Clinically, type I and type II PCT are similar, and the need for differentiating the two arises only during the management and patient counseling. The patients should be asked in detail about any of the susceptibility factors discussed above, like alcohol, smoking, chemical, or estrogen exposures. Any evidence of neurovisceral symptoms can help point to other porphyrias. Family history is usually not helpful, and a detailed medication history might be beneficial to rule out any drug-related eruptions. Since the porphyrin accumulation in the PCT can change the urine color to reddish-brown, a complete history will also include questions about the patient's urine color. 

Cutaneous Manifestations

Photosensitivity, along with the formation of skin blisters, vesicles, bullae, and increased fragility of the skin, is seen on sun-exposed parts of the body. This most commonly involves the back of the hands, forearms, neck, face, and feet. These repeated insults to the skin later resolve, leaving behind hyper- and hypopigmented scars and milia, which are small yellowish-white keratin filled papules.[10] Since PCT is delayed blistering photosensitivity, most patients do not associate sun exposure with their skin lesions.[4] These skin lesions arise from minor trauma and sometimes may get infected, causing intense pain and inflammation.[18] The scarring may lead to contractures mimicking the skin findings of a patient with scleroderma, thus labeling this phenomenon as "pseudoscleroderma."[19] Scarring alopecia on the scalp can lead to a diffuse hair loss.

Pigment changes can be seen in the facial, orbital, or malar regions ranging from blue to purplish-brown colors.[11] Occasionally an appearance akin to the plethora of polycythemia vera can be seen as an erythematous suffusion on sun-exposed areas.[10]

A non-virilizing type of hypertrichosis around the cheeks, temple, and forearms can be seen in women. Sometimes, this could be the only physical manifestation seen in PCT patients.

Evaluation of a patient with porphyria includes:

Urine or plasma levels of total porphyrins: Elevated in both PCT and Hepatoerythropoietic porphyria. Uroporphyrin and heptacarboxyl porphyrin are usually elevated along with normal levels of urinary ALA and Porphobilinogen. Checking for porphyrin levels in feces is not needed for diagnosis but may be useful in patients undergoing hemodialysis. 

Once the level of porphyrins has been found to be elevated, porphyrin fractionation and other tests are required to pinpoint PCT as the underlying cause of the skin lesions. Water-soluble carboxylated porphyrins are found in the urine point towards PCT and HEP, whereas increased levels of coproporphyrin do not. HEP shows a very high level of erythrocyte protoporphyrin and hence can be distinguished from PCT.[20] Using the plasma fluorescence peak wavelength at neutral pH, PCT can be differentiated from variegate porphyria, which is easily mistaken for the other on initial diagnosis.

A patient’s urine, blood, and stool can be tested for increased porphyrin levels. Below is the pattern of porphyrin accumulation specific to PCT.[10]

• Urine: ↑ Uroporphyrin, ↑ Coproporphyrin, normal Porphobilinogen, normal ALA
• Stool: ↑ Uroporphyrin, ↑ Isocoproporphyrin, ↑ Protoporphyrin
• Red blood cells: normal Uroporphyrin, Coproporphyrin, and Porphobilinogen
• Plasma: ↑ Uroporphyrin

Skin Biopsy: This is not needed for diagnosis and may only help in excluding some other skin conditions from the cutaneous porphyrias. Subepidermal blisters and depositions in vessel walls are some of the biopsy findings seen in porphyrias.[21]

The first step in the management of PCT is the avoidance of precipitating and susceptibility factors. Since this 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 400-410nm, and only titanium dioxide or zinc oxide containing sunscreen is effective.[10] 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. Other things to strictly avoid include alcohol, smoking, and estrogen therapy, along with limiting any excess intake of iron. 

The mainstay therapies of PCT are phlebotomy and hydroxychloroquine. Depending on the specific comorbidities and susceptibility factors, we can choose one over the other. 

Phlebotomy: Any condition leading to iron overload in the patient is a clear indication for phlebotomy, and in such 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. The skin manifestations resolve within four months, but the porphyrin levels can take up to 12 months to normalize. Serum ferritin levels may be used as an indicator to monitor for relapse of this condition since the levels change before porphyrin levels.[11] Contraindications to phlebotomy include patients with pulmonary or coronary artery disease. 

Hydroxychloroquine or chloroquine: These are preferred therapies in cases where ferritin levels are not elevated (below 600 ng/mL) or a patient without an HFE mutation. They act by inhibiting the formation and secretion of porphyrins.[11] Chloroquine 125mg twice weekly or in cases of intolerance, hydroxychloroquine can be used twice weekly at a dose of 200mg. The latter may be safer in terms of retinal toxicity.[24] These regimens can take between 6-9 months for complete remission. Contraindications to these drugs include pregnancy, liver disease, retinal disease, and the concomitant use of other hepatotoxic drugs. Regular ophthalmologic examination and liver function tests monitoring are required. 

Chelation therapy: Iron chelation was considered to be an alternative in people with iron overload-induced PCT, but after comparative studies with phlebotomy and hydroxychloroquine, it was not found to be as efficient. However, deferoxamine and deferasirox can be used in patients with contraindications to both phlebotomy and hydroxychloroquine. The disadvantages of 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. 

The most important differentials in a patient with suspected PCT include hereditary coproporphyria, variegate porphyria, and congenital erythropoietic porphyria due to the cutaneous manifestations seen in all four along with elevated porphyrin levels. As mentioned above for PCT, all other conditions will have specific patterns of porphyrin elevation, which would be diagnostic of that disease. Variegate porphyria, for example, would have an increased urinary level of coproporphyrins, ALA, and porphobilinogen, whereas congenital erythropoietic porphyria would have normal urinary ALA and porphobilinogen levels. However, both variegate porphyria and hereditary coproporphyria can be clinically differentiated from PCT based on their presenting neurovisceral symptoms, which is lacking in patients with PCT.[10]

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

• Pseudoporphyria cutanea tarda is clinically and histologically indistinguishable from PCT but without the porphyrin elevation. It is associated with Nonsteroidal anti-inflammatory drugs (NSAIDs), furosemide, antibiotics (nalidixic acid, tetracyclines), or retinoid use.[10]
• Epidermolysis bullosa acquisita is an autoimmune blistering disorder that presents with widespread blisters not limited to sun-exposed skin surfaces.[25]
• Polymorphous light eruption is a photo distributed pruritic rash that develops minutes to hours after sunlight exposure and is characterized by erythematous papules, vesicles, and plaques that are nonscarring.[26]

Porphyrin elevation is also seen in liver disease, advanced renal disease, and other porphyrias. However, they will not show the typical cutaneous manifestations seen in patients with PCT.

Life expectancy in patients of PCT is expected to be normal unless there are comorbid conditions like HCV that could lead to liver disease or carcinoma.  Full remission is achievable, but recurrence, however, is possible. Relapses of up to 35% have been recorded over a follow-up period of up to 11 years.[27] Patients with elevated iron levels may need periodic phlebotomy. Patients who continue to be exposed to susceptibility factors, such as excessive alcohol consumption and smoking, are also more likely to relapse. Annual monitoring of urine and plasma uroporphyrin levels is recommended to detect biochemical relapses before the clinical manifestations of the disease appear.[28]

Although the clinical manifestations of PCT are limited to the skin, patients are also at a high risk of hepatic complications. Liver biopsies usually reveal fatty changes along with porphyrin deposits and sometimes lobular necrosis. PCT independently increases the risk of liver cirrhosis and hepatocellular carcinoma, which may be accentuated by co-existing HCV infection, alcoholic hepatitis, or iron overload.[29]

Patients should be educated about the entire disease process and reassured about the non-fatality of this condition. Phlebotomy should be explained along with the need for regular appointments to check porphyrin levels in the blood. Avoidance of susceptibility factors like cessation of smoking, alcohol, estrogen, and iron therapies along with the importance of sun-protective measures like sunscreens, hats, and protective clothing should be emphasized. Any prior history of HCV or HIV should be disclosed, and the patient should strictly adhere to the treatment regimens advised by the treating physician.

Testing for ferritin levels, infections, and genetic testing are all part of the treatment strategy for PCT, and the patient should be made aware of this.

• Porphyria cutanea tarda is the most common porphyria caused by decreased activity in the uroporphyrinogen decarboxylase enzyme, leading to the accumulation of porphyrins.
• Alcohol, estrogen use, viral infections, smoking, and iron overload are susceptibility factors that are commonly associated with the development of porphyria cutanea tarda.
• Excessive circulating porphyrins react with light causing a delayed skin reaction manifesting as blisters, hypertrichosis, hyperpigmentation, and scleroderma-like changes on sun-exposed surfaces.
• Porphyria cutanea tarda may be treated by simply avoiding the precipitating factors. However, phlebotomy and hydroxychloroquine are both effective in achieving biochemical and clinical remission.

Porphyria cutanea tarda is one of the many porphyrias that result due to an abnormal enzyme in the heme biosynthesis pathway. Patients present with a blistering skin manifestation and notably lack any neurovisceral symptoms. It is essential to consider a urinalysis, stool analysis, and blood tests to establish the diagnosis. Along with this, a detailed account to uncover all susceptibility factors should be a priority as the avoidance of these factors is a vital aspect of the patient's management. 

Although an internist or a hematologist would generally handle this case, it is important to note the involvement of all other specialties in the diagnosis and management of this patient. The primary care physician or internist who might see the patient first should take a detailed personal and family history before they refer the patient to a dermatologist or a hematologist. The dermatologist plays a vital role in identifying this as a blistering skin condition, which would help narrow down the differentials. A skin biopsy is not necessary for diagnosis but may be done. If it is done, the role of the pathologist comes into play to view the specimen and give more clues that point to the diagnosis. The evaluation and management will be centered on the hematologist.

Laboratory investigations are required such as urine, fecal, and blood samples are usually sent for the measurement of porphyrin levels. This would typically establish the diagnosis, although porphyrin fractionation is needed to differentiate between porphyrias that present similarly biochemically. The management is centered on weekly or bi-weekly phlebotomies and hydroxychloroquine. Phlebotomists are, therefore, also an essential part of the treatment team. The nurse monitors the blood pressure of the patient at every visit and is part of the core team to educate the patient and families. Complications involving the liver can arise, which would require consultations with a hepatologist or gastroenterologist. Counselors are integral to help patients avoid or cease any habits that might be a trigger for the manifestation of this disease like smoking, alcohol, etc. Since PCT might have a familial component, the opinion and consultation with a genetic counselor may also be required. 

To improve patient care and provide the best line of management for these patients, an interprofessional collaboration between different specialties is highly recommended.[30]