Biochemistry Exam 4 - Heme Metabolism

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Porphyrins

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-made up of 4 pyrolle rings
-linked by 4 methyne groups
-substituted at positions 1-8

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Porphyrins Chelate Metals

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-Iron --> Heme
-Cobalt --> Cobalamine
-Magnessium --> Chlorophyll

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Heme Proteins

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-Hemoglobin (oxygen transport)
-Myoglobin (oxygen transport)
-Cytochromes (electron transport --> cellular respiration)
-Catalase (H2O2 utilization)

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Porphyrin (nomenclature)

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-Roman Numerals
-Normal: Type III (and later type IX)
-In some porphryias, type I
-no others occur

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Porphyrinogens

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-have 6 mor hydrogen atoms than porphryins
-differ from porphryins in pattern of double bonds

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Clinically Significant Porphyrin

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-Uroporphyrinogens
-Coproprophyrinogens
-Proctoporphyrinogens

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Properties of Porphyrins

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-dark red/purple color
-fluorescent

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Properties of Porphyrinogens

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-colorless
-non-fluorescent
-easily auto-oxidized to porphyrins, especially in acidic solutions

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Solubility of Porphyrins

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-Depends on the number of Carboxylate groups (COO-)
-Uropophyrinogens --> 8 carboxylates (most water soluble)
-Coproporphyrinognes --> 4 carboxylates
-Proctoporphyrinogens --> 2 carboxylates (least water soluble)

-This determines the route of excretion

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Heme Metabolism Steps

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1) ALA Synthase (mitochondria)
2) ALA dehydratase (cytoplasm)
3) PBG Deaminase (cytoplasm)
4) Cosynthetase (cytoplasm)
5) Decarboxylase (cytoplasm)
6) Oxidase (mitochondria)
7) Oxidase (mitochondria)
8) Ferrochelatase (mitochondria)

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Porphyrinogen (extra information)

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-all porphyrinogens may oxidize spontaneously (lose 6 H's) to form porphyrins
-Only Protoporhyrin can go on to make heme
-Uro-1 can be converted to Copro-1, but Copro-1 can go no further

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Where is heme synthesized?

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-Takes place throughout the body
-Major sites are bone marrow (~70-80% of total)
-also in liver (~15%)

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Regulation of Heme Synthesis (Liver)

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-ALA Synthase is rate limiting
-ALA Synthase has a short half-life (~1 hr)
-ALA Synthase is regulated by [heme]
-Heme inhibits transcription of ALA synthase gene
-Heme inhibits translation of ALA synthase gene
-Heme inhibits transfer of ALA synthase to mitochondria
-Heme inhibits activity of ALA synthase

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Heme Inhibits...

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-Heme inhibits transcription of ALA synthase gene
-Heme inhibits translation of ALA synthase gene
-Heme inhibits transfer of ALA synthase to mitochondria
-Heme inhibits activity of ALA synthase

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If Heme is overproduced...

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-excess heme may be oxidized to hemin (Fe+++)
-Hemin also inhibits ALA synthase
-Hemin is used to treat some porphyrias

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Induction of Heme Synthesis (Liver)

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-ALA synthase activity is induced by many drugs, steroids, and other chemicals

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Regulation of Heme Synthesis (eurythroid cells)

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-mRNA of eurythroid ALA synthase has an iron responsive element in the 5'-untranslated region
-Hypoxia stimulates ALA synthase production
-Erythropoietin stimulates ALA synthase production
-Barbiturates, etc. have no effet on ALA syntahse in erythroid cells

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Porphryias

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-a family of diseases
-acquired or inherited
-hepatic or erythropoietic
-overproduction or accumulation of heme or heme precursors

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Porphryias (clinical manifestations)

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2 Major Clases:
-Neurological manifestations
-Photosensitivity (skin)

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Porphryias (neurological)

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Neurological Symptoms:
-Abdominal Pain
-Peripheral Neuropathy
-Mental Disturbance
-Due to overproduction of ALA or PBG

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Porphyrias (photosensitivity)

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Photosensitivity:
-high levels of porphyrins
-highly saturated porphyrin tings can absorb UV/visible light & become photoreactive

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Porphyrias (accumulation)

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-result from incomplete block of heme synthesis
-Compensatory mechanisms attempt to make more heme
-at time, intermediates may accumulate

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Drug-Induced Porphyria

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-Some drugs can induce attacks (sulfanol, sedormid, hexachlorobenzene)
-These are highly lipid soluble drugs
-These induce cytochrome p450 & up-regulate ALA synthase (hepatic)

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Acute Intermittent Porphyria (general characteristics)

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-Hepatic
-No cutaneous sensitivity
-Autosomal dominant inheritance
-DEFECT --> PBG Deaminase
-90% of heterozygotes unaffected

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Acute Intermittent Porphyria (symptoms)

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-Abdominal Pain
-Motor System Neuropathies
-Hypertension
-Psychosis (in extreme cases)
-Respiratory Paralysis (in extreme cases)

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Acute Intermittent Porphyria (induced by)

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-Drugs
-Hormones
-Metabolic & Nutritional factors

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Acute Intermittent Porphyria (treatment)

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-IV hemin (Fe+++/heme) for acute attacks
-High Carbohydrate Diet
-Glucose may inhibit overproduction of ALA synthase
-Some patients' intial attack occurs when adopting a low-carb diet

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Porphyria Cutanea Tarda (types)

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-Type I --> acquired
-Types II & III --> inherited

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Porphyria Cutanea Tarda (defect)

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-characterized by photosensitivity & cutaneous lesions
-DEFECT --> Uroporphyrinogen Decarboxylase (hepatic)
-Result --> uroporphyrinogen accumulates
-Uroporphyrinogen auto-oxidizes to uroporphyrin

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Porphyria Cutanea Tarda (general characteristics)

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-usually occurs in adults
-may be triggered by alcohol, estrogen, drugs
-may see elevated serum iron, ferritin, iron absorption, iron turnover
-treatment may include phlebotomy
-also keep patient out of sun

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Failure to Diagnose Porphyria

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-can lead to explotatory abdominal surgery with no useful findings

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Lead Intoxication

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-Lead toxicity can mimic porphyria symptoms
-Lead displaces Zn++ from ALA dehydratase --> decreased activity --> accumulation of ALA
-Lead inhibits ferrochelatase --> accumulate protoporphyrin IX

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Porphyrin lab tests could give clues about lead toxicity (protoporphyrin IX)

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-Increased protoporphyrin IX in RBC's may lead to lead toxicity
-Limitation: RBC protoporphyrin IX is also increased by iron deficiency & other iron disorders

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Porphyrin lab tests could give clues about lead toxicity (Coproporphyrin)

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-Increased coproporphyrin in urine --> used as an initial screen for lead exposure

Limitations:
-Not very quantitative, especially in early stages
-There are many other causes of coproporphyrinuria

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Porphyrin lab tests could give clues about lead toxicity (ALA)

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-Increased ALA --> used as initial screen for lead
-A good indicator of lead intoxication
-Limitation: ALA breaks down rapidly in alkaline urine

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Porphyrin lab tests could give clues about lead toxicity (ALA Dehydratase)

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-Decrease in ALA Dehydratase in RBC's
-A good quantitative indicator of lead intoxication
-Differentiates lead tox & iron deficiency
-More expensive, less routine
-"Gold Standard" in testing for lead intoxication (gives best results)

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Stages of Heme Metabolism

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1) Formation of bilirubin
2) Bilirubin transport in plasma
3) Bilirubin transport into liver cells
4) Conjugation of bilirubin
5) Bilirubin transports into bile
6) Bile --> intestine/bilirubin processing

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Where does old heme come from?

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-Most is from old/damaged RBC's (hemoglobin)
-RBC's last ~120 days
-Reticuolendothelial System --> breaks down old RBC's
-Produces 6-8 g/day of hemoglobin
-10-20% from other heme-containing proteins

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"Direct" & "Indirect" Bilirubin

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-Conjugated (direct) bilirubin is water-soluble
-Unconjugated (indirect) bilirubin is not
-BR is measured by van den Bergh reaction --> diazotized sulfanilate produces a colored product which can be measured spectophotometrically
-BR-delta is rare & weird --> covalently attached to albumin & reacts as "direct" bilirubin

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What happens to reabsorbed urobilinogens?

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-Some returns to liver
-can be re-oxidized to biliruben
-Urobilinogens & bilirubin are conjugated & return to bile (enterohepatic circulation)
-Some (~4 mg/day) is excreted in urine

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What happens to urobilinogens?

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-converted from urobilinognes to urobilins
-orange-brown pigment which gives color to feces

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Normal BR excretion

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~40-280 mg/day or urobilinogens & urobilins in feces
~0.2-3.3 mg/day of urobilinogens in urine
-No Bilirubin in urine

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Bilirubin in urine

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-normally not present
-only conjugated BR can appear in urine
-only happens when high levels of conjugated BR are in the blood

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Excess bilirubin in blood (unconjugated)

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Due To:
-Increased BR formation
-Defective liver uptake
-Defective conjugation

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Excess bilirubin in blood (conjugated)

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Due To:
-Defective transport to bile
-Bile duct blockage

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Excess bilirubin in blood (in cases of liver damage)

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-in cases of liver damage (ex. cirrhosis or hepatitis) --> may see both conjugated & unconjugated BR is plasma

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Jaundice (icterus)

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-abnormal bilirubin metabolism
-Increase in BR in blood
-Brown-yellow pigmentation of skin, sclera, & mucous membranes
-Sclera has a lot of elastin which has high affinity for BR

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Jaundice (types)

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-abnormal metabolism or retention of bilirubin
-Pre-hepatic (hemolytic)
-Hepatic (liver problems)
-Post-hepatic (bile duct block)

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Prehepatic Jaundice

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-Usually results in a hemolytic process
-Excessive RBC breakdown produces more BR than liver can handle
-Increase in indirect (unconjugated) BR in plasma
-Increase in urobilinogen in plasma & urine

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Neonatal Jaundice (characteristics)

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-Not uncommon in premature babies & some full-term babies
-May be prehepatic and/or hepatic
-Serum BR > 6 mg% (normal < 1.2)
-Above 18 mg%, risk of kernicterus (brain damage due to uptake & deposition of unconjugated & unbound bilirubin)

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Neonatal Jaundice (treatment)

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May be precipitated or worsened by some drugs:
-Salicylates (aspirin)
-Sulfonamides

Treatment:
-UV light breaks down bilirubin (phototherapy)
-Exchange transfusion

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Hepatic Jaundice

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-Liver damage (cirrhosis, hepatitis, etc.)
-Less efficient uptake of BR
-Less efficient conjugation of BR
-Less efficient uptake of urobilinogens
-Leakage of conjugated and/or unconjugated BR into blood

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Dubin-Johnson Syndrome

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-Defective transporter for conjugated BR
-Uncommon
-Benign
-Increaed conjugated BR in blood & urine (hyperbilirubinemia)

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Rotor Syndrome

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-Impaired biliary excretion of conjugated BR
-Jaundice appearing in childhood
-Autosomal recessive
-Uncommon
-Benign

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Benign Familial Cholestias

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-May be defective ATPase
-Uncommon
-Benign

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Gilbert Syndrome

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-Defective UDPG Transferase
-Usually asymptomatic
-Serum BR < 3 mg%
-Increased BR-monoglucuronide
-Benign

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Crigler-Najjar Syndrome (Type I)

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-No UDPGT
-No BR conjugation
-Neonatal kernicterus, death
-Autosomal Recessive

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Crigler-Najjar Syndrome (Type II)

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-Reduced UDPGT activity
-Jaundice, 2d-3d decade of life
-Mostly monoglucuronide in bile
-Usually benign
-Treatment: phenobarbital induces more UDPGT

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Post Hepatic Jaundice

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-Bile duct obstruction
-Decreased urobilinogen
-Increased BR (conjugated & unconjugated) in blood
-Urine: no urobilinogen, increased conjugated BR
-Feces: light brown/chalky (no urobilins)

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Hemolytic Anemia

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-excess hemolysis
-increased unconjugated bilirubin in blood
-increased conjugated bilirubin released to bile duct
-example of hyperbilirubinemia

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Hepatitis

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-increased unconjugated bilirubin in blood
-increased conjugated bilirubin in blood
-example of hyperbilirubinemia

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Biliary Duct Stone

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-increase in unconjugated bilirubin in blood
-increase in conjugated bilirubin in blood
-example of hyperbilirubinemia