Porphyria cutanea tarda is the most common subtype of porphyria.
The disease is named because it is a porphyria that often presents with skin manifestations
later in life.
The disorder results from low levels of the enzyme responsible for the fifth step in heme
production.
Heme is a vital molecule for all of the body's organs.
It is a component of hemoglobin, the molecule that carries oxygen in the blood.
Hepatoerythropoietic porphyria has been described as a homozygous form of porphyria cutanea
tarda, although it can also be caused if two different mutations occur at the same locus.
Signs and symptoms Porphyria cutanea tarda is recognized as the
most prevalent subtype of porphyritic diseases.
The disease is characterized by onycholysis and blistering of the skin in areas that receive
higher levels of exposure to sunlight.
The primary cause of this disorder is a deficiency of uroporphyrinogen decarboxylase, a cytosolic
enzyme that is a step in the enzymatic pathway that leads to the synthesis of heme.
While a deficiency in this enzyme is the direct cause leading to this disorder, there are
a number of both genetic and environmental risk factors that are associated with PCT.
Typically, patients who are ultimately diagnosed with PCT first seek treatment following the
development photosensitivities in the form of blisters and erosions on commonly exposed
areas of the skin.
This is usually observed in the face, hands, forearms, and lower legs.
It heals slowly and with scarring.
Though blisters are the most common skin manifestations of PCT, other skin manifestations like hyperpigmentation
and hypertrichosis also occur.
PCT is a chronic condition, with external symptoms often subsiding and recurring as
a result of a number of factors.
In addition to the symptomatic manifestation of the disease in the skin, chronic liver
problems are extremely common in patients with the sporadic form of PCT.
These include hepatic fibrosis, cirrhosis, and inflammation.
However, liver problems are less common in patients with the inherited form of the disease.
Additionally, patients will often void a wine-red color urine with an increased concentration
of uroporphyrin I due to their enzymatic deficiency.
Cause Genetics
Inherited mutations in the UROD gene cause about 20% of cases.
UROD makes an enzyme called uroporphyrinogen III decarboxylase, which is critical to the
chemical process that leads to heme production.
The activity of this enzyme is usually reduced by 50% in all tissues in people with the inherited
form of the condition.
Nongenetic factors such as alcohol abuse, excess iron, and others listed above can increase
the demand for heme and the enzymes required to make heme.
The combination of this increased demand and reduced activity of uroporphyrinogen decarboxylase
disrupts heme production and allows byproducts of the process to accumulate in the body,
triggering the signs and symptoms of porphyria cutanea tarda.
The HFE gene makes a protein that helps cells regulate the absorption of iron from the digestive
tract and into the cells of the body.
Certain mutations in the HFE gene cause hemochromatosis.
People who have these mutations are also at an increased risk of developing porphyria
cutanea tarda.
In the 20% of cases where porphyria cutanea tarda is inherited, it is inherited in an
autosomal dominant pattern, which means one copy of the altered gene is sufficient to
decrease enzyme activity and cause the signs and symptoms of the disorder.
Other While inherited deficiencies in uroporphyrinogen
decarboxylase often lead to the development of PCT, there are a number of risk factors
that can both cause and exacerbate the symptoms of this disease.
One of the most common risk factors observed is infection with the Hepatitis C virus.
One review of a collection of PCT studies noted Hepatitis C infection in 50% of documented
cases of PCT.
Additional risk factors include alcohol abuse, excess iron, and exposure to chlorinated cyclic
hydrocarbons and Agent Orange.
It can be a paraneoplastic phenomenon.
Exacerbating factors Alcohol
Estrogen Iron
Pathogenesis Porphyria cutanea tarda is primarily caused
by uroporphyrinogen decarboxylase deficiency.
Uroporphyrinogen decarboxylase occurs in nature as a homodimer of two subunits.
It participates in the fifth step in heme synthesis pathway, and is active in the cytosol.
This enzymatic conversion results in coproporphyrinogen III as the primary product.
This is accomplished by the clockwise removal of the four carboxyl groups present in the
cyclic uroporphyrinogen III molecule.
Therefore, a deficiency in this enzyme causes the aforementioned buildup of uroporphyrinogen
in the urine, which can be helpful in the diagnosis of this disorder.
The dermatological symptoms of PCT that include blistering and lesions on sun-exposed areas
of the skin are caused by a buildup of porphyrin compounds close to the surface of the skin.
Due to the highly conjugated structure of porphyrins involving alternating single and
double carbon bonds, these compounds exhibit a deep purple color, resulting in the discoloration
observed in the skin.
The excess uroporphyrinogen that leads to these lesions is primarily produced in the
liver, but exposure to excess sunlight is thought to lead to the production of reactive
oxygen species, disrupting the activity of uroporphyrinogen decarboxylase and contributing
to the buildup of uroporphyrinogen.
This is thought to be the underlying biochemical pathway behind the photosensitivity observed
in patients with PCT.
The strong association of PCT with Hepatitis C infection is not entirely understood.
Studies have suggested that the cytopathic effect of the virus on hepatocytes can lead
to the release of free iron.
This iron can disrupt the activity of cytochrome p450, releasing activated oxygen species.
These can oxidize the UROD substrate uroporphyrinogen, which can result in the inhibition of UROD
and lead to deficient activity of this key enzyme.
Excess alcohol abuse is frequently associated with both inducing PCT and aggravating a preexisting
diagnosis of the disorder.
It is thought to do so by causing oxidative damage to liver cells, resulting in oxidized
species of uroporphyrinogen that inhibit the activity of hepatic UROD.
It is also felt to increase the uptake of iron in liver cells, leading to further oxidation
of uroporphyrinogen by the release of activated oxygen species.
Additionally, exposure to chlorinated cyclic hydrocarbons can lead to a deficiency in the
activity of uroporphyrinogen decarboxylase, causing the buildup of excess uroporphyrinogen.
Diagnosis While the most common symptom of PCT is the
appearance of skin lesions and blistering, their appearance does not single-handedly
lead to a conclusive diagnosis.
Laboratory testing will commonly reveal high levels of uroporphyrinogen in the urine, clinically
referred to as uroporphyrinogenuria.
Additionally, testing for common risk factors such as Hepatitis C and hemochromatosis is
strongly suggested, as their high prevalence in patients with PCT may require additional
treatment.
If clinical appearance of PCT is present, but laboratories are negative, one needs to
seriously consider the diagnosis of pseudoporphyria.
Classification Some sources divide PCT into two types: sporadic
and familial.
Other sources include a third type, but this is less common.
One study used 74% as the cutoff for UROD activity, with those patients under that number
being classified as type II, and those above classified as type III if there was a family
history, and type I if there was not.
Genetic variants associated with hemochromatosis have been observed in PCT patients, which
may help explain inherited PCT not associated with UROD.
Treatment Since PCT is a chronic condition, a comprehensive
management of the disease is the most effective means of treatment.
Primarily, it is key that patients diagnosed with PCT avoid alcohol consumption, iron supplements,
excess exposure to sunlight, as well as estrogen and chlorinated cyclic hydrocarbons, all of
which can potentially exacerbate the disorder.
Additionally, the management of excess iron can be achieved through phlebotomy, whereby
blood is systematically drained from the patient.
Low doses of antimalarials can be used.
They remove excess porphyrins from the liver by increasing the excretion rate.
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.
Finally, due to the strong association between PCT and Hepatitis C, the treatment of Hepatitis
C is vital to the effective treatment of PCT.
Chloroquine, hydroxychloroquine, and venesection are typically employed in the management strategy.
Epidemiology Porphyria cutanea tarda has a prevalence estimated
at approximately 1 in 10,000.
An estimated 80% of porphyria cutanea tarda cases are sporadic.
The exact frequency is not clear because many people with the condition never experience
symptoms.
Society and culture Porphyria Cutanea Tarda is also the name of
a song by the punk band AFI on their fourth album Black Sails in the Sunset, released
on May 18, 1999.
Porphyria is implicated in the origin of vampire myths because people with the disease tend
to avoid the sun due to blistering and desire iron rich foods due to their enzymatic deficiency.
References
External links Porphyria cutanea tarda at NIH's Office of
Rare Diseases www.porphyria-europe.com