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Hyperbilirubinemia

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Hyperbilirubinemia Porphyrins Porphyrins (Porphins) are cyclic tetrapyrol compounds formed by the linkage )). of four pyrrole rings through methenyl bridges (( HC In the reduced porphyrins (Porphyrinogens) the linkage of four pyrrole rings (tetrapyrol) through methylene bridges (( CH2 )) The characteristic property of porphyrins is the formation of complexes with the metal ion bound to nitrogen atoms of the pyrrole rings. e.g. Heme (iron porphyrin). Proteins which contain heme ((hemoproteins)) are widely distributed e.g. Hemoglobin, Myoglobin, Cytochromes, Catalase & Tryptophan pyrrolase. Natural porphyrins have substituent side chains on the eight hydrogen atoms numbered on the pyrrole rings. These side chains are: CH 1-Methyl-group (M)… (( 3 )) 2-Acetate-group (A)… (( CH2COOH )) 3-Propionate-group (P)… (( CH2CH2COOH )) 4-Vinyl-group (V)… (( CH CH2 )) Porphyrins with asymmetric arrangement of the side chains are classified as type III porphyrins while those with symmetric arrangement of the side chains are classified as type I porphyrins. Only types I & III are present in nature & type III series is more important because it includes heme. 1 Heme Biosynthesis Heme biosynthesis occurs through the following steps: 1-The starting reaction is the condensation between succinyl-CoA ((derived from citric acid cycle in the mitochondria)) & glycine, this reaction is a rate limiting reaction in the hepatic heme synthesis, it occurs in the mitochondria & is catalyzed by ALA synthase (Aminolevulinate synthase) enzyme in the presence of pyridoxal phosphate as a cofactor. The product of this reaction is α-amino-β-ketoadipate which is rapidly decarboxylated to form δ-aminolevulinate (ALA). 2-In the cytoplasm condensation reaction between two molecules of ALA is catalyzed by ALA dehydratase enzyme to form two molecules of water & one 2 molecule of porphobilinogen (PBG) which is a precursor of pyrrole. ALA dehydratase is a zinc-containing enzyme; it's inhibited by lead as occurred in lead poisoning. 3-Condensation of four molecules of PBG with loss of four molecules of ammonia lead to formation of linear tetrapyrrole called hydroxymethylbilane (HMB), this reaction is catalyzed by uroporphyrinogen I synthase (PBG deaminase, HMB synthase) enzyme. HMB cyclizes spontaneously to form uroporphyrinogen I or: 4- HMB converted to uroporphyrinogen III by the action of uroporphyrinogen III synthase enzyme, under normal conditions the uroporphyrinogen formed is almost exclusively the III isomer. Both of these uroporphyrinogens (I & III) contain A & P side chains & are colorless compounds, however, they readily reoxidized to their respective colored porphyrins (as in all porphyrinogens) by light with loss of six hydrogen atoms. 5-Uroporphyrinogen I & III are converted into coproporphyrinogen I & III by decarboxylation (loss of four CO2) of all of the acetate (A) groups to be converted into methyl (M) groups, this reaction is catalyzed by uroporphyrinogen decarboxylase enzyme. 6-Coproporphyrinogen III then enters the mitochondria to be converted into protoporphyrinogen III by oxidative decarboxylation of two (P) side chains into (V) side chains, this reaction is catalyzed by coproporphyrinogen oxidase enzyme, this enzyme acts only on coproporphyrinogen III, therefore, coproporphyrinogen I is not further progressed. Some times protoporphyrinogen III is also called protoporphyrinogen IX because it designated ninth in isomer. 7-Protoporphyrinogen III is oxidized into Protoporphyrin III ((loss of six hydrogen atoms), this reaction is catalyzed by protoporphyrinogen oxidase enzyme & it occurs in the mitochondria, however, this conversion can be induced by light in vitro. Some times protoporphyrin III is also called protoporphyrin IX. 8-The final step is the formation of heme by the incorporation of ferrous iron into protoporphyrin III in a reaction catalyzed by ferrochelatase (heme synthase) enzyme, this reaction occurs in the mitochondria. Heme synthesis occurs in most human cells with the exception of mature RBC because does not contain mitochondria, however, about 85% of heme synthesis occurs in erythroid precursors cells in the bone marrow to form hemoglobin & the majority of the remainder in the hepatocytes to form other hemoproteins mainly cytochrome P450. 3 ALA Synthase {ALAS} Two main forms: 1-Hepatic((ALAS 1)).. It is a regulatory (rate limiting) enzyme in the hepatic heme synthesis, heme acting as a negative regulator for this enzyme. Many drugs are porphyrogenic as barbiturates which can result in a marked increase of ALAS 1 activity by utilizing cytochrome P450 which in turn reduces the intracellular heme concentration lead to the activation of ALAS 1. Other factors can result in marked decrease of ALAS 1 activity as: A-Excess glucose which cause reduction of fat burn in which toxins are stored, therefore, excess glucose reduces toxin release so that the consumption of cytochrome P450 is reduced. B- Hematin (oxidized form of heme) leads to increase of intracellular heme concentration result in marked decrease of ALAS 1 activity. 2-Erythroid((ALAS 2)).. Its regulation is differ from that of ((ALAS 1)), therefore, it is not affected by drugs & does not undergoes feedback regulation by heme. 4 5 Properties of Porphyrins 1-The various porphyrinogens are colorless, where as the various porphyrins are colored because it contains double bonds joining pyrrole rings which is absent in porphyrinogens, therefore, all porphyrins ((in 5% HCl)) but not porphyrinogens have a significant sharp absorbance band near 400 nm wavelength, this band is called Soret band ((discovered by the French physicist; Charles Soret)) 2-When porphyrins is dissolved in strong mineral acids or in organic solvents & illuminated by ultraviolet light, they emit a strong red fluorescence because it contains double bonds joining pyrrole rings while porphyrinogens (because of absence of double bonds joining pyrrole rings) they have no fluorescence. 3-Coproporphyrins, uroporphyrins & protoporphyrins are of clinical importance because they are excreted in increased amounts in the porphyrias, these compounds when present in feces and/or urine; can be extracted & quantified using spectrophotometric methods. Generally uroporphyrins are present in urine; coproporphyrins are present in urine & feces while protoporphyrins are present in feces. 4-ALA & PBG can measured in urine by colorimetric method. Porphyrias Porphyrias are group of disorders due to abnormalities of the heme biosynthesis pathway, they can be genetic or acquired. They are not prevalent; however, their importance lies in the differential diagnosis of certain clinical presentations as abdominal pain, neuropsychiatric & dermatological findings. Seven types of genetic porphyrias were found according to enzyme involved: 6 Individuals with low activity of ALAS 2 develop anemia (not porphyria), inherited as X-linked condition. Low activity of ALA dehydratase is very rare while the remaining is more common. Generally porphyria is inherited as autosomal dominant except congenital erythropoietic porphyria is inherited as autosomal recessive. Clinical Features of Porphyria The clinical features of porphyria can result from a deficiency of metabolic products beyond the enzymatic block and/or from accumulation of metabolites before the block, the main clinical features are some or all of the followings: 1- Abdominal pain & neuropsychiatric presentations; It occurs mainly in acute intermittent porphyria. The exact biochemical cause of these symptoms has not been determined yet, however, probably may relate to elevated levels of ALA or PBG and /or deficiency of heme. 2- Photosensitivity; It occurs when porphyrinogens (as uroporphyrinogen, coproporphyrinogen & protoporphyrinogen) are accumulated ((as in porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria & protoporphyria)) which undergo oxidation on exposure to light into corresponding porphyrins which are exited on exposure to visible light of wave length 400 nm, these excited porphyrins react with molecular oxygen to form oxygen radicals which damage lysosomes causing release of their lysosomal enzymes that cause photosensitivity. 7 Classifications of Porphyrias *I-According to organs that are mostly affected: A-Erythropoietic porphyrias: heme synthesis in the bone marrow was affected as in congenital erythropoietic porphyria & protoporphyria. B-Hepatic porphyrias: heme synthesis in the liver was affected as in ALA dehydratase deficient porphyria, acute intermittent porphyria, porphyria cutanea tarda, hereditary coproporphyria & variegates porphyria. *II-According to clinical presentations: A-Acute porphyrias: Patient presented with abdominal pain & neuropsychiatric symptoms. B-Cutaneous porphyrias: Patient presented with photosensitivity. C-Latent porphyrias: Patient is relatively symptoms-free between the attacks. *III-According to cause: A-Genetic porphyrias: Inherited as autosomal dominant except congenital erythropoietic porphyria is inherited as autosomal recessive. B-Acquired porphyrias: as in lead poisoning can affect ALA dehydratase. 8 Diagnosis of Porphyrias 1-Clinical & family history. 2-Physical examination. 3-Laboratory tests include: A-Measure enzyme activity in blood. B-Urine test for uroporphyrins & coproporphyrins. C-Stool test for protoporphyrins. D-Urine test for ALA & PBG. Treatment of Porphyrias 1-Gene therapy. 2-Avoid porphyrogenic drugs as barbiturates. 3- Administration of excess glucose & hematin that cause block of ALAS1. 4-Administration of β-carotene which
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