Disorders of Porphyrin Metabolism Flashcards
What are the functions of heme in the body?
- Hb — oxygen transport
- Myoglobin — oxygen storage in skeletal muscle
- Cytochrome — catalyzes oxidative processes
- Catalase — breakdown of peroxidase
Describe the heme/porphyrin synthesis pathway. What are the major sites of porphyrin/heme synthesis?
- Synthesis of porphyrin ring
- Modification of side chains on porphyrin ring
- Insertion of iron into porphyrin ring
- Heme, the end product, acts in a -ve feedback
mechanisms to inhibit ALA synthase activity
- Heme, the end product, acts in a -ve feedback
➔ Major sites of porphyrin/heme synthesis are liver and bone marrow
List the 3 main porphyrins and their relative solubilities in water.
- Uroporphyrin — water soluble
➔ 8 COOH gps
➔ excreted in urine - Coproporphyrin — slightly water soluble
➔ 4 COOH gps
➔ excreted in urine/feces - Protoporphyrin — not water soluble
➔ 2 COOH gps
➔ excreted in feces
Name the 8 porphyria types and their associated enzyme defects.
- X-linked dominant protoporphyria
➔ ALA Synthase - ALA Dehydratase deficiency porphyria
➔ ALA dehydratase - Acute Intermittent porphyria (AIP)
➔ PBG Deaminase - Congenital Erythropoietic Porphyria (CEP)
➔ Uroporphyrinogen synthase - Porphyria Cutanea Tarda (PCT)
➔ Uroporphyrinogen decarboxylase - Hereditary Coproporphyria (HCP)
➔ Coproporphyrinogen oxidase - Variegate Porphyria (VP)
➔ Protoporphyrinogen oxidase - Erythropoietic Protoporphyria (EPP)
➔ Ferrochelatase
Classify porphyrias into neurological vs cutaneous.
Neurologic Porphyrias (Porphyrin precursors)
— ALA/PBG are neurotoxic
1. ALA Dehydratase Deficiency Porphyria
2. Acute Intermittent Porphyria (AIP)
Cutaneous Porphyrias (Porphyrins)
— Porphyrins absorb light ➔ become excited ➔ form free radicals (toxic)
1. X-linked Dominant Protoporphyria
2. Congenital Erythropoietic Porphyria (CEP)
3. Porphyria Cutanea Tarda (PCT)
4. Erythropoietic Protoporphyria (EPP)
Both
1. Hereditary Coproporphyria (HCP)
2. Variegate Porphyria (VP)
Arrange the neurological porphyrias by frequency. Who are they more common in and why? What are the 3 precipitants and 3 clinical features?
Frequency
AIP > VP > HCP
- More common in female, peak 30s/40s — hormonal factors
- acute attacks separated by periods of complete remission
- attack precipitated by
1. drugs
2. hormonal factors
3. stress
Symptoms
- Abdominal pain
- Tachycardia
- Chronic complications ➔ risk of liver cancer, renal impairment
What are the characteristics of porphyria cutanea tarda?
- Most common of all porphyrias
- Usually presents in adulthood
- Deficiency of uroprophyrinogen decarboxylase
→ Accumulation of uroporphyrins and 7-COOH porphyrins
2 types
1. Type 1 - Sporadic (80%)
→ defect in liver only
2. Type 2 - Familial (20%)
→ defect in all tissues
Mutations in both uroporphyrinogen decarboxylase genes lead to a rare variant called hepatoerythropoeitic porphyria → presents similar to CEP
What is the diagnosis of neurological porphyrias?
- High PBG (and ALA) in a random urine sample collected during an acute attack
- If PBG/ALA levels are normal, then all neurological porphyrias are ruled out
How to treat neurological porphyrias?
During Acute Attack
1. IV heme therapy → Decrease ALA synthase activity
2. Opiates → pain relief
3. Antiemetics → nausea/vomiting
4. Maintain fluid/electrolyte balance
5. IV glucose to avoid fasting & decrease ALA synthase activity
General Measures
1. Screen family members
2. Liver transplantation
3. Only prescribe drugs known to be non-porphyrinogenic
What is the clinical presentation of cutaneous porphyrias?
- Photosensitivity
- Accumulation of protoporphyrins in skin which absorb light → photoactivation of porphyrin ring → excited, unstable molecule reacts with O2 to form free radicals → skin damage
- Redness, burning, itching, swelling after sun exposure
- Lesions in sun-exposed areas - Fragile skin + bullae
- Accumulation of other porphyrins → fragile skin that tears following minor trauma → vesicles, bullae
Both can result in chronic scarring, pigmentation, secondary infections
- Hypertrichosis = excess hair growth usually on the forehead and temples
- Onycholysis = seperation of nail from nail bed, painless
What is the screening test for neurological porphyrias? Any special instruction for sample collection?
- Start with random urine PBG screen
- If +ve = confirm with 24-h urine for quantitative PBG
- Urine, fecal, and plasma porphyrins for follow-up testing
Samples must be protected from light
How to diagnose cutaneous porphyrias?
- Plasma porphyrin fluorescence scan
→ Normal results exclude cutaneous porphyria
→ Abnormal = follow-up w/ urine, fecal & RBC testing - Urine AND RBC porphyrins
→ High urine coproporphyrins = VP, HCP
→ High urine uroporphyrins, 7-COOH porphyrins = PCT
→ High RBC = EPP, CEP
→ Normal = No cutaneous porphyria
What are the lab findings of AIP?
Urine → High ALA, PBG
Feces → Normal
RBC → Normal
Plasma → High emission peak at 615-620 nm
What are the lab findings of Variegate Porphyria (VP)?
Present in adulthood
Deficiency of Protoporphyrinogen Oxidase → accumulation of protoporphyrins & coproporphyrins
- Accumulated metabolites also inhibit PBG Deaminase
Urine → High ALA, PBG, coproporphyrin III
Feces → High protoporphyrin > Coproporphryin III
RBC → Normal
Plasma → High emission peak ~626 nm
What are the lab findings of hereditary coproporphyria (HCP)?
- Neurological and cutaneous findings similar to porphyria cutanea tarda
- Present in adulthood
Urine → High ALA, PBG, coproporphyrin III
Feces → High coproporphyrin III (isomer III > isomer I)
RBCs → normal
Plasma → High emission peak at 615-620 nm
