Porphyrias: a review and case report. Anemia MCV=HCT/RBC 80-100 100 Microcytic Sudden massive blood lose Marrow failure hemolysis Megaloblastic anemia

Porphyrias: a review and case report

Anemia

MCV=HCT/RBC

80-100<80 >100

Microcytic Sudden massive blood loseMarrow failure hemolysis

Megaloblastic anemiaSpurious macrocytic anemia

Microcytic anemia

Defect in hemoglobin synthesis

3-dimensional structure of hemoglobin. The four subunits are shown in red and yellow, and the heme groups in green.

Microcytic anemia

Defect in hemoglobin sythesis

Iron binding capacityLow or normal High

High Low or normalIron

Iron deficiencyDefect in:Porphyrin synthesisHeme synthesisGlobin synthesis

Defect in:Porphyrin synthesisHeme synthesisGlobin synthesis

Hemoglobin electrophoresis

AbnormalNormal

Defect in:Porphyrin synthesisHeme synthesis

Defect in:Globin synthesis

Quantitative QualitativeBoth

Thalassemia Sickle-thal S,C,F,ect

Heme

Non-erythroid Erythroid

Haemoproteins Haemoglobin

Electron transfer and energy trapping

myoglobin Cytochromes Others

Porphyrins synthesis

URO ISpontaneous

COPRO I

Mitochondrion Cytosol

ALA synthase

D-ALA

ALA dehydrase

PBG deaminase

Hydroxymethylbilane

NH2-CH2-COOH+

Glycine

PBG

Water-solubleExcreted in urine


Hydroxymethylbilane

Uroporphyrinogen III

URO I

URO III synthase Spontaneous

Coproporphyrinogen III

COPRO I

URO III decarboxylase

Less water-solubleExcreted in urine/feces


CORPO III

Protoporphyrinogen IX

COPRO oxidase

PROTO oxidase

Protoporphyrin IX

FerrochelataseHeme

Poor water-solubilityExcreted in feces

Acute Porphyrias Acute Intermittent Porphyria

Variegate Porphyria

Hereditary Coproporphyria

Porphyria Cutanea Tarda

Congenital Erythropietic Porphyria

Non-acute Porphyrias

ALAD Deficiency Porphyria

Secondary Porphyrias

Lead Poisoning

Iron Deficiency

Coproporphyrinuria

Glycine +Succinyl CoA

ALA synthase

ALAALA dehydrase

PBGPBG deaminase

Hydroxymethylbilane

URO III URO I


COPRO IIICOPRO I

PROTO IX

COPRO oxidase


PROTO oxidase

Protoporphyrin IX

Ferrochelatase

Heme

Erythropoietic Protoporphyria

(NeurologicalPorphyrias)

(CutaneousPorphyrias)

(Unstable)

Main Types of Porphyria

Main Types of Porphyria

Acute Porphyrias

Acute Intermittent Porphyria

Variegate Porphyria







Lead Poisoning

Iron Deficiency

Coproporphyrinuria


(NeurologicalPorphyrias)

(CutaneousPorphyrias)

InheritanceTissue expression

Liver

Erythroid cells

E , L

Autosomal recessive

Liver

Liver

Liver

Liver

Autosomal dominant

Autosomal dominant

Autosomal dominant

Autosomal dominant

Autosomal dominant

Autosomal recessive


Variegate Porphyria







Lead Poisoning

Iron Deficiency

Coproporphyrinuria


ALA synthase

ALAALA dehydrase

PBGPBG deaminase

Hydroxymethylbilane

URO III URO I


COPRO IIICOPRO I

PROTO IX

COPRO oxidase


PROTO oxidase

Protoporphyrin IX

Ferrochelatase

Heme

urine



Variegate Porphyria







Lead Poisoning

Iron Deficiency

Coproporphyrinuria


ALA synthase

ALAALA dehydrase

PBGPBG deaminase

Hydroxymethylbilane

URO III URO I


COPRO IIICOPRO I

PROTO IX

COPRO oxidase


PROTO oxidase

Protoporphyrin IX

Ferrochelatase

Heme

urine

urine

Erythropoietic Protoporphyria urine


Variegate Porphyria







Lead Poisoning

Iron Deficiency

Coproporphyrinuria


ALA synthase

ALAALA dehydrase

PBGPBG deaminase

Hydroxymethylbilane

URO III URO I


COPRO IIICOPRO I

PROTO IX

COPRO oxidase

URO IIIdecarboxylase

PROTO oxidase

Protoporphyrin IX

Ferrochelatase

Heme

urine

urine


Urinefeces

urine


Variegate Porphyria







Lead Poisoning

Iron Deficiency

Coproporphyrinuria


ALA synthase

ALAALA dehydrase

PBGPBG deaminase

Hydroxymethylbilane

URO III URO I


COPRO IIICOPRO I

PROTO IX

COPRO oxidase


PROTO oxidase

Protoporphyrin IX

Ferrochelatase

Heme

urine

urine


Urinefeces

feces

urine


Variegate Porphyria



Congenital Erythropietic PorphyriaNon-acute Porphyrias



Lead Poisoning

Iron Deficiency

Coproporphyrinuria


ALA synthase

ALAALA dehydrase

PBGPBG deaminase

Hydroxymethylbilane

URO III URO I


COPRO IIICOPRO I

PROTO IX

COPRO oxidase


PROTO oxidase

Protoporphyrin IX

Ferrochelatase

Heme


Urine

UrineFeces


Variegate Porphyria






Lead Poisoning

Iron Deficiency

Coproporphyrinuria


ALA synthase

ALAALA dehydrase

PBGPBG deaminase

Hydroxymethylbilane

URO III URO I


COPRO IIICOPRO I

PROTO IX

COPRO oxidase


PROTO oxidase

Protoporphyrin IX

Ferrochelatase

Heme


urine Urine

UrineFeces


Variegate Porphyria






Lead Poisoning

Iron Deficiency

Coproporphyrinuria


ALA synthase

ALAALA dehydrase

PBGPBG deaminase

Hydroxymethylbilane

URO III URO I


COPRO IIICOPRO I

PROTO IX

COPRO oxidase


PROTO oxidase

Protoporphyrin IX

Ferrochelatase

Heme


Feces

Feces


Variegate Porphyria






Lead Poisoning

Iron Deficiency

Coproporphyrinuria


ALA synthase

ALAALA dehydrase

PBGPBG deaminase

Hydroxymethylbilane

URO III URO I


COPRO IIICOPRO I

PROTO IX

COPRO oxidase


PROTO oxidase

Protoporphyrin IX

Ferrochelatase

Heme


Feces

Feces

urine

UrineFeces

Zn-protoporphyrin


Variegate Porphyria






Lead Poisoning

Iron Deficiency

Coproporphyrinuria


ALA synthase

ALAALA dehydrase

PBGPBG deaminase

Hydroxymethylbilane

URO III URO I


COPRO IIICOPRO I

PROTO IX

COPRO oxidase


PROTO oxidase

Protoporphyrin IX

Ferrochelatase

Heme


Zn-protoporphyrin

Hepatic Porphyrias (normal RBC Porphyrins) Erythropoietic Porphyrias ( RBC Porphyrins)

Acute Intermittent Porphyria (AIP) Congenital Erythropoietic Porphyria (CEP)

Variegate porphyria (VP) Erythropoietic Protoporphyria (EP)

Hereditary Coproporphyria (HCP)

Porphyria Cutanea Tarda (PCT)

Sunnybrook Health Sciences Center Sampling Guide

Presentation: Porphyrias Tests to order Sample

Acute symptoms AIP 1. Urine Porphyrin Precursors Screen & Quantitation Random (50 ml) or 24-h with Tartaric acid

Acute symptoms + skin lesions (may occur independently)

VPHCP

2. Feces Porphyrins Screen & Quantitation Random

Skin lesions PCTCEPEP

1. Urine Porphyrin Precursors Screen & Quantitation2. Feces Porphyrins Screen & Quantitation3. Urine Porphyrins Screen & Quantitation4. RBC Porphyrins Screen & Quantitation

Random (50 ml) or 24-h with Tartaric acidRandom Random (50 ml) or 24-h with Na2CO3Lavender-top (EDTA) blood; need Hct

Notes:At time of acute attack:1. Collect a random urine sample first (50 ml with no preservatives), before attempting to collect a 24-h sample. 2. Request "Porphyrin Precursors" (ALA & PBG) instead of "Porphyrins" screen and quantitation. The Laboratory will have to adjust pH to 4-6 for "Porphyrin Precursors", but pH 8-10 for "Porphyrins". - The commonest problem causing confusion!3. All sample containers should be covered with tin foil to shield off from light.

Test Name Specimen Type Search / Alternate Name

Porphyrin Precursors (ALA & PBG)

Urine (24h) ALA,Aminolevulinic Acid,PBG,Porphobilinogen, -ALA, -aminolevulinic Acid

Porphyrin Precursors (ALA & PBG)

Urine (Random) ALA,Aminolevulinic Acid,PBG, -ALA,Porphobilinogen

Porphyrins: Quantitation

Urine (24h) Uroporphyrin,Heptacarboxylic Acid,Hexacarboxylic Acid,Pentacarboxylic Acid,Coproporphyrin


Urine (Random) Uroporphyrin,Heptacarboxylic Acid,Hexacarboxylic Acid,Pentacarboxylic Acid,Coproporphyrin


Whole blood (EDTA)

Free Protoporphyrin,Protoporphyrin - Free


Feces (Random) Coproporphyrin,Uroporphyrin,Heptacarboxylic Acid,Hexacarboxylic Acid,Pentacarboxylic Acid,Deuteroporphyrin,Mesoporphyrin,Protoporphyrin


Plasma (EDTA or Heparin)

Uroporphyrin,Heptacarboxylic Acid,Hexacarboxylic Acid,Pentacarboxylic Acid,Coproporphyrin

Bio-Rad Column

HPLC

Porphyrin assays provided through HICL

Isocoproporphyrin

Not Available - See Note.

Porphobilinogen Deaminase

Whole blood (Heparin)

Uroporphyrinogen 1 Synthetase,HMB,Hydroxymethylbilane Synthase

Porphyrins: Screen

Urine (24h)

Porphyrins: Screen

Feces (Random)

Porphyrins: Screen

Urine (Random)

Zinc Protoporphyrin

Whole blood (Heparin)

ZPP,Metal

ICP-MS Lead

Whole blood (heparin)

Pb,Zinc Protoporphyrin,ZPP,Metal

Enzymatic

Spectrophometric Screening

CASE

A boy, average hematologic parameters over the subsequent 3 years were as follows:

Defect in:Porphyrin synthesisHeme synthesisGlobin synthesis

microcytic

Iron studies were unremarkable →

Hemoglobin (Hb) level, 70.0 g/L;

Mean corpuscular volume (MCV), 67 fL →

Mean corpuscular hemoglobin level, consistently < 20 pg;

Reticulocyte counts ranged from 3.6% to 6.7%;

A physical examination revealed scars on the face, hands, and forearms. → photosensitive bullous dermatosis

A 50-mL urine sample contained 2003 ug uroporphyrin (normal, trace); 92% of this was uro-I. → CEP

The diapers exhibited brilliant pink fluorescence when illuminated with long-range ultraviolet light. → Photosensitive porphyrin rings

Fluorescent red cells were detected using a microscope fitted with a 405 nm light source. → CEP or EP

Erythrocyte UROS activity was 21% of the normal mean. Collectively, these findings confirmed the diagnosis of CEP.

Erythrocyte UROS activity was normal in both parents, an unexpected finding as obligate carriers (heterozygotes) for UROS mutations generally have half-normal enzymatic activity.

UROS was sequenced, and no mutations or deletions were found in thechild or the parents.

A GATA1 point mutation was found in the child at codon 216, changing arginine to tryptophan (R216W), as well as on 1 of the 2 GATA1 alleles of his mother and maternal grandmother.

GATA1 gene, at Xp11.23, encodes a transcription factor, GATA bindingfactor 1 (GATA-1), that is critical for normal erythropoiesis, globingene expression, and megakaryocyte development.

GATA-1 also regulates expression of UROS in developing erythrocytes.

General Symptomology: __Abdominal pain___Abdominal tenderness___Loss of appetite___Nausea___Vomiting___Constipation___Carbohydrate craving___Breast secretions___Diarrhea___Partial ileus [Intestinal blockage]___Abdominal distention___Dysuria [Painful Urination]___Bladder Dysfunction___Urinary Retention___Amenorrhea [Lack of menses]

Physical Findings of Acute Attack__Red or dark urine___Tachycardia [Pulse] >100___Labile hypertension >90 diastolic [blood pressure]___Fever [Pyrexia]___Profused sweating___Edema [Retention of fluids] [Swelling]___Postural Hypotension [Low Blood Pressure]___Hypertrichosis [excessive body hair growth]___Hyperpigmentation [skin coloring]

Neurological Symptoms of Acute Attack[Peripheral manifestations]

___Peripheral neuropathy___Muscle weakness___Paresis . paralysis___Sensory disorde___Respiratory paralysis___Foot drop___Wrist drop___Abnormal Gait___Pain: Arms, legs, hips and/or lower back___Loss of sensation___Dyesthesia ___Numbness ___Tingling ___Burning Sensation___Bulbar paresis ___Tongue paralization ___Mouth paralization ___Throat paralization

[Cerebral manifestations]

___Behavorial change___Anxiety___Irritability___Delirium___Depression___Confusion___Hallucination___Insomnia___ANS [altered neurological state]___Restlessness___Sensory loss___Seizure___Depressed or absent tendon reflexes___Cranial nerve involvement

Hematology/Blood Chemistry

___Hyponatremia [Below normal sodium level] <130___Increased Bun [Urea Nitrogen]___Increased AST [Aspartate Aminotransferase]___Elevated Alkaline Phosphatase [Liver panel test]___Increased ALT [Aspartate Aminotransferase]___Hypokalemia [Below normal potassium level]___Leukocytosis [Abnormal increase in WBC] > 10,000___Increased ESR >22___Hypochloremia < 90 [A decrease in the chloride level]___Anemia [Iron deficiency]

Cutaneous manifestations

___Skin photosensitivity___Blistering___Severe Tissue Scarring___Increased Hair growth___Pigmentation Darkening___Thickening of skin___Severe Itching

Special lab studies

___Decreased blood volume___EEG abnormalities___Electromyographic abnormalities___Muscle denervation___Decreased nerve conduction velocity___Abnormal CSF___Increased fibrillation potential

Documents

Porphyrias: a review and case report. Anemia MCV=HCT/RBC 80-100 100 Microcytic Sudden massive blood lose Marrow failure hemolysis Megaloblastic anemia