INTRODUCTION — The porphyrias are metabolic disorders caused by altered activity of enzymes in the heme biosynthetic pathway. Porphyria cutanea tarda (PCT; previously called symptomatic porphyria, chemical porphyria, toxic porphyria) is the most common of the porphyrias. PCT was named by Waldenström in 1937 to emphasize the predominant cutaneous manifestations and relatively late onset of disease [1]. An earlier name for PCT was chronic hematoporphyria (assigned by Günther in 1911) [2].
This topic review discusses the pathogenesis, clinical manifestations, and diagnostic evaluation for PCT, caused by deficient activity of uroporphyrinogen decarboxylase (UROD) in the liver, with heterozygous UROD mutation sometimes contributing, and hepatoerythropoietic porphyria (HEP), an extremely rare condition caused by biallelic UROD mutation.
The management and prognosis of PCT and HEP are discussed in detail separately. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis".)
Additional topic reviews discuss the other cutaneous, neurovisceral, and combined cutaneous/neurovisceral porphyrias:
●Cutaneous – (See "Congenital erythropoietic porphyria" and "Erythropoietic protoporphyria and X-linked protoporphyria".)
●Neurovisceral – (See "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis" and "Acute intermittent porphyria: Management" and "ALA dehydratase porphyria".)
●Combined cutaneous and neurovisceral – (See "Variegate porphyria" and "Hereditary coproporphyria".)
An overview of porphyrias is also presented separately. (See "Porphyrias: An overview".)
DISEASE CLASSIFICATION — PCT and HEP are cutaneous porphyrias, both due to deficient activity of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD) in the liver [3]. They cause blistering skin lesions as the predominant clinical manifestation; neurovisceral attacks do not occur.
●PCT – PCT is caused by acquired inhibition of hepatic UROD to less than approximately 20 percent of normal, which occurs in the presence of iron and a variable combination of acquired factors (eg, alcohol, smoking, hepatitis C, estrogens, human immunodeficiency virus [HIV] infection). Genetic factors are present in some patients; these may include heterozygosity for a UROD mutation, which predisposes to the disease by reducing UROD activity to 50 percent of normal in all tissues from birth, and HFE (hemochromatosis) mutations (homozygous or heterozygous), which increase iron absorption.
●HEP – HEP is caused by severely deficient UROD activity on a genetic basis due to mutation of both UROD alleles (eg, homozygous mutation, compound heterozygous mutation). Only approximately 40 cases of HEP have been documented worldwide.
PCT can be classified as "sporadic" or "familial" based on the absence or presence of a UROD mutation. Familial cases may present at an earlier age, but in these cases the family history is often negative for PCT. Finding a UROD mutation warrants genetic counseling. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis", section on 'Genetic counseling and management of individuals with asymptomatic UROD mutations'.)
●PCT type 1 (sporadic) – Absence of a UROD mutation; accounts for approximately 80 percent of cases [4,5].
●PCT type 2 (familial) – Inheritance of a UROD mutation affecting one allele (ie, heterozygous defect); present in approximately 20 percent of cases. Inheritance is autosomal dominant with low penetrance, so there are often no relatives with PCT. Other factors must be present to reduce UROD from 50 percent of normal (due to the mutation) to <20 percent of normal and cause significant porphyrin accumulation and clinical features.
●PCT type 3 (familial) – Apparent familial inheritance without a UROD mutation; may be due to other inherited factors (eg, HFE mutations) or shared acquired factors.
Individuals who are heterozygous for a UROD mutation but do not manifest clinical findings of PCT are referred to as asymptomatic carriers. Some may have subclinical elevations of plasma and urinary porphyrins.
PATHOGENESIS — PCT is caused by deficient activity of the fifth enzyme in the heme synthetic pathway, uroporphyrinogen decarboxylase (UROD), which is caused by acquired inhibition of UROD, with a heterozygous UROD mutation sometimes contributing (figure 1). Hepatoerythropoietic porphyria (HEP) is an extremely rare condition caused by homozygosity or compound heterozygosity for UROD mutations.
UROD is a cytosolic enzyme that catalyzes the four-step decarboxylation of uroporphyrinogen to coproporphyrinogen, which have eight and four carboxyl groups, respectively [6,7]. The four carboxyl groups are removed sequentially in a clockwise fashion starting from ring D. The enzyme has greater affinity for uroporphyrinogen III than uroporphyrinogen I.
Porphyrin accumulation due to reduced hepatic UROD activity — Reduced UROD activity is responsible for the accumulation of porphyrinogens that are auto-oxidized to photosensitizing porphyrins in PCT. Reduction of UROD activity in the liver to <20 percent of normal is required for clinical manifestations of PCT to occur.
Reduced hepatic UROD activity leads to hepatic accumulation of highly carboxylated porphyrinogens; these are oxidized to the corresponding porphyrins (mostly uroporphyrin and heptacarboxyl porphyrins), which appear in plasma and are excreted mostly in urine [8,9]. Excess porphyrins consist of both I and III isomers, in a complex, characteristic pattern (table 1). Pentacarboxyl porphyrinogen that accumulates is further metabolized by the next enzyme in the heme biosynthetic pathway (coproporphyrinogen oxidase) to dehydro-isocoproporphyrinogen, an atypical tetracarboxyl porphyrinogen. After oxidation, this appears in feces and urine in the form of isocoproporphyrins, with additional modifications by intestinal bacteria. Porphyrins are transported from the liver to skin, leading to cutaneous phototoxicity. (See 'Photosensitization' below.)
PCT does not appear to be associated with marked upregulation of delta-aminolevulinic acid (ALA) synthase (ALAS1), the first and rate-limiting enzyme in the heme biosynthetic pathway; this contrasts with acute intermittent porphyria (AIP), in which marked upregulation of ALAS1 is common. Little elevation of hepatic ALAS1 is needed to account for the amounts of excess porphyrins excreted in PCT. Accordingly, factors that increase ALAS1 synthesis, including a variety of drugs, hormones, caloric restriction, and metabolic stress, seldom appear to play a significant role in the pathogenesis of PCT. The major environmental/behavioral susceptibility factors in PCT impair UROD activity by promoting iron accumulation or oxidative stress in hepatocytes rather than by inducing ALAS1.
Photosensitization — Porphyrins that accumulate in PCT are photosensitizing; they are transported to the skin and cause photodamage on exposure to light with a wavelength near 400 nm (ie, wavelengths within the ultraviolet A and visible light ranges (figure 2)). These wavelengths of light cause porphyrins to enter an excited state and release photons that activate oxygen in the tissues to higher energy singlet oxygen, which damages proteins, lipids, and basement membranes [10,11]. This results in dermoepidermal separation and blister formation [12]. Activation of complement, degranulation of mast cells, and increases in levels of transforming growth factor (TGF)-beta may also play a role [11,13].
Significance of UROD mutations — Unlike other porphyrias, a mutation of the relevant enzyme is not required to cause PCT; rather, acquired and/or other genetic factors are important in causing reduced hepatic UROD activity in patients with or without heterozygosity for a UROD mutation [4]. (See 'UROD inhibitor' below and 'HFE mutations' below.)
Mutation of the UROD gene (OMIM #176100, OMIM 176090) is seen in approximately 20 percent of individuals with PCT who are classified as having type 2 familial PCT [4,5]. Mutation affects one UROD allele in PCT, whereas biallelic UROD mutation causes HEP [8,9,14,15]. Over 100 UROD mutations have been described in PCT and HEP, many of which are cataloged in the human genome mutation database. These include missense and nonsense mutations, deletions, and insertions [16-21].
Despite the central role of UROD deficiency in PCT, most patients with heterozygous UROD mutation will not develop symptomatic disease. This is because a single UROD mutation only reduces UROD activity to approximately 50 percent of normal, whereas reduction of the hepatic enzyme activity to <20 percent of normal is required for disease manifestations to occur. However, some heterozygotes have elevated porphyrins in the absence of skin manifestations; it is not known how frequently this occurs. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis", section on 'Genetic counseling and management of individuals with asymptomatic UROD mutations'.)
More severe reductions of UROD activity occur when both UROD alleles are mutated, resulting in HEP [3]. This leads to marked increases in highly carboxylated porphyrins in liver, plasma, urine, and feces, and (in contrast to PCT) marked increase in erythrocyte zinc protoporphyrin. The increase in zinc protoporphyrin in HEP is thought to result from the accumulation of heme pathway intermediates during hemoglobin synthesis, which are metabolized to protoporphyrin and then complexed with zinc after hemoglobin synthesis is complete [3]. At least one of the UROD mutations in HEP must permit expression of some UROD enzymatic activity, as a homozygous null mutation is presumed to be lethal [22].
Central importance of iron in PCT — Increased hepatic iron plays a central role in the pathogenesis of PCT, as illustrated by the following observations:
●Increased hepatic iron deposition (siderosis) is found in the great majority of patients with PCT who undergo liver biopsy.
●Repeated phlebotomy to reduce hepatic iron content is an effective and widely accepted treatment for PCT [8]. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis", section on 'Phlebotomy'.)
●Iron deficiency is protective in humans as well as animal models of PCT [23,24].
A common cause of iron accumulation in PCT may be reduced production of hepcidin by the liver, which has been demonstrated in PCT even in the absence of HFE mutations, and consequently, there is failure to appropriately down-regulate iron absorption [25,26]. However, higher levels of hepcidin have been reported in patients with PCT compared with patients who have chronic hepatitis C virus (HCV) infection and unaffected volunteers, suggesting differences in methodology and patient selection [27].
Iron may contribute to the pathogenesis of PCT by facilitating the formation of oxygen free radicals and thereby contributing to the oxidative formation of a UROD inhibitor (see 'UROD inhibitor' below) [22]. However, hepatic hemosiderosis alone is insufficient to cause PCT, as illustrated by the observations that the majority of individuals with hereditary hemochromatosis or transfusional iron overload do not develop PCT, and hepcidin gene deletion ("knockout") in mice does not produce a PCT syndrome.
UROD inhibitor — Acquired susceptibility factors for PCT are thought to lead to generation of a UROD inhibitor in the liver. Most of the environmental/behavioral susceptibility factors promote iron accumulation or oxidative stress in hepatocytes. In one series, most patients with PCT had multiple susceptibility factors, with three or more susceptibility factors identified in at least 70 percent of 143 patients [4]. (See 'Significance of UROD mutations' above.)
In studies in a mouse model of PCT, a UROD inhibitor was isolated as a uroporphomethene, a partially oxidized uroporphyrinogen molecule. Generation of the inhibitor from uroporphyrinogen I or III may be catalyzed by the cytochrome P450 (CYP) isoform CYP1A2, in the presence of increased hepatic iron (figure 3) [22]. However, iron itself is not considered to directly inhibit hepatic UROD.
In contrast to PCT, the hepatic UROD inhibitor is not thought to play a significant role in the pathogenesis of HEP, because UROD activity in these patients is already <20 percent of normal due to biallelic UROD mutations. (See 'Significance of UROD mutations' above.)
Susceptibility factors — Some factors that increase susceptibility to PCT can damage the liver (eg, alcohol use, HCV infection) as can PCT itself. These and other susceptibility factors are quite specific for PCT and distinct from those for other porphyrias. However, some of the susceptibility factors for PCT are unlikely to be hepatotoxic (eg, human immunodeficiency virus [HIV] infection, estrogen use, HFE and UROD mutations), and hepatic injury in general does not lead to development of PCT. Susceptibility factors are less likely to play a role in HEP because individuals with HEP have markedly reduced UROD activity at baseline.
Most of the susceptibility factors for PCT either decrease hepcidin expression (thereby increasing iron absorption), increase oxidative stress in hepatocytes (favoring the production of the UROD inhibitor), or both. As described in the following sections, susceptibility is unexplained for some of these factors. UROD mutations act as susceptibility factors by decreasing the amount of the enzyme in liver (and all tissues) from birth. Various combinations of these acquired and inherited factors are found in different patients.
Addressing relevant susceptibility factors is an important component of PCT management. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis", section on 'Avoidance of susceptibility factors'.)
Alcohol — Use of alcohol has been reported as an important and common susceptibility factor for PCT in many series [4,28-30]. As an example, in a large series of individuals with PCT, 115 of 131 (88 percent) reported alcohol use [4]. However, PCT remains rare in individuals with alcoholic liver disease. In one report of 360 patients with alcoholic cirrhosis followed for 10 years, only 2 percent had PCT [31]. Therefore, alcohol is never the sole cause of PCT. Alcohol may contribute to the pathogenesis of PCT by a variety of mechanisms including increased oxidative stress and downregulation of hepcidin [32,33].
HCV infection — Infection with hepatitis C virus (HCV) is strongly implicated in the pathogenesis of PCT. A systematic review and meta-analysis that included 50 studies (2167 patients with PCT) found an overall prevalence of HCV of 50 percent [34]. From eight case-control studies included in the meta-analysis, the odds of HCV infection in patients with PCT was 275:1 (95% CI 104-725). Geographic variability paralleled the baseline rates of HCV infection in the associated general population, with lowest prevalence rates observed in reports from Australia, the Czech Republic, and France (20 to 30 percent), and higher rates in Japan, Italy, and Spain (71 to 85 percent). The prevalence in North America was 66 percent. PCT is estimated to occur in approximately 0.5 percent of HCV-infected individuals and is among the extrahepatic manifestations that add to the disease burden and costs of HCV infection [35].
The exact mechanism by which HCV infection increases PCT risk is unknown [36]. Several potential mechanisms have been proposed, including the ability of HCV to decompartmentalize iron from within the hepatocyte, leading to the release of "free" iron that in turn leads to production of a UROD inhibitor by an oxidative process [37,38]. Most importantly, HCV increases oxidative stress in hepatocytes and increases iron absorption by dysregulating hepcidin [39,40]. Regardless of mechanism, evidence is emerging that successful treatment of HCV infection can lead to resolution of PCT [41].
HIV infection — PCT may occur early or late in the course of HIV infection [42-45]. A mechanism whereby HIV infection might contribute to development of PCT has not been established; HIV is often associated with concomitant HCV infection or other susceptibility factors. In a series involving seven people with PCT and HIV in the United States, HCV co-infection was present in three and absent in four [4]. In a series involving 26 people with PCT and HIV in Spain, all but one had HCV co-infection [46].
Estrogen exposure — Use of exogenous estrogens has been identified as a susceptibility factor for PCT, including estrogens in oral contraceptives, hormone replacement therapy, and therapy for prostate cancer [28-30,47-50]. Estrogen use was reported in 31 of 47 women with PCT in one series (66 percent) [4]. The mechanism by which estrogens increase susceptibility to PCT is unclear. Estrogens undergo redox cycling and cause oxidative damage in the kidney of rodents, but this has not been demonstrated in the liver [51]. Estrogens are not potent inducers of ALAS1, in contrast to progesterone and progestins, which are often implicated in exacerbating the acute hepatic porphyrias.
Smoking — Cigarette smoke containing polycyclic aromatic hydrocarbons may contribute to the pathogenesis of PCT by inducing CYP1A2 synthesis, leading to increased production of the UROD inhibitor [22] (see 'UROD inhibitor' above). In a large series, 81 percent of patients with PCT were smokers, and in a group of patients with PCT who did not have UROD mutations, disease onset was earlier among smokers than nonsmokers [4,52]. A genetic polymorphism that favors greater inducibility of CYP1A2 was also found more commonly in individuals with PCT than in age-matched controls in the community [53,54]. This CYP1A2 gene variation may represent an additional PCT susceptibility factor.
HFE mutations — HFE (the hemochromatosis gene) is mutated in individuals with hereditary hemochromatosis (HH) (see "HFE and other hemochromatosis genes"). HFE mutations are prevalent in PCT even in the absence of overt HH [30,55,56]. HFE encodes a component of a complex on the surface membrane of hepatocytes that senses the level of iron in plasma and regulates hepatic expression of the hormone hepcidin. Hepcidin reduces iron absorption from the gut by down-regulating ferroportin, the iron transporter found on the basolateral membrane of enterocytes. Iron absorption remains inappropriately high in HH, even with high levels of iron in the circulation, because liver expression of hepcidin is inappropriately low.
An increased prevalence of HFE mutations in individuals with PCT has been demonstrated in many studies. As an example, in a study that compared HFE genotypes in individuals with PCT versus controls without PCT, homozygosity for the HFE C282Y mutation (C282Y/C282Y) was found in 17 of 87 patients with PCT (19 percent, versus 0 percent of controls), and compound heterozygosity for C282Y and H63D mutations (C282Y/H63D) was found in six patients with PCT (7 percent, versus 0 percent of controls) [55]. The prevalence of heterozygosity for either mutation alone, which would have less effect on iron absorption, was increased in some studies but not others.
The increased likelihood of PCT in individuals with HFE mutations was further demonstrated in a meta-analysis that evaluated the risk of various diseases in patients according to HFE genotype [57]. This found greatly increased likelihood of PCT in individuals with the C282Y/C282Y and C282Y/H63D genotypes (odds ratios [ORs], 48 and 8, respectively).
Variants of other genes that modify iron absorption may also play a role in PCT. As an example, a polymorphism (D519G) of glyceronephosphate O-acyltransferase (GNPAT) was found by exome sequencing to be associated with a particularly high-iron phenotype in HFE C282Y homozygotes and to decrease hepcidin expression [58]. A study in 240 patients with PCT found an increased prevalence of this GNPAT variant particularly in patients with UROD mutations [59].
Other medical conditions — Medical conditions that can cause oxidative liver damage (eg, diabetes mellitus, hepatic steatosis) have been prevalent in some PCT series [28,60]. PCT also has been reported in late pregnancy; however, an increased prevalence during pregnancy or a causal relationship was not identified [47]. PCT has been reported in patients with myeloproliferative disorders, usually in association with substantial iron overload [61]. PCT may occur in patients undergoing hemodialysis or peritoneal dialysis for advanced chronic renal disease, often with associated iron overload [62,63]. The disease is often especially severe in such cases, reflecting plasma porphyrin levels that may be much higher than in patients with PCT and normal renal function.
Halogenated hydrocarbons — In the 1950s, PCT developed in thousands of adults and children in eastern Turkey who were exposed to hexachlorobenzene, a fungicide used to treat seed wheat, which was consumed during a famine [64,65]. Subsequently, it was shown that hexachlorobenzene and other halogenated hydrocarbons can cause deficient hepatic UROD activity and increased porphyrins in laboratory animals, with porphyrin patterns resembling those seen in PCT. Smaller outbreaks have been associated with industrial exposure to tetrachlorodibenzo-p-dioxin (TCDD) [66]. Sporadic cases attributed to exposure to other chemicals, such as lindane and diazinon, are of uncertain significance [67,68]. Such chemical exposures are rarely recognized as contributing to PCT in clinical practice.
EPIDEMIOLOGY — PCT is reported worldwide. The prevalence of symptomatic disease has been estimated to be 1 in 5000 in Czechoslovakia and 1 in 25,000 in the United States [69]. A series from the Norwegian Porphyria Centre (NAPOS) estimated a prevalence of 1 in 10,000 [70].
PCT is generally a disease of adults; it usually presents in mid or late life. Earlier onset is noted in some patients with UROD mutations or hereditary hemochromatosis gene (HFE) mutations [71].
In contrast, HEP, caused by mutation of both UROD alleles, is extremely rare, with only approximately 40 cases documented. Disease onset is in childhood, usually prior to two years of age, although onset in adulthood has been reported [19,72].
Females and males are probably equally susceptible to PCT and HEP. Certain risk factors for PCT such as alcohol use, smoking, and hepatitis C virus (HCV) infection, are more common in males in many populations, whereas estrogen use is more common in women.
As noted above, the incidence of PCT is increased in individuals with HFE mutations, even in the absence of hemochromatosis, and in individuals with alcoholic liver disease, HCV infection, smoking, and exogenous estrogen use. (See 'Susceptibility factors' above.)
CLINICAL FEATURES — PCT is characterized by chronic blistering skin lesions and is often accompanied by elevated hepatic transaminases. Hepatic manifestations may be related in part to manifestations of susceptibility factors (eg, hepatitis C virus [HCV] infection, heavy alcohol use).
Sporadic (type 1) and familial (types 2 and 3) PCT are clinically indistinguishable, but their differentiation (based on testing for UROD mutations) and identification of other susceptibility factors for PCT may affect management (eg, increased importance of phlebotomy in the setting of HFE mutation, management of HCV infection) and may have implications for genetic counseling. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis", section on 'Genetic counseling and management of individuals with asymptomatic UROD mutations'.)
Blistering skin lesions and other cutaneous manifestations — Characteristic cutaneous manifestations of PCT include chronic photosensitivity with bullae (blisters), increased skin fragility, scarring, and hyper- and hypopigmentation affecting sun-exposed areas of the body [8,9,28,73]. The backs of the hands, forearms, face, ears, neck, and feet are most commonly affected (picture 1 and picture 2 and picture 3). Itching may be especially troublesome for some individuals [74]. The reaction to sun exposure is delayed rather than immediate, and as a result patients may not be aware that such exposure is the problem. This contrasts markedly with the acute mostly non-blistering photosensitivity experienced in erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP).
Increased mechanical fragility of skin leads to blistering or superficial erosions from trivial trauma [8]. Bullae contain serous or serosanguinous fluid and are not inflamed. Skin lesions may be painful and may become infected [28]. Chronic manifestations include scarring and hyper- or hypopigmentation. Scarring in some patients may progress to "pseudoscleroderma" with contraction and calcification resembling the cutaneous findings in scleroderma [28,75]. Hirsutism is also common, especially on the cheeks and forearms. Alopecia can also occur [76]. The burden and severity of symptoms, as well as delays in treatment, impact health-related quality of life in PCT [77].
Cutaneous findings in HEP are similar to those in PCT, except they may be more severe and they often first develop during childhood. Some cases of PCT (eg, with greater than usual elevations of plasma porphyrins due to renal disease) may resemble findings seen in congenital erythropoietic porphyria (CEP), with bacterial superinfection, hypertrichosis, and severe/disfiguring scarring. (See "Congenital erythropoietic porphyria", section on 'Cutaneous'.)
Hepatic involvement — Hepatic abnormalities are seen in most cases of PCT, probably due to marked porphyrin accumulation in hepatocytes. Hepatic injury can result in part from the associated susceptibility factors such as alcohol or HCV infection. Advanced liver disease is uncommon at initial presentation but may be seen in older patients with recurrent disease [28,30]. Patients with PCT have an increased long-term risk for cirrhosis and hepatocellular carcinoma [28,78-80]. This risk can persist after treatment but has been little studied.
Liver biopsy is not required for diagnosis of PCT or HEP. However, massive porphyrin accumulation in the liver is characteristic and can be demonstrated by biochemical measurement of the accumulated porphyrins in liver tissue (mostly uroporphyrin and heptacarboxyl porphyrin), or by reddish fluorescence on illumination of fresh liver tissue using a Wood's lamp (a UVA light source) or fluorescence microscopy. The red fluorescence does not intensify on oxidation, suggesting that the accumulated porphyrins are in their oxidized form and are not porphyrinogens. Microscopy after fixation shows these as needle shaped crystals within hepatocytes [81]. However, fixation may alter the intracellular distribution of the accumulated porphyrins. Nonspecific histopathologic findings may include varying degrees of siderosis, steatosis, portal triaditis, focal lobular necrosis, and periportal fibrosis [28,78,82].
In HEP, mild and nonspecific abnormalities in liver function and histology are common, usually without siderosis. Hepatosplenomegaly may be seen and be associated with hemolytic anemia.
Laboratory abnormalities — The major laboratory abnormalities in PCT are increases in plasma and urinary porphyrins, with a characteristic pattern of highly carboxylated porphyrins; many patients also have increases in hepatic transaminases [26,83-88].
●Hematologic changes – Generally, the complete blood count (CBC) is normal in PCT. The hemoglobin level is sometimes elevated, possibly related to smoking and chronic lung disease. Anemia is uncommon and if present is due to a concurrent condition other than iron deficiency, which is protective. Serum ferritin levels are usually normal or modestly increased. Substantially increased ferritin levels suggest concurrent hemochromatosis (see 'HFE mutations' above) or the effects of an inflammatory condition.
In HEP, hematological abnormalities may include mild, normocytic and normochromic anemia, due in part to hemolysis [8]. Severe anemia has been reported but is unusual in HEP [72].
●Hepatic transaminase elevations – PCT is almost always associated with mild elevations in serum aminotransferase levels, with serum alanine aminotransferase (ALT) usually exceeding aspartate aminotransferase (AST). These elevations may be due to effects of large amounts of porphyrins in hepatocytes as well as hepatotoxic effects of iron, alcohol, and/or HCV infection. (See 'Hepatic involvement' above.)
However, PCT is not known to present with isolated transaminase elevations. Importantly, other causes of abnormal liver function tests should be excluded. (See "Approach to the patient with abnormal liver biochemical and function tests".)
●UROD activity and gene mutation – Erythrocyte UROD activity will be normal in individuals with sporadic (type 1) PCT, and approximately half-normal in individuals with familial (type 2) PCT. In HEP, erythrocyte UROD activity will be markedly reduced (typically <20 percent of normal). Because UROD activity is higher in younger erythrocytes and declines as these cells age in the circulation, increased erythropoiesis may cause an increase in measured erythrocyte UROD activity [89]. Therefore, deficient UROD activity may not be detected in erythrocytes of type 2 patients with increased erythropoiesis (eg, due to recent phlebotomies).
Genetic testing for a UROD mutation will be normal in the majority of patients with PCT. Those with familial disease typically will have heterozygosity for a UROD mutation (approximately 20 percent of individuals with PCT), and those with HEP will have biallelic UROD mutation [14,15,90]. (See 'Significance of UROD mutations' above.)
●Porphyrin elevations – These are discussed below. (See 'Laboratory testing' below.)
DIAGNOSTIC EVALUATION — PCT should be suspected in an adult (or rarely, a child) who presents with blistering lesions on sun-exposed skin, without neurovisceral symptoms such as attacks of unexplained abdominal pain; pain in the chest, back, or extremities; or neurologic symptoms including numbness, weakness, autonomic changes, or seizures. HEP may be suspected in a child or adult who presents with these symptoms, which are usually more severe than in PCT.
As with other porphyrias, the preferred approach to the evaluation is to perform a single first-line test for screening, followed by more extensive testing if the screening test is positive, and evaluation for other causes of blistering skin lesions if the screening test is negative (algorithm 1). Biopsies (skin, liver, bone marrow) are not necessary for diagnosing PCT, although they may be performed to evaluate the possibility of other diagnoses.
Once the diagnosis has been made, it may be appropriate to test family members for a uroporphyrin decarboxylase (UROD) and/or hereditary hemochromatosis (HFE) gene mutation; this subject is discussed separately. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis", section on 'Genetic counseling and management of individuals with asymptomatic UROD mutations'.)
Patient and family history — The patient history can be helpful for identifying a typical pattern of chronic blistering lesions on sun-exposed skin and absence of neurovisceral manifestations. The patient history is also important for determining which susceptibility factors have an etiologic role in disease activity for that patient. Attention should be paid to alcohol intake, smoking, estrogen use, and unusual chemical exposures.
Individuals with PCT or HEP usually have a negative family history for PCT, and the absence of a family history of porphyria does not reduce the likelihood of PCT, because most cases of PCT are sporadic and inherited susceptibility factors such as UROD and HFE mutations have low penetrance. However, the family history may reveal relatives with PCT or skin blistering and suggest shared susceptibility factors such as UROD mutations in familial (type 2) PCT, or other factors, such as HFE mutations, in type 3 PCT.
Laboratory testing — Measurement of total porphyrins in plasma (or serum) is the preferred first step in the laboratory evaluation for suspected PCT (or HEP) (algorithm 1). Measurement of total urine porphyrins on a spot urine sample can also be used, with the caveat that urine porphyrins are more often nonspecifically elevated in other medical conditions. A 24-hour urine collection is not required. Measuring creatinine in the same urine sample is recommended so results can be expressed per gram (or micromole) of creatinine.
Porphyrins are chronically elevated in the urine and plasma in patients with PCT and HEP (table 1), even though blistering may be absent or appear more suddenly (eg, in response to minor trauma to the backs of the hands). Thus, laboratory testing may detect porphyrin elevations even if skin lesions are absent at the time the laboratory testing is performed. Some patients have reduced erythrocyte uroporphyrinogen decarboxylase activity, indicating the presence of a heterozygous UROD gene mutation.
Testing is summarized in the table (table 2) [91]. The laboratory evaluation begins with a first-line test, which, if negative, excludes PCT and other blistering porphyrias; in this case, no further testing is required. If the first-line test is abnormal, this is followed by more comprehensive second-line testing to document either PCT, another blistering cutaneous porphyria, or a nonspecific porphyrin elevation due to a non-porphyria condition.
●First-line testing with measurement of total porphyrins in either plasma or urine – Urine or plasma total porphyrins, which are both elevated in PCT, HEP, and other blistering cutaneous porphyrias, should be measured as first-line tests whenever these porphyrias are suspected. Urine porphyrin results should be normalized to creatinine concentration if a spot (random) sample is obtained. Plasma and urine samples should be protected from light during processing and transit because porphyrins are light sensitive. However, substantially elevated porphyrin levels are very unlikely to be reduced to normal by even lengthy light exposure.
Normal total urine or plasma porphyrins exclude all porphyrias that cause blistering skin lesions, even if slight increases in some individual porphyrins are found [92]; in such cases, evaluation should focus on other bullous (blistering) skin diseases (see 'Differential diagnosis' below), with early input from the consulting dermatologist. However, erythropoietic protoporphyria (EPP), which causes non-blistering photosensitivity, is excluded only if erythrocyte protoporphyrin is measured by a reliable laboratory. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)
●Second-line testing – It is important to note that elevation of total porphyrins, especially in urine, is a nonspecific finding, and further second-line testing, including porphyrin fractionation, is needed for documenting a diagnosis of porphyria as a cause of blistering skin lesions. Although PCT is by far the most common type of porphyria to cause skin blistering, other less common porphyrias (including HEP) should be excluded. Other diagnostic possibilities include variegate porphyria (VP), hereditary coproporphyria (HCP), congenital erythropoietic porphyria (CEP), autosomal dominant forms of acute hepatic porphyrias, and harderoporphyria. VP and HCP, like PCT, usually present during adult life. Although the others usually become manifest in childhood, rare adult-onset cases are reported. Treatment for PCT is specific to PCT and should not begin until these other porphyrias are excluded. This evaluation involves the following testing:
•Fractionation of urine and/or plasma porphyrins – It is essential to demonstrate a predominance of highly carboxylated porphyrins (uroporphyrin, hepta-, hexa-, and pentacarboxyl porphyrins) rather than coproporphyrin, in order to make a diagnosis of PCT or HEP. These porphyrins are water soluble and therefore mostly excreted in urine. In HEP, the pattern of porphyrin elevations in urine and plasma closely resembles that seen in PCT, but HEP is distinguished especially by a marked elevation in erythrocyte protoporphyrin (mostly zinc protoporphyrin) [90,93-95].
•Determination of the plasma fluorescence peak wavelength at neutral pH (pH 7.4) – Patients with elevated total plasma porphyrins should also have determination of the plasma fluorescence peak (diluted at neutral pH). PCT (and HEP) are characterized by peak plasma fluorescence at approximately 620 nm (following excitation at approximately 410 nm, the Soret band); in contrast, a peak at approximately 626 nm is diagnostic for VP. Therefore, this test is especially useful for early differentiation of VP, which is often initially misdiagnosed (and mistakenly treated) as PCT.
•Measurement of erythrocyte total porphyrins, with fractionation if elevated – Patients with elevated plasma or urine porphyrins should have erythrocyte (red blood cell) porphyrins measured. Erythrocyte total porphyrins are normal or only mildly elevated in PCT. The purpose of this testing is to exclude HEP, autosomal dominant forms of acute hepatic porphyrias, and harderoporphyria (in which erythrocyte zinc protoporphyrin is substantially increased); and to exclude mild, adult-onset cases of congenital erythropoietic porphyria (CEP, in which uroporphyrin I, coproporphyrin I, and zinc protoporphyrin may be increased).
•Measurement of urinary delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) – Urinary ALA is usually normal in PCT and HEP but may be mildly elevated; urinary PBG is normal. These findings provide for additional exclusion of HCP and VP.
•Measurement of fecal total porphyrins, with fractionation if elevated – Fecal total porphyrins are usually normal or modestly elevated in PCT and are expected to be more substantially elevated in HEP and other blistering porphyrias. Porphyrin fractionation by high-performance liquid chromatography (HPLC) is likely to show a complex pattern including isocoproporphyrins as well as some highly carboxylated porphyrins in PCT and HEP. These findings provide additional confirmation and distinction from CEP, in which markedly elevated fecal porphyrins are predominantly coproporphyrin I. Marked elevation of fecal porphyrins is also found in HCP and VP and in autosomal dominant forms of acute hepatic porphyrias and harderoporphyria [8,86].
The use of plasma porphyrin levels (along with serum ferritin in individuals with iron overload) in monitoring disease and response to therapy is presented separately. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis", section on 'Monitoring'.)
Skin biopsy — Skin biopsy is not required for the diagnosis of PCT or HEP because the dermal histopathology is nonspecific and the diagnosis is made by documentation of biochemical abnormalities [96]; however, if performed, it may show characteristic histologic features including subepidermal blisters and deposition of periodic-acid-Schiff (PAS) positive amorphous hyaline material containing immunoglobulin around vessel walls, with little inflammation unless there is secondary infection [97]. Similar histologic findings are seen in other cutaneous porphyrias and in pseudoporphyria, but a skin biopsy may exclude some other conditions.
Diagnosis — The laboratory diagnosis of PCT (or HEP) is made in an individual with current or prior blistering skin lesions, as described above.
●PCT – The diagnosis of PCT requires documentation of the associated biochemical pattern of porphyrin increases, which includes increased plasma or urine porphyrins (especially uro-, hepta-, and to lesser extents, hexa-, and penta-carboxyl porphyrins); plasma peak fluorescence at approximately 620 nm; and little or no increase in erythrocyte porphyrins. Additional confirmation is provided by findings of normal (or mildly elevated) urinary ALA, normal urinary PBG, and normal or elevated fecal porphyrins (with a complex pattern including isocoproporphyrins).
Molecular analysis to identify or exclude UROD and HFE mutations is part of a complete assessment of susceptibility factors in PCT but is not required for diagnosis or prior to initiating therapy. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis", section on 'Overview of management'.)
●HEP – The diagnosis of HEP is made by documenting the same porphyrin increases as in PCT plus a marked increase in erythrocyte zinc protoporphyrin and should be confirmed by molecular studies that demonstrate mutations affecting both UROD alleles.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of PCT and HEP includes other cutaneous porphyrias (differentiated as described above (see 'Laboratory testing' above)), other causes of blistering skin lesions, and other causes of porphyrin elevation in urine, plasma, or feces.
●Cutaneous porphyrias – Cutaneous porphyrias are divided into blistering and non-blistering.
•Blistering – Other blistering cutaneous porphyrias include variegate porphyria (VP), hereditary coproporphyria (HCP), and congenital erythropoietic porphyria (CEP). Like PCT/HEP, these cutaneous porphyrias (VP, HCP, CEP) cause blistering lesions on sun-exposed skin, and porphyrin elevations in urine, plasma, and feces. Scarring is generally more severe in CEP than in PCT, but mild cases of CEP in adults are often initially misdiagnosed as having PCT. Unlike PCT/HEP, VP and HCP can cause acute neurovisceral attacks, although they can also present only with skin manifestations. Patients with CEP, VP, and HCP have clearly differentiated patterns of porphyrin elevation. Unlike PCT, in which ALA may be slightly elevated and PBG is always normal, in HCP and VP, ALA and PBG may be normal or substantially elevated. These differences are summarized in the table (table 3). (See "Variegate porphyria" and "Hereditary coproporphyria" and "Congenital erythropoietic porphyria".)
•Non-blistering – The non-blistering cutaneous porphyrias are erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP). Unlike other cutaneous porphyrias, EPP and XLP cause pain on sun-exposed areas of skin, often after a few minutes of sun exposure, which may be followed by swelling and erythema but little blistering or residual scarring. EPP and XLP, in contrast to PCT, cause substantial increases in erythrocyte protoporphyrin but do not increase urine porphyrins. (See "Erythropoietic protoporphyria and X-linked protoporphyria".)
●Other causes of blistering skin lesions – A variety of non-porphyric conditions can cause blistering lesions on sun-exposed skin. Examples include polymorphous light eruptions, epidermolysis bullosa, pseudoporphyria, and phototoxic drug reactions and eruptions. Like PCT, these conditions affect sun-exposed skin and some may cause scarring. Unlike PCT (or other cutaneous porphyrias), these conditions are not associated with elevated total porphyrins in urine or plasma. These disorders and approaches to their evaluation and diagnosis are discussed in detail separately. (See "Polymorphous light eruption" and "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features" and "Pseudoporphyria" and "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment" and "Approach to the patient with cutaneous blisters".)
●Other causes of porphyrin elevation – Increased total porphyrins in urine, plasma (or serum), and/or feces can result from cutaneous porphyrias other than protoporphyrias (as described in the first bullet point of this section, above), neurovisceral porphyrias, liver disease, and other medical conditions.
•Neurovisceral (acute) porphyrias – Neurovisceral (also called acute hepatic) porphyrias include ALA dehydratase porphyria (ADP), acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). Like PCT/HEP, these neurovisceral porphyrias may cause porphyrin elevations in urine, plasma, and feces, especially during or around the time of acute attacks of abdominal pain and/or neurologic symptoms (eg, extremity pain, seizures, motor weakness). However, neurologic or abdominal symptoms due to another cause sometimes occur in patients with subclinical PCT; diagnostic confusion is avoided in such cases by excluding acute porphyrias and obtaining clear biochemical documentation of PCT. (See "ALA dehydratase porphyria" and "Acute intermittent porphyria: Pathogenesis, clinical features, and diagnosis" and "Hereditary coproporphyria" and "Variegate porphyria".)
•Liver disease – Liver disease can cause elevations in urine porphyrins, especially coproporphyrin, which normally undergoes both urinary and biliary excretion. When hepatobiliary excretion is impaired, more coproporphyrin is excreted in urine. Unlike PCT and HEP, patients with liver disease from other causes do not have the characteristic PCT skin lesions. (See "Approach to the patient with abnormal liver biochemical and function tests".)
•Other medical conditions – A variety of other medical conditions and drugs can cause non-specific elevation of urinary porphyrins whereas plasma/serum porphyrins are less affected. Such effects of other diseases and medications on urine porphyrins have been little studied, so specific attributions are difficult. Advanced renal failure may cause slight elevations in plasma/serum porphyrins, and it may be unclear whether such elevations represent subclinical PCT. Rarely, hepatocellular tumors are associated with marked porphyrin elevations, but these cases were not described in enough detail to know if a deficiency in a heme biosynthetic pathway enzyme in the tumor itself was causative [98,99].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Porphyria".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Porphyria cutanea tarda (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Biology and prevalence – Porphyria cutanea tarda (PCT) and hepatoerythropoietic porphyria (HEP) are cutaneous porphyrias caused by reduced activity of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD) (figure 1). PCT is an iron-mediated disorder that generally presents in adulthood. PCT can be classified as inherited or sporadic (approximately 20 percent and 80 percent of cases, respectively) based on the presence or absence of heterozygosity for a pathogenic variant in UROD. In both familial and sporadic disease, acquired or other inherited susceptibility factor(s) such as alcohol use, smoking, estrogen use, hemochromatosis (HFE) gene variants, and hepatitis C virus (HCV) infection are typically required for the disease phenotype to manifest. HEP, an exceedingly rare porphyria, is due to biallelic pathogenic variants in UROD. HEP can present in children or adults depending on the degree of UROD deficiency. (See 'Disease classification' above and 'Pathogenesis' above and 'Epidemiology' above.)
●Typical findings – Typical features of PCT include chronic blistering photosensitivity, especially on the backs of the hands and other sun-exposed areas, which can lead to scarring and/or hyper- and hypopigmentation. In severe cases, the lesions can be complicated by secondary infection. Patients may have elevations in serum transaminases, but neurovisceral attacks do not occur. Manifestations of HEP are similar but more severe and often develop in early childhood. (See 'Clinical features' above.)
●Laboratory testing – As with other porphyrias, the evaluation for PCT is done in a stepwise fashion, with measurement of plasma or urinary total porphyrins as first-line diagnostic tests. Plasma and urine total porphyrins are elevated in PCT, with a characteristic pattern; normal porphyrin levels exclude PCT and all other blistering cutaneous porphyrias. If total plasma or urine porphyrins are elevated, more extensive second-line testing follows (algorithm 1). (See 'Diagnostic evaluation' above.)
●Confirmation of the diagnosis – The diagnosis of PCT is made by documenting the characteristic biochemical porphyrin profile, which includes increased plasma and urine porphyrins with a predominance of highly carboxylated porphyrins. Plasma peak fluorescence at 620 nm distinguishes PCT from variegate porphyria (VP). Total fecal porphyrins in PCT may be normal or modestly elevated with a characteristic pattern that includes isocoproporphyrins (table 2 and table 1). Molecular analysis is not required for diagnosis, but when performed, it shows a pathogenic variant in UROD in approximately 20 percent of cases. The biochemical porphyrin profile in HEP is similar to PCT. However, biochemical abnormalities are often more marked than in PCT. Further, there is a marked elevation of erythrocyte zinc protoporphyrin. HEP should be confirmed by molecular studies that demonstrate biallelic UROD variants. (See 'Diagnosis' above.)
●Differential diagnosis – The differential diagnosis of PCT includes other blistering cutaneous porphyrias, other phototoxic skin disorders including pseudoporphyria, and other causes of urinary or plasma porphyrin elevations. (See 'Differential diagnosis' above.)
●Management – All patients with PCT who have active skin lesions should be treated with phlebotomy or low-dose hydroxychloroquine. It is important to address the individual susceptibility factors present in a given patient. The choice between phlebotomy and hydroxychloroquine depends on the degree of iron overload and other susceptibility factors. Whether people with PCT who also have HCV infection should be treated initially with direct-acting antiviral agents is under study. A full discussion of the management and prognosis of PCT and HEP is presented in detail separately. (See "Porphyria cutanea tarda and hepatoerythropoietic porphyria: Management and prognosis".)
ACKNOWLEDGMENT — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.
