Updated: 3/8/2019

Trace Metals

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Overview
  • Definition
    • micronutrients required in the diet for necessary cellular functions
  • Major examples
    • iron (Fe)
    • copper (Cu)
    • zinc (Zn)
    • chromium (Cr)
    • fluoride (F)
    • iodide (I)
    • selenium (Se)
  • Others
    • V, Mo, Mn, Co, and Ni
  • Function
    • part of metalloenzyme
      • enzyme has no activity without the metal
      • metal is fixed
      • metal:protein is constant
      • example
        • carbonic anhydrase
    • part of metal-containing enzyme
      • enzyme may have activity without the metal
      • metal is reversibly bound
      • metal:protein ratio is variable
      • example
        • glycogen phosphorylase kinase
  • Oxidative stress
    • organometallic side reactions that damage tissue
      • many metals undergo the Fenton reaction in vivo
        • oxidation of metal and donation of an electron to oxygen
        • most common metals that undergo reaction are Fe2+ and Cu+
        • creation of hydroxyl radicals
      • heme iron can generate superoxide radicals (O2*)
    • reactions happen frequently, but the body can defend itself with anti-oxidants
      • oxidative stress occurs when pro-oxidants > anti-oxidants.
    • examples of oxidative stress damage
      • stroke
      • Parkinson’s
      • Alzheimer’s
Iron 
  • Source 
    • diet
    • recycled from destroyed erythrocytes
  • Forms
    • ferrous iron (Fe2+)
      • dangerous
      • causes oxidative stress
      • found in hemoglobin
    • ferric iron (Fe3+)
      • less dangerous
      • methemoglobinemia (metHb) occurs when Fe3+ is found in hemoglobin
  • Absorption
    • Fe-containing compounds are solubilized in low stomach pH
    • Fe3+ is reduced to Fe2+ (requires vitamin C) in intestine so it can cross gut lumen
    • ferroportin brings Fe3+ into bloodstream from enterocytes
      • mediates amount of Fe released into the blood
      • hepcidin inhibits ferroportin
        • antibacterial because it lowers the availability of iron in the plasma
  • Storage
    • must be immediately used or stored to prevent:
      • bacterial utilization
        • Fe required for growth
      • formation of iron oxides
      • free radicals (Fe + O2)
    • site
      • hepatocytes (main)
      • enterocytes
      • macrophages
    • stored as ferritin (Fe3+)
    • hemosiderin binds excess Fe3+ to prevent from entering the blood
  • Transport
    • carried as Fe3+ by transferrin in the blood
      • transferrin chelates the Fe3+ and transports it in the blood to tissues.
        • maintains solubility and keeps unreactive
        • transferrin receptors on cells endocytose transferrin:Fe complex
        • Fe3+ released into cell triggered by low pH
        • transferrin returns to cell surface to be used again
    • ferroxidase (aka ceruloplasmin) oxidizes Fe2+ to Fe3+ for transport and storage
      • ferritin can also oxidize Fe for storage
  • Excretion
    • no cellular mechanism for iron excretion
    • lost from blood loss and removal of skin cells and other epithelial cells
  • Toxicity
    • beyond the sequestration capacity of ferritin
    • causes oxidative stress
  • Disorders in iron handling
    • hereditary hemochromacytosis
Copper
  • Role
    • human metabolism
    • like other metals, free copper is potentially toxic by donating electrons
      • creates hydroxyl radicals and other reactive oxygen species
    • copper is a cofactor for many metalloproteins
      • examples
        • lysyl oxidase (collagen synthesis)
        • tyrosinase (melanin synthesis)
  • Transport
    • albumin and ceruloplasmin carry copper in the blood
      • similar role to transferrin in iron transport
    • metallothionein is a carrier of copper, zinc, and many other metals
      • role in preventing oxidative stress in the cell
      • thiol groups from many cysteine residues mediate binding
  • Excretion
    • excess copper removed in the bile
      • unlike iron with no mechanism of excretion
  • Deficiency
    • causes
      • excess zinc
        • metallothionein carries both copper and zinc
        • copper is displaced when zinc concentrations rise
    • symptoms
      • a function of what enzymes require copper
        • ferroxidase
          • catalyzes oxidation of iron from Fe2+ to Fe3+
          • result is microcytic anemia
        • lysyl oxidase
          • crosslinks collagen fibers
          • result is poor wound healing
          • aortic dissection
  • Disorders in copper handling
    • Wilson's disease
    • Menke’s disease 
      • X-linked gene mutation in ATP7A 
        • ATP-dependent copper efflux protein
      • aka Ehlers-Danlos syndrome type IX
      • inability of enterocytes to release absorbed copper
      • copper at toxic levels in small intestine and kidneys
      • copper in circulation and in brain at low levels
      • symptoms
        • presents like a copper deficiency
        • seizures, failure to thrive, and neurodegeneration
        • steel-colored and brittle hair
          • due to role of copper in metalloprotein lysyl oxidase which crosslinks collagen for added strength
          • at low serum concentrations of copper, this enzyme cannot function
Zinc
  • Function
    • hundreds of enzymes require zinc
      • important examples
        • carbonic anhydrase
        • ACE (angiotensin I converting enzyme)
        • RNA and DNA polymerase
  • Transport
    • metallothionein carries zinc
      • competes with copper
  • Deficiency 
    • causes
      • poor diet
      • alcoholism
        • liver unable to handle zinc properly
    • symptoms
      • impaired collagenase
        • delayed wound healing
      • impaired zinc finger transcription factor motifs
        • hypogonadism
          • ↓ adult hair (axillary, facial, and pubic)
      • ↓ in senses
        • dysgeusia (lack of taste)
        • anosmia (lack of smell)
      • diarrhea
      • hair loss (alopecia)
Chromium
  • Deficiency
    • causes
      • total parenteral nutrition (TPN)
    • symptoms
      • a function of what proteins/enzymes require chromium
        • hypothesized to play a role as part of glucose tolerance factor
          • ↓ glucose tolerance
Flouride
  • Source
    • mainly fluoridated water
  • Deficiency
    • plays a role in bone and teeth formation/strength
      • ↑ bone fractures
      • dental caries
Iodine
  • Source
    • mainly iodized salt
  • Deficiency
    • plays a role in synthesis of thyroid hormone
      • goiter
      • ↓ thyroid hormone output
Selenium
  • Deficiency
    • causes
      • total parenteral nutrition (TPN)
    • symptoms
      • plays a role in glutathione peroxidase that protects against oxidative stress
        • damage to tissues with high metabolic activity
          • muscle pain
          • cardiomyopathy

References

 

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Questions (2)
Lab Values
Blood, Plasma, Serum Reference Range
ALT 8-20 U/L
Amylase, serum 25-125 U/L
AST 8-20 U/L
Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL
Calcium, serum (Ca2+) 8.4-10.2 mg/dL
Cholesterol, serum Rec: < 200 mg/dL
Cortisol, serum 0800 h: 5-23 μg/dL //1600 h:
3-15 μg/dL
2000 h: ≤ 50% of 0800 h
Creatine kinase, serum Male: 25-90 U/L
Female: 10-70 U/L
Creatinine, serum 0.6-1.2 mg/dL
Electrolytes, serum  
Sodium (Na+) 136-145 mEq/L
Chloride (Cl-) 95-105 mEq/L
Potassium (K+) 3.5-5.0 mEq/L
Bicarbonate (HCO3-) 22-28 mEq/L
Magnesium (Mg2+) 1.5-2.0 mEq/L
Estriol, total, serum (in pregnancy)  
24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL
28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL
Ferritin, serum Male: 15-200 ng/mL
Female: 12-150 ng/mL
Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL
Female: premenopause: 4-30 mIU/mL
midcycle peak: 10-90 mIU/mL
postmenopause: 40-250
pH 7.35-7.45
PCO2 33-45 mmHg
PO2 75-105 mmHg
Glucose, serum Fasting: 70-110 mg/dL
2-h postprandial:<120 mg/dL
Growth hormone - arginine stimulation Fasting: <5 ng/mL
Provocative stimuli: > 7ng/mL
Immunoglobulins, serum  
IgA 76-390 mg/dL
IgE 0-380 IU/mL
IgG 650-1500 mg/dL
IgM 40-345 mg/dL
Iron 50-170 μg/dL
Lactate dehydrogenase, serum 45-90 U/L
Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL
Female: follicular phase: 5-30 mIU/mL
midcycle: 75-150 mIU/mL
postmenopause 30-200 mIU/mL
Osmolality, serum 275-295 mOsmol/kd H2O
Parathyroid hormone, serume, N-terminal 230-630 pg/mL
Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L
Phosphorus (inorganic), serum 3.0-4.5 mg/dL
Prolactin, serum (hPRL) < 20 ng/mL
Proteins, serum  
Total (recumbent) 6.0-7.8 g/dL
Albumin 3.5-5.5 g/dL
Globulin 2.3-3.5 g/dL
Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL
Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h
Thyroxine (T4), serum 5-12 μg/dL
Triglycerides, serum 35-160 mg/dL
Triiodothyronine (T3), serum (RIA) 115-190 ng/dL
Triiodothyronine (T3) resin uptake 25%-35%
Urea nitrogen, serum 7-18 mg/dL
Uric acid, serum 3.0-8.2 mg/dL
Hematologic Reference Range
Bleeding time 2-7 minutes
Erythrocyte count Male: 4.3-5.9 million/mm3
Female: 3.5-5.5 million mm3
Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/h
Female: 0-20 mm/h
Hematocrit Male: 41%-53%
Female: 36%-46%
Hemoglobin A1c ≤ 6 %
Hemoglobin, blood Male: 13.5-17.5 g/dL
Female: 12.0-16.0 g/dL
Hemoglobin, plasma 1-4 mg/dL
Leukocyte count and differential  
Leukocyte count 4,500-11,000/mm3
Segmented neutrophils 54%-62%
Bands 3%-5%
Eosinophils 1%-3%
Basophils 0%-0.75%
Lymphocytes 25%-33%
Monocytes 3%-7%
Mean corpuscular hemoglobin 25.4-34.6 pg/cell
Mean corpuscular hemoglobin concentration 31%-36% Hb/cell
Mean corpuscular volume 80-100 μm3
Partial thromboplastin time (activated) 25-40 seconds
Platelet count 150,000-400,000/mm3
Prothrombin time 11-15 seconds
Reticulocyte count 0.5%-1.5% of red cells
Thrombin time < 2 seconds deviation from control
Volume  
Plasma Male: 25-43 mL/kg
Female: 28-45 mL/kg
Red cell Male: 20-36 mL/kg
Female: 19-31 mL/kg
Cerebrospinal Fluid Reference Range
Cell count 0-5/mm3
Chloride 118-132 mEq/L
Gamma globulin 3%-12% total proteins
Glucose 40-70 mg/dL
Pressure 70-180 mm H2O
Proteins, total < 40 mg/dL
Sweat Reference Range
Chloride 0-35 mmol/L
Urine  
Calcium 100-300 mg/24 h
Chloride Varies with intake
Creatinine clearance Male: 97-137 mL/min
Female: 88-128 mL/min
Estriol, total (in pregnancy)  
30 wks 6-18 mg/24 h
35 wks 9-28 mg/24 h
40 wks 13-42 mg/24 h
17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 h
Female: 2.0-8.0 mg/24 h
17-Ketosteroids, total Male: 8-20 mg/24 h
Female: 6-15 mg/24 h
Osmolality 50-1400 mOsmol/kg H2O
Oxalate 8-40 μg/mL
Potassium Varies with diet
Proteins, total < 150 mg/24 h
Sodium Varies with diet
Uric acid Varies with diet
Body Mass Index (BMI) Adult: 19-25 kg/m2
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