Porphyrins and Porphyrias Flashcards
What are Haem Proteins?
- Haemoglobin
- Catalase
- Myoglobin
- Peroxidases
- Cyclooxygenase
- Tryptophan Pyrrolase
- Nitric Oxide Synthase
- Soluble Guanylate Cyclase
- Mitochondrial Cytochromes
- Microsomal Cytochrome P450s
What are Porphyrias?
- Due to partial deficiency of enzymes in the haem biosynthetic pathway. Defined by a unique biochemical pattern of accumulation and excretion of porphyrins and porphyrin precursors
- 8 main types; rare, mostly inherited disorders with variable penetrance
- Acute “porphyria attacks” or light sensitive skin disease or BOTH
What are the Acute Porphyrias?
Also Called Hepatic Porphyrias
- Acute intermittent porphyria (AIP): AIP does not have skin manifestations but all other porphyrias do.
- Variegate porphyria (VP)
- Hereditary coproporphyria (HCP)
- ALA Dehydratase porphyria (ADP)
What are the Non-Acute Porphyrias?
- Porphyria cutanea tarda (PCT): PCT is mainly sporadic, all others are inherited. It is Hepatic
- Erythropoietic protoporphyria (EPP)
- X-linked EPP (XLEPP)
- Congenital Erythropoietic Porphyria (CEP, syn. Günther’ s Disease)
What is the age of onset and inheritance of Congenital Erythropoietic Porphyria (CEP; Günther’ s)?
- Age of onset: Birth
- Inheritance: Autosomal recessive
What is the age of onset and inheritance of Erythropoietic Protoporphyria (EPP/XLEPP)?
- Age of onset: Birth
- Inheritance: Complex; several types
What is the age of onset and inheritance of Acute Intermittent Porphyria (AIP), Variegate Porphyria (VP) and Hereditary Coproporphyria (HCP)?
- Age of onset: 15-35y
- Inheritance: Autosomal Dominant
What is the age of onset and inheritance of ALA dehydratase Porphyria (ADP)?
- Age of Onset: Teens (but few kindreds described
- Inheritance: Autosomal Recessive
What is the age of onset and inheritance of Porphyria Cutanea Tarda (PCT)?
- Age of Onset: 35-55y
- Inheritance: ~90% sporadic;10% familial
How does Haem affect ALA Synthase?
- If increased requirement for production of Haem then ALA synthase is upregulated.
- Haem has negative feedback of ALA synthase
What are differential tissue regulation for Haem Biosynthesis?
Bone marrow:
- >80% haem biosynthesis (haemoglobin)
- Erythroid specific promotors and isoforms for key enzymes (ALAS2)
- Regulated by erythropoietin, iron supply and coupled to globin chain synthesis
Liver:
- ∼15% haem biosynthesis
- Haem exerts classical negative feedback on rate-limiting enzyme, ALA synthase (ALAS1)
What is the prevelance of Acute Hepatic Porphyrias?
Low penetrance: Only 10-20% of people “at risk” will develop overt, symptomatic disease with acute porphyria attacks
What are Features of Overt Symptomatic Acute Porphyria?
- Attacks are exceedingly rare before puberty
- More common in females
- Most people will experience only one attack and make a full recovery, BUT 5-10% patients (mostly young females) develop recurrent attacks
- Serious permanent, neurological morbidity and deaths still occur due to acute attacks
What are the clinical sign/symptoms of Acute Porphyria attacks?
- Severe abdominal pain
- Nausea
- Vomiting
- Constipation
- Progressive weakness
- Tachycardia
- Hypertension
- Hyponatraemia
- Convulsions, neuropathy, encephalopathy,
- Red urine: Urine darken on standing due to oxidation of colourless porphyrinogens to coloured porphyrins
What are triggers for Acute Porphyria Attacks?
- Drugs (many prescription drugs UNSAFE): increase in production of cytochrome enzymes
- Hormones (pre-menstrual phase): Women to avoid depo, cocp or implants
- Infection
- Calorie restriction,
- Alcohol
- Stress
- Smoking
What are the biochemical Hallmarks of Acute Porphyria Attack?
Accumulation of Porphyrin Precursors
- ALA
- PBG