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 zinc protoporphyrin whole blood testing 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 (see above) Pseudoporphyria, immunobullous disease, or connective tissue disease Consider other possibilities – skin biopsy for direct immunofluorescence and serum for indirect immunofluorescence, or connective tissue disease workup

  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 and PBG urine test (24-hour urine is optimal) Negative PBG and positive porphyrins* – PCT or CEP probable Pattern is convincing for PCT PBG negative for both PCT and CEP 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 whole blood testing for zinc protoporphyrin and erythrocyte porphyrin 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* CEP (see above)

  *Interpretation by medical expert necessary

Differential Diagnosis

• Neurological
  • Depression
  • Seizure disorder
• Abdominal
  • Acute surgical abdomen
  • Lead poisoning
• Cutaneous symptoms
  • Pemphigoid
  • Pemphigus
  • Pseudoporphyria
  • Stevens-Johnson syndrome/toxic epidermal necrolysis
  • Polymorphous light eruption
  • Lupus erythematosus or other connective tissue disease

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
  • Alcoholism
  • Hepatitis C
  • Hemochromatosis
  • Drugs (eg, estrogens, barbiturates, hexachlorobenzene)

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

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Porphyrins, Total with Reflex to Fractionation and Quantitation, Plasma 2006593 Method: Qualitative Extraction/Scanning Spectrofluorometry/Quantitative High Performance Liquid Chromatography

Diagnostic Algorithm

  Porphyrias Testing Algorithm