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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. 1 Woolf J, Marsden JT, Degg T, et al. Best practice guidelines on first-line laboratory testing for porphyria. Ann Clin Biochem. 2017;54(2):188-198.
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. 2 Karim Z, Lyoumi S, Nicolas G, et al. Porphyrias: a 2015 update. Clin Res Hepatol Gastroenterol. 2015;39(4):412-425. Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322. Schulenburg-Brand D, Katugampola R, Anstey AV, et al. The cutaneous porphyrias. Dermatol Clin. 2014;32(3):369-384, ix.
Quick Answers for Clinicians
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. 4 Schulenburg-Brand D, Katugampola R, Anstey AV, et al. The cutaneous porphyrias. Dermatol Clin. 2014;32(3):369-384, ix.
Patients with acute hepatic porphyrias are at greater risk for hepatic fibrosis or cirrhosis, as well as hepatocellular carcinoma (HCC). 2 Karim Z, Lyoumi S, Nicolas G, et al. Porphyrias: a 2015 update. Clin Res Hepatol Gastroenterol. 2015;39(4):412-425. Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322. Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322. Karim Z, Lyoumi S, Nicolas G, et al. Porphyrias: a 2015 update. Clin Res Hepatol Gastroenterol. 2015;39(4):412-425.
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, ultraviolet A (UVA) radiation, chronic renal failure or dialysis, or certain medications can be the cause. 1 Woolf J, Marsden JT, Degg T, et al. Best practice guidelines on first-line laboratory testing for porphyria. Ann Clin Biochem. 2017;54(2):188-198.
A biopsy is not required to diagnose porphyrias; laboratory testing alone can be used to diagnose any of the porphyrias. 4 Schulenburg-Brand D, Katugampola R, Anstey AV, et al. The cutaneous porphyrias. Dermatol Clin. 2014;32(3):369-384, ix.
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
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, ALA dehydratase-deficient porphyria; ALA, aminolevulinic acid; HEP, hepatoerythropoietic porphyria Sources: Woolf 1 Woolf J, Marsden JT, Degg T, et al. Best practice guidelines on first-line laboratory testing for porphyria. Ann Clin Biochem. 2017;54(2):188-198. Karim Z, Lyoumi S, Nicolas G, et al. Porphyrias: a 2015 update. Clin Res Hepatol Gastroenterol. 2015;39(4):412-425. |
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. 2 Karim Z, Lyoumi S, Nicolas G, et al. Porphyrias: a 2015 update. Clin Res Hepatol Gastroenterol. 2015;39(4):412-425. Laboratory Diagnosis - Acute Porphyrias. European Porphyria Network. Accessed May 2020. Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322.
Negative results in symptomatic patients rule out AIP, HCP, and VP. 3 Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322. Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322. Woolf J, Marsden JT, Degg T, et al. Best practice guidelines on first-line laboratory testing for porphyria. Ann Clin Biochem. 2017;54(2):188-198.
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. 5 Laboratory Diagnosis - Acute Porphyrias. European Porphyria Network. Accessed May 2020.
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. 4 Schulenburg-Brand D, Katugampola R, Anstey AV, et al. The cutaneous porphyrias. Dermatol Clin. 2014;32(3):369-384, ix.
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. 2 Karim Z, Lyoumi S, Nicolas G, et al. Porphyrias: a 2015 update. Clin Res Hepatol Gastroenterol. 2015;39(4):412-425. Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322. Laboratory Diagnosis - Acute Porphyrias. European Porphyria Network. Accessed May 2020.
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. 5 Laboratory Diagnosis - Acute Porphyrias. European Porphyria Network. Accessed May 2020. Karim Z, Lyoumi S, Nicolas G, et al. Porphyrias: a 2015 update. Clin Res Hepatol Gastroenterol. 2015;39(4):412-425.
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. 2 Karim Z, Lyoumi S, Nicolas G, et al. Porphyrias: a 2015 update. Clin Res Hepatol Gastroenterol. 2015;39(4):412-425.
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 3 Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322. Karim Z, Lyoumi S, Nicolas G, et al. Porphyrias: a 2015 update. Clin Res Hepatol Gastroenterol. 2015;39(4):412-425.
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.
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. 3 Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322. Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322. Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322.
Treatment of PCT should be monitored with serum ferritin or plasma or urine porphyrin testing, depending on therapy type. 6 American Porphyria Foundation. Healthcare Professional Portal. Accessed May 2020. American Porphyria Foundation. Healthcare Professional Portal. Accessed May 2020.
ARUP Laboratory Tests
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Quantitative High Performance Liquid Chromatography (HPLC)
Quantitative High Performance Liquid Chromatography (HPLC)/Quantitative Spectrophotometry/Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Fluorometry
Quantitative High Performance Liquid Chromatography (HPLC)
Quantitative Fluorometry
Qualitative Extraction/Scanning Spectrofluorometry/Quantitative High Performance Liquid Chromatography (HPLC)
Quantitative Ion Exchange Chromatography/Spectrophotometry
Quantitative Ion Exchange Chromatography/Spectrophotometry
Quantitative Enzymatic Assay/Spectrofluorometry
Quantitative Enzymatic Assay/Fluorometry
References
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27555665
Woolf J, Marsden JT, Degg T, et al. Best practice guidelines on first-line laboratory testing for porphyria. Ann Clin Biochem. 2017;54(2):188-198.
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26142871
Karim Z, Lyoumi S, Nicolas G, et al. Porphyrias: a 2015 update. Clin Res Hepatol Gastroenterol. 2015;39(4):412-425.
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28605040
Balwani M, Wang B, Anderson KE, et al. Acute hepatic porphyrias: recommendations for evaluation and long-term management. Hepatology. 2017;66(4):1314-1322.
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24891059
Schulenburg-Brand D, Katugampola R, Anstey AV, et al. The cutaneous porphyrias. Dermatol Clin. 2014;32(3):369-384, ix.
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EPN - Laboratory Diagnosis - Acute Porphyrias
Laboratory Diagnosis - Acute Porphyrias. European Porphyria Network. Accessed May 2020.
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APF - Porphyrias
American Porphyria Foundation. Healthcare Professional Portal. Accessed May 2020.