Chemistry · 11 min read
Chemistry
Carbohydrates and Glucose Metabolism
Glucose serves as the primary energy source for most cells. Glucose metabolism begins with glycolysis, the cytoplasmic pathway converting glucose to pyruvate, generating ATP and NADH. Under aerobic conditions, pyruvate enters mitochondria for oxidation through the citric acid cycle and oxidative phosphorylation. Under anaerobic conditions, pyruvate converts to lactate.
Gluconeogenesis synthesizes glucose from non-carbohydrate precursors including lactate, amino acids, and glycerol, occurring primarily in liver and kidney. Glycogenesis stores glucose as glycogen in liver and muscle, while glycogenolysis releases glucose from glycogen stores.
Insulin, secreted by pancreatic beta cells in response to elevated glucose, promotes glucose uptake into cells, glycogenesis, and lipogenesis while inhibiting gluconeogenesis and glycogenolysis. Glucagon from alpha cells has opposing effects, raising blood glucose during fasting.
Diabetes mellitus results from inadequate insulin secretion, action, or both. Type 1 diabetes involves autoimmune destruction of beta cells requiring exogenous insulin. Type 2 diabetes involves insulin resistance with relative insulin deficiency, associated with obesity and managed initially with lifestyle modification and oral agents. Gestational diabetes develops during pregnancy and increases risk for later Type 2 diabetes.
Diagnostic criteria for diabetes include fasting plasma glucose ≥126 mg/dL, two-hour glucose ≥200 mg/dL during oral glucose tolerance test (OGTT), hemoglobin A1c ≥6.5%, or random glucose ≥200 mg/dL with classic symptoms. Prediabetes includes impaired fasting glucose (100-125 mg/dL) and impaired glucose tolerance (2-hour OGTT 140-199 mg/dL).
Glucose measurement methods include hexokinase reference method (glucose phosphorylated, then oxidized with NAD+ reduction measured spectrophotometrically), glucose oxidase (enzymatic oxidation with peroxide detection), and glucose dehydrogenase. Point-of-care glucose meters use electrochemical biosensors.
Hemoglobin A1c reflects average glycemia over 2-3 months through non-enzymatic glycation of hemoglobin. HbA1c targets for most diabetic patients are <7%. Conditions affecting red cell survival alter HbA1c interpretation: hemolytic anemias and blood loss falsely decrease values, while iron deficiency anemia falsely increases them. Hemoglobin variants may interfere with certain measurement methods.
Hypoglycemia presents with adrenergic symptoms (sweating, tremor, palpitations) and neuroglycopenic symptoms (confusion, seizures, coma). Causes include insulin excess (therapeutic or insulinoma), counter-regulatory hormone deficiencies, liver failure, and inborn errors of metabolism.
Lipids and Lipoproteins
Lipids are hydrophobic molecules requiring protein carriers for plasma transport. Lipoproteins contain a core of triglycerides and cholesteryl esters surrounded by phospholipids, free cholesterol, and apolipoproteins.
Chylomicrons transport dietary lipids from intestine, largest and least dense lipoproteins. Very low-density lipoproteins (VLDL) transport endogenous triglycerides from liver. Intermediate-density lipoproteins (IDL) form during VLDL catabolism. Low-density lipoproteins (LDL) deliver cholesterol to peripheral tissues and represent the primary atherogenic fraction. High-density lipoproteins (HDL) mediate reverse cholesterol transport from periphery to liver, conferring cardioprotection.
Apolipoproteins provide structural stability and serve as enzyme cofactors and receptor ligands. ApoB-100 on LDL enables receptor-mediated uptake. ApoA-I on HDL activates lecithin-cholesterol acyltransferase (LCAT). ApoC-II activates lipoprotein lipase. ApoE enables hepatic remnant uptake.
Lipid panel includes total cholesterol, triglycerides, HDL cholesterol, and calculated LDL cholesterol using the Friedewald equation: LDL = Total cholesterol - HDL - (Triglycerides/5). This calculation is invalid when triglycerides exceed 400 mg/dL, requiring direct LDL measurement.
Desirable lipid levels include total cholesterol <200 mg/dL, LDL <100 mg/dL (optimal), HDL ≥40 mg/dL for men and ≥50 mg/dL for women, and triglycerides <150 mg/dL. Fasting specimens are preferred for accurate triglyceride measurement, though non-fasting panels are acceptable for screening.
Hyperlipidemias classified by Fredrickson phenotype include Type I (elevated chylomicrons, lipoprotein lipase deficiency), Type IIa (elevated LDL, familial hypercholesterolemia), Type IIb (elevated LDL and VLDL), Type III (elevated IDL, dysbetalipoproteinemia), Type IV (elevated VLDL), and Type V (elevated chylomicrons and VLDL).
Proteins and Amino Acids
Proteins perform structural, enzymatic, transport, immune, and regulatory functions. Total protein measurement by biuret reaction detects peptide bonds, producing purple color proportional to protein concentration. Serum contains 6-8 g/dL total protein.
Albumin, synthesized by liver, maintains oncotic pressure, transports numerous substances, and serves as nutritional marker. Hypoalbuminemia occurs in liver disease, nephrotic syndrome, malnutrition, and inflammation. Prealbumin (transthyretin) has shorter half-life (2 days versus 20 days for albumin), providing more sensitive nutritional assessment.
Serum protein electrophoresis (SPE) separates proteins by charge migration in electric field. Five major zones appear: albumin (largest, fastest migration toward anode), alpha-1 (α1-antitrypsin, α1-acid glycoprotein), alpha-2 (haptoglobin, α2-macroglobulin, ceruloplasmin), beta (transferrin, complement, β-lipoprotein), and gamma (immunoglobulins). Monoclonal gammopathies produce discrete bands (M-spikes) in gamma or beta regions.
Immunofixation electrophoresis (IFE) identifies monoclonal protein class and light chain type using antisera against IgG, IgA, IgM, kappa, and lambda. Multiple myeloma most commonly produces IgG kappa M-protein.
Acute phase reactants increase during inflammation, infection, and tissue injury. Positive acute phase reactants include C-reactive protein (CRP), fibrinogen, haptoglobin, ceruloplasmin, and complement components. CRP rises within hours and is used for cardiovascular risk assessment and infection monitoring. Negative acute phase reactants including albumin, prealbumin, and transferrin decrease during inflammation.
Amino acid disorders include phenylketonuria (phenylalanine hydroxylase deficiency causing phenylalanine accumulation), maple syrup urine disease (branched-chain amino acid decarboxylase deficiency), and homocystinuria (cystathionine synthase deficiency). Newborn screening detects these conditions using tandem mass spectrometry.
Enzymes
Enzymes are protein catalysts accelerating biochemical reactions without being consumed. Enzyme activity measurement reflects disease in tissues where enzymes are concentrated.
Cardiac markers: Troponins (TnI and TnT) are the preferred markers for myocardial infarction, rising 3-6 hours after injury, peaking at 12-24 hours, and remaining elevated 7-14 days. High-sensitivity troponin assays detect smaller elevations earlier. CK-MB (creatine kinase MB isoenzyme) rises 4-6 hours after MI, peaks at 12-24 hours, and returns to normal in 2-3 days, useful for detecting reinfarction. Myoglobin rises earliest (1-3 hours) but lacks cardiac specificity. BNP and NT-proBNP indicate heart failure severity.
Liver enzymes: Alanine aminotransferase (ALT) is most specific for hepatocellular injury. Aspartate aminotransferase (AST) is found in liver, heart, muscle, and other tissues. AST/ALT ratio >2 suggests alcoholic liver disease. Alkaline phosphatase (ALP) elevates in cholestatic liver disease and bone disorders. Gamma-glutamyltransferase (GGT) is most sensitive for hepatobiliary disease and alcohol use. 5'-nucleotidase specifically elevates in liver disease, differentiating hepatic from bone ALP elevation.
Pancreatic enzymes: Amylase rises within 2-12 hours of acute pancreatitis, returns to normal in 3-5 days. Lipase is more specific and remains elevated longer (7-14 days), making it the preferred marker.
Lactate dehydrogenase (LDH) is ubiquitous, with five isoenzymes: LD1 and LD2 predominate in heart and RBCs, LD3 in lung, LD4 and LD5 in liver and muscle. LDH elevation is nonspecific, occurring in hemolysis, tissue necrosis, and malignancy.
Acid phosphatase historically monitored prostate cancer but is replaced by PSA. Cholinesterase testing includes pseudocholinesterase (plasma) for organophosphate exposure monitoring and succinylcholine sensitivity.
Electrolytes and Blood Gases
Sodium (135-145 mEq/L) is the major extracellular cation, determining plasma osmolality and fluid distribution. Hyponatremia causes range from dilutional (SIADH, heart failure, cirrhosis) to depletional (diuretics, vomiting, adrenal insufficiency). Hypernatremia results from water deficit (diabetes insipidus, inadequate intake) or sodium excess.
Potassium (3.5-5.0 mEq/L) is the major intracellular cation critical for neuromuscular function and cardiac rhythm. Hypokalemia causes include GI losses, renal losses (diuretics, hyperaldosteronism), and intracellular shifts (alkalosis, insulin). Hyperkalemia results from decreased excretion (renal failure, hypoaldosteronism), increased release (hemolysis, tissue injury), and extracellular shifts (acidosis). Pseudohyperkalemia from in vitro hemolysis or prolonged tourniquet must be excluded.
Chloride (98-106 mEq/L) is the major extracellular anion, following sodium changes. Hypochloremia occurs with vomiting (loss of HCl) and metabolic alkalosis. Hyperchloremia accompanies diarrhea (loss of bicarbonate) and metabolic acidosis.
Bicarbonate (22-28 mEq/L) is the major blood buffer, measured as total CO2. Decreased levels indicate metabolic acidosis or respiratory alkalosis compensation. Increased levels indicate metabolic alkalosis or respiratory acidosis compensation.
Anion gap = Na - (Cl + HCO3), normally 8-12 mEq/L. Elevated anion gap acidosis (MUDPILES mnemonic): Methanol, Uremia, DKA, Propylene glycol, Isoniazid/Iron, Lactic acidosis, Ethylene glycol, Salicylates. Normal anion gap acidosis results from bicarbonate loss (diarrhea, renal tubular acidosis).
Osmolality measures solute concentration per kilogram of water. Serum osmolality = 2(Na) + Glucose/18 + BUN/2.8. Osmolal gap (measured minus calculated) >10 mOsm/kg suggests unmeasured osmoles such as ethanol, methanol, or ethylene glycol.
Blood gas analysis measures pH (7.35-7.45), pCO2 (35-45 mmHg), and pO2 (80-100 mmHg). Respiratory acidosis (low pH, high pCO2) results from hypoventilation. Respiratory alkalosis (high pH, low pCO2) results from hyperventilation. Metabolic acidosis (low pH, low HCO3) results from acid accumulation or bicarbonate loss. Metabolic alkalosis (high pH, high HCO3) results from acid loss or bicarbonate gain.
Henderson-Hasselbalch equation: pH = 6.1 + log([HCO3]/0.03 × pCO2). Compensation restores pH toward normal: respiratory disorders compensate metabolically over days, metabolic disorders compensate respiratorily within hours.
Calcium (8.5-10.5 mg/dL total, 4.5-5.3 mg/dL ionized) functions in bone mineralization, neuromuscular function, and coagulation. Ionized calcium is physiologically active; total calcium must be corrected for albumin. Hypercalcemia causes include hyperparathyroidism and malignancy. Hypocalcemia results from hypoparathyroidism, vitamin D deficiency, and chronic kidney disease.
Phosphorus (2.5-4.5 mg/dL) inversely relates to calcium through PTH regulation. Magnesium (1.5-2.5 mEq/L) is essential for enzyme function and neuromuscular activity. Iron studies include serum iron, TIBC, transferrin saturation (iron/TIBC × 100), and ferritin (storage form).
Non-Protein Nitrogen Compounds
Blood urea nitrogen (BUN, 7-20 mg/dL) reflects protein catabolism and renal excretion. Elevated BUN with normal creatinine (elevated BUN/creatinine ratio >20:1) suggests prerenal azotemia (dehydration, heart failure), GI bleeding, or high protein intake. Proportional elevation with creatinine indicates renal failure.
Creatinine (0.6-1.2 mg/dL) derives from muscle creatine metabolism and is filtered by glomeruli with minimal secretion. Creatinine is less affected by diet than BUN, making it more specific for renal function. Estimated GFR (eGFR) calculated from creatinine using CKD-EPI or MDRD equations stages chronic kidney disease.
Uric acid (2.5-8.0 mg/dL) is the end product of purine metabolism. Hyperuricemia causes gout and may indicate increased cell turnover, decreased excretion (renal disease, thiazides), or purine-rich diet. Hypouricemia occurs in SIADH and xanthine oxidase deficiency.
Ammonia derives from amino acid deamination and intestinal bacterial activity. Liver converts ammonia to urea through the urea cycle. Elevated ammonia in liver failure causes hepatic encephalopathy. Specimen requires immediate icing and rapid analysis to prevent in vitro elevation.
Bilirubin derives from heme catabolism. Unconjugated (indirect) bilirubin is lipid-soluble, bound to albumin, elevated in hemolysis and Gilbert syndrome. Conjugated (direct) bilirubin is water-soluble, excreted in bile, elevated in hepatocellular disease and biliary obstruction. Delta bilirubin is conjugated bilirubin covalently bound to albumin, prolonging elevation during recovery from hepatobiliary disease.
Endocrinology
Thyroid: TSH (0.4-4.0 mIU/L) is the primary screening test. Hypothyroidism shows elevated TSH with low free T4; causes include Hashimoto thyroiditis, iodine deficiency, and pituitary failure (secondary, with low TSH). Hyperthyroidism shows suppressed TSH with elevated free T4; causes include Graves disease, toxic nodular goiter, and thyroiditis. Thyroid antibodies (anti-TPO, anti-thyroglobulin) diagnose autoimmune thyroid disease.
Adrenal: Cortisol follows diurnal pattern (highest morning, lowest midnight). Cushing syndrome (cortisol excess) is screened with 24-hour urine free cortisol, late-night salivary cortisol, or dexamethasone suppression test. Adrenal insufficiency is diagnosed with ACTH stimulation test. Aldosterone and renin evaluate hyperaldosteronism. Catecholamines and metanephrines diagnose pheochromocytoma.
Therapeutic Drug Monitoring and Toxicology
Therapeutic drug monitoring (TDM) optimizes dosing for drugs with narrow therapeutic indices, significant toxicity, variable pharmacokinetics, or concentration-dependent effects. Trough levels (just before next dose) are typically monitored; peak levels (after distribution) apply for aminoglycosides.
Aminoglycosides (gentamicin, tobramycin) cause nephrotoxicity and ototoxicity. Vancomycin monitoring prevents nephrotoxicity. Digoxin toxicity causes arrhythmias; hypokalemia increases toxicity risk. Lithium has narrow range (0.6-1.2 mEq/L); toxicity causes neurologic and renal effects. Anticonvulsants (phenytoin, carbamazepine, valproic acid, phenobarbital) require monitoring due to variable metabolism and interactions. Immunosuppressants (cyclosporine, tacrolimus, sirolimus) prevent rejection while avoiding nephrotoxicity and infection.
Toxicology screens detect drugs of abuse including opiates, amphetamines, cocaine metabolite (benzoylecgonine), cannabinoids (THC-COOH), phencyclidine, and benzodiazepines. Immunoassays screen with confirmation by mass spectrometry.
Ethanol legal intoxication threshold is 0.08 g/dL (80 mg/dL) in most jurisdictions. Serum ethanol measurement uses enzymatic (alcohol dehydrogenase) or gas chromatography methods. Osmolal gap estimates ethanol contribution.
Acetaminophen overdose causes hepatotoxicity; Rumack-Matthew nomogram guides N-acetylcysteine treatment based on level and time post-ingestion. Salicylate toxicity causes respiratory alkalosis followed by metabolic acidosis; Done nomogram assesses severity.
Lead toxicity causes developmental delays in children and neuropathy in adults. Blood lead level <5 μg/dL is the CDC reference value. Iron overdose causes GI hemorrhage and hepatotoxicity; serum iron and TIBC guide chelation therapy.
Carbon monoxide binds hemoglobin forming carboxyhemoglobin, causing tissue hypoxia with normal PaO2. Co-oximetry directly measures COHb; pulse oximetry gives falsely normal readings. Treatment is 100% oxygen.
Finished reading?
Lock it in with a quick Chemistry quiz.