Long-term follow-up after liver transplantation for erythropoietic protoporphyria.

OBJECTIVE: Erythropoietic protoporphyria (EPP) is an inherited disorder of haem synthesis, causing excess of protoporphyrin in blood, skin, liver and other organs. Protoporphyrin causes rapidly progressive liver failure in a minority of EPP patients. Long-term follow-up after liver transplantation for EPP is poorly documented. DESIGN: Two EPP patients were followed for 7 years after liver transplantation. Porphyrin levels were monitored and serial liver biopsies were taken. RESULTS: After transplantation, serum protoporphyrin levels remained elevated. In one patient, long periods with normal liver tests, low protoporphyrin levels and the absence of photosensitivity were followed by episodes of cholestasis and elevated protoporphyrin levels in blood, faeces and liver tissue. These episodes could be managed successfully with blood transfusions and changes in medication. The simultaneous rise of protoporphyrin concentration in both blood and faeces in this patient argues for increased protoporphyrin production as the cause of liver cell injury. The other patient acquired hepatitis B infection during the transplantation. From 3 months onwards she had continuously elevated liver tests, cholestasis, elevated protoporphyrin levels in blood, faeces and liver tissue, and photosensitivity. In this case, cholestasis and impaired protoporphyrin excretion may have played an important role in the persistent liver injury. Sequential liver biopsies of both patients showed various degrees of liver injury related to variations of the hepatic protoporphyrin concentrations. Eight and six months respectively after liver transplantation the livers of both patients showed fibrosis and hepatocellular protoporphyrin accumulation. CONCLUSIONS: The main cause of liver damage in EPP is overproduction of protoporphyrin in the bone marrow. Liver transplantation must be considered as symptomatic therapy with a high-risk for recurrent disease.

Diseases associated with photosensitivity.

Photosensitive disorders may be classified as those entirely caused by solar exposure and the photoaggravated disorders. Those in the former category include polymorphic light eruption, juvenile spring eruption, actinic prurigo, hydroa vacciniforme, solar urticaria, also chronic actinic dermatitis. Genodermatoses whose expression mainly depends on UV or light exposure include the DNA repair deficient disorders, some disorders of cornification, the Smith-Lemli-Opitz syndrome and porphyria. Examples of photoaggravated diseases include lupus erythematosus, erythema multiforme, atopic eczema, psoriasis, viral exanthemata, pemphigus, dermatitis herpetiformis and rosacea. Drugs and chemicals may interact with UV to induce photosensitivity. In many of these diseases the action spectrum is known or may be determined by phototesting. Recognition of the reaction patterns associated with the photodermatoses greatly assists clinical classification of the photodermatoses.

Hepatoerythropoietic porphyria misdiagnosed as child abuse: cutaneous, arthritic, and hematologic manifestations in siblings with a novel UROD mutation.

BACKGROUND: Hepatoerythropoietic porphyria (HEP) is a rare autosomal recessive disorder resulting from the markedly deficient, but not absent, activity of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD). The disorder typically manifests during infancy or early childhood with extreme photosensitivity, skin fragility in sun-exposed areas, hypertrichosis, erythrodontia, and pink urine. OBSERVATIONS: Three siblings, offspring of parents of Puerto Rican and Dominican descent, had with excessive scarring on the face and dorsal aspect of the forearms, which initially led to the erroneous suspicion of child abuse. Although these lesions were photodistributed, overt photosensitivity had not been observed, with the exception of a single episode of blistering and onycholysis after intense sun exposure in 1 affected child. Mild facial hypertrichosis, chronic anemia, polyarticular arthritis, and developmental delay represented additional findings. Biochemical studies of urine, plasma, and erythrocyte porphyrins from the affected siblings established the diagnosis of HEP. Sequencing of the UROD gene revealed compound heterozygosity for a novel missense mutation, V166A, and a complex deletion/insertion, 645del1053ins10. CONCLUSIONS: Our report expands the phenotypic and genotypic spectrum of HEP, highlighting mild cutaneous presentations that can occur without obvious photosensitivity and masquerade as child abuse.

Porphyrins, porphyrin metabolism and porphyrias. IV. Pathophysiology of erythyropoietic protoporphyria--diagnosis, care and monitoring of the patient.

An extremely painful cutaneous condition with no or only slight visible skin changes, presenting in a child or an adult as an acute reaction to sun light, is probably a manifestation of the porphyrin metabolic disorder erythropoietic protoporphyria (EPP). The disease is the result of a genetically determined condition where a mutation in the gene for the final enzyme in the haem synthetic chain, ferrochelatase, results in impaired activity of the enzyme. In some predisposed individuals, the condition is accompanied by heavy accumulation of the substrate for the deficient enzyme, i.e. of protoporphyrin. Distributing to the skin, and there absorbing light of certain wavelengths, the metabolite generates free radicals that give rise to photodynamic cell injury. The primary event takes place in the endothelial cells of the superficial skin capillaries, but complement activation and mast cell degranulation in the surrounding tissue follow in the process. Even if the disease is primarily dermatological the hepatic and psychosocial complications are features requiring close attention by the physician. In order to provide a basis for suggestions regarding lege artis protocols for the diagnosis, treatment and monitoring of the patient with EPP, the pathophysiology of the cutaneous and hepatic manifestations are discussed in some detail in the article.

Hepatoerythropoietic porphyria: relationship with familial porphyria cutanea tarda.

Hepatoerythropoietic porphyria is characterized by an early beginning of severe photosensitivity, with an increase in urinary uroporphyrin excretion and other porphyrins, high isocoproporphyrin fecal levels and an accumulation of protoporphyrin in erythrocytes. It is caused by a dramatic decrease in the activity of the uroporphyrinogen decarboxylase. We report a clinical, biochemical and enzymatic study in a family, where a 2-year-old girl suffers from a hepatoerythropoietic porphyria, and the patient's maternal uncle from a porphyria cutanea tarda. We discuss the relationship between these diseases and their known mutations.

Erythropoietic protoporphyria, transfusion therapy and liver disease.

A 28-year-old man who had suffered from erythropoietic protoporphyria since infancy was referred because of worsening photosensitivity. Conventional therapy with beta-carotene, terfenadine and topical sunscreens was ineffective or not tolerated, and he was treated with transfusions of washed packed cells. Unexpectedly, his photosensitivity deteriorated further, his whole blood protoporphyrin levels doubled and he developed abnormal liver function tests. This is the first report of such an adverse response to blood transfusion therapy for erythropoietic protoporphyria and may have been related to subclinical hepatitis or the increased iron load associated with blood transfusion.

[Cholestatic erythrohepatic protoporphyria: porphyrin metabolism before and after liver transplantation]. / Cholestatische erythrohepatische Protoporphyrie: Porphyrinstoffwechsel vor und nach Lebertransplantation.

The ferrochelatase deficiency in protoporphyria leads to accumulation of protoporphyrin in erythrocytes and liver. Consequences are protoporphyrinemia with photosensitivity and liver damage (fibrosis, cirrhosis) with cholestasis. The latter are unpredictable and can be observed in about 10% of the patients. Protoporphyrin, the physiological main component of hepatocellular porphyrins, has a hepatotoxic effect in the high-concentrated crystalline storage form. The obligatory hepatobiliary excretion of the lipophil, erythropoietic increased accumulating protoporphyrin in protoporphyria strains the excretory function of the liver. Its restriction is followed by an exzessive protoporphyrin accumulation, which leads to protoporphyrin-induced, progressive cholestatic cirrhosis, icterus, and aggravation of the extrahepatic protoporphyrinemic cutaneous manifestation. In case of hepatobiliary complications a coproporphyria of diagnostic relevance develops with inversion of isomers. Simultaneously, the fecal protoporphyrin excretion decreases. After liver transplantation hyperbilirubinemia, protoporphyrinemia and coproporphyrinuria significantly went down. A protoporphyrinemia of about 20% of preoperative values reflects the persisting hereditary enzyme defect and the continuity of the metabolic disease.

Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP; MIM 177000) is an inherited disorder caused by partial deficiency of ferrochelatase (FECH), the last enzyme in the heme biosynthetic pathway. In EPP patients, the FECH deficiency causes accumulation of free protoporphyrin in the erythron, associated with a painful skin photosensitivity. In rare cases, the massive accumulation of protoporphyrin in hepatocytes may lead to a rapidly progressive liver failure. The mode of inheritance in EPP is complex and can be either autosomal dominant with low clinical penetrance, as it is in most cases, or autosomal recessive. To acquire an in-depth knowledge of the genetic basis of EPP, we conducted a systematic mutation analysis of the FECH gene, following a procedure that combines the exon-by-exon denaturing-gradient-gel-electrophoresis screening of the FECH genomic DNA and direct sequencing. Twenty different mutations, 15 of which are newly described here, have been characterized in 26 of 29 EPP patients of Swiss and French origin. All the EPP patients, including those with liver complications, were heterozygous for the mutations identified in the FECH gene. The deleterious effect of all missense mutations has been assessed by bacterial expression of the respective FECH cDNAs generated by site-directed mutagenesis. Mutations leading to a null allele were a common feature among three EPP pedigrees with liver complications. Our systematic molecular study has resulted in a significant enlargement of the mutation repertoire in the FECH gene and has shed new light on the hereditary behavior of EPP.

Successful therapeutic effect in a mouse model of erythropoietic protoporphyria by partial genetic correction and fluorescence-based selection of hematopoietic cells.

Erythropoietic protoporphyria is characterized clinically by skin photosensitivity and biochemically by a ferrochelatase deficiency resulting in an excessive accumulation of photoreactive protoporphyrin in erythrocytes, plasma and other organs. The availability of the Fech(m1Pas)/Fech(m1Pas) murine model allowed us to test a gene therapy protocol to correct the porphyric phenotype. Gene therapy was performed by ex vivo transfer of human ferrochelatase cDNA with a retroviral vector to deficient hematopoietic cells, followed by re-injection of the transduced cells with or without selection in the porphyric mouse. Genetically corrected cells were separated by FACS from deficient ones by the absence of fluorescence when illuminated under ultraviolet light. Five months after transplantation, the number of fluorescent erythrocytes decreased from 61% (EPP mice) to 19% for EPP mice engrafted with low fluorescent selected BM cells. Absence of skin photosensitivity was observed in mice with less than 20% of fluorescent RBC. A partial phenotypic correction was found for animals with 20 to 40% of fluorescent RBC. In conclusion, a partial correction of bone marrow cells is sufficient to reverse the porphyric phenotype and restore normal hematopoiesis. This selection system represents a rapid and efficient procedure and an excellent alternative to the use of potentially harmful gene markers in retroviral vectors.

Human protoporphyria: reduced cutaneous photosensitivity and lower erythrocyte porphyrin levels during pregnancy.

BACKGROUND: Women with erythropoietic protoporphyria (EPP) have reported increased sunlight tolerance during pregnancy. Review of clinical information in an existing database for an EPP population study found five women who had six pregnancies while enrolled. All had experienced attenuated photosensitivity during gestation. OBJECTIVE: Our purpose was to gain insight into whether altered porphyrin metabolism during pregnancy might explain this phenomenon. METHODS: Erythrocyte protoporphyrin levels obtained for these women during six periods of gestation were compared with data accumulated over the course of several years during nongestational periods. RESULTS: Erythrocyte porphyrin levels were lower during pregnancy. The differences of the means for values obtained during nongestational periods versus values obtained during pregnancy for each woman were found to reach or approach significance (p < 0.05) by a paired t test when analyzed without regard for seasonality (p = 0.042) or when adjusted for possible seasonal effects of sunlight on erythrocyte porphyrin levels by separation into data sets for low sunlight months (October-April) (p = 0.039) or high sunlight months (May-September) (p = 0.057). CONCLUSION: These observations suggest that a beneficial physiologic effect of pregnancy in patients with EPP may be a lower circulating erythrocyte protoporphyrin burden that leads to reduced photosensitivity.

Porfirias cutáneas / Cutaneous porphyrias

Las porfirias son un grupo heterogéneo de trastornos causados por un déficit parcial genético o adquirido de las enzimas que regulan la síntesis del grupo hemo. De acuerdo con la presencia o ausencia de fotosensibilidad cutánea, estas enfermedades pueden clasificarse en porfirias cutáneas y no cutáneas. Existen 5 tipos principales de porfirias cutáneas: la porfiria cutánea tarda (PCT); la porfiria variegata (PV); la coproporfiria hereditaria (CPH); la protoporfiria eritropoyética (PPE); y la porfiria eritropoyética congénita (PEC). La PV, CPH, PPE y la PCT tipo II son trastornos autonómicos dominantes con baja penetrancia. Las formas autosómicas recesivas (CEP y porfiria hepatoeritrocitaria, PHE) son trastornos de inicio precoz y muy raros. Las lesiones cutáneas en la PCT, la porfiria más frecuente, PV, CPH y PEC son similares: fragilidad mecánica, ampollas subepidérmicas, hipertricosis y pigmentación. PPE se caracteriza por una fotosensibilidad aguda y sin estas lesiones. Los ataques agudos de porfiria pueden ocurrir en la PV y CPH pero no en las otras porfirias cutáneas. La afectación hepática es una complicación infrecuente pero potencialmente fatal de la PPE. La PCT se asocia frecuentemente con enfermedad hepática crónica que a menudo es causada por el alcohol y suele ser leve. El diagnóstico clínico debe siempre confirmarse mediante análisis bioquimicos de porfirinas en orina, heces y sangre. La PCT puede ser tratada mediante sangrías repetidas para depleccionar los depósitos de hierro o mediante cloroquina a bajas dosis. El tratamiento de los otros tipos de porfiria cutánea es principalmente sintomático

The porphyrias are a heterogeneous group of disorders caused by genetically determined or acquired partial deficiencies of enzymes regulating heme biosynthesis. According to the presence or absence of cutaneous photosensitivity, these diseases can be classified into cutaneous and noncutaneous porphyrias. There are five main types of cutaneous porphyrias : porphyria cutanea tarda (PCT); variegate porphyria (VP); hereditary coproporphyria (He); erythropoietic protoporphyria (EPP); and congenital erythropoietic porphyria (CEP) Vp, HC, EPp, and one form of PCT (type II) are autosomal dominant conditions with low elinical penetrance. The autosomal recessive prophyrias (CEP and Hepatoerythropoietic porphyria, HEP) are rare disorders with early onset. The skin lesions in PCT (the commonest cutaneous porphyria), VP, HC, and CEP are similar: mechanical fragility, subepidermal bullae, hypertrichosis, and pigmentation. EPP is characterized by acute photosensitivity without these lesions. Acute attacks of porphyria may occur in VP and HC but not in other cutaneous porphyrias. Liver disease is an uncommon, potentially fatal, complication of EPP PCT is commonly associated with chronic liver disease, is often caused by alcohol and usually mild. The clinical diagnosis should always be confirmed by biochemical porphyrin analyses in urine, stool and blood. PCT can be treated by repeated venesection to deplete iron stores or with low-dose chloroquine. Treatment of the other cutaneous porphyrias is largely symptomatic

Porfiria hepatoeritrocitaria nueve años después:evolución de un caso y revisión de la literatura / Hepatoerythropoietic porphyria nine years later: evolution of a case and review of the literature

Se describe la evolución a lo largo de nueve años de una paciente afectada de porfiria hepatoeritrocitaria, que presenta clínica y hallazgos analíticos típicos, junto con una revisión bibliográfica de la evolución de otros casos de esta infrecuente enfermedad (AU)