Porphyrias and Sideroblastic Anemia (Koshy) PDF

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Porphyrias and Sideroblastic Anemia (Koshy) Porphyrias Clinical Presentation and Enzyme Deficiencies Urine/feces turns purple/red when exposed to light Inherited disorders due to abnormality of heme synthesis enzymes Acute (Hepatic) Porphyrias  Neurovisceral Attacks (severe abdominal pain, V, tachycardia, htn, peripheral neuropathy (can cause paralysis), seizure, psychiatric features) o Neuronal toxicity from buildup of ALA (first step) Clinical features depend on where the block in pathway occurs; end result = accumulation of heme precursors or porphyrins Late complications: chronic pain, hepatocellular carcinoma, chronic renal failure ***Acute Intermittent Porphyria (AIP) o Deficiency of hydroxymethylbilane synthase o  hyponatremia o Alcohol and oral contraceptives induce ALA synthetase  exacerbates disease o Treatment: hemin to inhibit ALA synthetase o Prevent future attacks by withdrawing offending substances Variegate Porphyria (VP) o Deficiency in protoporphyrinogen oxidase o Common in S. Africa and Dutch ancestry o  psych issues and/or skin lesions (different from cutaneous versions bc there are also neuro symptoms o Diagnosis: fecal protoporphyrins Hereditary Coproporphyria (DCP) o Mutation in coproporphyrinogen oxidase Delta Aminolevulinic acid dehydratase deficiency porphyria (ADP) - rarest o Deficiency in d-ALA dehydratase o Pb  attack due to inhibition of ALA dehydratase Cutaneous (Erythropoetic) Porphyrias  Photosensitive Skin Lesions ***Porphyria Cutanea Tarda o Disease of older people; acquired (only 20% genetic) o Uroporphyrinogen decarboxylase deficiency o No abd pain or neurovisceral attacks – only skin sx o Strong association with Hep C o Fe overload  hepatocellular carcinoma Erythropoietic Protoporphyria o Deficiency of ferrochelatase (last enzyme of heme synthesis pathway) o Can be induced by Pb poisoning o Mitochondrial enzyme Congenital Erythropoietic Porphyria o Deficiency of uroporphyrinogen III cosynthase o  brown teeth, splenomegaly from hemolysis o Start in infancy/childhood (“congenital”) o Diagnosis from reddish color of urine, stains diapers X-Linked Protoporphyria

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GAIN of function of ALAS2 gene (1st enzyme in heme synthesis)  Different from x-linked SA, which is loss of function

Heme’s Role in Body Fe atom in center of tetrapyrrole ring Functions: o Hb (O2 transport) o Myoglobin (O2 storage) o Cytochrome enzymes (e- transport) – in liver, important for metabolism o Catalase – prevent oxidative destruction of cells o NO synthase – vasodilation General Heme Biosynthesis Pathway and Heme Regulation Location: begins in mitochondria, goes into cytoplasm, then goes back into mitochondria to finish First Step: Gly + Succinyl CoA  ALA using ALA synthase (ALAS) o (build-up  neuro effects of acute porphyrias) o Gain of function of ALAS2 gene  X-linked protoporphyria Last Step: protoporphyrin IX + Fe  Heme using ferrochetalse o Deficiency of this enzyme  erythropoietic protoporphyria Majority takes place in bone marrow – used to make Hb o Regulation: Fe induces heme synthesis pathway The rest is made in liver (cytochrome P450 enzymes) o Regulation: Heme dec heme synthesis pathway Main Triggers for Porphyria Attacks Acute: o Drugs (barbituates, TB meds – isoniazid) o Pb poisoning  basophilic stippling o Alcohol o Hormonal changes o Fasting o Stress Laboratory Workup for Porphyrias Acute 1st line: urine porphobilinogen (protected from light) 2nd line (to establish type): total urine/fecal porphyrin Treatment for Porphyrias Remove precipitating factors Treat pain (often present with severe abd pain) – opioids Administration of IV hemin (dec ALA synthase in liver) Dextrose

Normal protoporphyrin IX levels (distinguish between this and porphyria – decreased protoporphyrin IX levels (near end of pathway)  Myelodysplastic Syndrome: neoplastic stem cell disease characterized by cytopenias, dysplasia, and risk of AML  PBS/BM: hypoblated/hypogranular neutrophils, dysplasia in erythroid precursor, ringed sideroblasts Pyridoxine Deficiency Pb Poisoning Copper Deficiency  Treatment: reverse with Cu supplements  excess zine (supplements, denture crema containing zinc) – activates metal-binding protein, which bind Copper (2ndary def) Medications:  Isoniazid – interferes with B6 metabolism  Treatment: stop offending medication Excess Alcohol – reversible 

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Sideroblastic Anemia (SA) Common Acquired and Congenital Causes of SA and Their Sx Group of disorders that result from defects involving incorporation of Fe into heme molecule  abnormal accumulation of iron in immature RBC (ringed sideroblasts) Clinical Presentation: o Microcytic hypochromic anemia o Dimorphic RBC on PBS (microcytic and normocytic) o Fe overload o Bone marrow has ringed sideroblasts

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Congenital: o X-Linked Sideroblastic Anemia  Associated with ALAS2 gene  Treatment: pyridoxine (vitamin B6)  Most common congenital cause  LOSS of function of ALAS2 (specific to BM RBC) – requires vitamin B6 as a cofactor  Different from x-linked protoporphyria – gain of function  Associated with Fe overload o X-Linked Sideroblastic Anemia with Ataxia  Associated with mutation in ABCB7 gene  Clinical presentation: motor delay and evidence of spinocerebellar dysfunction  Not associated with Fe overload – will not see ringed sideroblasts Acquired o Clonal (Neoplastic) Myelodysplastic Syndrome

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Diagnosis of SA CBC/BM Findings: o Microcytic, hypochromic anemia o Increased serum transferrin saturation and serum ferritin o Definitive diagnosis from Fe-stained BM smears that show ringed sideroblasts Define and ID Ringed Sideroblastic Sideroblast: abnormal accumulation of Fe in immature RBC in bone marrow; 5+ Fe granules encircling at least 1/3 of nucleus o Fe located in the MITOCHONDRIA o Must do iron stain to see this

Mnemonic for Microcytic Anemias TAILS: thalassemia, ACD, IDA, Lead poisoning, SA...