Further Outpatient Care

Patients on antimalarial medications are at risk for ophthalmological and central visual dysfunction, peripheral neuropathy, deafness, and blood dyscrasias. Periodic ophthalmologic examinations, including visual acuity and slitlamp, funduscopic, and visual field tests, should be performed. Periodically evaluate reflexes and muscular strength. Hearing should be periodically objectively tested. Periodically check CBC count.

Cholestyramine can cause vitamin K deficiency. All patients on long-term therapy should be examined for bleeding or bruising and should receive supplemental vitamin K.

Deterrence/Prevention

Many medications can induce or worsen porphyria, whereas others have not been associated with worsening porphyria. Furthermore, many medications have not been tested in patients with known porphyria. The list below is not exhaustive, and any medication used in a patient with porphyria should be researched.

An extensive list of safe drugs is available at the University of Queensland Porphyria Research Unit Web site. Medications likely to be safe for patients with porphyria include the following:

Acetaminophen
Adrenaline
Amitriptyline
Aspirin
Atropine
Bromides
Chloral hydrate
Chlordiazepoxide
Colchicine
Diazepam
Digoxin
Diphenhydramine
Ethylenediaminetetraacetic acid (EDTA)
Ether
Glucocorticoids
Guanethidine
Ibuprofen
Imipramine
Indomethacin
Insulin
Labetalol
Lithium
Methylphenidate
Naproxen
Narcotics
Neostigmine
Nitrous oxide
Penicillamine
Penicillin
Phenothiazines
Procaine
Propranolol
Succinylcholine
Tetracycline
Thyroxine
Tubocurarine

Many medications induce or worsen acute and cutaneous porphyria. Many of these medications are metabolized, at least to some extent, by the liver. Liver metabolism may induce the cytochrome P-450 enzymes that require heme, thus inducing heme production. Other medications sensitize the skin to solar damage. Only common medications are listed below, and any medication used in a patient known to have porphyria should be investigated. In addition, many medications have not been used for patients with porphyria, thus the potential for worsening porphyria is not known. The list below is a guide for determining if a medication could have triggered a porphyria reaction.

Patients should refrain from alcohol ingestion, estrogen use, and iron supplementation.

Medications that are potentially unsafe for use in patients with porphyria include the following:

Alfaxalone
Alkylating agents
Antipyrine
Arthrotec
Barbiturates
Busulfan
Butalbital
Carbamazepine
Carisoprodol
Chlordiazepoxide
Chloroquine
Clonidine
Danazol
Danocrine
Dapsone
Diclofenac
Ergot
Erythromycin
Erythropoietin
Estrogens
Ethchlorvynol
Fluroxene
Griseofulvin
Heavy metals
Hydralazine
Ketamine
Mafenide
Meprobamate
Methoxsalen
Methyldopa
Metoclopramide
Nitrazepam
Nortriptyline
Pargyline
Pentazocine
Phenazopyridine
Phenobarbital
Phenoxybenzamine
Phenylbutazone
Phenytoin
Plaquenil
Porfimer
Primidone
Progestins
Pyrazinamide
Ranitidine
Rifampin
Spironolactone
Succinimides
Sulfonamides
Sulfonylureas
Theophylline
Tolazamide
Tranylcypromine
Valproate
Voriconazole

Complications

Congenital erythropoietic porphyria (CEP) is associated with splenomegaly, hypersplenism, hemolytic anemia, and cholelithiasis.

Porphyria cutanea tarda (PCT) is associated with an increased incidence of hepatocellular carcinoma and cirrhosis.

Erythropoietic protoporphyria (EPP) is associated with cholelithiasis in a significant number of cases. Severe liver disease may develop as a result of periportal fibrosis and cirrhosis, leading to death in 20% of cases. Rapidly progressive liver failure associated with accelerating photosensitivity and cholestasis can occur and is accompanied by abdominal pain, splenomegaly, and hemolysis.

Prognosis

CEP is associated with a significantly decreased lifespan, whereas the other cutaneous porphyrias are associated with morbidity from the complications of skin lesions.

A literature review by Salameh et al indicated that in patients with PCT, relapse rates by 1-year follow-up are lower for those treated with phlebotomy (20%) than for patients who undergo high-dose or low-dose 4-aminoquinoline therapy (35-36%). The pooled relapse rate for phlebotomy was 5.1 per 100 person-years, compared with 8.6 and 17.1 per 100 person-years for high-dose and low-dose 4-aminoquinoline treatment, respectively.^[54]

Patient Education

The following web resources are useful for patient reference and education.

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Remenyik E, Lecha M, Badenas C, et al. Childhood-onset mild cutaneous porphyria with compound heterozygotic mutations in the uroporphyrinogen decarboxylase gene. Clin Exp Dermatol. 2008 Aug. 33(5):602-5. [QxMD MEDLINE Link].
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Barbieri L, Macrì A, Lupia Palmieri G, Aurizi C, Biolcati G. Association between porphyria cutanea tarda and beta-thalassemia major. Cell Mol Biol (Noisy-le-grand). 2009 Jul 1. 55(2):36-9. [QxMD MEDLINE Link].
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Van Tuyll Van Serooskerke AM, Schneider-Yin X, Schimmel RJ, Bladergroen RS, Poblete-Gutiérrez P, Barman J, et al. Identification of a recurrent mutation in the protoporphyrinogen oxidase gene in Swiss patients with variegate porphyria: clinical and genetic implications. Cell Mol Biol (Noisy-le-grand). 2009 Jul 1. 55(2):96-101. [QxMD MEDLINE Link].
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Frusciante V, Ferrari C, Totaro M, et al. Brain perfusion defects by SPET/CT and neurostat semi-quantitative analysis in two patients with congenital erythropoietic porphyria. Hell J Nucl Med. 2018 Jan-Apr. 21 (1):43-7. [QxMD MEDLINE Link]. [Full Text].
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Media Gallery

The heme production pathway. Heme production begins in the mitochondria, proceeds into the cytoplasm, and is then resumed in the mitochondria for the final steps. This figure outlines the enzymes and intermediates involved in the porphyrias. Enzymes names are presented in the boxes. Names of the intermediates are outside the boxes, between arrows. Multiple arrows leading to a box demonstrate that multiple intermediates are required as substrates for the enzyme to produce one product.

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Table 1. Frequency Varies with the Specific Porphyria

Type of Porphyria	Age of Onset	Incidence per 100,000 Population	Male-to-Female Ratio
CEP	Infancy to early childhood; rare in adults	300 cases total	1:1
PCT	Type I: Adulthood Type II (heterozygous mutations): Adulthood Type III (homozygous mutations): Childhood	United States: 4 United Kingdom: 0.05	1:1
HCP	Predominantly adulthood Youngest report was child aged 4 y	Japan: 1.5 Czech: 1.5 Israel: 0.7 Denmark: 0.05	1:20 1:4 2:1 1:1
VP	Heterozygous mutation: After puberty Homozygous mutation: Childhood (rare)	South Africa: 34	1:1
EPP	Infancy to childhood	0.02	1:1

Table 2. Causes by Type of Porphyria

Porphyria	Deficient Enzyme	Location	Inheritance	Chromosome Band
CEP	Uroporphyrinogen III synthase	Cytosol	Autosomal recessive (AR)	10q25.3-26.3
PCT	Uroporphyrinogen decarboxylase	Cytosol	Autosomal dominant (AD)	1p34
HEP	Uroporphyrinogen decarboxylase	Cytosol	AR	1p34
HCP	Coproporphyrinogen oxidase	Mitochondrial	AD	3q12
VP	Protoporphyrinogen oxidase	Mitochondrial	AD	1q22-23
EPP	Ferrochelatase	Mitochondrial	AD, AR	18q22

Table 3. Quantitative Fecal Porphyrins by Type of Porphyria

Porphyrin Type	CEP	PCT	HCP	VP	EPP
Uroporphyrin	Significantly increased	Increased	Within reference range	Within reference range	Within reference range
Coproporphyrin	Significantly increased	Increased	Significantly increased	Increased	Within reference range
Protoporphyrin	Within reference range	Within reference range	Increased	Significantly increased	Significantly increased

Table 4. Quantitative Urine Porphyrins

Porphyrin type	CEP and PCT	HCP and VP
5-Aminolevulinate	Within reference range	Significantly increased
PBG	Within reference range	Significantly increased
Uroporphyrin	Significantly increased	Increased
Coproporphyrin	Increased	Significantly increased

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Author

Richard E Frye, MD, PhD Professor of Child Health, University of Arizona College of Medicine at Phoenix; Chief of Neurodevelopmental Disorders, Director of Autism and Down Syndrome and Fragile X Programs, Division of Neurodevelopmental Disorders, Department of Neurology, Barrow Neurological Institute at Phoenix Children's Hospital

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

Disclosure: Nothing to disclose.

Coauthor(s)

Darius J Adams, MD Director, Personalized Genomic Medicine, Atlantic Health System; Director, Division of Genetics and Metabolism, Goryeb Children's Hospital

Disclosure: Nothing to disclose.

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

Hassan M Yaish, MD Medical Director, Intermountain Hemophilia and Thrombophilia Treatment Center; Professor of Pediatrics, University of Utah School of Medicine; Director of Hematology, Pediatric Hematologist/Oncologist, Department of Pediatrics, Primary Children's Medical Center

Hassan M Yaish, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Michigan State Medical Society, New York Academy of Sciences

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.

Acknowledgements

Vikramjit S Kanwar, MD, MBA, MRCP(UK), FAAP Associate Professor of Pediatric Hematology and Oncology, Department of Pediatrics, Albany Medical Center; Faculty, Alden March Bioethics Institute

Vikramjit S Kanwar, MD, MBA, MRCP(UK), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and Royal College of Physicians of the United Kingdom

Disclosure: Nothing to disclose.