Erythropoietic Protoporphyria (Protoporphyria, Heme synthetase deficiency, Ferrochelatase deficiency, X-linked dominant protoporphyria [XLDPP], Erythrohepatic protoporphyria [no longer used])

Are You Confident of the Diagnosis?

What you should be alert for in the history

Patients are usually diagnosed with erythropoietic protoporphyria (EPP) in infancy, with the rare exception of acquired EPP associated with certain types of cancers. EPP patients often present with photosensitivity (burning and stinging sensation when exposed to sunlight), weakness, malaise, easy fatigability, dyspnea on exertion, and orthopnea. Additionally, patients may complain of palpitations, and low grade fever. Although rarely seen, patients may also present with headache and decreased vision.

Characteristic findings on physical examination

Photosensitivity in the absence of bulla is a characteristic feature seen when diagnosing EPP. EPP should be considered in the differential diagnosis of any child with photosensitivity. A history of sun exposure inducing redness, vesiculation, burning, and stinging is notable.

The photosensitivity associated with EPP is acute and painful in sun-exposed areas and include signs of erythema (Figure 1), edema, petechiae, stinging, and burning; however, as noted previously, bullae should not be seen. Areas afflicted include any exposed to sun. The dominant areas involved are the face and the dorsa of the hands with initial symptoms depending on the duration and intensity of sunlight exposure.

Repeated chronic sun exposure episodes can cause irreversible damage, for example a waxy skin thickening (especially over the knuckles), and

hyperkeratosis of the skin (Figure 2). Lips may start showing signs of linear furrows and pseudo-rhagades (characteristic finding), and pitted scars (nose). Other noticeable symptoms on observation are pallor, purpura, and occasionally thin inelastic skin. Nail deformity is seen in early stages of EPP. In more advanced stages, physicians will notice cobblestone thickening of the skin and evidence of jaundice. Patients will seek relief with cooling of the skin with a wet cool towel/compress and or staying away from sunlight.

It is important to examine patients for milia, hypertrichosis or hyperpigmentation because these are not seen in EPP and may provide an alternate diagnosis, such as porphyria cutanea tarda (PCT). General and cardiac physical examinations reveal tachycardia, tachypnea, bounding pulse, cardiomegaly, mild anemia, and in rare cases cardiac failure.

Expected results of diagnostic studies

Hyaline PAS-positive perivascular deposits are seen on histological examination around dermal blood vessels along with vast amounts of fine fibrillar material, with reduplication of blood vessel walls. Fluorescence screening for the detection of fluorescent erythrocytes should be performed in fresh unstained blood smears and should be the initial step in verifying EPP as the primary cause of the symptoms mentioned. A fluorescence peak between 630 and 635nm is a good indication of EPP (maximum peak at 634nm).

High levels of free plasma protoporphyrin levels, and free erythrocyte protoporphyrin levels (may be greater than1000mcg/dl, whereas normal is less than 60mcg/dl) are indicative of EPP and elevated levels of zinc-protoporphyrin are indicative XLDPP. Patients with EPP often have a slightly decreased hemoglobin level.

Protoporphyrin is not excreted by the kidneys and urinary porphyrin levels are normal. Protoporphyrin in some cases can also be detected in the stool; however, this is a much less common finding. FECH enzyme levels should also be evaluated for lower than normal function.

Since liver function may deteriorate in EPP it is necessary to do base line viral hepatitis serologies, testing for hemochromatosis, liver imaging (magnetic resonance imaging), and urinary porphyrin profile as well as routinely checking liver function tests. It is important to perform an abdominal ultrasonographic examination to check for cholelithiasis.

Genetics testing that shows a FECH gene mutation with the presence of the IVS3-48C hypomorphic FECH allele is helpful in confirming a diagnosis. An ALAS2 mutation resulting in gain of function is indicative of XLDPP. There are only a few labs in the USA that can perform this test. I use the Mayo clinic molecular genetics laboratory or the University of Texas, Galveston Branch Porphyria Lab.

Diagnosis confirmation

The differential diagnosis includes:

Phototoxic drug reaction (hyperpigmentation with or without preceding blistering)

Hydroa vacciniforme (vesicles that heal with severe scarring. Condition improves with age)

Solar urticaria (hives after exposure to sunlight, no systemic symptoms)

Contact dermatitis (linear papulovesicles)

Angioedema (swelling of the face, tongue, etc, unrelated to sun exposure)

Porphyrias (PCT – milia, blisters, and hypertrichosis, adults, associated with alcohol use and hemochromatosis)

Lipoid proteinosis (Progressive deposition disease that begins in infancy. Infants have a characteristic cry. Patients are not photosensitive, but the appearance may mimic EPP with a waxy thickened appearance to the skin)

Scleromyxedema (Typically an adult onset. Infiltrative progressive papules. Rare liver disease. More neurological disease)

Polymorphous light eruption (rash of varying morphologies that occurs early in the spring and improves over the summer months, typically seen in adulthood)

In these scenarios, symptoms may be missing or associated with other diseases. It is vital that one perform the proper genetic tests as well determine the levels of free protoporphyrin in serum and check for a family history of EPP.

Who is at Risk for Developing this Disease?

EPP has been described globally with prevalence figures varying depending on the population being studied. Reports have suggested that the Netherlands and Wales have a prevalence of 1:75,000 and 1:200,000, respectively. It is considered the most common form of erythropoietic porphyria, and the second most common form of porphyria behind porphyria cutanea tarda (PCT). It is mostly seen in Caucasians. Males and females are affected equally.

Due to EPP’s inheritance pattern (both autosomal dominant and recessive inheritance patterns have been reported) a notable risk factor is a first-degree relative with EPP. It can also be acquired via alcohol/drug abuse, lead poisoning, and in other disease states (myelodysplastic syndromes, leukemia – due to a clonal expansion of red blood cells with a deletion of chromosome 18).

What is the Cause of the Disease?

Etiology

For the majority of cases, EPP is an inherited disorder. Most patients with the disease have deficient activity of the final enzyme in the biosynthetic pathway for heme, FECH (ferrohaemprotolyase, heme synthetase, ferrohaem-protolyase, EC4.99.1.1, ferrochelatase). A FECH mutation that decreases or even eliminates enzyme activity need only be identified on one allele. EPP patients rarely have mutations on both alleles of FECH. Preleukemia and myeloproliferative diseases have been shown to produce somatic FECH mutations causing EPP after the age of 40. The FECH gene is located at 18q21.3.

In roughly 2% of patients, the defective enzyme is ALAS (aminolevulinic acid synthase; however, this results in a ne protoporphyria: XLDPP (X-linked dominant protoporphyria). ALAS is produced by 2 separate genes, ALAS1 (located in the liver and other tissues on chromosome 3p21.1 and ALAS2 (located in erythroid tissue on chromosome X).

XLDPP patients have no abnormalities related to the FECH enzyme but rather have an increased activity of ALAS, the first enzyme involved in the heme biosynthetic pathway, combining glycine and succinyl CoA. These patients have higher total erythrocyte protoporphyrin concentrations than other described patients with EPP. Although 5% of EPP cases have no mutations in either FECH of ALAS, most are believed to be due to FECH gene mutations that cannot yet be found with current techniques.

Pathophysiology

As a result of the mutations describe above, EPP patients have a buildup of protoporphyrin. Due to the specific ultraviolet wavelength that protoporphyrin can absorb light in the range of 320–600nm, the energy content of the molecule increases and transforms oxygen molecules into oxygen radicals which can damage lipids (cell walls), DNA, and proteins. Protoporhyrin’s lipophilic nature gives it a propensity to collect in cellular membranes. The energized oxygen molecules damage the membranes and also cause tissue injury via complement activation and mast cell degranulation, resulting in vasodilatation and edema characteristic of the cutaneous photosensitivity symptoms seen in EPP.

In terms of liver distress, the exact mechanism of destruction via protoporphyrin is not understood. It is believed that deposits of the molecule saturate the biliary system and backlog the excretion capacity, leading to hepatic inflammation, fibrosis, and cirrhosis.

Systemic Implications and Complications

Hepatic issues arise in 4% of EPP cases with severity being highly variable. Liver problems include gallstones that can become lodged in the biliary duct, as well as liver disease that may progress to rapid hepatic failure. Cholelithiasis can occur in 20% of EPP patients and appears to be caused by protoporphyrin accumulation. Cholelithiasis may lead to pancreatitis. Biliary protoporphyrin concentration is also elevated and increases the risk for gallstones.

EPP patients with liver disease may develop rapid hepatic failure with symptoms related to portal hypertension and liver enlargement. The liver is unable to clear protoporphyrin via the entero-hepatic circulation, which causes paracrystalin protoporphyrin in hepatocytes to precipitate in the biliary canaliculi. At the current time it is not possible to determine which EPP patients will develop liver failure; however, preliminary work shows increased levels of protoporphyrinaemia, and coproporphyrin urinary excretion precede liver involvement. As hepatic complications worsen the patient will develop splenomegaly, leading to entrapment and hemolysis of erythrocytes.

In rare cases, neurological symptoms such as progressive polyneuropathy have been reported.

Treatment Options

Treatment options are summarized in Table I.