Porphyria: Difference between revisions

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==Background==
==Background==
* Porphyrias are inherited and/or acquired disorders of in which there are enzyme deficiencies involved in heme biosynthesis.  
*Related to defect(s) in heme synthesis causing a buildup of porphyrins
* Heme is a component of many essential hemoproteins, such as hemoglobin, myoglobin and cytochromes, including the cytochrome P450 enzymes
*Autosomal dominant, but poor penetrance
* 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.  
*Inherited and/or acquired disorders of in which there are enzyme deficiencies involved in heme biosynthesis.  
* The enzyme deficiencies in porphyria limit the capacity of the liver to increase heme synthesis.  
*Heme is a component of many essential hemoproteins, such as hemoglobin, myoglobin and cytochromes, including the cytochrome [[P450]] enzymes
* 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  
*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.  
==Clinical Features==
*The enzyme deficiencies in porphyria limit the capacity of the liver to increase heme synthesis.  
*Potential clues to a diagnosis of porphyria include use of potentially porphyrinogenic drugs such as sulfonamides, barbiturates, rifampin or metoclopramide, and premenstrual symptoms in women.
*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


* Gastrointestinal symptoms: Acute abdominal pain occurs in about 85-90% of attacks and is neurologic in origin. It can be associated with nausea, vomiting, constipation and/or diarrhea.
===Triggers===
*Infection, metabolic stress
*Carbohydrate deficiency
*[[Tobacco]], [[ETOH]]
*Porphyrinogenic drugs: [[sulfonamides]], [[barbiturates]], [[rifampin]] or [[metoclopramide]]


* Neurologic symptoms: Diffuse MSK pain and headache are common. Objective sensory loss may be found in up to 40% of cases. Peripheral motor neuropathy is an indication of a severe and potentially life-threatening attack. Neuropathy can progress to respiratory failure in hours or days. Sudden death, presumably from cardiac arrhythmia may occur. Bladder paresis may cause dysuria and hesitancy. CNS effects include presentations with agitation, confusion, combativeness and other acute neuropsychiatric, as well as seizure/coma/death.
==Clinical Features==
*Gastrointestinal symptoms
**Acute [[abdominal pain]] (85-90% of attacks)
***[[Nausea/vomiting]]
***Constipation and/or diarrhea
*Neurologic symptoms
**Diffuse musculoskeletal pain  
**[[headache]]
**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
**Agitation, confusion, combativeness, seizure


==Differential Diagnosis==
==Differential Diagnosis==
* Consider porphyria in patients with abdominal pain that is unexplained after an initial workup has excluded common causes (appendicitis, cholecystitis, pancreatitis, etc).
{{Abdominal Pain DDX Diffuse}}
 
{{Extra-abdominal sources of abdominal pain DDX}}


==Diagnosis==
==Evaluation==
* Measuring urinary porphobilinogen is most important for diagnosis of acute porphyrias. Porphobilinogen (PBG) excretion is normally 0-4 mg/day, but In an acute attack, spot urine porphobilinogen (PBG) levels can be 20-200 mg/L.
''Consider porphyria in patients with abdominal pain that is unexplained after an initial workup has excluded common causes (appendicitis, cholecystitis, pancreatitis, etc).''
* Recurrent attacks in a patient with proven acute porphyria are usually similar and can be diagnosed on clinical grounds, and without biochemical reconfirmation.
*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.


==Management==
==Management==
*The most effective therapy for the acute attack is hemin (Panhematin®). This drug corrects the deficiency of regulatory heme in the liver and down-regulates ALA synthase. The standard hemin treatment course is 3-4 mg/kg by vein once daily for 4 days. If the diagnosis is confirmed, the first dose can be given in the ED.
*Opioid analgesia
* Glucose loading has a similar effect, but is much less potent and effective and should be used only for mild attacks.
*Avoid/discontinue offending medications
* Discontinue any inciting drugs
**Most seizure medications contraindicated: [[Benzodiazepines]], [[gabapentin]], [[levetiracetam]], and [[vigabatrin]] okay
* Treat any electrolyte abnormalities
**Avoid [[reglan]]
* Treat pain with narcotic analgesia and nausea with phenothiazines
*Treat any [[electrolyte abnormalities]]
* beta blockers can be used to treat tachycardia
*[[beta-blockers]] can be used to treat tachycardia
* Seizures should be treated with gabapentin, benzodiazepines and vigabatrin. Patients who have a seizure during an acute porphyria attack rarely need long term anticonvulsant therapy.
*Glucose load
**Decreases porphyrin production
**Typical protocol is D10W 3-4 liters daily x 4 days
**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==
==Disposition==
* Admission to a monitored bed
*Admission to a monitored bed


==See Also==
==See Also==
*[[Abdominal pain]]
*[[Acute intermittent porphyria]]


==External Links==
==External Links==
http://www.porphyriafoundation.com/


==References==
==References==
#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.
#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
#Deacon AC, Peters TJ, Identification of acute porphyria: evaluation of a commercial screening test for urinary porphobilinogen. Ann Clin Biochem. 1998;35:726-32
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[[Category:Heme/Onc]]

Revision as of 04:18, 5 April 2019

Background

  • Related to defect(s) in heme synthesis causing a buildup of porphyrins
  • Autosomal dominant, but poor penetrance
  • Inherited and/or acquired disorders of in which there are enzyme deficiencies involved in heme biosynthesis.
  • Heme is a component of many essential hemoproteins, such as hemoglobin, myoglobin and cytochromes, including the cytochrome P450 enzymes
  • 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

Clinical Features

  • Gastrointestinal symptoms
  • Neurologic symptoms
    • Diffuse musculoskeletal pain
    • headache
    • 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
    • Agitation, confusion, combativeness, seizure

Differential Diagnosis

Diffuse Abdominal pain

Extra-abdominal Sources of Abdominal pain

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.

Management

  • Opioid analgesia
  • Avoid/discontinue offending medications
  • Treat any electrolyte abnormalities
  • beta-blockers can be used to treat tachycardia
  • Glucose load
    • Decreases porphyrin production
    • Typical protocol is D10W 3-4 liters daily x 4 days
    • 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

External Links

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