Porphyrias

The porphyrias are caused by loss (or gain, in the case of X-linked erythropoietic protoporphyria [XLP]) of specific enzyme functions in the heme biosynthesis pathway. Signs and symptoms of porphyrias are variable and nonspecific.  Porphyrias are generally classified as either acute or cutaneous, but some types can have overlapping symptoms, which can complicate diagnosis. The acute porphyrias (also referred to as acute hepatic porphyrias), which include acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP), are characterized by neurovisceral attacks that can cause neurologic damage and death if not treated promptly. Individuals with any of the cutaneous porphyrias, which include porphyria cutanea tarda (PCT), congenital erythropoietic porphyria (CEP), erythropoietic protoporphyria (EPP), and XLP, can experience photosensitivity resulting from sun exposure, which can manifest as either blisters and scarring or immediate redness and pain. PCT is the most common porphyria and is most often seen in middle-aged adults; however, a child or infant who presents with photosensitivity is most likely to have EPP.

Initial testing includes porphobilinogen (PBG) measurement, urine porphyrin fractionation, and erythrocyte protoporphyrin measurements. Treatment should be initiated immediately if any first-line test result is positive. An accurate and prompt diagnosis is important during an acute attack of an acute porphyria because delayed treatment can cause permanent damage or death.  Secondary testing includes porphyrin analysis of stool and plasma. All specimens should be protected from light to preserve sample integrity. Genetic testing can provide definitive diagnosis  but is usually not required.  See the Porphyrias Testing Algorithm for testing recommendations for suspected porphyria types.

Quick Answers for Clinicians

What are the differential diagnoses for porphyrias?

Lead poisoning and hereditary tyrosinemia type I can cause neuropathies similar to those of acute intermittent porphyria (AIP) as well as elevated porphyrins and aminolevulinic acid (ALA). Conditions with similar presentations to AIP but without elevated porphobilinogen (PBG) excretions include Guillain-Barré syndrome and seizures. Conditions with similar cutaneous symptoms include pemphigoid, pemphigus, pseudoporphyria, epidermolysis bullosa, dermatitis herpetiformis, and other connective tissue diseases. 

What are potential complications for patients with acute hepatic porphyrias?

Patients with acute hepatic porphyrias are at greater risk for hepatic fibrosis or cirrhosis, as well as hepatocellular carcinoma (HCC).   Screening for HCC should be performed every 6-12 months in patients older than 50 years.  Other complications include hypertension, kidney impairment, and increased risk for depression and anxiety. 

What is pseudoporphyria?

Pseudoporphyria is a photodistributed bullous disorder. It has the same clinical and histologic features as porphyria cutanea tarda (PCT) but does not cause biochemical porphyrin abnormalities. Excessive sun exposure, UVA radiation, chronic renal failure or dialysis, or certain medications can be the cause. 

What is the role of skin biopsy in the diagnosis of porphyrias?

A biopsy is not required to diagnose porphyrias; laboratory testing alone can be used to diagnose any of the porphyrias.  However, a biopsy may be helpful when pseudoporphyria, immunobullous disease, or connective tissue disease is suspected.

Which testing algorithms are related to this topic?

Indications for Testing

Diagnostic testing for porphyrias should be performed in individuals who present with severe, diffuse neuropathic abdominal pain and accompanying symptoms and in individuals with cutaneous photosensitivity. Certain tests are also indicated for treatment monitoring.

Classification

Characteristics of Porphyrias by Type
Porphyria Type Characteristics
Acute Porphyrias
AIP Autosomal dominant inheritance

Most common of the acute porphyrias

Characterized by acute onset abdominal pain (sometimes beginning in the back or chest) with nausea, vomiting, constipation, tachycardia, and no fever

Skin is never affected

HCP Autosomal dominant inheritance

Symptoms include acute onset abdominal pain with nausea, vomiting, constipation, and tachycardia (identical to those of AIP)

Skin symptoms are rare but can present with or without neurovisceral symptoms

VP Autosomal dominant inheritance

Symptoms include acute onset abdominal pain with nausea, vomiting, constipation, and tachycardia (identical to those of AIP)

Skin symptoms are common and can present with or without neurovisceral symptoms

ADP Autosomal recessive inheritance

Extremely rare (<10 kindreds)

Symptoms are identical to those of AIP

Cutaneous Porphyrias
PCT Mainly an acquired condition presenting in middle age

Most common porphyria

Characterized by photosensitivity that manifests with blisters

CEP Extremely rare, severe multisystem disease

Usually presents soon after birth

Red urine is a characteristic indicator

Causes lifelong skin fragility and blistering photosensitivity that lead to scarring and photomutilation

Also called Gunther disease

HEP Rare homozygous familial PCT

Clinically similar to CEP, but biochemical concentrations are similar to those in PCT

Usually presents in infancy or childhood

EPP Third most common porphyria in adults but the most common in children

Often manifests in infancy and childhood, but a lack of clinical signs at presentation may delay diagnosis for years

Characterized by acute skin pain after only minutes of sun exposure and photosensitivity that manifests with redness, burning, and itching, without blisters

It is common for patients to be asymptomatic, despite having inherited the gene

XLP Often manifests in infancy and childhood, but a lack of clinical signs at presentation may delay diagnosis for years

Characterized by acute skin pain after only minutes of sun exposure (symptoms are identical to those of EPP) and photosensitivity that manifests with redness, burning, and itching, without blisters

ADP, aminolevulinic acid (ALA) dehydratase-deficient porphyria; HEP, hepatoerythropoietic porphyria

Sources: Woolf , Karim 

Laboratory Testing

Diagnosis

Initial Testing

Porphobilinogen

PBG measurement is the initial test recommended when AIP, HCP, or VP is suspected on the basis of clinical symptoms, particularly during an acute attack. If PBG is increased, acute porphyria is diagnosed and treatment should begin immediately.  During an episode, the urinary PBG level is at least 10-fold the normal reference range  and can easily identify an acute porphyria. An increased PBG level also excludes PCT. Because PBG excretion is high, random urine collection is sufficient during attacks; a 24-hour collection unnecessarily delays diagnosis.  Fecal porphyrin testing to differentiate type should follow a positive PBG result.

Negative results in symptomatic patients rule out AIP, HCP, and VP.  If results are negative for asymptomatic patients, testing should be repeated during an attack, as PBG excretion may be less elevated between attacks.  When blistering cutaneous symptoms are present in addition to neurologic and abdominal symptoms, or when HCP or VP is suspected, urine porphyrin analysis should be performed concurrently with PBG measurement to ensure a diagnosis of HCP or VP is not overlooked, because PBG levels can return to normal when acute symptoms subside. 

Urine Porphyrin Fractionation and Quantitation

Urine porphyrin fractionation and quantitation is the initial test used to evaluate patients for porphyrias that manifest with blistering cutaneous photosensitivity. Excretion is elevated in all active cases, and the resulting excretion pattern can determine whether the diagnosis is PCT, CEP, or either HCP or VP. Significantly increased coproporphyrin suggests HCP or VP, even if PBG is negative. Urine tests are irrelevant to the diagnosis of EPP, except to exclude other types of porphyria, because protoporphyrins are not excreted in urine. 

Erythrocyte Porphyrin

Erythrocyte porphyrin analysis is the first-line test for evaluating patients for suspected protoporphyrias (EPP or XLP), which are characterized by elevated protoporphyrin levels. Testing should differentiate total, free, and zinc protoporphyrins.  Patients with EPP have less zinc protoporphyrin in the erythrocytes than do those with XLP.

Secondary Testing

Fecal Porphyrins

Once a diagnosis of acute porphyria has been made, porphyrin analysis of stool can be used to differentiate among the specific types; samples should be collected before treatment. Fecal porphyrin excretion is normal or slightly elevated in AIP; excretion of coproporphyrin III is markedly increased in HCP, and both coproporphyrin and protoporphyrin excretion is increased in VP.   Fecal porphyrin analysis also can support the initial findings of erythrocyte porphyrin analysis. 

Total Plasma Porphyrins

Total plasma porphyrin analysis is useful as a confirmatory test. Plasma porphyrin testing can be used to help differentiate VP from other porphyria types, identify protoporphyria, and monitor PCT.

Erythrocyte Porphyrins​

Erythrocyte porphyrin analysis is used as a first-line test in the diagnosis of protoporphyria. It can also be used as secondary testing to differentiate PCT from HEP and CEP. Concentrations are normal or mildly increased in PCT and are noticeably elevated in CEP.  Erythrocyte zinc protoporphyrin concentrations are increased in HEP but normal in PCT. 

Aminolevulinic Acid

If strong clinical suspicion exists despite a negative PBG result, measuring ALA to identify ADP may be indicated. Negative PBG excretion with substantially elevated ALA suggests ADP. ALA dehydratase testing in blood and molecular testing can be used to confirm ADP. ALA may also be increased in lead intoxication and hereditary tyrosinemia type I. 

Enzyme and Variant Analysis

After laboratory testing has identified the type of porphyria, additional testing of enzymes and/or variants may help confirm the diagnosis. Erythrocyte PBG deaminase testing is optional for suspected AIP ; patients with AIP may have a 50% decrease in PBG deaminase concentrations, whereas patients with HCP and VP will have normal concentrations.  However, normal erythrocyte PBG deaminase activity does not exclude AIP. Genetic testing can identify the variant or variants associated with the porphyria type. Variant testing is not necessary to confirm the biochemical diagnosis, but it may be helpful in identifying family members with the same disorder. The following table shows associations between genes, enzymes, and particular types of porphyria.

Porphyria Gene and Enzyme Associations
Porphyria Type Corresponding Gene Corresponding Enzyme
AIP PBGD PBG deaminasea
HCP CPOX Coproporphyrinogen-III oxidase
VP PPOX Protoporphyrinogen oxidase
ADP ALAD Delta-aminolevulinate dehydrataseb
PCT, HEP UROD Uroporphyrinogen decarboxylase
CEP UROS Uroporphyrinogen III synthase
EPP FECH Ferrochelatase
XLP ALAS2 5'-aminolevulinate synthase 2
aAlso known as hydroxymethylbilane synthase (preferred nomenclature of the Enzyme Commission), with the corresponding gene HMBS

bAlso known as porphobilinogen synthase (preferred nomenclature of the Enzyme Commission), with the corresponding gene PBGS

Diagnostic Patterns

Porphyria types are diagnosed based on the test result patterns, as shown in the following table.

Diagnostic Patterns
Porphyria Urine Porphyrins and Precursors Fecal Porphyrins Plasma Porphyrins and Precursors Erythrocyte Porphyrins
Acute Porphyrias
AIP ↑ PBG

↑ Uroporphyrin I

Negative ↑ PBG

↑ Uroporphyrin

Peak: ~620 nm

Negative
HCP ↑ PBGa

↑ Coproporphyrin III

↑ Coproporphyrin III ↑ Coproporphyrin

Peak: 615-620 nm

Negative
VP ↑ PBGa

↑ Coproporphyrin III

↑ Coproporphyrin

↑ Protoporphyrin

↑ Porphyrins

Peak: 624-627 nm

Negative
ADP Negative PBG

↑ ALA

↑ Coproporphyrin

Negative ↑ ALA

Peak: none

↑ Zinc protoporphyrin
Cutaneous Porphyrias
PCT Negative PBG, ALA

↑ Uroporphyrin

↑ 7-carboxyporphyrin

↑ Isocoproporphyrin ↑ Uroporphyrin

↑ 7-carboxyporphyrin

Peak: 615-620 nm

Negative
CEP Negative PBG, ALA

↑ Uroporphyrin I

↑ Coproporphyrin I

↑ Coproporphyrin I ↑ Uroporphyrin I

↑ Coproporphyrin

Peak: 615-620 nm

↑ Uroporphyrin I
EPP Negative PBG, ALA, porphyrin ↑ Protoporphyrin ↑ Protoporphyrin

Peak: 626-634 nm

↑ Free protoporphyrin
XLP Negative PBG, ALA, porphyrin ↑ Protoporphyrin ↑ Protoporphyrin

Peak: 626-634 nm

↑ Free protoporphyrin

↑ Zinc protoporphyrin

aPBG excretion may be negative in cases of cutaneous manifestations only.

Monitoring

Patients with any of the acute porphyrias and sporadic or recurrent attacks should be monitored annually at a minimum and should undergo follow-up 1 month after hospitalization; annual tests should include PBG and ALA measurement, a CBC, a metabolic panel, and a hepatic function panel.  Ferritin and iron testing and liver imaging should be performed every 3 months.  Because of the additional risk for hepatocellular carcinoma (HCC), serum alpha-fetoprotein measurements should be performed every 6 months for patients older than 50 years. 

Treatment of PCT should be monitored with serum ferritin or plasma or urine porphyrin testing, depending on therapy type.  Patients with EPP or XLP should have a CBC, ferritin test, and liver function test performed annually, along with erythrocyte and plasma porphyrin measurements and serum 25-hydroxy vitamin D testing. 

ARUP Lab Tests

Initial Testing

Urine Porphobilinogen

Essential first-line test for suspected acute porphyrias

Monitor response to intravenous hematin treatment

Urine Porphyrins

Diagnose cutaneous porphyrias and distinguish type

Urine PBG and Porphyrins

Identify acute or cutaneous porphyrias and determine type (especially useful for HCP and VP when cutaneous symptoms are present)

Erythrocyte Porphyrins

Evaluate for erythropoietic protoporphyrias

Differentiate PCT from HEP and CEP

Secondary Testing

Fecal Porphyrins

Differentiate acute porphyrias, AIP, HCP, and VP

Plasma Porphyrins

Differentiate VP from other acute porphyrias

Identify protoporphyria

Monitor PCT

Screen and evaluate for porphyrias

Testing performed by Mayo Medical Laboratories

Aminolevulinic Acid

Identify ADP

Erythrocyte Porphobilinogen Deaminase

Confirm AIP

Evaluate risk in family members of patient with confirmed AIP

Medical Experts

Contributor

Frank

Elizabeth L. Frank, PhD, DABCC
Professor of Clinical Pathology, University of Utah Health
Medical Director, Analytic Biochemistry, Calculi and Manual Chemistry; Co-Medical Director, Mass Spectrometry, ARUP Laboratories

References

Additional Resources