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Hepatoerythropoietic Porphyria (HEP)

HEP is a deficiency of the enzyme uroporphyrinogen decarboxylase; it is the autosomal recessive form of f-PCT. The manifestations of HEP resemble Congenital Erythropoietic Porphyria (CEP), with symptoms of skin blistering that usually begin in infancy.

Skin photosensitivity results in severe blistering and scarring, often with mutilation and loss of facial features and fingers. Increased hair growth (hypertrichosis) on sun-exposed skin, brownish-colored teeth (erythrodontia), and reddish-colored urine are common. There may be bone fragility due to expansion of the bone marrow and vitamin deficiencies, especially vitamin D. Red blood cells have a shortened life-span, and mild or severe hemolytic anemia often results. Synthesis of heme and hemoglobin is actually increased to compensate for the shortened red blood cell survival and is associated with splenomegaly. Bacteria may infect the damaged skin and contribute to mutilation and scarring.

HEP is a very rare type of autosomal recessive porphyria. Each parent of an affected individual must have a mutation in one of their UROD genes and both must pass their mutation on to their child.  This also means that both parents have f-PCT. Hepatoerythropoietic Porphyria (HEP) is an extremely rare genetic disorder characterized by deficiency of the enzyme, uroporphyrinogen decarboxylase. This deficiency is caused by mutations of both copies of a person’s UROD gene, which means that the disorder is inherited as an autosomal recessive trait. Most affected individuals have a profound deficiency of this enzyme and onset of the disorder is usually during infancy or early childhood. However, some individuals may have a mild form that can go undiagnosed until adulthood. The childhood form of HEP is often associated with painful, blistering skin lesions that develop on sun-exposed skin (photosensitivity). Affected areas of skin can scar and become discolored. There may be risk of bacterial infection. Abnormal, excessive hair (hypertrichosis) on affected skin is also common. Mild anemia and abnormal enlargement of the liver and/or spleen (hepatosplenomegaly) have also been reported. Mild cases of HEP may go unrecognized until adulthood and can be clinically indistinguishable from Porphyria Cutanea Tarda (PCT), a related disorder that may be acquired or occur in individuals with a mutation of one UROD gene (autosomal dominant inheritance). Cutaneous photosensitivity is generally much more severe in HEP than in PCT. NORD has a separate report on Porphyria Cutanea Tarda.

HEP is an extremely rare disorder that affects males and females in equal numbers. Approximately 40 cases have been reported in the medical literature. The exact incidence or prevalence of HEP in the general population is unknown.

Synonyms of Hepatoerythropoietic Porphyria (HEP):
  • autosomal recessive PCT
  • HEP

CAUSE

The UROD gene creates (encodes) an enzyme known as uroporphyrinogen decarboxylase (UROD), which is the fifth enzyme in the heme biosynthetic pathway. In HEP, UROD enzyme activity is usually less than 10% its normal levels. Such low enzyme activity results in the abnormal accumulation of specific porphyrins and related chemicals in body, especially within the bone marrow, red blood cells, liver and skin. Symptoms develop because of this abnormal accumulation of porphyrins and related chemicals. When porphyrins accumulate in the skin, they absorb sunlight and enter an excited state (photoactivation). This abnormal activation results in the characteristic damage to the skin found in individuals with HEP. The liver removes porphyrins from the blood plasma and secretes it into the bile. When porphyrins accumulate in the liver, they can cause toxic damage to the liver.

HEP is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms.

SIGNS AND SYMPTOMS

The symptoms and severity of HEP can vary from one person to another. Onset is usually within the first two years of life, but mild cases that go undiagnosed until adulthood have been reported. Although HEP is associated with specific, characteristic symptoms, several factors, including the small number of identified cases, make it difficult to establish the full range of associated symptoms of the disorder.

Severe cutaneous photosensitivity is usually the first sign. Affected infants may have extremely fragile skin that can peel or blister on minimal impact is common. Reddening of the skin is also common (erythema). Blistering skin lesions can develop on sun-exposed skin such as the hands and face. Photosensitivity can be severe and can cause scarring, erosion, and disfigurement. Bacterial infection of skin lesions can occur. Abnormal, excessive hair growth (hypertrichosis) may also occur on sun-exposed skin. Affected skin may darken or lose color (hyper- or hypopigmentation). Small bumps with a distinct white head (milia) may also develop. Some affected individuals have teeth that are reddish-brown colored (erythrodontia). Low levels of circulating red blood cells (anemia) may also occur. Anemia may be due to the premature destruction of red blood cells (hemolysis). Anemia associated with HEP may be mild or severe. Severe anemia may be associated with fatigue, pale skin, irregular heartbeat, chest pain, dizziness, and abnormally cold hands and feet. Some individuals may have an abnormally enlarged liver and/or spleen (hepatosplenomegaly).

Mild cases of HEP can go undiagnosed until adulthood. Overt photosensitivity may not be seen, and mild skin damage can be mistaken for other conditions during childhood.

DIAGNOSIS

Diagnosis of HEP can be made by demonstrating significant elevations of specific porphyrins in urine and stool, as well as identification of a specific fluorescence emission peak in plasma.  DNA testing to identify the specific mutations in an individual’s UROD genes is the most specific and sensitive test to confirm the diagnosis of HEP.

A diagnosis of HEP is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. HEP may be considered in infants and children with chronic, blistering photosensitivity.

Porphyrin patterns in HEP are similar to those seen in PCT with elevation of highly carboxylated porphyrins and isocoproporphyrins. In contrast to PCT, there are markedly increased levels of zinc protoporphyrin in red blood cells in HEP patients which is due to accumulation of pathway intermediates being metabolized to protoporphyrins.

Molecular genetic testing can confirm a diagnosis of HEP by detecting mutations in both UROD genes but is available only on a clinical basis.

TREATMENT

Treatment is the same as for PCT: regularly scheduled phlebotomies (removal of blood) to lower the amount of porphyrins in the liver or a low dose regimen of hydroxychloroquine as well as removal of factors (for example, certain medications) that activated the disease and avoidance and/or protection from sunlight.

Avoidance of sunlight will benefit affected individuals and can include the use of clothing styles with long sleeves and pant legs, made with double layers of fabric or of light-exclusive fabrics, wide brimmed hats, gloves, and sunglasses. Topical sunscreens are generally ineffective, but certain tanning products with ingredients that increase pigmentation may be helpful. Affected individuals may also benefit from window tinting and the use of vinyl or films to cover the windows of their homes and cars.

The treatment of HEP is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan an affected child’s treatment. Genetic counseling may benefit affected individuals and their families.

Anemia may require treatment in some cases. Blood transfusions have been used to treat some individuals. Recombinant erythropoietin, which helps the body produce more red blood cells, was successfully used to treat severe anemia in an individual with HEP whose anemia was not associated with increased red cell destruction.

There is no specific, FDA-approved therapy for individuals with HEP. Because the disorder is so rare, most treatment information is based on other forms of porphyria.

Investigational Therapies

Gene therapy is also being studied as another approach to therapy for individuals with genetic disorders associated with enzyme deficiency. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of the active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a “cure”. However, at this time, there remain some technical difficulties to resolve before gene therapy can be advocated as a viable alternative approach for genetic disorders like HEP.

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