Porphyrias

Diagnosis

Indications for Testing

  • Patient with abdominal symptoms and/or cutaneous symptoms compatible with porphyria

Laboratory Testing

  • Neurological and abdominal symptoms
    • Consider acute porphyria (acute intermittent porphyria [AIP], variegate porphyria [VP], hereditary coproporphyria [HCP]) – order porphobilinogen (PBG) urine testing (random specimen is adequate)
      • Negative
        • Patient likely does not have porphyria; when active symptoms are present – repeat testing
        • When no symptoms are present but strong suspicion exists – consider aminolevulinic acid dehydratase deficiency porphyria (ADP) (very rare)
          • Aminolevulinic acid (ALA) urine testing
            • Negative – repeat testing when active symptoms are present
            • Positive – ADP probable; confirm with enzyme and mutation analysis
              • Positive – ADP confirmed*
      • Positive – order fecal porphyrins testing
        • Negative – AIP probable; confirm with erythrocyte PBG deaminase testing or mutation analysis (if strongly indicated, send proband sample; because of ambiguous results, this test is not generally recommended for diagnosis of individuals)
        • Positive – VP or HCP probable
          • Confirm with porphyrins, total, plasma or serum – pattern aids in discriminating between VP and HCP
            • Positive – VP or HCP confirmed*
    *Interpretation by medical expert necessary
    Neurological and abdominal symptoms along with cutaneous photosensitivity
    • Consider VP and HCP
      • Porphyrins and PBG, urine testing
        • Positive – see above table
        • Negative – see above table
    Cutaneous photosensitivity (nonacute porphyria)
    • Adults – consider porphyria cutanea tarda (PCT) (more likely) or congenital erythropoietic porphyria (CEP) (would be late onset and unusual occurrence)
      • Consider other possibilities – pseudoporphyria, immunobullous disease, or connective tissue disease
        • Porphyrins fractionation and quantitation urine testing  
          • Positive porphyrins* – PCT or CEP probable
            • Pattern is convincing for PCT – porphyrins, total, plasma or serum  (use to monitor but not diagnose PCT)
            • Fecal porphyrins testing
              • PCT  – isocoproporphyrin present
              • CEP – coproporphyrin I increased
            • May also consider erythrocyte porphyrin testing
          • Negative porphyrins – porphyria unlikely
    • Children – consider erythropoietic protoporphyria (EPP) (more likely) or CEP (very rare)
      • EPP – erythrocyte porphyrin whole blood testing, followed by porphyrins total, plasma or serum
        • Positive – EPP confirmed*
        • Negative – EPP unlikely
      • CEP
        • Porphyrins fractionation and quantitation urine testing  
          • Positive – see above
          • Negative – see above
    *Interpretation by medical expert necessary

Differential Diagnosis

Monitoring

  • Acute porphyrias – use urine porphobilinogen (PBG) to assess metabolic response to IV hematin
  • Porphyria cutanea tarda (PCT) – use porphyrins, total, plasma or serum, for monitoring

Clinical Background

Porphyrias are a group of inherited or acquired enzyme disorders of the heme biosynthetic pathway that result in overproduction of porphyrins or porphyrin precursor compounds.

Epidemiology

  • Prevalence
    • Porphyria cutanea tarda (PCT) – 1/10,000
    • Acute intermittent porphyria (AIP) – 1-2/20,000
    • Variegate porphyria (VP) – 3/1,000 in Caucasians
      • Less common in other populations
    • Erythropoietic protoporphyria (EPP) – 2-5/1,000,000
    • Hereditary coproporphyria (HCP) – ≤2/1,000,000
    • Congenital erythropoietic porphyria (CEP) – ≤1/1,000,000
    • Aminolevulinic acid dehydratase deficiency porphyria (ADP) – <10 cases reported
  • Age – varies according to porphyria
    • Adults
      • PCT – manifests after 30s
      • AIP – rarely occurs before puberty; usually occurs in 30s
    • Children
      • EPP – most common childhood porphyria
      • CEP – manifests soon after birth, occasionally later
        • Late onset CEP has been documented in older adults

Classification

  • Rare disorders – all forms of porphyria together afflict fewer than 200,000 people in the U.S.
  • Classification
    • Acute
      • Neurologic symptoms
        • AIP
        • ADP
      • Neurologic and cutaneous symptoms
        • VP
        • HCP
    • Nonacute
      • PCT
      • EPP
      • CEP

Clinical Features

  • Acute porphyrias
    • AIP – accumulation of smaller porphyrin precursor compounds
      • Age – rarely occurs before puberty; usually occurs in 30s
      • Sex – M<F
      • Most common acute porphyria
        • May occur more frequently in individuals of northern European descent
      • Neurologic, abdominal signs and symptoms
      • Skin lesions do not occur
    • VP
      • Often presents only with skin lesions (60%)
      • Shares portions of major symptoms with AIP, hereditary coproporphyria (HCP), and porphyria cutanea tarda (PCT)
    • HCP
      • Skin lesions uncommon; found in 5% of cases
      • Abdominal pain, nausea, vomiting, neurologic, and psychologic symptoms predominate
    • ADP
      • May present with sudden, life-threatening attacks
        • Low genetic penetrance results in infrequent attacks
      • Very rare (<10 cases reported worldwide)
  • Nonacute porphyrias
    • PCT – accumulation of larger porphyrin intermediates
      • Age – manifests after 30s
      • Sex – M>F
      • Most common porphyria worldwide
      • Cutaneous signs and symptoms only
      • 75% of cases are sporadic with no family history
      • May be induced by environmental toxins or other syndromes
      • Hepatoerythropoietic porphyria (HEP) – homozygous form of PCT type II
        • Severe skin blistering and scarring, often with loss of facial features and fingers
    • EPP
      • Age – childhood
      • Acute phototoxic reaction followed by edema, erythema, and burning pain in sun-exposed areas
        • Petechiae and vesicles eventually develop
        • Purpura rarely develops
      • Chronic changes include “velvet knuckles” (marked by thick hyperkeratotic skin), lichenification, pigmentation, and premature aging
    • CEP
      • Age – infants
        • May occur as late-onset disease (adults)
      • Erythrodontia accompanied by staining of the bones, hemolysis, dark urine, and photosensitivity
      • Cutaneous symptoms as in other porphyrias, but skin changes tend to become chronic

Risk Factors

  • Genetics – predominantly transmitted as autosomal dominant disorders
    • ADP and CEP have autosomal recessive transmission
  • PCT – associated with the following

Pathophysiology

  • Heterogenous group of inherited or acquired disorders of heme biosynthesis
    • Partial deficiency of one of seven enzymes in the pathway causes the clinical features of porphyria
    • Defined by accumulation and excretion of heme precursors specific for the individual disease
    • Heme Biosynthetic Pathway

Clinical Presentation

  • Acute
    • Acute attacks are rare before puberty and after menopause
    • Neurologic symptoms (may be life threatening)
      • Most patients have one or a few attacks then fully recover
      • Muscular weakness and pain (proximal myopathy of arms is common)
        • Can progress to tetraplegia
        • Respiratory – bulbar paralysis and death
      • Mild sensory neuropathy (bathing trunk distribution), paresthesias
      • Psychiatric symptoms – confusion, hallucinations, psychosis
        • Usually last <1-2 weeks
    • Abdominal symptoms – abdominal pain (may be colicky or mimic acute surgical abdomen), nausea, emesis, marked constipation, dark brown or red urine
    • Precipitating factors
      • Drugs (inducers of heme synthesis) – anticoagulants, barbiturates, estrogen, ethanol, nicotine, sulfonamides
      • Diminished caloric intake, fasting
      • Infections
    Nonacute
    • Cutaneous symptoms – bullous lesions on sun-exposed skin
      • Skin becomes fragile with minor trauma, leading to erosion and crusting
      • Blisters and bullae take weeks to heal
      • Symptoms differ in EPP – patients develop seasonal, lifelong acute photosensitivity of sun-exposed skin
        • Phototoxic reactions take place within minutes of sun exposure
        • Hyperpigmentation of exposed skin
        • Hypertrichosis develops primarily on exposed skin
      • With chronic disease, patients may develop sclerodermoid features
    • Precipitating factors – see Risk Factors, above
    Pseudoporphyria
    • Presents with cutaneous findings of PCT but without biochemical markers
    • Seen in dialysis patients – monitor for underlying porphyria
    • Induced by multiple drugs
      • Nonsteroidal anti-inflammatory drug (NSAID) ingestion especially in patients who have connective tissue disease
      • Tetracycline-class antibiotics
      • Many others

Treatment

  • Acute porphyrias
    • Opiates and antiemetics plus phenothiazine
    • Careful management of fluid balance (acid hyponatremia)
    • IV hemin administration (intravenous glucose may be used initially in mild attacks)
    • Patients with recurrent attacks (10%) may benefit from prophylactic hematin administration
    • Treatment of porphyria may induce irreversible neuropathy
    Nonacute porphyrias
    • Limit sun exposure
    • Discontinue exposure to potential and known inciting factors, especially drugs (including estrogens and progestogens) and alcohol
    • If no hemochromatosis is present, low-dose chloroquine is helpful
      • Phlebotomy used when hemochromatosis is present
    • Avoid trauma
    • PCT
      • Therapeutic phlebotomy
      • Low-dose chloroquine
    • Rare disorders
      • CEP
        • Blood transfusion
        • Allogenic bone marrow transplantation
        • Stem cell transplantation
      • EPP
        • Beta-carotene (nonsmokers only)
        • Bone marrow transplantation
    Pseudoporphyria
    • Discontinue use of precipitating drugs
    • Avoid ultraviolet light exposure, especially UV-A

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Porphobilinogen (PBG), Urine 0080260
Method: Quantitative Ion Exchange Chromatography/Spectrophotometry

Essential first-line test during suspected attack of acute porphyria

Use in determining metabolic response to IV hematin

May use random sample

24-hour specimen is more sensitive

If result is negative but high clinical suspicion exists, repeat when symptoms are present

Porphyrins, Fractionation and Quantitation, Urine 2002058
Method: Quantitative High Performance Liquid Chromatography
Evaluate cutaneous photosensitivity to exclude or include PCT, CEP

24-hour specimen is more sensitive

Urine coproporphyrin is elevated in many common disorders

If test is negative but high clinical suspicion still exists, repeat when symptoms are present 
Porphyrins and Porphobilinogen (PBG), Urine 2002181
Method: High Performance Liquid Chromatography/Ion Exchange Chromatography/Quantitative Spectrophotometry

Evaluate patients with suspected porphyria presenting with neurologic/psychiatric, abdominal, and/or cutaneous symptoms

24-hour specimen is more sensitive

 
Porphyrins, Fecal 0099824
Method: Quantitative High Performance Liquid Chromatography
Distinguish among AIP, VP, HCP

Bacterial modification of fecal porphyrins is extensive

Meat in diet may influence test results

 
Porphyrins, Total, Plasma or Serum 0080429
Method: Quantitative Fluorometry

Monitor PCT

Confirm VP and EPP

Does not identify specific porphyrin

 
Porphobilinogen (PBG) Deaminase, Erythrocyte 0099550
Method: Quantitative Enzymatic/Fluorometry
Useful in family studies to determine which members are most at risk for AIP

Not recommended for diagnosis of an individual patient

Best performed in association with a specimen from an unaffected family member

 
Erythrocyte Porphyrin (EP), Whole Blood 0020610
Method: Fluorometry

Screen for EPP

Also elevated in early and late iron deficiency, anemia of chronic disease, and chronic lead poisoning

If lead poisoning suspected, order whole blood lead testing

Aminolevulinic Acid (ALA), Urine 0080103
Method: Quantitative Ion Exchange Chromatography/Spectrophotometry

Evaluate suspected ADP or other acute porphyria, lead poisoning, or hereditary tyrosinemia

24-hour specimen is more sensitive

If lead poisoning suspected, order whole blood lead testing

Aminolevulinic Acid Dehydratase (ALAD), Blood  2011012
Method: Quantitative Enzymatic/Spectrofluorometry

Confirm a diagnosis of ALAD (aminolevulinic acid dehydratase), a very rare form of porphyria

   
Cutaneous Direct Immunofluorescence, Biopsy 0092572
Method: Direct Immunofluorescence
(Direct Fluorescent Antibody Stain)

Biopsy of skin for unusual cutaneous presentations

Characteristic pattern of staining but not specific

 
Epithelial Skin Antibody 0090299
Method: Indirect Immunofluorescence
(Indirect Fluorescent Antibody)

Serum testing for epithelial antibodies

Negative in porphyria and pseudoporphyria; positive in immunobullous diseases

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
Porphyrins, Total with Reflex to Porphyrins Fractionation, Plasma 2006593
Method: Qualitative Extraction/Scanning Spectrofluorometry/Quantitative High Performance Liquid Chromatography