Porphyria

Background

Heme synthesis with reactions occuring in the cytoplasm and some in the mitochondrion (yellow).

• Inherited and/or acquired disorders in which there are enzyme deficiencies involved in heme biosynthesis, resulting in build up of porphyrins (Porphobilinogen and δ-Aminolevulinic acid [ALA])
• Heme is a component of many essential hemoproteins, such as hemoglobin, myoglobin and cytochromes, including the cytochrome P450 enzymes
• Acute intermittent porphyria is most salient to EM
• The first enzyme in the heme production pathway is ALA synthase (ALAS), which controls the rate of heme synthesis in the liver. This enzyme is down-regulated by heme.
• The enzyme deficiencies in porphyria limit the capacity of the liver to increase heme synthesis.
• When drugs, hormones or other factors that induce ALAS and CYPs are given, ALA and porphobilinogen (PBG) are overproduced and accumulate, and a neurovisceral attack may develop

Triggers

• Infection, metabolic stress
• Carbohydrate deficiency
• Tobacco, ETOH
• Porphyrinogenic drugs: sulfonamides, barbiturates, rifampin or metoclopramide

Clinical Features

Urine on the first day (left) compared to urine after three days of sun exposure (right) showing the classic change in color to "port wine-color."

• Gastrointestinal symptoms
  • Acute abdominal pain (85-90% of attacks)
    • Nausea/vomiting
    • Constipation and/or diarrhea
• Port wine-colored urine
• Diffuse musculoskeletal pain
• Neurologic symptoms
  • Headache
  • Seizure
  • Sensory loss (40%)
    • An indication of a severe and potentially life-threatening attack
    • Neuropathy can progress to respiratory failure in hours or days
  • Bladder paresis
• Psychiatric symptoms
  • Increased risk of schizophrenia and bipolar disorder
  • Agitation, confusion, combativeness
  • Anxiety & depression (55%)

Differential Diagnosis

Diffuse Abdominal pain

• Abdominal aortic aneurysm
  • Aortocaval fistula
• Acute gastroenteritis
• Aortoenteric fisulta
• Appendicitis (early)
• Bowel obstruction
  • Large bowel obstruction
    • Ogilvie's syndrome
  • Small bowel obstruction
  • Malignant bowel obstruction
• Bowel perforation
• Diabetic ketoacidosis
• Gastroparesis
• Hernia
• Hypercalcemia
• Inflammatory bowel disease
• Mesenteric ischemia
  • Mesenteric vein thrombosis
• Pancreatitis
• Peritonitis
• Sickle cell crisis
• Spontaneous bacterial peritonitis
• Volvulus

Extra-abdominal Sources of Abdominal pain

• MI
• Aortic Dissection
• PNA
• PE
• Testicular Torsion
• Herpes Zoster
• Muscle spasm
• Spinal pathology
• Strep Pharyngitis (peds)
• Mononucleosis
• DKA
• ETOH Ketoacidosis
• Uremia
• Sickle Cell Crisis
• SLE
• Vasculitis
• Glaucoma
• Hyperthyroidism
• Methanol Poisoning
• Heavy Metal toxicity
• Addison's disease
• Porphyria
  • Acute intermittent porphyria
• Paroxysmal nocturnal hemoglobinuria
• Black widow spider bite

Evaluation

Consider porphyria in patients with abdominal pain that is unexplained after an initial workup has excluded common causes (appendicitis, cholecystitis, pancreatitis, etc).

• Spot urinary porphobilinogen (sendout at most hospitals)
  • Normal = 0-4mg/day
  • acute attack, spot urine can be 20-200mg/L
• Recurrent attacks in a patient with proven acute porphyria are usually similar and can be diagnosed on clinical grounds without biochemical reconfirmation.
• Hyponatremia has been documented in up to 60% of acute attacks & is attributed to elevated levels of antidiuretic hormone

Management

• Opioid analgesia
• Avoid/discontinue offending medications
  • Most seizure medications are contraindicated
  • Acceptable AEDs include: benzodiazepines, gabapentin, levetiracetam, and vigabatrin
  • Avoid Reglan
• Treat any electrolyte abnormalities
• Beta-blockers can be used to treat tachycardia

Decrease heme synthesis

• Glucose load
  • Decreases porphyrin production
  • E.g. D5NS at 2L/hr x 24h==
  • Avoid D5/D10W due to risk of hyponatremia given significant free water load
• Hemin (Panhematin®)
  • Decreases porphyrin production, significantly more potent than glucose
  • Recommended for most cases requiring hospitalization, or any with neurologic symptoms
  • 3-4mg/kg IV daily x 4 days
  • Can cause significant infusion site phlebitis - minimize by reconstituting in 25% albumin; consider central venous administration
  • Very expensive - around $8000 per 313mg vial

Disposition

• Admission to a monitored bed

See Also

• Abdominal pain
• Acute intermittent porphyria

External Links

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http://www.porphyriafoundation.com/

References

1. NR Pimstone, KE. Anderson, B Freilich. (n.d.). Emergency Room Guidelines for Acute Porphyria. American Porphyria Foundation. Retrieved January 11, 2016. From http://www.porphyriafoundation.com/for-healthcare-professionals/emergency-guidelines-for-acute-porphyria#Treatment.
2. Anderson KE, Bloomer, JR Bonkovsky HL, Kushner JP, Pierach CA, Pimstone NR and Desnick RJ. Recommendations for the Diagnosis and Treatment of the Acute Porphyrias. Ann Intern Med 2005; 142:439-450
3. Deacon AC, Peters TJ, Identification of acute porphyria: evaluation of a commercial screening test for urinary porphobilinogen. Ann Clin Biochem. 1998;35:726-32