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Porphyria: a Difficult Disease to Diagnose by Marelda Abney RN

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Porphyria: a Difficult Disease to Diagnose by Marelda Abney RN 1 Porphyria: A difficult disease to diagnose By Marelda Abney RN, BSN A Manuscript submitted in partial fulfillment ofthe requirement for the degree Master ofNursing Washington State University Intercollegiate College ofNursing Spokane, Washington July 2003 11 To the faculty ofWashington State University: The members ofthe committee appointed to examine the Intercollegiate College of Nursing research requirements and manuscript of MARELDA MARY ABNEY fmd it satisfactory and recommend that it be accepted. ,~~ 5ctl(.~~v~ Lorna Schumann, PhD, FAANP, ARNP ~~ 2u J:~ AhJ5uv Billie Severtsen, PhD, RN _~-/A~-t~£0 Sheila Masteller, MN, BSN, RN 111 Acknowledgements I would like to thank everyone who has supported me in one way or another in completing my manuscript and fulfilling my dream ofbecoming a family nurse practitioner. My deepest gratitude goes out to those who served on my committee for my clinical project. Dr. Billie Severtsen, committee member, whom I fIrst met in my undergraduate program. She was an inspiration then as she is now, in the ways ofmedical ethics and compassionate care. I have been forttmate to have had her be a part ofmy education from the beginning ofmy career through to the end ofthis project. Sheila Masteller, committee nlember and role model. I have been privileged to work with Sheila at Visiting Nurses Association where she is president and an exemplary leader in home health care. Her concern for the welfare ofpatients and staffhas made her the ideal example of leadership. Lorna Schumann, committee member and mentor. Lorna has always been there for me as I struggled down this path. She has listened when I just needed to talk which is a priceless gift. She is the ideal ofwhat a mentor and practitioner should be and I have been fortunate to have had her guidance and support. Finally, I would like to thank my husband, Michael and our four children, Adam, Derrick, Cassandra and Chandra. My family has been both understanding and supportive ofthis educational experience. They have been there to share in my laughter and my tears and they have sacrificed so much for my dreams and goals. I could not have done it without their constant love and support. IV Abstract Porphyria: A difficult disease to diagnose By Marelda Abney Washington State University Chair: Dr. Lorna Schumann Porphyria describes a group ofdisorders in which there is an inborn error ofheme metabolism. The error is deficient or defective enzymes needed in the production of heme. There are at least seven different know types ofporphyria based upon which enzyme is affected. Essentially, the person who is suffering with porphyria has a build up ofenzymatic particles, called porphyrins, due to the defective pathway (Thadani, Deacon & Peters, 2000). All ofthe porphyrias are rare, some more than others. They are mainly an inherited, but may be acquired (Rich, 1999). Because oftheir rarity, clinicians often forget to include them in their differential diagnosis (Crimslick, 1997). The clinical manifestations ofporphyria are easily misinterpreted for other illnesses. There is no cure for porphyria, but early diagnosis and treatment can reduce the number ofhospital admissions and potential for death and disfigurement (http://www.cpf-inc.ca/guide.htm). Most treatment usually consists ofavoidance of triggers factors such as alcohol, specific drugs, and sunlight. In acute porphyrias the use ofphlebotomy or administration ofheme can be used. (Thadani et aI., 2000). v Table of Contents TIt· Ie Page 1 · Signature Page ii Acknowledgements iii Abstract iv Table ofContents v List ofTables vii · f· ... LIst 0 FIgures V111 Introduction 1 Manifestation Theories 2 Definitions and Pathogenesis 4 Etiology and Epidemiology 6 Clinical Features in Diagnosis 10 The Acute Porphyrias 11 The Non-acute Porphyrias 14 Laboratory Testing 17 Differential Diagnosis 18 Treatment 20 Conclusion 23 Table 1 25 Table 2 26 Table 3 27 Table 4 28 VI Figure 1 29 Figure 2 30 Figure 3 31 Figure 4 32 Figure 5 33 Figure 6 34 Figure 7 35 References 36 VII List of Tables Table 1 Porphyria Synonyms 25 Table 2 Classifications ofPorphyria 26 Table 3 Laboratory Testing 27 Table 4 Drug Safety 28 VIII List of Figures Figure 1 Heme Biosynthesis 29 Figure 2 Liver Cirrhosis as seen by CT 30 Figure 3 Fatty Liver as seen by CT 31 Figure 4 Hepatocellular Carcinoma caused from uncontrolled Porphyria 32 Figure 5 Bullae ofthe Skin 33 Figure 6 Hand Scarring and Lichenification ofPCT 34 Figure 7 Algorithm 35 1 Porphyria: A difficult disease to diagnose Introduction Porphyria results from an inherited or acquired error in heme metabolism. There are eight known types ofporphyria namely congenital erythropoietic porphyria (CEP), hereditary coproporphyria (RCP), variegate porphyria (VP), erythropoietic protoporphyria (EPP), delta-amniolevulinic acid dehydratase (ALAD), acute intermediate porphyria (AlP), and porphyria cutanea tarda (PCT). PCT is further subdivided into I PCT, II PCT also known as hepatoerythropoietic porphyria (REP), and III PCT. Some name confusion exists depending on the literature reviewed and the country in which the literature is published (Table 1). Types ofporphyria are also categorized in many ways; by their clinical presentations; cutaneous or neurologic, or a mix ofboth, their functional site, hepatic or erythropoietic, or their type ofattack, acute or non-acute (Table 2). Classification in the United States (U.S.) is usually either acute or non acute depending on presenting symptoms (Desnick, 2001). Regardless ofhow porphyria is classified, the disease is caused by the accumulation ofthe by-products ofa disrupted metabolism. These by-products or enzymatic substrates are called porphyrins, hence the name porphyria. As the system ofheme synthesis is disrupted, an accumulation ofporphyrins or their precursors are deposited in different bodily tissues such as urine, bone, skin, liver and kidney. The buildup ofporphyrins causes the clinical picture seen in practice, such as severe abdominal pain, purple urine, 2 mental disturbances, skin disease or parathesias (Canadian Porphyria Foundation, n.d.). Porphyrins cause urine to look red or purple in sunlight due to fluorescent properties (Kamel, 1998). King George III ofEngland is thought to have had porphyria because he had "purple urine" and sporadic bouts of madness (Arnold, 1996). In general, all types ofporphyria are influenced by genetic function. Each individual gene influences several enzymes and each porphyrin is generally influenced by more than one gene (Canadian Porphyria Foundation, n.d). All ofthe porphyrias are rare and if averaged together the incidence is about 1: 100,000. These are the people who actually manifest the disease. Some forms ofporphyria are recessive and some forms are dominant. People who have porphyria, but never express the disease are called "latent porphyries" (Crimslick, 1997). As many as 80% offamily members may be "latent", having the genetic predisposition, but not the disease (Crimslick, 1997). Porphyria is primarily inherited, but one form, porphyria cutanea tarda (PCT) can be acquired. Porphyria is also a disease ofpercentages, meaning that at least 50% ofan enzyme must be dysfunctional, before the disease will express itself Even then, porphyria is only expressed when the body is put under unusual stress. Manifestation Theories There have been many studies worldwide that have looked at the prevalence of porphyria. Ofgreatest concern and confusion are the acute porphyrias, as they are sporadic and often can be life threatening due to their neurological consequences. Because there is evidence that the number ofcases are growing, new research is attempting to answer why. 3 One popular theory for the increase ofporphyria, especially Porphyria Cutanea Tarda, is the increasing use ofdrugs, specifically those that use the cytochrome P450 (CYP450) system. The CYP450 system in the liver is critical in the production ofcertain cytochromes needed for cellular function. Drugs that induce the CYP450 system are the same drugs that increase the synthesis ofamniolevulinic acid dehydratase (ALA) (Adams, 2001). The increase in ALA synthesis causes the system to be overwhelmed and the porphyrin by-products to build up, which triggers the disease. The increase in ALA synthesis may be the trigger that exposes "latent porphyrics" and disease manifestation (Thadani, Deacon & Peters, 2000). The use ofcertain herbicides may also have an affect on heme biosynthesis in humans. Studies on mice at Charles University in Prague, Czech Republic, have shown that certain herbicides cause an oxidative reaction that inhibits protoporphyrinogen oxidase (Krijt, 1999). This inhibition disrupts heme biosynthesis and causes II PCT. Another theory focuses on the overproduction ofdelta-amniolevulinic acid dehydrase (ALAD) and porphobilinogen (PBO). These enzymes are released into the circulation and are taken up by the nervous system, causing the neurological symptoms seen with the acute porphyrias, such as mental disturbances and severe peripheral neuropathy (Krijt, 1999). Other studies are trying to fmd the reason for the seemingly unexplainable neurological symptoms associated with acute porphyrias. The hope is that answers regarding triggers and ways to prevent reoccurrences will be developed (Krijt, 1999). More research needs to be done to determine what environmental factors and drugs interfere with heme biosynthesis. 4 Definitions and Pathogenesis There are eight enzymatic pathways used to create one porphyrin molecule. Each pathway creates
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