Diabetic Ketoacidosis (DKA)

Definition

1. Hyperglycemia - blood glucose elevated (or known history of diabetes)
2. Ketonemia/ketonuria - urinary ketones ≥ 2+ or serum ketones ≥ 3.0 mmol/L
3. Acidosis - arterial or venous pH < 7.3 (bicarbonate < 18 mmol/L)

• Goldman-Cecil Medicine, p. 2484

Pathophysiology

• Insulin deficiency prevents glucose uptake into cells
• Glucagon stimulates hepatic gluconeogenesis and glycogenolysis
• Substrates flood the liver: amino acids + lactate from muscle, free fatty acids + glycerol from adipose tissue
• Glucose released into circulation faster than it can be utilized

• Insulin deficiency activates hormone-sensitive lipase in adipose tissue
• Free fatty acids (FFAs) surge in the bloodstream
• Liver converts long-chain FFAs to acetoacetate and beta-hydroxybutyrate (+ small amounts of acetone)
• These ketone bodies accumulate, causing high-anion-gap metabolic acidosis

• Hyperglycemia exceeds the renal threshold → osmotic diuresis
• Water, sodium, potassium, magnesium, calcium, and phosphorus are lost in urine
• Vomiting worsens fluid and electrolyte losses
• Fluid depletion → hemoconcentration → worsens hyperglycemia

• Rosen's Emergency Medicine, p. 2542

Precipitants

• Infections (pneumonia, UTI, cellulitis)
• Inadequate insulin / non-adherence
• New-onset type 1 diabetes
• Acute coronary syndrome
• Unknown cause

• Stroke, pulmonary embolism, acute pancreatitis
• Alcohol intoxication
• Endocrinopathies: Cushing syndrome, thyrotoxicosis, acromegaly
• Drugs: corticosteroids, SGLT-2 inhibitors, clozapine, olanzapine, cocaine, lithium, sympathomimetics, thiazide diuretics
• Severe burns, hyperthermia/hypothermia
• Goldman-Cecil Medicine, Table 210-11

Clinical Features

• Polyuria, polydipsia (classic hyperglycemia symptoms)
• Weakness, lethargy, nausea, anorexia
• Abdominal pain (can mimic acute abdomen)
• Vomiting

• Dry skin and mucous membranes, decreased skin turgor
• Tachycardia, orthostatic hypotension
• Kussmaul breathing - deep, rapid respirations (compensatory respiratory alkalosis for metabolic acidosis)
• Fruity/acetone breath (from exhaled acetone)
• Depressed consciousness - ranges from lethargy to frank coma (correlates with hyperosmolality)
• Reduced jugular venous pressure

Diagnosis

• High anion gap metabolic acidosis - the anion gap rise is proportional to the bicarbonate fall
• Pseudo-hyponatremia - measured serum Na+ is low due to osmotic shift of water from cells (correct: add 1.6 mEq/L Na+ for every 100 mg/dL glucose above normal)
• Elevated WBC - can be due to metabolic acidosis itself, not necessarily infection
• Elevated serum amylase - often non-pancreatic origin; can falsely suggest pancreatitis
• Elevated hematocrit/Hgb - hemoconcentration
• Prerenal azotemia (elevated BUN/Cr)
• Goldman-Cecil Medicine, p. 2484

Management

Immediate priorities: Fluids, Insulin, Electrolytes

• Adult fluid deficit is typically 3-5 L
• If in hypovolemic shock: give isotonic crystalloid (0.9% NaCl) as rapidly as possible (20 mL/kg boluses in children until SBP >80 mmHg)
• After stabilization: continue 0.9% NaCl or 0.45% NaCl at appropriate rate
• Switch to D5W / 0.45% NaCl when glucose drops to ≤ 300 mg/dL (prevents hypoglycemia while continuing insulin to clear ketones)

• Regular insulin IV infusion: 0.1 units/kg/hour (standard protocol)
• Do not give insulin until potassium is ≥ 3.5 mEq/L (insulin drives K+ intracellularly and can cause fatal hypokalemia)
• Goal: glucose decrease of ~50-75 mg/dL/hour
• Recent evidence: subcutaneous insulin protocols are an alternative to IV infusion in mild-moderate DKA - a 2024 systematic review (PMID 39090718) found comparable outcomes between subcutaneous and IV insulin in adults; a 2026 meta-analysis (PMID 41208563) supports early addition of subcutaneous basal insulin during IV infusion to reduce rebound hyperglycemia

• If K+ < 3.5: replace K+ BEFORE starting insulin, 20-40 mEq/hr
• If K+ 3.5-5.0: add 20-30 mEq K+ to each liter of IV fluid
• If K+ > 5.0: hold potassium, monitor every 2 hours

• Generally NOT recommended unless pH < 6.9 (severe acidosis)
• Routine bicarbonate may worsen intracellular acidosis and hypokalemia

• Correct if severe depletion is present

• Correct with 1-2 g MgSO4 if depleted

• Blood glucose < 200 mg/dL
• Serum bicarbonate ≥ 15 mEq/L
• pH > 7.3
• Anion gap closed

Special Considerations

Ketogenesis

Overview

• Acetoacetate (primary product)
• Beta-hydroxybutyrate (3-hydroxybutyrate) (most abundant in blood)
• Acetone (minor, volatile - exhaled via lungs)

• Harper's Illustrated Biochemistry, 32nd Ed, p. 232

Why Does Ketogenesis Happen? (The Setup)

1. Acetyl-CoA overload from beta-oxidation of fatty acids accumulates faster than the TCA cycle can handle
2. OAA (oxaloacetate) is depleted - because:
   • Fatty acid oxidation raises NADH, which shifts OAA to malate
   • OAA is consumed by gluconeogenesis (liver prioritizes making glucose)
   • Without OAA, acetyl-CoA cannot enter the TCA cycle (citrate synthase reaction is blocked)
3. The excess acetyl-CoA is therefore shunted into ketogenesis

• Lippincott's Illustrated Reviews: Biochemistry, 8th Ed, p. 555

The Ketogenesis Pathway (Step by Step)

• 2 molecules of acetyl-CoA condense
• Enzyme: Thiolase (reversal of the last step of beta-oxidation)
• Product: Acetoacetyl-CoA

• Acetoacetyl-CoA + another acetyl-CoA + H₂O
• Enzyme: Mitochondrial HMG-CoA synthase (rate-limiting, liver-specific)
• Product: 3-Hydroxy-3-methylglutaryl CoA (HMG-CoA)
• Note: HMG-CoA synthase is found in significant quantities only in the liver - this is why only the liver produces ketone bodies in quantity

• HMG-CoA is cleaved
• Enzyme: HMG-CoA lyase
• Products: Acetoacetate + acetyl-CoA
• The released CoA is important - it is recycled back to support continued fatty acid oxidation

• Acetoacetate + NADH + H⁺ → 3-hydroxybutyrate + NAD⁺
• Enzyme: 3-Hydroxybutyrate dehydrogenase (mitochondrial)
• The equilibrium is driven toward 3-hydroxybutyrate when the NAD⁺/NADH ratio is low (i.e., during active fatty acid oxidation), so 3-HB is the predominant ketone in DKA

• Acetoacetate spontaneously decarboxylates → acetone + CO₂
• Not enzymatic; acetone is metabolically inert and exhaled (fruity breath in DKA)

Three Key Regulatory Steps

• Ketosis cannot occur unless FFAs are mobilized from adipose triacylglycerol
• Insulin inhibits hormone-sensitive lipase → suppresses lipolysis
• Glucagon/epinephrine activate lipolysis
• Low insulin (fasting, DKA) = FFA flood → ketogenesis substrate available

• Carnitine palmitoyl transferase I (CPT-I) transports long-chain acyl-CoA into mitochondria for beta-oxidation
• Malonyl-CoA (the first intermediate in fatty acid synthesis) is a potent inhibitor of CPT-I
• In the fed state: high insulin → high malonyl-CoA → CPT-I inhibited → fatty acids go to esterification, not oxidation
• In fasting/DKA: low insulin → malonyl-CoA falls → CPT-I active → beta-oxidation and ketogenesis increase

• As FFA flux increases, acetyl-CoA outpaces the TCA cycle capacity (OAA is depleted)
• Proportionately more acetyl-CoA is diverted into ketogenesis
• At very high FFA concentrations, essentially all excess acetyl-CoA goes to ketone bodies
• Harper's Illustrated Biochemistry, 32nd Ed, p. 234-235

Ketolysis (Use of Ketones by Peripheral Tissues)

1. 3-Hydroxybutyrate → Acetoacetate (by 3-HB dehydrogenase)
2. Acetoacetate + succinyl-CoA → Acetoacetyl-CoA + succinate (by succinyl-CoA transferase - absent in liver)
3. Acetoacetyl-CoA → 2 Acetyl-CoA (by thiolase)
4. Acetyl-CoA enters TCA cycle → ATP production

• Lippincott's Illustrated Reviews: Biochemistry, 8th Ed, p. 556

Physiological vs. Pathological Ketogenesis

Key Enzymes Summary

Vitamin A

Forms and Chemical Structure

• Harper's Illustrated Biochemistry, 32nd Ed

Dietary Sources and Units

• Liver (richest source), fish liver oils, eggs, milk, butter

• Yellow/orange vegetables: carrots, squash, sweet potato
• Dark leafy greens: spinach, kale
• The most important is beta-carotene, symmetrically cleaved by carotene dioxygenase to yield 2 molecules of retinaldehyde

• 1 RAE = 1 µg retinol = 12 µg β-carotene = 24 µg other provitamin A carotenoids
• Old units: 1 IU = 0.3 µg retinol (still seen on food labels)
• Carotenoids contribute ~30% of dietary vitamin A in humans
• Harrison's Internal Medicine, 22nd Ed, p. 2654

Absorption and Metabolism

1. Digestion: Retinyl esters (animal sources) are hydrolyzed to retinol in the intestinal lumen. Beta-carotene is cleaved to retinaldehyde then reduced to retinol in intestinal mucosal cells. Absorption requires bile salts, pancreatic enzymes, and antioxidants (fat-soluble vitamin)
2. Transport to liver: Retinol is packaged into chylomicrons and transported via lymph to the circulation, then taken up by the liver via apolipoprotein E receptors
3. Liver storage: >90% of body's vitamin A is stored in the liver - specifically in perisinusoidal stellate (Ito) cells as retinyl esters. Reserves last at least 6 months on adequate diet
4. Mobilization: For release from the liver, retinol binds to retinol-binding protein (RBP), which then associates with transthyretin (prealbumin) to form a trimolecular complex. This:
   • Prevents glomerular filtration of retinol (protects against toxicity)
   • Allows recognition by cell-surface RBP receptors on peripheral tissues
5. Cellular uptake: After internalization, retinol binds cellular retinol-binding proteins (CRBPs) for transport to nucleus. Can be stored as retinyl ester or oxidized to retinoic acid

• Robbins & Kumar Basic Pathology, p. 292 | Harrison's 22nd Ed

Functions

1. Vision (Retinal)

• In the pigment epithelium: all-trans-retinol → isomerized to 11-cis-retinol → oxidized to 11-cis-retinaldehyde
• 11-cis-retinaldehyde binds to opsin (via a Schiff base to a lysine residue) to form rhodopsin (in rods) or iodopsins (in cones - 3 types for color)
• On light absorption: 11-cis-retinaldehyde isomerizes to all-trans-retinaldehyde → conformational change in opsin → triggers a guanine nucleotide amplification cascade → nerve impulse
• Rhodopsin is hydrolyzed; all-trans-retinaldehyde is released and recycled

• Harper's Illustrated Biochemistry, 32nd Ed

2. Epithelial Cell Differentiation (Retinoic Acid)

• Binds Retinoic Acid Receptors (RARs) and Retinoid X Receptors (RXRs)
• RAR/RXR heterodimers bind Retinoic Acid Response Elements (RAREs) in target gene promoters
• Regulates: epithelial differentiation, cell-cycle control, growth factor receptor expression, tumor suppressor genes

• Vitamin D receptor (VDR)
• Thyroid hormone receptor (TR)
• PPARs (peroxisome proliferator-activated receptors) - regulates fatty acid and carbohydrate metabolism; basis for thiazolidinedione drugs (rosiglitazone, pioglitazone)

3. Immune Function

4. Lipid Metabolism

• Robbins & Kumar Basic Pathology, p. 293 | Harrison's 22nd Ed

Deficiency

Causes

• Dietary (most common worldwide): inadequate intake of animal products and vegetables, especially in children in developing countries
• Malabsorption: celiac disease, Crohn disease, colitis, bariatric surgery, prolonged mineral oil laxative use
• Concurrent zinc deficiency: impairs hepatic mobilization of vitamin A

Clinical Manifestations (in order of appearance)

1. Night blindness - earliest symptom; impaired rod function in dim light
2. Xerosis conjunctivae - dryness of the conjunctiva; normal lacrimal/mucus epithelium replaced by keratinized epithelium
3. Bitot spots - small opaque plaques of keratin debris on conjunctiva (pathognomonic)
4. Keratomalacia - softening and destruction of the cornea → blindness

• Respiratory tract: squamous metaplasia of bronchial epithelium → loss of mucociliary clearance → recurrent pulmonary infections
• Urinary tract: keratin debris desquamation → renal/bladder stones
• Skin: follicular/papular dermatosis (hyperkeratosis of hair follicles - "phrynoderma")
• Immune system: increased susceptibility to infections (measles, diarrheal illness)
• Robbins & Kumar Basic Pathology, p. 293

Toxicity (Hypervitaminosis A)

Acute Toxicity

• Headache, dizziness, vomiting, stupor, blurred vision
• Can mimic pseudotumor cerebri (raised intracranial pressure)
• Historical note: Arctic explorers developed acute toxicity from eating polar bear liver (extremely rich in vitamin A)

Chronic Toxicity

• Weight loss, anorexia, nausea, vomiting
• Bone and joint pain
• Retinoic acid stimulates osteoclast activity → increased bone resorption → high fracture risk
• Hepatotoxicity (liver fibrosis with very high chronic intake)

Teratogenicity

• Retinoids are potent teratogens - cause craniofacial, cardiovascular, thymic, and CNS malformations
• Isotretinoin (synthetic retinoid for acne) is strictly contraindicated in pregnancy
• Vitamin A supplements >10,000 IU/day should be avoided in pregnancy
• Robbins & Kumar Basic Pathology, p. 293

Summary Table

Vitamin A - Quick Reference

Forms

Key Functions

1. Vision - 11-cis-retinal forms rhodopsin in rods; iodopsins in cones
2. Epithelial differentiation - maintains mucus-secreting epithelium via nuclear RAR/RXR receptors
3. Immune function - supplementation reduces child mortality 20-30% in deficient populations
4. Lipid metabolism - RXR dimerizes with PPARs

Deficiency (in order)

• Night blindness → Xerosis conjunctivae → Bitot spots → Keratomalacia → Blindness
• Squamous metaplasia of respiratory/urinary epithelium
• Follicular dermatosis (phrynoderma)

Toxicity

• Acute: Headache, pseudotumor cerebri, vomiting
• Chronic: Bone resorption, fractures, hepatotoxicity
• Pregnancy: Potent teratogen - isotretinoin strictly contraindicated

Storage & Transport

• 90% stored in hepatic stellate (Ito) cells

• Transported bound to RBP + transthyretin