Short summary

Porphyria cutanea tarda(PCT) is a rare disease. It arises due the decreased activity of the fifth enzyme, UROD, in the haem biosynthesis. The excact reason for decreased enzyme activity is not know.

We will analyze 340 genes involved in the metabolism of substances in the liver to see if the reason for developing PCT, can be found at gene level.

Rationale

Background 

Porphyrias are a group of rare diseases defined by defects in the biosynthesis of haem. Haem synthesis involves eight enzymes, and a defective enzyme causes specific haem precursors to accumulate, primarily in the liver and skin. Decreased activity of the fifth enzyme, UROD, in the haem biosynthesis causes the most prevalent porphyria - porphyria cutanea tarda, PCT and for symptoms to develop, the activity of UROD must be less than 25% of normal,

PCT is divided into familiar PCT, fPCT (25-50% of PCT patients) and sporadic PCT, sPCT. fPCT is inherited in an autosomal dominant pattern with low penetrance, and heterozygous patients may never develop symptoms. In sPCT there is no mutation in the gene coding for URDO and decreased enzyme activity is located only to the liver. The exact mechanism behind decreased UROD activity in PCT has not been clarified, but several factors are known to reduce enzyme activity in both sPCT and fPCT: alcohol intake, smoking, iron overload, hepatitis C or HIV infection. Because iron overload reduces UROD activity, hemochromatosis patients (an inherited iron overload disorder) have a 48-fold increased risk of getting PCT. It is not clear how iron overload leads to reduced UROD activity and clinical PCT, but its key role is demonstrated by the relief of PCT symptoms upon phlebotomy. Hexachlorobenzene and intake of estrogen in females are also well-known precipitating factors for development of PCT and in case reports different types of medications have shown to be involved in developing PCT e.g Tamoxifen, statins and Rifampicin.

PCT and metabolism

The development of PCT is complex and not fully understood. However the liver is involved either because the patient has a liver disease, as hepatitis, or the patient has been prescribed a drug like e.g. estrogen, which is inactivated in the liver, or like Rifampicin, which is an inducer of cytochrome p450 enzymes. The cytochrome P450 is a complex of many enzymes produced in the liver and involved not only in metabolism of endogenous substances, but also metabolism of different medications.  

CYP1A2, one of the cytochrome P450 enzymes, is involved in the metabolism of xenobiotics in the body. A study on mice has shown that CYP1A2 knockout mice don't develop PCT and the genotype CYP1A2 A/A is suggested to induce more CYP1A2 activity than the C/A genotype. A former Danish case control study of 53 PCT patients showed that the genotype CYP1A2 A/A was more frequent in PCT patients. However a French case control study of 93 PCT found no statistical significance. 

The fact that not all patients having haemochromatosis or hepatitis and not all patients taking oestrogen or Rifampicin develop PCT indicates that PCT patients may have a special metabolism that somehow leads to decreased activity of UROD, when exposed to the above mentioned risk factors.     

Hypothesis:

We hypothesize that patients with PCT have a pharmacogenetic profile, which may be involved in the development of PCT. 

Description of the cohort

The study will investigate PCT patients treated at the dermatological department at Odense University Hospital and Aarhus University hospital

Data and biological material

8 mL of blood drawn in two glasses, EDTA glasses

Collaborating researchers and departments

Department of Clinical Genetics, Odense University Hospital

• Associate professor Klaus Brusgaard

Department of Clinical Biochemistry and Pharmacology. Centre for Individualized Medicine in Arterial Diseases (CIMA), Odense University Hospital

• Professor, MD, Consultant Lars Melholt Rasmussen 

Department of Dermatology and Allergy Centre, Odense University Hospital

• Professor Anette Bygum

Department of Clinical Genetics, Odense University Hospital

• Professor Jens Michael Hertz

Department of Dermatology, Aarhus University hospital

• Associate professor Uffe Koppelhus