Erythropoietic protoporphyria

Author: Vanessa Ngan, Staff Writer, 2003. Updated by Hon A/Prof Amanda Oakley, August 2015.


What is erythropoietic protoporphyria?

Erythropoietic protoporphyria (EPP) is one of a group of genetic diseases called the porphyrias. EPP is due to an inherited deficiency of the enzyme ferrochelatase. Reduced activity of this enzyme causes a build-up of the chemical protoporphyrin in the skin; resulting in photosensitivity i.e. the skin is damaged by light. Abnormally high levels of protoporphyrin can rarely cause liver disease.

Who gets erythropoietic protoporphyria?

Prevalence of EPP in Europe varies from 1 in 55,000 to 1 in 150,000 of the population. It affects males and females equally, and people of all races may get EPP.

EPP is thought to be due to a compound loss-of-function mutation in the gene encoding ferrochelatase (FECH; 612386) found on chromosome 18q21. Typically, there is a mutation on one gene as well as a second, low-expression allele. Both males and females are equally affected. Rarely, there is a gain in function mutation in ALA synthase (ALAS)-2 (X-linked dominant inheritance).  Thus, inheritance can be autosomal recessive or autosomal dominant with incomplete penetrance (96% of patients in the UK). 

Myelodysplasia is a neoplastic proliferation of bone marrow cells and causes chromosomal instability. Acquired EPP has been described in an older woman with myelodysplasia and was found to be due to knock-out loss of chromosome 18. 

What are the clinical features of erythropoietic protoporphyria?

Cutaneous symptoms and signs of EPP

First symptoms usually appear in infancy or early childhood and present as an uncomfortable or painful burning sensation of the skin after sun exposure. It occurs most often on the tops of the hands and feet, face and ears. In most cases visible changes to the skin are mild. The affected skin may become red and swollen and blistered. Later there are pitted scars and sometimes crusty thickened skin, particularly over the cheeks, nose and knuckles of the hands. 

Mild EPP causes visible swelling and mild discomfort following exposure to the sun. It affects the face and the backs of the hands and feet.

Erythropoietic protoporphyria

Liver disease in EPP

People with EPP-induced liver disease often have mild changes in liver blood tests. About 10% develop more severe liver disease, presenting with malaise, pain under the ribs on the right, jaundice and increasing photosensitivity.

Gallstones are common in patients with EPP.

How is erythropoietic protoporphyria diagnosed?

Diagnosis of EPP is often made during childhood.

  • The patient's red blood cells may be noted to fluoresce by ultraviolet microscopy.
  • Diagnosis of EPP is confirmed by finding increased levels of protoporphyrin in the blood and reduced ferrochelatase enzyme activity. The severity of the biochemical findings is variable.  
  • Gene testing is available in some centres.
  • Biopsy can also be useful, as EPP has some characteristic features on histopathology.

The following monitoring tests are often performed from time to time.

  • Full blood count to evaluate anaemia
  • Iron tests: iron deficiency may be present and should be monitored 
  • Liver function tests
  • Vitamin D levels 

What treatment is available for erythropoietic protoporphyria?

Lifelong photosensitivity is the major problem for EPP uncomplicated by liver disease.

  • Avoid unnecessary exposure to sunlight and wear protective clothing and wide-brimmed hats. Consider tinting windows.
  • Other strong sources of light may also cause symptoms, including fluorescent and halogen lights.
  • Protect the skin from exposure to operating lamps during a surgical procedure. 
  • Sunscreens may be helpful, especially formulations containing zinc oxide or titanium dioxide that reflect visible light.
  • Vitamin D supplementation is appropriate in patients that strictly avoid exposure to sunlight.

Trials of treatment for EPP have been difficult to assess. Effective treatment should reduce pain and increase time outdoors without pain.

  • Afamelanotide, an α-melanocyte stimulating hormone given by subcutaneous implantation, has been reported to provide good clinical effectiveness and safety in EPP. It is approved under exceptional circumstances by the European Medicines Agency for treatment of EPP (October 2014).
  • Narrowband UVB phototherapy increases melanin content and induces skin thickening so may reduce sun sensitivity in some patients. 

Individual patients may experience benefit from oral anti-oxidants such as beta-carotene and N-acetyl cysteine. They should avoid iron supplementation (unless severely iron deficient), as iron can increase photosensitivity in EPP.   

  • Colestyramine reduces hepatic protoporphyrin content but does not reduce photosensitivity.
  • Patients with EPP that also have liver disease require specialist medical treatment and possibly liver transplantation.

Another more serious condition, congenital erythropoietic porphyria, is now curable by stem cell transfusion, paving hope for the future, but there is not yet a cure available for EPP.

 

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