|Other common terms: PCT|
|ICD-10 classification: E80.1|
|Prevalence: Uncommon; 1:25,000|
|Causes: Inherited disease; defective enzyme causes inability to properly produce haem (heme).|
|Symptoms: Skin photosensitivity causing extremely fragile skin and changes in pigmentation (melanin). Discoloured urine.|
|Treatments/cures: Cannot be cured. Avoidance of sunlight and certain artificial lights.|
|Differential diagnosis: Erythropoietic protoporphyria, polymorphous light eruption|
Porphyria cutanea tarda (PCT) is the most frequently seen disease of a group of disorders (the Porphyrias) that can be acquired or inherited. It is caused by low levels of an enzyme (uroporphyrinogen decarboxylase or UROD) involved in the production of haem (heme).
Haem is a component of hemoglobin in red blood cells and is vital as it needs it to carry oxygen around the body. These result in a build-up of chemicals called porphyrins. In PCT, porphyrins accumulate in the skin, causing the skin to be very sensitive to light (photosensitive).
In PCT, porphyrins accumulate in the skin, causing the skin to be very sensitive to light (photosensitive), causing blistering of the skin in areas that receive higher levels of exposure to sunlight.
Porphyria cutanea tarda is the most common of all the Porphyrias and occurs throughout the world, yet PCT is considered to be an uncommon condition, affecting about 1 in 25,000 of the population. All races are equally affected.
Before the widespread use of oestrogens in hormone replacement therapies and oral contraceptives, the disease developed predominantly in males but the incidence among sexes is approximately equal now. It should also be noted that males that are on oestrogen therapy have also developed PCT. Age of onset is usually around the ages of 30 - 40; to see the disorder before puberty it quite unusual.
An estimated 80% of porphyria cutanea tarda sufferers have sporadic PCT (Type I - acquired, not inherited) and the remaining 20% have familial PCT (Type II - inherited). Onset of the disease is usually in late adulthood between the ages of 30 - 40 years. It is unusual for the disease to manifest before puberty.
Porphyria cutanea tarda is caused by either an inherited or acquired deficiency of Uroporphyrin Decarboxylase (UROD), the enzyme involved in fifth step of haem synthesis. A decreased level of UROD causes accumulation of haem building-blocks (porphyrins) that have failed to be incorporated into haem. The porphyrins build up in the skin where they absorb both visible and ultraviolet light, causing the main symptoms of PCT. Porphyrin accumulation does not occur in normal people.
Not all family members that inherit the gene mutations associated with PCT will present with the disorder, therefore it is proposed that PCT requires other factors that increase the production of porphyrins to be present as well.
Most classifications of PCT separate it into two types, in which both are associated with low UROD activity.
- Type I - Sporadic or acquired PCT. It encompasses around 80% of cases. The enzyme deficiency is restricted to the liver with an approximated 50% of UROD levels. Acquired PCT occurs most commonly in patients who also have haemochromatosis or chronic hepatitis C infection. This form most often occurs after use of alcohol, oestrogens, oral contraceptives, other drugs and certain environmental pollutants but sometimes no cause can be found. Most people who consume alcohol and take estrogens do not develop a porphyria; therefore, it is likely that genetic factors are of higher importance even though there is no family history of PCT.
- Type II - Familial or hereditary. This type of PCT is an autosomal dominant disorder but inheritance of the mutated gene/s does not necessarily mean expression of skin disease nor can it predict the severity of the condition.The UROD gene has been mapped to chromosome 1p34. Mutations have been identified in the UROD gene, including DNA base substitutions and deletions. These mutations result in reduced activity of the enzyme. Some mutations result in PCT and others result in the recessively inherited HEP. HEP is the homozygous forms of familial PCT. Levels of UROD are also decreased to approximately to 50% in all tissues although porphyrins only accumulate in the liver. Many UROD mutations have been identified in patients with familial PCT and most carriers of mutant UROD alleles do not express a clinical phenotype unless additional factors are present.
Numerous precipitating factors are known to contribute to the development of both types of PCT. Each of these is discussed briefly in the following sections.
Ethanol has long been recognized to precipitate PCT. It has been shown to induce the hepatic enzyme ALA-synthase in patients along with diminished UROD activity after acute ingestion or in those who are chorinic alcoholics. Alcohol and cyclic hydrocarbons may also induce the ALA-synthetase gene, increasing Urogen, the precursor of UROD inhibitors thereby also decrease the activity of available UROD. Chronic alcoholism can also lead to the suppression of erythropoesis and increased absorption of dietary iron.
The important role of iron the in the pathogenesis of PCT is confirmed by elevated levels of ferritin and serum iron in individuals with PCT. Hepatic iron overload is almost present in all cases of PCT with total iron stores being approximately twice of normal levels. PCT is particularly common in those with alcoholism and iron overload together.
There are many complex hypotheses proposed about iron and its role in PCT pathogenesis:
- It may directly inhibit UROD.
- An ionic state of iron acts as a catalyst for the formation if reactive oxygen species that can cause lipid peroxidation and damage the lipid rich membranes of microsomes and mitochondria in the liver.
- Increased mutations in the HFE gene (encodes a human leukocyte antigen class I-like protein) have been found in British patients with type I PCT. This hemochromatosis mutation appears to be responsible for iron overload in many populations.
- Induction of the enzyme ALA-synthase by iron could also participate in the accumulation of porphyrins.
Reduction of iron levels has been shown to lead to the improvement or remission of many cutaneous lesions.
Research has found an association between human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Their roles in the pathogenesis of PCT is unclear but it has been suggested that chronic viral hepatitis may cause increased deposition of iron in the liver, which has been observed in biopsy specimens from patients with chronic hepatitis C.
The role of oestrogens in PCT is also unclear but an association between the use of oral contraceptives containing oestrogen and hormone supplements for both males, as an adjunct therapy for prostatic cancer and females, as post-menopausal hormone replacement therapy, has been found.
From the known of the affects from the above factors, it is possible that all or any of these could contribute to the excessive porphyrinogenesis characteristic of PCT.
The main clinical manifestation is blistering of the skin of sun-exposed areas, such as the back of the hands, forearms, face, ears, and neck. The skin becomes increasingly sensitive and fragile and any minor trauma leads to lesions and ulcerations that can become crusty and result in scarring when they resolve. Numerous small milia (cysts commonly known as ‘milk spots’) can also develop and patients find that they become very sensitive to light. This photosensitivity is due to the overproduction of porphyrins in the liver, due to the enzyme deficiency. They then leak out into the blood and build up in the skin, absorbing both UV and visible light. Other skin changes that can be seen include hyper or hypopigmentation, particularly on the face in spotty of diffuse patterns. Sclerodermoid plaques can also develop on sun exposed areas. These come in the form of scattered, white to yellow waxy plaques.
Hypertrichosis is frequently observed on the cheeks, temples, eyebrows and, less frequently, arms, legs and trunk. The hair can vary from a fine or course texture, vary in length and differ in colour. The hair may continue to grow, darken or thicken and is more apparent in females. Males often complain about changes in growth pattern of their beards and difficulty in shaving.
There is no curative treatment for porphyria cutanea tarda but avoidance of trigger factors that may have caused exacerbation of the disease can result in improvement. The main focus of treatment is to remove or decrease any triggers for PCT, reduce iron levels and to remove the excess porphyrin that has accumulated in the body. Avoidance of sunlight, alcohol and oestrogens and paying attention to skin care is particularly helpful in PCT. The most widely recommended treatment is repeated phlebotomies (removal of blood, see below) to deplete excess iron levels in the liver, thereby effectively reducing iron stores in the body. Antimalarials, chloroquine or hydroxychloroquin, are another approach to treatment when phlebotomies are contraindicated in patients with other medical conditions, as these work to increase porphyrin excretion through the urine.
If there is an inadequate response to either treatment alone, a combination of both therapies is used. Any viral infections found to be present should be treated accordingly.
Phlebotomies are the treatment of choice for PCT. It is effective because it depletes the excessive stores of iron in the liver and reducing iron levels in the body. Phlemboomies are considered safe and are associated with minimum morbidity. The amount of blood removed varies but is repeated every 2nd or every 3rd week; shorter intervals unnecessarily risk causing anemia. When serum iron or ferritin levels fall slightly below normal, phlebotomy is stopped. Usually, only 5 to 6 sessions are needed. Urine and plasma porphyrins fall gradually with treatment and continue to fall even after therapy is stopped. The skin eventually returns to normal but this can take several months to several years. After remission, further phlebotomy is needed only if there is a recurrence.
Phlebotomies are contraindicated in some patients because of the presence of anemia and cardiovascular disorders. Instead, low dose antimalarials such as chloroquine and hydroxychloroquine as used. They work by removing excess porphyrins from the liver by increasing the excretion rate. The mechanism might relate to forming water solubledrug-porphyrin complexes that are easily excreted. Remission can be seen within 6-12 months. Originally, higher doses were used to treat the condition but are no longer recommended because of liver toxicity.
If a trigger factor has been identified to have set off the disease then effort should be taken to reduce or eliminate exposure to that factor. Patients should avoid sun exposure where possible. Typical sunscreens that block UV light are ineffective, but UVA-absorbing sunscreens may be more beneficial. Wearing a hat and protective clothing is also highly recommended and considered the best form of protection from the sun.
Alcohol ingestion should be avoided permanently, but oestrogen supplementation can usually be resumed safely after the disease undergoes remission.
These treatments are not suitable for PCT patients who have advance renal disease. This is because there is usually underlying anemia and since renal activity is already low, drug-porphyrin complexes are not filtered out by the kidneys. The use of human recombinant erythropoietin mobilizes and reduces excess iron. It resolves the anemia enough to permit successful low volume phlebotomy.
Porphyria cutanea tarda is an important medical condition because it can be disfiguring if skin lesions are not treated. Remission can be achieved through avoidance of trigger factors or treatment and any reoccurrences respond well to the same treatments.
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- American Porphyria Foundation
- Australian Porphyria Association
- Brazilian Porphyria Association
- British Porphyria Association
- Canadian Association for Porphyria/Association Canadienne de Porphyrie
- Columbia Foundation for Porphyria
- Danish Porphyria Support Group
- European Porphyria Initiative
- French Prophyria Center - Centre Francais des Porphyries
- German EPP Association (Selbsthilfe EPP e.V.) - Available in German and English
- Italian Porphyria Association
- Mount Sinai Department of Genetics and Genomic Sciences
- Nordic Porphyria Support Group
- Norway Porphyria Foundation
- Porphyria Association Denmark
- SAKURA - Japanese porphyria patients group
- South African Porphyria Association
- Spanish Porphyria Foundation
- Swedish Porphyria Association
- Swiss Porphyria Association