Hepatoerythropoietic Porphyria
Summary
Clinical characteristics.
Hepatoerythropoietic porphyria (HEP) is characterized by blistering skin lesions, hypertrichosis, and scarring over the affected skin areas. Disease manifestations occur during infancy or childhood and with similar frequency in females and males. Individuals with HEP are not reported to be at increased risk for hepatocellular carcinoma.
Diagnosis/testing.
The diagnosis of HEP is established in a proband by identification of elevated porphyrins in the urine (predominantly uroporphyrin and heptacarboxylporphyrin) and significantly increased erythrocyte zinc protoporphyrin. Identification of biallelic pathogenic variants in UROD confirms the diagnosis.
Management.
Treatment of manifestations: Avoidance of sunlight (including the long-wave ultraviolet light sunlight that passes through window glass) by use of protective clothing and topical application of opaque sunscreens. Phlebotomy and chloroquine, which are usually effective in treating familial porphyria cutanea tarda, are generally less effective in individuals with HEP.
Prevention of primary manifestations: Protection from sunlight.
Agents/circumstances to avoid: Exposure to sunlight in persons of all ages. Older individuals should avoid known precipitating factors: alcohol, oral estrogen, smoking, and drugs that induce the cytochrome P450s.
Evaluation of relatives at risk: If the family-specific UROD pathogenic variants are known, clarify the genetic status of at-risk relatives so that those with biallelic UROD pathogenic variants can be counseled regarding sun protection and avoidance of known susceptibility factors.
Genetic counseling.
HEP is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being heterozygous and at risk of developing familial porphyria cutanea tarda, and a 25% chance of being unaffected and not heterozygous. Once the UROD pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for HEP are possible.
Diagnosis
Suggestive Findings
Hepatoerythropoietic porphyria (HEP) should be considered in individuals who present during infancy or childhood with the following clinical features and laboratory findings.
Clinical features
- Blistering skin lesions
- Hypertrichosis
- Scarring
- Passage of red urine
Note: The features of HEP generally resemble those of congenital erythropoietic porphyria.
Laboratory findings (see Table 1)
- Hepatic uroporphyrinogen decarboxylase (UROD) enzyme activity is approximately 15%-20% of normal.
- The UROD protein level is determined by genotype (e.g., ~50% in individuals with a null allele and a partial loss-of-function allele).
- Erythrocyte zinc protoporphyrin levels are significantly increased.
- Plasma porphyrins are increased. Fluorescence emission peaks (at neutral pH) at approximately 620 nm following excitation with light of approximately 400-410 nm (Soret band) [Poh-Fitzpatrick & Lamola 1976].
- Porphyrins are elevated in the urine. There is a predominance of uroporphyrin and heptacarboxylporphyrin; hexa- and pentacarboxylporphyrins and coproporphyrin levels are also increased. Note: Isomer analysis of the uroporphyrin shows a significant increase in isomer I uroporphyrin.
- Levels of fecal isocoproporphyrin and hepta- and pentaporphyrins are increased.
- Urine delta-aminolevulinic acid (ALA) is normal or minimally increased.
- Porphobilinogen (PBG) levels are normal.
Table 1.
Biochemical Characteristics of Hepatoerythropoietic Porphyria
| Biochemical Finding | |
|---|---|
| Deficient enzyme | Uroporphyrinogen decarboxylase |
| Enzyme activity | ~15%-20% of normal |
| Erythrocytes | ↑ Zinc protoporphyrin |
| Plasma | ↑ Uroporphyrin, heptacarboxylporphyrin (~620 nm) 1 |
| Urine | ↑ Uroporphyrin, heptacarboxylporphyrin |
| Stool | ↑ Heptacarboxylporphyrin, isocoproporphyrins + pentacarboxylporphyrins |
- 1.
Fluorescence emission peak of diluted plasma at neutral pH, following excitation at 400-410 nm
Note: Histologic findings on skin biopsy are not diagnostic of HEP.
Establishing the Diagnosis
The diagnosis of HEP is established in a proband by the presence of increased uroporphyrin and heptacarboylporphyrin in the urine in addition to significantly increased erythrocyte zinc protoporphyrin, and/or by the identification of biallelic pathogenic variants in UROD (see Table 2).
Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:
- Single-gene testing. Sequence analysis of UROD is performed first and followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.
- A multigene panel that includes UROD and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
- More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes UROD) fails to confirm a diagnosis in an individual with features of HEP. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation). For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 2.
Molecular Genetic Testing Used in Hepatoerythropoietic Porphyria
| Gene 1 | Test Method | Proportion of Probands with Pathogenic Variants 2 Detectable by This Method |
|---|---|---|
| UROD | Sequence analysis 3 | 14/16 4, 5 |
| Gene-targeted deletion/duplication analysis 6 | 2/16 7 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Author communication
- 5.
Additional variants associated with F-PTC have been detected.
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
Large deletions involving UROD have been described in HEP, including deletion of the entire gene in one individual [de Verneuil et al 1992] and a 1-kb deletion in another [Mendez et al 1998]. Cantatore-Francis et al [2010] described compound heterozygosity for a complex deletion/insertion allele and a pathogenic missense variant.
Clinical Characteristics
Clinical Description
Clinical manifestations of HEP include extreme photosensitivity, skin lesions with fluid-filled blisters that break and heal slowly, hypertrichosis, and scarring over the affected skin areas. Repeated sun exposure can lead to scleroderma-like changes that result in photomutilation [Elder 1997]. With high levels of circulating porphyrins there may be a red/brown discoloration of teeth due to the deposition of porphyrins in the enamal layer of the developing tooth. Signs and symptoms of HEP start during infancy or childhood, with similar frequency in females and males, and generally resemble those of congenital erythropoietic porphyria. Note: The clinical features of porphyria cutanea tarda (PCT) (see Differential Diagnosis) and HEP are indistinguishable.
No increased risk for hepatocellular carcinoma has been identified in persons with HEP.
Susceptibility factors. The rare nature of this disease makes identification of additional risk factors difficult to assess; however, the same susceptibility factors shown to modulate the phenotype of familial porphyria cutanea tarda (F-PCT) are likely to be important in HEP (see Differential Diagnosis) [Bonkovsky et al 2013].
Susceptibility factors to some extent reflect their frequency in the general population to which the individual belongs. The frequency and the degree to which these risk factors are involved in type I PCT (sporadic) and F-PCT also differ in HEP [Aarsand et al 2009, Muñoz-Santos et al 2010].
The genetic and environmental susceptibility factors may reflect their frequency in the general population (e.g., hepatitis C infection, HFE pathogenic variant).
- Iron and HFE pathogenic variants. Mild-to-moderate iron overload is typically found in persons with F-PCT; some degree of hepatic siderosis is seen in almost all affected individuals.
- Alcohol. PCT has long been associated with excessive alcohol use.
- Smoking and cytochrome P450 enzymes. Smoking is commonly associated with alcohol use in PCT [Egger et al 2002].
- Hepatitis C. Reported prevalence of hepatitis C in individuals with PCT has ranged from 21% to 92% in various countries [Ryan Caballes et al 2012]; it is seen more frequently in type I PCT than in F- PCT [Muñoz-Santos et al 2010]. Note that the frequency in HEP has not been determined.
- Estrogens. Estrogen use is a common susceptibility factor in women with PCT [Grossman et al 1979, Sixel-Dietrich & Doss 1985, Egger et al 2002] and also presents a risk for men (e.g., those taking estrogen for treatment of prostatic cancer). Discontinuation of oral estrogen use leads to resolution of the symptoms. Use of transdermal estrogens in women has been shown to be safe [Bulaj et al 2000].
- Antioxidants. Substantial reductions in plasma levels of ascorbate and carotenoids have been noted in some individuals with PCT [Percy et al 1975, Sinclair et al 1997, Rocchi et al 1999].
Pathophysiology
UROD deficiency (in all tissues) leads to the accumulation of substrate, uroporphyrinogen, and the intermediate products of the reaction in all cells. Cells with a high demand for heme production include the erythron and the hepatocyte, and thus, accumulation may be more pronounced in these cell types. The substrates and intermediates accumulate in cells in the form of oxidized porphyrins (mostly uroporphyrin and heptacarboxylporphyrin) that are then transported into the plasma and eventually into the urine. These excess porphyrins are deposited in the skin and other tissues. For more information about the proposed pathophysiology of HEP, click here.
Genotype-Phenotype Correlations
No clinically significant genotype-phenotype correlations have been found (see Molecular Genetics).
Nomenclature
Prevalence
Fewer than 100 cases of HEP have been reported in the literature. The frequency of HEP can only be inferred based on that of familial PCT, which occurs in one in 20,000.
Differential Diagnosis
Type I porphyria cutanea tarda (sporadic; no UROD pathogenic variant). Type I porphyria cutanea tarda (PCT) is highly influenced by susceptibility factors associated with PCT; often several are present in individuals with type I PCT, including a pathogenic variant in HFE. Type I PCT is clinically indistinguishable from HEP and familial PCT.
Familial porphyria cutanea tarda (F-PCT). The skin lesions of F-PCT resemble those of HEP, however they are less severe. The skin changes of F-PCT typically begin later, in the fourth or fifth decade of life. Disease manifestations are more common in men than women. Because the laboratory findings in individuals with F-PCT and HEP can be clinically indistinguishable at the time of diagnosis, molecular genetic testing is necessary to discriminate between these two disorders. Measurement of UROD enzyme activity is not an accurate method to distinguish between F-PCT and HEP. Heterozygous UROD pathogenic variants are causative. Inheritance is autosomal dominant with reduced penetrance.
Variegate porphyria (VP) and hereditary coproporphyria (HCP). Blistering skin lesions in VP and HCP are nearly identical to those in HEP. Although the cutaneous manifestations of HEP are also chronic and blistering, they are usually more severe than those of VP because circulating porphyrin levels are usually much higher (by an order of magnitude) than in VP. HCP is generally accompanied by neurovisceral features, especially bouts of severe abdominal pain, which are not observed in HEP. In both HCP and VP, the principal source of overproduction of heme precursors is the liver. VP is caused by a heterozygous pathogenic variant in PPOX and HCP is caused by a heterozygous pathogenic variant in CPOX. Both disorders are inherited in an autosomal dominant manner with low penetrance. Although mild manifestations of HEP can be mistaken for those of VP and HCP, the erythropoietic porphyrias (e.g., HEP, CEP, or EPP) are differentiated particularly by the presence of high levels of erythrocyte porphyrins.
Congenital erythropoietic porphyria (CEP). The skin lesions of CEP, like those seen in HEP, appear early in life (i.e., in infancy or childhood) and are severe and mutilating. In both CEP and HEP the increased severity is attributed to the plasma concentration of porphyrin. Although CEP can be mistaken for HEP, urine porphyrin analysis (which demonstrates uroporphyrin and coproporphyrin type I) rules out other types of cutaneous porphyria. Fecal analysis may be necessary, particularly for late-onset cases. CEP caused by biallelic pathogenic variants in UROS is inherited in an autosomal recessive manner; CEP caused by a hemizygous pathogenic variant in GATA1 (rare) is inherited in an X-linked manner.
Pseudoporphyria. Although the skin histopathologic findings of pseudoporphyria are indistinguishable from those of HEP, pseudoporphyria does not cause porphyrin biochemical abnormalities. Drugs are implicated in the appearance of this condition [Barzilay et al 2001].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with hepatoerythropoietic porphyria (HEP), the following evaluations are recommended:
- Evaluation for excess hepatic iron
- Targeted analysis for HFE pathogenic variants (see HFE hemochromatosis)
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
There are no effective treatment regimens to restore enzyme levels in individuals with HEP. Hence, treatment recommendations at this time are similar to the ones for familial porphyria cutanea tarda (F-PCT): the avoidance of sunlight, including the long-wave ultraviolet light sunlight that passes through window glass.
Prevention of Primary Manifestations
The following measures are recommended:
- Protection from sunlight because of the high risk for severe skin damage and possible mutilation
- Identification and avoidance of susceptibility factors (where applicable) . See Agents/Circumstances to Avoid.
- Avoidance of drugs and agents that induce the hepatic P450
- Vaccination against hepatitis A and B
Surveillance
There are currently no recommendations or guidelines for surveillance in those with HEP.
Agents/Circumstances to Avoid
Persons of all ages should avoid exposure to sunlight.
Older individuals should avoid the known precipitating factors (e.g., alcohol, oral estrogen, smoking, and drugs that induce the cytochrome P450s).
Evaluation of Relatives at Risk
If the family-specific UROD pathogenic variants are known, it is reasonable to clarify the genetic status of at-risk relatives so that those with biallelic UROD pathogenic variants can be counseled regarding sun protection and avoidance of known susceptibility factors.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.