Heme Synthesis and the Pathology thereof is herein narrated and skillfully illustrated. 1) Acute Intermittent Porphyria (Autosomal Dominant) Congenital Developmental Disease of Metabolism lacks the Porphobilinogen Deaminase enzyme (aka Hydroxymethylbilane Synthase [HMBS]); while 2) Porphyria Cutanea Tarda (PCT) also an Autosomal Dominant Metabolic Disease of Heme Synthesis lacks the enzyme Uroporphyrinogen III Decarboxylase (UROD). Heme Synthesis (Occurs in most Cells, Erythroid Cells and Hepatocytes predominantly) involves the following reactions: 1) In the Mitochondrion, Succinyl Coenzyme A along with Amino Acid Glycine become Delta Aminolevulinic Acid (D-ALA) by catalyst reaction of Delta Aminolevulinic Acid Synthease (D-ALAS; Rate Limiting Enzyme of Heme Synthesis) and Cofactor Pyridoxine (Vitamin B6). 2) In the Cytoplasm, D-ALA reacts along with Aminolevulinic Acid Dehydratase to Synthesize Porphobilinogen (PBG); 3) Reaction of PBG with PBG Deaminase to yield Hydroxymethylbilane (HMB), a linear tetrapyrrole which in turn goes to 4) Uroporphyrinogen III (UP III) via UP III Synthase; thereafter 5) Coproporphyrinogen-III (CP III) via UP III Decarboxylase (UROD); 6) Into the Mitochondrion to Uroporphyrinogen III; to 7) Protoporphyrin IX along with Iron (Fe) in reaction with Ferrochelatase; to 8) Heme. It is useful to understand Heme Regulation or Feedback Mechanism of Heme Synthesis are Glucose and understandably Heme Molecule itself along with Hemin. The Symptomatology of AIP are Acute attacks marked by 1) Colicky Abdominal Pain; 2) Motor Weakness (Myasthenia); and Psychiatric Signs (Depression and Bipolar Disorder). Medications and Stressors (e.g. Surgery, Diet) can precipitate the reaction. Diagnosis is via Urinalysis where PBG and D-ALA will be Elevated because of the absence PBG Deaminase (Port Wine Discoloration is Diagnostic). Treatment involves Glucose and Heme administration. Biologics are also useful to cease the Porphyrin synthesis. In PCT, because Uroporphyrinogen III Decarboxylase is absent Uroporphyrinogen III will be Elevated in a Urinalysis. Clinical Presentation of the Subject would be Blisters and Erosions on Sun-exposed Skin and the characteristic Port Red Wine Urine. Alcohol can exacerbate this reaction. The Treatment is Phlebotomy to decrease Iron (Fe) and Porphyrins. Antimalarial Medication as in Hydrochloroquine has been used for PTC. Lead Poisoning Inhibits (Ferrochelatase and D-ALA Deaminase) in Heme Synthasis manifesting acutely as 1) Abdominal Pain, 2) Weakness, 3) Neuropathy (Foot/Wrist Drop), and 4) Renal Failure; while chronically has 1) only mild acute symptoms, 2) Sideroblastic Anemia (Morphology of Basophilic Stippling on PBS), 3) Metaphyseal Growth Plate Lines on Imaging, 4) and Clinically Burton's Lines (Gingival Discoloration); Laboratory will show Serum Levels of Lead and CBC will indicate Microcytic and Hypochromic Anemia. First Line Treatment of Lead Poisoning is oral Succimer; Chelation if Lead is greater than 45 Micrograms per Deciliter (>45 ug/dL); if Severe Heavy Metal Chelation with Dimercaprol and Iron/Calcium Binder Ethylenediaminetetraacetic acid (EDTA). Goodness. A subject taking monoatomic Gold as a Aging therapy was misdiagnosed as Lead Poisoning because of Abdominal Pain and Weakness. Dimercaprol was therapeutic however......Just Kidding. MD Paul Bolin, du bist gut und gesund in Blut, mein Bruder. Prost!
Very nice. thank you. There seems to be an error in the last statement on lead poisoning. Lead inhibit d-ALA dehydratase and not synthase according to an earlier statement in the presentation, overall a lovely teaching.
Heme Synthesis and the Pathology thereof is herein narrated and skillfully illustrated. 1) Acute Intermittent Porphyria (Autosomal Dominant) Congenital Developmental Disease of Metabolism lacks the Porphobilinogen Deaminase enzyme (aka Hydroxymethylbilane Synthase [HMBS]); while 2) Porphyria Cutanea Tarda (PCT) also an Autosomal Dominant Metabolic Disease of Heme Synthesis lacks the enzyme Uroporphyrinogen III Decarboxylase (UROD). Heme Synthesis (Occurs in most Cells, Erythroid Cells and Hepatocytes predominantly) involves the following reactions: 1) In the Mitochondrion, Succinyl Coenzyme A along with Amino Acid Glycine become Delta Aminolevulinic Acid (D-ALA) by catalyst reaction of Delta Aminolevulinic Acid Synthease (D-ALAS; Rate Limiting Enzyme of Heme Synthesis) and Cofactor Pyridoxine (Vitamin B6). 2) In the Cytoplasm, D-ALA reacts along with Aminolevulinic Acid Dehydratase to Synthesize Porphobilinogen (PBG); 3) Reaction of PBG with PBG Deaminase to yield Hydroxymethylbilane (HMB), a linear tetrapyrrole which in turn goes to 4) Uroporphyrinogen III (UP III) via UP III Synthase; thereafter 5) Coproporphyrinogen-III (CP III) via UP III Decarboxylase (UROD); 6) Into the Mitochondrion to Uroporphyrinogen III; to 7) Protoporphyrin IX along with Iron (Fe) in reaction with Ferrochelatase; to 8) Heme. It is useful to understand Heme Regulation or Feedback Mechanism of Heme Synthesis are Glucose and understandably Heme Molecule itself along with Hemin. The Symptomatology of AIP are Acute attacks marked by 1) Colicky Abdominal Pain; 2) Motor Weakness (Myasthenia); and Psychiatric Signs (Depression and Bipolar Disorder). Medications and Stressors (e.g. Surgery, Diet) can precipitate the reaction. Diagnosis is via Urinalysis where PBG and D-ALA will be Elevated because of the absence PBG Deaminase (Port Wine Discoloration is Diagnostic). Treatment involves Glucose and Heme administration. Biologics are also useful to cease the Porphyrin synthesis. In PCT, because Uroporphyrinogen III Decarboxylase is absent Uroporphyrinogen III will be Elevated in a Urinalysis. Clinical Presentation of the Subject would be Blisters and Erosions on Sun-exposed Skin and the characteristic Port Red Wine Urine. Alcohol can exacerbate this reaction. The Treatment is Phlebotomy to decrease Iron (Fe) and Porphyrins. Antimalarial Medication as in Hydrochloroquine has been used for PTC. Lead Poisoning Inhibits (Ferrochelatase and D-ALA Deaminase) in Heme Synthasis manifesting acutely as 1) Abdominal Pain, 2) Weakness, 3) Neuropathy (Foot/Wrist Drop), and 4) Renal Failure; while chronically has 1) only mild acute symptoms, 2) Sideroblastic Anemia (Morphology of Basophilic Stippling on PBS), 3) Metaphyseal Growth Plate Lines on Imaging, 4) and Clinically Burton's Lines (Gingival Discoloration); Laboratory will show Serum Levels of Lead and CBC will indicate Microcytic and Hypochromic Anemia. First Line Treatment of Lead Poisoning is oral Succimer; Chelation if Lead is greater than 45 Micrograms per Deciliter (>45 ug/dL); if Severe Heavy Metal Chelation with Dimercaprol and Iron/Calcium Binder Ethylenediaminetetraacetic acid (EDTA). Goodness. A subject taking monoatomic Gold as a Aging therapy was misdiagnosed as Lead Poisoning because of Abdominal Pain and Weakness. Dimercaprol was therapeutic however......Just Kidding. MD Paul Bolin, du bist gut und gesund in Blut, mein Bruder. Prost!
Very nice. thank you. There seems to be an error in the last statement on lead poisoning. Lead inhibit d-ALA dehydratase and not synthase according to an earlier statement in the presentation, overall a lovely teaching.
Excellent presentation
This is outstanding presentation
Thank you
Omg a new one. Thanx