Erythropoietic protoporphyria

Overview

Erythropoietic protoporphyria (EPP) belongs to a group of rare metabolic disorders called porphyrias, which result from impaired haem biosynthesis. Haem is an essential molecule that forms part of haemoglobin in red blood cells and serves numerous other functions throughout the body. In EPP, a deficiency in the enzyme ferrochelatase leads to accumulation of protoporphyrin IX, a light-sensitive compound, primarily in erythrocytes and subsequently in plasma and skin.

The condition typically manifests in early childhood, often between the ages of 2 and 6 years, when affected children experience immediate painful reactions upon sun exposure. The estimated prevalence ranges from 1 in 75,000 to 1 in 200,000 individuals, making EPP the most common form of erythropoietic porphyria in Europe. Because symptoms can be misinterpreted initially, diagnosis may be delayed until later childhood or even adulthood in milder cases.

Symptoms & clinical features

The hallmark feature of EPP is acute photosensitivity, which develops within minutes of exposure to sunlight or bright artificial light. Affected individuals describe intense burning, stinging, or prickling sensations in exposed skin, particularly on the face and hands. This pain can be excruciating and may persist for hours or even days following brief exposure. Unlike typical sunburn, there is often minimal visible change initially - redness and swelling may be subtle or absent in the acute phase.

With repeated episodes, some people develop chronic skin changes including thickening, scarring, and a waxy or pebbled texture over the knuckles, nose, and cheeks. Blistering occasionally occurs but is not a prominent feature in most cases. Young children may become extremely distressed during episodes but struggle to articulate the pain, leading to behavioural changes or avoidance of outdoor activities. A subset of individuals, estimated at 2-5 per cent of those with EPP, develop progressive liver disease ranging from mild abnormalities in liver function tests to severe hepatic failure requiring transplantation.

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Affected organs

The skin bears the primary burden in EPP, specifically sun-exposed areas such as the face, hands, arms, and legs. The photosensitivity reaction occurs because protoporphyrin IX absorbs light energy in the visible spectrum, particularly around 400-410 nanometres, generating reactive oxygen species that damage cellular membranes and tissues.

The liver is the second major organ at risk. Protoporphyrin IX is normally excreted through bile, but excessive accumulation can precipitate within bile ducts, causing cholestasis and progressive liver damage. Hepatic complications may develop insidiously over years or present acutely with rapid deterioration. Rarely, gallstones composed of protoporphyrin may form. The bone marrow, where red blood cells are produced, is the primary site of protoporphyrin overproduction, though it does not typically suffer direct clinical damage.

Multiple body systems

Systemic involvement

Cellular impact

Mechanism at cellular level

Risks & severity

Severity varies considerably between individuals with EPP. Most people experience significant photosensitivity that substantially impacts quality of life, restricting outdoor activities and requiring constant vigilance about light exposure. Pain episodes can be severe enough to require emergency medical attention, though there is often limited awareness among healthcare professionals unfamiliar with the condition.

The risk of progressive liver disease represents the most serious long-term concern. Whilst the majority of individuals maintain normal or near-normal liver function throughout life, a minority develop complications including cirrhosis and end-stage liver failure. Liver disease may progress rapidly once established, and acute hepatic crises can occur. Monitoring liver function is therefore essential in ongoing management. Life expectancy is generally normal for those without hepatic involvement, but liver complications can be life-threatening without timely intervention including transplantation when indicated.

Genetic causes

EPP results from pathogenic variants in FECH, located on chromosome 18. This gene encodes ferrochelatase, the enzyme responsible for the final step in haem biosynthesis - inserting an iron atom into protoporphyrin IX to form haem. When ferrochelatase activity is reduced below a critical threshold, protoporphyrin IX accumulates instead of being converted to haem.

The molecular mechanism typically involves a severe pathogenic variant on one chromosome inherited from one parent, combined with a common low-expression variant on the other chromosome inherited from the other parent. This low-expression variant reduces but does not eliminate enzyme production from that chromosome. The combination results in overall ferrochelatase activity of approximately 15-35 per cent of normal levels, which is insufficient to prevent protoporphyrin accumulation. The excess protoporphyrin IX is incorporated into developing red blood cells in the bone marrow, then released into plasma where it circulates and deposits in skin and liver tissue.

• FECH
  ferrochelatase

Inheritance pattern

EPP follows an autosomal recessive inheritance pattern in most cases, although the genetic mechanism is somewhat unusual. The condition typically requires two pathogenic changes in FECH - one severe variant from one parent and either another severe variant or a common low-expression variant from the other parent. The low-expression variant is present in approximately 10 per cent of the general population and causes reduced but not absent enzyme production.

This means that if both parents carry a severe FECH variant, each pregnancy has a 25 per cent chance of the child inheriting both variants and developing EPP. However, if one parent carries a severe variant and the other carries the more common low-expression variant, the recurrence risk is lower. Family members who carry a single severe variant without a second pathogenic change typically do not develop symptoms. Genetic counselling can help families understand their specific risks based on the variants identified through testing.

Diagnosis & testing

Diagnosis of EPP is confirmed through biochemical testing demonstrating markedly elevated levels of free protoporphyrin in red blood cells, typically measured using fluorescence spectroscopy or high-performance liquid chromatography. Plasma protoporphyrin levels are also characteristically raised. These tests should be performed in specialised laboratories familiar with porphyria diagnostics, as samples require specific handling to prevent degradation.

Genetic testing of FECH confirms the molecular diagnosis and is important for family counselling and determining recurrence risks. In the NHS, EPP falls under the inherited metabolic disorders pathway, and suspected cases are typically referred to clinical genetics or metabolic medicine services. Testing may be arranged via the NHS Genomic Medicine Service using appropriate gene panels that include FECH. Regular monitoring of liver function through blood tests and periodic liver imaging is recommended once the diagnosis is established, even in asymptomatic individuals.

Management & lifestyle

Management of EPP focuses on preventing photosensitivity reactions and monitoring for hepatic complications. Strict photoprotection is the cornerstone of care - affected individuals must avoid direct sunlight and use protective clothing including wide-brimmed hats, long sleeves, and gloves when outdoors. Standard sunscreens offer limited benefit because they primarily block ultraviolet radiation, whilst the problematic wavelengths in EPP are in the visible light spectrum. Specialised sunscreens containing reflectant pigments such as zinc oxide or titanium dioxide provide better protection.

Window films that block visible light and careful management of indoor lighting can reduce symptoms at home and in vehicles. Some individuals find that oral beta-carotene or cysteine supplementation provides modest improvement in light tolerance, though evidence remains limited and responses vary. For those with significant hepatic involvement, specialist hepatology input is essential. Afamelanitide, a synthetic hormone that stimulates melanin production, has been approved in Europe for increasing light tolerance in EPP and may be accessible through specialist centres. Regular follow-up with metabolic or dermatology services familiar with porphyrias ensures appropriate monitoring and access to emerging therapies.

UK care pathway

Within the UK NHS, individuals suspected of having EPP should be referred to specialist services with expertise in porphyrias or inherited metabolic disorders. The National Acute Porphyria Service provides diagnostic testing and ongoing clinical support for patients across England. Scotland, Wales, and Northern Ireland have equivalent specialist centres. Genetic testing is arranged through the NHS Genomic Medicine Service, typically via clinical genetics departments, using panels that include FECH and related genes. Patients benefit from access to genetic counsellors who can explain inheritance patterns, recurrence risks for family members, and coordinate cascade testing where appropriate. Ongoing care often involves collaboration between metabolic specialists, dermatologists, and hepatologists to address both photosensitivity and potential liver complications.

Related conditions

EPP should be distinguished from other forms of porphyria, particularly X-linked protoporphyria, which presents with very similar photosensitivity but results from variants in the ALAS2 gene rather than FECH. Biochemical testing patterns differ subtly between these conditions, and genetic testing confirms the specific diagnosis. Congenital erythropoietic porphyria also causes severe photosensitivity but typically presents with more prominent blistering and mutilating skin lesions, along with red discolouration of teeth and urine. Other photosensitivity disorders such as polymorphic light eruption or drug-induced photosensitivity have different clinical features and time courses. Accurate diagnosis is important because management strategies and prognosis vary between these conditions.

Frequently asked questions

References

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