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Last updated:
June 01, 2022
Years published: 2013, 2016
NORD gratefully acknowledges Ashwani K Singal, MD, MSc, Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, for assistance in the preparation of this report.
Summary
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.
Introduction
HEP belongs to a group of disorders known as the porphyrias. This group of at least seven disorders is characterized by abnormally high levels of porphyrins and porphyrin precursors due to deficiency of certain enzymes essential to the creation (synthesis) of heme, a part of hemoglobin and other hemoproteins. There are eight enzymes in the pathway for making heme and at least seven major forms of porphyria. The symptoms associated with the various forms of porphyria differ. It is important to note that people who have one type of porphyria do not develop any of the other types. Porphyrias are generally classified into two groups: the “hepatic” and “erythropoietic” types. Porphyrins and porphyrin precursors and related substances originate in excess amounts predominantly from the liver in the hepatic types and mostly from the bone marrow in the erythropoietic types. Porphyrias with skin manifestations are sometimes referred to as “cutaneous porphyrias”. The term “acute porphyria” is used to describe porphyrias that can be associated with sudden attacks of pain and other neurological symptoms. HEP is a hepatic and cutaneous porphyria.
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 that can peel or blister on minimal impact is common. Reddening of the skin is 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.
HEP is caused by mutations of both alleles of the UROD gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
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 gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Investigators have determined that the UROD gene is located on the short arm (p) of chromosome 1 (1p34.1). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 1p34.1” refers to band 34.1 on the short arm of chromosome 1. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
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. For example 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 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.
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.
Clinical Testing and Workup
Screening tests can help diagnose HEP by measuring the levels of certain porphyrins in blood plasma, urine and red blood cells. These tests can help to differentiate the disorder from congenital erythropoietic porphyria by the different patterns of individual porphyrins and/or by demonstrating markedly decreased activity of the UROD enzyme. There is elevation of porphyrins in plasma, urine, and feces. 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
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.
There is no specific, FDA-approved therapy for individuals with HEP. Because the disorder is so rare, most treatment information is based other forms of porphyria.
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.
Phlebotomies, which are used to treat individuals with PCT, are generally ineffective in individuals with HEP since elevated iron levels are not a feature of the disorder. Another treatment for PCT, the antimalarial drug chloroquine, was effective in at least one case reported in the medical literature.
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.
Gene therapy is also being studied as another approach to therapy for individuals with genetic disorder associated with enzyme deficiency. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the produce 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.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLE
Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Blood. 2012;120:4496-4504. https://www.ncbi.nlm.nih.gov/pubmed/22791288
To-Figueras J, Phillips JD, Gonzalez-Lopez JM, et al. Hepatoeythropoetic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene. Br J Dermatol. 2011;165:499-505. https://www.ncbi.nlm.nih.gov/pubmed/21668429
Cantatore-Francis JL, Cohen J, Balwani M, et al. Hepatoerythropoietic porphyria misdiagnosed as child abuse: cutaneous, arthritic, and hematologic manifestations in siblings with a novel UROD mutation. Arch Dermatol. 2010;146:529-533. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092549/
Phillips JD, Whitby FG, Stadmueller BM, et al. Two novel uroporphyrinogen decarboxylase (URO-D) mutations causing hepatoerythropoietic porphyria (HEP). Transl Res. 2007;149:85-91. https://www.ncbi.nlm.nih.gov/pubmed/17240319
Armstrong DK, Sharpe PC, Chambers CR, et al. Hepatoerythropoietic porphyria: a missense mutation in the UROD gene is associated with mild disease and an unusual porphyrin excretion pattern. Br J Dermatol. 2004;151:920-923. https://www.ncbi.nlm.nih.gov/pubmed/15491440
Ged C, Ozalla D, Herrero C, et al. Description of a new mutation in hepatoerythropoietic porphyria and prenatal exclusion of a homozygous fetus. Arch Dermatol. 2002;138:957-960. https://www.ncbi.nlm.nih.gov/pubmed/12071824
Horina JH, Wolf P. Epoetin for severe anemia in hepatoerythropoietic porphyria. N Engl J Med. 2000;342:1294-1295. https://www.ncbi.nlm.nih.gov/pubmed/10787339
Moran-Jimenez MJ, Ged C, Romana M, et al. Uroporphyrinogen decarboxylase: complete human gene sequence and molecular study of three families with hepatoerythropoietic porphyria. Am J Hum Genet. 1996;58:712-721. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1914669/
INTERNET
Deybach JC. Hepatoerythropoietic Porphyria. Orphanet Encyclopedia, February 2009. Available at: https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=12580&Disease_Disease_Search_diseaseGroup=Hepatoerythropoietic-Porphyria&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Hepatoerythropoietic-porphyria&title=Hepatoerythropoietic-porphyria&search=Disease_Search_Simple Accessed March 17, 2016.
Singal AK, Anderson KE. Porphyria Cutanea Tarda and Hepatoerythropoietic Porphyria. UpToDate, Inc. Last Updated: October 5, 2015. Available at: https://www.uptodate.com/contents/porphyria-cutanea-tarda-and-hepatoerythropoietic-porphyria Accessed March 17, 2016.
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