Approach
Confirm the diagnosis of PCT by: history and physical examination, elevation of urine or plasma porphyrins (which excludes pseudoporphyria), and further tests to specifically diagnose PCT and exclude other porphyrias.[1][14] It is important to confirm PCT biochemically and exclude other less common porphyrias, which can also cause the same blistering skin lesions.
History and physical examination
Blisters and crusted lesions on the backs of the hands and other sun-exposed areas are characteristic and strongly suggest the diagnosis. However, these are not specific. Other skin manifestations like hyperpigmentation and hypertrichosis are common. Scarring alopecia can be seen in more severely affected patients. Red urine due to large concentrations of porphyrins can also often be seen. The presence of one or more risk factors (namely, excess alcohol intake, smoking, estrogen therapy, hepatitis C, HIV, hereditary hemochromatosis gene [HFE] mutations and other causes of iron overload, and inherited partial deficiency of uroporphyrinogen decarboxylase [UROD] due to mutations of the gene for this enzyme) is suggestive, but should be identified to help in planning management rather than establishing a diagnosis of PCT. Some patients have been found to be deficient in vitamin C and other antioxidants.[11][12]
Biochemical tests
If PCT is suspected after assessment of historical and physical examination, use biochemical tests to confirm the diagnosis.[14]
Urine or plasma porphyrin levels
Measure urine or plasma porphyrin levels whenever PCT and other blistering porphyrias are suspected. Normal results exclude all of these disorders. Elevated levels are most commonly due to PCT; however, other blistering porphyrias, which are managed differently, must also be considered. Plasma porphyrin levels may be preferred for screening because urine porphyrins are more subject to nonspecific elevations in other conditions.
Urine total porphyrins are expected to be markedly elevated and plasma total porphyrins are expected to be in the range of 5 to 30 micrograms/dL (ref range <0.9 micrograms/dL) in PCT patients. Plasma total porphyrins may be much higher in PCT patients with end-stage renal failure.
If the total porphyrins are elevated, urine and/or plasma porphyrins are fractionated by high-performance liquid chromatography, showing a characteristic predominance of uroporphyrin and heptacarboxyl porphyrin.
Plasma fluorescence scanning detecting a peak at approximately 619 nm differentiates PCT from variegate porphyria, but not from other blistering cutaneous porphyrias.
Erythrocyte total porphyrins are normal or modestly elevated in PCT. Substantial elevation may indicate a concurrent marrow disorder (e.g., myelofibrosis) in which PCT is related in part to iron overload. Erythrocyte porphyrins are also markedly elevated in other, less common, blistering porphyrias, such as congenital erythropoietic porphyria, hepatoerythropoietic porphyria, and homozygous forms of acute intermittent porphyria, hereditary coproporphyria (including a variant form termed harderoporphyria), and variegate porphyria; all of which can present with skin lesions that mimic PCT in children or adults.
Serum ferritin and liver biopsy
After the diagnosis of PCT is established, assess the degree of iron overload by serum ferritin, and by liver biopsy when clinically indicated, as in other conditions associated with iron overload (e.g., hemochromatosis).
Serum ferritin may be increased in part due to liver inflammation (acute phase response), but ferritin is still a useful target for therapeutic phlebotomy.
Consider liver biopsy in patients with iron overload (e.g., serum ferritin >1000 nanograms/mL [>2250 picomoles/L]).
Liver abnormalities may include mild elevation of liver transaminases, and liver histopathology may include porphyrin-containing inclusions within hepatocytes, siderosis, and nonspecific histological abnormalities.
Skin biopsy
Skin biopsy will show features of subepidermal blister formation, but this is seen in other blistering porphyrias and is not specific for PCT. Therefore, diagnosis is based on characteristic porphyrin elevations.[15]
DNA studies
After biochemical confirmation, it is important to carry out DNA studies to identify patients who are heterozygous for a UROD mutation, which is an inherited susceptibility factor, and to identify HFE mutations.
Liver function tests
In addition to the cutaneous clinical features of PCT, there are also hepatic abnormalities that can be evidenced by abnormal liver function tests. Serum alanine amino transferase, aspartate amino transferase, alkaline phosphatase, gamma glutamyl transferase, and total, direct, and indirect bilirubin should be measured.
Confirmatory tests
A substantial increase in total porphyrins with a predominance of uroporphyrin and heptacarboxyl porphyrin in urine or plasma is characteristic of PCT. Increased fecal isocoproporphyrin is also characteristic, but technically more difficult to perform and usually not required for confirmation.
Further confirmation includes exclusion of other blistering cutaneous porphyrias that, unlike PCT, markedly increase erythrocyte porphyrins.
Exclusion or detection of other comorbid risk factors
Management of PCT includes identification and management of susceptibility factors, a number of which have implications for management of PCT. Timing of treatment for HIV or hepatitis C requires consideration when PCT is also being managed; therefore it is necessary to confirm diagnosis of these conditions if they are suspected and have not yet been confirmed.
Test hereditary hemochromatosis gene mutations because they are common in PCT and their presence may partially explain excess iron accumulation.
End-stage renal disease is a contraindication to treatment with low-dose hydroxychloroquine or chloroquine.
Monitoring during repeated phlebotomies
Monitor hematocrit or hemoglobin during repeated phlebotomies.[16] Anemia is a contraindication to phlebotomy, so this should be corrected prior to considering or resuming repeat phlebotomy, if possible. Serum ferritin is monitored until it decreases to a target value of 15 to 20 nanograms/mL (35 to 45 picomoles/L).
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