Porphyria cutanea tarda

Alternate names

Porphyria, hepatic

Definition

Porphyria cutanea tarda is a condition that affects the liver and skin by reduction and inhibition of uroporphyrinogen decarboxylase enzyme in erythrocytes.

Summary

The porphyrias are a rare group of metabolic disorders that can either be inherited or acquired. Along the heme biosynthetic pathway, porphyrias can manifest with neurovisceral and/or cutaneous symptoms, depending on the defective enzyme. Porphyria cutanea tarda, the most common type of porphyria worldwide, is caused by a deficiency of uroporphyrinogen decarboxylase, a crucial enzyme in heme biosynthesis, which results in an accumulation of photosensitive byproducts, such as uroporphyrinogen, which leads to the fragility and blistering of sun-exposed skin.

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Cause

In most cases, PCT is a complex or multifactorial condition that is likely associated with the effects of multiple genes in combination with lifestyle and environmental factors. For example, factors such as excess iron, alcohol, estrogens, smoking, chronic hepatitis C, HIV and mutations in the HFE gene (which is associated with the disease hemochromatosis) can all contribute to the development of PCT.

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 (an iron overload disorder). People who have these mutations are also at an increased risk of developing porphyria cutanea tarda.

Less commonly, PCT can run in families (called familial PCT). Familial PCT is caused by changes (mutations) in the UROD gene.Inherited mutations in the UROD gene cause about 20% of cases (the other 80% of cases do not have mutations in UROD, and are classified as sporadic). 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.

Types

The disease has been classified into three subtypes. Type I PCT has decreased hepatic UROD activity and is found in a sporadic fashion without family history.

Type II PCT is an autosomal dominant disorder with genetic mutations of the UROD gene causing decreased UROD activity in all tissues.

Type III PCT is similar to type II with respect to familial occurrence, but erythrocyte UROD activity is normal.

Homozygous familial PCT is extremely rare and is known as hepatoerythropoietic porphyria (HEP). This type of PCT is much more severe and develops during childhood, while the familial and sporadic forms appear at mid to late adulthood.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

Less commonly, PCT can run in families (called familial PCT). Familial PCT is caused by changes (mutations) in the UROD gene and is inherited in an autosomal dominant manner.

Signs and symptoms

People affected by this condition generally experience "photosensitivity," which causes painful, blistering lesions to develop on sun-exposed areas of the skin (i.e. the hands and face). Skin in these areas may also be particularly fragile with blistering and/or peeling after minor trauma. In some cases, increased hair growth as well as darkening and thickening of the affected skin may occur. 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.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 80%-99% of people have these symptoms

• Abnormal blistering of the skin(Blistering, generalized)
• Cutaneous photosensitivity(Photosensitive skin)
• Erythema
• Hyperpigmentation of the skin(Patchy darkened skin)
• Hypopigmented skin patches(Patchy loss of skin color)
• Skin rash
• Skin vesicle
• Thin skin

5%-29% of people have these symptoms

• Atypical scarring of skin(Atypical scarring)
• Cerebral palsy
• Cirrhosis(Scar tissue replaces healthy tissue in the liver)
• Edema(Fluid retention)
• Generalized hirsutism(Excessive hairiness over body)
• Hepatic steatosis(Fatty infiltration of liver)
• Hepatocellular carcinoma
• Sudden cardiac death(Premature sudden cardiac death)

Diagnosis

• The diagnosis of PCT depends on the definition of characteristic symptoms, a detailed history, clinical evaluation, and some special tests (blood test, urine test, stool test and skin biopsy). An increase in uroporphyrin and heptacarboxyl porphyrin levels in urine is important for diagnosis.
• Familial PCT can be diagnosed by the presence of a low amount of UROD enzyme in erythrocytes. A diagnosis is made by testing the urine of the patient or a family member for porphyrins and/or analyzing UROD enzyme activity.

Treatment

• PCT treatment targets specific symptoms of patients. Treatment needs to involve a team of experts including general internists, hematologists, dermatologists, and hepatologists. PCT is the most benign type of porphyria and the treatment is effective for both familial and sporadic forms. The standard treatment of PCT is regular phlebotomy to decrease iron and porphyrin levels in the liver. The suggested approach is to make a phlebotomy of one whole blood unit (450 cc) every 2 weeks until the ferritin level reaches approximately 20 ng/mL . Independent from verified iron overload, this is the routine treatment in most porphyria centers.

• Phlebotomy is a safe and easy method of extraction of blood via blood vessels. As most of the iron in the body is in blood cells, regular phlebotomies decrease extreme iron levels. Regularly performed phlebotomies cause full remission in most cases. Usually 5–8 phlebotomies are needed to achieve full remission.

• In some cases, patients can be treated with low-dose antimalarial drugs such as hydroxychloroquine or chloroquine, drugs that act as mobilizers of porphyrins from the liver, by transforming hepatocyte porphyrins into water-soluble complexes which are excreted in urine. This method is usually applied to patients who have anemia or blood vessel problems or do not want to have multiple phlebotomies. The dosage of the medication here is important. Actual doses might cause worsening of the photosensitivity and elevation of porphyrin levels. The suggested dose is 100 mg hydroxychloroquine twice a week or 125 mg chloroquine twice a week . This regime is as effective as phlebotomy treatment, has lower cost, and is easier.

• Iron chelators are iron binding drugs that cause iron to dissolve in water and get renally extracted. Iron chelators are less effective than phlebotomy or antimalarial treatments. However, they can be used in selected patients such as patients with end-stage renal disease on dialysis.

• Patients with PCT are suggested to quit smoking tobacco and alcohol intake as these might trigger their disease. They should avoid direct exposure to the sun using a double layer of clothing, wide hats, gloves, and sun glasses. Orally administered analgesics might be used for painful skin lesions. It is important to prevent infection of skin lesions and, when it occurs, antibiotics need to be used. Full remission is possible with treatment of PCT but relapse is possible. Relapse treatment is the same as primary treatment.

NIH genetic and rare disease info

• NIH info on Porphyria cutanea tarda

Porphyria cutanea tarda is a rare disease.

Porphyria cutanea tarda Resources
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