 6. Succinate → Fumarate — succinate dehydrogenase (FADH₂ produced; this enzyme is also Complex II of ETC). 7. Fumarate → Malate — fumarase. 8. Malate → Oxaloacetate — malate dehydrogenase (NADH produced).

Net yield per acetyl-CoA: 3 NADH, 1 FADH₂, 1 GTP (≈ 10 ATP equivalents via oxidative phosphorylation).

Regulation: - Key regulated enzymes: Isocitrate dehydrogenase (activated by ADP, inhibited by ATP and NADH) and α-ketoglutarate dehydrogenase (inhibited by succinyl-CoA, ATP, NADH). - Citrate synthase is inhibited by ATP and NADH.

Clinical relevance: - TCA cycle intermediates are withdrawn for biosynthesis (e.g., citrate for fatty acid synthesis, α-ketoglutarate for amino acid synthesis) — these are replenished via anaplerotic reactions (e.g., pyruvate → oxaloacetate by pyruvate carboxylase). - Succinate dehydrogenase deficiency — mitochondrial disorder causing encephalopathy, myopathy, and in pregnancy, potential for pre-eclampsia-like symptoms.

1.4 Oxidative Phosphorylation & Electron Transport Chain

Location: Inner mitochondrial membrane. Function: Transfer of electrons from NADH and FADH₂ to O₂, coupled with ATP synthesis.

Complexes of the ETC:

Complex	Name	Electron Carrier	Proton Pumping	Features
Complex I	NADH dehydrogenase (NADH:ubiquinone oxidoreductase)	NADH → CoQ	Yes (4 H⁺)	Contains FMN and Fe-S clusters. Inhibited by rotenone, amytal.
Complex II	Succinate dehydrogenase	FADH₂ → CoQ	No	Also part of TCA cycle. Contains FAD and Fe-S. Inhibited by malonate.
Complex III	Cytochrome bc1 complex (CoQ:cytochrome c oxidoreductase)	CoQ → Cyt c	Yes (4 H⁺)	Contains cytochromes b and c1, Fe-S. Q cycle transfers electrons. Inhibited by antimycin A.
Complex IV	Cytochrome c oxidase	Cyt c → O₂	Yes (2 H⁺)	Contains cytochromes a and a₃, Cu centres. Inhibited by cyanide (CN⁻), carbon monoxide (CO), azide.
Complex V	ATP synthase	—	Uses H⁺ gradient	Chemiosmotic coupling — F₀ (proton channel) + F₁ (catalytic head).

Chemiosmotic Theory (Peter Mitchell, Nobel 1978): - Electron transport creates a proton gradient (proton motive force) across the inner mitochondrial membrane. - Protons flow back through ATP synthase, driving the conformational change that synthesizes ATP from ADP + Pi. - P/O ratio: ~2.5 ATP per NADH (≈ 10 H⁺), ~1.5 ATP per FADH₂ (≈ 6 H⁺).

Uncoupling: - Brown adipose tissue (BAT): Contains UCP1 (uncoupling protein 1) — dissipates the proton gradient as heat. Critical for non-shivering thermogenesis in neonates (see Section 9). - Chemical uncouplers: 2,4-dinitrophenol (DNP) — causes hyperthermia, historically used for weight loss, now banned.

Clinical relevance in obstetrics: - Hypoxia-ischaemia in the fetus/newborn → failure of oxidative phosphorylation → ATP depletion → cell death (necrosis/apoptosis). - Mitochondrial inheritance — maternal transmission. Mitochondrial disorders can present in pregnancy with fatigue, myopathy, lactic acidosis. - Pre-eclampsia — mitochondrial dysfunction (impaired Complex I activity) implicated in placental oxidative stress.

Key Points for MRCOG: - Complexes I, III, IV pump protons; Complex II does not. - ATP synthase = Complex V. - Cyanide toxicity in pregnancy — rare but catastrophic; fetal compromise. - Neonatal thermogenesis via UCP1 in BAT is crucial — failure contributes to neonatal hypothermia.

1.5 Gluconeogenesis

Location: Primarily liver (also renal cortex in prolonged fasting). Function: Synthesis of glucose from non-carbohydrate precursors — lactate, amino acids (especially alanine), and glycerol. When: During fasting, starvation, low-carbohydrate diet, and between meals.

Key differences from glycolysis (the "bypass reactions"):

Glycolysis (forward)	Gluconeogenesis (reverse) — Bypass enzyme
Hexokinase/Glucokinase: G → G6P	Glucose-6-phosphatase: G6P → G (not present in muscle/brain)
PFK-1: F6P → F1,6BP	Fructose-1,6-bisphosphatase: F1,6BP → F6P
Pyruvate kinase: PEP → Pyruvate	Pyruvate carboxylase + PEP carboxykinase (PEPCK): Pyruvate → OAA → PEP

Overall equation: 2 Pyruvate + 6 ATP + 2 NADH + 2 H₂O → Glucose + 6 ADP + 6 Pi + 2 NAD⁺.

Important Enzymes:

1. Pyruvate Carboxylase: - Converts pyruvate → oxaloacetate in mitochondria. - Requires biotin (Vitamin B7) as cofactor. - Activated by acetyl-CoA (high levels signal need for gluconeogenesis). - Provides oxaloacetate to replenish TCA cycle intermediates (anaplerosis) or for gluconeogenesis.

2. Phosphoenolpyruvate Carboxykinase (PEPCK): - Converts oxaloacetate → PEP (in cytosol or mitochondria, depending on species; in humans: cytosolic).

3. Fructose-1,6-bisphosphatase: - Hydrolyses fructose-1,6-bisphosphate → fructose-6-phosphate + Pi.

4. Glucose-6-phosphatase: - Converts G6P → glucose + Pi. - Critically absent from muscle and brain — these tissues cannot release free glucose into the circulation. - Deficiency causes von Gierke's disease (glycogen storage disease type I).

Substrates:

Precursor	Tissue Source	Pathway
Lactate	RBCs, exercising muscle, fetus (labour)	Lactate → Pyruvate → Gluconeogenesis (Cori cycle)
Alanine	Muscle (protein breakdown)	Alanine → Pyruvate → Gluconeogenesis (Alanine cycle / Cahill cycle)
Glycerol	Adipose tissue (lipolysis)	Glycerol → Glycerol-3-P → DHAP → Gluconeogenesis

The Cori Cycle: - Muscle produces lactate (anaerobic glycolysis) → lactate released into blood → taken up by liver → converted to glucose via gluconeogenesis → glucose returned to muscle.

The Alanine Cycle (Cahill Cycle): - Muscle breaks down amino acids → transamination produces alanine → alanine transported to liver → deaminated → pyruvate → glucose → returned to muscle. - Accounts for ~30–50% of gluconeogenic substrate during prolonged fasting.

Hormonal Regulation: - Glucagon (↑) — stimulates gluconeogenesis, inhibits glycolysis. - Insulin (↓) — inhibits gluconeogenesis, stimulates glycolysis. - Cortisol (↑) — induces key gluconeogenic enzymes (PEPCK, G6Pase). - Growth hormone (↑) — increases gluconeogenic substrate availability.

Clinical relevance in obstetrics: - Pregnancy is a diabetogenic state — placental hormones (hPL, oestrogen, progesterone) cause insulin resistance, leading to higher postprandial glucose and increased gluconeogenesis between meals. - Hyperemesis gravidarum — prolonged vomiting → starvation ketosis, reliance on gluconeogenesis from amino acids → muscle wasting. - Pre-eclampsia — altered gluconeogenesis and insulin resistance are features of the metabolic syndrome associated with pre-eclampsia.

1.6 Glycogen Metabolism

Glycogen: A branched polymer of glucose (α-1,4 linkages with α-1,6 branch points), the storage form of glucose in the body.

Storage sites: Liver (up to 10% of weight, ~100g) and skeletal muscle (1–2% of weight, ~400g total). Function: Liver glycogen maintains blood glucose homeostasis (for brain, RBCs); muscle glycogen provides fuel for contraction (muscle lacks glucose-6-phosphatase, so cannot export glucose).

1.6.1 Glycogenesis (Synthesis)

• Enzymes involved:
• UDP-glucose pyrophosphorylase: Glucose-1-P + UTP → UDP-glucose + PPi.
• Glycogen synthase: Adds UDP-glucose to the non-reducing end of glycogen chain (α-1,4 bond). Rate-limiting enzyme.

• Branching enzyme (amylo-1,4→1,6-transglucosylase): Transfers 6–8 glucose blocks to create α-1,6 branches.

• Glycogenin: A primer protein; the first few glucose molecules are attached to a tyrosine residue of glycogenin (autoglucosylation), then glycogen synthase takes over.

Regulation of glycogen synthase: - Active form: Dephosphorylated (glycogen synthase a). - Inactive form: Phosphorylated (glycogen synthase b) — phosphorylated by protein kinase A (PKA, activated by cAMP → glucagon/adrenaline). - Insulin activates protein phosphatase 1 (PP1) → dephosphorylates glycogen synthase → activates it. - Allosteric activation: Glucose-6-phosphate.

1.6.2 Glycogenolysis (Breakdown)

• Key enzyme: Glycogen phosphorylase — cleaves α-1,4 linkages, releasing glucose-1-phosphate. Rate-limiting enzyme.
• Debranching enzyme: Removes α-1,6 branches.
• Glucose-1-phosphate → Glucose-6-phosphate (by phosphoglucomutase).
• In liver: G6P → Glucose (via glucose-6-phosphatase) → released into blood.
• In muscle: G6P enters glycolysis directly (no G6Pase).

Regulation of glycogen phosphorylase: - Liver form: Activated by glucagon (cAMP cascade → phosphorylase kinase → phosphorylase a) and by low glucose (allosteric effect). - Muscle form: Activated by adrenaline (cAMP cascade) and by AMP (allosteric, signals energy need). - Ca²⁺ activates phosphorylase kinase in muscle (during contraction).

1.6.3 Glycogen Storage Diseases

Type	Name	Enzyme Defect	Clinical Features
I	von Gierke's disease	Glucose-6-phosphatase	Severe hypoglycaemia, lactic acidosis, hyperuricaemia, hepatomegaly, growth retardation. Most severe. Cannot release glucose from liver.
II	Pompe disease	α-1,4-glucosidase (lysosomal)	Cardiomegaly, hypotonia, death in infancy (cardiac form).
III	Cori disease	Debranching enzyme	Milder than type I; hepatomegaly, hypoglycaemia.
IV	Andersen disease	Branching enzyme	Cirrhosis, liver failure.
V	McArdle disease	Muscle glycogen phosphorylase	Exercise intolerance, muscle cramps, myoglobinuria.
VI	Hers disease	Liver glycogen phosphorylase	Mild hypoglycaemia, hepatomegaly.

Key point for MRCOG: von Gierke's (type I) — glycogen cannot be released as glucose; patients require frequent feeds, uncooked cornstarch to provide sustained glucose; pregnancy in these patients is high-risk.

1.7 Pentose Phosphate Pathway (PPP)

Location: Cytosol. Alternate name: Hexose monophosphate shunt. Function: Generates NADPH (for reductive biosynthesis and antioxidant defence) and ribose-5-phosphate (for nucleotide synthesis).

Two Phases:

1. Oxidative Phase (irreversible): - Glucose-6-phosphate → 6-phosphogluconate → Ribulose-5-phosphate. - Key enzyme: Glucose-6-phosphate dehydrogenase (G6PD) — rate-limiting, produces NADPH. - Produces 2 NADPH + 1 ribulose-5-phosphate per G6P.

2. Non-Oxidative Phase (reversible): - Ribulose-5-phosphate → Ribose-5-phosphate (for nucleotide synthesis). - Interconversions with glycolytic intermediates (fructose-6-phosphate, glyceraldehyde-3-phosphate) allow the cell to balance NADPH and pentose needs.

NADPH Uses: - Fatty acid synthesis (liver, adipose, mammary gland during lactation). - Steroid synthesis (ovary, placenta, testis, adrenal cortex). - Reduced glutathione (GSH) maintenance — glutathione reductase uses NADPH to convert GSSG (oxidised) to GSH (reduced). GSH is critical antioxidant, especially in RBCs. - Cytochrome P450 system (liver, placenta) — uses NADPH for drug metabolism and steroid hydroxylation. - Phagocytosis — NADPH oxidase produces superoxide for bacterial killing (respiratory burst). Deficiency → chronic granulomatous disease.

G6PD Deficiency

Epidemiology: X-linked recessive — affects ~400 million people worldwide. Common in Africa, Mediterranean, Middle East, and Southeast Asia (malaria-endemic regions — provides partial resistance to P. falciparum).

Biochemistry: - Defective G6PD → reduced NADPH → reduced GSH → inability to detoxify H₂O₂ → oxidative haemolysis. - RBCs are vulnerable (no mitochondria, no other NADPH source).

Triggers of haemolysis: - Drugs: Primaquine, sulphonamides, nitrofurantoin, dapsone, aspirin, NSAIDs (some). - Infections: Bacterial/viral — immune response produces oxidants. - Foods: Fava beans (favism) — contain vicine and divicine, potent oxidants. - Neonatal jaundice — common presentation in G6PD-deficient infants.

Clinical presentation: Acute haemolytic anaemia, jaundice, dark urine (haemoglobinuria), back pain. Self-limiting in many cases (older RBCs are destroyed; younger cells with higher enzyme activity survive).

Pregnancy considerations: - Screening for G6PD deficiency is not routine in the UK but is considered in high-prevalence ethnic groups. - Avoid oxidant drugs in pregnancy. - G6PD deficiency does not increase pregnancy complications per se, but drug-induced haemolysis is a risk. - Neonatal jaundice: G6PD-deficient newborns are at higher risk, requiring phototherapy.

Key Point for MRCOG: G6PD is the most common enzyme deficiency worldwide; X-linked; triggers: fava beans, sulphonamides, primaquine; leads to oxidative haemolysis.

1.8 Fructose Metabolism

Dietary sources: Fruit, honey, sucrose (table sugar → glucose + fructose), high-fructose corn syrup.

Two main pathways:

1. Fructolysis (major pathway, in liver, kidney, small intestine):
2. Fructose → Fructose-1-phosphate (by fructokinase, not PFK — bypasses glycolytic regulation).
3. Fructose-1-phosphate → Glyceraldehyde + DHAP (by aldolase B).
4. Glyceraldehyde → Glyceraldehyde-3-phosphate → enters glycolysis at triose phosphate level.

5. Net effect: Fructose enters glycolysis below the rate-limiting PFK-1 step — rapid glycolysis independent of insulin regulation.

6. Minor pathway (in adipose, muscle):

7. Fructose → Fructose-6-phosphate (by hexokinase — but hexokinase has high affinity for glucose; only significant at high fructose concentrations).

Fructose Disorders

1. Essential Fructosuria: - Defect: Fructokinase deficiency (autosomal recessive, benign). - Biochemistry: Fructose accumulates in blood → excreted in urine (fructosuria). - Clinical: Asymptomatic, incidental finding on urinalysis. No hypoglycaemia, no liver disease.

2. Hereditary Fructose Intolerance (HFI): - Defect: Aldolase B deficiency (autosomal recessive, more common in children). - Biochemistry: Fructose-1-phosphate accumulates → traps phosphate → depletes ATP and Pi → inhibits gluconeogenesis and glycogenolysis. - Clinical: Symptoms appear after fructose ingestion (fruits, sucrose) in infancy: - Acute: Nausea, vomiting, hypoglycaemia, abdominal pain, sweating. - Chronic: Hepatomegaly, jaundice, cirrhosis, renal Fanconi syndrome (phosphaturia, aminoaciduria, metabolic acidosis). - Severe → liver failure, death if not recognized. - Diagnosis: Avoidance of fructose leads to rapid improvement. - Management: Strict fructose-free diet. Unlike essential fructosuria, HFI is potentially lethal.

Clinical Relevance in Obstetrics: - Hereditary fructose intolerance is rare; but undiagnosed women who maintain a diet high in fruit/sucrose may present with unexplained hypoglycaemia or liver dysfunction in pregnancy. - Sorbitol (used in some diabetic foods) is converted to fructose in the liver; may trigger symptoms in HFI.

1.9 Galactose Metabolism

Dietary source: Lactose (milk sugar) → glucose + galactose (by lactase in small intestine).

Galactose Metabolism Pathway:

1. Galactose → Galactose-1-phosphate (by galactokinase).
2. Galactose-1-phosphate + UDP-glucose → UDP-galactose + Glucose-1-phosphate (by galactose-1-phosphate uridylyltransferase (GALT) — key enzyme).
3. UDP-galactose → UDP-glucose (by UDP-galactose-4-epimerase — reversible in most tissues).

Alternative pathway: Galactose → Galactitol (by aldose reductase). This pathway becomes significant when GALT is deficient — galactitol accumulation causes damage.

Galactosaemia

Classic Galactosaemia (Type I): - Defect: Galactose-1-phosphate uridylyltransferase (GALT) deficiency. - Inheritance: Autosomal recessive. - Incidence: ~1:30,000–60,000 live births.

Biochemistry: - Galactose-1-P accumulates → inhibits phosphoglucomutase → blocks glycogenolysis and gluconeogenesis → hypoglycaemia. - Galactose → Galactitol (via aldose reductase) — accumulates in lens → osmotic damage → cataracts. - Galactose-1-P and galactitol cause liver, kidney, and brain damage.

Clinical presentation (in newborn, after milk feeding): - Acute: Vomiting, diarrhoea, failure to thrive, jaundice (conjugated hyperbilirubinaemia), hepatomegaly, hypoglycaemia. - Chronic: Cataracts, intellectual disability (if untreated), ovarian failure (in females — hypergonadotropic hypogonadism, 80% of affected females). - Sepsis: E. coli sepsis is a frequent complication (galactose impairs neutrophil function).

Diagnosis: - Newborn screening (UK heel-prick test) — elevated galactose or low GALT activity. - Beutler test (fluorescent spot test for GALT). - Confirm by enzyme assay in RBCs.

Management: - Strict lactose/galactose-free diet for life. - Even with diet, long-term complications (speech delay, cognitive issues, ovarian failure) may occur due to endogenous galactose production. - Pregnancy: Affected women need dietary counselling; higher risk of ovarian failure → fertility issues. Pregnancy outcomes generally good with dietary compliance.

Galactokinase Deficiency (Type II): - Defect: Galactokinase. - Clinical: Cataracts only (no liver/brain disease). Galactitol accumulates. - Treatment: Galactose-restricted diet.

UDP-Galactose-4-Epimerase Deficiency (Type III): - Very rare. Can be benign (RBC-limited) or severe (generalized) with features similar to classic galactosaemia.

Lactose Intolerance (not a galactosaemia): - Defect: Lactase deficiency in gut (primary adult-onset hypolactasia — common; or secondary to gastroenteritis). - Clinical: Bloating, diarrhoea after milk ingestion. No systemic galactose toxicity.

1.10 Lactose Synthesis (Mammary Gland)

Significance in pregnancy & lactation: Lactose is the major carbohydrate in human milk (~7 g/100 mL). Its synthesis increases dramatically in late pregnancy and during lactation, under hormonal control.

Enzyme: Lactose Synthase:

• Components: Galactosyltransferase (catalytic subunit) + α-Lactalbumin (modifier protein).
• Substrates: UDP-galactose + Glucose → Lactose + UDP.
• Normally, galactosyltransferase transfers galactose to N-acetylglucosamine in glycoprotein synthesis.
• α-Lactalbumin binds to galactosyltransferase, reducing its Km for glucose ~1000-fold, making it a high-affinity glucose acceptor → lactose synthesis.

Regulation: - α-Lactalbumin is induced by the hormone prolactin (acting via JAK-STAT signalling pathway). - Prolactin levels rise during pregnancy and peak after delivery with suckling stimulus. - Progesterone inhibits α-lactalbumin expression during pregnancy — expression rises sharply after delivery (progesterone withdrawal). - Glucocorticoids and insulin also facilitate lactogenesis.

Clinical relevance: - Lactogenesis failure can occur with: retained placental fragments (progesterone persists), Sheehan's syndrome (postpartum pituitary necrosis → prolactin deficiency), or severe illness. - Galactosaemia mothers cannot metabolise galactose; they can breastfeed? Actually, affected women have dietary restrictions but breast milk contains lactose; the infant with galactosaemia should not receive breastmilk (lactose-free formula required). - Galactocele: Milk-filled cyst in breast, contains inspissated milk rich in lactose and fat.

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2. Lipid Metabolism

2.1 Overview of Lipids in Pregnancy

Pregnancy is characterised by physiological hyperlipidaemia — serum triglycerides increase 2–3 fold, cholesterol increases ~25–50%. This is driven by: - Increased oestrogen → increased hepatic VLDL synthesis. - Increased adipose tissue lipolysis (hPL → insulin resistance). - Placental progesterone → decreased lipoprotein lipase activity.

These changes ensure a continuous supply of fatty acids for placental transfer to the fetus, for steroid hormone synthesis (progesterone, oestrogens), and for milk fat production in lactation.

2.2 Fatty Acid Synthesis (Lipogenesis)

Location: Cytosol (mainly liver, adipose, and lactating mammary gland). Substrates: Acetyl-CoA (from mitochondrial pyruvate, or from citrate exported from mitochondria). Key enzyme: Acetyl-CoA carboxylase (ACC) — rate-limiting step.

Pathway:

1. Acetyl-CoA → Malonyl-CoA:
2. Acetyl-CoA carboxylase (ACC) — requires biotin as cofactor (carboxyl group carrier).
3. Activated by citrate (allosteric) and insulin (dephosphorylation).

4. Inhibited by glucagon/adrenaline (phosphorylation) and palmitoyl-CoA (feedback inhibition).

5. Fatty Acid Synthase (FAS): A large multifunctional enzyme complex (single polypeptide with 7 active sites in mammals).

6. Substrates: 1 acetyl-CoA (primer) + 7 malonyl-CoA (2C donors) + 14 NADPH.
7. Product: Palmitate (C16:0) — released as free fatty acid.
8. NADPH comes from the pentose phosphate pathway (see 1.7) and the malic enzyme (malate → pyruvate + NADPH).

Elongation & Desaturation: - Palmitate can be elongated (to stearate C18:0) and desaturated (e.g., stearoyl-CoA desaturase → oleic acid C18:1, ω-9). - Mammals cannot insert double bonds at the ω-3 or ω-6 positions — these must come from the diet (essential fatty acids).

Regulation Summary: | Stimulates FA synthesis | Inhibits FA synthesis | |------------------------|----------------------| | Insulin (↑) | Glucagon (↑) | | Citrate | Adrenaline | | High-carbohydrate diet | Fasting/starvation | | | Palmitoyl-CoA (feedback) |

Lipogenesis in pregnancy: - Early to mid-pregnancy: Increased maternal fat deposition (oestrogen + insulin). - Late pregnancy: Fat deposition slows, lipolysis increases (hPL → insulin resistance) — mobilisation of FFAs to support fetal growth.

2.3 β-Oxidation of Fatty Acids

Location: Mitochondrial matrix (short & medium chain); also peroxisomes (very long chain, >C22). Function: Degradation of fatty acids to acetyl-CoA, producing NADH and FADH₂ for ATP generation.

The Carnitine Shuttle: - Problem: Fatty acyl-CoA cannot cross the inner mitochondrial membrane. - Solution: The carnitine shuttle transfers the acyl group across.

Steps: 1. Carnitine palmitoyltransferase I (CPT I) — outer mitochondrial membrane. Transfers acyl group from CoA to carnitine → Acyl-carnitine. - Rate-limiting step of β-oxidation. - Inhibited by malonyl-CoA (product of ACC — coordinates FA synthesis vs degradation; when synthesis is active, β-oxidation is suppressed). 2. Translocase (carnitine-acylcarnitine translocase, CACT) — transports acyl-carnitine across inner membrane. 3. Carnitine palmitoyltransferase II (CPT II) — inner mitochondrial membrane. Transfers acyl group back to CoA → Acyl-CoA (matrix) + carnitine (returned to cytosol).

The β-Oxidation Spiral (4 steps per cycle):

Each cycle removes 2 carbons as acetyl-CoA, producing 1 NADH + 1 FADH₂.

1. Oxidation: Acyl-CoA → trans-Δ²-Enoyl-CoA (by acyl-CoA dehydrogenase — FAD → FADH₂, enters ETC via ETF/ETF-QO to CoQ).
2. Hydration: Enoyl-CoA → L-3-Hydroxyacyl-CoA (by enoyl-CoA hydratase).
3. Oxidation: Hydroxyacyl-CoA → 3-Ketoacyl-CoA (by 3-hydroxyacyl-CoA dehydrogenase — NAD⁺ → NADH).
4. Thiolysis: Ketoacyl-CoA → Acyl-CoA (shortened by 2C) + Acetyl-CoA (by β-ketothiolase).

Disorders of β-Oxidation:

MCAD Deficiency (Medium-Chain Acyl-CoA Dehydrogenase): - Incidence: ~1:10,000–15,000 (most common FAO disorder). - Biochemistry: Impaired oxidation of medium-chain fatty acids (C6–C12) → accumulation of medium-chain acyl-CoAs → hypoglycaemia, low ketones (hypoketotic hypoglycaemia). - Presentation: In infancy or early childhood, precipitated by fasting or illness — vomiting, lethargy, hypoglycaemia, seizures, sudden death (mimics Reye syndrome). - Diagnosis: Newborn screening (tandem MS — elevated C8 acylcarnitine). Confirm by genetic testing or enzyme assay. - Management: Avoid fasting, frequent feeds, L-carnitine supplementation, MCT oil (provides medium-chain fats that bypass MCAD). - Pregnancy: Women with MCAD deficiency should avoid prolonged fasting (e.g., in labour, hyperemesis). IV dextrose in labour, careful perioperative management for CS. - Genetics: Autosomal recessive; ACADM gene.

VLCAD Deficiency, LCHAD Deficiency, CPT I/II Deficiency: All present with hypoketotic hypoglycaemia, rhabdomyolysis, cardiomyopathy.

Acute Fatty Liver of Pregnancy (AFLP): - Pathophysiology: Associated with LCHAD deficiency (long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency) in the fetus (autosomal recessive). - The mother is heterozygous; fetal fatty acid oxidation defect leads to accumulation of long-chain 3-hydroxy fatty acids, which are hepatotoxic to the mother. - Clinical: Third-trimester onset of nausea, vomiting, abdominal pain, jaundice, hypoglycaemia, coagulopathy, hepatic encephalopathy. Can progress to fulminant liver failure. - Management: Immediate delivery, supportive care. Affected infants need LCHAD-deficient diet (low long-chain fats, MCT supplementation).

2.4 Ketone Body Synthesis (Ketogenesis)

Location: Liver — mitochondrial matrix. When: Prolonged fasting, starvation, high-fat low-carb diet, uncontrolled diabetes (DKA), and in pregnancy (accelerated starvation). Function: Provide a water-soluble fuel source (acetoacetate, β-hydroxybutyrate) for extrahepatic tissues (brain, muscle, heart, kidney). The liver cannot use ketones (lacks the key enzyme of ketolysis, succinyl-CoA:3-ketoacid-CoA transferase).

Pathway: 1. Acetyl-CoA (from β-oxidation) → Acetoacetyl-CoA (by β-ketothiolase). 2. Acetoacetyl-CoA + Acetyl-CoA → HMG-CoA (by HMG-CoA synthase — rate-limiting step of ketogenesis). 3. HMG-CoA → Acetoacetate + Acetyl-CoA (by HMG-CoA lyase).

Three ketone bodies: - Acetoacetate — the primary ketone body. - β-Hydroxybutyrate (3-hydroxybutyrate) — reduced form of acetoacetate (NADH/NAD⁺ ratio determines proportion; in DKA, β-HB predominates). - Acetone — spontaneously decarboxylation product of acetoacetate. Excreted via breath (fruity smell).

Ketolysis (utilization in peripheral tissues): - β-Hydroxybutyrate → Acetoacetate (β-hydroxybutyrate dehydrogenase). - Acetoacetate → Acetoacetyl-CoA (succinyl-CoA:3-ketoacid-CoA transferase — not present in liver). - Acetoacetyl-CoA → 2 Acetyl-CoA (β-ketothiolase) → TCA cycle.

Regulation: - Ketogenesis stimulated by: Low insulin, high glucagon (fasting, DKA) → increased lipolysis → increased FA delivery to liver → increased β-oxidation → increased acetyl-CoA. - HMG-CoA synthase is activated when malonyl-CoA levels are low (malonyl-CoA normally inhibits CPT I, limiting FA entry to mitochondria; low malonyl-CoA → increased β-oxidation → acetyl-CoA → ketogenesis).

Clinical relevance in obstetrics:

1. Starvation ketosis of pregnancy:

2. Pregnant women develop ketonuria more rapidly than non-pregnant (accelerated starvation). Overnight fast in late pregnancy can produce mild ketonuria.

3. Hyperemesis gravidarum:

4. Severe vomiting → starvation → ketosis → ketonuria. May require IV dextrose and antiemetics.

5. Diabetic Ketoacidosis (DKA) in pregnancy:

6. Life-threatening emergency for both mother and fetus.
7. Pregnancy predisposes to DKA at relatively low glucose levels (euglycaemic DKA) due to accelerated starvation and insulin resistance.
8. Ketones cross the placenta → fetal ketoacidosis.

9. Management: IV fluids, insulin (IV infusion), dextrose, correction of electrolyte abnormalities (K⁺), close fetal monitoring.

10. GDM and ketone monitoring:

11. Controversial — some guidelines recommend monitoring for ketonuria in GDM to detect inadequate caloric intake.

2.5 Cholesterol Synthesis

Location: Cytosol of all cells (primarily liver and intestine). Substrates: Acetyl-CoA (→ mevalonate pathway). Key Enzyme: HMG-CoA reductase — rate-limiting step.

Pathway Overview:

1. Acetyl-CoA → HMG-CoA (by HMG-CoA synthase — same enzyme as in ketogenesis, but in cytosol vs mitochondrial in ketogenesis).
2. HMG-CoA → Mevalonate (by HMG-CoA reductase — rate-limiting step, target of statins).
3. Mevalonate → Isopentenyl pyrophosphate (IPP) → Squalene → Lanosterol → Cholesterol.

Regulation of HMG-CoA Reductase:

Stimulus	Effect	Mechanism
Insulin	↑ Activity	Dephosphorylation (activates)
Glucagon	↓ Activity	Phosphorylation (inactivates)
Cholesterol (dietary)	↓ Synthesis	Feedback inhibition via SREBP pathway (↓ transcription, ↑ degradation)
Statins	↑ Synthesis (rebound)	Inhibition of reductase → ↓ cholesterol → SREBP activation → ↑ reductase transcription
AMPK	↓ Activity	Phosphorylation (inactivates)

SREBP Pathway (Sterol Regulatory Element-Binding Protein): - When cholesterol is low: SREBP leaves ER, transports to Golgi, is cleaved by proteases (SCAP, S1P, S2P), enters nucleus → activates transcription of HMG-CoA reductase and LDL receptor. - When cholesterol is high: SREBP retained in ER (bound to SCAP, inhibited by INSIG).

Functions of Cholesterol: - Membrane fluidity — modulates lipid bilayer properties. - Steroid hormone synthesis — precursor for progesterone, oestrogen, testosterone, cortisol, aldosterone (see Section 6.2). - Bile acid synthesis — major pathway for cholesterol excretion. - Vitamin D synthesis — 7-dehydrocholesterol + UV light (skin) → cholecalciferol (Vitamin D₃). - Myelin — cholesterol is a major component of the myelin sheath.

Statins (HMG-CoA Reductase Inhibitors):

Statin	Features
Atorvastatin	Potent, long half-life, synthetic
Simvastatin	Prodrug, natural product derivative
Pravastatin	Hydrophilic, less muscle penetration
Rosuvastatin	Most potent, hepatorenal elimination

• Mechanism: Competitive inhibition of HMG-CoA reductase → ↓ mevalonate → ↓ cholesterol synthesis → ↑ LDL receptor expression → ↓ plasma LDL.
• Side effects: Myopathy, rhabdomyolysis, ↑ LFTs.
• Pregnancy: Contraindicated — statins are teratogenic in animal studies (cholesterol essential for fetal development and steroidogenesis). Women must stop statins before conception or at first missed period. However... some recent evidence is emerging about safety in specific high-risk conditions (e.g., pre-eclampsia prevention — still investigational, not routine).

2.6 Steroid Hormones from Cholesterol

Cholesterol is the precursor for all steroid hormones. The key conversion occurs in mitochondria:

Rate-limiting step: Cholesterol → Pregnenolone (by CYP11A1 / P450scc — side-chain cleavage enzyme). This step is stimulated by ACTH (adrenal) and LH/hCG (ovary/placenta).

Steroidogenic Tissues: - Adrenal cortex: Zona glomerulosa (mineralocorticoids), Zona fasciculata (glucocorticoids), Zona reticularis (androgens). - Ovary: Theca interna (androstenedione), Granulosa cells (oestradiol). - Testis: Leydig cells (testosterone). - Placenta: Converts maternal/fetal precursors to progesterone and oestrogens (see Section 9). - Corpus luteum: Progesterone.

Major pathways:

1. Progesterone: Pregnenolone → Progesterone (3β-HSD). Critical in pregnancy maintenance.
2. Cortisol: Progesterone → 17-OH-progesterone → 11-deoxycortisol → Cortisol (CYP21A2, CYP11B1). Defects → congenital adrenal hyperplasia (CAH).
3. Oestrogens: Androstenedione/Testosterone → Oestrone/Oestradiol (aromatase — CYP19A1). Placenta is rich in aromatase.
4. Testosterone: Androstenedione → Testosterone (17β-HSD).
5. Aldosterone: Progesterone → Deoxycorticosterone → Corticosterone → Aldosterone (CYP11B2).

Clinical relevance: - CAH (21-hydroxylase deficiency) → virilization of female fetus → ambiguous genitalia. Diagnosis by elevated 17-OH-progesterone. Prenatal dexamethasone therapy is controversial. - Placental steroidogenesis is critical for pregnancy maintenance (progesterone) and parturition (oestrogen-mediated events).

2.7 Lipoproteins

Function: Transport hydrophobic lipids (triglycerides, cholesterol, phospholipids) in the aqueous plasma.

Structure: Core (TG, cholesterol esters) + Surface coat (phospholipids, free cholesterol, apoproteins).

Classification by Density (ultracentrifugation) — increasing density, decreasing size:

Lipoprotein	Density	Size	Major Lipids	Major Apoproteins	Function
Chylomicrons	Lowest	Largest	Dietary TG (90%)	B48, A-I, A-IV, C-II, E	Transport dietary fat from intestine to tissues
VLDL (Very Low Density)	0.95–1.006	↓	Endogenous TG (60%)	B100, C-II, E	Transport hepatic TG to peripheral tissues
IDL (Intermediate Density)	1.006–1.019	↓↓	TG + CE	B100, E	VLDL remnant; converted to LDL
LDL (Low Density)	1.019–1.063	Small	Cholesterol esters	B100	Delivers cholesterol to peripheral tissues and liver
HDL (High Density)	1.063–1.21	Smallest	PL, CE	A-I, A-II, C-II, E	Reverse cholesterol transport; antioxidant

Apoproteins (Apo):

Apoprotein	Source	Function
Apo A-I	Liver, intestine	Activates LCAT (lecithin:cholesterol acyltransferase); structural component of HDL
Apo B48	Intestine (chylomicrons)	Structural for chylomicrons; truncated form of B100
Apo B100	Liver (VLDL, LDL)	Ligand for LDL receptor on peripheral cells
Apo C-II	Liver	Activates lipoprotein lipase (LPL) — required for TG hydrolysis in chylomicrons and VLDL
Apo E	Liver, macrophages	Ligand for LDL receptor and LDL receptor-related protein (LRP) — hepatic uptake of remnants
Apo(a)	Liver	Covalently linked to Apo B100 in Lp(a) — prothrombotic (homology with plasminogen)

Lipoprotein Processing:

1. Exogenous pathway (dietary fat):

2. Intestine → Chylomicrons (via lymph/thoracic duct) → C-II activates LPL on capillary endothelium → TG hydrolysed → FFAs enter adipose/muscle → Chylomicron remnants → Liver (via Apo E receptor).

3. Endogenous pathway (hepatic TG):

4. Liver → VLDL → LPL hydrolyses TG → IDL → (a) LDL receptor uptake (liver) or (b) Further TG hydrolysis → LDL (cholesterol-rich).

5. Reverse cholesterol transport (HDL):

6. Nascent HDL (disc-shaped, from liver/intestine) picks up free cholesterol from peripheral cells (via ABCA1 transporter — Tangier disease if deficient).
7. LCAT (activated by Apo A-I) esterifies cholesterol → cholesterol esters move into HDL core → HDL becomes spherical.
8. HDL transports cholesterol to liver (via SR-B1 receptor) → either excreted as bile acids or repackaged into VLDL.

Lipoprotein Disorders:

Disorder	Defect	Biochemical Finding	Clinical Features
Familial Hypercholesterolaemia (FH)	LDL receptor mutation	↑ LDL, ↑ total cholesterol	Xanthomas, corneal arcus, premature CVD
Familial Combined Hyperlipidaemia	Apo B overproduction	↑ LDL, ↑ VLDL	Premature CAD
Tangier Disease	ABCA1 deficiency	↓ HDL, ↓ Apo A-I	Orange tonsils, neuropathies, CAD
Abetalipoproteinaemia	MTTP mutation	Absent chylomicrons, VLDL, LDL	Fat malabsorption, acanthocytosis, neuropathies
Lipoprotein(a) elevated	Genetic variation	↑ Lp(a)	Increased CVD/stroke risk, independent of LDL

Pregnancy-related changes: - TG ↑ 2–3 fold (oestrogen-driven VLDL synthesis; decreased LPL activity). - LDL ↑ 30–50% (increased hepatic production). - HDL ↑ in early pregnancy, ↓ in late pregnancy (changes in LCAT activity). - Lp(a) ↑ in pregnancy — may contribute to thrombotic risk. - These changes are physiological but can exacerbate pre-existing dyslipidaemia.

2.8 Essential Fatty Acids & Eicosanoids

2.8.1 Essential Fatty Acids

The body cannot introduce double bonds beyond C9 (Δ-9 desaturase). Therefore, two polyunsaturated fatty acids (PUFAs) are essential (must be obtained from diet):

1. Linoleic acid (18:2, ω-6) — precursor of ω-6 series.
2. α-Linolenic acid (18:3, ω-3) — precursor of ω-3 series.

Metabolism:

ω-6 Series	ω-3 Series
Linoleic acid (18:2) ↓ Δ-6 desaturase	α-Linolenic acid (18:3) ↓ Δ-6 desaturase
γ-Linolenic acid (GLA, 18:3) ↓ Elongase	Stearidonic acid (18:4) ↓ Elongase
Dihomo-γ-linolenic acid (DGLA, 20:3) ↓ Δ-5 desaturase	Eicosatetraenoic acid (20:4) ↓ Δ-5 desaturase
Arachidonic acid (AA, 20:4) ↓ Further elongation	Eicosapentaenoic acid (EPA, 20:5) ↓ Elongase + Δ-4 desaturase
Docosatetraenoic acid (22:4)	Docosahexaenoic acid (DHA, 22:6)

Functions of Arachidonic Acid: - Esterified in membrane phospholipids. - Released by phospholipase A₂ (PLA₂) in response to stimuli (inflammation, labour, tissue damage). - Substrate for COX (cyclooxygenase) → prostaglandins, thromboxanes, prostacyclin. - Substrate for LOX (lipoxygenase) → leukotrienes. - Substrate for CYP450 epoxygenase → epoxyeicosatrienoic acids (EETs).

Functions of EPA & DHA: - DHA is critical for fetal brain and retina development — accumulates rapidly in third trimester. - EPA produces "3-series" prostaglandins (less inflammatory than 2-series). - Fish oil supplements (EPA/DHA) in pregnancy: May reduce risk of preterm birth, but evidence is mixed. Guidelines recommend 1–2 portions of oily fish per week. - Omega-3 deficiency is associated with impaired neurodevelopment.

Trans fats: - Not essential, harmful. Increase LDL, decrease HDL, linked to CVD and preterm birth. Should be avoided in pregnancy.

2.8.2 Eicosanoids

Eicosanoids are short-lived signalling molecules derived from 20-carbon PUFAs (eicosan- = twenty). They act locally (autocrine/paracrine) via GPCRs.

Major classes and functions relevant to obstetrics & gynaecology:

Eicosanoid	Enzyme	Primary Functions	Relevance in O&G
Prostaglandins (PGD₂, PGE₂, PGF₂α, PGI₂)	COX-1, COX-2	Vasodilation/constriction, uterine contraction, inflammation, gastroprotection, renal function	PGE₂ & PGF₂α — induce labour, cervical ripening; PGF₂α — postpartum haemorrhage treatment (Hemabate®); menstrual cramps
Prostacyclin (PGI₂)	COX-2 + prostacyclin synthase	Vasodilation, inhibits platelet aggregation	Protective in pregnancy (maintains uterine blood flow); levels ↓ in pre-eclampsia (imbalance with thromboxane)
Thromboxane A₂ (TXA₂)	COX-1 + thromboxane synthase	Vasoconstriction, promotes platelet aggregation	In pre-eclampsia: ↑ TXA₂ (from platelets/placenta) → vasoconstriction, platelet activation; imbalance with PGI₂
Leukotrienes (LTA₄, LTB₄, LTC₄, LTD₄, LTE₄)	5-LOX	Bronchoconstriction, inflammation, chemotaxis	Asthma in pregnancy; preterm labour (inflammatory role)
Lipoxins	LOX interactions	Anti-inflammatory, pro-resolving	Resolution of inflammation — role in pregnancy unclear

COX-1 vs COX-2:

Feature	COX-1	COX-2
Expression	Constitutive — most tissues	Inducible — inflammation, labour, cancer
Function	Homeostatic: gastric protection, platelet function, renal blood flow	Inflammatory response, pain, fever, parturition
Inhibition by aspirin	Irreversible (low dose)	Less sensitive
Inhibition by NSAIDs	Non-selective COX-1/COX-2	Selective COX-2 inhibitors (celecoxib) — contraindicated in pregnancy (fetal renal toxicity, oligohydramnios, ductus arteriosus constriction)

Aspirin Mechanism: - Irreversibly acetylates COX-1 (serine 530) → blocks active site → prevents TXA₂ synthesis in platelets (for life of platelet, ~7–10 days). - Low-dose aspirin (75–150 mg) → selective inhibition of platelet COX-1 → used for: - Pre-eclampsia prevention (identified high-risk women, from 12 weeks to 36 weeks). - Prevention of fetal growth restriction (ASPRE trial evidence). - In pre-eclampsia, the imbalance between PGI₂ (↓) and TXA₂ (↑) is partially corrected by aspirin.

NSAIDs in Pregnancy: - First trimester: Linked to increased risk of miscarriage (inhibition of prostaglandin-dependent implantation). - Third trimester: Contraindicated — cause premature closure of ductus arteriosus, oligohydramnios (fetal renal effects), and may delay labour. - Short-term postpartum use: Acceptable for pain relief (especially after CS), but monitor for bleeding (platelet inhibition) — ibuprofen preferred (short half-life).

Prostaglandins in Labour: - Cervical ripening: PGE₂ (dinoprostone) — applied vaginally to soften/favour cervix. - Induction of labour: PGE₂, or misoprostol (PGE₁ analogue, oral/vaginal). - Management of PPH: PGF₂α (carboprost) — intramuscular. Also misoprostol (rectal PGE₁) in settings where injectable oxytocin is not available.

2.9 Phospholipids

Structure: Glycerol backbone with two fatty acid tails + phosphate-containing head group.

Major Classes:

Phospholipid	Head Group	Function
Phosphatidylcholine (PC = lecithin)	Choline	Major membrane phospholipid; DPPC — main surfactant component
Phosphatidylethanolamine (PE)	Ethanolamine	Membrane component (inner leaflet)
Phosphatidylserine (PS)	Serine	Inner leaflet, apoptosis marker (externalized in apoptotic cells)
Phosphatidylinositol (PI)	Inositol	PIP₂ → IP₃ + DAG — second messenger system (Section 6.7)
Cardiolipin (diphosphatidylglycerol)	—	Inner mitochondrial membrane; antigen in syphilis serology (Wassermann), antiphospholipid syndrome
Sphingomyelin	Choline (sphingosine backbone)	Myelin sheath; milk fat globule membrane

Membrane Asymmetry: - Outer leaflet: PC, sphingomyelin. - Inner leaflet: PE, PS, PI. - ATP-dependent flippases maintain this asymmetry. Loss of asymmetry (PS externalization) is an early marker of apoptosis.

Lecithin:Sphingomyelin (L:S) Ratio: - Clinical test for fetal lung maturity (see Section 9.7 for full details). - Sphingomyelin remains constant throughout pregnancy. - Lecithin (DPPC) increases after 32–34 weeks. - L:S ratio > 2.0 (some labs > 2.5) indicates fetal lung maturity.

DPPC (Dipalmitoylphosphatidylcholine): - Dipalmitoyl = two saturated 16:0 palmitic acid chains → tightly packed, high surface tension resistance. - Produced by alveolar type II pneumocytes from 32 weeks, major increase around 35–36 weeks. - Surfactant reduces surface tension at air-liquid interface → prevents alveolar collapse. - Corticosteroids (betamethasone, dexamethasone) given to mothers threatened with preterm labour → induce lung maturation → ↑ DPPC, improve neonatal respiratory outcomes.

Antiphospholipid Syndrome (APS): - Autoantibodies against cardiolipin, β₂-glycoprotein I, lupus anticoagulant. - Obstetric complications: Recurrent miscarriage, late pregnancy loss, FGR, pre-eclampsia, preterm birth. - Treatment: Low-dose aspirin + low-molecular-weight heparin in pregnancy.

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3. Amino Acid & Protein Metabolism

3.1 Amino Acid Classification

Essential (must be obtained from diet — body cannot synthesize):

Amino Acid	Mnemonic
Phenylalanine	PVT TIM HALL (for the 9 essential):
Valine	Phenylalanine
Threonine	Valine
Tryptophan	Threonine
Isoleucine	Tryptophan
Methionine	Isoleucine
Histidine	Methionine
Arginine (semi-essential — need during growth)	Histidine
Lysine	Arginine
Leucine	Lysine
	Leucine

Non-essential (body can synthesize): Alanine, Asparagine, Aspartic acid, Glutamic acid, Glutamine, Glycine, Proline, Serine, Tyrosine (from phenylalanine), Cysteine (from methionine, but methionine is essential so cysteine is conditionally essential).

Conditionally essential in certain situations: - Arginine (neonates, growth) - Glutamine (critical illness, catabolic states) - Tyrosine (PKU — can't make from phenylalanine) - Cysteine (preterm infants, liver disease)

3.2 Transamination

Definition: Transfer of an α-amino group from an amino acid to an α-keto acid, producing a new amino acid and a new keto acid.

Enzymes: Aminotransferases (transaminases) — require pyridoxal phosphate (PLP, Vitamin B6) as cofactor.

Key Transaminases in Clinical Medicine:

1. ALT (Alanine Aminotransferase):
2. Alanine + α-KG ↔ Pyruvate + Glutamate.
3. ALT = Alanine Aminotransferase (also called GPT).
4. Found in high concentration in liver — specific marker of hepatocellular injury.

5. ↑ ALT in pregnancy: Pre-eclampsia with HELLP, AFLP, cholelithiasis, viral hepatitis, drug-induced liver injury.

6. AST (Aspartate Aminotransferase):

7. Aspartate + α-KG ↔ Oxaloacetate + Glutamate.
8. AST = Aspartate Aminotransferase (also called GOT).
9. Found in liver, heart, skeletal muscle, kidney, RBCs — less specific than ALT.
10. AST:ALT ratio > 2 suggests alcoholic liver disease (also elevated in AFLP, HELLP).

Physiological Role: - Transamination allows amino acid nitrogen to be collected as glutamate, which then enters the urea cycle via glutamate dehydrogenase. - It also allows interconversion of amino acids to match metabolic needs.

3.3 Deamination

Definition: Removal of the amino group from an amino acid, producing NH₃ and a keto acid.

Two main types:

1. Oxidative Deamination (via Glutamate Dehydrogenase — GDH):
2. Glutamate → α-KG + NH₃ + NAD(P)H.
3. GDH is allosterically regulated: inhibited by GTP, activated by ADP.
4. GDH is unique in using both NAD⁺ and NADP⁺.

5. This is the main route for releasing NH₃ from amino acids (the "gateway" between amino acid metabolism and urea cycle).

6. Non-Oxidative Deamination:

7. Serine → Pyruvate + NH₃ (by serine dehydratase).
8. Histidine → Urocanic acid + NH₃ (by histidase).

Fate of NH₃: - Toxic to the brain — must be rapidly removed. - Liver: NH₃ → Urea (via urea cycle) → excreted in urine. - Kidney: NH₃ → NH₄⁺ (buffered in urine) — important for acid-base regulation.

3.4 Urea Cycle

Location: Liver (mitochondria + cytosol). Function: Converts toxic NH₃ into non-toxic urea for excretion. Energy cost: 4 ATP per urea.

Cycle Steps:

1. Mitochondrial matrix:
2. NH₃ + CO₂ + 2ATP → Carbamoyl phosphate (by Carbamoyl phosphate synthetase I — CPS I).
   • CPS I requires N-acetylglutamate (NAG) as allosteric activator. NAG is synthesized by NAG synthase in response to arginine and protein intake.

3. Carbamoyl phosphate + Ornithine → Citrulline (by Ornithine transcarbamoylase — OTC).

4. Cytosol:

5. Citrulline + Aspartate → Argininosuccinate (by Argininosuccinate synthetase).
6. Argininosuccinate → Arginine + Fumarate (by Argininosuccinate lyase).
7. Arginine + H₂O → Urea + Ornithine (by Arginase).
8. Ornithine is transported back into the mitochondria to repeat the cycle.

Key Enzymes and Deficiencies (Urea Cycle Disorders):

Enzyme	Deficiency	Inheritance (all AR)	Key Lab Finding	Clinical Features
CPS I	CPS I deficiency	AR	↓ Ammonia, no orotic acid	Hyperammonaemia, lethargy, coma
OTC	OTC deficiency	X-linked (most common urea cycle disorder)	↑ Orotic acid, ↑ Citrulline (low/normal)	Severe hyperammonaemia in males; variable in females (X-inactivation)
Argininosuccinate synthetase	Citrullinaemia	AR	↑ Citrulline	Hyperammonaemia
Argininosuccinate lyase	Argininosuccinic aciduria	AR	Argininosuccinic acid in urine, ↑ Citrulline	Hyperammonaemia, trichorrhexis nodosa (brittle hair)
Arginase	Argininaemia	AR	↑ Arginine, hyperammonaemia (milder)	Spastic diplegia, progressive neurological deterioration (later onset)

OTC Deficiency — Key Points for MRCOG: - X-linked inheritance — male infants typically present in first days of life with hyperammonaemic crisis (vomiting, lethargy, seizures, coma, cerebral oedema). - Diagnosis: ↑ NH₃, low BUN, ↑ orotic acid (accumulated carbamoyl phosphate leaks into cytosol → pyrimidine synthesis pathway generates orotic acid). - Carrier females may develop postpartum hyperammonaemia (protein catabolism → urea cycle overwhelmed) — can present with confusion, psychosis, coma postpartum. - Management: Protein restriction, sodium benzoate/phenylbutyrate (alternative NH₃ disposal), arginine supplementation, consideration of liver transplant. - Prenatal diagnosis available.

Hyperammonaemia — General Features: - Ammonia toxicity → astrocyte swelling → cerebral oedema. - Symptoms: vomiting, lethargy, ataxia, seizures, coma. - Can be mistaken for sepsis or birth asphyxia in newborns.

3.5 Phenylalanine & Tyrosine Metabolism

Phenylalanine → Tyrosine → Further metabolism.

Key Enzyme: Phenylalanine hydroxylase (PAH) — converts phenylalanine to tyrosine. Requires: - Tetrahydrobiopterin (BH₄) as cofactor. - Molecular oxygen. - Deficiency → Phenylketonuria (PKU).

3.5.1 Phenylketonuria (PKU)

Defect: Phenylalanine hydroxylase (PAH) deficiency. Inheritance: Autosomal recessive. Incidence: ~1:10,000–15,000 (varies by population).

Biochemistry: - Phenylalanine accumulates → alternative metabolites produced via phenylalanine transaminase → Phenylpyruvate (phenylketone) → Phenyllactate, Phenylacetate. - These metabolites are neurotoxic → severe intellectual disability if untreated. - Tyrosine becomes conditionally essential (cannot be made from phenylalanine).

Clinical features (untreated): - Profound intellectual disability. - Microcephaly, seizures, hyperactivity. - Fair skin, blonde hair, blue eyes (lack of melanin — tyrosine is precursor for melanin). - Musty odour (phenylacetate in sweat/urine).

Newborn screening: - Guthrie test (blood spot) — elevated phenylalanine. - Confirmed with repeat/quantitative measurement. - UK: Heel-prick test at 5–8 days of life.

Management: - Low-phenylalanine diet (strictly restrict natural protein; use special amino acid formula). - Tyrosine supplementation. - Diet must be commenced within first 2–3 weeks of life to prevent brain damage. - Lifelong dietary adherence recommended (especially for women of childbearing age). - Tetrahydrobiopterin (BH₄)-responsive PKU — some patients respond to sapropterin (BH₄ analogue).

Maternal PKU: - Critical for MRCOG: Women with PKU must maintain strict diet before conception and throughout pregnancy. - Uncontrolled maternal PKU → high maternal phenylalanine levels → teratogenic effects on fetus (not genetic — the fetus is usually a heterozygote carrier, not affected by PKU). - Fetal consequences: - Intellectual disability (fetal brain most sensitive to high Phe). - Microcephaly. - Congenital heart disease. - Intrauterine growth restriction (IUGR). - Dysmorphic features. - Target blood phenylalanine: 120–360 µmol/L (2–6 mg/dL) before conception and during pregnancy. - Specialist metabolic dietitian + high-risk obstetric care.

3.5.2 Other Disorders of Tyrosine Metabolism

1. Alkaptonuria (Ochronosis): - Defect: Homogentisate 1,2-dioxygenase (HGD) deficiency. - Inheritance: Autosomal recessive (rare; ~1:250,000). - Biochemistry: Homogentisic acid accumulates → oxidised and polymerised → dark pigment deposited in connective tissue. - Clinical: - Urine turns black on standing (oxidation in air). - Ochronosis — blue-black pigmentation of cartilage, sclera, ears. - Ochronotic arthritis — degenerative joint disease (knees, hips, spine) presenting in 30s–40s. - Diagnosis: Elevated homogentisic acid in urine. - Treatment: No cure. Nitisinone (inhibits HPPD) reduces HGA levels. Symptomatic joint management.

2. Albinism (Oculocutaneous): - Defect: Tyrosinase deficiency (or other melanin synthesis enzymes). - Biochemistry: Inability to convert tyrosine → DOPA → melanin. - Clinical: Absent/reduced pigment in skin, hair, eyes; photophobia, nystagmus, reduced visual acuity; increased risk of skin cancers. - Pregnancy: Sun protection counselling.

3. Tyrosinaemia Type I (Hepatorenal): - Defect: Fumarylacetoacetase (FAH) deficiency. - Biochemistry: Accumulation of fumarylacetoacetate → converted to succinylacetone (toxic). - Clinical: Liver failure, renal Fanconi syndrome, rickets, neurological crises, hepatocellular carcinoma. - Treatment: Nitisinone (NTBC — inhibits 4-hydroxyphenylpyruvate dioxygenase, upstream of FAH) + low-tyrosine/phenylalanine diet. Liver transplant if end-stage.

3.6 Branched-Chain Amino Acids (BCAAs)

Leucine, Isoleucine, Valine — essential amino acids with branched hydrocarbon side chains.

Metabolism: 1. Transamination: BCAA + α-KG → Branched-chain α-keto acids + Glutamate. - Enzyme: Branched-chain aminotransferase (BCAT). 2. Oxidative decarboxylation: Branched-chain α-keto acids → CoA derivatives. - Enzyme: Branched-chain α-keto acid dehydrogenase (BCKDH) complex — a large multienzyme complex similar to pyruvate dehydrogenase. - Requires: Thiamine pyrophosphate (TPP), lipoic acid, FAD, NAD⁺, CoA. 3. Further degradation to succinyl-CoA or acetyl-CoA.

Maple Syrup Urine Disease (MSUD)

Defect: BCKDH complex deficiency. Inheritance: Autosomal recessive (~1:185,000).

Biochemistry: - Branched-chain α-keto acids (leucine, isoleucine, valine-derived) accumulate → spill into urine. - Isovaleryl-CoA (from leucine) gives characteristic maple syrup (burnt sugar) odour to urine, sweat, earwax.

Clinical features: - Classic (neonatal) form: Within first 1–2 weeks: poor feeding, vomiting, lethargy, seizures, coma, cerebral oedema. - Acute metabolic crisis → death if untreated. - Chronic intellectual disability despite treatment.

Diagnosis: Newborn screening (tandem MS — elevated leucine/isoleucine/alloisoleucine). Management: - Strict dietary restriction of BCAAs (special formula). - Thiamine supplementation (some cases are thiamine-responsive). - Acute crisis: Haemodialysis to remove toxic metabolites; high-calorie IV fluids to suppress catabolism. - Liver transplant can be curative (provides functional BCKDH).

3.7 Amino Acid Transport Disorders

Cystinuria: - Defect: Defective renal tubular and intestinal transport of dibasic amino acids (cysteine, ornithine, arginine, lysine — COAL). - Transport protein: rBAT/b⁰⁺AT (heterodimeric) — defect in SLC3A1 or SLC7A9 genes. - Inheritance: Autosomal recessive (commonest amino acid transport disorder, ~1:7,000). - Biochemistry: High urinary excretion of cystine, ornithine, arginine, lysine. - Clinical: - Recurrent cystine kidney stones (cystine is poorly soluble in acidic urine → hexagonal crystals). - Stones are radio-opaque (sulphur content). - Presents with renal colic, UTI, haematuria. - Management: High fluid intake, urinary alkalinisation (K⁺ citrate), D-penicillamine or tiopronin (thiols that form soluble cysteine-drug complexes). Lithotripsy or surgery for stones. - Pregnancy: Increased risk of UTI, nephrolithiasis. Adequate hydration critical.

Other transport disorders: - Hartnup disease: Defective neutral amino acid transport (SLC6A19) → aminoaciduria (tryptophan, etc.). May present with pellagra-like symptoms (↓ tryptophan → ↓ niacin). - Lysinuric protein intolerance: Defect in cationic amino acid transport (SLC7A7) → ↓ ornithine, lysine, arginine absorption → hyperammonaemia.

3.8 Protein Synthesis & Degradation

3.8.1 Protein Synthesis (Translation)

Location: Ribosomes (cytosol, RER). Process: mRNA → Polypeptide chain.

Stages: 1. Initiation: mRNA binds to small ribosomal subunit (40S); initiator tRNA (Met-tRNA) binds AUG codon; large subunit (60S) joins. 2. Elongation: Successive tRNAs bring amino acids to A site → peptidyl transferase (23S rRNA in ribosome) forms peptide bond → translocation (ribosome moves 3 nucleotides). 3. Termination: Stop codon (UAA, UAG, UGA) → release factors → polypeptide released.

Post-Translational Modifications (PTMs): - Cleavage: Signal peptides, prohormone processing (see Section 6.1). - Glycosylation: N-linked (ER) or O-linked (Golgi). Critical for hormone receptors, glycoproteins. - Phosphorylation: Ser/Thr/Tyr — reversible, controls enzyme activity. - Disulphide bond formation: Stabilises protein structure (ER). - Ubiquitination: Targets proteins for degradation. - Acetylation, methylation, lipidation, hydroxylation (collagen → proline hydroxylation requires Vitamin C).

Protein Folding and Quality Control:

1. Chaperonins (Hsp60, Hsp70, Hsp90):
2. Facilitate proper protein folding.
3. HSP heat shock proteins — induced by stress (heat, hypoxia).
4. Hsp60 forms a barrel-shaped "cage" where folding occurs.

5. Hsp70 binds to hydrophobic patches to prevent aggregation.

6. Endoplasmic Reticulum Quality Control:

7. Misfolded proteins are retained in ER → refolded by chaperones or sent for ER-associated degradation (ERAD) → retrotranslocation to cytosol → proteasome degradation.
8. Unfolded Protein Response (UPR): ER stress activates signalling to reduce protein load, increase chaperones, or trigger apoptosis.

3.8.2 Protein Degradation

Ubiquitin-Proteasome System (UPS):

1. Ubiquitination — tagging proteins for degradation:
2. E1 (ubiquitin-activating) → E2 (ubiquitin-conjugating) → E3 (ubiquitin ligase) — transfers ubiquitin to lysine on target protein.
3. Polyubiquitin chain (K48 linkage) → proteasomal degradation.

4. E3 ligases provide specificity — >600 types in humans.

5. 26S Proteasome:

6. 20S core (proteolytic chamber, barrel-shaped) + 19S regulatory cap.
7. Recognises polyubiquitinated proteins → unfolds → translocates into core → degrades into 7–9 amino acid peptides.

8. Regulated degradation of cell cycle proteins, transcription factors, misfolded proteins.

9. Autophagy:

10. Bulk degradation of cytoplasm, organelles, long-lived proteins.
11. Forms a double-membrane autophagosome → fuses with lysosome → contents degraded.
12. Important in cellular stress response, nutrient deprivation, and quality control.

Clinical relevance in obstetrics: - Pre-eclampsia: Increased ER stress and UPR in placenta → may contribute to trophoblast dysfunction. - Autophagy in placenta is important for nutrient sensing and trophoblast survival. - Proteasome inhibitors (bortezomib) are teratogenic — contraindicated in pregnancy (used in multiple myeloma). - Polyubiquitination of cyclins regulates cell cycle — important in ovarian function and placental growth.

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4. Nucleotide Metabolism

4.1 Overview

Nucleotides are essential for: - Energy metabolism (ATP, GTP). - RNA and DNA synthesis (building blocks). - Second messengers (cAMP, cGMP, IP₃). - Coenzymes (NAD⁺, NADP⁺, FAD, CoA).

Structure: Nitrogenous base (purine/pyrimidine) + Pentose sugar (ribose/deoxyribose) + Phosphate(s).

Purines: Adenine (A), Guanine (G) — double-ring structure. Pyrimidines: Cytosine (C), Thymine (T) — DNA; Uracil (U) — RNA. Single-ring structure.

Nucleoside = Base + Sugar (e.g., adenosine, guanosine). Nucleotide = Base + Sugar + Phosphate (e.g., AMP, GMP).

4.2 Purine Synthesis

4.2.1 De Novo Purine Synthesis

Location: Cytosol (primarily liver). Pathway: Builds the purine ring stepwise on a ribose-5-phosphate scaffold.

Key steps: 1. Ribose-5-phosphate (from PPP) → PRPP (5-phosphoribosyl-1-pyrophosphate). - Enzyme: PRPP synthetase. 2. PRPP + Glutamine → 5-Phosphoribosyl-1-amine. - Rate-limiting step of purine synthesis. - Enzyme: PRPP amidotransferase. - Inhibited by AMP, GMP, IMP (feedback inhibition). 3. A series of 9 more reactions add atoms from glycine, aspartate, formyl-THF (two times), glutamine, and CO₂. 4. First complete purine nucleotide: IMP (Inosine monophosphate — hypoxanthine ribonucleotide).

IMP branched-pathway:

• IMP → AMP: Requires GTP (energy input).
• IMP → Adenylosuccinate (adenylosuccinate synthetase) → AMP (adenylosuccinate lyase).
• IMP → GMP: Requires ATP (energy input).
• IMP → XMP (IMP dehydrogenase) → GMP (GMP synthetase).

Regulation: PRPP amidotransferase is the key control point. Feedback inhibition by end products (AMP, GMP, IMP). Activated by high PRPP.

4.2.2 Salvage Pathways

Recycle preformed purine bases (adenine, guanine, hypoxanthine) using phosphoribosyltransferases.

1. Adenine phosphoribosyltransferase (APRT):
2. Adenine + PRPP → AMP + PPi.

3. Deficiency → 2,8-dihydroxyadenine stones (rare).

4. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT):

5. Hypoxanthine + PRPP → IMP + PPi.
6. Guanine + PRPP → GMP + PPi.
7. Deficiency → Lesch-Nyhan syndrome (X-linked).

Importance of salvage pathway: - Brain and RBCs rely heavily on salvage (limited de novo synthesis). - Saves energy (recycling is cheaper than de novo synthesis).

4.2.3 Lesch-Nyhan Syndrome

Defect: HGPRT deficiency (complete deficiency). Inheritance: X-linked recessive. Incidence: ~1:380,000.

Biochemistry: - Hypoxanthine and guanine cannot be recycled → accumulate → converted to uric acid (via xanthine oxidase). - PRPP levels increase → PRPP amidotransferase is activated → de novo purine synthesis increases → further uric acid production.

Clinical features: - Hyperuricaemia → gout, uric acid stones, tophi. - Neurological: Severe dystonia, choreoathetosis, spasticity, intellectual disability. - Behavioural: Self-mutilation (compulsive biting of lips, fingers; head-banging) — pathognomonic. - Dysphagia, aspiratory pneumonia.

Diagnosis: Elevated uric acid, low HGPRT enzyme activity in RBCs or fibroblasts. Management: Allopurinol (for hyperuricaemia, but does NOT affect neurological symptoms). No treatment for neurological/behavioural aspects. Supportive care, dental extraction. Prenatal diagnosis: Enzyme assay on chorionic villus or amniotic fluid cells.

4.3 Pyrimidine Synthesis

De Novo Pyrimidine Synthesis:

Location: Cytosol (enzyme CAD = Carbamoyl phosphate synthetase II, Aspartate transcarbamoylase, Dihydroorotase — all on one polypeptide in mammals).

Key steps: 1. Glutamine + CO₂ + 2ATP → Carbamoyl phosphate. - Enzyme: Carbamoyl phosphate synthetase II (CPS II) — cytosolic. - Different from CPS I (mitochondrial, urea cycle): CPS II uses glutamine as N donor; CPS I uses NH₃. CPS II is inhibited by UTP (feedback) and activated by PRPP. 2. Carbamoyl phosphate + Aspartate → Carbamoylaspartate (by aspartate transcarbamoylase). 3. Ring closure → Dihydroorotate (by dihydroorotase). 4. Dihydroorotate → Orotate (by dihydroorotate dehydrogenase — at inner mitochondrial membrane, produces NAD⁺). This step is the only mitochondrial step. 5. Orotate + PRPP → Orotidine-5'-phosphate (OMP) (by orotate phosphoribosyltransferase). 6. OMP → UMP (by OMP decarboxylase). UMP is the first complete pyrimidine nucleotide.

Pathway from UMP: - UMP → UDP → UTP. - UTP → CTP (by CTP synthetase — amination by glutamine). - UTP → dTTP (via thymidylate synthase, using 5,10-methylene-THF — see folate metabolism).

OTC Deficiency vs CPS II: - OTC deficiency: ↑ Carbamoyl phosphate (mitochondrial) → leaks to cytosol → stimulates CPS II → orotic aciduria (see urea cycle 3.4). - Pure orotic aciduria (deficiency of orotate phosphoribosyltransferase or OMP decarboxylase) → orotic aciduria + megaloblastic anaemia (orotic acid cannot be converted to UMP → block in pyrimidine synthesis → impaired DNA synthesis). Differentiated from OTC deficiency: no hyperammonaemia.

4.4 Uric Acid & Gout

Uric acid is the final breakdown product of purine metabolism in humans (we lack uricase).

Production: - Purine nucleotides → Inosine → Hypoxanthine → Xanthine → Uric acid. - Key enzyme: Xanthine oxidase (converts hypoxanthine → xanthine → uric acid). Located in liver, intestine. Produces H₂O₂ and superoxide.

Excretion: - ~70% via kidney (glomerular filtration + tubular secretion/reabsorption). - ~30% via intestine (gastrointestinal excretion, metabolism by gut bacteria). - Uric acid transporters: URAT1 (reabsorption), GLUT9 (reabsorption/export), ABCG2 (intestinal excretion). Genetic variants affect serum uric acid levels.

Normal serum uric acid: 240–360 µmol/L (males); 180–300 µmol/L (females). Pregnancy: Uric acid normally ↓ in early pregnancy (increased GFR), rises in late pregnancy but ≤350 µmol/L.

Gout: - Deposition of monosodium urate crystals in joints → acute inflammatory arthritis. - Risk factors: Hyperuricaemia, obesity, male sex, post-menopausal women, high-purine diet, alcohol (beer, spirits), fructose-sweetened drinks, diuretics (thiazides), CKD. - In pregnancy: Gout is rare (oestrogen is uricosuric). Pre-eclampsia increases uric acid; hyperuricaemia (>350 µmol/L in second trimester, >380 µmol/L in third trimester) is associated with pre-eclampsia severity.

Drug Therapy:

1. Xanthine Oxidase Inhibitors: - Allopurinol (and its active metabolite oxypurinol): - Competitive inhibitor of xanthine oxidase → ↓ uric acid production. - Also causes orotic aciduria (orotidine accumulation) — not clinically significant. - Side effects: Rash (Stevens-Johnson syndrome risk with HLA-B5801), hypersensitivity. - Pregnancy: Considered low risk; used in women with recurrent uric acid stones or gout. Not teratogenic in animal studies. - Febuxostat:* Non-purine xanthine oxidase inhibitor, used if allopurinol intolerant. Less data in pregnancy.

2. Uricosuric Agents: - Probenecid — inhibits URAT1 (increases uric acid excretion). Contraindicated in CKD, stone formers. - Benzbromarone — potent but hepatotoxic, withdrawn.

3. Acute Gout Treatment: - NSAIDs (colchicine, naproxen) — but NSAIDs are contraindicated in third trimester. - Colchicine — inhibits microtubule assembly, reduces neutrophil chemotaxis. Can be used in pregnancy (low but not zero risk). - Corticosteroids — in pregnancy, preferred over NSAIDs for acute gout (intra-articular or oral).

4.5 Nucleotide Breakdown

Purine Catabolism:

• AMP → Adenosine (5'-nucleotidase) → Inosine (adenosine deaminase — ADA) → Hypoxanthine → Xanthine (xanthine oxidase) → Uric acid.
• GMP → Guanosine → Guanine → Xanthine (guanase) → Uric acid.

ADA deficiency: Severe combined immunodeficiency (SCID) — accumulation of dATP → inhibits ribonucleotide reductase → blocks DNA synthesis → T-cell and B-cell deficiency.

Pyrimidine Catabolism: - Pyrimidines are broken down to β-alanine (uracil) or β-aminoisobutyrate (thymine) → then further to acetyl-CoA or succinyl-CoA → enters TCA cycle. - Unlike purines, pyrimidines are fully metabolised to CO₂ + NH₄⁺ + β-amino acids; no uric acid is formed.

4.6 DNA Repair Mechanisms

DNA is constantly damaged by endogenous (reactive oxygen species, replication errors) and exogenous (UV radiation, chemicals) agents. Multiple repair pathways exist.

1. Base Excision Repair (BER): - Damage: Single-base changes (deamination, oxidation, alkylation), AP sites (apurinic/apyrimidinic). - Key steps: 1. DNA glycosylase recognises and removes the damaged base → AP site (abasic site). 2. AP endonuclease nicks the backbone. 3. DNA polymerase β fills the gap. 4. DNA ligase III/XRCC1 seals. - Example: Uracil removal (from cytosine deamination).

2. Nucleotide Excision Repair (NER): - Damage: Bulky adducts, pyrimidine dimers (UV light → thymine dimers). - Key steps: 1. Damage recognition (XPC, RAD23B). 2. Unwinding (TFIIH, XPA, RPA). 3. Incision (ERCC1-XPF on 5' side, XPG on 3' side) → removes ~24–32 nucleotide oligonucleotide. 4. Resynthesis (Pol δ/ε). 5. Ligation (Ligase I/XRCC1). - Deficiencies: - Xeroderma Pigmentosum (XP): Defect in any of 7 XP genes (XPA-XPG) → inability to repair UV damage → extreme sun sensitivity, 1000× increased skin cancer risk, neurological degeneration. - Cockayne syndrome: Defective transcription-coupled NER → photosensitivity, dwarfism, neurological decline. - Trichothiodystrophy: Brittle hair, ichthyosis, photosensitivity (XPD, XPB mutations).

3. Mismatch Repair (MMR): - Damage: Replication errors — base mismatches, insertion-deletion loops (slippage in repetitive sequences). - Key proteins: MSH2, MSH3, MSH6 (recognise mismatch), MLH1, PMS2 (incision). - Steps: Mismatch recognition → excision (includes daughter strand) → resynthesis. - Deficiencies: - Lynch Syndrome (Hereditary Non-Polyposis Colorectal Cancer — HNPCC): Germline mutations in MSH2, MLH1, MSH6, PMS2 → defective MMR → microsatellite instability → increased risk of colorectal (70%), endometrial (40–60%), ovarian (10–12%), and other cancers. - Relevance in O&G: Women with Lynch syndrome need regular endometrial sampling, risk-reducing hysterectomy ± BSO after completion of childbearing.

4. Double-Strand Break Repair:

a) Homologous Recombination (HR): - Error-free, uses sister chromatid as template. - Key proteins: BRCA1, BRCA2, RAD51, ATM. - BRCA1/BRCA2 mutations: Defective HR → genomic instability → increased risk of breast and ovarian cancer. - PARP inhibitors (olaparib, niraparib) exploit this defect in BRCA-mutated cancers (synthetic lethality).

b) Non-Homologous End Joining (NHEJ): - Error-prone. Directly joins broken ends. - Key proteins: Ku70/Ku80, DNA-PKcs, XRCC4, Ligase IV. - Active throughout cell cycle, especially G1 phase.

5. Direct Reversal: - O⁶-methylguanine-DNA methyltransferase (MGMT): Removes methyl groups from O⁶-methylguanine (single protein, suicide enzyme — inactivated after one reaction).

Clinical relevance in obstetrics: - Pre-eclampsia: Increased DNA damage in placental cells (oxidative stress) → activation of repair pathways. Defective repair may contribute to placental dysfunction. - Chemotherapy in pregnancy: DNA-damaging agents (cisplatin, doxorubicin) — cross placenta, potential for fetal toxicity. DNA repair in fetal tissues may be less efficient. - Advanced maternal age: Accumulated DNA damage in oocytes contributes to aneuploidy and reduced fertility.

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5. Vitamins & Coenzymes

5.1 Vitamin B1 (Thiamine)

Active form: Thiamine pyrophosphate (TPP) — cofactor for several key enzymes.

Functions (TPP-dependent enzymes): 1. Pyruvate dehydrogenase (PDH): Pyruvate → Acetyl-CoA (link between glycolysis and TCA cycle). 2. α-Ketoglutarate dehydrogenase: TCA cycle. 3. Branched-chain α-keto acid dehydrogenase (BCKDH): BCAA metabolism. 4. Transketolase: Pentose phosphate pathway (non-oxidative phase). 5. Pyruvate decarboxylase (acetaldehyde production in yeast).

Deficiency:

Form	Context	Key Features
Dry Beriberi	Chronic deficiency (low thiamine intake)	Peripheral neuropathy (symmetric, sensorimotor), muscle wasting, areflexia
Wet Beriberi	High-output cardiac stress	High-output heart failure, peripheral oedema, tachycardia, cardiomegaly
Wernicke-Korsakoff Syndrome	Alcoholism (most common in developed world); also hyperemesis gravidarum, malnutrition	Wernicke encephalopathy: Acute confusion, ataxia, ophthalmoplegia (nystagmus, lateral rectus palsy). Korsakoff psychosis: Chronic amnesia, confabulation — due to irreversible thiamine deficiency

High-risk groups: Alcoholics, patients with hyperemesis gravidarum (prolonged vomiting → thiamine depletion), post-bariatric surgery, malabsorption.

In pregnancy: - Thiamine requirements increase in pregnancy (25–30% ↑ in 3rd trimester). - Hyperemesis gravidarum — IV dextrose without thiamine can precipitate Wernicke's encephalopathy (thiamine is a cofactor in glucose metabolism; giving glucose without thiamine → rapid depletion). Always give IV thiamine before or with dextrose in hyperemesis.

TRMA (Thiamine-responsive megaloblastic anaemia): - Genetic defect in thiamine transporter (SLC19A2) → diabetes mellitus, sensorineural deafness, megaloblastic anaemia. Responds to high-dose thiamine.

5.2 Vitamin B2 (Riboflavin)

Active forms: FAD (flavin adenine dinucleotide) and FMN (flavin mononucleotide). Function: Cofactor for flavoprotein enzymes involved in redox reactions (transfer of electrons).

Key FAD/FMN-dependent enzymes: - Succinate dehydrogenase (Complex II, TCA cycle). - Acyl-CoA dehydrogenase (β-oxidation). - Monoamine oxidase (MAO) — neurotransmitter metabolism. - Glutathione reductase — requires FAD to reduce GSSG → GSH. - Methylenetetrahydrofolate reductase (MTHFR) — FAD-dependent.

Deficiency: - Rare in isolation; often with other B vitamin deficiencies. - Clinical: Angular stomatitis (cheilitis), glossitis (red, smooth tongue), seborrhoeic dermatitis, photophobia, corneal neovascularisation.

Pregnancy: Requirements increased. Deficiency may be associated with pre-eclampsia (due to altered glutathione metabolism). Not commonly supplemented.

5.3 Vitamin B3 (Niacin)

Active forms: NAD⁺ (nicotinamide adenine dinucleotide) and NADP⁺ (nicotinamide adenine dinucleotide phosphate). Precursors: Dietary niacin (nicotinic acid, nicotinamide) and tryptophan (60 mg tryptophan → 1 mg niacin).

Functions: - NAD⁺/NADH: Catabolic reactions (glycolysis, TCA cycle, β-oxidation). - NADP⁺/NADPH: Anabolic reactions (FA synthesis, steroidogenesis, PPP, glutathione reduction). - NAD⁺ is also a substrate for poly(ADP-ribose) polymerase (PARP) (DNA repair) and sirtuins (deacetylases, ageing-related).

Deficiency — Pellagra: - Classic triad: - Dermatitis: Photosensitive rash on sun-exposed areas (Casal necklace — around neck). - Diarrhoea: Gastrointestinal inflammation. - Dementia: Confusion, depression, memory loss (reversible if caught early). - Risk factors: Maize-based diet (niacin in corn is bound and unavailable), alcoholism, carcinoid syndrome (tryptophan diverted to serotonin). - Pellagra in pregnancy: Poor maternal and fetal outcomes.

Toxicity: - Niacin (nicotinic acid) high dose → flushing, pruritus, hepatotoxicity, hyperglycaemia. - Nicotinamide form is better tolerated.

5.4 Vitamin B5 (Pantothenic Acid)

Active form: Coenzyme A (CoA) and Acyl carrier protein (ACP) (component of fatty acid synthase).

CoA Functions: - Carrier of acyl groups (acetyl-CoA, succinyl-CoA, fatty acyl-CoA). - Essential for: TCA cycle, FA synthesis & oxidation, ketone body synthesis, cholesterol synthesis, acetylation reactions.

Deficiency: Very rare (widely distributed in foods). Experimental deficiency → fatigue, insomnia, "burning feet" syndrome, glucose intolerance.

5.5 Vitamin B6 (Pyridoxine)

Active form: Pyridoxal phosphate (PLP). Functions: Cofactor for >100 enzymes, primarily in amino acid metabolism.

Key PLP-dependent enzymes: - Aminotransferases (ALT, AST): Transamination (see 3.2). - Decarboxylases: - DOPA decarboxylase → dopamine. - Glutamate decarboxylase → GABA. - Histidine decarboxylase → histamine. - Cystathionine β-synthase & Cystathionase: Transsulphuration pathway (homocysteine → cysteine). - δ-Aminolevulinic acid (ALA) synthase: Heme synthesis (rate-limiting step). - Glycogen phosphorylase: Releases glucose-1-P from glycogen.

Deficiency:

Condition	Features
General deficiency	Dermatitis, glossitis, cheilitis, depression, confusion, microcytic anaemia (↓ heme synthesis)
Infantile seizures	PLP deficiency → ↓ GABA → seizures. Treat with B6 supplementation
Homocysteinaemia	Impaired transsulphuration → ↑ homocysteine → CVD risk
Isoniazid-induced deficiency	INH (TB drug) inactivates PLP → peripheral neuropathy. Supplement with B6

Pregnancy: - Morning sickness / Nausea & Vomiting: Vitamin B6 (pyridoxine, 10–25 mg TDS) is first-line treatment (NICE guidance). Combined with doxylamine (antisickness antihistamine). - Pre-eclampsia: Low B6 levels reported; supplementation not proven to reduce risk. - Requirements increase in pregnancy (↑ amino acid metabolism).

Toxicity: High dose (>200 mg/day long-term) → peripheral neuropathy (sensory).

5.6 Vitamin B7 (Biotin)

Function: Cofactor for carboxylation reactions — carries activated CO₂ (carboxyl group).

Biotin-dependent carboxylases:

Enzyme	Location	Function
Acetyl-CoA carboxylase (ACC)	Cytosol	FA synthesis: Acetyl-CoA → Malonyl-CoA
Pyruvate carboxylase	Mitochondria	Gluconeogenesis: Pyruvate → Oxaloacetate
Propionyl-CoA carboxylase	Mitochondria	Propionate → Methylmalonyl-CoA (odd-chain FA, BCAA metabolism)
3-Methylcrotonyl-CoA carboxylase	Mitochondria	Leucine catabolism

Deficiency: - Rare in general population (wide food sources, gut bacteria also produce biotin). - Egg white injury: Raw egg white contains avidin — a glycoprotein that binds biotin with high affinity, preventing absorption. Cooking denatures avidin. - Pregnancy: Mild biotin deficiency is common in pregnancy ("accelerated biotin depletion") — may contribute to birth defects (cleft palate, limb defects) in animal studies. - Clinical: Dermatitis (perioral, perianal rash), alopecia, glossitis, depression, hallucinations, ataxia, developmental delay in infants. - Diagnosis: Elevated 3-hydroxyisovalerate in urine. - Treatment: Biotin 5–10 mg/day.

Multiple Carboxylase Deficiency: - Holocarboxylase synthetase deficiency: Cannot attach biotin to carboxylases → severe metabolic acidosis, dermatitis, feeding difficulties, seizures in infancy. Treat with high-dose biotin. - Biotinidase deficiency: Cannot recycle biotin → similar presentation later in infancy.

5.7 Vitamin B9 (Folate)

Active forms: Tetrahydrofolate (THF) and its derivatives — 5-methyl-THF, 5,10-methylene-THF, 10-formyl-THF.

Function: One-carbon metabolism — transfers single carbon units (methyl, methylene, formyl, formimino) in: - Purine synthesis: 10-formyl-THF (donates C2 and C8 of purine ring). - Thymidylate synthesis: 5,10-methylene-THF (donates methyl group to dUMP → dTMP by thymidylate synthase). - Methionine synthesis: 5-methyl-THF donates methyl to homocysteine → methionine (via methionine synthase, requires B12). - Histidine metabolism: Formiminoglutamate (FIGLU) → glutamate.

Folate Cycle:

1. Tetrahydrofolate (THF) + Serine → 5,10-methylene-THF + Glycine (reversible, via serine hydroxymethyltransferase — PLP-dependent).
2. 5,10-methylene-THF → 5-methyl-THF (irreversible, by MTHFR — methylenetetrahydrofolate reductase). Key regulatory step.
3. 5-methyl-THF + Homocysteine → THF + Methionine (via methionine synthase, B12-dependent).
4. 5,10-methylene-THF can also be used for thymidylate synthesis or oxidised to 10-formyl-THF for purine synthesis.

Dietary Sources: - Green leafy vegetables, fortified flour/grains, liver, legumes, citrus fruit. - Folic acid (synthetic, in supplements/fortified foods) — more bioavailable than natural folate.

Deficiency:

Feature	Details
Megaloblastic anaemia	Impaired DNA synthesis → large, abnormal RBC precursors (megaloblasts) in bone marrow; macrocytic anaemia (MCV ↑)
Neural tube defects (NTDs)	Spina bifida, anencephaly, encephalocele — failure of neural tube closure by day 28 post-conception (before most women know they're pregnant)
Pregnancy complications	Increased risk of (in some studies): miscarriage, preterm birth, FGR, placental abruption
Homocysteine elevation	Folate deficiency → ↑ homocysteine (independent CVD risk factor)

MTHFR Polymorphisms: - C677T (rs1801133): 30–40% of population have variant allele. - TT homozygotes (~10%): Reduced MTHFR enzyme activity (~30% of normal) → decreased conversion of 5,10-methylene-THF to 5-methyl-THF. - Result: ↑ homocysteine, ↓ 5-methyl-THF (may reduce methyl group availability for homocysteine re-methylation). - A1298C: Another common variant, milder effect. - Relevance: - TT genotype in mother — increased risk of NTDs (odds ratio ~2.0). - High-dose folic acid (5 mg) may overcome the block. - Association with recurrent miscarriage controversial (meta-analyses show weak or no association). - Screening for MTHFR in pregnancy is NOT routinely recommended (no proven benefit; folic acid supplementation is effective regardless of genotype).

Folic Acid Supplementation in Pregnancy:

Recommendation	Dose	Timing
General population	400 µg (0.4 mg) daily	Pre-conception to 12 weeks
High-risk for NTD	5 mg daily	Pre-conception to 12 weeks
High-risk groups:
Previous pregnancy with NTD	5 mg
Family history of NTD (first-degree)	5 mg
Maternal anti-epileptic drugs (valproate, carbamazepine)	5 mg
Diabetes mellitus (type 1 or 2)	5 mg
Obesity (BMI >30)	5 mg (some guidelines)
Sickle cell disease, thalassaemia	5 mg
Coeliac disease, malabsorption	5 mg
Multiple pregnancies	0.4 mg (some recommend 1–5 mg)

Mechanism of NTD prevention: - Folic acid before and during early pregnancy → ensures adequate 5-methyl-THF for neural tube closure, cell proliferation, and methylation reactions.

Folate Antagonists / Methotrexate (MTX):

• Methotrexate inhibits dihydrofolate reductase (DHFR) → blocks conversion of folate (dihydrofolate) to THF → ↓ purine and thymidine synthesis → ↓ cell division.
• Uses:
• Medical termination of ectopic pregnancy (single-dose MTX) — but teratogenic, so used only when non-viable.
• Chemotherapy for malignancies (gestational trophoblastic disease — GTD).
• Rheumatoid arthritis, psoriasis (low-dose weekly).
• Teratogenicity: MTX is a known teratogen — fetal MTX syndrome (craniofacial abnormalities, skeletal defects, CNS anomalies). Must ensure effective contraception during therapy and for 3 months after stopping.
• Folinic acid (leucovorin) — used as "rescue" after high-dose MTX (bypasses the DHFR block). NOT the same as folic acid (which requires DHFR to activate).

Trimethoprim: - Weak DHFR inhibitor (bacterial DHFR is much more sensitive) — used as urinary antiseptic. In pregnancy, theoretical risk of folate antagonism; avoid in first trimester, use with folic acid if needed.

5.8 Vitamin B12 (Cobalamin)

Active forms: Methylcobalamin (methyl-B12) and Adenosylcobalamin (adenosyl-B12). Structure: Corrin ring with central cobalt ion (hence cobalamin).

Two B12-dependent reactions in humans:

1. Methionine synthase (cytosol): Homocysteine + 5-methyl-THF → Methionine + THF.
2. Requires Methyl-B12 as cofactor.

3. Links folate and B12 metabolism — the methyl folate trap (see below).

4. Methylmalonyl-CoA mutase (mitochondria): Methylmalonyl-CoA → Succinyl-CoA.

5. Requires Adenosyl-B12 as cofactor.
6. Involved in odd-chain FA and branched-chain amino acid metabolism.

Absorption & Transport: 1. Dietary B12 bound to R-protein (haptocorrin) in saliva/stomach. 2. In duodenum, pancreatic proteases digest R-protein → B12 released. 3. B12 binds to Intrinsic Factor (IF) — produced by gastric parietal cells. 4. B12-IF complex absorbed in terminal ileum (via cubilin receptor). 5. Transported in plasma bound to transcobalamin II (holo-TC) — delivers to tissues.

Causes of B12 Deficiency:

Cause	Mechanism
Pernicious anaemia	Autoimmune destruction of parietal cells → ↓ IF production → ↓ B12 absorption
Gastrectomy / bariatric surgery	Loss of IF-producing cells
Terminal ileal disease (Crohn's, coeliac)	Impaired B12-IF absorption
Vegan / strict vegetarian	No dietary B12 (B12 only in animal products — meat, eggs, dairy)
Pancreatic insufficiency	Reduced R-protein digestion
Long-term PPI use	↓ gastric acidity → impaired B12 release from food
Fish tapeworm	Competes for B12
Nitrous oxide (N₂O) abuse	Oxidises cobalt in B12 → inactivates methionine synthase

Clinical Features of B12 Deficiency:

• Megaloblastic anaemia (identical to folate deficiency — macrocytic, hypersegmented neutrophils, MCV ↑).
• Neurological symptoms: Peripheral neuropathy, subacute combined degeneration of the cord (demyelination of dorsal columns + corticospinal tracts → loss of vibration/proprioception, spasticity, ataxia), cognitive impairment, depression.
• Glossitis (smooth, red, sore tongue).
• Methylmalonic aciduria (↑ methylmalonate in urine — diagnostic marker to distinguish from folate deficiency).

Diagnosis: - ↓ Serum B12 (<150 pmol/L). - ↑ Methylmalonic acid (MMA) and/or homocysteine (both elevated in B12 deficiency; only homocysteine elevated in folate deficiency). - Intrinsic factor antibodies (pernicious anaemia — highly specific, 50% sensitivity). - Parietal cell antibodies (more sensitive, less specific).

Treatment: - Hydroxocobalamin (injection) — 1 mg IM 3×/week for 2 weeks, then 1 mg 3-monthly. - Oral B12 (high dose, 1000–2000 µg/day) can be effective for dietary deficiency. - Start B12 before folic acid in megaloblastic anaemia — giving folic acid alone in B12 deficiency can correct the anaemia but precipitate/worsen neurological symptoms (because methionine synthase is still inactive, and folic acid "traps" methyl-THF — see below).

The Methyl Folate Trap: - B12 deficiency → methionine synthase is inactive → 5-methyl-THF cannot be converted back to THF. - 5-methyl-THF accumulates (the "trap"). - THF is depleted → nucleotide synthesis impaired → megaloblastic anaemia. - Folic acid (dihydrofolate) given to B12-deficient patient → converted to THF → 5,10-methylene-THF → 5-methyl-THF → accumulates → folate is trapped again. But some 5,10-methylene-THF can be used for thymidine synthesis, so haematological improvement occurs — but neurological symptoms progress because the B12-dependent methionine synthase reaction (necessary for myelin maintenance) remains uncorrected.

Pregnancy & B12: - B12 requirements increase in pregnancy (fetal uptake, increased maternal erythropoiesis). - B12 deficiency in pregnancy: Increased risk of NTDs (even without folate deficiency), miscarriage, preterm birth, FGR. - Vegetarian/vegan mothers: At high risk for B12 deficiency; need B12 supplementation (2.6 µg/day in pregnancy, higher for deficiency). - Breastfed infants of B12-deficient mothers → neurological damage, failure to thrive. - Routine screening for B12 deficiency in pregnancy is not recommended unless risk factors present.

5.9 Vitamin A (Retinol)

Active forms: Retinol (alcohol), Retinal (aldehyde), Retinoic acid (acid). Also provitamin A carotenoids (β-carotene, α-carotene, β-cryptoxanthin) from plants.

Functions:

1. Vision (Retinal):
2. 11-cis-Retinal + Opsin → Rhodopsin (rod cells) — photopigment.
3. Light → 11-cis → all-trans retinal (isomerisation) → conformational change → signal via transducin (G-protein) → nerve impulse → vision.

4. Night blindness: First sign of vitamin A deficiency (impaired dark adaptation).

5. Gene Regulation (Retinoic acid):

6. All-trans-retinoic acid (ATRA) and 9-cis-retinoic acid bind to nuclear receptors:
   • RAR (retinoic acid receptor) — binds ATRA.
   • RXR (retinoid X receptor) — binds 9-cis-RA.
7. Heterodimers (RAR/RXR) regulate transcription of genes involved in cell differentiation, proliferation, apoptosis, and embryogenesis.

8. Critical for limb development, heart development, neural crest cell migration, and eye development.

9. Immune function, epithelial integrity, reproduction.

Deficiency: - Night blindness → Xerophthalmia (dry conjunctiva → Bitot spots → keratomalacia → blindness). - Impaired immunity (increased infections, measles severity). - Squamous metaplasia of epithelial surfaces. - Pregnancy: Night blindness in late pregnancy (due to increased demands, particularly in developing countries). Supplementation recommended if deficient (but careful with dose — see below).

Teratogenicity / Toxicity:

	Acute	Chronic
Hypervitaminosis A	Headache, vomiting, blurred vision, peeling skin	Liver damage, bone pain, pseudotumour cerebri, alopecia, cheilitis
Isotretinoin (Retinoids)	—	Highly teratogenic — see below

Isotretinoin (13-cis-retinoic acid): - Used for severe acne (Roaccutane). - Teratogenicity: Retinoic acid embryopathy / Retinoid syndrome: - CNS: Hydrocephalus, microcephaly, cognitive impairment. - Craniofacial: Cleft palate, micrognathia, ear deformities. - Cardiovascular: Conotruncal heart defects. - Thymic hypoplasia. - Approximately 20–35% risk of major malformations with in-utero exposure. - Precautions: Strict pregnancy prevention — negative pregnancy test before initiation, effective contraception during treatment and for 1 month after stopping (isotretinoin has a short half-life, but must ensure no pregnancy during use). - Accutane lawsuit: Well-known for birth defects; strict pregnancy prevention programs are mandatory.

Pregnancy Requirements: - RDA: 700 µg RAE (retinol activity equivalents) — non-pregnant; 770 µg in pregnancy; 1300 µg in lactation. - Upper limit: 3000 µg/day (3 mg) — to avoid teratogenicity. - β-carotene: Considered safe (not teratogenic even at high doses — body regulates conversion). - Liver: Very high in retinol — pregnant women advised to avoid liver/liver products (contain >30000 µg/100g → could exceed safe limit with regular consumption).

5.10 Vitamin D (Cholecalciferol)

Forms: - Vitamin D₂ (Ergocalciferol): From plant sources, UV-treated mushrooms. - Vitamin D₃ (Cholecalciferol): Synthesised in skin from 7-dehydrocholesterol + UVB (sunlight) + dietary (oily fish, eggs, fortified foods).

Activation Pathway:

1. Skin: 7-Dehydrocholesterol + UVB → Cholecalciferol (Vitamin D₃).
2. Liver: Cholecalciferol → 25-Hydroxyvitamin D [25(OH)D] — by 25-hydroxylase (CYP2R1).
3. This is the major circulating form (measured to assess D status).
4. Kidney: 25(OH)D → 1,25-Dihydroxyvitamin D [1,25(OH)₂D] — by 1α-hydroxylase (CYP27B1).
5. The active form (calcitriol).
6. Stimulated by ↓ Ca²⁺ (via ↑ PTH).
7. Suppressed by ↑ Ca²⁺ and FGF23.

Functions of Calcitriol (1,25(OH)₂D):

1. Calcium Homeostasis:
2. Intestine: ↑ Ca²⁺ absorption (via TRPV6 calcium channels, calbindin).
3. Bone: Stimulates osteoclast activity (via RANKL on osteoblasts) → bone resorption → ↑ Ca²⁺ and PO₄³⁻.
4. Kidney: ↑ Ca²⁺ reabsorption (distal tubule).
5. Phosphate Homeostasis: ↑ intestinal phosphate absorption.
6. Immune modulation: Enhances innate immunity (cathelicidin production). Modulates adaptive immunity (T cell regulation).
7. Cell differentiation, proliferation, and gene regulation via Vitamin D Receptor (VDR) — a nuclear receptor.

Deficiency:

Condition	Features
Rickets (children)	Growth retardation, bowing of legs, widened wrists, rachitic rosary (costochondral swelling), craniotabes (soft skull), hypocalcaemic tetany/seizures
Osteomalacia (adults)	Bone pain, proximal myopathy, waddling gait, fractures; undermineralised bone matrix
Pregnancy	Increased risk of: pre-eclampsia, GDM, preterm birth, small-for-gestational-age, neonatal rickets/hypocalcaemia (controversial; some studies show associations)

Vitamin D in Pregnancy: - Requirements increase significantly in pregnancy and lactation (fetal skeletal development places high demand). - Maternal 25(OH)D crosses placenta — fetal levels are ~50–80% of maternal levels. - Placental 1α-hydroxylase converts 25(OH)D to active 1,25(OH)₂D — placental levels of active D are high → involved in immune regulation at the maternal-fetal interface. - Deficiency: More common in women with darker skin, limited sun exposure (veiled/hijab), high-latitude climates, obesity, malabsorption. - Supplementation: - UK guidelines: 400 IU (10 µg) daily for all pregnant and breastfeeding women. - At-risk women: Higher doses (1000–2000 IU/day) may be needed. - Screening for deficiency: Not routine — but measure 25(OH)D if high risk. - Upper limit: 4000 IU/day (safe in pregnancy).

Vitamin D Toxicity: - Very rare from sunlight (regulated by skin). - Excessive supplementation → hypercalcaemia, hypercalciuria, nephrocalcinosis, soft tissue calcification.

5.11 Vitamin E (Tocopherol)

Active form: α-Tocopherol — most biologically active. Function: Lipid-soluble antioxidant — protects cell membranes from oxidative damage (lipid peroxidation).

Mechanism: - Breaks the chain reaction of lipid peroxidation by scavenging peroxyl radicals. - Acts synergistically with Vitamin C (water-soluble antioxidant = recycles vitamin E), glutathione, and β-carotene. - Membrane-associated — incorporated into phospholipid bilayers.

Deficiency: - Rare (wide food sources: vegetable oils, nuts, seeds, green leafy veg). - Causes: - Fat malabsorption: Cystic fibrosis, cholestasis, abetalipoproteinaemia. - Genetic: α-TTP (α-tocopherol transfer protein) deficiency → severe deficiency → ataxia, peripheral neuropathy, retinopathy. - Newborns: Low vitamin E stores at birth (placental transfer limited). Preterm infants are especially deficient → increased risk of haemolytic anaemia, intraventricular haemorrhage, retinopathy of prematurity (controversial — excessive E may increase sepsis risk).

Pregnancy: - Requirements increase (oxidative stress in pregnancy is elevated). - Pre-eclampsia: Increased oxidative stress; some trials with vitamin E + C supplementation showed no reduction in pre-eclampsia (actually increased low birthweight in one large trial — WHO Vitamin C/E trial). Therefore, routine supplementation is NOT recommended. - Antioxidant defence in pregnancy is complex — balance of pro-oxidants and antioxidants.

5.12 Vitamin K

Forms: - Vitamin K₁ (Phylloquinone): From green leafy vegetables (kale, spinach, broccoli). - Vitamin K₂ (Menaquinones): Synthesised by gut bacteria; also in fermented foods (natto, cheese). Longer side chains (MK-4 to MK-13).

Function: Cofactor for γ-glutamyl carboxylase — adds CO₂ to glutamate residues to form γ-carboxyglutamate (Gla) — critical for Ca²⁺ binding.

Vitamin K-dependent proteins:

Protein	Function
Clotting factors II (prothrombin), VII, IX, X	Blood coagulation (liver-synthesised zymogens)
Clotting factors: Protein C & Protein S	Anticoagulant — inactivates factors Va and VIIIa (natural anticoagulants)
Osteocalcin (bone Gla protein)	Bone mineralisation, binds Ca²⁺ in bone matrix
Matrix Gla protein (MGP)	Inhibits vascular calcification
Gas6	Cell survival, proliferation (TAM receptor signalling)

Vitamin K Cycle:

1. Hydroquinone (KH₂) + CO₂ + O₂ → γ-carboxylation of Glu → Epoxide (KO).
2. Vitamin K epoxide reductase (VKORC1) — reduces KO back to KH₂ (regeneration).
3. Warfarin inhibits VKORC1 → blocks regeneration → promotes anticoagulation.

Deficiency:

Neonatal Vitamin K Deficiency Bleeding (VKDB): - Newborns are born with low vitamin K stores (limited placental transfer, sterile gut, low K in breast milk). - Prophylaxis: Intramuscular vitamin K (1 mg) at birth — standard in UK. - Prevents classic VKDB (Days 1–7): Usually mild (bruising, umbilical bleeding). - Prevents late VKDB (Weeks 2–12): Severe (intracranial haemorrhage, GI bleeding) — prevented by IM K; oral K requires multiple doses. - Risk factors: Preterm, instrumental delivery, liver disease, maternal anti-epileptic drugs (phenytoin, carbamazepine — induce fetal liver enzymes → ↑ vitamin K catabolism). - In VKDB: ↓ Factors II, VII, IX, X; prolonged PT (first to rise, factor VII has shortest half-life); normal PTT; normal platelets.

Pregnancy: - Vitamin K does NOT cross placenta efficiently → fetal levels are low; that's why neonates need prophylaxis. - Anticonvulsants (enzyme-inducing): Increase risk of neonatal VKDB → pregnant women on these drugs may benefit from oral vitamin K (10–20 mg/day) in the last month (though IM K still needed for baby). - Malabsorption: Cystic fibrosis, coeliac, short bowel → may need parenteral K. - Warfarin: Teratogenic in first trimester (warfarin embryopathy — nasal hypoplasia, stippled epiphyses, CNS anomalies). Avoid in pregnancy; use LMWH instead.

5.13 Vitamin C (Ascorbic Acid)

Function: Water-soluble antioxidant and enzyme cofactor (reducing agent — donates electrons).

Enzymatic functions:

1. Collagen Synthesis:
2. Prolyl-4-hydroxylase and Lysyl-hydroxylase — hydroxylate proline and lysine residues in procollagen → required for triple helix formation and cross-linking.
3. Vitamin C keeps the iron atom (Fe²⁺) in the active sites in the reduced state.

4. Deficiency → unstable collagen → weak blood vessels, poor wound healing, fragile skin.

5. Carnitine synthesis — required for FA transport into mitochondria.

6. Neurotransmitter synthesis: Dopamine → Noradrenaline (dopamine β-hydroxylase).
7. Iron absorption: Reduces Fe³⁺ → Fe²⁺ in gut → increases absorption (take with iron in anaemia).
8. Antioxidant: Protects against ROS; recycles vitamin E (tocopherol).
9. Peptide hormone amidation (C-terminal amidation of peptide hormones).

Deficiency — Scurvy:

System	Features
General	Fatigue, malaise, weight loss
Skin	Perifollicular haemorrhages, bruising, hyperkeratosis
Gums	Gingival swelling, bleeding, loosening of teeth
Wounds	Poor wound healing, wound dehiscence
Bones	Bone pain, fractures, subperiosteal haemorrhage (in children)
Haematological	Anaemia (iron deficiency + bleeding)
Vascular	Capillary fragility → petechiae, ecchymoses

Risk groups: Alcoholics, elderly, smokers (↑ catabolism), food faddists, malabsorption, severe hyperemesis.

Pregnancy: - Requirements increased in pregnancy (85 mg/day vs 75 mg non-pregnant). - Important for fetal collagen synthesis and antioxidant protection. - Pre-eclampsia: Lower vitamin C levels in affected women; trials with C+E supplementation were negative (see vit E). - Smoking in pregnancy: ↑ vitamin C catabolism → increased requirement. - Preterm prelabour rupture of membranes (PPROM): Some studies suggest low vitamin C may be a risk factor (role in collagen integrity of fetal membranes), but supplementation trials have not shown clear benefit.

Toxicity: - Generally well-tolerated (water-soluble, excreted in urine). - High doses (>2 g/day): Diarrhoea (osmotic), GI upset, renal stones (oxalate → risk in predisposed individuals). - High-dose vitamin C in pregnant women: Theoretical risk of oxalate stones; probable safe in moderate doses.

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6. Hormone Biochemistry

6.1 Peptide Hormone Synthesis

Peptide hormones (e.g., insulin, glucagon, hPL, PTH, hCG, ACTH, FSH, LH) are synthesised as larger precursors and processed.

Biosynthesis Pathway:

1. Preprohormone (mRNA translation on RER):
2. Contains a signal peptide (hydrophobic 15–30 aa) that directs the ribosome to the RER membrane.

3. Signal peptide is cleaved in the RER lumen → Prohormone.

4. Prohormone (RER lumen):

5. Folding, disulphide bond formation.

6. Transported to Golgi apparatus in transport vesicles.

7. Golgi processing:

8. Prohormone convertases (PC1/3, PC2) cleave at paired basic residues (Lys-Arg, Arg-Arg).
9. Carboxypeptidase E removes basic C-terminal residues.
10. C-terminal amidation (by peptidylglycine α-amidating monooxygenase — PAM, requires Vitamin C).

11. Glycosylation (for glycoprotein hormones: hCG, FSH, LH — α and β subunits).

12. Secretory granules: Mature hormone stored in dense-core secretory vesicles → released on demand (regulated exocytosis).

Examples:

Hormone	Precursor	Cleavage products
Insulin	Preproinsulin (110 aa) → Proinsulin (86 aa, with A, B, C chains) →	Insulin (A+B chain, 51 aa) + C-peptide (31 aa)
PTH	PreproPTH (115 aa) → ProPTH (90 aa) →	PTH (84 aa)
ACTH (POMC)	Pro-opiomelanocortin (POMC, 265 aa) → multiple cleavage sites	ACTH (39 aa), β-endorphin, α-MSH, CLIP, β-lipotropin
Glucagon	Proglucagon →	Glucagon (29 aa, pancreatic α-cells) or GLP-1 (intestine)
hCG	α-subunit (92 aa) + β-subunit (145 aa, unique C-terminal tail)	Non-covalently linked αβ dimer

C-peptide measurement: - Used to differentiate endogenous vs exogenous insulin (e.g., in hypoglycaemia investigation, factitious insulin use). - C-peptide is co-secreted with insulin 1:1. - Endogenous insulin → high C-peptide. - Exogenous insulin → low C-peptide.

Clinical relevance in obstetrics: - Insulin therapy in GDM: Human insulin or insulin analogues (some cross placenta minimally). C-peptide is low in maternal blood when using exogenous insulin. - POMC processing in placenta — produces ACTH and other peptides during pregnancy.

6.2 Steroid Hormone Synthesis

Precursor: Cholesterol (from LDL, de novo synthesis, or stored cholesteryl esters).

General principle: Steroid hormones are not stored — they are synthesised on demand from cholesterol and released immediately.

Key conversion — Rate-limiting Step:

Cholesterol → Pregnenolone (in mitochondria): - Enzyme: CYP11A1 (P450scc) — side-chain cleavage enzyme. - Requires: NADPH, O₂, adrenodoxin, adrenodoxin reductase. - Stimulated by: ACTH (adrenal), LH/hCG (gonads/placenta), Angiotensin II (aldosterone).

Major Steroidogenic Pathways:

1. Δ⁵ Pathway (pregnenolone → 17-OH-pregnenolone → DHEA → DHEA-S):

2. Predominant in zona reticularis (adrenal androgens) and placenta (DHEA-S from fetal adrenal → for oestrogen synthesis).

3. Δ⁴ Pathway (progesterone → 17-OH-progesterone → androstenedione → testosterone):

4. Predominant in corpus luteum (progesterone), testis, ovary.

Key Enzymes:

Enzyme	Function	Location	Defect / Disease
CYP11A1 (P450scc)	Cholesterol → Pregnenolone	Mitochondria (all steroidogenic tissues)	Rare — adrenal insufficiency, 46,XY DSD
3β-HSD (type 2)	Pregnenolone → Progesterone; 17-OH-pregnenolone → 17-OH-progesterone; DHEA → Androstenedione	ER (adrenal, gonad, placenta)	3β-HSD deficiency — CAH variant, ambiguous genitalia in 46,XX, salt-wasting
CYP17 (17α-hydroxylase/17,20-lyase)	Pregnenolone/Progesterone → 17-OH derivatives; also 17,20 lyase (DHEA production)	ER (adrenal, gonad)	CYP17 deficiency — hypertension, hypokalaemia, 46,XY DSD, primary amenorrhoea
CYP21A2 (21-hydroxylase)	Progesterone → Deoxycorticosterone; 17-OH-progesterone → 11-Deoxycortisol	ER (adrenal only)	21-OH deficiency — most common CAH (>90%)
CYP11B1 (11β-hydroxylase)	Deoxycortisol → Cortisol; DOC → Corticosterone	Mitochondria (adrenal)	11β-OH deficiency — CAH, hypertension
CYP11B2 (Aldosterone synthase)	Corticosterone → Aldosterone	Mitochondria (zona glomerulosa)	CMO deficiency — salt-wasting, growth failure
CYP19A1 (Aromatase)	Androstenedione → Oestrone; Testosterone → Oestradiol	ER (ovary, placenta, adipose, brain)	Aromatase deficiency — virilisation in pregnancy
17β-HSD (17β-hydroxysteroid dehydrogenase)	Androstenedione → Testosterone; Oestrone → Oestradiol	ER (testis, ovary)	17β-HSD deficiency — 46,XY DSD, gynaecomastia

Tissue-specific Steroidogenesis:

1. Adrenal Cortex:

Zone	Hormones	Key enzyme
Zona glomerulosa	Aldosterone	CYP11B2 (aldosterone synthase); requires Ang II, high K⁺
Zona fasciculata	Cortisol	CYP21A2, CYP11B1; stimulated by ACTH
Zona reticularis	DHEA, DHEA-S (androgens)	CYP17 (17,20-lyase); stimulated by ACTH

2. Placenta: - Lacks CYP17 activity until late pregnancy (minimal). - Placental progesterone synthesis: Cholesterol → Pregnenolone → Progesterone (3β-HSD). - Placental oestrogen synthesis (see Section 9.4): - Fetal adrenal DHEA-S → Placenta → DHEA → Androstenedione → Oestrone (E1) / Oestradiol (E2). - Fetal adrenal 16-OH-DHEA-S → Placenta → Oestriol (E3). - Aromatase (CYP19A1) is abundant in placenta — protects mother from fetal androgens.

3. Ovary: - Theca interna (LH-stimulated): Progesterone → Androstenedione/Testosterone. - Granulosa cells (FSH-stimulated): Androgens → Oestradiol (aromatase). - Corpus luteum (LH/hCG): Progesterone (for pregnancy maintenance).

Plasma Transport of Steroid Hormones: - Cortisol: Bound to corticosteroid-binding globulin (CBG, transcortin) ~90%; free = active. - Oestradiol/Testosterone: Bound to sex hormone-binding globulin (SHBG). - Progesterone: Bound to CBG and albumin. - Aldosterone: Minimally protein-bound (~40% free). - DHEA-S: Bound to albumin (weak androgen, acts as precursor reservoir). - Only free, unbound hormone is biologically active and diffusible into target cells.

Pregnancy changes: - CBG ↑ (oestrogen → hepatic synthesis) → ↑ total cortisol but free cortisol also rises in late pregnancy (Cushing's-like state, but physiologically normal). - SHBG ↑ (oestrogen) → ↓ free testosterone → protects against maternal virilisation. - Progesterone levels: Luteal phase ~30 nmol/L; pregnancy peaks at term ~600–1000 nmol/L.

6.3 Catecholamine Synthesis

Sites: Adrenal medulla (chromaffin cells), sympathetic nerve terminals, CNS (brainstem).

Synthesis Pathway (Tyrosine → Catecholamines):

Tyrosine (from diet, or from phenylalanine hydroxylation)

↓ Tyrosine hydroxylase (TH) — Rate-limiting step. Requires: - Tetrahydrobiopterin (BH₄) , O₂, Fe²⁺. - Inhibited by dopamine and noradrenaline (feedback inhibition). - Induced by prolonged sympathetic activity.

↓ L-DOPA (L-3,4-dihydroxyphenylalanine)

↓ DOPA decarboxylase (aromatic L-amino acid decarboxylase) - Requires PLP (Vitamin B6) .

↓ Dopamine

↓ Dopamine β-hydroxylase (DBH) — in synaptic vesicles of sympathetic nerves and chromaffin granules. - Requires Vitamin C (ascorbic acid) and O₂.

↓ Noradrenaline (Norepinephrine)

↓ Phenylethanolamine N-methyltransferase (PNMT) — in adrenal medulla (cytosol). - Requires S-adenosylmethionine (SAM) as methyl donor. - Induced by cortisol (adrenal medulla receives cortisol-rich blood from adrenal cortex via portal system). - This explains why adrenaline is synthesised mainly in the adrenal medulla, not in sympathetic nerves (which lack PNMT).

↓ Adrenaline (Epinephrine)

Summary: - Tyrosine → L-DOPA → Dopamine → Noradrenaline → Adrenaline. - Storage: Adrenal medulla stores adrenaline (~80%) and noradrenaline (~20%) in chromaffin granules (with ATP, chromogranins). - Release: Acetylcholine (preganglionic sympathetic) → nicotinic receptor → Ca²⁺ influx → exocytosis. - Degradation: - MAO (monoamine oxidase, mitochondria) → aldehydes. - COMT (catechol-O-methyltransferase, cytosol) → metanephrines. - Final product: VMA (vanillylmandelic acid) — excreted in urine.

Clinical relevance: - Phaeochromocytoma (rare catecholamine-secreting tumour of adrenal medulla): - Presents with: Paroxysmal hypertension, palpitations, sweating, headache, anxiety. - Diagnosis: ↑ Urinary metanephrines / VMA, or plasma metanephrines. - Pregnancy: Life-threatening if undiagnosed (hypertensive crisis, pre-eclampsia mimic, myocardial infarction, CVA). Diagnosis often delayed because symptoms overlap with pre-eclampsia. Treatment: α-blockade (phenoxybenzamine) then β-blockade, then surgical resection (adrenalectomy) — ideally in second trimester, or postpartum. - Key point: Always exclude phaeochromocytoma before any planned CS in a woman with hypertension.

6.4 Thyroid Hormone Synthesis

Sites: Thyroid follicular cells (thyrocytes).

Steps:

1. Iodine Trapping: - Sodium-iodide symporter (NIS) — basolateral membrane — actively transports I⁻ into thyrocytes (co-transport with Na⁺, gradient maintained by Na⁺/K⁺ ATPase). - Iodine trapping is stimulated by TSH. - Perchlorate (ClO₄⁻), thiocyanate (SCN⁻) compete — goitrogens in some foods (cabbage, cassava).

2. Iodination & Organification: - I⁻ is oxidised to active iodine (I⁰) by thyroid peroxidase (TPO) — uses H₂O₂. - Iodine is incorporated into thyroglobulin (Tg) — a large glycoprotein synthesised by thyrocytes. - Iodination of tyrosine residues in Tg → MIT (monoiodotyrosine) and DIT (diiodotyrosine).

3. Coupling (also by TPO): - Two DIT → T₄ (thyroxine, 3,5,3',5'-tetraiodothyronine). - One MIT + one DIT → T₃ (triiodothyronine, 3,5,3'-triiodothyronine). - Reverse T₃ (rT₃) — one DIT + one MIT — inactive.

4. Storage & Secretion: - T₄/T₃ remain incorporated in Tg (stored in follicular colloid). - Secretion: TSH stimulates endocytosis of colloid → Tg proteolysis in lysosomes → release of T₄ (~90%) and T₃ (~10%) into circulation. - Uncoupling (deiodination) of MIT/DIT → recycling of iodine.

5. Transport in Blood: - Thyroid-binding globulin (TBG) — binds T₄ and T₃ (high affinity). - Transthyretin (TTR) and Albumin — minor carriers. - Free T₄/T₃ = <0.1% of total.

6. Peripheral Conversion — 5'-Deiodinases:

Enzyme	Location	Function
D1 (type 1 5'-deiodinase)	Liver, kidney, thyroid	T₄ → T₃ (major source of circulating T₃). Also rT₃ → T₂
D2 (type 2 5'-deiodinase)	Brain, pituitary, brown fat, placenta	T₄ → T₃ (local T₃ production for specific tissues). Critical for brain development
D3 (type 3 5-deiodinase)	Brain, skin, placenta, fetal tissues	T₄ → rT₃ (inactivates T₄). T₃ → T₂. Protects the fetus from excess T₃

Regulation: - Hypothalamus: TRH (thyrotropin-releasing hormone) → pituitary. - Pituitary: TSH (thyroid-stimulating hormone) → thyroid. - Negative feedback: T₃ inhibits TRH and TSH secretion at pituitary and hypothalamic levels. - Sodium iodide — Wolff-Chaikoff effect: High iodide → ↓ thyroid hormone synthesis (temporary). Used to treat hyperthyroidism before surgery.

Pregnancy & Thyroid:

Parameter	Change in Pregnancy
TBG	↑ 2–3 fold (oestrogen → hepatic synthesis)
Total T₄	↑ (due to ↑ TBG)
Free T₄	Normal (slightly ↓ in late pregnancy)
TSH	↓ in first trimester (due to hCG cross-reactivity with TSH receptor — hCG has weak thyrotropic activity). Upper limit of normal adjusted downwards in pregnancy (2.5 mIU/L)
Iodine	↑ requirements (fetal needs, ↑ maternal renal clearance). Iodine deficiency in pregnancy → maternal goitre, fetal hypothyroidism, cretinism

Thyroid in Pregnancy — Key Clinical Points: - Hyperthyroidism: Usually Graves' disease (TSH receptor antibodies — TRAb). Risk of thyroid storm in labour/CS, fetal hyperthyroidism (TRAb crosses placenta). Treatment: Propylthiouracil (PTU) first trimester (risk of agranulocytosis is lower than methimazole/carbimazole-associated aplasia cutis); carbimazole after 1st trimester. - Hypothyroidism: Levothyroxine dose often needs ↑ 20–30% in pregnancy. TSH should be kept in pregnancy-specific ranges (0.2–2.5 mIU/L 1st trim, 0.3–3.0 2nd/3rd). - Postpartum thyroiditis: Autoimmune (anti-TPO antibodies) → transient hyperthyroid (destruction phase) then hypothyroid. Can occur 3–6 months postpartum.

6.5 Hormone Receptors

Hormones act via two major classes of receptors:

6.5.1 Cell Surface Receptors (for peptide hormones, catecholamines)

Three main types:

1. G Protein-Coupled Receptors (GPCRs): - Structure: 7 transmembrane α-helices, intracellular domain coupled to heterotrimeric G protein (α, β, γ subunits). - Mechanism: Hormone binding → conformational change → Gα exchanges GDP→GTP → dissociates from βγ → activates effector (adenylyl cyclase, phospholipase C, ion channels). - Hormones acting via GPCRs: Many — ACTH, TSH, FSH, LH, hCG, PTH, glucagon, adrenaline (β-adrenergic), noradrenaline (α-adrenergic), oxytocin, TRH, GnRH, CRH, vasopressin, prostaglandins.

2. Receptor Tyrosine Kinases (RTKs): - Structure: Single transmembrane domain with extracellular ligand-binding domain and intracellular tyrosine kinase domain. - Mechanism: Ligand binding → dimerisation → autophosphorylation of tyrosine residues → signal cascades (Ras-MAPK, PI3K-Akt, PLCγ). - Hormones: Insulin, IGF-1, GH (GH receptor dimerises with JAK2 — not RTK but similar cytokine receptor family), EGF, VEGF, PDGF. - Insulin receptor: α₂β₂ heterotetramer; after autophosphorylation → IRS (insulin receptor substrate) → PI3K → Akt → GLUT4 translocation, metabolic effects.

3. Guanylyl Cyclase Receptors: - Structure: Single transmembrane domain with intracellular guanylyl cyclase domain. - Mechanism: Hormone binding → cGMP production → protein kinase G (PKG). - Hormones: Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), guanylin, uroguanylin. - Nitric oxide (NO) activates soluble guanylyl cyclase (cytosolic) → also cGMP.

6.5.2 Intracellular Receptors (for steroid hormones, thyroid hormone, vitamin D, retinoids)

• Structure: All share a common domain structure — N-terminal transactivation domain, central DNA-binding domain (zinc fingers), C-terminal ligand-binding domain.
• Location:
• Steroid receptors (glucocorticoid, mineralocorticoid, androgen, progesterone, oestrogen): Inactive in cytosol bound to heat shock proteins (HSPs) ; ligand binding → dissociation, translocation to nucleus.
• Thyroid hormone receptors (TR), Vitamin D receptor (VDR), Retinoic acid receptors (RAR, RXR): Located in nucleus (even unliganded, bound to DNA response elements, repressing transcription).
• Mechanism: Ligand binds → receptor dimerises (homodimer or heterodimer with RXR) → binds hormone response element (HRE) on DNA → recruits coactivators/corepressors → regulates transcription → affects protein synthesis.

Key differences:

Feature	GPCR / RTK	Nuclear receptor
Response time	Seconds to minutes	Hours to days
Mechanism	Second messengers, phosphorylation cascades	Transcriptional regulation (new protein synthesis)
Location	Cell surface	Cytosol or nucleus
Hormones	Peptides, catecholamines, prostaglandins	Steroids, T₃/T₄, Vitamin D, retinoids

6.6 Second Messengers

6.6.1 cAMP Pathway (Gs/Gi)

Gs (stimulatory G protein): - Gαs → activates adenylyl cyclase → ↑ cAMP. - cAMP → binds to protein kinase A (PKA) catalytic subunits → PKA phosphorylates target proteins. - Examples: β-adrenergic receptors, glucagon, ACTH, FSH, LH, PTH, TRH.

Gi (inhibitory G protein): - Gαi → inhibits adenylyl cyclase → ↓ cAMP. - Examples: α₂-adrenergic, muscarinic M₂/M₄, adenosine receptors.

cAMP degradation: By phosphodiesterases (PDEs) — inhibited by caffeine, theophylline (methylxanthines — used in neonatal apnoea, bronchodilators).

PKA targets: - CREB (cAMP response element-binding protein) — transcription factor → cAMP-responsive genes (e.g., gluconeogenic enzymes). - Phosphorylase kinase → glycogen phosphorylase → glycogenolysis. - Lipase → lipolysis.

6.6.2 IP₃ / DAG Pathway (Gq)

Gq → activates phospholipase Cβ (PLCβ) → cleaves PIP₂ (phosphatidylinositol 4,5-bisphosphate) into:

1. IP₃ (inositol trisphosphate) — water-soluble, diffuses to ER → opens IP₃-gated Ca²⁺ channels → ↑ cytoplasmic Ca²⁺.
2. DAG (diacylglycerol) — remains in membrane → activates protein kinase C (PKC) .

Ca²⁺ effects: - Activates calmodulin → CaM kinases → various targets (contraction, secretion, metabolism). - Calmodulin is a small Ca²⁺-binding protein that mediates many intracellular Ca²⁺ effects. - Calcineurin — Ca²⁺/calmodulin-dependent phosphatase — target of immunosuppressants (tacrolimus, cyclosporine).

PKC targets: - Various transcription factors, ion channels, contractile proteins, enzymes. - Phorbol esters mimic DAG and are potent tumour promoters (activate PKC constitutively).

Examples of Gq-coupled receptors: α₁-adrenergic, Angiotensin II, GnRH, TRH, vasopressin V₁, oxytocin, muscarinic M₁/M₃.

6.6.3 Tyrosine Kinase Cascades

Insulin, IGF-1 signalling: 1. Insulin → insulin receptor (RTK) → autophosphorylation → IRS-1/2. 2. IRS activates PI3K → PIP₃ (phosphatidylinositol 3,4,5-trisphosphate) → PDK1 → Akt (PKB). 3. Akt: - GLUT4 translocation → glucose uptake. - Glycogen synthase activation (via GSK3 inhibition). - Protein synthesis (via mTOR). - Lipogenesis activation. 4. Also: Ras-MAPK pathway (cell growth, differentiation).

JAK-STAT Pathway (cytokines, GH, prolactin, leptin, hPL, interferons): 1. Ligand → receptor dimerisation → JAK (Janus kinase) associates and autophosphorylates. 2. JAK phosphorylates receptor → recruits STAT (signal transducer and activator of transcription) → STAT phosphorylated → dimerises → translocates to nucleus → regulates gene transcription. 3. Prolactin signalling via JAK2-STAT5 → α-lactalbumin induction, milk protein gene expression. 4. GH → JAK2-STAT5 → IGF-1 production. 5. hPL → similar JAK-STAT → metabolic adaptation in pregnancy. 6. SOCS (suppressors of cytokine signalling) — negative feedback.

6.6.4 cGMP Pathway

• Soluble guanylyl cyclase (sGC) — cytosolic, activated by NO.
• Natriuretic peptide receptors (NPR-A, NPR-B) — receptor guanylyl cyclase, activated by ANP, BNP.
• cGMP → PKG (protein kinase G) → vasodilation, natriuresis, smooth muscle relaxation.
• NO-cyclic GMP pathway in pregnancy:
• Endothelial NO synthase (eNOS) produces NO → maintains vasodilation in uterine, placental, and systemic circulations.
• Impaired NO production → pre-eclampsia (vasoconstriction, hypertension).
• Sildenafil (PDE5 inhibitor) → ↓ cGMP breakdown → vasodilation. Investigated for pre-eclampsia and FGR — results mixed, some trials show no benefit or harm.

6.7 G Proteins & Clinical Correlates

G protein cycle: 1. Inactive: Gα-GDP + βγ. 2. Activation: Ligand-GPCR → Gα exchanges GDP → GTP → dissociates from βγ. 3. Effector activation: Gα-GTP activates adenylyl cyclase (Gs) or PLCβ (Gq) or inhibits adenylyl cyclase (Gi). 4. Deactivation: GTPase (intrinsic) hydrolyses GTP → GDP → Gα re-associates with βγ → inactive. 5. RGS proteins (Regulators of G protein Signalling) increase GTPase activity — accelerate deactivation.

Mutations in G protein signalling:

Mutation	Mechanism	Disease
Gsα activating	Constitutive activation of adenylyl cyclase (↑cAMP)	McCune-Albright syndrome (post-zygotic, mosaic) — Café-au-lait spots, polyostotic fibrous dysplasia, endocrine adenomas (precocious puberty, acromegaly, Cushing's)
Gsα inactivating	Loss of function → resistance to PTH, TSH, etc.	Pseudohypoparathyroidism (Albright hereditary osteodystrophy) — hypocalcaemia, hyperphosphataemia, short stature, obesity (maternal inheritance through imprinting — GNAS is imprinted)
Gq/G11 activating	Constitutive activation of PLCβ	Uveal melanoma (mutations in GNAQ, GNA11)
RAS (small G protein) activating	Constitutive MAPK signalling	RASopathies: Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome — facial dysmorphism, congenital heart disease, developmental delay

Bacterial toxins affecting G proteins:

Toxin	Mechanism	Effect
Cholera toxin (Vibrio cholerae)	ADP-ribosylates Gsα → inhibits GTPase → Gsα permanently active → ↑↑ cAMP	Severe watery diarrhoea (CFTR channel activation → Cl⁻/H₂O secretion into gut)
Pertussis toxin (Bordetella pertussis)	ADP-ribosylates Giα → prevents Gi activation → loss of inhibitory control → ↑ cAMP in some cells	Whooping cough; lymphocytosis

Relevance in obstetrics: - McCune-Albright syndrome may present with precocious puberty, fibrous dysplasia complicating pregnancy, and may have ovarian cysts or hyperthyroidism in pregnancy. - Cholera in pregnancy → severe dehydration → fetal distress, preterm labour. - Pertussis vaccination in pregnancy (UK: 16–32 weeks) → protects newborn (maternal antibodies).

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7. Enzymology

7.1 Enzyme Classification

The International Union of Biochemistry and Molecular Biology (IUBMB) classifies enzymes into 6 classes:

Class	Type of Reaction	Example
1. Oxidoreductases	Oxidation-reduction	Dehydrogenases, oxidases, reductases, peroxidases, hydroxylases
2. Transferases	Transfer of a group	Kinases (transfer PO₄), aminotransferases, methyltransferases
3. Hydrolases	Hydrolysis (cleavage with H₂O)	Lipases, proteases, phosphatases, glycosidases
4. Lyases	Cleavage without H₂O or oxidation	Decarboxylases, aldolases, synthases (note: synthase ≠ synthetase — see below)
5. Isomerases	Isomerisation	Epimerases, racemases, mutases
6. Ligases (Synthetases)	Joining two molecules with ATP	Carboxylases, glutamine synthetase, DNA ligase

Important nomenclature distinction: - Synthase (Class 4 or 5) — catalyses joining of molecules WITHOUT ATP (e.g., HMG-CoA synthase; glycogen synthase; citrate synthase). - Synthetase (Class 6, Ligase) — catalyses joining WITH ATP breakdown (e.g., argininosuccinate synthetase; glutathione synthetase; PRPP synthetase).

7.2 Enzyme Kinetics — Michaelis-Menten

Michaelis-Menten equation: [ v = \frac{V_{max} \times [S]}{K_m + [S]} ]

• v = initial reaction velocity.
• Vmax = maximum velocity (when enzyme is fully saturated with substrate).
• [S] = substrate concentration.
• Km = Michaelis constant = substrate concentration at which v = ½ Vmax.
• Low Km = high affinity for substrate (less S needed to reach half-Vmax).
• High Km = low affinity for substrate.

Lineweaver-Burk Plot (double reciprocal plot): - 1/v = (Km/Vmax)(1/[S]) + 1/Vmax. - x-axis: 1/[S]; y-axis: 1/v. - y-intercept: 1/Vmax. - x-intercept: -1/Km. - Slope: Km/Vmax. - Use: Determine Km and Vmax, and to identify type of enzyme inhibition.

Turnover number (kcat): Maximum number of substrate molecules converted to product per enzyme molecule per second. Catalytic efficiency: kcat/Km.

7.3 Enzyme Inhibition

Type	Km	Vmax	Lineweaver-Burk pattern	Mechanism
Competitive	↑	↔	Lines intersect at y-axis	Inhibitor binds to active site, competes with S. Overcome by high [S]
Non-competitive (pure)	↔	↓	Lines intersect at x-axis	Inhibitor binds to allosteric site (not active site). Does not affect S binding but reduces catalysis. Cannot be overcome by [S]
Uncompetitive	↓	↓	Parallel lines	Inhibitor binds only to ES complex. Km decreases (seems higher affinity) but Vmax also decreases
Mixed	↑ or ↓	↓	Lines intersect off axes (above or below x-axis)	Inhibitor binds to both free E and ES complex (different affinities)

Clinical examples of competitive inhibition:

Drug	Target Enzyme	Effect
Statins (atorvastatin, simvastatin)	HMG-CoA reductase (HMG → Mevalonate)	↓ Cholesterol synthesis
Allopurinol	Xanthine oxidase	↓ Uric acid production (gout)
Methotrexate	Dihydrofolate reductase (DHFR)	↓ Folate → ↓ DNA synthesis (anti-cancer, ectopic, immunosuppressive)
Captopril (ACE inhibitors)	Angiotensin-converting enzyme (ACE)	↓ Ang II → vasodilation ↓ aldosterone (hypertension, HF, diabetic nephropathy)
Disulfiram	Aldehyde dehydrogenase	Alcohol aversion therapy
Neostigmine	Acetylcholinesterase	↑ ACh (myasthenia gravis)

Clinical examples of non-competitive inhibition: - Aspirin/NSAIDs: COX-1/COX-2 inhibition (aspirin is irreversible — covalently modifies COX-1). - Omeprazole: H⁺/K⁺ ATPase (proton pump) in stomach → irreversible. - Metformin: Complex I (mitochondrial ETC) → ↓ ATP → ↑ AMPK (indirect).

7.4 Allosteric Regulation

Definition: Regulation by binding of a molecule (effector/modulator) at a site distinct from the active site → conformational change → altered enzyme activity.

Characteristics: - Allosteric enzymes are often multi-subunit (oligomeric) and show cooperativity. - Sigmoidal (not hyperbolic) kinetics in v vs [S] plots. - Homotropic effectors — effector = substrate itself (e.g., O₂ binding to haemoglobin). - Heterotropic effectors — effector is a different molecule.

Examples:

Enzyme	Activator(s)	Inhibitor(s)
PFK-1	AMP, ADP, fructose-2,6-BP	ATP, citrate
Pyruvate kinase	Fructose-1,6-BP	ATP, alanine
Pyruvate carboxylase	Acetyl-CoA	—
Acetyl-CoA carboxylase	Citrate, insulin	Palmitoyl-CoA, glucagon
Glycogen phosphorylase	AMP, Ca²⁺ (muscle)	ATP, glucose (liver)
Glutamate dehydrogenase	ADP	GTP
PRPP amidotransferase	PRPP	AMP, GMP, IMP
CPS I (urea cycle)	N-acetylglutamate (NAG)	—
CPS II (pyrimidine synth)	PRPP	UTP
Thymidylate synthase	dUMP	FdUMP (5-FU metabolite)

7.5 Covalent Modification (Phosphorylation)

• Reversible addition of phosphate (PO₄³⁻) to Ser, Thr, or Tyr residues.
• Kinases add phosphate; Phosphatases remove.
• Effect: Can either activate or inhibit the target enzyme.

Examples of regulation by phosphorylation:

Enzyme	Phosphorylation effect	Kinase	Phosphatase
Glycogen phosphorylase	Activates	Phosphorylase kinase (activated by PKA)	PP1 (protein phosphatase 1)
Glycogen synthase	Inactivates	PKA, GSK3	PP1
Pyruvate dehydrogenase	Inactivates	PDH kinase	PDH phosphatase
Acetyl-CoA carboxylase	Inactivates	AMPK, PKA	PP2A
HMG-CoA reductase	Inactivates	AMPK	PP2A
Hormone-sensitive lipase	Activates	PKA	PP1

PKA (Protein Kinase A): - Activated by cAMP (binds to regulatory subunits → releases catalytic subunits). - cAMP rises in response to glucagon, adrenaline, etc.

PKC (Protein Kinase C): - Activated by DAG (+ Ca²⁺). - Phorbol esters are potent PKC activators (and tumour promoters).

AMPK (AMP-activated Protein Kinase): - Cellular energy sensor — activated by ↑ AMP/ATP ratio (low energy state). - Activates: Catabolism (glycolysis, FA oxidation, autophagy). - Inhibits: Anabolism (FA synthesis, cholesterol synthesis, protein synthesis). - Metformin activates AMPK (indirectly, via Complex I inhibition → ↑ AMP). - Exercise activates AMPK in muscle → ↑ glucose uptake (GLUT4 + TBC1D1).

7.6 Zymogen Activation

Zymogen (proenzyme): Inactive precursor of an enzyme that requires proteolytic cleavage to become active.

Examples:

System	Zymogen	Active Enzyme	Activator
Digestion (pancreas)	Trypsinogen	Trypsin	Enteropeptidase (duodenum)
	Chymotrypsinogen	Chymotrypsin	Trypsin
	Proelastase	Elastase	Trypsin
	Procarboxypeptidase	Carboxypeptidase	Trypsin
Blood coagulation	Prothrombin	Thrombin	Factor Xa + Va
	Fibrinogen	Fibrin	Thrombin
	Factor XIII	XIIIa	Thrombin
Fibrinolysis	Plasminogen	Plasmin	tPA, uPA
Complement	C1–C9	Various proteases	C1q, immune complexes
Apoptosis	Procaspases	Caspases	Initiator caspases
Hormone activation	Proinsulin	Insulin	PC1/3, PC2
	Pro-opiomelanocortin (POMC)	ACTH, β-endorphin, etc.	PC1/3, PC2

Clinical relevance: - Acute pancreatitis: Premature activation of trypsinogen in pancreas (by cathepsin B in lysosomes) → autodigestion → pancreatic necrosis. - α₁-Antitrypsin deficiency: Uninhibited neutrophil elastase → emphysema (lung destruction). Also liver disease (polymerised α₁-AT accumulates in hepatocytes). - Warfarin: Carboxylation of prothrombin and other vitamin K-dependent clotting factors (Gla formation) — not a zymogen defect but impairs zymogen activation capacity.

7.7 Isoenzymes (Isozymes)

Definition: Different enzyme variants that catalyse the same reaction but differ in amino acid sequence, kinetics, regulation, or tissue distribution.

Key isoenzymes relevant to MRCOG:

1. Lactate Dehydrogenase (LDH): - Catalyses: Lactate ↔ Pyruvate (with NAD⁺/NADH). - Tetramer of two subunits: H (heart) and M (muscle). - Five isoenzymes: LDH-1 (H₄) through LDH-5 (M₄).

Isoenzyme	Subunit	Predominant Tissue
LDH-1 (H₄)	Heart, RBC, kidney cortex	Heart
LDH-2 (H₃M)	Heart, RBC
LDH-3 (H₂M₂)	Lung, placenta, pancreas, kidney medulla	Placenta
LDH-4 (HM₃)	Liver, skeletal muscle
LDH-5 (M₄)	Liver, skeletal muscle

• Clinical use:
• Myocardial infarction: LDH-1 > LDH-2 (flipped ratio) — but now largely replaced by troponin.
• Pre-eclampsia / HELLP: Total LDH can be markedly elevated (>600 IU/L). LDH-3 (placental) may contribute.
• Ovarian germ cell tumours (dysgerminoma): LDH is a tumour marker (total and isoenzymes).
• Uterine leiomyomas: LDH isoenzyme pattern may differentiate degenerate fibroids from sarcomas (limited clinical utility).

2. Creatine Kinase (CK): - Catalyses: Creatine + ATP ↔ Creatine phosphate + ADP. - Dimer of two subunits: B (brain) and M (muscle).

Isoenzyme	Subunit	Predominant Tissue
CK-MM	M₂	Skeletal muscle
CK-MB	MB	Heart (~20% of heart CK; also some in skeletal muscle)
CK-BB	B₂	Brain, placenta, uterus, fetal tissues
Mitochondrial CK	—	Mitochondria

• Clinical use:
• Myocardial infarction: CK-MB >5% of total CK (old marker — replaced by troponin).
• Uterine activity: CK-BB released from myometrium during labour — measurable in maternal serum.
• Placenta: High CK-BB content; placental trauma/abruption → ↑ maternal CK-BB.
• Neuromuscular weakness/pain: Total CK (mostly CK-MM) elevated in muscle injury, inflammatory myositis, rhabdomyolysis.

3. Alkaline Phosphatase (ALP): - Catalyses: Hydrolysis of phosphate esters at alkaline pH. - Multiple isoenzymes (tissue-specific):

Isoenzyme	Source	Features
Liver ALP	Hepatocytes, bile canaliculi	Elevated in cholestasis, gallstones, hepatitis
Bone ALP	Osteoblasts	Elevated in bone turnover (Paget's, fractures, metastases, growing children)
Intestinal ALP	Small intestine	After fatty meal (postprandial)
Placental ALP (PALP)	Placental syncytiotrophoblast	Heat-stable — increases as pregnancy progresses; peaks at term
Germ cell ALP	Seminoma, dysgerminoma	Tumour marker

• Pregnancy: Total serum ALP rises progressively (due to placental + bone isoenzyme). Normal levels reach ~2–3× non-pregnant range by term.
• Pre-eclampsia: Liver isoenzyme may be elevated if HELLP syndrome develops.
• Heat inactivation test: Differentiating PALP (heat-stable) from liver/bone ALP (heat-labile) — not commonly used now; isoform assays available.

4. Amylase: - Pancreatic amylase (P-type) — pancreas. - Salivary amylase (S-type) — salivary glands, fallopian tube epithelium, ovarian cyst fluid. - Macroamylase: Complex with IgA — elevated in serum, low urine amylase (benign).

• O&G relevance:
• Ovarian cysts: Some rupture → ↑ serum amylase (S-type from fallopian tube epithelium or cyst fluid).
• Ectopic pregnancy: Rarely, ruptured ectopic → haemoperitoneum → ↑ amylase (from peritoneal irritation).
• Hyperemesis gravidarum: Dehydration → mild ↑ amylase; rule out acute pancreatitis.

5. Acid Phosphatase (ACP): - Prostatic ACP — prostate (not O&G relevant). - Lysosomal ACP — present in many tissues. - Platelet ACP — may be elevated in myeloproliferative disorders. - Tartrate-resistant ACP (TRAP) — osteoclasts, activated macrophages.

7.8 Enzyme Induction & Repression

Definition: Change in enzyme quantity (synthesis rate) in response to a stimulus — affecting transcription or translation.

Examples:

Inducer	Enzyme(s)	Effect
Phenobarbital	CYP450 enzymes (CYP3A4, CYP2C9, CYP2B6)	↑ Drug metabolism; ↑ vitamin K catabolism → neonatal VKDB risk
Rifampicin	CYP450, UGT	↑ Drug metabolism; oral contraceptive failure
Carbamazepine	CYP3A4	↑ Hormone metabolism → ↓ effectiveness of OCP, ↑ VKDB risk
Ethanol	CYP2E1, MEOS	Tolerance; ↑ acetaminophen toxicity risk (↓ glutathione)
Glucocorticoids	Gluconeogenic enzymes (PEPCK, G6Pase)	↑ Glucose production
Insulin	Glucokinase, lipogenic enzymes	↑ Glucose uptake, FA synthesis
Oestrogen	TBG, SHBG, CBG, coagulation factors	Pregnancy changes
Cigarette smoke	CYP1A2	↑ Metabolism of caffeine, theophylline

Clinical importance in obstetrics: - Enzyme-inducing anti-epileptic drugs (phenytoin, carbamazepine) - ↑ Metabolise steroid hormones → OCP failure (use high-dose or alternative contraception). - ↑ Fetal vitamin K catabolism → neonatal VKDB — give maternal oral vitamin K (10–20 mg/day) in last month. - Rifampicin for TB in pregnancy → OCP failure, may reduce fetal corticosteroid levels. - Glucocorticoids given for fetal lung maturation (betamethasone 2 doses, 24h apart) → transient maternal hyperglycaemia (induction of gluconeogenic enzymes).

7.9 Therapeutic Enzyme Inhibitors

Drug	Target Enzyme	Clinical Use in O&G
Aspirin (low-dose)	COX-1 (irreversible)	Pre-eclampsia prevention, anti-platelet
NSAIDs (ibuprofen, diclofenac)	COX-1/COX-2	Postpartum pain (short-term)
Methotrexate	DHFR	Ectopic pregnancy, GTD
Allopurinol	Xanthine oxidase	Gout in pregnancy (rarely needed); may reduce perinatal asphyxia injury (investigational)
Danazol	Pituitary gonadotropin suppression; also inhibits steroidogenic enzymes	Endometriosis — but androgenic; contraindicated in pregnancy
GnRH agonists (leuprolide, goserelin)	Pituitary GnRH receptor — desensitisation	Endometriosis, fibroids, IVF protocols
Aromatase inhibitors (letrozole, anastrozole)	CYP19A1 (aromatase)	Ovulation induction (letrozole — off-label), breast cancer
Tamoxifen	Oestrogen receptor (competitive antagonist)	Breast cancer; ovulation induction in some cases
Metformin	Complex I (ETC) → ↑ AMPK	GDM, PCOS, T2DM
Oxytocin receptor antagonists (atosiban)	Oxytocin receptor	Preterm labour tocolysis
Prostaglandin synthase inhibitors (indomethacin)	COX	Tocolysis (short-term, <48h) — risk of fetal ductal constriction
Protease inhibitors (ritonavir)	HIV protease	Prevention of MTCT of HIV
Ulipristal acetate	Progesterone receptor modulator	Emergency contraception, fibroid treatment

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8. Acid-Base & Body Fluids

8.1 pH & Henderson-Hasselbalch Equation

Definition of pH: pH = -log₁₀[H⁺]. Normal blood pH: 7.35–7.45 (H⁺ = 35–45 nmol/L). Life-threatening ranges: <6.8 or >7.8.

Henderson-Hasselbalch Equation: [ pH = pK_a + \log_{10}\frac{[HCO_3^-]}{[H_2CO_3]} ]

For the bicarbonate buffer system (pKa = 6.1): [ pH = 6.1 + \log_{10}\frac{[HCO_3^-]}{0.03 \times P_aCO_2} ]

• [HCO₃⁻]: Regulated by kidneys (metabolic component).
• PₐCO₂: Regulated by lungs (respiratory component).
• Normal ratio [HCO₃⁻]/[PₐCO₂ × 0.03] = 20:1 (giving pH 7.4).

8.2 Buffer Systems

1. Bicarbonate Buffer System (most important extracellular): - H⁺ + HCO₃⁻ ↔ H₂CO₃ ↔ CO₂ + H₂O (via carbonic anhydrase). - Open system — CO₂ can be eliminated by the lungs → powerful buffering capacity despite low pKa.

2. Phosphate Buffer System: - H⁺ + HPO₄²⁻ ↔ H₂PO₄⁻ (pKa = 6.8). - Important in urine (high phosphate concentration; tubular fluid), less important in blood.

3. Protein Buffers: - Histidine residues (imidazole group, pKa ~6.8) in haemoglobin, albumin, globulins. - Haemoglobin buffer system: H⁺ binds to Hb → CO₂ transported as carbamino compounds. - Albumin: Major plasma protein buffer.

4. Haemoglobin Buffer System: - Deoxyhaemoglobin (HHb) is a stronger base than oxyhaemoglobin (HbO₂) → binds H⁺ → Haldane effect: deoxygenated blood can carry more CO₂. - Bohr effect: ↓ pH → ↓ haemoglobin O₂ affinity → O₂ unloading in tissues.

8.3 Acid-Base Disorders

Primary Disorders:

Disorder	Primary Change	Compensation	pH
Respiratory acidosis	↑ PCO₂ (hypoventilation)	Renal: ↑ HCO₃⁻ reabsorption (slow, days)	↓
Respiratory alkalosis	↓ PCO₂ (hyperventilation)	Renal: ↓ HCO₃⁻ reabsorption, ↑ HCO₃⁻ excretion	↑
Metabolic acidosis	↓ HCO₃⁻ (loss or acid gain)	Respiratory: hyperventilation → ↓ PCO₂ (fast, minutes to hrs)	↓
Metabolic alkalosis	↑ HCO₃⁻ (gain or acid loss)	Respiratory: hypoventilation → ↑ PCO₂ (limited compensation)	↑

Compensation Rules:

Disorder	Expected Compensation
Acute respiratory acidosis	Δ[HCO₃⁻] ↑ 1 mmol/L per 10 mmHg ↑ PCO₂
Chronic respiratory acidosis	Δ[HCO₃⁻] ↑ 4 mmol/L per 10 mmHg ↑ PCO₂
Acute respiratory alkalosis	Δ[HCO₃⁻] ↓ 2 mmol/L per 10 mmHg ↓ PCO₂
Chronic respiratory alkalosis	Δ[HCO₃⁻] ↓ 5 mmol/L per 10 mmHg ↓ PCO₂
Metabolic acidosis	PCO₂ = (1.5 × HCO₃⁻) + 8 ± 2 (Winter's formula)
Metabolic alkalosis	PCO₂ = (0.7 × HCO₃⁻) + 20 ± 5

Winter's Formula (for metabolic acidosis): - Expected PCO₂ = (1.5 × HCO₃⁻) + 8 ± 2. - If measured PCO₂ > expected → coexisting respiratory acidosis. - If measured PCO₂ < expected → coexisting respiratory alkalosis.

8.4 Anion Gap

Definition: Unmeasured anions in plasma. [ \text{Anion Gap (AG)} = [Na^+] - ([Cl^-] + [HCO_3^-]) ] Normal: 6–12 mmol/L (varies by lab).

High Anion Gap Metabolic Acidosis (HAGMA):

MUDPILES mnemonic:

| M | Methanol (formic acid) | | U | Uraemia (renal failure) | | D | Diabetic ketoacidosis (DKA) | | P | Propylene glycol / Paraldehyde | | I | Iron (overdose), Isoniazid | | L | Lactic acidosis | | E | Ethylene glycol (glycolic acid, oxalic acid) | | S | Salicylates (ASA overdose) |

Hyperchloraemic (Normal AG) Metabolic Acidosis: - HCO₃⁻ loss (diarrhoea, renal tubular acidosis, ureterosigmoidostomy). - Compensation: Cl⁻ retention to balance the anion gap? Actually: loss of HCO₃⁻ → Cl⁻ rises to maintain electroneutrality. - In pregnancy — normal AG may be slightly lower (due to haemodilution → ↓ albumin → ↓ unmeasured anions).

Delta-delta (Δ/Δ) ratio: - Used in mixed disorders. - ΔAG = patient AG - 12 (expected). - ΔHCO₃ = 24 - patient HCO₃. - ΔAG / ΔHCO₃: - <0.4: Non-AG metabolic acidosis (diarrhoea) + HAGMA? Or primary HAGMA with overcompensation? - 0.4–0.8: HAGMA + hyperchloraemic acidosis. - 0.8–1.0: Pure HAGMA. - 1.0–2.0: HAGMA + concomitant metabolic alkalosis. - >2.0: Primary metabolic alkalosis with HAGMA.

8.5 Base Excess / Deficit

Base Excess (BE): Amount of strong acid/base needed to titrate blood to pH 7.4 at PCO₂ 40 mmHg. - Normal: 0 ± 2 mmol/L. - Negative BE (Base deficit): Metabolic acidosis (↓ HCO₃⁻). - Positive BE: Metabolic alkalosis (↑ HCO₃⁻).

Standard Base Excess (SBE): Corrected for Hb; used in clinical algorithms.

BD (Base Deficit) — CORD BLOOD: - Used to assess fetal acidosis at birth. - Normal: BD < 5 mmol/L. - Mild acidosis: BD 5–10. - Moderate acidosis: BD 10–15. - Severe acidosis: BD > 15. - Cord pH < 7.0 + BD > 12 — associated with neonatal encephalopathy and cerebral palsy.

8.6 Mixed Acid-Base Disorders

Common scenarios in obstetrics:

Scenario	Disorder 1	Disorder 2	Pattern
Pre-eclampsia / HELLP	Metabolic alkalosis (vomiting) + Metabolic acidosis (lactic acidosis from poor perfusion)	Mixed: Variable
DKA + vomiting	Metabolic acidosis (HAGMA — ketoacids) + Metabolic alkalosis (vomiting, loss of HCl)	ΔAG/ΔHCO₃ > 1.0
Sepsis in pregnancy	Metabolic acidosis (lactic) + Respiratory alkalosis (hyperventilation)	Low PCO₂ + low HCO₃
Renal failure + sepsis	Metabolic acidosis + Metabolic acidosis (HAGMA + hyperchloraemic)	Two AG patterns
Acute asthma in pregnancy	Respiratory alkalosis (early) → Respiratory acidosis (severe, tiring)	Changing pattern
Placental abruption	Metabolic acidosis (lactic) + Respiratory compensation	PCO₂ low
Hyperemesis gravidarum	Metabolic alkalosis (loss of gastric HCl)	↑ pH, ↑ HCO₃

8.7 Fluid Compartments

Body Water Distribution (average 70 kg adult):

Compartment	Volume (L)	% Body Weight
Total body water	42 L	60%
Intracellular fluid (ICF)	28 L	40%
Extracellular fluid (ECF)	14 L	20%
• Interstitial fluid	10.5 L	15%
• Plasma volume	3.5 L	5%
• Transcellular (CSF, pleural, peritoneal, etc.)	1 L	—

Differences between compartments: - ICF: High K⁺ (~140 mmol/L), Mg²⁺, PO₄³⁻, protein. - ECF: High Na⁺ (~140 mmol/L), Cl⁻, HCO₃⁻. - Interstitial: Low protein. - Plasma: Protein-rich (albumin, globulins).

8.8 Osmotic Pressure & Starling Forces

Osmolarity / Osmolality: - Plasma osmolality: 285–295 mOsm/kg H₂O. - Calculated: 2 × [Na⁺] + [Glucose]/18 + [BUN]/2.8 (US units: BUN mg/dL). - Tonicity: Effective osmolality = contribution of impermeable solutes.

Colloid Osmotic Pressure (Oncotic Pressure): - Created by albumin (~25 mmHg contribution from plasma proteins). - Opposes filtration at the capillary (pulls water IN).

Starling Forces: [ J_v = K_f \times [(P_c - P_i) - (\pi_c - \pi_i)] ]

Symbol	Meaning	Effect
P_c	Capillary hydrostatic pressure	Pushes fluid OUT
P_i	Interstitial hydrostatic pressure	Pushes fluid IN (usually small/negative)
π_c	Capillary oncotic pressure (plasma proteins)	Pulls fluid IN
π_i	Interstitial oncotic pressure	Pulls fluid OUT (small in most tissues)
K_f	Filtration coefficient	Permeability × surface area

Edema formation in pregnancy: - Increased total body water (6–9 L average gain in pregnancy). - Increased P_c (↓ systemic vascular resistance, increased blood volume). - ↓ Plasma oncotic pressure (haemodilution → ↓ albumin 25–30%). - Result: Physiological oedema — lower extremities, hands, face. - Pathological oedema: Pre-eclampsia (↑ capillary leak), heart failure, nephrotic syndrome.

8.9 Electrolyte Distribution

Ion	Plasma (mmol/L)	ICF (mmol/L)	Primary Regulation
Sodium (Na⁺)	135–145	10–15	Aldosterone, ADH, ANP, kidney
Potassium (K⁺)	3.5–5.0	140–150	Na⁺/K⁺ ATPase, aldosterone, insulin
Calcium (Ca²⁺)	Total: 2.2–2.6 Ionised: 1.1–1.3	—	PTH, Vitamin D, calcitonin
Magnesium (Mg²⁺)	0.7–1.1	0.5–1.0 (free)	Paracellin, kidney
Chloride (Cl⁻)	100–106	5–15	Na⁺-linked
Bicarbonate (HCO₃⁻)	22–28	10–15	Kidneys, lungs

Sodium — Water determines Na⁺ concentration: - Hyponatraemia (<135): Water excess (SIADH, polydipsia) or Na⁺ loss (diarrhoea, diuretics, adrenal insufficiency). - In pregnancy: ↓ osmolality set point — serum Na⁺ 130–135 mmol/L is physiological (reset osmostat). - Hypernatraemia (>145): Water deficit (diabetes insipidus, insufficient intake) or Na⁺ gain.

Potassium — Cardiotoxic: - Hypokalaemia (<3.5): Vomiting, diuretics, Conn's, Gitelman/Bartter, DKA treatment. - Hyperkalaemia (>5.0): Renal failure, acidosis, K⁺-sparing diuretics, Addison's, tumour lysis. - ECG changes: Tented T waves (hyperkalaemia); U waves, flat T (hypokalaemia).

Calcium — Ionised vs Total: - Ionised Ca²⁺ is the biologically active form. - Total Ca²⁺ includes ionised + protein-bound (mainly albumin) + complexed (citrate, phosphate, etc.). - Albumin adjustment: Corrected Ca²⁺ = measured Ca²⁺ + 0.02 × (40 - albumin). - Pregnancy: Total Ca²⁺ is low (physiological ↓ albumin) but ionised Ca²⁺ is normal.

Magnesium — Obstetric significance: - MgSO₄ used for: - Pre-eclampsia/eclampsia prophylaxis and treatment. - Neuroprotection in preterm labour (<30 weeks) — reduces risk of cerebral palsy in the infant. - Tocolysis (no longer recommended). - Toxicity monitoring: - Loss of patellar reflex (Mg²⁺ 3.5–5 mmol/L). - Respiratory depression (Mg²⁺ 5–7.5 mmol/L). - Cardiac arrest (Mg²⁺ >7.5 mmol/L). - Antidote: IV calcium gluconate.

8.10 Fluid Shifts in Pregnancy

Total Body Water increases by ~6–9 L (from ~28 L to 34–37 L): - Plasma volume ↑ 40–50% (from ~2500 mL to ~3500–4000 mL). - Red cell mass ↑ 20–30% (less than plasma → physiological haemodilution → Hb ↓ from ~13.3 g/dL to ~11.5–12 g/dL). - Interstitial fluid ↑ (oedema).

Osmolality set point decreases: - Plasma osmolality ↓ by ~10 mOsm/kg (from 290 to 280 mOsm/kg). - Serum Na⁺ ↓ by ~5 mmol/L to 130–135 mmol/L. - Reset osmostat: Thirst threshold and ADH release occur at lower osmolality. - This is mediated by human chorionic gonadotropin (hCG) and relaxin.

ADH in pregnancy: - Placental vasopressinase (oxytocinase) — an enzyme that breaks down ADH and oxytocin. - Activity increases in pregnancy → increased ADH turnover. - Transient Diabetes Insipidus of Pregnancy: Particularly in third trimester; presents with polyuria, polydipsia; due to increased vasopressinase activity. Treat with desmopressin (DDAVP) — resistant to vasopressinase.

Renal changes: - GFR ↑ 50% (from ~100 to ~150 mL/min) — reaches peak by mid-pregnancy. - Renal plasma flow ↑ 70% — increased up to ~800 mL/min. - Tubular reabsorption: Many solutes have ↑ reabsorption (e.g., Na⁺, glucose, amino acids) but may be overwhelmed → physiological glycosuria (↑ glucose filtered load → transporters overwhelmed). - Urine osmolality: Variable; pregnancy has unique handling of water and electrolytes.

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9. Placental & Fetal Biochemistry

9.1 Placental Transport of Nutrients

The placenta is a metabolically active organ — not a passive filter. It facilitates nutrient transfer via multiple mechanisms:

1. Simple Diffusion: - O₂, CO₂, H₂O, ethanol, anaesthetic gases (isoflurane, propofol), urea. - Driven by concentration gradient.

2. Facilitated Diffusion (carrier-mediated, no energy): - Glucose — via GLUT1 (abundant on both microvillous and basal membranes of syncytiotrophoblast). - Fructose — via GLUT3/5.

3. Active Transport (energy-dependent, against gradient): - Amino acids — via over 15 transporter systems (e.g., System A — small neutral amino acids; System L — leucine/isoleucine/valine; System y+ — lysine/arginine; System β — taurine). - Amino acid transport is concentrative — fetuses have higher plasma AA levels than mothers. - Transport is Na⁺-dependent (System A) or exchange-driven (System L). - Placental AA transporters are downregulated in IUGR/FGR → contributes to fetal growth restriction. - Ca²⁺ — via active Ca²⁺ ATPase (basal membrane, pumping against gradient to fetal side). - Mg²⁺, PO₄³⁻, Zn²⁺, Fe²⁺, I⁻, Vitamin C — specific transporters. - Vitamin B12, folate — via receptor-mediated endocytosis (folate receptor α and cubilin).

4. Endocytosis / Transcytosis: - Lipids: Fatty acids (via FAT/CD36, FABPpm → placental fatty acid binding protein pm), cholesterol (via LDL receptor → endocytosis). - IgG: Transferred via FcRn (neonatal Fc receptor) — from 16 weeks, increases towards term → passive immunity. - Vitamin B12, iron — transferrin-bound iron → transferrin receptor → endocytosis → iron released to fetus.

5. Triglyceride transport: - Maternal TG is not directly transported. - Lipoprotein lipase (LPL) on microvillous membrane → hydrolyses TG → FFAs → taken up. - hPL → lipolysis → maternal FFAs → placental uptake → esterified, then released as FFA to fetus.

Fetal metabolic demands: - Glucose: Primary energy source. Fetal glucose consumption: 4–6 mg/kg/min (compared to ~2 mg/kg/min in adults). - Lactate: Fetal produce lactate (anaerobic metabolism in some tissues) → re-used as fuel by fetal liver (Cori cycle) or placenta. - Amino acids: Essential for protein synthesis, carbon skeletons. - FFAs: For membrane synthesis, energy, fat deposition (especially third trimester — brown fat). - Ketone bodies: Cross the placenta — can be used by fetal brain in maternal starvation.

9.2 Fetal Metabolism in Labour

During labour, the fetus faces repeated hypoxic stress with each uterine contraction: - Uterine contractions → ↓ uteroplacental blood flow. - Intermittent hypoxia → anaerobic glycolysis → lactate accumulation. - Contractions also compress umbilical cord → variable decelerations.

Fetal coping mechanisms:

1. Anaerobic metabolism:
2. Glucose → pyruvate → lactate (LDH, regenerating NAD⁺).
3. Lactic acidosis (metabolic acidosis): ↓ pH, ↓ HCO₃⁻, ↑ base deficit.

4. Fetal heart rate changes (late decelerations, minimal variability) correlate with acidosis.

5. Cardiovascular redistribution:

6. Brain, heart, adrenal: Maintain perfusion (brain-sparing effect).

7. Peripheral, renal, GI: Vasoconstriction.

8. Catecholamine surge:

9. High noradrenaline/adrenaline → ↑ heart rate, ↑ blood pressure, stimulates glycogenolysis.

10. Fetal haemoglobin (HbF):

11. Higher O₂ affinity (P50 = 19 mmHg vs 27 mmHg for adult HbA) → facilitates O₂ loading at low placental O₂ tensions.
12. 2,3-BPG: HbF binds 2,3-BPG less strongly → left-shifted O₂ dissociation curve.

Fetal acid-base status assessment: - Fetal scalp blood sampling (FBS): pH, lactate, base deficit. - Normal: pH > 7.25. - Pre-acidosis: pH 7.20–7.25. - Acidosis: pH < 7.20 → consider delivery. - Cord blood gas at delivery: - Arterial (umbilical artery): Reflects fetal status. - Venous (umbilical vein): Reflects placental function. - Normal: arterial pH 7.25–7.30 (venous ~0.05 higher).

9.3 Fetal Hepatic Biochemistry

The fetal liver has unique functional characteristics:

1. Limited Gluconeogenesis: - Fetal glucose is primarily from placental transfer. - Key gluconeogenic enzymes (PEPCK, glucose-6-phosphatase, fructose-1,6-bisphosphatase) are low in activity until near term. - Late gestation: Liver starts expressing these enzymes in preparation for birth.

2. Glycogen Storage: - Fetal liver glycogen accumulates in third trimester (from ~20 weeks, accelerates after 35 weeks) → stores for immediate postnatal life. - Glycogen synthase activity ↑, glycogen phosphorylase ↓ → net glycogen deposition. - At term, fetal liver glycogen content is ~50–100 mg/g liver (similar to adult). - Preterm infants: Reduced glycogen stores → higher risk of neonatal hypoglycaemia.

3. Conjugation — UDP-Glucuronyltransferase: - UDP-glucuronyltransferase (UGT): Conjugates bilirubin → bilirubin glucuronide → water-soluble → excretion in bile. - Fetal UGT activity is very low (~0.1% of adult levels at mid-gestation; 10% at term). - Neonatal jaundice: After birth, RBC breakdown ↑ (shortened RBC lifespan) → ↑ bilirubin load + immature UGT → physiological jaundice (peaks day 3–5). - Preterm infants: Even less UGT → more severe jaundice. - UGT1A1: The isoform responsible for bilirubin conjugation. Deficiency → Crigler-Najjar or Gilbert's syndrome. - Phototherapy: Converts bilirubin to water-soluble photosomers (luminubin) that can be excreted without conjugation.

4. Other fetal liver functions: - Haematopoiesis: Fetal liver is the main site of erythropoiesis (mid-gestation), before bone marrow takes over (from ~20 weeks). - Coagulation factors: Synthesised by fetal liver from 10–12 weeks. Vitamin K-dependent factors (II, VII, IX, X) are low at birth (especially preterm). - Drug metabolism: CYP450 enzymes have limited activity → slower drug clearance (consider when giving drugs in labour).

9.4 Brown Adipose Tissue Metabolism

Brown Adipose Tissue (BAT): Specialised for non-shivering thermogenesis — critical in the newborn.

Location in newborn: - Interscapular, perirenal, around blood vessels in neck/axillae/mediastinum. - Richly vascularised.

Morphology: - Multilocular fat droplets (multiple small droplets). - Many mitochondria — high cytochrome content → brown colour. - UCP1 (uncoupling protein 1 / thermogenin) — present in inner mitochondrial membrane.

Thermogenesis Mechanism:

1. Triglyceride lipolysis (noradrenaline from sympathetic nerves → β₃-adrenergic → ↑ cAMP → hormone-sensitive lipase).
2. FFAs → β-oxidation → electron transport → H⁺ gradient.
3. UCP1 uncouples the gradient: H⁺ flows back through UCP1 (not ATP synthase) → heat production (not ATP).
4. Heat warms the blood → distributed throughout body.

Regulation: - Sympathetic stimulation: Cold → noradrenaline → BAT activation. - Thyroid hormones: T₃ → ↑ UCP1 expression, ↑ mitochondrial biogenesis. - Cortisol (permissive) and insulin also influence BAT.

Newborn Considerations: - BAT is abundant at term (5–8% of body weight in full-term neonate). - Preterm infants: Less BAT, less UCP1 → higher risk of neonatal hypothermia. - Hypothermia → ↑ metabolic rate (attempted shivering is inefficient in newborns) → ↑ O₂ consumption → risk of hypoglycaemia, metabolic acidosis, and worsening respiratory distress. - Skincare after birth: Dry, wrap, skin-to-skin contact, warm environment to minimise heat loss. - C-section: May have less catecholamine surge → slower BAT activation → more prone to hypothermia.

9.5 Surfactant Biochemistry

Pulmonary surfactant is a lipoprotein complex that reduces surface tension at the air-liquid interface in alveoli → prevents alveolar collapse at end-expiration.

Production: Type II pneumocytes (alveolar epithelial cells).

Composition: - ~90% lipids: Phospholipids (~80% of total), neutral lipids (cholesterol, TG ~10%). - ~10% proteins: SP-A, SP-B, SP-C, SP-D.

Phospholipid Composition:

Component	% of Phospholipid	Function
Phosphatidylcholine (PC) — DPPC	~50–60%	Primary surface tension-lowering agent
Unsaturated PC	~15%	Facilitates spreading
Phosphatidylglycerol (PG)	~5–10%	Increases stability; marker of lung maturity
Phosphatidylethanolamine (PE)	~5%	Structural
Phosphatidylinositol (PI)	~5%	Precursor for PG; helps with layer ordering
Sphingomyelin	~10%	Constant throughout gestation

Dipalmitoylphosphatidylcholine (DPPC): - Two saturated palmitic acid (C16:0) chains → tightly packed in monolayer. - At end-expiration: DPPC compresses tightly → reduces surface tension to near zero → prevents collapse. - At inspiration: DPPC spreads → surface tension rises. - Saturated chains are critical — unsaturated would prevent tight packing.

Surfactant Proteins:

Protein	MW	Function	Features
SP-A	28–36 kDa	Innate immunity, tubular myelin formation, regulates surfactant secretion and uptake	C-type lectin (collectin). Binds pathogens, activates macrophages
SP-B	8–14 kDa	Essential for surface film formation — accelerates adsorption of DPPC to the interface	Hydrophobic. Deficiency → lethal neonatal respiratory failure
SP-C	4 kDa	Enhances DPPC spreading and stabilisation	Very hydrophobic (palmitoylated). Specific to type II cells
SP-D	43 kDa	Innate immunity (opsonin, agglutinates pathogens)	Collectin, antiviral

Surfactant Synthesis & Secretion: - Synthesis begins: ~24 weeks gestation. - Major increase: 32–36 weeks. - Stimulated by: - Cortisol (↑ PC synthesis, ↑ SP-A/B/C/D expression). - Thyroid hormones (↑ surfactant production). - Prolactin, oestrogen (may contribute — complex interactions). - cAMP, β-adrenergic agonists.

Surfactant Deficiency in Preterm Infants → Neonatal Respiratory Distress Syndrome (RDS):

• Pathophysiology: Surfactant deficiency → high surface tension → atelectasis (alveolar collapse) → ventilation-perfusion mismatch → hypoxaemia.
• Clinical: Tachypnoea, grunting, chest retractions, nasal flaring, cyanosis.
• Chest X-ray: Ground-glass appearance, air bronchograms, low lung volumes.
• Prevention:
• Antenatal corticosteroids (betamethasone, dexamethasone): Given to mothers at risk of preterm delivery (24–34 weeks) → induce fetal type II cell maturation → ↑ surfactant production → ↓ RDS severity and survival benefit.
• Thyrotropin-releasing hormone (TRH) — studied but not proven.
• Treatment:
• Exogenous surfactant (poractant alfa — Poractant; or calfactant) — via endotracheal tube.
• Continuous positive airway pressure (CPAP) to maintain alveolar recruitment.

Lecithin:Sphingomyelin (L:S) Ratio: - Clinical test for fetal lung maturity (amniotic fluid analysis). - Lecithin (DPPC) increases with gestation; sphingomyelin remains fairly constant. - L:S ratio: - <1.5: Immature → high risk of RDS. - 1.5–2.0: Transitional. - >2.0: Mature → low risk of RDS (some labs use >2.5). - Also measured: Presence of phosphatidylglycerol (PG) — more reliable in contaminated samples (blood, meconium). - Now less commonly used — replaced by clinical criteria (gestational age 37+ weeks) or used selectively.

Surfactant Dysfunction in Term Infants: - Surfactant protein B (SP-B) deficiency → congenital alveolar proteinosis → lethal respiratory failure. - Surfactant protein C (SP-C) mutations → interstitial lung disease (childhood). - ABCA3 mutations → defective surfactant phospholipid transport → severe neonatal RDS. - Meconium aspiration: Meconium components inhibit surfactant function → contribute to respiratory distress.

9.6 Summary of Fetal Blood Gas & Metabolic Changes at Birth

At the moment of birth, profound changes occur:

Parameter	Fetal (In Utero)	Newborn (After birth)
O₂ supply	Placenta (umbilical vein ~30 mmHg O₂)	Lungs (~100 mmHg)
PₐO₂	~20–30 mmHg	60–80 mmHg
PₐCO₂	~40–50 mmHg	35–45 mmHg
pH	7.25–7.30 (umbilical artery)	7.35–7.45
HCO₃⁻	~20–25 mmol/L	22–28 mmol/L
Glucose	3.0–5.5 mmol/L	2.5–4.5 mmol/L (first hours: lower)
Lactate	1–3 mmol/L (↑ in labour)	1–2 mmol/L (resolves over hours)
Hb	15–18 g/dL (HbF ~70–80%)	14–20 g/dL (HbF: 50–70% decreasing over weeks)
Energy source	Glucose (placental), lactate, AA	Glucose (glycogen stores → gluconeogenesis), FA
Thermogenesis	None (in warm uterus)	BAT (non-shivering thermogenesis)

First Breath: - Stimulus: Cold, clamping of cord, handling, mild hypoxia/hypercapnia. - Mechanics: Large negative intrathoracic pressure (30–60 cmH₂O) → air enters → surfactant reduces surface tension → functional residual capacity established. - Circulatory changes: ↓ Pulmonary vascular resistance (↑ O₂, vasodilation) → ↑ pulmonary blood flow → closure of ductus arteriosus and foramen ovale → transition from fetal to postnatal circulation.

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Clinical Mnemonics & Exam Pearls

The following mnemonics, tables, and clinical pearls are designed for rapid revision. Use them to anchor key biochemical facts with memorable triggers.

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1. Glycolysis Mnemonic

Mnemonic: 'Good Boys Eat Apples, Peachy Plums Force People To Smoke'

Step	Metabolite	Enzyme
Good	Glucose	Hexokinase / Glucokinase
Boys	G6P (Glucose-6-phosphate)	Phosphoglucose isomerase
Eat	F6P (Fructose-6-phosphate)	PFK-1
Apples	F1,6BP (Fructose-1,6-bisphosphate)	Aldolase
Peachy	GA3P (Glyceraldehyde-3-phosphate)	GAPDH
Plums	1,3-BPG	Phosphoglycerate kinase
Force	3-PG	Phosphoglycerate mutase
People	2-PG	Enolase
To	PEP	Pyruvate kinase
Smoke	Pyruvate	—

Clinical Pearl: - PFK-1 is the rate-limiting enzyme of glycolysis - Activated by: AMP, fructose-2,6-bisphosphate - Inhibited by: ATP, citrate (negative feedback — high energy charge slows glycolysis) - In hypoxia/ischaemia: PFK-1 is activated (↑ AMP/ATP ratio) → ↑ glycolytic flux → lactate accumulation → metabolic acidosis

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2. TCA Cycle Mnemonic

Mnemonic: 'Can I Keep Selling Sex For Money, Officer?'

Step	Metabolite	Enzyme	Co-factor
Can	Citrate	Citrate synthase	CoA-SH
I	Isocitrate	Aconitase	—
Keep	Ketoglutarate (α-KG)	Isocitrate dehydrogenase	NAD⁺ → NADH
Selling	Succinyl-CoA	α-KGDH complex	NAD⁺ → NADH
Sex	Succinate	Succinyl-CoA synthetase	GDP → GTP
For	Fumarate	Succinate dehydrogenase	FAD → FADH₂
Money	Malate	Fumarase	H₂O
Officer?	Oxaloacetate	Malate dehydrogenase	NAD⁺ → NADH

Key Enzymes & Their Products: - Citrate synthase — first step, condenses acetyl-CoA + oxaloacetate - Isocitrate dehydrogenase — produces NADH (rate-limiting, activated by ADP, inhibited by ATP/NADH) - α-KGDH complex — produces NADH (structurally similar to PDH complex) - Succinate dehydrogenase — only TCA enzyme bound to inner mitochondrial membrane; produces FADH₂ (also Complex II of ETC) - Total per turn: 3 NADH + 1 FADH₂ + 1 GTP (≈ 10 ATP equivalents)

Clinical Pearl: - Fluoroacetate poisoning → fluorocitrate formed → inhibits aconitase → citrate accumulates → "lethal synthesis" - Succinate dehydrogenase deficiency → respiratory chain Complex II defect → encephalomyopathy

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3. Branched-Chain Amino Acids (BCAAs)

Mnemonic: LIV — Leucine, Isoleucine, Valine

• Key fact: BCAAs are the only amino acids metabolised primarily in muscle, not the liver
• Most amino acids undergo transamination in the liver
• BCAAs are transaminated in muscle → branched-chain α-ketoacids → transported to liver for oxidation

Clinical Condition — Maple Syrup Urine Disease (MSUD): - Deficiency: Branched-chain α-ketoacid dehydrogenase complex - Biochemistry: ↑ Leucine, isoleucine, valine in blood and urine - Urine odour: Sweet, burnt sugar (maple syrup) — due to isoleucine metabolite sotolone - Presentation: Neonatal — poor feeding, lethargy, vomiting, neurological deterioration, seizures, coma - Treatment: Dietary restriction of BCAAs; thiamine supplementation in thiamine-responsive forms - Mnemonic: 'MSUD = Maple Syrup Urine Disease — sweet urine, sour outcome'

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4. Essential Amino Acids Mnemonic

Mnemonic: PVT TIM HALL

Letter	Amino Acid	Notes
P	Phenylalanine
V	Valine
T	Threonine
T	Tryptophan
I	Isoleucine
M	Methionine
H	Histidine	Conditionally essential in pregnancy
A	Arginine	Conditionally essential in pregnancy
L	Leucine
L	Lysine

Clinical Pearl: - 9 essential amino acids (histidine + arginine are essential in infants/pregnancy) - In pregnancy: histidine and arginine become conditionally essential due to increased fetal demands - Phenylketonuria (PKU): Deficiency of phenylalanine hydroxylase → ↑ phenylalanine → intellectual disability — requires dietary restriction before and during pregnancy (maternal PKU → fetal microcephaly, growth restriction, congenital heart disease) - Tryptophan is a precursor of serotonin and niacin

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5. Ketone Bodies

Formation: Acetoacetate, β-hydroxybutyrate (β-HB), acetone

Production site: Liver mitochondria Pathway: HMG-CoA pathway (HMG-CoA synthase is rate-limiting)

• HMG-CoA synthase — induced by low insulin, high glucagon (fasting state)
• HMG-CoA lyase — cleaves HMG-CoA to acetoacetate + acetyl-CoA
• β-HB dehydrogenase — converts acetoacetate ↔ β-hydroxybutyrate (NADH/NAD⁺ dependent)

Utilisation: - Extracted from blood by peripheral tissues (muscle, kidney, brain) - Brain adapts to use ketone bodies during starvation after 3–5 days — spares glucose - Converted back to acetyl-CoA → enters TCA cycle

Clinical Relevance — Diabetic Ketoacidosis (DKA): - Pathophysiology: Insulin deficiency + glucagon excess → ↑ lipolysis → ↑ fatty acids → ↑ ketogenesis - β-Hydroxybutyrate : Acetoacetate ratio — shifts from 1:1 to 3:1 – 7:1 (increased NADH/NAD⁺) - Rothera's test (sodium nitroprusside): detects acetoacetate only — not β-HB — can give false-negative in early DKA when β-HB predominates - Kussmaul breathing (deep, sighing respirations) — compensatory hyperventilation for metabolic acidosis - Acetone → sweet, fruity breath odour

Pregnancy Context: - Accelerated starvation in pregnancy → faster transition to ketogenesis after fasting - Ketonuria common in hyperemesis gravidarum - Controversial association between maternal ketones and adverse neurodevelopmental outcomes; avoid prolonged fasting in labour

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6. Steroid Naming Mnemonics

Quick classification by carbon count:

Class	Carbon #	Example	Mnemonic
Estrogens	C₁₈	17β-Estradiol, Estrone, Estriol	'Estrogen = 18 — E for 18, E for Estrogen'
Androgens	C₁₉	Testosterone, Dihydrotestosterone, Androstenedione	'Androgen = 19 — A is 9th letter, 19'
Progesterone	C₂₁	Progesterone	'P for Progesterone, P for Pregnant — 21 carbons'
Corticosteroids	C₂₁	Cortisol, Aldosterone	'Corticosteroids too = 21 — Everything else is 21'

Estrogen Structural Note: - Aromatic A ring — characteristic of estrogens (phenolic) - 17β-Estradiol is the most potent natural estrogen - Estriol (E3) — produced by fetoplacental unit; used in triple/quad screening

Androgen Structural Note: - Testosterone → DHT via 5α-reductase (more potent) - 5α-reductase deficiency → ambiguous genitalia at birth, virilisation at puberty

Clinical Pearl: - Congenital adrenal hyperplasia (CAH): 21-hydroxylase deficiency → ↓ cortisol, ↓ aldosterone, ↑ androgens → virilisation of female genitalia - Aromatase deficiency in pregnancy → ↑ androgens, virilisation of mother, ambiguous genitalia in female fetus

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7. Lesch-Nyhan Syndrome

Definition: X-linked recessive disorder caused by deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

Mnemonic: 'Lesch-Nyhan Loves Self-Harm: X-linked, HGPRT deficiency'

Biochemistry: - HGPRT normally recycles purine bases (hypoxanthine, guanine) → IMP/GMP (salvage pathway) - Deficiency → ↑ purine degradation → ↑ uric acid (hyperuricaemia)

Clinical Features (Recall: STAR-G): - Self-mutilating behaviour (compulsive biting of lips, fingers) - Topographically — choreoathetosis, dystonia, spasticity - Atomic — hyperuricaemia → gout, urate nephropathy - Retardation — intellectual disability (variable) - G — Gout, Growth retardation

Diagnosis: - ↑ Serum uric acid - ↓ HGPRT enzyme activity in RBCs or fibroblasts - Genetic testing for HPRT1 gene mutations

Treatment: - Allopurinol → ↓ uric acid (prevents gout, nephropathy — does NOT improve neurological symptoms) - Behavioural therapy, supportive care

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8. Von Gierke vs McArdle Disease

Feature	Von Gierke (Type I GSD)	McArdle (Type V GSD)
Deficient enzyme	Glucose-6-phosphatase (G6Pase)	Muscle glycogen phosphorylase
Affected tissue	Liver, kidney, intestine	Skeletal muscle
Presentation	Infancy: fasting hypoglycaemia, hepatomegaly, growth failure	Young adults: exercise-induced muscle pain, cramps, myoglobinuria
Fasting hypoglycaemia	Severe — cannot release glucose from G6P	Absent — liver function intact
Lactic acidosis	Present (shunting of G6P → glycolysis → lactate)	Absent
Hyperuricaemia	Present (↑ lactate competes for urate excretion)	Absent
Hyperlipidaemia	Present (↑ fatty acid mobilisation)	Absent
'Second wind' phenomenon	Absent	Characteristic — after brief rest, muscle adapts to use fatty acids
Myoglobinuria	Absent	Present with strenuous exercise

Mnemonics: - 'Gierke Got Glucose problem' — liver, glucose-6-phosphatase, fasting hypoglycaemia - 'McArdle Makes Muscle pain' — myoglobinuria, 'second wind', muscle phosphorylase - 'Von Gierke = Von't release glucose'

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9. Vitamin Mnemonics Table

Vitamin	Active Form	Key Function	Deficiency Disease	Mnemonic
B₁ (Thiamine)	Thiamine pyrophosphate (TPP)	Oxidative decarboxylation (PDH, α-KGDH, transketolase)	Beriberi (wet/dry), Wernicke-Korsakoff syndrome	'Thiamine = TPP, Think Peripheral Polyneuropathy'
B₂ (Riboflavin)	FAD, FMN	Redox reactions (ETC, fatty acid oxidation)	Cheilosis, angular stomatitis, glossitis	'B₂ = FAD — Flavins Are Delicious (skin/mouth)'
B₃ (Niacin)	NAD⁺, NADP⁺	Redox carrier in hundreds of reactions	Pellagra (dermatitis, dementia, diarrhoea, death)	'Niacin = 3 Ds → Death — Pellagra's 4th D'
B₅ (Pantothenate)	CoA (coenzyme A)	Acyl carrier in TCA, FA synthesis	Rare: burning feet syndrome, fatigue	'Pantothenate = Part of CoA — CoA is Everywhere'
B₆ (Pyridoxine)	Pyridoxal phosphate (PLP)	Transamination, decarboxylation, heme synthesis	Sideroblastic anaemia, dermatitis, neuropathy	'Pyridoxine = PLP, Prevents convulsions in INH overdose'
B₇ (Biotin)	Biotin	Carboxylation reactions (pyruvate carboxylase, acetyl-CoA carboxylase)	Periorificial dermatitis, alopecia, neurological symptoms	'Biotin = Bakes Bread (carboxylation adds CO₂ → 'bakes' it)'
B₉ (Folate)	Tetrahydrofolate (THF)	One-carbon transfer, DNA synthesis, homocysteine metabolism	Megaloblastic anaemia, neural tube defects (NTD)	'Folate = Fetus needs it! NTD prevention'
B₁₂ (Cobalamin)	Methylcobalamin, Adenosylcobalamin	Methylmalonyl-CoA → succinyl-CoA; methionine synthesis	Pernicious anaemia, subacute combined degeneration of spinal cord	'B₁₂ = Brain and Blood'
A	Retinaldehyde, Retinoic acid	Vision (rhodopsin), cell differentiation, immune function	Night blindness, xerophthalmia, keratomalacia	'A for Acuity (vision) — Apples Antioxidants (retinoids)'
C	Ascorbic acid	Collagen hydroxylation, antioxidant, iron absorption	Scurvy (perifollicular haemorrhages, poor wound healing, gingival hyperplasia)	'C = Collagen, and Scurvy = 'C' breakdown'
D	1,25(OH)₂D₃ (calcitriol)	Calcium & phosphate homeostasis, bone mineralisation	Rickets (children), osteomalacia (adults)	'D for Deposition of calcium'
E	α-Tocopherol	Antioxidant (membrane protection, free radical scavenging)	Haemolytic anaemia, peripheral neuropathies, ataxia	'E for mEmbrane — protects lipid membranes'
K	Phylloquinone (K₁), Menaquinone (K₂)	Clotting factors II, VII, IX, X; protein C/S	Neonatal haemorrhagic disease, coagulopathy	'K = Koagulation (German spelling)'

Pregnancy-Specific Vitamin Pearls: - Folate: 400–500 μg/day pre-conception and first trimester → ↓ NTD risk by 70% - Vitamin D: 400–800 IU/day recommended, especially in high-risk groups (darker skin, limited sun exposure, BMI > 30) - Vitamin B₁₂: Monitor in vegetarians/vegans — deficiency → megaloblastic anaemia + fetal neurological risk - Vitamin A: Upper limit 3000 μg/day (retinol) — teratogenic in excess (isotretinoin — highly teratogenic) - Vitamin K: Prophylactic IM vitamin K at birth → prevents haemorrhagic disease of the newborn

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10. Acid-Base Quick Reference

Winter's Formula (Metabolic Acidosis Compensation)

Expected PaCO₂ = (1.5 × [HCO₃⁻]) + 8 ± 2

• If measured PaCO₂ > expected → concomitant respiratory acidosis
• If measured PaCO₂ < expected → concomitant respiratory alkalosis

Example: A patient with DKA has HCO₃⁻ = 8 mmol/L - Expected PaCO₂ = (1.5 × 8) + 8 = 20 ± 2 (18–22 mmHg) - Actual PaCO₂ = 30 → respiratory acidosis (inadequate compensation) - Actual PaCO₂ = 15 → respiratory alkalosis (hyperventilation beyond compensation)

Anion Gap

AG = Na⁺ − (Cl⁻ + HCO₃⁻)

• Normal = 8–12 mEq/L (using K⁺ → 12–16)
• Corrected AG = AG + 2.5 × (4 − albumin) → for low albumin states

High Anion Gap Metabolic Acidosis (HAGMA)

Mnemonic: MUDPILES

Letter	Cause	Notes
M	Methanol	Formic acid → retinal toxicity, optic neuropathy
U	Uraemia	Chronic kidney disease → retention of organic acids
D	DKA (Diabetic Ketoacidosis)	β-hydroxybutyrate + acetoacetate
P	Paraldehyde	Rare — now largely historical
I	Iron / INH (Isoniazid)	INH → lactic acidosis in overdose
L	Lactic acidosis	Type A (hypoxia) vs Type B (drugs, toxins, inborn errors)
E	Ethylene glycol	Glycolic acid, oxalic acid → calcium oxalate crystals, renal failure
S	Salicylates	Mixed AG metabolic acidosis + respiratory alkalosis

Alternative mnemonic: 'MUD PILES' + Salicylates

Non-Anion Gap Metabolic Acidosis (NAGMA)

Mnemonic: HARDUPS

Letter	Cause	Mechanism
H	Hyperalimentation (TPN)	NH₄⁺ load, renal acid excretion overwhelmed
A	Acetazolamide	Carbonic anhydrase inhibitor → ↓ HCO₃⁻ reabsorption
R	Renal Tubular Acidosis (RTA)	Types 1, 2, 4 → impaired H⁺ or HCO₃⁻ handling
D	Diarrhoea	Loss of HCO₃⁻ in stool
U	Ureterosigmoidostomy	Urine in colon → Cl⁻ reabsorbed, HCO₃⁻ excreted
P	Pancreatic fistula	Loss of HCO₃⁻-rich pancreatic fluid
S	Spironolactone	Aldosterone antagonist → hyperkalaemia → impaired NH₄⁺ excretion

Alternative mnemonic: 'HARD ASS' — Hyperalimentation, Acetazolamide, RTA, Diarrhoea, Acid loads (ammonium chloride), Spironolactone, Saline (excessive), Ureterosigmoidostomy

Metabolic Alkalosis

Causes mnemonic: 'C V M D' → Chloride-responsive (↓Cl⁻, ↓K⁺): vomiting, diuretics, NGT suction; Volume contraction; Mineralocorticoid excess: Conn's, Cushing's; Diuretics

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11. Pregnancy-Specific Biochemistry Pearls

Parameter	Normal Change in Pregnancy	Pitfall
ALP	Rises 2–4× in 3rd trimester (placental isoenzyme — heat-stable ALP)	❗ NOT pathological — do NOT investigate as liver disease
Albumin	Falls (~25% decrease) due to haemodilution	❗ NOT liver disease — corrected Ca²⁺ remains normal
Creatinine	Falls (↑ GFR by 40–60%) → normal range 35–75 μmol/L	❗ A 'normal' non-pregnant creatinine may reflect impairment
Urea	Falls (↑ GFR + anabolic state) → normal 2.0–5.5 mmol/L	❗ Same caution as creatinine
Uric acid	Rises mildly in pregnancy; >300 μmol/L is suspicious for preeclampsia	↓ Uric acid excretion → hyperuricaemia precedes clinical preeclampsia
D-dimer	Rises in ALL pregnancies — levels increase progressively	❗ Not useful for VTE diagnosis in pregnancy — use compression US + clinical probability
BNP / NT-proBNP	Can rise in preeclampsia with cardiac strain	Differentiate from physiological dyspnoea of pregnancy
Bilirubin	Stable or slightly ↓	Elevated bilirubin = investigate
AST/ALT	Stable or slightly ↓ (↑ GFR clears them faster)	Even mild transaminitis warrants investigation
Cholesterol	Increases 25–50% (↑ oestrogen → ↑ hepatic production)	Physiological — important for placental steroidogenesis
Triglycerides	Increases 2–3× (↑ VLDL production, ↓ lipoprotein lipase)	Provides energy for mother, spares glucose for fetus
Ferritin	Falls (iron mobilisation + haemodilution)	Low ferritin = iron deficiency; ferritin rises in inflammation
Ca²⁺ (total)	Falls (↓ albumin)	Ionised Ca²⁺ unchanged
Phosphate	Stable or slightly ↓	—
TSH	Lower in 1st trimester (hCG cross-reactivity)	Use pregnancy-specific reference ranges
HbA1c	Falls (↓ RBC lifespan, haemodilution)	Pregnancy-specific targets: OGTT preferred for GDM screening

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12. Drug-Enzyme Interactions Table

Drug	Enzyme/Pathway Targeted	Inhibition Type	Clinical Relevance & Pearls
Methotrexate	Dihydrofolate reductase (DHFR)	Competitive	— Megaloblastic anaemia — Rescue with folinic acid (NOT folic acid — bypasses blocked DHFR) — Used in ectopic pregnancy, molar pregnancy, medical termination
Trimethoprim	DHFR (bacterial — 10⁵× greater affinity than mammalian)	Competitive	— Folate deficiency with prolonged use (especially with sulfamethoxazole — sequential blockade) — Avoid in 1st trimester (theoretical NTD risk)
5-FU (Fluorouracil)	Thymidylate synthase	Irreversible	— Hand-foot syndrome (palmar-plantar erythrodysaesthesia) — Used topically for cervical intraepithelial neoplasia — Tetrahydrofolate stabilises the inhibitory complex
Allopurinol	Xanthine oxidase	Competitive	— Gout prophylaxis, tumour lysis syndrome — ↓ Uric acid + ↑ Hypoxanthine + Xanthine (more soluble) — Drug interaction: ↑ 6-mercaptopurine/azathioprine toxicity (inhibit same enzyme) — Pregnancy: limited safety data; avoid if possible
Febuxostat	Xanthine oxidase	Non-competitive	— Alternative to allopurinol — Contraindicated with ischaemic heart disease
Finasteride	5α-reductase (type II)	Competitive	— Male pattern baldness, BPH — ↓ DHT → ↓ prostate growth — Hands off if pregnant — highly teratogenic (antiandrogenic)
Metformin	Mitochondrial Complex I (respiratory chain)	Inhibits gluconeogenesis	— First-line in T2DM + gestational diabetes — Lactic acidosis (rare — risk with renal impairment) — Improves ovulation in PCOS (↓ insulin → ↓ LH/androgens)
Statins (Atorvastatin, etc.)	HMG-CoA reductase	Competitive	— Inhibits rate-limiting step of cholesterol synthesis — Contraindicated in pregnancy (↓ cholesterol needed for placental steroidogenesis → theoretical fetal harm) — Myopathy risk ↑ with CYP3A4 inhibitors (e.g., azole antifungals, macrolides) — Atorvastatin, simvastatin — CYP3A4; pravastatin — renal excretion (preferred in some contexts)
NSAIDs (Ibuprofen, Diclofenac)	COX-1 / COX-2	Non-selective (most)	— GI ulcers, renal impairment, platelet dysfunction — Premature ductal closure in 3rd trimester (prostaglandins maintain ductus arteriosus patency) — Oligohydramnios — reversible with discontinuation — Avoid after 28–30 weeks GA — Low-dose aspirin (60–150 mg) safe for preeclampsia prevention
Omeprazole (PPIs)	H⁺/K⁺ ATPase (proton pump — gastric parietal cells)	Irreversible (covalent binding)	— Long-term use → risk of B₁₂ deficiency (↓ gastric acid → ↓ B₁₂ release from food) — Clopidogrel interaction (omeprazole inhibits CYP2C19 → ↓ activation) — Generally safe in pregnancy
ACE Inhibitors (Lisinopril, etc.)	Angiotensin-Converting Enzyme	Competitive	— Contraindicated in pregnancy — fetotoxic (renal tubular dysplasia, oligohydramnios, skull ossification defects) — Avoid preconception and throughout pregnancy — Alternatives: methyldopa, labetalol, nifedipine
Angiotensin Receptor Blockers	AT1 receptor	Competitive blockade	— Same fetotoxic effects as ACE inhibitors — Avoid in pregnancy
Carbamazepine	Voltage-gated Na⁺ channels	—	— Induces CYP3A4 → accelerates steroid/incretin metabolism — ↑ Risk of NTD (folate antagonist) — high-dose folate (5 mg/day) recommended
Valproate	Multiple (HDAC inhibition, GABA ↑)	—	— Highly teratogenic — NTD (10× risk), neurodevelopmental effects — Contraindicated in pregnancy for epilepsy (except if no alternative)

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Summary of Key Mnemonics for Quick Review

Topic	Mnemonic
Glycolysis steps (10)	Good Boys Eat Apples, Peaches Please Fussy People To Smoke
TCA cycle steps	Can I Keep Selling Sex For Money, Officer?
BCAAs	LIV — Leucine, Isoleucine, Valine
Essential amino acids (9)	PVT TIM HALL
High AG metabolic acidosis	MUDPILES
Non-AG metabolic acidosis	HARDUPS
Lesch-Nyhan	Loves Self-Harm: X-linked, HGPRT deficiency
Von Gierke	Got Glucose problem (liver — G6Pase)
McArdle	Makes Muscle pain (muscle glycogen phosphorylase)
Steroid carbon counts	Estrogen=18, Androgens=19, Everything else=21
Ketone bodies	Produced in liver via HMG-CoA — brain uses after 3–5 days of starvation

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References & Further Reading

1. Baynes J, Dominiczak M. Medical Biochemistry. 5th ed. Elsevier; 2018.
2. Murray RK, et al. Harper's Biochemistry. 31st ed. Appleton & Lange; 2018.
3. Lieberman M, Marks AD. Marks' Basic Medical Biochemistry. 5th ed. Wolters Kluwer; 2017.
4. Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 7th ed. WH Freeman; 2017.
5. Berg JM, Tymoczko JL, Stryer L. Biochemistry. 8th ed. WH Freeman; 2015.
6. RCOG. MRCOG Part 1 syllabus. Royal College of Obstetricians and Gynaecologists.
7. Creasy RK, Resnik R, Iams JD. Maternal-Fetal Medicine. 8th ed. Elsevier; 2019.
8. Cunningham FG, et al. Williams Obstetrics. 26th ed. McGraw-Hill; 2022.
9. Cotran RS, Kumar V, Robbins SL. Pathologic Basis of Disease. 10th ed. Elsevier; 2021.
10. Ganong WF. Review of Medical Physiology. 26th ed. McGraw-Hill; 2021.
11. Devlin TM. Textbook of Biochemistry with Clinical Correlations. 7th ed. Wiley; 2010.
12. NICE Guidelines: Antenatal care (NG201), Diabetes in pregnancy (NG3), Hypertension in pregnancy (NG133).

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End of Document — Revision Date: May 2026

Summary: This document provides a comprehensive revision guide covering all biochemical domains of the MRCOG Part 1 syllabus, with special emphasis on obstetric and gynaecological applications of metabolic pathways, vitamin functions, enzyme regulation, placental biochemistry, and fetal metabolism.

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