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Disorders of Haem Metabolism – The Porphyrias
  1. The porphyrias are rare disorders of the haem biosynthetic pathway. 
  2. Are due to partial enzyme deficiencies with a dominant mode of inheritance. 
  3. They are categorized as either hepatic or erythropoietic, depending on whether the major site of excess porphyrin production is in the liver or the red cell.
  4. The porphyrias are characterized by a low penetrance in the order of 25%. 
Factors which can precipitate acute attack of porphyria
  1. Alcohol
  2. Excess iron
  3. Exogenous estrogens and exposure to various chemicals, sulpha drugs
  4. While many cases are associated with hepatitis C infection.
Drugs causing porphyria (Ref. Hari. 18th ed., Pg - 3174, table 358.4)
  1. Carbamazepine (LQ 2012)
  2. Chloramphenicol
  3. Dihydroergotamine  
  4. Dydrogesterone
  5. Hydralazine
  6. Indinavir
  7. Ketamine
  8. Ketoconazole
  9. Lidocaine
  10. Estrogen (LQ 2012)
  11. Medroxyprogesterone
  12. Methyldopa
  13. Mifepristone
  14. Nicotinic acid
  15. Nitrofurantoin  
  16. Phenobarbital
  17. Phenytoin (LQ 2012)
  18. Primidone
  19. Rifampicin
  20. Ritonavir
  21. Spironolactone  
  22. Sulfadiazine + trimethoprim
  23. Tamoxifen
  24. Testosterone, inj.
  25. Thiopental
  26. Valproic acid
Classification And Principal Features of The Porphyrias
  1. Hepatic
    1. Acute intermittent porphyria (AIP)
      1. Autosomal dominant
      2. Porphobilinogen synthase Abnormality
      3. Precipitated by drugs and Alcohol
      4. Abdominal pain, polyneuropathY
    2. Variegate porphyria
      1. Autosomal dominant
      2. Protoporphyrinogen oxidase Abnormality
      3. Features of AIP and cutaneous
      4. Bullous eruption with sunlight
    3. Hereditary coproporphyria
      1. Autosomal dominant
      2. Similar to variegate porphyria
      3. Very rare
      4. Due to deficiency of coproporphyrinogen oxidase
    4. Porphyria cutanea tarda
      1. Autosomal dominant
      2. Hepatic uroporphyrinogen Decarboxylase abnormality
      3. Associated with alcohol; hepatic tumour
  2. Erythropoietic
    1. Congenital porphyria
      1. Autosomal recessive
      2. Uroporphyrin synthase abnormality  
      3. Extreme sensitivity to sunlight (severe scarring) 
      4. Dystrophy of nails and teeth, blindness Hypertension, neuropsychiatric Disorders   
    2. Erythropoietic protoporphyria
      1. Autosomal dominant
      2. Ferrochelatase abnormality
      3. Cutaneous photosensitivity, Porphyria
      4. Hepatic dysfunction
(Ref: Hari. 18th ed., Page - 3168, Fig 358.1)
The human heme biosynthetic pathway indicating in linked boxes the enzyme  hat, when deficient, causes the respective porphyria. Hepatic porphyrias are shown in yellow boxes and erythropoietic porphyrias in pink boxes.
Clinical features
The clinical features of porphyria fall into two broad categories. 
  1. Photosensitive skin manifestations,
    1. Attributable to excess production and accumulation of porphyrins in the skin, 
    2. Occur in PCT, congenital erythropoietic porphyria (CEP), hereditary coproporphyria (HCP), variegate porphyria (VP) and erythrohepatic protoporphyria (EHP). 
    3. Pain, erythema, bullae, erosions, hirsutism and hyper¬pigmentation are characteristic
    4. Occur predominantly on areas of the skin that are exposed to sunlight .
    5. The skin also becomes especially sensitive to damage from mild trauma.
  2. An acute relaps¬ing and remitting neurological syndrome, 
    1. Characteristic of acute intermittent porphyria (AlP), HCP, VP and ALA dehydratase deficiency (plumb porphyria). 
    2. This presents invariably with acute abdominal pain together
    3. Autonomic dysfunction such as tachycardia, hypertension and constipation. 
Other frequent associations include
  1. Neuro¬psychiatric manifestations, 
  2. Hyponatremia due to SIADH.
  3. Acute neuropathy which is usually motor, and can result in some cases in respiratory failure. 
The forms HCP and VP can present with either symptom pattern or with a mixed picture.
There is episodic pattern of these attacks. they are provoked by drugs such as anticonvulsants, Sulphonamide, estrogen and progesterone, especially the oral contraceptive pill, or by alcohol and even fasting. 

Diagnosis (Ref. Hari. 18th ed., Pg - 3173)
ALA and PBG levels are substantially increased in plasma and urine, especially during acute attacks, and become normal only after prolonged latency.

Treatment of AIP
  1. Treatment with a high-carbohydrate diet diminishes the number of attacks. 
  2. Acute attacks may be life-threatening withdrawal of the inciting agent and treatment with analgesics and intravenous glucose and hematin. 
Porphyria Cutanea Tarda
  1. Reducing or stopping alcohol consumption may alone lead to improvement. 
  2. Phlebotomy without oral iron supplementation. 
  3. Very low dose antimalarials (as low as 200 mg of hydroxychloroquine twice weekly), alone or in combination with phlebotomy, will increase the excretion of porphyrins, improving the skin disease.

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