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Acute Porphyria Treatment & Management

  • Author: Richard E Frye, MD, PhD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
 
Updated: Apr 07, 2016
 

Medical Care

Consider an appropriate period of first-line conservative therapy in patients with acute porphyria before administering heme for injection. The duration of conservative treatment depends on the patient's presenting condition and clinical course. Start a hematin infusion immediately if clinical deterioration is evident to prevent neuronal damage.

Conservative first-line therapy includes the following:

  • Remove potentially offending medications.
  • Administer intravenous (IV) fluid with a substantial carbohydrate supply (eg, dextrose 500 g/d).
  • Control pain with opiates.
  • Relieve nausea and vomiting with phenothiazines.

If conservative treatment proves unsatisfactory, administer an IV heme infusion for 3-14 days.

Hematin is the only heme compound currently approved for use in the United States. Heme arginate (Normosang) is a more stable heme compound and has a lower frequency of adverse effects. Although this compound has been used with success in Europe and South Africa, it has not been approved for use in the United States.[8]

Heme requires prompt administration for clinical benefit. Episodes of porphyria can cause irreversible neuronal damage. Heme therapy is intended to prevent an episode from reaching the critical stage of neuronal degeneration.

Fecal urobilinogen increases in proportion to the amount of hematin administered; this observation suggests an enterohepatic pathway as a route of elimination. Bilirubin metabolites are also excreted in the urine after hematin administration.

Urinary concentrations of porphyrins can be followed to monitor treatment efficacy. A decrease in aminolevulinic acid (ALA), uroporphyrinogen, porphobilinogen (PBG), and/or coproporphyrin values indicates successful treatment.

Strictly follow recommended dosing guidelines because asymptomatic reversible renal shutdown can occur when a greatly excessive dose of hematin is administered in a single infusion. However, recommended doses of hematin do not impair renal function.

Liver transplantation was effective in a case of severe acute intermittent porphyria (AIP). Studies of gene therapy in animal models to restore PBG activity are ongoing.

Several factors complicate the treatment of seizures in porphyria. The liver metabolizes most anticonvulsants are metabolized, at least to some extent, and most anticonvulsants induce the cytochrome P-450 enzyme system.

Acute seizure control includes the following:

  • Magnesium sulfate and diazepam are first-line drugs for acute seizure control.
  • Lorazepam is generally the first-line drug for status epilepticus and is safe to use in patients with porphyria.
  • Correct acute electrolyte abnormalities because seizures are commonly associated with such abnormalities.

Epilepsy control includes the following:

  • Gabapentin is not metabolized by the liver and is reportedly successful for long-term seizure control.
  • Diazepam per rectal is useful for outpatient control of prolonged seizures.

Correct electrolyte abnormalities. Hyponatremia can be corrected with an infusion of normal saline or half normal saline, depending on the level of volume depletion and hyponatremia. However, fluid restriction and diuretics may be needed if the patient exhibits signs of syndrome of inappropriate antidiuretic hormone secretion.

Autonomic outflow is managed by the administration of beta-blockers. Acute hypertension must be managed with appropriate emergency agents.

Psychiatric symptoms are typically controlled by administering phenothiazines (eg, chlorpromazine). These medications can also help relieve nausea.

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Consultations

An expert in porphyria should assist in the diagnosis and treatment of patients with acute and chronic cases, as the management of porphyria involves many disciplines. Such experts may be certified in metabolic diseases, gastroenterology, or hematology.

Consultation with a neurologist may be needed if seizures or neuropathy develop.

Consultation with a physical therapist may be needed if muscle weakness develops.

Consultation with a psychiatrist may be necessary for the management of short-term and/or long-term psychiatric issues.

Consultation with a specialist in reproductive medicine may be necessary for menses and birth control.

Consultation with a cardiologist may be needed if hypertension develops.

Consultation with an anesthesiologist is necessary before a patient is sedated for a minor procedure or surgery.[9]

Seek a consultation with an ophthalmologist if ocular manifestations arise.

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Diet

A high-carbohydrate diet can mitigate the disease. A low-carbohydrate diet is strictly forbidden.

The patient should maintain adequate fluid intake to ensure good clearance of porphyrins.

A low-salt, low-fat, and low-cholesterol diet may be prudent if hypertension develops.

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Activity

Instruct patients to avoid activities that put them at risk for dehydration, exhaustion, or carbohydrate depletion.

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Contributor Information and Disclosures
Author

Richard E Frye, MD, PhD Associate Professor of Pediatrics, University of Arkansas for Medical Sciences College of Medicine; Director of Autism Research, Child and Behavioral Neurologist, Arkansas Children's Hospital Research Institute

Richard E Frye, MD, PhD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, Child Neurology Society, International Neuropsychological Society

Disclosure: Nothing to disclose.

Coauthor(s)

Thomas G DeLoughery, MD Professor of Medicine, Pathology, and Pediatrics, Divisions of Hematology/Oncology and Laboratory Medicine, Associate Director, Department of Transfusion Medicine, Division of Clinical Pathology, Oregon Health and Science University School of Medicine

Thomas G DeLoughery, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American College of Physicians, American Society of Hematology, International Society on Thrombosis and Haemostasis, Wilderness Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

James L Harper, MD Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Associate Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center

James L Harper, MD is a member of the following medical societies: American Society of Pediatric Hematology/Oncology, American Federation for Clinical Research, Council on Medical Student Education in Pediatrics, Hemophilia and Thrombosis Research Society, American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology

Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA Executive Vice President, Chief Medical and Academic Officer, Renown Heath

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American College of Healthcare Executives, American Society of Pediatric Hematology/Oncology, Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Sharada A Sarnaik, MBBS Professor of Pediatrics, Wayne State University School of Medicine; Director, Sickle Cell Center, Associate Hematologist/Oncologist, Children's Hospital of Michigan

Sharada A Sarnaik, MBBS is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, Society for Pediatric Research, Children's Oncology Group, American Academy of Pediatrics, Midwest Society for Pediatric Research

Disclosure: Nothing to disclose.

References
  1. Billoo AG, Lone SW. A family with acute intermittent porphyria. J Coll Physicians Surg Pak. 2008 May. 18(5):316-8. [Medline].

  2. Ulbrichova D, Hrdinka M, Saudek V, Martasek P. Acute intermittent porphyria--impact of mutations found in the hydroxymethylbilane synthase gene on biochemical and enzymatic protein properties. FEBS J. 2009 Apr. 276(7):2106-15. [Medline].

  3. Besur S, Hou W, Schmeltzer P, Bonkovsky HL. Clinically important features of porphyrin and heme metabolism and the porphyrias. Metabolites. 2014 Nov 3. 4(4):977-1006. [Medline].

  4. Pandey U, Dixit VK. Acute intermittent porphyria in pregnancy: a case report and review of literature. J Indian Med Assoc. 2013 Dec. 111(12):850-1. [Medline].

  5. Kuo HC, Huang CC, Chu CC, Lee MJ, Chuang WL, Wu CL, et al. Neurological complications of acute intermittent porphyria. Eur Neurol. 2011. 66(5):247-52. [Medline].

  6. Cederlof M, Bergen SE, Larsson H, Landen M, Lichtenstein P. Acute intermittent porphyria: comorbidity and shared familial risks with schizophrenia and bipolar disorder in Sweden. Br J Psychiatry. 2015 Dec. 207 (6):556-7. [Medline].

  7. Anyaegbu E, Goodman M, Ahn SY, Thangarajh M, Wong M, Shinawi M. Acute Intermittent Porphyria: A Diagnostic Challenge. J Child Neurol. 2011 Dec 21. [Medline].

  8. Bonkovsky HL, Maddukuri VC, Yazici C, Anderson KE, Bissell DM, Bloomer JR, et al. Acute Porphyrias in the USA: Features of 108 Subjects from Porphyria Consortium. Am J Med. 2014 Jul 9. [Medline].

  9. Olutunmbi Y, Gurnaney HG, Galvez JA, Simpao AF. Ultrasound-guided regional anesthesia in a pediatric patient with acute intermittent porphyria: literature review and case report. Middle East J Anaesthesiol. 2014 Jun. 22(5):511-4. [Medline].

  10. [Guideline] Finnish Medical Society Duodecim. Viral hepatitis. In: EBM Guidelines. Evidence-Based Medicine [Internet]. Helsinki, Finland: Wiley Interscience. John Wiley & Sons; 2008 Mar 10. [Full Text].

  11. Aarsand AK, Petersen PH, Sandberg S. Estimation and application of biological variation of urinary delta-aminolevulinic acid and porphobilinogen in healthy individuals and in patients with acute intermittent porphyria. Clin Chem. 2006 Apr. 52(4):650-6. [Medline].

  12. Hift RJ, Meissner PN. An analysis of 112 acute porphyric attacks in Cape Town, South Africa: Evidence that acute intermittent porphyria and variegate porphyria differ in susceptibility and severity. Medicine (Baltimore). Jan 2005. 84(1):48-60. [Medline].

  13. Kauppinen R. Molecular diagnostics of acute intermittent porphyria. Expert Rev Mol Diagn. 2004 Mar. 4(2):243-9. [Medline].

  14. Kauppinen R. Porphyrias. Lancet. 2005 Jan 15-21. 365(9455):241-52. [Medline].

  15. Onuki J, Chen Y, Teixeira PC, et al. Mitochondrial and nuclear DNA damage induced by 5-aminolevulinic acid. Arch Biochem Biophys. 2004 Dec 15. 432(2):178-87. [Medline].

  16. Pandey U, Dixit VK. Acute intermittent porphyria in pregnancy: a case report and review of literature. J Indian Med Assoc. 2013 Dec. 111(12):850-1. [Medline].

  17. Schoenfeld N, Mamet R. Individualized workup: a new approach to the biochemical diagnosis of acute attacks of neuroporphyria. Physiol Res. 2006. 55 Suppl 2:S103-8. [Medline].

  18. Solis C, Martinez-Bermejo A, Naidich TP, et al. Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias. Arch Neurol. 2004 Nov. 61(11):1764-70. [Medline].

  19. Soonawalla ZF, Orug T, Badminton MN, et al. Liver transplantation as a cure for acute intermittent porphyria. Lancet. 2004 Feb 28. 363(9410):705-6. [Medline].

  20. von und zu Fraunberg M, Pischik E, Udd L, Kauppinen R. Clinical and biochemical characteristics and genotype-phenotype correlation in 143 Finnish and Russian patients with acute intermittent porphyria. Medicine (Baltimore). Jan 2005. 84(1):35-47. [Medline].

  21. Yamamori I, Asai M, Tanaka F, et al. Prevention of premenstrual exacerbation of hereditary coproporphyria by gonadotropin-releasing hormone analogue. Intern Med. Apr 1999. 38(4):365-8. [Medline].

 
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Heme production pathway. Heme production begins in the mitochondria, proceeds into the cytoplasm, and resumes in the mitochondria for the final steps. Figure outlines the enzymes and intermediates involved in the porphyrias. Names of enzymes are presented in the boxes; names of the intermediates, outside the boxes. Multiple arrows leading to a box demonstrate that multiple intermediates are required as substrates for the enzyme to produce 1 product.
Table 1. Known Chromosomal Location of Enzymes Involved in Porphyria and Inheritance Patterns
Type of Porphyria Deficient Enzyme Location Inheritance Pattern Band  
ALAD deficiency ALAD Cytosol Autosomal recessive 9q34  
AIP PBG deaminase Cytosol Autosomal dominant 11q23  
HCP Coproporphyrinogen oxidase Mitochondrial Autosomal dominant 3q12  
VP Protoporphyrinogen oxidase Mitochondrial Autosomal dominant 1q22-23  
Table 2. Frequencies of Porphyria
Type of Porphyria Age of Onset Incidence Male-to-Female Ratio
ALAD deficiency Mostly adolescence to young adulthood, but variable (2-63 y) 6 cases total 6:0
AIP After puberty (third decade) General 0.01/1000



Sweden 1/1000



Finland 2/1000



France 0.3/1000



M>F
HCP Predominantly adulthood (youngest patient aged 4 y) Japan 0.015/1000



Czech 0.015/1000



Israel 0.007/1000



Denmark 0.0005/1000



1:20



1:4



2:1



1:1



VP Heterozygous mutation: after puberty (fourth decade) Homozygous mutation (rare): childhood South Africa 0.34/1000 1:1
Table 3. Quantitative Urine Porphyrin Levels
Level ALAD Deficiency Acute Intermittent Porphyria (AIP) Congenital Erythropoietic Porphyria (CEP) and Porphyria Cutanea Tarda (PCT) HCP and VP
ALA Significantly increased Significantly increased Normal Significantly increased
PBG Increased Significantly increased Normal Significantly increased
Uroporphyrin Normal Increased Significantly increased Increased
Coproporphyrin Significantly increased Increased Increased Significantly increased
Table 4. Quantitative Stool Porphyrin levels
Level HCP VP
Coproporphyrin Significantly increased Increased
Protoporphyrin Increased Significantly increased
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