Acute Porphyria Clinical Presentation

  • Author: Richard E Frye, MD, PhD; Chief Editor: Max J Coppes, MD, PhD, MBA   more...
 
Updated: Mar 12, 2012
 

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).

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Physical

Vital signs

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

GI symptoms

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

Neurologic symptoms

Autonomic neuropathy symptoms include the following[3] :

  • 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

Other symptoms

  • 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).[4]

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  Assistant Professor, Departments of Pediatrics and Neurology, University of Texas Medical School at Houston

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

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Sharada A Sarnaik, MBBS is a member of the following medical societies: American Association of Blood Banks, American Association of University Professors, American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, and Society for Pediatric Research

Disclosure: Nothing to disclose.

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; Assistant 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 Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society

Disclosure: Nothing to disclose.

Helen SI Chan, MBBS, FRCP(C), FAAP  Associate Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto Faculty of Medicine, Canada

Helen SI Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA  Senior Vice President, Center for Cancer and Blood Disorders, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University School of Medicine; Clinical Professor of Pediatrics, George Washington University School of Medicine and Health Sciences

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

Disclosure: Nothing to disclose.

References

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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 PorphyriaDeficient EnzymeLocationInheritance PatternBand
ALAD deficiencyALADCytosolAutosomal recessive9q34
AIPPBG deaminaseCytosolAutosomal dominant11q23
HCPCoproporphyrinogen oxidaseMitochondrialAutosomal dominant3q12
VPProtoporphyrinogen oxidaseMitochondrialAutosomal dominant1q22-23
Table 2. Frequencies of Porphyria
Type of PorphyriaAge of OnsetIncidenceMale-to-Female Ratio
ALAD deficiencyMostly adolescence to young adulthood, but variable (2-63 y)6 cases total6:0
AIPAfter puberty (third decade)General 0.01/1000



Sweden 1/1000



Finland 2/1000



France 0.3/1000



M>F
HCPPredominantly 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



VPHeterozygous mutation: after puberty (fourth decade) Homozygous mutation (rare): childhoodSouth Africa 0.34/10001:1
Table 3. Quantitative Urine Porphyrin Levels
LevelALAD DeficiencyAcute Intermittent Porphyria (AIP)Congenital Erythropoietic Porphyria (CEP) and Porphyria Cutanea Tarda (PCT)HCP and VP
ALASignificantly increasedSignificantly increasedNormalSignificantly increased
PBGIncreasedSignificantly increasedNormalSignificantly increased
UroporphyrinNormalIncreasedSignificantly increasedIncreased
CoproporphyrinSignificantly increasedIncreasedIncreasedSignificantly increased
Table 4. Quantitative Stool Porphyrin levels
LevelHCPVP
CoproporphyrinSignificantly increasedIncreased
ProtoporphyrinIncreasedSignificantly increased
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