Porphyria Cutanea Tarda (PCT) is the most common of all porphyrias (one of the hepatic porphyrias) and results from a deficiency of the enzyme uroporphyrinogen decarboxylase or uroporphyrinogen III decarboxylase (UROD) ¹, ², ³, ⁴, ⁵, ⁶, ⁷. The hallmark of porphyria cutanea tarda (PCT) is photosensitivity (sunlight sensitivity or abnormal skin reaction triggered by exposure to sunlight or other forms of ultraviolet (UV) light) ⁸, ⁹. Liver (hepatic) uroporphyrinogen decarboxylase or uroporphyrinogen III decarboxylase (UROD) enzyme is tasked with the conversion of uroporphyrinogen III to coproporphyrinogen III, the fifth step in heme biosynthesis and failure to do so results in the accumulation of the preceding compounds (highly carboxylated porphyrinogens predominately uroporphyrinogen and the porphyrinogens that get oxidized to their respective porphyrins, uroporphyrin and 7-carboxylate porphyrin) in the liver that eventually appears in the plasma and urine ¹⁰, ¹¹. The accumulation of these toxic compounds (uroporphyrin and 7-carboxylate porphyrin) in different organs, especially the liver and skin, leads to the signs and symptoms seen in porphyria cutanea tarda patients. Porphyrins are photoactive molecules that efficiently absorb light energy in the visible violet spectrum. Photoexcited porphyrins in the skin cause oxidative damage to biomolecular targets, causing the skin lesions in porphyria cutanea tarda. The most common photocutaneous manifestations of porphyria cutanea tarda are due to increased mechanical fragility after sunlight exposure; erosions and blisters form painful indolent sores that heal with milia, dyspigmentation, and scarring. An important point to note is that the uroporphyrinogen decarboxylase or uroporphyrinogen III decarboxylase (UROD) enzymatic activity should drop below 20% before signs and symptoms can be seen ¹.

Porphyria cutanea tarda (PCT) is essentially an acquired disease, but some individuals have a genetic (autosomal dominant) deficiency of enzyme uroporphyrinogen decarboxylase (UROD) that contributes to development of familial porphyria cutanea tarda (F-PCT).

Porphyria cutanea tarda type 1 (Sporadic porphyria cutanea tarda): In approximately 75% to 80% of cases the uroporphyrinogen decarboxylase (UROD) enzyme deficiency is associated with an underlying liver diseases that include iron overload from hemochromatosis, multiple blood transfusions, or iron supplements, chronic hepatitis B and hepatitis C infection and excessive alcohol consumption resulting in the inhibition of uroporphyrinogen decarboxylase (UROD) enzyme, the fifth enzyme in the heme synthetic pathway in the liver. Hormones such as oral contraceptive or hormone replacement therapy may also trigger porphyria cutanea tarda. Kidney dialysis patients can also develop porphyria cutanea tarda as they cannot excrete the porphyrins. Rarely, other conditions such as systemic lupus erythematosus (SLE) and human immunodeficiency virus (HIV) infection can cause porphyria cutanea tarda. Furthermore, many patients have more than one risk factor.
Porphyria cutanea tarda type 2 (Familial porphyria cutanea tarda or F-PCT): In the remaining cases (20% to 25%), individuals have a genetic predisposition to developing porphyria cutanea tarda (PCT), specifically a mutation in the UROD (uroporphyrinogen decarboxylase) gene inherited from one parent and are classified as having familial porphyria cutanea tarda (F-PCT). Most individuals with UROD genetic mutation do not develop porphyria cutanea tarda (PCT); the mutation is a predisposing factor and additional factors are required for the development of the disorder in these individuals. These factors are called susceptibility factors and are required for the development of both sporadic and familial porphyria cutanea tarda.
Porphyria cutanea tarda type 3. This rare type of porphyria cutanea tarda is very similar to type 1 porphyria cutanea tarda because of normal UROD genes ¹². Yet, type 3 porphyria cutanea tarda is observed in more than one family member suggesting the presence of a genetic mechanism other than UROD gene mutation ¹³.
In extremely rare cases, individuals have mutations in both UROD (uroporphyrinogen decarboxylase) genes. This autosomal recessive form of familial porphyria cutanea tarda or Homozygous familial porphyria cutanea tarda is known as hepatoerythropoietic porphyria (HEP). Hepatoerythropoietic porphyria (HEP) occurs in childhood and is usually more severe than porphyria cutanea tarda types 1 sporadic or 2 familial porphyria cutanea tarda ¹⁴. Mild cases of hepatoerythropoietic porphyria (HEP) may resemble porphyria cutanea tarda (PCT) but are readily differentiated by marked elevation in erythrocyte zinc protoporphyrin.

Generally, porphyria cutanea tarda develops in mid to late adulthood. Porphyria cutanea tarda symptoms usually occur after the age of 30 and its onset in childhood is rare. The symptoms of porphyria cutanea tarda (PCT) are limited to your skin. It does not cause people to become acutely unwell, as in the acute types of porphyria. Sun-exposed areas of your skin most commonly the backs of your hands can become friable and prone to blistering, scarring and excess hair growth.

Porphyria cutanea tarda is found worldwide that affect both males and females equally and in individuals of all races. Porphyria cutanea tarda is a rare disorder with the prevalence being estimated to be approximately 1 in 10,000 to 25,000 individuals in the general population. Porphyria cutanea tarda (PCT) has a prevalence of about 1 in 10,000 people according to a Norwegian study and occurs most commonly in middle-aged adults ¹⁵. A 1 in 25000 prevalence has been reported in the United States ¹³.

Porphyria cutanea tarda (PCT) is a multifactorial disorder, which means that several different factors such as genetic and environmental factors occurring in combination are necessary for the development of porphyria cutanea tarda. These factors are not necessarily the same for each individual. These factors contribute either directly or indirectly to decreased levels or ineffectiveness of an enzyme known as uroporphyrinogen decarboxylase (UROD) within your liver. When uroporphyrinogen decarboxylase (UROD) levels in your liver decrease to approximately 20% of normal levels, the symptoms of porphyria cutanea tarda may develop.

The uroporphyrinogen decarboxylase (UROD) enzyme is essential for breaking down (metabolizing) certain chemicals in the body known as porphyrins. Low levels of functional uroporphyrinogen decarboxylase (UROD) result in the abnormal accumulation of specific porphyrins in your body, especially within the blood, liver and skin. The symptoms of porphyria cutanea tarda occur because of this abnormal accumulation of porphyrins and related chemicals. For example when porphyrins accumulate in your skin, they absorb sunlight and enter an excited state (photoactivation). This abnormal activation results in the characteristic damage to the skin (photosensitivity) found in individuals with porphyria cutanea tarda. Your liver removes porphyrins from the blood plasma and secretes it into the bile. When porphyrins accumulate in your liver, they can cause toxic damage to your liver.

The exact, underlying mechanisms that cause porphyria cutanea tarda are complex and varied. It is determined that iron accumulation within the liver plays a central role in the development of the disorder in most individuals (sporadic or acquired porphyria cutanea tarda [PCT type 1]). Recently, researchers have discovered that a substance called uroporphomethene, which is an oxidized form of a specific porphyrin known as uroporphyrinogen, is an inhibitor that reduces the activity of the uroporphyrinogen decarboxylase (UROD) enzyme in the liver. The oxidation of uroporphyrinogen into uroporphomethene has been shown to be iron dependent, emphasizing the importance or elevated iron levels in the development of porphyria cutanea tarda.

The relationship between iron levels and porphyria cutanea tarda has long been established and porphyria cutanea tarda is classified as an iron-dependent disease. Clinical symptoms often correlate with abnormally elevated levels of iron in the liver (iron overloading). Iron overloading in the liver may only be mild or moderate. The exact relationship between iron accumulation and porphyria cutanea tarda is not fully understood, however, as there is no specific level of iron in the liver that correlates to disease in porphyria cutanea tarda (e.g. some individuals with symptomatic porphyria cutanea tarda have normal iron levels).

Porphyria Cutanea Tarda (PCT) becomes active when predisposing factors such as excess iron, alcohol, chronic hepatitis C (hepatitis C Virus [HCV]), HIV infection, estrogens (used, for example, in oral contraceptives and prostate cancer treatment) and possibly smoking, combine to cause a deficiency of enzyme uroporphyrinogen decarboxylase (UROD) in the liver ¹⁶. Hemochromatosis, a inherited iron overload disorder, also can predispose individuals to porphyria cutanea tarda. Some of these factors and marked accumulation of porphyrins in the liver due to porphyria cutanea tarda (PCT) itself can lead to chronic liver damage and liver cancer.

The treatment of porphyria cutanea tarda is directed toward the underlying liver problem and the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan your treatment.

The first step in the management of porphyria cutanea tarda is the avoidance of all risk factors such as strictly avoiding alcohol, smoking, and estrogen therapy, along with limiting any excess intake of iron. Since porphyria cutanea tarda (PCT) is a photosensitive skin condition, sunlight avoidance is the key until the porphyrin levels have normalized. The wavelengths inducing porphyrins are in the range of 400-410 nm, and only titanium dioxide or zinc oxide containing sunscreen is effective ¹⁷. Protective clothing is also helpful in protecting the skin from harmful sunlight rays. Any affected skin areas should be kept clean to prevent the development of skin infections, and associated pain can be managed with oral analgesics.

Presently, there are no effective treatments that restore UROD enzyme levels in individuals with familial porphyria cutanea tarda (F-PCT) ¹⁸. However, treatment seems to be equally effective in familial porphyria cutanea tarda (F-PCT) and non-familial porphyria cutanea tarda. Factors that tend to activate the disease should be removed and may result in the resolution of porphyria cutanea tarda. Treatment may include reducing alcohol consumption, stopping estrogen or hormone treatment, avoiding excessive iron intake, or antiviral treatment for underlying hepatitis C.

Reduction of liver iron content is the general recommendation and the most widely recommended treatment is a schedule of repeated phlebotomies (removal of blood), with the aim of reducing iron in the liver ¹⁸, ¹³, ¹⁹, ²⁰, ²¹. This actually reduces iron stores throughout the body. Usually, removal of only 5 to 6 pints of blood (one pint [approximately 450 ml of blood] every one to two weeks) is sufficient, which indicates that iron stores are not excessively increased in most porphyria cutanea tarda patients. The best guides to response are measurements of serum ferritin and plasma porphyrins. Phlebotomies are stopped when the ferritin falls to ~20 ng/ml ²², ²³. Normal ferritin levels vary by gender and age, but generally, for adult males, ferritin level is between 30-300 ng/mL, and for adult females, it’s between 13-150 ng/mL.

Iron chelation therapy i.e., deferasirox or deferoxamine may be considered when phlebotomy is contraindicated, and low iron diet may be beneficial if the latter fails ¹⁸.

If phlebotomy cannot be done, as in elderly patients or those who are anemic, antimalarial tablets such as low doses of either chloroquine (125mg twice weekly) or hydroxychloroquine (100mg twice weekly) to allow the porphyrins to be excreted more easily. Usual dosages of these drugs should not be used because they can cause transient but sometimes severe liver damage and worsening of photosensitivity in porphyria cutanea tarda patients.

Furthermore, use of antiviral therapy may benefit patients with chronic hepatitis C infections and reduce risk of progressing to liver cancer ¹⁹.

After treatment for porphyria cutanea tarda, periodic measurement of plasma porphyrins may be advised, especially if a contributing factor such as estrogen exposure is resumed. If a recurrence does occur, it can be detected early and treated promptly. The treatment of porphyria cutanea tarda is almost always successful, and the prognosis is usually excellent.

Figure 1. Porphyria Cutanea Tarda

Footnotes: Porphyria cutanea tarda (PCT) is caused by deficiency in uroporphyrinogen decarboxylase (UROD) enzyme, and is subdivided into two categories: Type 1 (sporadic PCT), and Type 2 (familial PCT). Porphyria cutanea tarda (PCT) presents mainly with skin manifestations which are triggered by susceptibility factors (risk factors) such as alcohol, hepatitis C virus (HCV), estrogen, hemochromatosis, smoking, and others. Porphyria cutanea tarda (PCT) is the most common type of porphyria, and is managed by reduction of hepatic iron content and avoidance of susceptibility factors.

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Figure 2. Porphyria cutanea tarda

Figure 3. Porphyrin molecular structure

Footnote: Molecular structure of porphyrin (M represent metal ions, such as Mg, Cu, Fe, Zn, etc.).

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Figure 4. Heme (haem) molecular structure

Footnote: Heme A and heme B molecular structures

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Figure 5. Heme biosynthesis pathway

Footnotes: The heme biosynthetic pathway requires 8 enzymatic steps. Heme synthesis pathway showing the enzymes involved in the heme synthesis pathway and the associated porphyrias with the disruption of each specific enzyme. Gain-of-function variants in ALAS2 result in X-linked protoporphyria (XLP), and loss-of-functions variants in FECH result in erythropoietic protoporphyria (EPP). In both X-linked protoporphyria (XLP) and erythropoietic protoporphyria (EPP), metal-free protoporphyrin IX (PPIX) accumulates in erythroblasts, erythrocytes, the plasma, and the biliary system. Metal-free protoporphyrin IX (PPIX) is photosensitive, particularly to visible light in the blue range, and the light-mediated activation of metal-free protoporphyrin IX (PPIX) produces free radicals that damage the surrounding tissues.

Enzymes, encoded by genes, catalyze each of the steps. Gene mutations cause deficient enzyme production. Disruptions are indicated by red lines connecting enzymes with the resultant porphyrias. ALAS (ALAS2) = aminolevulinate synthase (aminolevulinate synthase 2); ALAD = delta-aminolevulinic acid dehydratase; PBGD = porphobilinogen dehydratase; HMBS = hydroxymethylbilane synthase; UROS = uroporphyrinogen-III synthase; UROD = uroporphyrinogen III decarboxylase; CPOX = coproporphyrinogen-III oxidase; PPOX = protoporphyrinogen oxidase; FECH = ferrochelatase.

Porphyrias resulting from disruption of enzyme production. XLP (X-linked protoporphyria); ADP (aminolevulinic acid dehydratase porphyria); AIP (acute intermittent porphyria); CEP (congenital erythropoietic porphyria); PCT (porphyria cutanea tarda); HCP (hereditary coproporphyria); VP (variegate porphyria); EPP (erythropoietic protoporphyria).

Heme is a term used for ferrous protoporphyrin IX (PPIX) that is easily oxidized in vitro to hemin also called ferric protoporphyrin IX (PPIX).

Abbreviations: ALA = aminolevulinic acid; PBG = porphobilinogen; HMB = hydroxymethylbilane; URO III = uroporphyrinogen III; COPRO III = coproporphyrinogen III; PROTO’gen IX protoporphyrinogen IX; PPIX = protoporphyrin IX; Fe2+ = iron.

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Figure 6. Porphyria cutanea tarda pathophysiology

Footnotes: Inhibition of uroporphyrinogen decarboxylase (UROD) enzyme by uroporphomethene leads to the accumulation of porphyrins and manifestations of disease in porphyria cutanea tarda (PCT). Under normal conditions, UROD (uroporphyrinogen decarboxylase) converts uroporphyrinogen to coproporphyrinogen by a series of 4 sequential decarboxylations. In the presence of iron and free radicals, uroporphyrinogen is partially oxidized, leading to the formation of a uroporphomethene inhibitor of UROD (uroporphyrinogen decarboxylase). Decarboxylated uroporphyrinogen intermediates subsequently accumulate and auto-oxidize to their corresponding porphyrins, predominantly uroporphyrins. Photosensitive porphyrins accumulate in the plasma and are responsible for the cutaneous manifestations of porphyria cutanea tarda (PCT).

Abbreviations: Fe = iron; PCT = porphyria cutanea tarda; UROD = uroporphyrinogen decarboxylase; ROS = reactive oxygen species.

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Figure 7. Porphyria cutanea tarda diagnostic and treatment algorithm

Abbreviations: HAV = hepatitis A virus; HBV = hepatitis B virus; PBG = porphobilinogen deaminase; TIBC = total iron-binding capacity.

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Porphyria Cutanea Tarda Cause

Porphyria cutanea tarda (PCT) is a multifactorial disorder, which means that several different factors such as genetic, infectious and environmental factors occurring in combination are necessary for the development of porphyria cutanea tarda ²⁸. These factors are not necessarily the same for each individual. These factors contribute either directly or indirectly to decreased levels or ineffectiveness of an enzyme known as uroporphyrinogen decarboxylase (UROD) within your liver ²⁹, ³⁰, ³¹. When uroporphyrinogen decarboxylase (UROD) levels in your liver decrease to approximately 20% of normal levels, the symptoms of porphyria cutanea tarda may develop.

There is an increased prevalence of mutations in the HFE (homeostatic iron regulator) gene in individuals with porphyria cutanea tarda ¹⁶. The HFE gene provides instructions for producing a protein called HFE protein that is located on the surface of cells, primarily liver and intestinal cells ³². The HFE protein is also found on some immune system cells ³². The HFE protein interacts with other proteins on the cell surface to detect the amount of iron in the body. When the HFE protein is attached (bound) to a protein called transferrin receptor 1, the receptor cannot bind to a protein called transferrin. When transferrin receptor 1 is bound to transferrin, iron enters liver cells. So, it is likely that the HFE protein regulates iron levels in liver cells by preventing transferrin from binding to transferrin receptor 1. The HFE protein regulates the production of a protein called hepcidin ³². Hepcidin is produced by the liver, and it determines how much iron is absorbed from your diet and released from storage sites in your body ³². When the HFE protein is not bound to transferrin receptor 1, it binds to a group of other proteins that includes hepcidin. The formation of this protein complex (HFE protein+Hepcidin) triggers the production of hepcidin. So when the HFE protein is bound to transferrin receptor 1, hepcidin production is turned off and when the HFE protein is not bound to transferrin receptor 1, hepcidin production is turned on. When the proteins involved in iron sensing and absorption are functioning properly, iron absorption is tightly regulated. On average, the body absorbs about 10 percent of the iron obtained from the diet.

Mutations in the HFE gene can cause hemochromatosis, a genetic disorder causing the body to absorb and store excessive amounts of iron especially the liver, leading to potential organ damage ³³. It’s also known as iron overload, and if left untreated, the excess iron can accumulate in vital organs like the liver, heart, and pancreas. Hemochromatosis occurs when a person inherited two mutated HFE genes (one from each parent). Hemochromatosis is associated with low levels of hepcidin, a specialized protein that is the primary regulator of iron absorption in the body, including regulating the uptake of iron by the gastrointestinal tract and liver.

Additional risk factors that have been associated with porphyria cutanea tarda include alcohol, certain infections such as hepatitis C or HIV, and drugs such as estrogens. Some studies have indicated that smoking is a risk factor for porphyria cutanea tarda in susceptible individuals. Less often, certain chemical exposures (e.g. hexachlorobenzene), kidney dialysis, and lupus appear to be connected to the development of porphyria cutanea tarda. It is believed that these susceptibility factors reduce hepcidin in the body and consequently lead to iron accumulation in the liver. However, the exact relationship among most susceptibility factors with the development of symptoms in porphyria cutanea tarda is not fully understood. For example, alcohol clearly contributes to the development of the disorder in some cases, but porphyria cutanea tarda is not common in alcoholics. Most individuals with porphyria cutanea tarda have three or more susceptibility factors present.

In some cases, individuals develop porphyria cutanea tarda without a known susceptibility factor, suggesting that additional, as yet unidentified risk factors exist.

The underlying cause of uroporphyrinogen decarboxylase deficiency in the acquired form of porphyria cutanea tarda is unknown. Affected individuals have approximately 50% residual uroporphyrinogen decarboxylase activity and do not develop symptoms unless additional factors are present. The most common factors associated with acquired porphyria cutanea tarda are hemochromatosis or chronic hepatitis C infection. In individuals with acquired porphyria cutanea tarda, uroporphyrinogen decarboxylase levels are only deficient in the liver.

In the familial form of porphyria cutanea tarda (familial porphyria cutanea tarda [PCT type 2]), individuals have a mutation in the uroporphyrinogen decarboxylase (UROD) gene. This mutation is inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new (de novo) mutation in the affected individual with no family history. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

The uroporphyrinogen decarboxylase (UROD) gene creates (encodes) the uroporphyrinogen decarboxylase enzyme, which is the fifth enzyme in the heme synthesis pathway. A mutation in one of these genes leads to abnormally low levels of this enzyme in all tissues of the body (not just the liver). However, one mutation alone is insufficient to cause familial porphyria cutanea tarda (F-PCT) as residual uroporphyrinogen decarboxylase enzyme levels remain above 20% of normal. In fact, most individuals with a mutation in the uroporphyrinogen decarboxylase gene do not develop the disorder. Additional factors must be present for the disorder to develop.

Risk Factors for developing porphyria cutanea tarda

Mild to moderate iron overload alongside amplified serum ferritin levels and hepatic siderosis reportedly occurs in 90% of porphyria cutanea tarda cases ³⁴, ³⁵, ³⁶. Iron overload can also be caused by mutations in the hemochromatosis gene (HFE gene) ³⁷, ³⁶. Hereditary hemochromatosis is a inherited disease causes the body to absorb too much iron from the diet triggering iron accumulation in organs such as liver ³⁷, ³⁸. The excess iron is stored in the body’s tissues and organs, particularly the skin, heart, liver, pancreas, and joints. Because humans cannot increase the excretion of iron, excess iron can overload and eventually damage tissues and organs. For this reason, hereditary hemochromatosis is also called an iron overload disorder. Early symptoms of hereditary hemochromatosis may include extreme tiredness (fatigue), joint pain, abdominal pain, weight loss, and loss of sex drive. As the condition worsens, affected individuals may develop arthritis, liver disease (cirrhosis) or liver cancer, diabetes, heart abnormalities, or skin discoloration. The appearance and severity of symptoms can be affected by environmental and lifestyle factors such as the amount of iron in the diet, alcohol use, and infections.

Mutations in several genes can cause hereditary hemochromatosis. Type 1 hemochromatosis results from mutations in the HFE gene, and type 2 hemochromatosis results from mutations in either the HJV or HAMP gene ³⁷, ³⁸. Mutations in the TFR2 gene cause type 3 hemochromatosis, and mutations in the SLC40A1 gene cause type 4 hemochromatosis ³⁷, ³⁸.

In type 1 hereditary hemochromatosis you inherit one HFE gene from each of your parents. The HFE gene has two common mutations, C282Y and H63D. Genetic testing can reveal whether you have these changes in your HFE gene. If you inherit two altered genes, you may develop hemochromatosis. You also can pass the altered gene on to your children. But not everyone who inherits two genes develops problems linked to the iron overload of hemochromatosis. If you inherit one altered gene, you’re unlikely to develop hemochromatosis. However, you are considered a carrier and can pass the altered gene on to your children. But your children wouldn’t develop hemochromatosis unless they also inherited another altered gene from the other parent.

Patients with porphyria cutanea tarda express more mutations in the HFE gene than the general population ³⁴, ³⁶. Data from several large studies indicate that the HFE gene mutation is present in almost 73% of porphyria cutanea tarda cases ³⁴. Another study found 64.9% of porphyria cutanea tarda patients carried at least one HFE mutated allele ³⁹. Other factors that can increase iron levels include hepatitis C virus infection, alcohol, and increased absorption of iron ³⁴.

Heavy alcohol use (>40g/day) is recorded in almost 90% of porphyria cutanea tarda cases ³⁴, and is more prevalent in males ³⁹. Alcohol consumption exacerbates porphyria cutanea tarda by inhibiting the activity of delta-aminolevulinic acid dehydratase (ALAD), uroporphyrinogen decarboxylase (UROD), coproporphyrinogen-III oxidase (CPOX) and ferrochelatase (FECH), while enhancing the activity of aminolevulinate synthase (ALAS) and hydroxymethylbilane synthase (HMBS) thereby promoting accumulation of porphyrin ²⁴. While the correlation between the effects of alcohol on aminolevulinate synthase (ALAS) and clinical expression of porphyria cutanea tarda is yet to be elucidated, chronic alcoholics are known to suffer from suppression of erythropoiesis and increased dietary iron absorption ¹⁹, ⁴⁰. Alcohol is also thought to contribute to increased iron absorption, alcohol induced oxidative stress, and downregulation of hepcidin ³⁴.

Smoking can induce earlier onset of Type 1 porphyria cutanea tarda (sporadic porphyria cutanea tarda) and is therefore a risk factor ⁴¹. Mechanisms of smoking mediating the development of porphyria cutanea tarda remain unclear, but increased oxidative stress and induction of hepatic cytochrome P450 enzymes are thought to contribute to disease pathology ³⁴.

Infections with Hepatitis C Virus (HCV), and comorbid Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) infections are associated with development of porphyria cutanea tarda ³⁰. Hepatitis C Virus (HCV) is the most common porphyria cutanea tarda-related viral infection, and although associated with both subtypes, it is observed more frequently in Type 1 porphyria cutanea tarda (sporadic porphyria cutanea tarda) and Type 2 porphyria cutanea tarda (familial porphyria cutanea tarda) ⁴², ¹⁹, ⁴³. A large study of 152 patients with porphyria cutanea tarda indicated that Hepatitis C Virus (HCV) infection is the most prevalent risk factor, especially in men ³⁹. Although mechanisms are unclear, there is some indication that hepatitis C virus (HCV)-induced reactive oxygen species can trigger disease manifestations by fostering reduced hepcidin levels and promoting hepatic iron accumulation ⁴⁴. Chronic hepatitis C virus (HCV) infection also lessens glutathione in hepatocytes, decreasing their ability to reduce oxidized porphyrins and causing their accumulation ¹⁹. It is important to note that hepatitis C virus (HCV)-infected persons develop porphyria cutanea tarda at an earlier age than those without the virus. HFE gene mutations also cause iron overload that further promote hepatocellular injury and fibrosis in patients with hepatitis C virus (HCV) ¹⁹.

Estrogens have been identified as precipitating factors for women with type 2 porphyria cutanea tarda (familial porphyria cutanea tarda [F-PCT]) ³⁹, ³⁰. Reports indicate use of oral contraceptives, hormone replacement therapy, and use of tamoxifen for breast cancer to be associated with porphyria cutanea tarda ³⁴, ⁴⁵, ⁴⁶. Diethylstilbestrol, a synthetic nonsteroidal estrogen, also induces hepatic aminolevulinate synthase (ALAS), though there is currently no clear understanding of the accompanying increased porphyrin excretion in porphyria cutanea tarda patients ¹⁹. Estrogen as a treatment for prostate cancer has also been identified as a risk factor in men ⁴⁷. Administration of estrogens via transdermal route is safe and recommended for at-risk women previously treated for porphyria cutanea tarda ⁴⁶.

Hepatic siderosis (hepatic iron overload or the abnormal accumulation of iron in the liver caused by various factors, including hereditary hemochromatosis and secondary causes like chronic liver disease or repeated blood transfusions), systemic lupus erythematosus (SLE), end-stage renal disease on hemodialysis, diabetes mellitus, and hematologic malignancies are all associated with the development of porphyria cutanea tarda ⁴⁸, ⁴⁶, ⁴⁹, ⁵⁰, ⁵¹, ⁵², ³⁴, ¹⁹.

Exposure to toxins such as polychlorinated biphenyls, hexachlorobenzene, and other polyhalogenated hydrocarbons that significantly induce cytochrome P450 enzymes are also associated with the development of porphyria cutanea tarda ¹⁸.

Porphyria Cutanea Tarda Pathophysiology

Porphyria cutanea tarda results from the inhibition of liver uroporphyrinogen decarboxylase (UROD) enzyme, a cytoplasmic housekeeping enzyme that converts uroporphyrinogen to coproporphyrinogen ². The uroporphyrinogen decarboxylase (UROD) enzyme is encoded by the UROD gene, located on chromosome 1 with 10 exons spanning over 3 kb ⁵³, ⁵⁴. The uroporphyrinogen decarboxylase (UROD) enzyme carries out a complex reaction, sequentially decarboxylating the 4 acetyl groups of uroporphyrinogen (an octacarboxyl porphyrin) to hepta-, hexa-, penta-, and finally coproporphyrinogen (a tetracarboxyl porphyrin) ³⁴, ⁵⁵. Both uroporphyrinogen I and III isomers are decarboxylated by uroporphyrinogen decarboxylase (UROD), but uroporphyrinogen III is preferred because coproporphyrinogen oxidase is specific for coproporphyrinogen III, and the III isomers are intermediates in heme synthesis ⁵⁶, ⁵⁷, ⁵⁸, ⁵⁸.

The liver uroporphyrinogen decarboxylase (UROD) protein level remains at its genetically determined level in all types of porphyria cutanea tarda, but liver enzyme activity is reduced to less than about 20% of normal, suggesting the presence of an enzyme inhibitor ². Phillips and colleagues ¹⁰ identified this inhibitor as a uroporphomethene, probably derived from the partial oxidization of uroporphyrinogen. At least in mice models, cytochrome P450 enzyme activity is involved in the generation of uroporphomethene inhibitor. Uroporphomethene differs from uroporphyrinogen by a single oxidized bridge carbon, and although it is able to bind strongly to the active site of UROD, it is unable to serve as a substrate ¹⁰ However, other researchers have questioned whether uroporphomethene is in fact a true inhibitor of UROD based on its fragmentation pattern on mass spectrometry ⁵⁹.

When hepatic UROD activity is reduced to less than 20% of normal activity, uroporphyrinogen and the porphyrinogens that are intermediates in its 4-step decarboxylation accumulate in the liver and are auto-oxidized to their corresponding porphyrins ⁶⁰. After considerable accumulation in the liver, these porphyrins (uroporphyrinogen and porphyrinogens) appear in plasma and bile and are excreted in the urine and stool ⁵⁶. These porphyrins are activated by light exposure (especially at wavelengths near 400 nm) and generate reactive oxygen species that damage sun-exposed skin ⁶⁰. Furthermore, in UROD-deficient mice, the upregulation of delta-aminolevulinic acid synthase 1 (ALAS-1) by drugs that induce hepatic P450 enzymes and the supplementation of δ-aminolevulinic acid (ALA) in the drinking water have been shown to induce a porphyria cutanea tarda phenotype ⁶¹.

Porphyria Cutanea Tarda Signs and Symptoms

The symptoms of porphyria cutanea tarda (PCT) can vary greatly from one individual to another. The symptoms of porphyria cutanea tarda are confined mostly to your skin. Excess porphyrin in your skin results in photosensitivity (a condition in which the skin becomes very sensitive to sunlight or other forms of ultraviolet light and may burn easily). Individuals with porphyria cutanea tarda (PCT) develop blisters on sun-exposed areas of their skin (photosensitivity), such as the back of the hands and the forearms. Other sun-exposed sites such as the face, scalp, neck, and arms may also be affected. The skin in these areas may blister or peel after minor trauma. Eventually, scarring may develop and affected skin may darken (hyperpigmentation) or fade (hypopigmentation) in color. Abnormal, excessive hair growth (hypertrichosis), especially on the face may also occur. The hair may be very fine or coarse and can differ in color. In some patients, their hair may grow, thicken and darken. Small bumps with a distinct white head (milia) may also develop, especially on the backs of the hands. In some cases, the skin in affected areas may thickened and harden, resembling a condition known as sclerosis, this is sometimes known as pseudosclerosis. Pseudosclerosis in individuals with porphyria cutanea tarda appears as scattered, waxy, harden patches or plaques of skin. Characteristically, the urine is darker than usual, with a reddish or tea-colored hue.

Neurological and abdominal symptoms are not characteristic of porphyria cutanea tarda.

Liver abnormalities may develop in some affected individuals including the accumulation of iron in the liver (hepatic siderosis), the accumulation of fat in the liver (steatosis), inflammation of certain parts of the liver (portal triaditis), and thickening and scarring around the portal vein (periportal fibrosis). Affected individuals may be at a greater risk than the general population of developing scarring of the liver (cirrhosis) or liver cancer known as hepatocellular carcinoma (HCC). Advanced liver disease is uncommon, except in older individuals with recurrent disease. In some cases, liver disease is due to an associated condition such as hepatitis B or hepatitis C infection.

Porphyria cutanea tarda, Hepatitis C Virus and HIV

Because porphyria cutanea tarda is frequently associated with hepatitis C virus (HCV) infection, it is worth noting the issues involved in treating a patient with both porphyria cutanea tarda and hepatitis C virus infection.

Infection with hepatitis C virus is much more common than porphyria cutanea tarda, and most people with hepatitis C virus do not have porphyria cutanea tarda. However, at least in some locations, as many as 80 percent of individuals with porphyria cutanea tarda are infected with hepatitis C virus. Therefore, hepatitis C virus needs to be added to the list of factors that can activate porphyria cutanea tarda alongside alcohol, iron and estrogens. Other hepatitis viruses are seldom implicated in porphyria cutanea tarda, and it is not known how hepatitis C virus activates porphyria cutanea tarda.

There are several different viruses that cause hepatitis. A blood test for hepatitis C virus infection has not been available for very long. Hepatitis C virus is most readily transmitted from one person to another by blood products. Although most people who are infected with hepatitis C virus have a history of exposure to blood or needles contaminated with blood, in some cases it is not known how the infection was acquired. Hepatitis C virus (unlike the hepatitis B Virus and HIV) is seldom transmitted by sexual contact. It is also not readily transmitted by casual contact with other people. Therefore, people infected with hepatitis C virus are not hazardous unless they somehow expose others to their blood.

It is recommended that patients with porphyria cutanea tarda be tested for hepatitis C virus infection. This is done by a blood test that detects antibodies to the virus. If hepatitis C virus infection is found, it may not change the treatment of porphyria cutanea tarda by phlebotomy or low-dose chloroquine. Treatment for porphyria cutanea tarda is highly successful even in patients with hepatitis C virus. Therefore, it is reasonable to treat the porphyria cutanea tarda first and then look into treatment for hepatitis C virus later.

There are reasons not to treat the hepatitis C virus infection before treating the porphyria cutanea tarda. Hepatitis C virus treatment with alpha-interferon and ribavirin is available but is often not effective. Also, liver damage progresses slowly if at all in many people with hepatitis C virus. However, once the porphyria cutanea tarda is in remission it is important to assess the amount of liver damage the virus has already caused and to have follow-up visits to a doctor to monitor the liver. In some cases it may be important to treat hepatitis C virus infection to try and prevent progressive liver damage.

Porphyria Cutanea Tarda Complications

Although the signs and symptoms of porphyria cutanea tarda are limited to the skin, patients are also at a high risk of liver complications. Liver biopsies usually reveal fatty changes along with porphyrin deposits and sometimes lobular necrosis. Porphyria cutanea tarda independently increases the risk of liver cirrhosis and hepatocellular carcinoma, which may be accentuated by co-existing hepatitis C virus (HCV) infection, alcoholic hepatitis, or iron overload ⁶².

Porphyria Cutanea Tarda Diagnosis

Porphyria cutanea tarda (PCT) may be clinically suspected but should always be confirmed by laboratory tests. The preferred screening test for porphyria cutanea tarda is a measurement of porphyrins in plasma and urin. This can differentiate porphyria cutanea tarda (PCT) from Variegate Porphyria (VP). Urine and feces need to be sent to analyse the porphyrin levels, which will be elevated. The specimens need to be protected from light with aluminium foil to ensure testing is accurate. Examination of the urine with a Wood’s lamp (Wood’s lamp emits long-wave ultraviolet (UV) light) may reveal coral pink fluorescence due to excessive porphyrins.

Porphyria cutanea tarda (PCT) is diagnosed biochemically by high levels of porphyrins in the plasma and urine, with a predominance of uroporphyrinogen and hepta- and hexa- and pentacarboxyl porphyrins. This pattern of porphyrin elevation is characteristic but not completely specific since uroporphyrin elevation occurs in other porphyrias, and a PCT-like pattern occurs in some patients with variegate porphyria (VP) ⁶³. Therefore, analysis of porphyrins in the red blood cells (erythrocytes) and feces should be considered. Urine measurements using random urine samples with normalization to creatinine is recommended. Urine porphobilinogen is normal in porphyria cutanea tarda (PCT), and delta-aminolevulinic acid (ALA) is normal or only mildly increased ³⁴. The patterns of porphyrins in urine (predominately uroporphyrin and 7-carboxylate porphyrin) and feces (predominately isocoproporphyrin) help to confirm the diagnosis. Plasma fluorescence scanning is useful for rapid differentiation of variegate porphyria (VP), which has a diagnostic peak at approximately 626 nm. Fecal total porphyrins may be normal or elevated in porphyria cutanea tarda (PCT), and an elevation of fecal isocoproporphyrins is specific for UROD inhibition ⁶³, ⁶⁴.

Familial porphyria cutanea tarda (F-PCT), an inherited deficiency of uroporphyrinogen decarboxylase (UROD) enzyme, can be diagnosed by the presence of a reduced amount of the uroporphyrinogen decarboxylase (UROD) enzyme in red blood cells (erythrocytes) and is present in about 20% of patients with porphyria cutanea tarda ⁵⁶. Molecular genetic testing is available for familial porphyria cutanea tarda if the diagnosis has been confirmed in the patient or a family member by urinary porphyrin analysis and/or enzyme assay of uroporphyrinogen decarboxylase activity ⁶⁵, ⁶⁶.

A skin biopsy can be helpful to distinguish porphyria cutanea tarda (PCT) from other skin blistering conditions. The skin changes are identical to Variegate Porphyria (VP) and Hereditary Coproporphyria (HCP).

Tests to determine the cause of the porphyria may include:

Blood count, liver function, and kidney function tests
Iron studies (ferritin level)
Hepatitis B, C, and human immunodeficiency virus (HIV) serology
Transferrin saturation and genotyping for HFE gene mutations for hereditary hemochromatosis ³⁷
Tests for cutaneous lupus erythematosus and diabetes
Urodecarboxylase (UROD) enzyme levels and genetic tests.

Porphyria Cutanea Tarda Differential Diagnosis

The most important differentials in a patient with suspected porphyria cutanea tarda include hereditary coproporphyria (HCP), variegate porphyria (VP) and congenital erythropoietic porphyria (CEP) due to the cutaneous manifestations seen in all four porphyrias along with elevated porphyrin levels ¹³. All other porphyrias will have specific patterns of porphyrin elevation, which would be diagnostic of that disease. Variegate porphyria (VP), for example, would have an increased urinary level of coproporphyrins, aminolevulinic acid (ALA), and porphobilinogen, whereas congenital erythropoietic porphyria (CEP) would have normal urinary aminolevulinic acid (ALA) and porphobilinogen levels. However, both variegate porphyria (VP) and hereditary coproporphyria (HCP) can be clinically differentiated from porphyria cutanea tarda (PCT) based on their presenting neurovisceral symptoms (acute symptoms characterized by attacks of abdominal pain), which is lacking in patients with porphyria cutanea tarda (PCT) ¹⁷.

Blistering skin diseases: Epidermolysis bullosa, polymorphous light eruptions, and pseudoporphyria cutanea trade. All three conditions, although clinically similar to porphyria cutanea tarda, will not cause a rise in porphyrin levels and hence can be distinguished from porphyria cutanea tarda using laboratory investigations.

Pseudoporphyria cutanea tarda is clinically and histologically indistinguishable from porphyria cutanea tarda but without the porphyrin elevation. It is associated with nonsteroidal anti-inflammatory drugs (NSAIDs), furosemide, antibiotics (nalidixic acid, tetracyclines), or retinoid use ¹⁷.
Epidermolysis bullosa acquisita is an autoimmune blistering disorder that presents with widespread blisters not limited to sun-exposed skin surfaces ⁶⁷.
Polymorphous light eruption is a light distributed pruritic rash that develops minutes to hours after sunlight exposure and is characterized by erythematous papules, vesicles, and plaques that are nonscarring ⁶⁸.

Porphyrin elevation is also seen in liver disease, advanced kidney disease, and other porphyrias. However, they will not show the typical skin manifestations seen in patients with porphyria cutanea tarda.

Porphyria Cutanea Tarda Treatment

Porphyria cutanea tarda is the most treatable of the porphyrias. The treatment of porphyria cutanea tarda is directed toward the underlying liver problem and the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, general internists, hematologists, dermatologists, hepatologists, and other healthcare professionals may need to systematically and comprehensively plan your treatment.

Iron chelation therapy i.e., deferasirox or deferoxamine may be considered when phlebotomy is contraindicated, and low iron diet may be beneficial if the latter fails ¹⁸.

Furthermore, use of antiviral therapy may benefit patients with chronic hepatitis C infections and reduce risk of progressing to liver cancer ¹⁹.

Phlebotomy

Any condition leading to iron overload in the patient is a clear indication for phlebotomy, and in porphyria cutanea tarda cases, phlebotomy is preferred over hydroxychloroquine. Different protocols have been tried, such as removing one unit or 450 ml of blood every two weeks. Strict serial monitoring of ferritin levels is done, and a downward trend in serum ferritin level is the goal of phlebotomy (till a ferritin level of less than 20 ng/ml is seen) ²², ²³. Alternatively, 300ml of blood removed weekly is another treatment strategy that can be used. Care should be taken not to induce anemia or hemoglobin less than 10 gm/dL. Contraindications to phlebotomy include patients with pulmonary or coronary artery disease.

The skin manifestations resolve within four months, but the porphyrin levels can take up to 12 months to normalize ¹³. Serum ferritin levels may be used as an indicator to monitor for relapse of porphyria cutanea tarda since the levels change before porphyrin levels ⁶⁹.

Hydroxychloroquine or chloroquine

Hydroxychloroquine or chloroquine are preferred therapies in cases where ferritin levels are not elevated (below 600 ng/mL) or a patient without an HFE gene mutation ¹³. Hydroxychloroquine or chloroquine act by inhibiting the formation and secretion of porphyrins ⁶⁹. Chloroquine 125 mg twice weekly or in cases of intolerance, hydroxychloroquine can be used twice weekly at a dose of 200mg ¹³. Hydroxychloroquine may be safer in terms of retinal toxicity ⁷⁰. These regimens can take between 6 to 9 months for complete remission. Contraindications to these drugs include pregnancy, liver disease, retinal disease, and the concomitant use of other hepatotoxic drugs. Regular eye (ophthalmologic) examination and liver function tests monitoring are required.

Iron chelation therapy

Iron chelation was considered to be an alternative in people with iron overload-induced porphyria cutanea tarda, but after comparative studies with phlebotomy and hydroxychloroquine, it was not found to be as efficient ¹³. However, deferoxamine and deferasirox can be used in patients with contraindications to both phlebotomy and hydroxychloroquine ¹³. The disadvantages of iron chelation therapy other than being expensive due to the use of a subcutaneous pump were the failure to normalize the porphyrin level even after 12 months of treatment ¹³.

Porphyria Cutanea Tarda Prognosis

Porphyria cutanea tarda is the most treatable of the porphyrias. Once clear, porphyria cutanea tarda is unlikely to recur unless the underlying risk factors (susceptibility factors) have not been addressed. Relapses of up to 35% have been recorded over a follow-up period of up to 11 years ⁷¹. People with porphyria cutanea tarda with elevated iron levels may need periodic phlebotomy (removal of blood). Patients who continue to be exposed to risk factors (susceptibility factors), such as excessive alcohol consumption and smoking, are also more likely to relapse ¹³. Annual monitoring of urine and plasma uroporphyrin levels is recommended to detect biochemical relapses before the clinical manifestations of the disease appear ⁴². If porphyria cutanea tarda is ongoing, there can be an increased risk of developing hepatocellular carcinoma (HCC) or liver cancer, especially in populations of older men with long-standing active disease, heavy alcohol intake, and cirrhosis ⁷². Most of the studies predate recognition of hepatitis C prevalence in populations with porphyria cutanea tarda or hepatocellular carcinoma (HCC); many reported liver cancers may have been, at least in part, as complication of chronic hepatitis C infection ⁷³.

Porphyria Cutanea Tarda Life Expectancy

Life expectancy in patients of porphyria cutanea tarda is expected to be normal unless there are additional diseases like hepatitis C infection (HCV) that could lead to liver disease or liver cancer ¹³.

Kakoullis L, Louppides S, Papachristodoulou E, Panos G. Porphyrias and photosensitivity: pathophysiology for the clinician. Postgrad Med. 2018 Nov;130(8):673-686. doi: 10.1080/00325481.2018.1533380[↩][↩]
Leaf RK, Dickey AK. Porphyria cutanea tarda: a unique iron-related disorder. Hematology Am Soc Hematol Educ Program. 2024 Dec 6;2024(1):450-456. doi: 10.1182/hematology.2024000664[↩][↩][↩][↩][↩]
Usta Atmaca H, Akbas F. Porphyria cutanea tarda: a case report. J Med Case Rep. 2019 Jan 21;13(1):17. doi: 10.1186/s13256-018-1956-9[↩]
DeMaria BL, Franke AJ. Porphyria Cutanea Tarda in a Patient With Hereditary Hemochromatosis: A Complex Overlap Disorder. Cureus. 2024 Nov 20;16(11):e74091. doi: 10.7759/cureus.74091[↩]
Baravelli CM, Aarsand AK, Sandberg S, Tollånes MC. Porphyria cutanea tarda and patterns of long-term sick leave and disability pension: a 24-year nationwide matched-cohort study. Orphanet J Rare Dis. 2022 Feb 22;17(1):72. doi: 10.1186/s13023-022-02201-3. Erratum in: Orphanet J Rare Dis. 2022 May 4;17(1):180. doi: 10.1186/s13023-022-02329-2[↩]
Bonkovsky HL, Rudnick SP, Ma CD, Overbey JR, Wang K, Faust D, Hallberg C, Hedstrom K, Naik H, Moghe A, Anderson KE. Ledipasvir/Sofosbuvir Is Effective as Sole Treatment of Porphyria Cutanea Tarda with Chronic Hepatitis C. Dig Dis Sci. 2023 Jun;68(6):2738-2746. doi: 10.1007/s10620-023-07859-8[↩]
Awad A, Nirenberg A, Sinclair R. Case Report: Treatment of porphyria cutanea tarda with low dose hydroxychloroquine. F1000Res. 2022 Aug 17;11:945. doi: 10.12688/f1000research.124022.1[↩]
Norman RA. Past and future: porphyria and porphyrins. Skinmed. 2005 Sep-Oct;4(5):287-92. doi: 10.1111/j.1540-9740.2005.03706.x[↩]
Badenas C, To-Figueras J, Phillips JD, Warby CA, Muñoz C, Herrero C. Identification and characterization of novel uroporphyrinogen decarboxylase gene mutations in a large series of porphyria cutanea tarda patients and relatives. Clin Genet. 2009 Apr;75(4):346-53. doi: 10.1111/j.1399-0004.2009.01153.x[↩]
Phillips JD, Bergonia HA, Reilly CA, Franklin MR, Kushner JP. A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5079-84. doi: 10.1073/pnas.0700547104[↩][↩][↩]
Anderson KE, Sassa S, Bishop DF, Desnick RJ. Disorders of Heme Biosynthesis: X-Linked Sideroblastic Anemia and the Porphyrias. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw–Hill; 2001. pp. 2991–3062.[↩]
Sassa S. Modern diagnosis and management of the porphyrias. Br J Haematol. 2006;135(3):281–292. doi: 10.1111/j.1365-2141.2006.06289.x[↩]
Shah A, Bhatt H. Porphyria Cutanea Tarda. [Updated 2023 Apr 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK563209[↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩]
Farrag MS, Mikula I, Richard E, Saudek V, De Verneuil H, Martásek P. Hepatoerythropoietic Porphyria Caused by a Novel Homoallelic Mutation in Uroporphyrinogen Decarboxylase Gene in Egyptian Patients. Folia Biol (Praha) 2015;61(6):219–226. doi: 10.14712/fb2015061060219[↩]
Mykletun M, Aarsand AK, Støle E, Villanger JH, Tollånes MC, Baravelli C, Sandberg S. Porphyrias in Norway. Tidsskr Nor Laegeforen. 2014 Apr 29;134(8):831-6. English, Norwegian. doi: 10.4045/tidsskr.13.0649[↩]
Bulaj ZJ, Phillips JD, Ajioka RS, Franklin MR, Griffen LM, Guinee DJ, Edwards CQ, Kushner JP. Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood. 2000 Mar 1;95(5):1565-71. https://doi.org/10.1182/blood.V95.5.1565.005k42_1565_1571[↩][↩]
Frank J, Poblete-Gutiérrez P. Porphyria cutanea tarda–when skin meets liver. Best Pract Res Clin Gastroenterol. 2010 Oct;24(5):735-45. doi: 10.1016/j.bpg.2010.07.002[↩][↩][↩][↩]
Rudnick S, Phillips J, Bonkovsky H; Porphyrias Consortium of the Rare Diseases Clinical Research Network. Familial Porphyria Cutanea Tarda. 2013 Jun 6 [Updated 2022 Jun 9]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK143129[↩][↩][↩][↩][↩][↩][↩]
Handler NS, Handler MZ, Stephany MP, Handler GA, Schwartz RA. Porphyria cutanea tarda: an intriguing genetic disease and marker. Int J Dermatol. 2017 Jun;56(6):e106-e117. doi: 10.1111/ijd.13580[↩][↩][↩][↩][↩][↩][↩][↩][↩][↩]
Ryan Caballes F, Sendi H, Bonkovsky HL. Hepatitis C, porphyria cutanea tarda and liver iron: an update. Liver Int. 2012 Jul;32(6):880-93. doi: 10.1111/j.1478-3231.2012.02794.x[↩][↩]
Ellervik C, Birgens H, Tybjaerg-Hansen A, Nordestgaard BG. Hemochromatosis genotypes and risk of 31 disease endpoints: meta-analyses including 66,000 cases and 226,000 controls. Hepatology. 2007 Oct;46(4):1071-80. doi: 10.1002/hep.21885[↩][↩]
Ratnaike S, Blake D, Campbell D, Cowen P, Varigos G. Plasma ferritin levels as a guide to the treatment of porphyria cutanea tarda by venesection. Australas J Dermatol. 1988 Apr;29(1):3-8. doi: 10.1111/j.1440-0960.1988.tb01216.x[↩][↩][↩]
Rocchi E, Gibertini P, Cassanelli M, Pietrangelo A, Borghi A, Ventura E. Serum ferritin in the assessment of liver iron overload and iron removal therapy in porphyria cutanea tarda. J Lab Clin Med. 1986 Jan;107(1):36-42.[↩][↩][↩]
Balogun O, Nejak-Bowen K. Understanding Hepatic Porphyrias: Symptoms, Treatments, and Unmet Needs. Semin Liver Dis. 2024 May;44(2):209-225. doi: 10.1055/s-0044-1787076[↩][↩]
Lin, Jou & Shi, Donglu. (2021). Photothermal and photovoltaic properties of transparent thin films of porphyrin compounds for energy applications. Applied Physics Reviews. 8. 011302. https://doi.org/10.1063/5.0036961[↩]
Heme and Bilirubin Metabolism. https://themedicalbiochemistrypage.org/heme-and-bilirubin-metabolism/[↩]
Edel Y, Mamet R. Porphyria: What Is It and Who Should Be Evaluated? Rambam Maimonides Med J. 2018 Apr 19;9(2):e0013. doi: 10.5041/RMMJ.10333[↩]
Porphyria Cutanea Tarda. https://emedicine.medscape.com/article/1103643-overview#a7[↩]
Egger NG, Goeger DE, Payne DA, Miskovsky EP, Weinman SA, Anderson KE. Porphyria cutanea tarda: multiplicity of risk factors including HFE mutations, hepatitis C, and inherited uroporphyrinogen decarboxylase deficiency. Dig Dis Sci. 2002 Feb;47(2):419-26. doi: 10.1023/a:1013746828074[↩]
Cruz-Rojo J, Fontanellas A, Morán-Jiménez MJ, Navarro-Ordóñez S, García-Bravo M, Méndez M, Muñoz-Rivero MC, de Salamanca RE. Precipitating/aggravating factors of porphyria cutanea tarda in Spanish patients. Cell Mol Biol (Noisy-le-grand). 2002 Dec;48(8):845-52.[↩][↩][↩]
Jalil S, Grady JJ, Lee C, Anderson KE. Associations among behavior-related susceptibility factors in porphyria cutanea tarda. Clin Gastroenterol Hepatol. 2010 Mar;8(3):297-302, 302.e1. doi: 10.1016/j.cgh.2009.11.017[↩]
HFE gene. https://medlineplus.gov/genetics/gene/hfe/[↩][↩][↩][↩]
Porter JL, Rawla P. Hemochromatosis. [Updated 2024 Oct 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430862[↩]
Singal AK. Porphyria cutanea tarda: Recent update. Mol Genet Metab. 2019 Nov;128(3):271-281. doi: 10.1016/j.ymgme.2019.01.004[↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩]
Bonkovsky HL, Lambrecht RW, Shan Y. Iron as a co-morbid factor in nonhemochromatotic liver disease. Alcohol. 2003 Jun;30(2):137-44. doi: 10.1016/s0741-8329(03)00127-7[↩]
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 Jun;27(6):1661-9. doi: 10.1002/hep.510270627[↩][↩][↩]
Barton JC, Parker CJ. HFE-Related Hemochromatosis. 2000 Apr 3 [Updated 2024 Apr 11]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1440[↩][↩][↩][↩][↩]
Hereditary hemochromatosis. https://medlineplus.gov/genetics/condition/hereditary-hemochromatosis/[↩][↩][↩]
Muñoz-Santos C, Guilabert A, Moreno N, To-Figueras J, Badenas C, Darwich E, Herrero C. Familial and sporadic porphyria cutanea tarda: clinical and biochemical features and risk factors in 152 patients. Medicine (Baltimore). 2010 Mar;89(2):69-74. doi: 10.1097/MD.0b013e3181d50928[↩][↩][↩][↩]
McColl KE, Moore MR, Thompson GG, Goldberg A. Abnormal haem biosynthesis in chronic alcoholics. Eur J Clin Invest. 1981 Dec;11(6):461-8. doi: 10.1111/j.1365-2362.1981.tb02014.x[↩]
Fontanellas A, Martínez-Fresno M, Garrido-Astray MC, Perucho T, Morán-Jiménez MJ, García-Bravo M, Méndez M, Poblete-Gutiérrez P, Frank J, Henriques-Gil N, de Salamanca RE. Smoking but not homozygosity for CYP1A2 g-163A allelic variant leads to earlier disease onset in patients with sporadic porphyria cutanea tarda. Exp Dermatol. 2010 Aug;19(8):e326-8. doi: 10.1111/j.1600-0625.2009.01040.x[↩]
Bissell DM, Anderson KE, Bonkovsky HL. Porphyria. N Engl J Med. 2017 Aug 31;377(9):862-872. doi: 10.1056/NEJMra1608634[↩][↩]
Quansah R, Cooper CJ, Said S, Bizet J, Paez D, Hernandez GT. Hepatitis C- and HIV-induced porphyria cutanea tarda. Am J Case Rep. 2014 Jan 21;15:35-40. doi: 10.12659/AJCR.889955[↩]
Nishina S, Hino K, Korenaga M, Vecchi C, Pietrangelo A, Mizukami Y, Furutani T, Sakai A, Okuda M, Hidaka I, Okita K, Sakaida I. Hepatitis C virus-induced reactive oxygen species raise hepatic iron level in mice by reducing hepcidin transcription. Gastroenterology. 2008 Jan;134(1):226-38. doi: 10.1053/j.gastro.2007.10.011[↩]
Cruz MJ, Alves S, Baudrier T, Azevedo F. Porphyria cutanea tarda induced by tamoxifen. Dermatol Online J. 2010 Sep 15;16(9):2. https://doi.org/10.5070/D38xm7n81b[↩]
Bulaj ZJ, Franklin MR, Phillips JD, Miller KL, Bergonia HA, Ajioka RS, Griffen LM, Guinee DJ, Edwards CQ, Kushner JP. Transdermal estrogen replacement therapy in postmenopausal women previously treated for porphyria cutanea tarda. J Lab Clin Med. 2000 Dec;136(6):482-8. doi: 10.1067/mlc.2000.111024[↩][↩][↩]
Roenigk HH, Gottlob ME. Estrogen-Induced Porphyria Cutanea Tarda: Report of Three Cases. Arch Dermatol. 1970;102(3):260–266. doi:10.1001/archderm.1970.04000090022004[↩]
Ajioka RS, Phillips JD, Weiss RB, Dunn DM, Smit MW, Proll SC, Katze MG, Kushner JP. Down-regulation of hepcidin in porphyria cutanea tarda. Blood. 2008 Dec 1;112(12):4723-8. doi: 10.1182/blood-2008-02-138222[↩]
Gibson GE, McEvoy MT. Coexistence of lupus erythematosus and porphyria cutanea tarda in fifteen patients. J Am Acad Dermatol. 1998 Apr;38(4):569-73. doi: 10.1016/s0190-9622(98)70119-7[↩]
Rodrigues N, Caeiro F, Santana A, Mendes T, Lopes L. Porphyria Cutanea Tarda in a Patient with End-Stage Renal Disease: A Case of Successful Treatment with Deferoxamine and Ferric Carboxymaltose. Case Rep Nephrol. 2017;2017:4591871. doi: 10.1155/2017/4591871[↩]
Christiansen AL, Bygum A, Hother-Nielsen O, Rasmussen LM. Diagnosing diabetes mellitus in patients with porphyria cutanea tarda. Int J Dermatol. 2018 Jul;57(7):763-769. doi: 10.1111/ijd.13938[↩]
McKenna DB, Browne M, O’Donnell R, Murphy GM. Porphyria cutanea tarda and hematologic malignancy–a report of 4 cases. Photodermatol Photoimmunol Photomed. 1997 Aug;13(4):143-6. doi: 10.1111/j.1600-0781.1997.tb00218.x[↩]
Dubart A, Mattei MG, Raich N, Beaupain D, Romeo PH, Mattei JF, Goossens M. Assignment of human uroporphyrinogen decarboxylase (URO-D) to the p34 band of chromosome 1. Hum Genet. 1986 Jul;73(3):277-9. doi: 10.1007/BF00401245[↩]
Romana M, Dubart A, Beaupain D, Chabret C, Goossens M, Romeo PH. Structure of the gene for human uroporphyrinogen decarboxylase. Nucleic Acids Res. 1987 Sep 25;15(18):7343-56. https://pmc.ncbi.nlm.nih.gov/articles/instance/306252/pdf/nar00262-0144.pdf[↩]
Felsher BF, Carpio NM, Engleking DW, Nunn AT. Decreased hepatic uroporphyrinogen decarboxylase activity in porphyria cutanea tarda. N Engl J Med. 1982 Apr 1;306(13):766-9. doi: 10.1056/NEJM198204013061302[↩]
Phillips JD. Heme biosynthesis and the porphyrias. Mol Genet Metab. 2019 Nov;128(3):164-177. doi: 10.1016/j.ymgme.2019.04.008[↩][↩][↩]
Phillips JD, Bergonia HA, Reilly CA, Franklin MR, Kushner JP. The uroporphomethene inhibitor causitive for porphyria cutanea tarda (PCT) is generated by oxidation of hydroxymethylbilane (HMB). Blood. 2008; 112(11):3454.[↩]
Phillips JD, Whitby FG, Kushner JP, Hill CP. Structural basis for tetrapyrrole coordination by uroporphyrinogen decarboxylase. EMBO J. 2003 Dec 1;22(23):6225-33. doi: 10.1093/emboj/cdg606[↩][↩]
Danton M, Lim CK. Porphomethene inhibitor of uroporphyrinogen decarboxylase: analysis by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry. Biomed Chromatogr. 2007 Jul;21(7):661-3. doi: 10.1002/bmc.860[↩]
Poh-Fitzpatrick MB. Pathogenesis and treatment of photocutaneous manifestations of the porphyrias. Semin Liver Dis. 1982 May;2(2):164-76. doi: 10.1055/s-2008-1040706[↩][↩]
Phillips JD, Jackson LK, Bunting M, Franklin MR, Thomas KR, Levy JE, Andrews NC, Kushner JP. A mouse model of familial porphyria cutanea tarda. Proc Natl Acad Sci U S A. 2001 Jan 2;98(1):259-64. doi: 10.1073/pnas.98.1.259[↩]
Sarkany RP. The management of porphyria cutanea tarda. Clin Exp Dermatol. 2001 May;26(3):225-32. doi: 10.1046/j.1365-2230.2001.00825.x[↩]
Di Pierro E, De Canio M, Mercadante R, Savino M, Granata F, Tavazzi D, Nicolli AM, Trevisan A, Marchini S, Fustinoni S. Laboratory Diagnosis of Porphyria. Diagnostics (Basel). 2021 Jul 26;11(8):1343. doi: 10.3390/diagnostics11081343[↩][↩]
Elder GH. Differentiation of porphyria cutanea tarda symptomatica from other types of porphyria by measurement of isocoproporphyrin in faeces. J Clin Pathol. 1975 Aug;28(8):601-7. https://pmc.ncbi.nlm.nih.gov/articles/instance/475786/pdf/jclinpath00142-0001.pdf[↩]
Wang Y, Gatti P, Sadílek M, Scott CR, Turecek F, Gelb MH. Direct assay of enzymes in heme biosynthesis for the detection of porphyrias by tandem mass spectrometry. Uroporphyrinogen decarboxylase and coproporphyrinogen III oxidase. Anal Chem. 2008 Apr 1;80(7):2599-605. doi: 10.1021/ac702130n[↩]
Yasuda M, Chen B, Desnick RJ. Recent advances on porphyria genetics: Inheritance, penetrance & molecular heterogeneity, including new modifying/causative genes. Mol Genet Metab. 2019 Nov;128(3):320-331. doi: 10.1016/j.ymgme.2018.11.012[↩]
Vorobyev A, Ludwig RJ, Schmidt E. Clinical features and diagnosis of epidermolysis bullosa acquisita. Expert Rev Clin Immunol. 2017 Feb;13(2):157-169. doi: 10.1080/1744666X.2016.1221343[↩]
Gruber-Wackernagel A, Byrne SN, Wolf P. Polymorphous light eruption: clinic aspects and pathogenesis. Dermatol Clin. 2014 Jul;32(3):315-34, viii. doi: 10.1016/j.det.2014.03.012[↩]
Bleasel NR, Varigos GA. Porphyria cutanea tarda. Australas J Dermatol. 2000 Nov;41(4):197-206; quiz 207-8. doi: 10.1046/j.1440-0960.2000.00437.x[↩][↩]
Easterbrook M. An ophthalmological view on the efficacy and safety of chloroquine versus hydroxychloroquine. J Rheumatol. 1999 Sep;26(9):1866-8.[↩]
Salameh H, Sarairah H, Rizwan M, Kuo YF, Anderson KE, Singal AK. Relapse of porphyria cutanea tarda after treatment with phlebotomy or 4-aminoquinoline antimalarials: a meta-analysis. Br J Dermatol. 2018 Dec;179(6):1351-1357. doi: 10.1111/bjd.16741[↩]
Porphyria Cutanea Tarda. https://emedicine.medscape.com/article/1103643-overview#a2[↩]
Gisbert JP, García-Buey L, Alonso A, Rubio S, Hernández A, Pajares JM, García-Díez A, Moreno-Otero R. Hepatocellular carcinoma risk in patients with porphyria cutanea tarda. Eur J Gastroenterol Hepatol. 2004 Jul;16(7):689-92. doi: 10.1097/01.meg.0000108318.52416.c9[↩]