pct
Porphyria Cutanea Tarda
Porphyria cutanea tarda (PCT) is the most common human porphyria due to acquired deficient activity of hepatic uropophyrinogen decarboxylase (UROD), fifth enzyme in the heme biosynthetic pathway. UROD is present in the cytosol of the hepatocytes and red blood cells. Iron is a major co-factor in the generation of uroporphomethane, which inhibits UROD (Figure 1). Iron overload to a variable degree is present in all cases of PCT. UROD catalyzes the decarboxylation of uroporphyrinogen to coproporphyrinogen and its deficiency in PCT results in accumulation of uropophyrinogens in the liver. Uropophyrinogen is oxidized to porphyrins which are damaging to the tissues. Accumulated porphyrins enter the plasma and excreted in the urine.
Majority of patients (80%) have sporadic or acquired deficiency of the UROD (type 1 PCT). About 20% of patients have familial UROD mutation (Type 2 PCT), an autosomal dominant condition with low penetrance. Patients with familial deficiency of the UROD require acquired deficiency of the hepatic UROD to < 20% of normal to cause the phenotype of the disease.
Figure 1. Pathophysiological basis of Poprhyria Cutanea Tarda. Iron acts a cofactor in the generation of inhibitor for the fifth enzyme of the heme biosynthetic pathway, uroporphyrinogen decarboxylase (UROD). Accumulated uroporhyrinogen due to inhibition of UROD is oxidized by cytochrome P450 enzymes (especially CYP1A2) to uroporphyrin, which accumulates in the liver.
Prevalence and epidemiology
In the United States, prevalence of symptomatic disease is 4 in 100,000 typically with onset after the age of 30 years. Onset is usually in the fourth decade of life or later, and occurs slightly more commonly in males. Lack of availability of literature makes it difficult to estimate the prevalence of this rare disease condition in India.
Susceptibility factors
SPCT is a heterogeneous disease and multiple susceptibility factors being associated with the disease. These include alcohol abuse, smoking, hepatitis C virus (HCV) infection, hemochromatosis (HFE) mutations, use of estrogens, human immunodeficiency virus (HIV) infection, and UROD mutation. Usually multiple factors are present in a given patient and in one series, 3 or more factors were present in 92% of cases. Alcohol abuse is the most common susceptibility factor reported in about 80-90% cases of PCT. Prevalence of HCV is reported at 8-85% with higher rates reported from the US and Southern Europe and lower rates from Northern Europe and Asia. Mechanisms of causing PCT are postulated to be due to suppression of hepcidin expression leading to iron overload and increase in oxidative stress in the liver by the HCV infection and alcohol abuse.
Clinical features
PCT is a cutaneous porphyria manifesting clinically as blisters, bullae, increased fragility, scarring, and hyper/hypo-pigmentation of sun-exposed areas (Figure 2). The lesions can become super infected. Rarely, these lesions heal with scarring leading to scleroderma like thickening of the skin (pseudo scleroderma). Exposure to wavelengths of light near 400 nanometers causes porphyrins to enter an excited state with release of reactive oxidizing species with subsequent damage to proteins, lipids, and basement membranes. Histologic features include sub epidermal blister formation and periodic-acid-Schiff (PAS) positive hyaline material containing immunoglobulin’s around the vessel walls.
Hepatic findings include elevated serum liver enzymes, primarily alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Liver disease may be due to associated susceptibility factors such as alcohol abuse, HCV, HIV, and hemochromatosis, but, the accumulation of porphyrins also contributes to hepatic injury. Patients with PCT are at increased risk of developing cirrhosis and hepatocellular carcinoma. Histologic examination reveals varying degrees of steatosis, siderosis, focal lobular necrosis, and periportal fibrosis. Accumulated porphyrins may be visible as birefringent needle shaped crystals within the hepatocytes.
Figure 2. Crusted lesions on the sun exposed areas in a patient with Porphyria Cutanea Tarda.
Diagnosis
Blistering skin lesions on the sun-exposed areas of the skin such as the backs of the hands and back should increase suspicion for PCT although such skin conditions may also occur in other porphyrias. The diagnosis is confirmed with demonstration of increased plasma (normal: <0.9 mcg/dl with no peak fluorescence) and urinary (normal <300 nmol/L with coproporphyrins or tetracarboxyporphyrins as major component) porphyrins. PCT is characterized with peak fluorescence of plasma at wavelength of 618-620 nm and urine porphyrin fractionation on high pressure liquid chromatography (HPLC) showing predominant uroporphyrins instead of coproporhyrins. Further, uroporhyrins in PCT predominantly consist of hepta- and hexa- carboxyporphyrins. Measurement of erythrocyte UROD activity may be used in confirmed PCT patients to determine if UROD mutations are present for classification as type 2 or familial with additional molecular and genetic studies. This may be useful for academic reasons only as the prognosis and treatment of both the types of PCT are similar.
Treatments
PCT is the most readily treatable of porphyrias. Patients should avoid exposure to sunlight use protective clothing. If the lesions are infected, antibiotics may be prescribed. Exposure to known susceptibility factors should be avoided. Patients should stop alcohol abuse and smoking. Estrogens should be discontinued. However, if needed, estrogens can be safely resumed as a skin patch after the PCT is in remission. Drugs known to exacerbate acute porphyrias are usually not reported to exacerbate PCT. However, they may be contributors and should be avoided.
Repeated phlebotomy: Iron being a major cofactor, repeated phlebotomy is the standard and accepted treatment modality for PCT. Typically, one unit of whole blood (450 mL) is removed approximately every two weeks until serum ferritin is reduced to below 20 ng/mL (near lower limit of normal). Once the phlebotomies are discontinued, patient usually enters into remission (normalization of plasma porphyrins) over the next few weeks to months. Phlebotomy alone achieves remission in almost all patients with PCT. On an average 5-7 phlebotomies are needed for achieving target serum ferritin levels. This treatment is well tolerated and only 2-3% of patients may develop anemia (< 10 g/dl or hematocrit < 33) requiring interruption or rarely discontinuation of the treatment. Patients with baseline anemia such as end-stage renal disease patients on dialysis and patients with poor venous access such as IV drug users are not candidates for this treatment modality.
4-aminoquinolines: If repeated phlebotomy is not tolerable or is contraindicated, use of oral 4-aminoquinolines in low dose (chloroquine 125 mg or hydroxychloroquine 100 mg twice a week) is an alternative option. These are continued until the plasma porphyrins are normal which usually takes about 6 (range: 4-11) months. These drugs are quite effective with achievement of remission in almost all cases and are well tolerated. Mechanism of action of these drugs is not entirely clear. It has been postulated that hydroxychloroquine concentrates within the lysosomes of the hepatocytes, binds the porphyrins and excrete them in the urine. It is suggested that patients with substantial iron overload and hemochromatosis (C282Y homozygote) should be preferably treated with phlebotomy. These drugs are also contraindicated in pregnancy, lactation, advanced liver or renal disease, continued alcohol and other hepatotoxic drug use (acetaminophen, isoniazid, valproic acid, etc.), glucose-6-phosphate dehydrogenase (G6PD) deficiency, and active psoriasis. Ophthalmologic examination is essential for any retinal disease prior to starting the treatment.
Limitations of phlebotomy are patient discomfort, low compliance due to need for visit to blood bank every 2 weeks, and its cost. These limitations are overcome with the use of low dose 4-aqminoquinolines. Studies comparing the two treatment modalities are scanty. In one study on 48 PCT patients, both phlebotomy and low dose hydroxychloroquine achieved normalization of urinary porphyrins in all patients. In another randomized controlled study on 61patients, both treatments were equally effective, however, urinary porphyrins normalized much more frequently with hydroxychloroquine compared to phlebotomy at the end of 1 year. However, response rate to phlebotomy in this study was only 32% at 1 year which is much lower than reported by most studies in the literature. Recently, data are emerging to suggest that both phlebotomy and hydroxychloroquine 100 mg twice a week have similar efficacy in the treatment of PCT. After remission is achieved, relapse of PCT is always a possibility. In one study, relapse rates between those treated with hydroxychloroquine versus phlebotomy were comparable (12% at one year, 49% after three years, 35% at four years).
Other treatment modalities: include use of iron chelating agents and erythropoietin. These are used when both the above mentioned modalities cannot be used. One of the clinical situations is patients with end stage renal disease on dialysis as these patients have anemia limiting the use of phlebotomy and advanced renal disease limits use 4-aminoquinolines. These patients should undergo treatment with combination of phlebotomy and erythropoietin or with chelating agents. However, the limitation of the chelators is their lower efficacy. Further, they are slow in onset of action and take much longer time to achieve remission.
Treatment of hepatitis C and HIV in PCT: There are no set guidelines on treatment of HCV in PCT patients due to relative lack of data. In general it is advisable to wait for PCT to go into remission before starting the anti-HCV treatment. One study reported lower rates of achieving sustained virologic response (SVR) with HCV treatment in PCT patients despite PCT in remission at the time of HCV treatment. Another potential problem is relapse of PCT by RBV induced hemolysis increasing the iron overload. Hydroxychloroquine may be used concomitant with anti-HCV treatment so as to prevent PCT relapse and allowing anti-HCV treatment to be completed. Treatment for HIV is unchanged in patients with PCT.
Genetic counseling: Penetrance of familial (type 2) PCT is low. As the risk for developing PCT in other family members is somewhat increased, asymptomatic carriers should be advised to avoid susceptibility factors such as heavy alcohol use, smoking and oral estrogens.
References and further readings:
1. Singal AK, Anderson KE. Porphyria cutanea tarda and hepatoerythropoietic porphyria. Up-To-Date chapter. 2010.
2. Bonkovsky HL, Poh-Fitzpatrick M, Pimstone N, Obando J, Di Bisceglie A, Tattrie C, Tortorelli K, LeClair P, Mercurio MG, Lambrecht RW. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology. 1998;27:1661-9.
3. Fargion S, Piperno A, Cappellini MD, Sampietro M, Fracanzani AL, Romano R, Caldarelli R, Marcelli R, Vecchi L, Fiorelli G. Hepatitis C virus and porphyria cutanea tarda: evidence of a strong association. Hepatology. 1992;16:1322-6.
4. Ippen, H., Treatment of porphyria cutanea tarda by phlebotomy. Semin Hematol, 1977; 14:253-9.
5. Ashton, R.E., J.L. Hawk, and I.A. Magnus, Low-dose oral chloroquine in the treatment of porphyria cutanea tarda. Br J Dermatol, 1984;111:609-13.
6. Singal AK, H.C., Lee C, Grady JJ, Anderson KE. , Prospective comparison of phlebotomy and low-dose hydroxychloroquine in the treatment of porphyria cutanea tarda. Hepatology, 2009. 50 (Suppl): p.748A.
7. Hisamuddin, K., C. Veluru, and K.D. Mullen, Skin lesions in a patient on therapy for chronic hepatitis C. Clin Gastroenterol Hepatol, 2009;7:A24.
Contributors:
Sarat C. Jampana, MD
Department of Internal Medicine
University of Texas Medical Branch
Galveston, TX, USA
and
Ashwani K. Singal, MD., DM*
Division of Gastroenterology
University of Texas Medical Branch
Galveston, TX, USA
Reviewer:
Mohammad Khan MD, PhD
Children's Hospital of Philadelphia
University of Pennsylvania, Philadelphia, PA, USA.
May 2011
*Corresponding author