Overview & Clinical Context

Most Common Exam Setting: Pts on prolonged Total Parenteral Nutrition (TPN) lacking trace element supplementation, malabsorption syndromes (e.g., Crohn disease, celiac disease), or post-bariatric surgery (Roux-en-Y).
Core Trace Elements: Zinc, Copper, Selenium, Chromium, Iron, Manganese, Iodine.

Zinc (Zn)

Physiology: Cofactor for >300 metalloenzymes (DNA/RNA polymerases, carbonic anhydrase, collagenase).
Risk Factors: Inadequate TPN, chronic diarrhea/malabsorption, gastric bypass, alcoholism, acrodermatitis enteropathica (autosomal recessive mutation in SLC39A4 zinc transporter).
Clinical Features of Deficiency:
- Acrodermatitis: Periorificial and acral erythematous, crusted/vesiculobullous dermatitis.
- Alopecia: Generalized hair loss.
- Hypogonadism: Decreased spermatogenesis, delayed puberty in adolescents.
- Impaired wound healing: Decreased collagen cross-linking.
- Sensory/Immune: Dysgeusia/anosmia (loss of taste/smell), impaired cell-mediated immunity (frequent infections).
Diagnosis:
- Low serum/plasma zinc level.
- Low serum alkaline phosphatase (zinc-dependent enzyme).
Management:
- Oral or IV zinc supplementation (Zinc sulfate or gluconate).
Toxicity / Drug Interaction:
- High-dose oral zinc competes with copper for absorption via metallothionein in enterocytes $\to$ secondary copper deficiency.

Physiology: Component of ceruloplasmin, cytochrome c oxidase, lysyl oxidase, dopamine $β$ -hydroxylase, and ferroxidase.
Risk Factors: TPN without trace elements, bariatric surgery/gastrectomy, malabsorption, excess zinc ingestion (e.g., denture cream, high-dose supplements).
Clinical Features of Deficiency: c
- Hematologic: Microcytic or normocytic anemia (refractory to iron), leukopenia/neutropenia, thrombocytopenia (simulates myelodysplastic syndrome).
- Neurologic: Myeloneuropathy resembling Subacute Combined Degeneration (SCD):
  - Posterior column dysfunction: Loss of vibration and proprioception, ataxia, (+) Romberg.
  - Lateral corticospinal dysfunction: Spasticity, hyperreflexia, weakness.
  - Key Distinction: Clinically identical to Vitamin B12 deficiency, but B12 and methylmalonic acid (MMA) levels are normal.
- Skin/Hair: Brittle, hypopigmented hair (Menkes kinky hair disease if congenital ATP7A mutation), skin depigmentation (tyrosinase dysfunction).
- Skeletal: Osteopenia, skeletal abnormalities (lysyl oxidase deficiency).
Diagnosis:
- Low serum copper and low serum ceruloplasmin.
Management:
- Oral or IV copper supplementation.
- Discontinue excess zinc intake if applicable.

Physiology: Component of selenoproteins, including glutathione peroxidase (antioxidant defense) and iodothyronine deiodinases ( $T_{4} \to T_{3}$ conversion).
Risk Factors: Prolonged TPN, regional soil deficiency (Keshan region in China), severe malnutrition.
Clinical Features of Deficiency:
- Cardiomyopathy: Dilated cardiomyopathy (classic for Keshan disease), congestive HF, arrhythmias.
- Musculoskeletal: Proximal myopathy, skeletal muscle pain, elevated CK.
- Hematologic: Macrocytosis (without anemia or with mild anemia).
- Thyroid: Impaired peripheral conversion of $T_{4} \to T_{3}$ (mild hypothyroidism).
Toxicity (Selenosis):
- Garlic-like breath odor.
- Alopecia, brittle and ridged nails.
- Nausea, vomiting, diarrhea, peripheral neuropathy.
Diagnosis & Management:
- Deficiency: Serum selenium level $\to$ Supplementation.

Physiology: Potentiates insulin action at the peripheral receptor level (glucose tolerance factor).
Risk Factors: Long-term TPN without micronutrient supplementation.
Clinical Features of Deficiency:
- Impaired Glucose Tolerance: Insulin resistance and persistent hyperglycemia (elevated insulin requirements in TPN pts).
- Neurologic: Peripheral neuropathy, ataxia, mild encephalopathy (confusion).
Diagnosis & Management:
- Suspect in TPN pt with unexplained, new-onset refractory hyperglycemia.
- Tx: Chromium chloride supplementation.

Physiology: Core constituent of heme for $O_{2}$ transport (hemoglobin/myoglobin) and electron transport (cytochromes).
Clinical Features of Deficiency:
- Microcytic, hypochromic anemia with elevated RDW.
- Fatigue, pallor, exertional dyspnea.
- Pica (craving ice/clay/dirt), koilonychia (spoon nails), angular cheilitis, atrophic glossitis.
- Restless Legs Syndrome (RLS).
- Plummer-Vinson Syndrome: Triad of microcytic anemia, esophageal webs, and dysphagia.
Key Diagnostic Labs:
- $↓$ Ferritin (most sensitive and specific), $↑$ TIBC, $↓$ Serum iron, $↓$ Transferrin saturation (<15-20%).
Management:
- Oral ferrous sulfate (take with Vitamin C/acid; avoid with antacids/calcium).
- IV iron (iron sucrose, ferric carboxymaltose) for malabsorption, intolerance to oral iron, or chronic kidney disease (CKD on HD).

Physiology: Activates enzymes involved in gluconeogenesis (pyruvate carboxylase) and antioxidant defense (mitochondrial SOD).
Excretion: Excreted via the biliary system.
Deficiency: Extremely rare (impaired growth, skeletal defects, dermatitis).
Toxicity (Hypermanganesemia):
- Setting: Pts with chronic cholestatic liver disease on TPN (cannot excrete manganese) or welders/miners inhaling manganese dust.
- Features: “Manganism” / Parkinsonism-like symptoms (extrapyramidal signs, tremor, rigidity, gait instability), neuropsychiatric symptoms (“manganese madness”: psychosis, hallucinations, mood lability).
- Imaging: T1 hyperintensity in the basal ganglia / globus pallidus on brain MRI.
Management:
- Remove manganese from TPN formulations in pts with liver dysfunction/hyperbilirubinemia.

Physiology: Essential substrate for thyroid hormone ( $T_{3} / T_{4}$ ) synthesis.
Deficiency:
- Adults: Non-toxic goiter, primary hypothyroidism (elevated TSH, weight gain, fatigue, cold intolerance).
- Congenital / Pregnancy: Cretinism (severe intellectual disability, short stature, coarse facial features, umbilical hernia, hypotonia).
Toxicity:
- Wolff-Chaikoff Effect: High iodine load temporarily blocks organification $\to$ transient hypothyroidism.
- Jod-Basedow Phenomenon: High iodine load induces thyrotoxicosis in autonomous thyroid nodules/latent Graves disease.

Trace Element	Classic Etiology	Key Deficiency Presentation	Toxicity Buzzword / Exam Key
Zinc (Zn)	TPN, malabsorption, genetic	Periorificial/acral rash, alopecia, dysgeusia, impaired wound healing, hypogonadism	Excess causes secondary Copper deficiency
Copper (Cu)	Bariatric surgery, excess zinc	SCD-like myeloneuropathy (dorsal column signs) + Microcytic anemia/leukopenia (B12 & MMA normal)	Wilson Disease (KF rings, basal ganglia degeneration)
Selenium (Se)	TPN, Keshan region soil	Dilated cardiomyopathy, proximal myopathy, macrocytosis	Garlic breath, brittle nails, alopecia
Chromium (Cr)	TPN	Insulin resistance / hyperglycemia, peripheral neuropathy	Industrial exposure: contact dermatitis, lung CA
Manganese (Mn)	TPN in liver disease	Extremely rare	Parkinsonism, T1 basal ganglia hyperintensity
Iron (Fe)	Blood loss, poor intake	Microcytic anemia, pica, koilonychia, RLS, Plummer-Vinson	Hemochromatosis, acute pediatric overdose

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