4.3 Minerals, Water, Electrolytes, and Acid-Base Balance

Minerals and fluids are tested both as basic biochemistry and as the foundation for clinical problems such as anemia, refeeding syndrome, kidney disease, and diabetic ketoacidosis. This section covers the major and trace minerals that appear most often, then water, electrolyte, and acid-base regulation.

Major Minerals and Trace Elements

                                   Systemic Iron Regulation

  High Plasma Iron / Inflammation (IL-6)           Low Plasma Iron / Hypoxia / Anemia
                   │                                                │
                   ▼                                                ▼
      Hepatic Hepcidin Synthesis Upregulated           Hepatic Hepcidin Synthesis Downregulated
                   │                                                │
                   ▼                                                ▼
  Hepcidin binds basolateral Ferroportin           Ferroportin remains stable on basolateral membrane
                   │                                                │
                   ▼                                                ▼
  Ferroportin internalized and degraded           Iron exported smoothly into portal circulation
                   │                                                │
                   ▼                                                ▼
  Iron trapped in enterocytes & macrophages        Transferrin Saturation maintained for erythropoiesis
                   │
                   ▼
  Anemia of Chronic Disease (Functional Deficiency)

1. Iron ($Fe$)

• Forms and Absorption:
  • Heme Iron ($Fe^{2+}$): Found in animal flesh (meat, poultry, fish). Absorbed efficiently (15–35%) via heme carrier protein 1 (HCP-1) and hydrolyzed within enterocytes by heme oxygenase.
  • Non-Heme Iron ($Fe^{3+}$): Found in plant foods, grains, and dairy. Exists as ferric iron ($Fe^{3+}$); must be reduced to ferrous iron ($Fe^{2+}$) by apical duodenal cytochrome b (Dcytb) or dietary ascorbate, then absorbed via Divalent Metal Transporter 1 (DMT-1). Inhibited by dietary phytates, polyphenols (tea/coffee), and calcium.
• The Hepcidin Master Regulator: Synthesized by hepatocytes in response to elevated circulating iron or systemic inflammation (interleukin-6). Hepcidin binds to the basolateral iron exporter ferroportin, inducing its phosphorylation, internalization, and lysosomal degradation. This traps iron inside enterocytes (shed in feces) and reticuloendothelial macrophages, preventing systemic iron overload. In chronic inflammatory states, prolonged hepcidin elevation restricts iron availability for erythropoiesis, producing anemia of chronic disease (anemia of inflammation).
• Biomarkers: Serum ferritin reflects total body iron storage ($< 15–30\text{ ng/mL}$ confirms iron deficiency anemia). In iron deficiency, serum iron drops, Total Iron-Binding Capacity (TIBC) increases, and Transferrin Saturation drops below 16%, producing a microcytic, hypochromic anemia.

2. Calcium and Phosphorus

• Calcium ($Ca$): 99% resides in skeleton as hydroxyapatite [$Ca_{10}(PO_4)_6(OH)_2$]. Ionized calcium ($Ca^{2+}$, 50% of serum total) regulates cardiac excitation-contraction coupling, neuronal membrane potentials, and coagulation cascades. Regulated primarily by PTH (elevates calcium via bone resorption and renal reabsorption) and calcitriol.
  • Hypoalbuminemia Correction Formula: Because 40–45% of serum calcium is bound to albumin: $\text{Corrected } Ca\text{ (mg/dL)} = \text{Serum } Ca + 0.8 \times \left( 4.0 - \text{Serum Albumin [g/dL]} \right)$
• Phosphorus ($P$): 85% in bone. Essential component of high-energy phosphate bonds (ATP, creatine phosphate), nucleic acid backbones, 2,3-BPG in erythrocytes, and the primary intracellular acid-base buffer system ($HPO_4^{2-}/H_2PO_4^-$).
  • Refeeding Syndrome: Rapid re-introduction of carbohydrates in severely malnourished patients stimulates massive insulin release, driving phosphorus, potassium, and magnesium into cells for glycolysis and glycogen synthesis. This induces acute, profound hypophosphatemia ($< 1.0–1.5\text{ mg/dL}$), leading to respiratory failure, cardiac arrhythmias, rhabdomyolysis, and death.

3. Trace Elements: Zinc, Iodine, and Selenium

• Zinc ($Zn$): Structural and catalytic cofactor for $> 300$ metalloenzymes (carbonic anhydrase, alkaline phosphatase, alcohol dehydrogenase, Cu/Zn superoxide dismutase SOD1, RNA polymerases) and "zinc finger" DNA-binding motifs. Essential for taste acuity via the salivary peptide gustin, immune function, and wound healing (collagenase).
  • Acrodermatitis Enteropathica: A rare autosomal recessive mutation in the apical enterocyte zinc transporter ZIP4 (SLC39A4). Presents in infants upon weaning from breast milk with periorificial and acral pustular dermatitis, alopecia, intractable diarrhea, and failure to thrive; completely resolved by life-long high-dose oral zinc supplementation.
• Iodine ($I$): Essential substrate for thyroid hormones thyroxine ($T_4$) and triiodothyronine ($T_3$) synthesized in thyroid follicular cells via thyroid peroxidase. Deficiency causes compensatory thyroid hypertrophy (endemic goiter) and, during pregnancy, severe irreversible fetal neurodevelopmental impairment and short stature (cretinism), addressed nationally through universal salt iodization under the Philippine ASIN Law (Republic Act 8172).
• Selenium ($Se$): Incorporated as selenocysteine into selenoproteins, including glutathione peroxidase (GPx) (which neutralizes lipid hydroperoxides), thioredoxin reductase, and iodothyronine deiodinases (converting $T_4$ into active $T_3$). Severe geographic soil deficiency causes Keshan Disease, an endemic congestive cardiomyopathy triggered by coxsackievirus infection.

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Water, Osmolality, and Electrolyte Homeostasis

Fluid Compartments

Total Body Water (TBW) constitutes approximately 60% of total body weight in adult males and 50–55% in adult females (due to higher adipose mass):

• Intracellular Fluid (ICF): Constitutes $2/3$ of TBW (~40% of body weight). Principal cation is Potassium ($K^+$); primary anions are organic phosphates (ATP) and proteins.
• Extracellular Fluid (ECF): Constitutes $1/3$ of TBW (~20% of body weight). Divided into Interstitial Fluid ($3/4$ of ECF, ~15% body weight) and Intravascular Plasma ($1/4$ of ECF, ~5% body weight). Principal cation is Sodium ($Na^+$); primary anions are Chloride ($Cl^-$) and Bicarbonate ($HCO_3^-$).

Serum Osmolality and Osmoregulation

Normal serum osmolality ranges between 275 and 295 mOsm/kg and is calculated as:

$\text{Serum Osmolality (mOsm/kg)} = 2 \times [Na^+\text{ (mEq/L)}] + \frac{\text{Glucose (mg/dL)}}{18} + \frac{\text{BUN (mg/dL)}}{2.8}$

• Osmoreceptor Response: Hypothalamic osmoreceptors detect subtle changes in ECF tonicity ($1–2\%$ shift). An increase in osmolality stimulates the posterior pituitary to secrete Arginine Vasopressin (AVP / Antidiuretic Hormone ADH).
• Renal Action of ADH: ADH binds basolateral $V_2$ receptors on renal medullary collecting duct principal cells, activating adenylate cyclase. Elevated cAMP stimulates protein kinase A to translocate intracellular vesicles containing Aquaporin-2 (AQP2) water channels into the apical membrane, increasing water reabsorption and producing concentrated urine.

Volume Regulation: The RAAS Axis

When effective arterial blood volume decreases, renal perfusion drops:

1. Renin Secretion: Juxtaglomerular cells secrete the aspartyl protease renin, which cleaves hepatic angiotensinogen to release angiotensin I.
2. ACE Cleavage: Pulmonary vascular endothelial angiotensin-converting enzyme (ACE) converts angiotensin I to angiotensin II.
3. Angiotensin II Actions: Triggers systemic arteriolar vasoconstriction and stimulates the adrenal cortex (zona glomerulosa) to secrete aldosterone.
4. Aldosterone Action: Aldosterone diffuses into collecting duct principal cells, binding mineralocorticoid receptors. This upregulates apical epithelial sodium channels (ENaC) and basolateral $Na^+/K^+$ ATPase pumps, driving active $Na^+$ and water reabsorption in exchange for urinary $K^+$ and $H^+$ excretion.

Clinical Acid-Base Balance

Blood pH is defended between 7.35 and 7.45 according to the Henderson-Hasselbalch relationship:

$pH = 6.1 + \log\left( \frac{[HCO_3^-]}{0.03 \times PaCO_2} \right)$

• Serum Anion Gap: Used to evaluate metabolic acidosis: $\text{Anion Gap} = [Na^+] - \left( [Cl^-] + [HCO_3^-] \right) \quad (\text{Normal: } 8–12\text{ mEq/L})$
• High Anion Gap Metabolic Acidosis: Occurs when unmeasured organic acid anions accumulate: ketoacidosis (diabetic, alcoholic, starvation), lactic acidosis (hypoperfusion, shock), uremia (renal failure), or toxin ingestion (methanol, ethylene glycol, salicylates).
• Normal Anion Gap (Hyperchloremic) Acidosis: Characterized by bicarbonate loss compensated by reciprocal chloride retention: severe diarrhea, proximal/distal renal tubular acidosis, or excessive $0.9\%$ saline infusion.