The porphyrias are a group of metabolic disorders, each caused by impairment of one of the enzymes in the heme biosynthetic pathway (Figure 1). In affected people, buildup of specific pathway intermediates (porphyrins and porphyrin precursors) causes characteristic signs and symptoms. Most porphyrias are inherited disorders (Table 1). However, environmental factors, other genetic factors, and underlying disease states can influence severity and disease course, such that some people with impaired enzyme function remain asymptomatic. Timely and accurate diagnosis is important for determining appropriate management. However, diagnosing porphyrias is challenging owing to the rarity of these disorders and nonspecific symptoms. Biochemical testing on urine, blood, and/or stool specimens is used to identify and differentiate porphyrias based on patterns of accumulated porphyrins and porphyrin precursors, which are unique to each porphyria (Table 2).

Figure 1. Porphyrias Caused by Enzyme Deficiencies in the Heme Biosynthetic Pathway

Table 1. Characteristics of the Porphyrias1,3-6

Table 2. Porphyrins and Porphyrin Precursors That Typically Accumulate in the Porphyrias3,4,7-10

The porphyrias are categorized based on clinical presentation (Table 1): neurovisceral, cutaneous, or dual (neurovisceral and/or cutaneous symptoms possible). Neurovisceral porphyrias are characterized by acute symptoms, which can include severe abdominal pain, vomiting, nausea, tachycardia, hypertension, peripheral neuropathy, and psychiatric symptoms (eg, insomnia, anxiety, depression).2-4 These acute porphyric attacks can be precipitated by certain medications, alcohol, heavy metal toxicity, or hormonal changes, and may be life-threatening.3

In contrast, cutaneous porphyrias are characterized by skin photosensitivity. They can be categorized further into 2 subgroups based on the nature of the photosensitivity (Table 1): (1) chronic skin blistering, fragility, and scarring; or (2) acute, painful photosensitivity, redness, and swelling.1,4-6,11 However, symptoms may overlap between these subgroups to some extent.4 Additional symptoms are possible in congenital erythropoietic porphyria (CEP) (hypertrichosis, hyperpigmentation, hemolytic anemia, erythrodontia, and prenatal hydrops) and porphyria cutanea tarda (PCT) (hypertrichosis, hyperpigmentation, pseudoscleroderma, and liver dysfunction).4

The categorical clinical presentation of the patient dictates which first-line laboratory tests to use. If first-line tests suggest porphyria or clinical suspicion is high (eg, characteristic signs such as reddish urine, or family history of porphyria), second-line tests may be needed to identify the specific porphyria.1-3 Owing to variability in biochemical test results, the porphyrin profile of an individual patient may not exactly match those provided in Table 2. However, a subset of characteristic analytes may still be sufficient to identify a specific porphyria. Genetic testing for variants in the associated gene is typically recommended to facilitate genetic counseling for the affected person and for potentially affected family members.3,8,9,12

This Test Guide provides an overview of the use of laboratory tests in the diagnosis of porphyria. A list of relevant tests is provided in Table 3. This information is provided for informational purposes only and is not intended as medical advice. A physician's test selection and interpretation, diagnosis, and patient-management decisions should be based on his/her education, clinical expertise, assessment of the patient, and consultation with subject matter experts, if needed. If the ordering/treating physician has any questions, please contact the Quest Diagnostics Biochemical Genetics Laboratory at 1.800.642.4657 (extensions 4817 or 4423) and ask to speak with the laboratory director on call. For general questions about Quest Biochemical Genetics testing, please call genomics client services at 1.866.GENE.INFO (1.866.436.3463).

Porphyrins and porphyrin precursors degrade when exposed to ultraviolet light, so all specimens should be protected from light.1,3

Table 3. Available Tests Used for Screening and Diagnosis of Porphyria

Testing for Porphyrias With Neurovisceral Symptoms

A single algorithm (Figure 2) guides testing for neurovisceral and dual porphyrias in patients with unexplained acute neurovisceral symptoms, with or without concurrent cutaneous symptoms.2-4

Figure 2. Laboratory Evaluation for Porphyrias With Neurovisceral Symptoms

Urine porphobilinogen (PBG) analysis is an essential, specific, first-line test for neurovisceral and dual porphyrias (Figure 2).1-3,6,8-10,12 Urine delta-aminolevulinic acid (ALA) and urine or plasma porphyrin analyses can also be included as first-line tests (Figure 2); recommendations vary.1-4,6,8-10,12 Including a test for urine ALA helps detect ALA dehydratase deficiency porphyria (ADP).3,9,10 Although ADP is very rare, it can be missed if only a PBG test is used for screening because PBG levels are typically normal.3 Including a test for fractionated urine or plasma porphyrins helps to (1) detect hereditary coproporphyria (HCP) and variegate porphyria (VP) because, in these 2 disorders, porphyrins remain elevated longer than ALA and PBG after an attack3,9; and (2) inform which second-line tests to perform (Figure 2). However, unlike elevated PBG or ALA, isolated porphyrin elevation is not specific for porphyria and is also found in other conditions.2,8,10

Second-line tests for differentiating among neurovisceral and dual porphyrias may include analyses of fractionated urine or plasma porphyrins (if not already done), urine ALA (if not already done), fractionated fecal porphyrins, and erythrocyte ALA dehydratase (ALAD) and hydroxymethylbilane synthase (also called PBG deaminase) activities (Figure 2). ALAD deficiency, while consistent with ADP, is also found in other, more common conditions, including heavy metal toxicity and tyrosinemia.3 Thus, screening tests for these conditions may also be appropriate, alongside second-line porphyria tests, if the results of first-line tests suggest ALAD deficiency (Figure 2).

Testing for Porphyrias With Cutaneous Symptoms

The 2 subgroups of cutaneous porphyrias require different laboratory tests.9 One algorithm (Figure 3) guides testing for PCT, CEP, and the dual porphyrias in patients with chronic skin blistering, fragility, and scarring (Table 1).1,4,6 The other algorithm (Figure 4) guides testing for erythropoietic (EPP) and X-linked protoporphyrias (XLP) in patients with acute, painful photosensitivity, redness, and swelling upon exposure to light (Table 1).1,4-6,11

Figure 3. Laboratory Evaluation for Cutaneous Porphyrias With Chronic Skin Blistering, Fragility, and Scarring

Figure 4. Laboratory Evaluation for Cutaneous Porphyrias With Acute Painful Photosensitivity, Redness, and Swelling

Urine or plasma porphyrin analyses are the essential first-line tests for PCT, CEP, HCP, and VP.1,8,9 Using fractionated urine or plasma tests allows for rapid identification of PCT, the most common porphyria, and CEP without the need for second-line tests (Figure 3). This strategy also helps distinguish PCT from pseudoporphyria, a condition that causes symptoms like those of PCT, but without characteristic porphyrin abnormalities. Reported causes of pseudoporphyria include several types of medications, ultraviolet radiation, and hemodialysis.13

Second-line tests may include fractionated plasma or fecal porphyrin analyses, which help distinguish between HCP and VP (Figure 3).4,6,7 In some cases, plasma porphyrin analysis may not provide enough information to differentiate HCP and VP, and fecal porphyrin analysis may be necessary.

The protoporphyrias (EPP and XLP) are both caused by elevated erythrocyte protoporphyrin.5,7,11 Analysis of the proportions of erythrocyte protoporphyrin that are metal-free or zinc-bound is ultimately needed to differentiate EPP and XLP (Figure 4).1,6,11 However, total erythrocyte porphyrins or protoporphyrins could be used as a first-line screening test, if available.1,6,8