BASICS
Porphyria cutanea tarda (PCT) is a condition caused by a defect in the heme biosynthesis pathway in which there is decreased activity of the hepatic uroporphyrinogen decarboxylase (UROD) enzyme " ”the fifth enzyme of the heme biosynthesis pathway. This leads to a buildup of uroporphyrinogen in the blood and urine. Porphyrins in the skin absorb ultraviolet light and cause oxidative damage and inflammation. ‚
DESCRIPTION
- There are eight types of porphyrias, with PCT being the most common. It results in cutaneous manifestations including painful photosensitivity, skin fragility, blistering, burning, and scarring.
- Can exist as sporadic (type 1), inherited (type 2), or familial (type 3) (1)
- Sporadic (type 1) involves the skin and liver. Accounts for 80 " “90% of cases
- Inherited (type 2) accounts for 10 " “20% of cases.
- Familial (type 3) is rare and accounts for approximately 5% (1).
EPIDEMIOLOGY
- Sporadic type is more common in men.
- Onset usually after age 30 years
Prevalence
1 in 25,000 in the United States (1) ‚
ETIOLOGY AND PATHOPHYSIOLOGY
- When UROD enzyme activity becomes <20% of normal, porphyrins accumulate in the liver and are transported to the skin.
- Once in the skin, porphyrins are activated by ultraviolet light forming active oxygen species which cause damage to proteins, lipids, and the basement membranes. This results in complement activation and mast cell degranulation leading to skin fragility and blistering (2).
- Sporadic PCT is caused by an acquired deficiency of hepatic UROD. Other tissues are not involved.
- Inherited PCT results from an inherited defect in the UROD gene causing decreased enzyme activity. This affects all tissues.
- Familial (type 3) does not affect the UROD gene directly. There is a decreased hepatic UROD level but normal erythrocyte UROD level. Therefore, it is an inherited defect of an unknown factor (1).
- Exposure to certain substances may be exacerbating factors for PCT including alcohol, estrogens, chemicals, drugs, and iron overload (3).
- Sun-exposed areas of the body, such as the hands, are affected.
Genetics
- Type 2, or inherited PCT, is an autosomal dominant condition with low penetrance.
- The UROD gene is located on chromosome 1p34.1 (1). Multiple mutations have been studied that lead to type 2 PCT.
- Type 3 is an inherited defect that is not directly related to UROD gene.
RISK FACTORS
- Alcohol
- Hepatitis C
- Estrogens
- Smoking
- HIV infection
- Diabetes mellitus type 2
- Hemochromatosis (4 times more likely to develop PCT) (3)
- Iron overload
- Dialysis-dependent renal failure
COMMONLY ASSOCIATED CONDITIONS
- Hepatitis C
- Hemochromatosis
- Alcoholic liver disease
- Hepatocellular carcinoma
- Systemic lupus erythematosus (4)
DIAGNOSIS
Presentation may vary depending on the type of PCT because of the different pathophysiologic processes associated with each type. ‚
HISTORY
- Development of skin changes with sun exposure such as burning, itching, erythema, fragile skin, subepidermal bullae, changes in skin pigmentation, increased hair growth, and scleroderma-like plaques
- Skin findings occur in areas exposed to sun. Often present on the dorsal side of the hands and forearms
- History of exposure to triggers such as alcohol, estrogens, or a history of hepatitis C or HIV
- History of iron overload
- Review of systems is negative for GI/neurologic symptoms (differentiates PCT from acute intermittent porphyria).
PHYSICAL EXAM
- Skin findings in sun-exposed areas
- Skin erythema
- Hyper-/hypopigmentation
- Hemorrhagic bullae/vesicles (might get secondarily infected) (5)
- Increased hair growth
- Fragile skin with slow healing
- Lid scarring, lacrimal scarring, and corneal thinning is due to the deposition of the photoactive porphyrins.
- Hepatomegaly may be present on physical exam.
- Port wine or tea-colored urine (6)
- Pink fluorescence of teeth under ultraviolet light secondary to buildup of porphyrins in teeth (7)
DIFFERENTIAL DIAGNOSIS
- Other porphyrias, including congenital erythropoietic porphyria (CEP), hepatoerythropoietic porphyria (HEP), hereditary coproporphyria, and variegate porphyria
- Photodrug reactions
- Pseudoporphyrias
- Bullous lupus
- Chronic hand eczema
- Epidermolysis bullosa acquisita
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
Markedly elevated urine porphyrins levels ‚
- 24-hour urine collection may show urinary porphyrins >800 Ž ¼g/day.
- Normal levels 10 to 50 Ž ¼g/day
- Urine may demonstrate orange-red fluorescence under ultraviolet light (8).
- Total plasma porphyrin measurement demonstrating markedly elevated porphyrin levels
- 24-hour stool collection for porphyrins may be normal/moderately increased. However, elevated levels of fecal isocoproporphyrin can be used to diagnose UROD deficiency (8).
- Hepatic involvement of PCT involves elevated aminotransferases and gamma-glutamyl transpeptidases (1).
Follow-Up Tests & Special Considerations
- Measurement of UROD enzyme activity can confirm the diagnosis.
- Molecular studies aiming to measure erythrocyte UROD is helpful in differentiating type 1 from familial type 2 (5).
- Patients with PCT should be evaluated for risk factors because management may be affected.
- Other labs to consider:
- Iron studies to evaluate for iron overload
- Hepatitis panel
- HIV screening
- α-Fetoprotein (AFP) for hepatocellular carcinoma screening
- Serum glucose and/or HbA1c
- Consider genetic testing for HFE mutation causing hemochromatosis because there is an association.
- Hepcidin levels have been found to be elevated in patients with PTC and correlate with elevated IL-6 and ferritin levels (9).
Diagnostic Procedures/Other
- Skin biopsy of active lesion
- Liver biopsy may be considered to determine extent of liver disease. Tissue may show immunofluorescence under ultraviolet light.
Test Interpretation
- Skin biopsy may show nonspecific pathology, including subepidermal bullae with minimal dermal infiltrate and dermal papillae protruding upward into blister cavity (6).
- Caterpillar bodies may be seen on skin biopsy, which are diagnostic for PCT (5).
- Fluorescence may be seen when tissue sample (liver, skin) or urine is placed under ultraviolet light, indicating accumulation of porphyrins.
TREATMENT
- Therapeutic phlebotomy is the preferred treatment, especially for patients with iron overload. Phlebotomy decreases serum ferritin levels, reducing iron stores, and improving hemoglobin synthesis (3,6)[A].
- Oral low-dose hydroxychloroquine (100 mg twice daily) or chloroquine (125 mg twice daily) should be considered as an alternative to repeated phlebotomies. This works to increase excretion of porphyrins in the urine (8,10)[A].
- Avoidance of sunlight. Use of reflective sunscreen/protective clothing is recommended (10)[C].
- Avoidance of alcohol and estrogens (3,10)[C]
- Supportive care of skin lesions
- Smoking cessation (3,10)[C]
- Consider treatment of hepatitis C in patients with PCT (1).
ADDITIONAL THERAPIES
Treatment of underlying conditions should be considered such as hepatitis C, HIV infection, and hemochromatosis. ‚
ONGOING CARE
Patients with PCT are at increased risk of developing hepatocellular carcinoma if they have chronic liver disease. ‚
FOLLOW-UP RECOMMENDATIONS
May need periodic phlebotomies with recurrence of symptoms ‚
REFERENCES
11 Lambrecht ‚ RW, Thapar ‚ M, Bonkovsky ‚ HL. Genetic aspects of porphyria cutanea tarda. Semin Liver Dis. 2007;27(1):99 " “108.22 Lan ƒ §oni ‚ G, Ravinal ‚ RC, Costa ‚ RS, et al. Mast cells and transforming growth factor-beta expression: a possible relationship in the development of porphyria cutanea tarda skin lesions. Int J Dermatol. 2008;47(6):575 " “581.33 Thadani ‚ H, Deacon ‚ A, Peters ‚ T. Diagnosis and management of porphyria. BMJ. 2000;320(7250):1647 " “1651.44 Gibson ‚ GE, McEvoy ‚ MT. Coexistence of lupus erythematosus and porphyria cutanea tarda in fifteen patients. J Am Acad Dermatol. 1998;38(4):569 " “573.55 Horner ‚ ME, Alikhan ‚ A, Tintle ‚ S, et al. Cutaneous porphyrias part I: epidemiology, pathogenesis, presentation, diagnosis, and histopathology. Int J Dermatol. 2013;52(12):1464 " “1480.66 Welsh ‚ B. Blistering skin conditions. Aust Fam Physician. 2009;38(7):484 " “490.77 Kuwahara ‚ RT, Swann ‚ MH, Rasberry ‚ RD. Glowing teeth. Am Fam Physician. 2005;71(1):123 " “124.88 Balwani ‚ M, Desnick ‚ RJ. The porphyrias: advances in diagnosis and treatment. Hematology Am Soc Hematol Educ Program. 2012;2012:19 " “27.99 Darwich ‚ E, To-Figueras ‚ J, Molina-L ƒ ³pez ‚ RA, et al. Increased serum hepcidin levels in patients with porphyria cutanea tarda. J Eur Acad Dermatol Venereol. 2013;27(1):e68 " “e74.1010 Tintle ‚ S, Alikhan ‚ A, Horner ‚ ME, et al. Cutaneous porphyrias part II: treatment strategies. Int J Dermatol. 2014;53(1):3 " “24.
ADDITIONAL READING
- Anderson ‚ KE, Bloomer ‚ JR, Bonkovsky ‚ HL, et al. Recommendations for the diagnosis and treatment of the acute porphyrias. Ann Intern Med. 2005;142(6):439 " “450.
- Cloeren ‚ M, Craig ‚ E. Images in clinical medicine. Porphyria cutanea tarda. N Engl J Med. 2001;345(14):e3.
- Jalil ‚ S, Grady ‚ JJ, Lee ‚ C, et al. Associations among behavior-related susceptibility factors in porphyria cutanea tarda. Clin Gastroenterol Hepatol. 2010;8(3):297.e1 " “302.e1.
- Puy ‚ H, Gouya ‚ L, Deybach ‚ JC. Porphyrias. Lancet. 2010;375(9718):924 " “937.
CODES
ICD10
E80.1 Porphyria cutanea tarda ‚
ICD9
277.1 Disorders of porphyrin metabolism ‚
SNOMED
- Porphyria cutanea tarda (disorder)
- Sporadic porphyria cutanea tarda (disorder)
- Familial porphyria cutanea tarda (disorder)
CLINICAL PEARLS
- PCT is a condition that results from a defect in the UROD enzyme in the heme synthesis pathway, causing skin and liver manifestations.
- Diagnosis should be considered in patients presenting with skin lesions such as bullae, fragile skin, hemorrhagic lesions, and blisters associated with sun exposure.
- Marked increase in porphyrin levels in the blood, urine, and/or stool may confirm the diagnosis.
- Treatment includes therapeutic phlebotomy, oral hydroxychloroquine or chloroquine, and avoidance of sun exposure with supportive care of skin lesions.
- Multiple risk factors have been associated with PCT including hepatitis C, hemochromatosis, HIV infection, alcohol use, and estrogen use.