Clinical Information

The porphyrias are a group of inherited disorders resulting from enzyme defects in the heme biosynthetic pathway. Depending on the specific enzyme involved, various porphyrins and their precursors accumulate in different specimen types. The patterns of porphyrin accumulation in erythrocytes and plasma and excretion of the heme precursors in urine and feces allow for the detection and differentiation of the porphyrias.

The porphyrias are typically classified as erythropoietic or hepatic based upon the primary site of the enzyme defect. In addition, hepatic porphyrias can be further classified as chronic or acute, based on their clinical presentation.

The primary acute hepatic porphyrias: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP), are associated with neurovisceral symptoms that typically onset during puberty or later. Common symptoms include severe abdominal pain, peripheral neuropathy, and psychiatric symptoms. Crises may be precipitated by a broad range of medications (including barbiturates and sulfa drugs), alcohol, infection, starvation, heavy metals, and hormonal changes. Photosensitivity is not associated with AIP but may be present in HCP and VP.

Cutaneous photosensitivity is associated with the chronic hepatic porphyrias: porphyria cutanea tarda (PCT) and the erythropoietic porphyrias; erythropoietic protoporphyria (EPP), X-linked dominant protoporphyria (XLDPP), and congenital erythropoietic porphyria (CEP). Although genetic in nature, environmental factors may exacerbate symptoms, significantly impacting the severity and course of disease.

CEP is an erythropoietic porphyria caused by uroporphyrinogen III synthase deficiency. Symptoms typically present in early infancy with red-brown staining of diapers, severe cutaneous photosensitivity with fluid-filled bullae and vesicles. Other common symptoms may include thickening of the skin, hypo- and hyperpigmentation, hypertrichosis, cutaneous scarring, and deformities of the fingers, eyelids, lips, nose, and ears. A few milder adult-onset cases have been documented as well as cases that are secondary to myeloid malignancies.

PCT is the most common form of porphyria and caused by hepatic inhibition of the enzyme uroporphyrinogen decarboxylase (UROD). It is most often sporadic (acquired), but in about 20% of cases, a heterozygous variant in UROD increases the susceptibility to disease. The most prominent clinical characteristics are cutaneous photosensitivity and scarring on sun-exposed surfaces. Patients experience chronic blistering lesions resulting from mild trauma to sun-exposed areas. These fluid-filled vesicles rupture easily, become crusted, and heal slowly. Secondary infections can cause areas of hypo- or hyperpigmentation or sclerodermatous changes and may result in the development of alopecia at sites of repeated skin damage. Liver disease is common in patients with PCT as evidenced by abnormal liver function tests and with 30% to 40% of patients developing cirrhosis. In addition, there is an increased risk of hepatocellular carcinoma.

Hepatoerythropoietic porphyria (HEP) is a rare autosomal recessive form of porphyria caused by homozygous or compound heterozygous variants in UROD. It typically presents in early childhood with both erythropoietic and cutaneous manifestations and is similar to what is seen in CEP.

Urinary porphyrin determination is helpful in the diagnosis of most porphyrias including CEP, PCT, AIP, HCP, and VP. In addition, measurement of porphobilinogen (PBG) in urine is important in establishing the diagnosis of the acute neurologic porphyrias (AIP, HCP and VP). Neither urine porphyrins nor PBG is helpful in evaluating patients suspected of having EPP or XLDPP.

Of note, porphyrinuria may result from exposure to certain drugs and toxins or other medical conditions (ie, hereditary tyrosinemia type I). Heavy metals, halogenated solvents, various drugs, insecticides, and herbicides can interfere with heme production and cause "intoxication porphyria." Chemically, the intoxication porphyrias are characterized by increased excretion of, uroporphyrin and/or coproporphyrin in urine.

The workup of patients with a suspected porphyria is most effective when following a stepwise approach. See Porphyria (Acute) Testing Algorithm and Porphyria (Cutaneous) Testing Algorithm or call 800-533-1710 to discuss testing strategies.