Introduction:

• These are diseases that result from derangements of specific enzymes in the heme biosynthetic pathway that lead to overproduction and accumulation of pathway intermediates and cause neurologic symptoms, photocutaneous symptoms or both.
• All of these diseases are inherited, except prophyria cutanea tarda which is caused by acquired deficiency.
• Bone marrow produces 85% of heme and liver produced rest 15%.  Heme synthesis occurs within the mitochondria.

Etiology:

• Inherited enzyme deficiency- Most of them are autosomal dominant
• Acquired/ toxic- Inhibition of enzymes by hexachlorobenzene, lead and other heavy metals.

Pathogenesis:

• Excess of porphyrins deposit within normoblasts which leads to ineffective erythropoiesis
• RBCs containing porphyrins get lysed when exposed to light in capillaries. This leads to intravascular hemolysis and splenomegaly.
• Excess of porphyrins transported in plasma get accumulated in skin which results in photosensitivity.
• Heme pathway intermediates are neurotoxic. Accumulation of these compounds leads to abnormality in autonomic innervation of gut, which causes abdominal pain.

Clinical features:

• Neurovisceral:
  • Present with abdominal or neuropathic pain
  • Precipitated by agents that increase cytochrome p 450- Alcohol, OCPs, barbiturates, carbamazepine, sulphonamides, erythromycin, danazol
  • Peripheral neuropathy occurs at a later stage
  • Sometimes may develop seizures, psychosis and disorders of basal ganglia.
• Photosensitivity
  • Present with cutaneous photosensitivity which results in burning, edema, itching, erythema and blistering skin lesions
  • Chronic lesions develop lichenification resulting in leathery, hyperpigmented skin.
  • Sometimes there can be photomutilation of face and fingers
  • Pink/ dark staining of diapers
  • Brown staining of teeth
• Expanding bone marrow leads to pathological fractures, vertebral compressions, short stature, osteolytic and osteosclerotic lesions
• Vitamin D deficiency due to avoiding of sunlight
• Anemia- which can be transfusion dependent.

Investigations:

• Peripheral smear- Polychromasia, poikilocytosis, anisocytosis, basophilic stippling, nRBCs
• Levels of various heme precursors (24 hour urine sample/ plasma)- Depending on this type of porphyria can be diagnosed
• Assessment of enzyme activity
• DNA study- To identify causative mutation

Treatment: Following are general measures. Specific measures depend on type of porphyria and clinical manifestation.

• Avoid sunlight, trauma to skin and infections
• Topical sunscreens
• Oral- Beta carotene
  • Probably quenches activated oxygen free radicals
  • 120-180mg- OD
• Transfusions to maintain hemoglobin >11.5gm/dL. Phelotomy helps in some types of porphyrias.
• Narcotic analgesics for pain
• Inj. Hemin/Hematin- IV- 4mg/kg- OD- for 4 days. Inhibits porphyrin synthesis by negative feed back.
• High carbohydrate diet/ IV glucose- 300gm glucose per day
• Iron chelation in case of iron overload
• Vitamin D supplementation
• For liver involvement- Cholestyramine/ Urso deoxy cholic acid
• Hydroxyurea- Suppresses erythropoiesis and hence porphyrin production
• Splenectomy
• Bone marrow transplant- Treatment of choice if donor is available
• Liver transplantation
• Gene therapy
• Stop precipitating drug if any
• Nausea/ vomiting- Ondansetron
• Short acting benzodiazepines in low doses
• Clonazepam is better antiepileptic if there is seizures

Recent advances:

Dersimelagon in Erythropoietic Protoporphyrias 

Dersimelagon is a new, orally administered, selective melanocortin 1 receptor agonist that increases levels of skin eumelanin. Present randomized, placebo-controlled, phase 2 trial investigated the efficacy and safety of dersimelagon with respect to the time to onset and the severity of symptoms associated with sunlight exposure in patients with erythropoietic protoporphyria or X-linked protoporphyria. Dersimelagon was administered at a dose of 100 or 300 mg once daily for 16 weeks. Dersimelagon significantly increased the duration of symptom-free sunlight exposure in patients with erythropoietic protoporphyria or X-linked protoporphyria.

https://doi.org/10.1056/NEJMoa2208754