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Porphyria Cutanea Tarda

PCT

Porphyria cutanea tarda (PCT) is the most common type of porphyria [1], a group of rare diseases consisting in the overproduction of porphyrins, the compounds necessary to produce heme, due to the deficiency of an enzyme responsible for their transformation.


Presentation

The most common early sign of PCT is a general cutaneous fragility, especially apparent after mechanical trauma leading to the formation of characteristic crusted skin erosions. Very common is also blistering, which appears mainly on hands and forearms, but sometime on feet and face as well. Hypertrichosis appears both on arms and legs and might be accompanied by substantial pigmentary changes like melasma-like hyperpigmentation, especially on the face. Scarring alopecia and separation of nail plates might also be noted, particularly in the most severe cases, together with marked changes in hair growth.

Frequent is also a history of previous episodes of exposure to one or more environmental or biological factors, like hepatitis C virus infection or alcohol, both in sporadic and familial cases of PCT. Furthermore, urine frequently appears dark or reddish in color, with a tea- or wine-like appearance. As previously said, childhood cases are rare, but their occurrence suggests the presence of either heterozygous or homozygous familial forms of PCT, unless it is observed in the context of clear exposure to etiological factors.

PCT is classified into three types:

  • Type I, Sporadic PCT including the cases caused by non-genetic factors. The subjects affected by this form of PCT do not carry mutations on the UROD gene.
  • Type II, Familial PCT including the cases mainly caused by mutations on the UROD gene which are inherited from generation to generation with an autosomal dominant patter. 
  • Type III [7] where the patients possess normal UROD gene. This indicates the substantial role played by other genetic components unrelated to UROD expression in the origin of this PCT form. Type III is the less common of the three forms observed. 
Acute Intermittent Porphyria
  • So-called congenital or erythropoietic 1 porphyria with severe light sensitivity is probably inherited as a recessive trait in man, and is certainly recessive in cattle. 2 Acute intermittent porphyria is a dominant character. 3, 4 Dean and Barnes 5, 6[annals.org]
  • Intermittent Porphyria (AIP) Hereditary Coproporphyria (HCP) Variegate Porphyria (VP) ALAD-Deficiency Porphyria (ADP) Porphyria Cutanea Tarda (PCT) Erythropoietic Protoporphyria (EPP) and X-Linked Protoporphyria (XLP) Congenital Erythropoietic Porphyria[porphyriafoundation.com]
  • intermittent porphyria ALAD deficiency porphyria Congenital erythropoietic porphyria Erythropoietic protoporphyria Hepatoerythropoietic porphyria Hereditary coproporphyria Porphyria cutanea tarda Variegate porphyria GeneReviews acute intermittent porphyria[genome.gov]
Turkish
  • A 59-year-old Turkish man presented with hyperpigmented skin lesions, fatigue, and elevated ferritin level and liver function tests. He was diagnosed as having porphyria cutanea tarda after a clinical investigation and treated with phlebotomy.[ncbi.nlm.nih.gov]
Blister
  • Patients were treated with 250 mg/d of deferasirox, with an increase to 500 mg/d after 2 months if new blisters continued to develop.[ncbi.nlm.nih.gov]
  • Another blistering disease that has been described in association with cutaneous and systemic LE is porphyria cutanea tarda (PCT).[ncbi.nlm.nih.gov]
  • SCLE with blister formation is a rare cause of bullous skin eruptions and has to be distinguished from bullous autoimmune diseases as well as from bullous SLE.[ncbi.nlm.nih.gov]
  • A hemodialysis patient with hepatitis C virus infection developed painful blisters on her hands that burst spontaneously. She was found to have serum porphyrin levels 2000 nmol/L.[ncbi.nlm.nih.gov]
  • From Wikidata Jump to navigation Jump to search acute porphyria characterized by painful, blistering skin lesions that develop on sun-exposed skin edit English porphyria cutanea tarda acute porphyria characterized by painful, blistering skin lesions that[wikidata.org]
Photosensitivity
  • Liver abnormalities may develop in some people with the condition and PCT, in general, is associated with an increased risk of liver cirrhosis and liver cancer. 0008066 Cutaneous photosensitivity Photosensitive skin Photosensitive skin rashes Photosensitivity[rarediseases.info.nih.gov]
  • Systemic lupus erythematosus, of complex pathophysiology and pleomorphic clinical manifestations, is similar to PCT regarding photosensitivity.[ncbi.nlm.nih.gov]
  • We describe three HIV-positive patients, which showed photosensitivity as well as the emergence of tense blisters on sun-exposed areas during the use of highly active antiretroviral therapy (HAART) and discuss the possibility of PCT after the use of these[ncbi.nlm.nih.gov]
  • Porphyria is a condition of cutaneous photosensitivity. It is unclear if radiotherapy (RT) is safe in patients with porphyria.[ncbi.nlm.nih.gov]
  • The porphyrias are a group of inherited disorders that result in defects in the enzymes of the haem biosynthetic pathway, causing photosensitive bullous skin eruptions or abdominal and neurological attacks.[ncbi.nlm.nih.gov]
Hypertrichosis
  • Of our patients, 11.8% did not present the typical clinical onset of the disease, with facial hypertrichosis and hyperpigmentation the more frequent complaints in these cases.[ncbi.nlm.nih.gov]
  • Here, we report on a 57-year-old Caucasian woman of Dutch origin with a medical history of mild cutaneous LE who developed skin fragility, blistering skin lesions, milia, and facial hypertrichosis.[ncbi.nlm.nih.gov]
  • […] extremely rare circumstances, patients with PCT initially are misdiagnosed as having generalized morphea, or PSS, because they lack the typical skin findings of PCT, such as blisters, skin fragility, scarring on the dorsal aspects of the hands, and facial hypertrichosis[ncbi.nlm.nih.gov]
  • Facts : Deficiency of uroporphyrinogen decarboxylase (enzyme in heme synthesis) Triggered by certain substances (eg. ethanol, estrogrens) History / PE : Painless blisters Facial hypertrichosis Increased skin fragility Hyperpigmentation Diagnosis : Elevated[medlibes.com]
  • Additionally, hyperpigmentation, hypertrichosis, sclerodermoid plaques, and scarring alopecia might be observed.[ncbi.nlm.nih.gov]
Skin Lesion
  • This case identifies porphyria cutanea tarda as an important differential diagnosis for the rheumatologist to consider when evaluating patients with bullous skin lesions.[ncbi.nlm.nih.gov]
  • From Wikidata Jump to navigation Jump to search acute porphyria characterized by painful, blistering skin lesions that develop on sun-exposed skin edit English porphyria cutanea tarda acute porphyria characterized by painful, blistering skin lesions that[wikidata.org]
  • During antiviral therapy, he developed skin lesions on his hands characterized by vesicles and erosions consistent with PCT. PCT was confirmed by skin biopsy and elevated urinary uroporphyrin levels (1,469 mg/24 h).[ncbi.nlm.nih.gov]
  • The porphyrias are a group of disorders of the heme biosynthesis pathway that present with acute neurovisceral symptoms, skin lesions or both.[ncbi.nlm.nih.gov]
  • Here, we report on a 57-year-old Caucasian woman of Dutch origin with a medical history of mild cutaneous LE who developed skin fragility, blistering skin lesions, milia, and facial hypertrichosis.[ncbi.nlm.nih.gov]
Cutaneous Manifestation
  • We report a unique cutaneous manifestation of PCT that is not well documented: unusually large, nonhealing ulcers in the setting of sclerodermatous skin changes and scarring alopecia.[ncbi.nlm.nih.gov]
  • Although apparently rare, PCT has been described as possible cutaneous manifestation both of hepatic tumors and interferon treatment.[ncbi.nlm.nih.gov]
  • While patients with erythropoietic protoporphyria and those with porphyria cutanea tarda both have skin lesions on sun-exposed areas, there are differences in their cutaneous manifestations.[ncbi.nlm.nih.gov]
  • Cutaneous manifestations of the disease are characterized chiefly by a light- and trauma-sensitive eruption of exposed areas. In two cases occurring secondary to estrogens, improvement followed estrogen withdrawal.[jamanetwork.com]
Malar Rash
  • A 29-year-old woman with a 1.5 year history of photosensitive skin lesions on her hands presented with a malar rash, bullous lesions on her hands, and was diagnosed with subacute lupus erythematosus after serologies revealed a positive antinuclear antibody[ncbi.nlm.nih.gov]
Tonic-Clonic Seizure
  • Tonic- clonic seizures were eventually controlled by a combination of clonazepam (9 mg/day) and lamotrigine (150 mg/day), but absences persisted and this treatment caused significant adverse effects consisting of sedation and memory disturbances.[ncbi.nlm.nih.gov]
Red Urine
  • HEP usually presents in infancy or childhood with red urine, blistering skin lesions and scarring. Hemolytic anemia, associated with splenomegaly, is commonly present in these patients due in part to the deposition of porphyrins in the bone marrow.[themedicalbiochemistrypage.org]
  • Diagnostically meaningful is also red urine, whose dark color is the result of the great concentration of porphyrins.[symptoma.com]
Dark Urine
  • Porphyric symptoms were skin lesions, blisters, pigmentation, hypertrichosis, cutaneous fragility and dark urine was present in the majority of the individuals.[omicsonline.org]

Workup

The workup of PCT usually requires historical and physical examination followed by biochemical and confirmatory tests [8]. The historical and physical examination includes the search for blisters and crusted lesions on the key spots, that is the back of the hands and the sun-exposed areas of the skin, together with other skin manifestations such as hyperpigmentation, hypertrichosis and scarring alopecia. Diagnostically meaningful is also red urine, whose dark color is the result of the great concentration of porphyrins.

The presence of risks factors, like excess alcohol intake or smoking, might be very important for diagnostic purposes, since their increase the susceptibility to develop PCT. In some patients it can also be noticed a certain deficiency of antioxidants like vitamin C [9] [10], which can be seen as additional diagnostic conformation.

Biochemical tests should be performed after the historical and physical examination. These include urine and porphyrin levels, serum ferritin and liver or skin biopsy. DNA studies might also be useful to identify the mutations on the UROD gene and their influence on the pathogenesis of the disorder. Measurement of total porphyrins is an important confirmatory test, as the increase of these compounds in urine or blood plasma is a highly specific aspect of PCT. Increased fecal isocoproporphyrin is another highly specific feature, but less frequently used due to its technical difficulties.

Human Herpesvirus 6
  • Here we describe a case that might deliver a link between sporadic porphyria cutanea tarda (PCT) and human-herpesvirus-6 (HHV6) hepatitis. Sporadic PCT is a rare disease of the heme synthesis pathway.[ncbi.nlm.nih.gov]
Hepatocellular Carcinoma
  • Patients with severe hepatic pathology or longstanding untreated PCT need to be monitored for the development of hepatocellular carcinoma in the long term.[ncbi.nlm.nih.gov]
  • In the literature, concomitant presentation of porphyria with hepatocellular carcinoma is common; however, no case of porphyria cutanea tarda associated with cholangiocarcinoma has been seen.[ncbi.nlm.nih.gov]
  • Liver damage might present in a wide range of ways from liver function test abnormalities to hepatocellular carcinoma. The toxic effect of iron plays a role in liver damage pathogenesis.[ncbi.nlm.nih.gov]
  • Liver fibrosis and cirrhosis are predisposing factors for the development of hepatocellular carcinoma (HCC). Hemosiderosis has also been described to trigger carcinogenesis.[ncbi.nlm.nih.gov]
  • One patient developed hepatocellular carcinoma (HCC) during a median follow-up of 24 years.[ncbi.nlm.nih.gov]

Treatment

The first treatment for PCT is undoubtedly the avoidance of all those factors which might exacerbate the disorder, such as alcohol consumption, iron supplements, estrogens or exposure to sunlight. Management of the excess of iron is carried out by performing therapeutic phlebotomy. Antimalarials (oral chloroquine phosphate or hydroxychloroquine sulfate) have also proved to be very effective, although taken in low doses, because higher ones might cause liver toxicity.

Prognosis

The prognosis of PCT is usually excellent when an appropriate treatment is provided, which should give a positive outcome within 6 months from its beginning. Recurrence is highly possible.

Etiology

The major causes of PCT include the inherited mutations of the UROD gene, which together are responsible for around 20% of all the cases. The mutations are inherited with an autosomal dominant pattern, because of which just one copy of the mutated gene is already sufficient to decrease substantially the activity of UROD and cause the typical signs and symptoms of this disorder. In the inherited forms of PCT, the activity of UROD is usually reduced by 50% in all the tissues of the affected subjects.

Another genetic cause of PCT is represented by the mutations on the already mentioned HFE gene, which when mutated causes hemochromatosis, a well known type of disorder due to plasma iron overload. The subjects affected by HFE are also at high risk of developing PCT because of the iron overload itself.

The other 80% of the cases involve no mutation and are defined as sporadic. These include all the other non-genetic factors which increase the demand of heme and the enzymes required to produce it. In other words, all those specific environmental factors and infectious agents which increase the susceptibility towards PCT through a substantial oxidative stress. These factors include the previously mentioned alcohol abuse, iron overload, and all the other factors which lead to iron retention, such as hemochromatosis, myelofibrosis, and end-stage renal disease.

Whatever is the main etiological factor, heme synthesis is disrupted and the byproducts of this process begin to spread and accumulate throughout the body triggering the signs of PCT.

Epidemiology

PCT is rare in children but very common in middle-aged men and in women who make use of estrogens. The incidence of PCT has not yet established with accuracy, but from the available statistical data it appears that the incidence varies according to the geographical area, a trend that is believed to reflect geographic variations in the prevalence of the susceptibility factors. On the contrary, incidence has been better determined in UK, where it is estimated to be around 2 to 5 cases every million inhabitants [5]. Prevalence too has not been established yet, apart from the US where it appears to be around 1 case every 25,000 inhabitants [5].

Sex distribution
Age distribution

Pathophysiology

The primary cause of PCT is the deficiency in the activity of the UROD enzyme. As already mentioned, this is a protein regulating the fifth step of the biochemical pathway leading to the heme synthesis. When this deficiency is substantial, the biochemical pathway is blocked which leads to a buildup of porphyrin compounds, which cannot be turned in heme, near the surface of the skin, causing the appearance of numerous stains and crusted lesions in deep purple color as the dermatological evidence of the pathological biochemical process underway.

Excess of sunlight is believed to cause the synthesis of active oxygen species, which in turn disrupt the activity of UROD leading to the buildup of porphyrin compounds previously mentioned. This explains the characterizing photosensitivity usually observed in subjects affected by PCT.

The association between PCT and hepatitis C infection, instead, is not yet precisely determined. However, according to several studies the cytopathic effect of this virus might cause a substantial iron release, which in turn increases the synthesis of activated oxygen species and thus the oxidation of UROD substrate (uroporphyrinogen). The increase in the synthesis of oxidized species is also thought to be caused by excess of alcohol, which determines a further oxidation of uroporphyrinogen and thus a further inhibition of the UROD enzyme itself.

Smoking is especially associated with the early symptoms of sporadic PCT, maybe through the induction of an hepatic cytochome which might contribute in uroporphyringen oxidation [6]. In any case, experimental evidence is still feeble to demonstrate the status of smoking as independent pathogenic factor.

Prevention

Patients are strongly advised to discontinue or reduce exposure to all those factors which increase susceptibility to develop PCT, such as alcohol intake, smoking, and estrogen use. The exposure to some of them should be avoided even after remission, like in the case of the already mentioned alcohol abuse or smoking, while the exposure to others might be resumed if clinically indicated, like in the case of estrogen use. Compliance with clinical treatment is highly recommended, together with a follow-up at 6-month intervals, to control the plasma levels and avoid any future recurrence of PCT.

Summary

The pathological condition underlying porphyria cutanea tarda (PCT) is the low level of uroporphyrinogen decarboxylase (UROD), the enzyme regulating the fifth step of the biochemical synthesis of heme in the liver, as a consequence of a substantial and often acquired deficiency of this protein.

The disorder is easily recognizable by blisters or crusted skin lesions usually found on the back of hands or in other sun-exposed areas of the body. Other characteristic signs of PCT include dark or reddish urine, general skin fragility, hyperpigmentation, and hypertrichosis.

Apart from the mutations on UROD gene, mutations on the hereditary hemochomatosis gene (HFE), a membrane protein similar to MCH class I-type believed to regulate iron intake by modulating the interaction between transferrins and their receptor, appear to contribute substantially to the susceptibility of this disorder. Other contributing factors include alcohol use [2], smoking, iron overload [3], and HIV and hepatitis C infection [4].

Patient Information

Porphyria cutanea tarda (PCT) is the most common type of porphyria, a group of rare diseases consisting in the overproduction of porphyrins which are necessary to produce heme, a component of hemoglobin and certain other proteins. The disorder is easily recognizable by the blistering or the crusted skin lesions usually found on the back of hands or in other sun-exposed points of the body. Other characteristic signs of PCT include dark or reddish urine and hyperpigmentation. PCT can be either acquired or familial (inherited). Other contributing factors include alcohol use, smoking, iron overload as well as HIV and hepatitis C infection. PCT is very rare in children but very common in middle-aged men and in women who make use of estrogens.

Management includes the avoidance of triggering factors, phlebotomy and taking a small dose of antimalarials. The prognosis of PCT is usually excellent when the appropriate treatment is provided. If properly performed, treatment should give a positive outcome within 6 months from its beginning. Recurrence is highly possible, and when it occurs the patient should be treated in the same manner. In any case, patients are strongly advised to discontinue or reduce exposure to all those factors which increase susceptibility to develop PCT, such as alcohol intake, smoking, and estrogen use.

References

Article

  1. Phillips JD, Bergonia HA, Reilly CA, Franklin MR, Kushner JP. A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proc. Natl. Acad. Sci. U.S.A. 2007 104 (12): 5079–84.
  2. Frank J, Poblete-Gutiérrez P, Weiskirchen R, Gressner O, Merk HF, Lammert F. Hemochromatosis gene sequence deviations in German patients with porphyria cutanea tarda. Physiol Res 2006 55 (Suppl 2): S75–83.
  3. Sampietro M, Fiorelli G, Fargion S. Iron overload in porphyria cutanea tarda. Haematologica 1999 84 (3): 248–53.
  4. Azim J, McCurdy H, Moseley RH. Porphyria cutanea tarda as a complication of therapy for chronic hepatitis C. World J. Gastroenterol. 2008 14 (38): 5913–5.
  5. Phillips JD, Anderson KE. The porphyrias. In: Kaushansky K, Lichtman MA, Beutler E, et al, eds. Williams hematology. 8th ed. New York, NY: McGraw-Hill; 2010:839-863.
  6. Fontanellas A, Martinez-Fresno M, Garrido-Astray MC, et al. Smoking but not homozygosity for CYP1A2 g-163A allelic variant leads to earlier disease onset in patients with sporadic porphyria cutanea tarda. Exp Dermatol. Feb 16 2010.
  7. Méndez M, Poblete-Gutiérrez P, García-Bravo M et al. Molecular heterogeneity of familial porphyria cutanea tarda in Spain: characterization of 10 novel mutations in the UROD gene. Br. J. Dermatol. 2007 157 (3): 501–7.
  8. Balwani M, Desnick RJ. The porphyrias: advances in diagnosis and treatment. Blood. 2012;120:4496-4504.
  9. Sinclair PR, Gorman N, Shedlofsky SI, et al. Ascorbic acid deficiency in porphyria cutanea tarda. J Lab Clin Med. 1997;130:197-201.
  10. Rocchi E, Stella AM, Cassanelli M, et al. Liposoluble vitamins and naturally occurring carotenoids in porphyria cutanea tarda. Eur J Clin Invest. 1995;25:510-514.

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Last updated: 2019-07-11 20:44