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 acute hepatic or chronic cutaneous, 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. A broad range of medications (including barbiturates and sulfa drugs), alcohol, infection, starvation, heavy metals, and hormonal changes may precipitate crises. Photosensitivity is not associated with AIP but may be present in HCP and VP. Aminolevulinic acid dehydratase deficiency porphyria (ADP) is a rare, autosomal recessive porphyria that has a variable age at presentation.

Clinical manifestations of acute porphyria include attacks of neurologic dysfunction, commonly characterized as abdominal pain. However, these acute attacks are variable and can include vomiting, diarrhea, constipation, urinary retention, acute episodes of neuropathic symptoms, psychiatric symptoms, seizures, respiratory paralysis, tachycardia, and hypertension. Respiratory paralysis can progress to coma and death.

 

HCP and VP are also associated with cutaneous manifestations, including edema, sun-induced erythema, acute painful photodermatitis, and urticaria. In some cases, patients present with isolated photosensitivity.

Acute attacks may be prevented by avoiding both endogenous and exogenous triggers. These triggers include porphyrogenic drugs, hormonal contraceptives, fasting, alcohol, tobacco, and cannabis.

Acute hepatic porphyrias are caused by autosomal dominant variants in 1 of 3 genes: HMBS, associated with AIP; CPOX, associated with HCP; and PPOX, associated with VP. Variants in these genes show incomplete penetrance, and patients with a confirmed deleterious variant may be asymptomatic. ADP is inherited in an autosomal recessive manner, due to two disease-causing variants in ALAD.

The recommended first-tier tests to screen for acute hepatic porphyria are quantitative urinary porphyrins analysis (PQNRU / Porphyrins, Quantitative, Random, Urine) and fecal porphyrins analysis (FQPPS / Porphyrins, Feces).

Cutaneous photosensitivity is associated with the chronic porphyrias: porphyria cutanea tarda (PCT) and the erythropoietic porphyrias; erythropoietic protoporphyria (EPP), X-linked protoporphyria (XLP), 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 (sometimes referred to as erythropoietic uroporphyria).

PCT is the most common form of porphyria and is most commonly sporadic (acquired), but approximately 25% of cases are inherited in an autosomal dominant manner. 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 observed when an individual inherits PCT from both parents. Patients exhibit a similar clinical presentation to what is seen in CEP.

The clinical presentation of EPP and XLP is identical with onset of symptoms typically occurring in childhood. Cutaneous photosensitivity in sun-exposed areas of the skin generally worsens in the spring and summer months. Common symptoms may include itching, edema, erythema, stinging or burning sensations, and occasionally scarring of the skin in sun-exposed areas.

Chronic porphyrias are caused by autosomal dominant disease-causing variants in UROD that are associated with inherited PCT or autosomal recessive variants in UROD that are associated with HEP. They are also due to autosomal recessive disease-causing variants in UROS or X-linked variants in GATA1 that are associated with CEP, or autosomal recessive variants in FECH that are associated with EPP. In addition, autosomal dominant variants in CLPX, associated with EPP2, and X-linked variants in ALAS2, associated with XLP, are also causes of chronic porphyrias.

A comprehensive gene panel is a helpful tool to establish a targeted diagnosis for patients with suggestive clinical and biochemical features of porphyria.

The recommended first-tier biochemical testing for patients with a suspected porphyria is most effective when following a stepwise approach.

The following algorithms are available:

-Porphyria (Acute) Testing Algorithm

-Porphyria (Cutaneous) Testing Algorithm