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Acute Porphyria Workup

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

Laboratory Studies

During acute episodes of porphyria, monitor electrolytes and serum osmolarity because hyponatremia and/or syndrome of inappropriate secretion of antidiuretic hormone can develop and cause seizures.

With the exception of aminolevulinic acid dehydratase (ALAD) deficiency, acute porphyrias can be diagnosed during acute episodes with 2 quick bedside tests to identify PBG. Both tests require porphobilinogen (PBG) levels 4 times the upper limit of normal. In either test, PBG reacts with para-dimethylaminobenzaldehyde (DMAB) to form a red compound. (Phenazopyridinium chloride, methyl red, and urosein may also turn the urine red under acidic conditions; these confounding factors can be excluded by testing a mixture of urine with hydrochloric acid. No simple tests are available to exclude compounds such as cascara sagrada, levomepromazine, methyldopa, antipyrine, phylloerythrinogen, indoles, and pyrrolic acids.)

Hoesch test is the simpler of the 2 tests and less prone to misinterpretation. For this test, mix 1-2 drops of urine with 1 mL of 6-mol/L hydrochloric acid (HCl) and 20 mg of DMAB. Immediate development of a cherry-red color at the top of the mixture indicates a positive result.

For the Watson-Schwartz test, mix 7.5 mL of a DMAB solution (10 mg/mL HCl) with 5 mL water. Mix 1 mL of the solution with 1 mL urine. Immediate formation of a red color suggests PBG excess. A positive result is confirmed by adding 2 mL saturated sodium acetate and then 3 mL chloroform to the positive mixture. After vigorous shaking, a red upper aqueous phase and a pink lower organic solution phase confirms a positive result.

Quantitative urine porphyrin levels vary. PBG levels vary approximately 20% when measured on a week-to-week basis and vary 25% when measured at a 10-week interval. This means that the probability that the 2-fold increase in PBG concentration is actually related to the patient's disease is 80%. Porphyrin levels are elevated during an episode; hereditary coproporphyria (HCP) and variegate porphyria (VP) have identical urine porphyrin profiles and can be differentiated by examining stool porphyrins.

Table 3. Quantitative Urine Porphyrin Levels (Open Table in a new window)

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

 

Comparing the relative increase in PBG levels during acute attacks with the asymptomatic period may be a more sensitive marker for acute neuroporphyria when compared with absolute PBG values. Patients with AIP, VP, or HCP have 2.3-50.5–fold increases in PBG levels during acute attacks.

ALAD deficiency can be diagnosed by detecting numerous fluorescent erythrocytes by microscopically examining the blood with a 100-W iodine-tungsten lamp.

Quantitative stool studies help differentiate between HCP and VP because these disorders have identical urine porphyrin profiles.

Table 4. Quantitative Stool Porphyrin levels (Open Table in a new window)

Level HCP VP
Coproporphyrin Significantly increased Increased
Protoporphyrin Increased Significantly increased

 

Despite their limitations, functional assays can help in diagnosing porphyria. ALAD and PBG enzymes are measured in erythrocytes. In ALAD deficiency, a functional deficiency of 25% or greater is diagnostic. This deficit is also detected in lead poisoning and in hereditary tyrosinemia. PBG deaminase is deficient in many patients with AIP; however, in 10% of patients with AIP, the enzyme defect is limited to the liver or housekeeping enzyme. Other assays (eg, test for coproporphyrinogen oxidase in lymphocytes) are available but unreliable.

Many genetic defects responsible for porphyria have been identified. In general, a large number of defects account for each porphyria. This finding limits the use of genetic testing to only 2 situations:

  • If a genetic defect is known in an individual, his or her family members can be screened.
  • Certain ethnic groups have a high prevalence of a particular mutation. For example, Dutch and Swedish Laplanders have a specific mutation in AIP, and many South African families have a specific mutation in VP.
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Imaging Studies

MRI may reveal selective disturbance on white matter tracts that become myelinated and develop postnatally.

Gray matter and white matter in the brainstem and cerebellum appear to be preserved.

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Other Tests

Electromyography and nerve conduction studies are nonspecific.

In patients with porphyrias, motor nerve conduction velocities are usually normal.

Partial antidromic block with significantly slowed conductance may be seen during asymptomatic periods in patients with VP or AIP.

Changes consistent with reinnervation may occur during the recovery of muscle weakness.

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Histologic Findings

Peripheral nervous system

Histology shows axonal degeneration and patchy demyelination of motor axons, particularly short motor axons, which innervate the proximal and bulbar muscles. Axons are thin and irregular, with vacuolization, degeneration, and cellular infiltration. Neuronal loss and chromatolysis of the anterior horn cells may be secondary to retrograde degeneration. Chromatolysis of cranial nerve nuclei, commonly the dorsal vagus nucleus and autonomic nervous system ganglia (eg, celiac ganglion), may be observed.

CNS

Histologic evaluation may show chromatolysis and vacuolization of neurons and selective involvement of oligodendrocytes. Other findings include focal perivascular demyelination, reactive gliosis, and localized changes in the supraoptic and paraventricular nuclei of the hypothalamus.

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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
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  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].

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  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].

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  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].

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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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