Mineral and Trace Element Deficiencies

Inadequate intake (modifiable)

• Diet composition: phytate- and fiber-rich, largely plant-based diets bind iron and zinc in the gut lumen; non-heme iron is far less bioavailable than heme iron
• Food insecurity, alcohol use disorder, anorexia nervosa, restrictive elderly diets: multi-micronutrient rather than isolated deficiency is the rule
• Parenteral nutrition without trace element additives: ASPEN advises that PN provide trace elements including zinc, copper, and selenium; omission produces the classic TPN-associated zinc, copper, and selenium deficiencies. ASPEN qualifies manganese and chromium, however — doses should be limited and monitored, with manganese reduced or withheld in cholestasis because biliary excretion fails and manganese accumulates in the basal ganglia (neurotoxicity), and chromium contamination of PN solutions already supplies unintended amounts

Malabsorption

• Mucosal disease: celiac disease, Crohn's disease, tropical sprue, radiation enteritis
• Anatomic loss: short bowel syndrome and Roux-en-Y gastric bypass, which excludes the duodenum and proximal jejunum where iron, zinc, copper, and calcium are absorbed
• Achlorhydria: atrophic gastritis, H. pylori, chronic PPI use — gastric acid is required to reduce ferric to absorbable ferrous iron

Increased losses

• Chronic blood loss: menorrhagia, occult GI malignancy, and hookworm infection, a major contributor to iron deficiency in endemic regions; globally, low dietary intake of bioavailable iron remains the dominant cause (WHO)
• Renal/GI wasting: loop and thiazide diuretics, aminoglycosides, amphotericin B, cisplatin, and calcineurin inhibitors cause magnesium wasting; PPIs carry an FDA warning for hypomagnesemia; high-output fistulas, chronic diarrhea, and exudative burns waste zinc

Non-modifiable risk factors

• Age extremes and female sex (menstrual losses)
• Genetic: acrodermatitis enteropathica (SLC39A4/ZIP4 zinc transporter), Menkes disease (X-linked ATP7A copper transport), familial hypomagnesemia
• Geography: iodine-poor inland/mountainous soil and selenium-poor soil belts (Keshan and Kashin-Beck regions)

• Cofactor depletion: Many minerals (zinc, iron, copper, magnesium) and trace elements function as essential cofactors for metalloenzymes; their absence impairs enzymatic reactions in cellular respiration, DNA synthesis, immune function, and antioxidant defense (e.g., copper/zinc in cytochrome oxidase; iron in cytochrome P450; zinc in alkaline phosphatase)

• Structural and regulatory roles: Minerals maintain bone mineral density (calcium, phosphorus, magnesium), stabilize protein tertiary structure (zinc finger proteins, iron-sulfur clusters), regulate electrolyte homeostasis (potassium, sodium, chloride), and modulate neuromuscular excitability (magnesium, calcium, potassium)

• Immune and antioxidant dysfunction: Deficiencies of zinc, selenium, and iron impair T-cell and neutrophil function, reduce production of antioxidant enzymes (glutathione peroxidase requires selenium; superoxide dismutase requires copper/zinc), and increase oxidative stress leading to cellular injury

• Intestinal barrier dysfunction: Zinc deficiency impairs tight junction protein expression and increases intestinal permeability, creating a vicious cycle of worsening malabsorption; similarly, iron deficiency alters mucosal integrity

• Alterations in gene expression: Zinc acts as a transcription factor via metallothionein regulation; magnesium and calcium are critical for signal transduction; their deficiency disrupts normal gene expression patterns affecting cell proliferation, differentiation, and apoptosis

Iron Deficiency (IDA)

• Microcytic, hypochromic anemia with fatigue, dyspnea, exercise intolerance; koilonychia (spoon nails), pagophagia (ice craving), pica (unusual eating habits); glossitis and angular cheilitis (rare)
• Impaired cognitive development in children; restless leg syndrome in severe cases
• Often asymptomatic until hemoglobin significantly decreased; women of childbearing age and young children most affected

Zinc Deficiency

• Perioral and perianal dermatitis (eczematous, scaly rashes around mouth and anus), alopecia, diarrhea, and immune dysfunction (recurrent infections, impaired wound healing)
• Hypogeusia (altered taste), hyposmia (altered smell), behavioral changes (irritability, depression, confusion in severe cases)
• Classic presentation in Total Parenteral Nutrition (TPN) patients without zinc supplementation; acrodermatitis-like presentation pathognomonic for deficiency

Copper Deficiency

• Microcytic or normocytic anemia refractory to iron supplementation, neutropenia, and thrombocytopenia (bone marrow suppression)
• Myelopathy with posterior column involvement (paresthesias, ataxia, spasticity), dementia, and neuropathy; hypercholesterolemia
• Presentation mimics vitamin B12 deficiency with neurologic symptoms; often missed diagnosis in chronic TPN or malabsorptive patients

Magnesium Deficiency

• Neuromuscular manifestations: tremor, muscle weakness, cramps, tetany, personality changes, and seizures in severe deficiency
• Cardiac arrhythmias (premature ventricular contractions, atrial fibrillation, torsades de pointes), hypertension, and electrocardiographic changes (prolonged PR/QT intervals)
• Often coexists with hypokalemia (magnesium required for Na-K-ATPase function); difficult to correct potassium without magnesium replacement

Calcium Deficiency (Hypocalcemia)

• Tetany, paresthesias (circumoral and in fingers/toes), muscle cramps, and seizures from increased neuromuscular excitability
• Cardiac arrhythmias, prolonged QT interval on ECG; laryngospasm and bronchospasm in severe cases
• Positive Chvostek's sign (tapping facial nerve causes facial twitching) and positive Trousseau's sign (blood pressure cuff inflation causes hand cramping)

Selenium Deficiency

• Keshan disease: endemic cardiomyopathy in selenium-deficient regions (China, parts of Central Asia)
• Kashhin-Beck disease: osteoarthropathy with joint deformities and chronic arthralgia
• Myalgia, weakness, and increased infection risk; exacerbates Graves' disease and increases progression to hypothyroidism

Iodine Deficiency

• Goiter (diffuse thyroid enlargement), hypothyroidism with fatigue, cold intolerance, and weight gain
• Cretinism in severe neonatal deficiency: intellectual disability, growth retardation, hearing impairment, and neuromotor abnormalities
• Most common cause of preventable intellectual disability worldwide; endemic in regions without iodized salt

Phosphate Deficiency

• Muscle weakness, rhabdomyolysis, and respiratory failure (from respiratory muscle involvement)
• Hemolysis, leukocyte dysfunction, and thrombocytopenia from impaired red/white cell ATP production
• Often missed because normal serum phosphate maintained until severe depletion; total body phosphate may be markedly depleted

Manganese Deficiency

• Rare in humans; presentations include bone abnormalities, growth retardation, reproductive dysfunction, and impaired carbohydrate metabolism
• Neurologic manifestations (ataxia, tremor) and altered collagen synthesis

General Diagnostic Approach

• Serum mineral/trace element levels (iron, zinc, copper, selenium, magnesium, calcium, phosphate, iodine); timing critical as many are poorly reflective of total body stores in acute deficiency
• Dietary and clinical history: assess intake, malabsorption risk (celiac, Crohn's, short bowel), medications (diuretics causing magnesium wasting), parenteral nutrition duration, alcoholism
• Functional markers: ferritin and transferrin saturation (iron); ceruloplasmin (copper); 24-hour urine magnesium; alkaline phosphatase (zinc indicator)

Iron Deficiency

• Serum ferritin <15 ng/mL (most sensitive early marker); low serum iron, elevated TIBC, low transferrin saturation (<16%)
• Microcytic, hypochromic indices on CBC; elevated RDW (red cell distribution width)
• Peripheral blood smear shows microcytic hypochromic cells; bone marrow biopsy (iron stain) confirms absent iron stores but rarely needed

Zinc Deficiency

• Serum zinc <60 mcg/dL (normal >70 mcg/dL); affected by recent meals, stress, infection (acute phase response)
• 24-hour urine zinc more stable; plasma zinc:albumin ratio accounts for protein status
• Clinical response to supplementation often diagnostic given poor lab reliability

Copper Deficiency

• Serum copper <70 mcg/dL and low ceruloplasmin (<20 mg/dL); ceruloplasmin more specific as it reflects copper-dependent protein synthesis
• Elevated 24-hour urine copper (normal <40 mcg/day) in deficiency from mobilization of remaining stores
• Bone marrow shows hypercellularity with microcytic anemia; peripheral neuropathy confirmed by EMG/NCS

Magnesium Deficiency

• Serum magnesium <1.7 mg/dL (normal 1

Immediate stabilization (do this before repletion chemistry)

• Symptomatic hypocalcemia (tetany, laryngospasm, seizure): IV calcium gluconate — preferred peripherally over calcium chloride, which is sclerosing; check and correct magnesium simultaneously or calcium will not stay corrected
• Torsades de pointes or hypomagnesemic arrhythmia: IV magnesium sulfate 2 g push regardless of the serum level
• Hemodynamically significant anemia: transfuse red cells — iron replacement does not stabilize an unstable patient
• Severe hypophosphatemia with respiratory muscle weakness, rhabdomyolysis, or hemolysis: IV sodium or potassium phosphate

First-line oral repletion

• Oral iron salts (ferrous sulfate): ACG guidance on iron deficiency anemia supports oral iron as initial therapy in uncomplicated cases; give with ascorbic acid and separate from PPIs, calcium, levothyroxine, and tetracyclines. Hepcidin surges after a dose, so once-daily or alternate-day dosing is favored over divided daily dosing
• Zinc salts (zinc sulfate/gluconate): WHO/UNICEF recommend zinc for 10–14 days as adjunct to ORS in childhood diarrhea, endorsed by the AAP
• Copper gluconate for acquired copper deficiency — and stop the offending zinc source
• Iodine: universal salt iodization (WHO); the ATA recommends a daily iodine-containing supplement for pregnant and lactating women

Escalation

• IV iron (ferric carboxymaltose, iron sucrose, ferumoxytol) for intolerance, malabsorption/post-bariatric anatomy, IBD, ongoing losses, or ESA-treated CKD (KDIGO)
• IV magnesium, IV copper, or PN trace element supplementation when the gut is non-functional (ASPEN)

Complications of the deficiency itself

• High-output heart failure and demand ischemia from severe iron deficiency anemia: reduced oxygen-carrying capacity drives compensatory tachycardia and stroke volume; signaled by a flow murmur, widened pulse pressure, and troponin leak without epicardial disease — emergency
• Neurodevelopmental impairment: iodine deficiency in utero (cretinism) causes irreversible damage to myelination and cortical development during a fixed developmental window; iron deficiency in infancy is associated with cognitive and behavioral deficits that may persist despite later repletion
• Copper deficiency myelopathy: posterior column and corticospinal demyelination mimicking subacute combined degeneration; hematologic indices normalize with copper but the neurologic deficit is often permanent — the reason early recognition is tested
• Keshan cardiomyopathy (selenium): loss of glutathione peroxidase permits oxidative myocyte injury; presents as dilated cardiomyopathy or cardiogenic shock — emergency
• Hypocalcemic laryngospasm, seizure, and QT prolongation with torsades: increased neuromuscular excitability from a lowered depolarization threshold — emergency
• Refeeding syndrome: insulin surge drives phosphate, potassium, and magnesium intracellularly; heralded by falling phosphate with new weakness, arrhythmia, hemolysis, or respiratory failure — emergency

Complications of treatment

• Oral iron intolerance: unabsorbed iron irritates mucosa — nausea, constipation, black stools (do not mistake for melena)
• Acute pediatric iron overdose: corrosive GI injury, anion-gap acidosis, then shock; treated with deferoxamine — emergency
• IV iron hypersensitivity/infusion reactions, and hypophosphatemia after ferric carboxymaltose via FGF23 elevation, which can cause osteomalacia with prolonged use
• Zinc-induced copper deficiency: metallothionein-mediated copper trapping; signaled by anemia plus neutropenia in a patient on supplements
• **Iodine repletion in nodular goiter → Jod-Basedow thyrotoxicosis**; large acute loads can also transiently suppress the thyroid (Wolff-Chaikoff)
• Selenosis: garlic odor on the breath, brittle nails, alopecia
• Hypermagnesemia from repletion in renal impairment: loss of deep tendon reflexes precedes respiratory depression; antidote is IV calcium

• Copper deficiency is the B12 mimic: myelopathy with ataxia and paresthesias plus anemia and neutropenia, with a normal B12 level. Look in the stem for bariatric surgery, chronic zinc supplements, or zinc-containing denture cream. Cytopenias respond to copper; the neurologic injury often does not.
• Refractory hypokalemia or hypocalcemia = check magnesium. Magnesium is required for Na-K-ATPase function and for PTH secretion and end-organ action; potassium and calcium will not correct until magnesium is repleted.
• New iron deficiency anemia in an adult man or postmenopausal woman: the single best next step is bidirectional endoscopy to exclude GI malignancy (ACG), not empiric iron alone.
• The one association examiners love: acrodermatitis enteropathica — an infant developing perioral/perianal dermatitis, alopecia, and diarrhea at weaning from breast milk, from an SLC39A4 (ZIP4) zinc transporter defect. Also remember zinc as a metalloenzyme cofactor, so alkaline phosphatase runs low in zinc deficiency.
• Buzzwords worth memorizing: pagophagia and koilonychia (iron), hypogeusia and poor wound healing (zinc), Keshan cardiomyopathy and Kashin-Beck osteoarthropathy (selenium), goiter/cretinism (iodine), Chvostek and Trousseau (calcium).
• Common distractor #1: a low serum zinc or iron during acute illness. Zinc falls and ferritin rises as acute-phase reactants — a normal or high ferritin does not exclude iron deficiency in inflammation; transferrin saturation and the clinical context settle it.
• Common distractor #2: transfusing or supplementing iron for anemia of chronic inflammation. Hepcidin-mediated iron sequestration is not iron deficiency; oral iron is ineffective and, in hemochromatosis, harmful.
• Torsades de pointes gets IV magnesium sulfate 2 g regardless of the measured magnesium level — serum levels poorly reflect intracellular stores.