Updated: 4/17/2019

Heme Metabolism

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Heme sythesis
  • Functions 
    • hemoglobin
    • cytochrome b4
    • P450
  • Location of synthesis
    • involves both the mitochondria and the cytosol
    • occurs in nearly every cell
      • occurs in RBC progenitor cells
        • CANNOT occur in RBCs because they lack mitochondria
  • Pathway
    • ALA synthase is rate limiting enzyme (see above)
  • Deficiencies in heme synthesis
    • hemin
      • occurs when Fe3+ is incorporated instead of Fe2+
    • porphyria 
      • causes
        • symptoms due toxic accumulation of pathway intermediates
          • aminolevulinic acid (ALA) causes neurological symptoms
          • protoporphyrins cause photosensitivity
            • conjugated structure what absorbs light energy and forms free radicals
        • symptoms worsened by
          • sunlight
          • P450 inducing drugs
            • stimulate the heme synthesis pathway to ↑ production
            • ex.) barbiturates, alcohol
      • treatment
        • limit exposure to sun and P450 inducing substances
        • hemin
          • inhibits new heme production
      • types
        • porphyria cutanea tarda
          • deficiency in uroporphyrinogen decarboxylase 
          • AD
          • late onset (4th or 5th decade)
            • symptoms often noticed with alcohol consumption
          • presentation
            • photosensitivity
            • hyperpigmentation
              • body's attempt to protect the skin
            • dark red/brown colored urine
        • acute intermittent porphyria
          • deficiency in porphobilinogen deaminas
          • AD
          • late onset
          • presentation
            • NO photosensitivity
            • episodic psychological symptoms (paranoia, anxiety, depression)
            • vague abdominal pain
              • patients can present with a history of laparoscopies
            • dark red/brown colored urine
              • ALA and porphobilinogen (PBG) present in urine during symptoms
    • poisoning
      • lead
        • induced deficiency in ALA dehydratase and ferrochelatase
          • both enzymes are Zn2+ dependent metalloenzymes
          • Pb2+ replaces the Zn2+ at the active site
        • presentation
          • ↓ in IQ
          • microcytic anemia with coarse basophilic stippling
          • abdominal pain
          • ↑ in ALA without ↑ in PBG
            • differentiates from porphyrias
          • lead lines in bone and teeth xrays
          • nephrotoxicity
            • deposition in nuclei of proximal renal tubular cells
      • hexachlorobenzene
        • induced deficiency in uroporphyrinogen decarboxylase
        • presentation
          • hypertrichosis (↑ body hair coverage)
        • found in (now banned in USA) pesticides
    • iron deficiency
      • iron incorporated in the final step
      • result is microcytic hypochromic anemia
      • see Trace metals topic
    • vitamin B6 deficiency
      • rate limiting enzyme (ALA synthase) requires
      • most commonly due to isoniazid therapy
      • see Vitamins topic
Degradation of Heme
  • Function
    • rid body of hemoglobin removed from degraded RBCs
  • Location of degradation
    • spleen
      • site of RBC destruction
    • liver
      • site of bilirubin conjugation
    • intestine
      • conversion by normal gut flora
  • Pathway  
Bilirubin
  • Properties
    • insoluble
      • must travel in blood bound to albumin
    • conjugation
      • direct (conjugated)
        • glucuronate group added
          • soluble
      • indirect (unconjugated)
        • glucuronate group not yet added
          • insoluble
  • Modified forms
    • urobilinogen
      • gives urine yellow color
    • stercobilin
      • gives feces brown color
        • with a blocked bile duct no stercobilin in feces and it is clay colored

ces

 

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Questions (4)
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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(M1.BC.7) A young man with history of seizure disorder is seen in the ED with complaints of confusion and stomach pain. His seizures are currently being treated with phenytoin. After talking with the patient you examine a urine sample (Figure A). You suspect he has a deficit in which of the following enzymes? Review Topic

QID: 100072
FIGURES:
1

Pyruvate dehydrogenase

20%

(6/30)

2

Phosphofructokinase

0%

(0/30)

3

Glucose-6-phosphatase

17%

(5/30)

4

Porphobilinogen deaminase

33%

(10/30)

5

Uroporphyrinogen decarboxylase

30%

(9/30)

M1

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