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Acute Porphyria Clinical Presentation

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

History

Recent provoking factors for acute porphyria include the following:

  • Alcohol ingestion
  • Infection
  • Surgical procedure
  • Known provoking drug (see Deterrence/Prevention)
  • Low-carbohydrate diet or fasting
  • Menstruation

Seizures that are difficult to control or that worsen with standard anticonvulsants drug administration

Pregnancy can precipitate hereditary coproporphyria (HCP) but not acute intermittent porphyria (AIP).[4]

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Physical

Vital signs

See the list below:

  • High blood pressure and tachycardia during acute attacks
  • Chronic changes (eg, sustained hypertension in 20% of patients)

GI symptoms

See the list below:

  • Abdominal pain
  • Nausea, vomiting
  • Partial ileus with accompanying severe nonfocal abdominal pain
  • Absent peritoneal signs

Neurologic symptoms

Autonomic neuropathy symptoms include the following[5] :

  • Unstable vital signs
  • Excessive sweating
  • Dysuria and bladder dysfunction
  • Fever
  • Restlessness
  • Tremor
  • Catecholamine hypersecretion

Peripheral neuropathy symptoms include the following:

  • Guillain-Barré–like syndrome after prolonged and severe episodes
  • Focal, asymmetric, or symmetric weakness beginning proximally and spreading distally with foot or wrist drop
  • Focal, patchy mild-to-severe paresthesias, numbness, and dysesthesias
  • Tetraplegia (reported in cases of hereditary coproporphyria [HCP])
  • Respiratory paralysis (rare but can occur)

Cranial nerve symptoms include the following:

  • Motor nerve palsies (particularly cranial nerves VII and X)
  • Optic nerve involvement (may lead to blindness)

Seizures symptoms include the following:

  • Seizures are most common during acute attacks.
  • Tonic-clonic (more common) and/or partial (less common) seizures with secondary generalization are most common.
  • The lifetime prevalence of seizures is 4%.
  • The risk of seizure during an acute episode is 5%.

Cortical symptoms are as follows:

  • Encephalopathy
  • Aphasia
  • Apraxia
  • Cortical blindness

Psychiatric symptoms

Acute symptoms include the following:

  • Anxiety
  • Agitation
  • Confusion
  • Depression
  • Hallucinations
  • Insomnia
  • Paranoia
  • Violent behavior

Chronic symptoms include the following:

  • Depression
  • Anxiety

A study by Cederlöf et al indicated that the risk of schizophrenia or bipolar disorder is fourfold higher in persons with acute intermittent porphyria and is twofold higher in first-degree relatives of these individuals. The study included 717 individuals with the disease.[6]

Other symptoms

See the list below:

  • Muscular symptoms ( rhabdomyolysis)
  • Urine changes (may turn red or dark when exposed to light)
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Causes

Porphyria is considered a genetic disorder. Phenotypic expression of the genetic defect is highly variable and appears to be more common in familial cases than in others (see Table 1).[7]

A 50% deficit in aminolevulinic acid dehydratase (ALAD) activity occurs in as many as 2% of the general population, although ALAD deficiency requires more than 90% inhibition of this enzyme. The low incidence of homozygous patients, given the relatively high prevalence of the heterozygous enzyme deficit, suggests that the homozygous deficit may result in death in utero.

Both the tissue and erythropoietic isoforms of porphobilinogen (PBG) deaminase are produced from the same gene by means of alternative splicing controlled by separate promoters. More than 100 mutations have been identified. Specific mutations are conserved within families, allowing for the screening of family members when a patient's genetic defect is known. Clinical disease is associated with a 50% or greater reduction in enzyme function. PBG deaminase has 3 mutation patterns:

  • Type I is a single-base error resulting in an amino acid substitutions or truncated proteins.
  • Type II (the Finish mutation) is localized to the tissue isoform of the enzyme.
  • Type III is a deletion in 1 of 2 exons that produces a structurally abnormal protein.

Coproporphyrinogen oxidase is located in the intermembrane space of the mitochondria and loosely associated with the outer face of the inner mitochondrial membrane. A single promoter site appears to be differentially regulated to produce the erythroid and nonerythroid isoforms. Significant genetic heterogeneity accounts for the abnormal function of coproporphyrinogen oxidase in HCP, making routine genetic screening impossible. Heterozygous and homozygous individuals have a 50% and 90-98% reduction in enzyme activity, respectively.

Protoporphyrinogen oxidase is located on the outer face of the inner mitochondrial membrane. A 50% reduction in activity consistently occurs across all tissue tested in affected individuals. The R59W defect may account for 95% of affected individuals in South Africa, whereas mutations in others are heterogeneous. Homozygous and doubly heterozygous individuals typically develop severe photomutilation with brachydactyly, nystagmus, seizures, and sensory neuropathy without acute episodes. Mental retardation is common in this neonatal form of variegate porphyria (VP).

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Contributor Information and Disclosures
Author

Richard E Frye, MD, PhD Associate Professor, Department of Pediatrics, University of Arkansas for Medical Sciences

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

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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