Tuesday, December 29, 2015

Healthwell Foundation Offers Financial Assistance To Acute Porphyria Patients

Healthwell Foundation Offers Financial Assistance To Acute Porphyria Patients

 Krista Zoset, President Healthwell Foundation
Krista Zodet, President
HealthWell Foundation

We are pleased to join forces with the American Porphyria Foundation to increase porphyria awareness and spread the word about resources available through the HealthWell Foundation for people living with porphyria. Since 2006, the HealthWell Foundation has provided copayment and premium assistance to eligible acute porphyria patients. Through our fully-automated grants process, patients are able to determine eligibility and apply online.  Patients also have the option to contact our hotline at 800-675-8416 to speak directly with a HealthWell representative. The HealthWell Foundation is an independent, 501(c)(3) charitable organization that provides financial assistance to insured individuals who struggle with high out-of-pocket medical expenses. You can learn more about the HealthWell Foundation by visiting us at www.HealthWellFoundation.org.

"Remember.....Research is the key to your cure!"

Sunday, December 27, 2015

Tracy Yelen ~ Research Experience with AIP

Tracy Yelen ~ Research Experience

Type of Porphyria: 
Acute Intermittent Porphyria (AIP)
"If you're at all interested in what they are doing to me in this Panhematin trial, I am happy to share. During the entire stay, the medical team accessed my port.  They drew all the blood they wanted without all the usual IV sticks, which is nice. Every morning after breakfast we did the infusions, which may or may not be a placebo.  Neither the nurses nor I were allowed to see what was pumping into me.  So I am blindfolded and there are sheets hung in the room to cover the medicine and tinfoil around the lines. It takes only a couple hours to complete.  I snoozed and chatted with the sweet nurse.  Outside of that, the dextrose fluids are flowing in through my port 24/7. Otherwise, it was pretty uneventful.  Why do I tell you this?  Basically, I want to remind you of how important it is to volunteer as a research patient if you ever get the opportunity. There are lots of trials that even perfectly well people can do for various different studies and various different medical reasons."
~Tracy Yelen, AIP

We need Acute Porphyria Research Volunteers for the Panhematin study.  Please call the APF to learn more 1-866-APF-3635

             "Remember....Research is the key to your cure!"

Thursday, December 24, 2015

We wish you a Merry Christmas, Happy Holidays and a Happy, Healthy New Year!

We wish you a Merry Christmas, Happy Holidays and a Happy, Healthy New Year!
It has been our pleasure to provide you and your families with the most up to date porphyria information available and to offer support for your needs.  We also have enjoyed meeting so many of you over the past thirty years and have been blessed by the lasting friendships we have cultivated.  We look forward to meeting many more of you and serving you in the future.
Please contact us if we can help in any way 713.266.9617!
Your friends at the American Porphyria Foundation.

"Remember....Research is the key to your cure!"

Friday, December 18, 2015

Who is the Scientific Advisory Board made up of?

Scientific Advisory Board

 Who is the Scientific Advisory Board made up of?  Please read the profiles of the Doctors.  Please get involved in Research so you can meet An APF expert or a PTF DR.  

Karl E. Anderson, MD, Chairman (profile)
University of Texas Medical Branch
D. Montgomery Bissell, MD (profile)
University of California
Joseph R. Bloomer, MD
University of Alabama
Sylvia S. Bottomley, MD
University of Oklahoma
Robert J. Desnick, PhD, MD (profile)
Mount Sinai School of Medicine
John H. Epstein, MD (profile)
University of California
Richard Galbraith, MD, PhD
University of Vermont
Micheline M. Mathews-Roth, MD (profile)
Harvard University School of Medicine
Claus A. Pierach, MD
University of Minnesota
Neville Pimstone, MD, PhD
University of California
Maureen B. Poh-Fitzpatrick, MD
University of Tennessee
Steven Shedlofsky, MD (profile)
University of Kentucky

Protect the Future
The following doctors and scientists are participants in the APF Protect the Future program to develop the next generation of porphyria experts. They work directly with members of the APF Scientific Advisory Board as part of a rigorous program of study, clinical and laboratory work, research and publishing. Read more about this pioneering project.
Manisha Balwani, MD
Mount Sinai Medical Center
Bradley Freilich, MD
Kansas City, MO
Charles Marques Lourenço, MD
University of São Paulo, Brazil
Tarun Narang, MD
Carolinas Medical Center
Manish Thapar, MD
University of Missouri
Jeffrey Wickliffe, PhD
Tulane University

Below is a list of some of the Porphyrias Research Consortium (PC) publications.  The PC includes Drs.  Karl Anderson, Montgomery Bissell, Joseph Bloomer, Herbert Bonkovsky, Robert Desnick, John Phillips. There are a number of other texts ready for publication.   All PC members are also members of the APF Scientific Advisory Board.  We hope as you read this list of publications, you will appreciate the depth of knowledge of our experts and their dedication to porphyria patients.  At a recent meeting, the experts said,  "Because our retirement is approaching, we must train as many future experts as possible lest our fifty years of expertise is lost."   

RDCRN Porphyrias Consortium Publication List

Peer Reviewed
1.    Gunn GB, Anderson KE, Patel AJ, Gallegos J, Hallberg C, Sood G, Hatch SS, Sanguineti, G: Severe radiation therapy-related soft tissue toxicity in a patient with porphyria cutanea tarda: case report and review of the literature. Head and Neck. 2010; 32:1112-7. PMID: 19536857; PMCID: PMC2891307
2.    Hou W, Tian Q, Zheng J, Bonkovsky HL. Zinc mesoporphyrin induces rapid proteasome-mediated degradation of hepatitis C non-structural 5A protein in human hepatoma cells. Gastroent. 2010; 138:1909-19. PMID: 19909748; PMCID: PMC2860067
3.    Jalil S; Grady JJ, Lee C, Anderson KE, Associations among behavior-related susceptibility factors in porphyria cutanea tarda.  Clin Gastroenterol Hepatol. 2010; 8:297-302. PMID: 19948245; PMCID: PMC2834813
4.    Bishop DF, Clavero S, Mohandas N, Desnick RJ.  Congenital erythropoietic porphyria: characterization of murine models of the severe common (C73R/C73R) and later-onset genotypes.  Mol Med. 2011; 17:748-56. PMID: 21365124; PMCID: PMC3146604
5.    Boynton TO, Gerdes S, Craven SH, Neidle EL, Phillips JD, Dailey HA. Discovery of a Gene Involved in a Third Bacterial Protoporphyrinogen Oxidase Activity through Comparative Genomic Analysis and Functional Complementation.  Appl Environ Microbiol. 2011;77:4795-801. PMID: 21642412; PMCID: PMC3147383
6.    Dailey HASepter ANDaugherty LThames DGerdes SStabb EVDunn AKDailey TAPhillips JD. The Escherichia coli Protein YfeX Functions as a Porphyrinogen Oxidase, Not a Heme Dechelatase. MBio. 2011; 8; 2. PMID: 22068980; PMCID: PMC3215433
7.    Hasanoglu A, Balwani M, Kasapkara CS, Ezgü FS, Okur I, Tümer L, Cakmak A, Nazarenko I, Yu C, Clavero S, Bishop DF, Desnick RJ.  Harderoporphyria due to homozygosity for coproporphyrinogen oxidase missense mutation H327R.  J Inherit Metab Dis. 2011; 34:225-31. PMID: 21103937; PMCID: PMC3091031
8.    Huang ZChen KXu TZhang JLi YLi WAgarwal AKClark AMPhillips JDPan X. Sampangine inhibits heme biosynthesis in both yeast and human. Eukaryot Cell. 2011; 10:1536-44. PMID: 21908598; PMCID: PMC3209050
9.    Hwang SI, Lee YY, Park JO, Norton HJ, Clemens E, Schrum LW, Bonkovsky HL.  Effects of a single dose of oral iron on hepcidin concentrations in human urine and serum analyzed by a robust LC-MS/MS method.  Clin Chim Acta. 2011; 412: 2241-2247. PMID:  21867695; PMCID: PMC3207492
10.  Lakner, A, Bonkovsky HL, Schrum L.  MiRNA’s:  fad or future of liver disease.  World J Gastroent. 2011;17: 2536-42. PMID: 21633658; PMCID: PMC3103811
11.  Li T, Bonkovsky HL, Guo J-T.  Structural analysis of heme proteins:  implications for design and prediction. BMC Struct Biol. 2011; 11:13. PMID: 21371326; PMCID: PMC3059290
12.  Lorenzo FR, Phillips JD, Nussenzveig R, Lingam B, Koul PA, Schrier SL, Prchal JT. Molecular Basis of Two Novel Mutation Found in Type I Methemoglobinemia. Blood Cells Mol Dis. 2011; 46:277-81. PMID: 21349748; PMCID: PMC3075332
13.  Phillips JD, Kushner JP, Bergonia HA, Franklin MR. Uroporphyria in the Cyp1a2-/- mouse.Blood Cells Mol Dis. 2011; 15:249-254. PMID: 21880518; PMCID: PMC3223295 
14.  Tian Q, Li T, Hou W, Zheng J, Schrum LW, Bonkovsky HL.  Lon peptidase 1 (LONP1)-dependent breakdown of mitochondrial 5-aminolevulinic acid synthase protein by heme in human liver cells.  J Biol Chem. 2011; 286:26424-30. PMID: 21659532; PMCID: PMC3143606
15.  To-Figueras J, Phillips JD, Gonzalez-López JM, Badenas C, Madrigal I, González-Romarís EM, Ramos C, Aguirre JM, Herrero C. Hepatoerythropoietic porphyria due to a novel mutation in the uroporphyrinogen decarboxylase gene. Br J Dermatol. 2011; 165:499-505. PMID: 21668429
16.  Troadec MB, Warner D, Wallace J, Thomas K, Spangrude GJ, Phillips J, Khalimonchuk O, Paw BH, Ward DM, Kaplan J. Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria. Blood. 2011; 117:5494-502. PMID: 21310927; PMCID: PMC3109720
17.  Wang Y, Langer NB, Shaw GC, Yang G, Li L, Kaplan J, Paw BH, and Bloomer JR:  Abnormal Mitoferrin-1 expression in patients with erythropoietic protoporphyria.  Exp Hematology. 2011; 39:784-794. PMID: 21627978; PMCID: PMC3143264
18.  Wickliffe JK, Abdel-Rahman SZ, Lee C, Kormos-Hallberg C, Sood G, Grady JJ, Desnick RJ, Anderson KE, CYP1A2*1F and GSTM1 alleles are associated with susceptibility to porphyria cutanea tarda. Mol Med. 2011; 17:241-247. PMID: 20957336; PMCID: PMC3060985
19.  Zhang J, Yasuda M, Desnick RJ, Balwani M, Bishop D, Yu C.  A LC-MS/MS method for the specific, sensitive, and simultaneous quantification of 5-aminolevulinic acid and porphobilinogen. J Chromatogr B Analyt Technol Biomed Life Sci. 2011; 879:2389-96. PMID: 21783436; PMCID: PMC3269068
20.  Caballes FR, Hossein S, Bonkovsky HL. Hepatitis C, porphyria cutanea tarda and liver iron: an update. Liver Int. 2012; 32:880-93. PMID: 22510500; PMCID: PMC3418709
21.  Bonkovsky HL. Risk factors for porphyria cutanea tarda—the iron/HFE connection. Liver Int. 2012; 33:162. PMID: 23121614
22.  Balwani M. Desnick R.J. The Porphyrias: Advances in Diagnosis and Treatment. Hematology Am Soc Hematol Educ Program. 2012; 2012:19-27. PMID: 23233556
23.  Balwani M. Desnick R.J. The Porphyrias: Advances in Diagnosis and Treatment. Blood. 2012; 120:4496-504. PMID: 22791288; PMCID: PMC3512229
24.  Singal AK, Kormos-Hallberg C, Lee C, Sadagoparamanujam VM, Grady JJ, Freeman DH, Anderson KE.  Low-dose hydroxychloroquine is as effective as phlebotomy in treatment of patients with porphyria cutanea tarda. Clin Gastroenterol Hepatol. 2012; 10:1402-9. PMID: 22985607; PMCID: PMC3501544
25.  Singal AK, Gou E, Albuerne M, Hallberg CK, Anderson KE. Relapse of PCT after achieving remission with phlebotomy or low dose hydroxychloroquine. Hepatology 2013; 58:299A
26.  Bonkovsky HL, Hou W, Steuerwald N, Tian Q, Parsons J, Hamilton A, Hwang S, Schrum L.  Heme status affects human hepatic messenger RNA and microRNA expression.  World J Gastroenterology 2013; 19: 1593-1601.  PMID 23538684; PMCID: PMC3602476
27.  Balwani M, Doheny D, Bishop DF, Nazarenko I, Yasuda M, Dailey HA, Anderson KE, Bissell DM, Bloomer J, Bonkovsky HL, Phillips JD, Liu L, Desnick RJ. Loss-of-Function Ferrochelatase and Gain-of-Function Erythroid 5-Aminolevulinate Synthase Mutations Causing Erythropoietic Protoporphyria and X-Linked Protoporphyria in North American Patients Reveal Novel Mutations and a High Prevalence of X-Linked Protoporphyria. Mol Med. 2013; 19:26-35. PMID: 23364466; PMCID: PMC3646094
28.  Bishop DF, Tchaikovskii V, Nazarenko I, Desnick RJ. Molecular Expression and Characterization of Erythroid-Specific 5-Aminolevulinate Synthase gain-of-function mutations causing X-Linked Protoporphyria. Mol Med. 2013; 19:18-25. PMID: 23348515; PMCID: PMC3592931
29.  Larion S, Caballes FR, Hwang S-I, Lee J-G, Rossman WE, Parsons J, Steuerwald N, Li T, Maddukuri V, Groseclose G, Finkielstein CV, Bonkovsky HL. Circadian rhythms in acute intermittent porphyria—a pilot study. Eur J Clin Invest. 2013; 43:727-39.  PMID: 23650938; PMCID PMC3687345
30.  Clavero, S., Ahuja, Y., Bishop, D.F., Giger, U., Kwait, B., Haskins, M.E., and Desnick, R.J.: Feline Porphyria: Two novel mutations causing acute intermittent porphyria. Molecular studies faciltate accurate diagnosis of erythrodontia. Vet. Med. 2013 Epub ahead of print PMID: 24239138 PMCID: PMC3963809
31.  Singal AK, Parker C, Bowden C, Thapar M, Liu L, McGuire BM. Liver transplantation in the management of porphyria. Hepatology. 2014. 60: 1082-89 PMID: 24700519
32.  Yasuda M, Gan L, Chen B, Kadirvel S, Yu C, Phillips JD, New MI, Liebow A, Fitzgerald K, Querbes W, Desnick RJ. RNAi-mediated silencing of hepatic Alas1 effectively prevents and treats the induced acute attacks in acute intermittent porphyria mice. PNAS. 2014 Epub ahead of print. PMID: 24821812
33.  Bonkovsky HL, Maddukuri VC, Yazici C, Anderson KE, Bissell DM, Bloomer JR, Phillips JD, Naik H, Peter I, Baillargeon G, Bossi K, Gandolfo L, Light C, Bishop D, Desnick RJ. Acute Porphyrias in the USA: Features of 108 Subjects from Porphyria Consortium. Am J Med. 2014. Epub ahead of print.PMID: 25016127
34.  Bissell DM, Lai JC, Meister RK, Blanc PD. Role of Delta-aminolevulinic Acid in the Symptoms of Acute Porphyria. Am J Med. 2014 Nov 8. Epub ahead of print PMID: 25446301
35.  Besur S, Hou W, Schmeltzer P, Bonkovsky HL.  Clinically important features of porphyrin and heme metabolism and the porphyrias.  Metabolites, 2014; 4:977-1006. PMID: 25372274
36.  Brancaleoni VBalwani MGranata FGraziadei GMissineo PFiorentino VFustinoni S,Cappellini MDNaik HDesnick RJPierro ED. X-chromosomal inactivation directly influences the phenotypic manifestation of X-linked Protoporphyria. Clin Genet. 2015. Epub ahead of print. PMID: 25615817

Chapters in Medical Textbooks
37.  Phillips, J.D., Kushner, J.P.  The porphyrias. In: Hematology of Infancy and Childhood, Saunders, 2008.
38.  Sood G, Anderson KE: Porphyrias. in Crowther MA, Ginsberg J, Schunemann H, Meyer RM, Lottenberg R (eds): Evidence-Based Hematology, Hoboken, Wiley, 2008. pp 229-237.
39.  Sood, G, Anderson KE: Porphyria Cutanea Tarda.  In: Best Practice, BMJ Publishing Group, 2008. 
40.  Anderson KE, Sood, G: Acute intermittent porphyria.  In: Best Practice, BMJ Publishing Group, 2008. 
41.  Phillips, J.D., Anderson, K.  Porphyria. In: A practical handbook to Williams Hematology, McGraw-Hill 2010, Chapter 57, pp 839-863.
42.  Phillips JD, Anderson KE.  The porphyrias (Chapter 57).  In: Kaushansky K, Lichtman MA, Beutler E, Kipps TJ, Seligson U, Prchal JT, eds.  Williams Hematology, 8th edition.  New York: McGraw-Hill 2010: 839-863. 
43.  Anderson KE, Lee C, Balwani M, Desnick RJ.  The porphyrias (Chapter 85).  In: Kliegman RM, Stanton BMD, St. Geme J, Schor N, Behrman RE, eds. Nelson Textbook of Pediatrics, 19th edition. Philadelphia: Elsevier, 2011, pp 517e1-e17. 
44.  Anderson KE. The porphyrias (Chapter 217). In: L. Goldman and A.I. Schafer, eds. Goldman’s Cecil Medicine, 24th edition, Philadelphia, Elsevier Saunders 2012:1363-71. 
45.  Lourenco, CM, Lee, C, Anderson KE. Disorders of heme biosynthesis (Chapter 37). In: Saudubray J-M, Van den Berghe G, Walter, JH, eds. Inborn Metabolic Diseases: Diagnosis and Treatment. 5th edition. Berlin:Springer-Verlag; 2012: 519-532. 
46.  Phillips, J.D.  Side chain modification during heme biosynthesis. In: Handbook of Porphyrin Sciences, Academic Press 2012, Vol. 19, Chapter 91, pp 283-337. 
47.  Bonkovsky HL, Hou W, Guo J-T, Narang T, Thapar M. Porphyrin and heme metabolism and the porphyrias. In Wolkoff A, Lu S, and Omary B (Eds). Comprehensive Physiology, 3:1-37, 2013. PMID: 23720291
48.  Gou E, Anderson KE. The Porphyrias.  In: Hamblin MR, Huang YY, eds. Handbook of Photomedicine. Philadelphia, CRC Press, Taylor and Francis, 2014: 123-132.
49.  Besur S, Bonkovsky HL. The porphyrias. Encyclopedia of Life Sciences, John Wiley and Co, London, UK, 2014.
50.  Bissell DM. The porphyrias. In Rosenberg RN, Pascual JM, eds. Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease, 5th Edition. Academic Press, Chapter 66, pp 725-43. 2014.
51.  Desnick RJ, Balwani MB, Anderson KE. Heme Biosynthesis and the Porphyrias. In: Liver Diseases in Children, Fourth Ed., Suchy FJ, Sokol RJ, Balistreri WF, eds., Cambridge University Press, 2014:509-525
52.  Anderson KE. Clinical and Laboratory Diagnosis of the Porphyrias, In: Ferreira GC, Kadish KM, Smith K, Guilard R eds. Handbook of Porphyrin Science. Hackensack, World Scientific Publishing Co., 2013: 370-415
53.  Anderson KE. Porphyrias – acute manifestations, In: Loriaux L, ed. Endocrine Emergencies. New York, Springer/Humana Press, Contemporary Endocrinology Vol. 74, 2014: 241-261.
54.  Singal AK, Phillips J. Porphyria cutanea tarda and related disorders. In: The Porphyrins Handbook. Eds. Kadish K, Smith K, Guilard R, Ferrira G, Elsevier Science, 2014; 29: 219-262

Online resources
55.  Anderson KE: Porphyria – an Overview.  In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2010
56.  Bloomer JR.  ALAD Porphyria.  National Organization for Rare Disorders (NORD) Database, Danbury, CT, 2010.
57.  Singal, AK, Anderson KE: Porphyria cutanea tarda and hepatoerythropoietic porphyria.  In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2010
58.  Singal, AK, Anderson KE: Variegate Porphyria.  In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2010
59.  Sood, G, Anderson KE: Etiology and pathogenesis of acute intermittent porphyria.  In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2010. 
60.  Sood, G, Anderson KE: Clinical manifestations and diagnosis of acute intermittent porphyria. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2010. 
61.  Sood, G, Anderson KE: Management of acute intermittent porphyria.  In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2010. 
62.  Bloomer JR: Managing acute porphyrias: practice considerations in inpatient and outpatient settings. Medscape Education Gastroenterology, 2010.
63.  Mittal, S, Anderson KE: Erythropoietic protoporphyria.  In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2011.
64.  Balwani M, Bloomer J, Desnick RJ. Porphyrias Consortium of the RDCRN. Erythropoietic Protoporphyria, Autosomal Recessive. Gene Reviews, 2012. Updated October 2014 PMID 23016163
65.  Bissell M, Wang B, Cimino T, Lai J. Porphyrias Consortium of the RDCRN. Hereditary Coproporphyria. Gene Reviews, 2012. PMID 23236641
66.  Anderson KE: Congenital erythropoietic porphyria.  In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2013
67.  Anderson KE: ALA dehydratase porphyria.  In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA, 2013. 
68.  Anderson KE: Porphyria, variegate.  National Organization for Rare Disorders (NORD) Rare Disease Database, Danbury, CT, 2010, updated 2013.
69.  Balwani M, Bloomer J, Desnick RJ. Porphyrias Consortium of the RDCRN. X-Linked Protoporphyria. Gene Reviews, 2013. PMID 23409301
70.  Liu L, Phillips J, Bonkovsky HL. Porphyrias Consortium of the RDCRN. Porphyria Cutanea Tarda, Type II. Gene Reviews, 2013. PMID 23741761
71.  Liu L, Phillips J, Bonkovsky HL. Porphyrias Consortium of the RDCRN. Hepatoerythropoietic Porphyria. Gene Reviews, 2013. PMID 24175354
72.  Singal AK, Anderson KE: Porphyrias Consortium of the RDCRN. Variegate Porphyria. Gene Reviews, 2013. PMID 23409300
73.  Erwin A, Balwani M, Desnick RJ: Porphyrias Consortium of the RDCRN. Congenital Erythropoietic Porphyria. Gene Reviews, 2013. PMID 24027798

Presented Abstracts
74.  Bishop DF, Tchaikovskii V, Nazarenko I, Balwani M, Doheny D, Desnick RJ.  Expression and characterization of the ALAS2 carboxy-terminal gain-of-function mutations causing X-linked Protoporphyria. Presented at the 12th International Congress of Human Genetics/The American Society of Human Genetics 61st Annual Meeting, Montreal, Canada, October 14, 2011.
75.  Doheny D., Nazarenko I., Balwani M., Liu L., Naik H., Anderson K., Bissell D.M., Bloomer J., Bonkovsky H., Kushner J., Phillips J., Bishop D., Desnick R.J.  Erythropoietic Protoporphyrias:  Frequency of Mutations in the Ferrochelatase Gene Causing Autosomal Recessive Erythropoietic Protoporphyria and Mutations in the 5’-Aminolevulinate Synthase 2 Gene Causing X-Linked Protoporphyria. Presented at the 12th International Congress of Human Genetics/The American Society of Human Genetics 61st Annual Meeting, Montreal, Canada, October 13, 2011.
76.  Hou W, Tian Q, Lu QL, Schrum WL, Bonkovsky HL. Zinc protoporphyrin, a novel endogenous HCV NS3-4A protease inhibitor, displays anti-viral activity.  Presented at the 62ndAnnual Meeting of AASLD, San Francisco, CA, November 4-8, 2011.
77.  Tian Q, Hou W, Steuerwald NM, Schrum WL, Bonkovsky HL. Heme markedly up-regulates RNA-binding motif protein 24 gene expression in human hepatocytes.  Presented at the 62ndAnnual Meeting of AASLD, San Francisco, CA, November 4-8, 2011.
78.  Tian Q, Hou W, Zheng J, Schrum WL, Bonkovsky HL. LONP1-dependent breakdown of mitochondrial 5-aminolevulinicacid synthase protein by heme in human liver cells.  Presented at the 62nd Annual Meeting of AASLD, San Francisco, CA, November 4-8, 2011.
79.  Hwang S-I, Lee Y-Y, Park J-O, Norton HJ, Clemens E, Schrum LW, Bonkovsky HL.  The measurement of hepcidin from human urine and serum to study effects of a single dose of oral iron by an optimized LC-MS/MS method. Presented at the 62nd Annual Meeting of AASLD, San Francisco, CA, November 4-8, 2011.
80.  Singh, A, Pierson, K, Wilkinson, G, Anderson, K. Porphyrias: Prevalence and Frequency of Testing in a National Health Care Database. Presented at the 63rd Annual Meeting of AASLD, Boston, MA, November 9-13, 2012.
81.  Ludtke A, Yasuda M, Lin G, Clavero S, Nazarenko I, Jungmin K, Doheny D, Balwani M, Desnick RJ. Acute Intermittent Porphyria: Identification of 23 Novel Hydroxymethylbilane Synthase Mutations and Functional Characterization of Six Novel Missense Mutations. Presented at the ACMG Annual Clinical Genetics Meeting, Phoenix, AZ, March 19-23, 2013.
82.  Balwani M, Bishop DF, Nazarenko I, Yasuda M, Doheny D, Dailey HA, Liu L, Anderson KE, Bissell DM, Bloomer JR, Bonkovsky HL, Phillips JD, Desnick RJ. Mutation analysis of 155 North American Patients with Erythropoietic Protoporphyria reveals novel Ferrochelatase Mutations and a high prevalence of X-Linked Protoporphyria due to previous and novel 5-Aminolevulinate Synthase 2 mutations.  Presented at the Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias, Lucerne, Switzerland, May 16-18, 2013.
83.  Balwani M, Naik H, Peter I, Anderson KE, Bissell DM, Bloomer JR, Bonkovsky HL, Phillips JD, Desnick RJ. Erythropoietic Protoporphyria and X-Linked Protoporphyria in the United States: Results from the Longitudinal Study of the NIH/RDCRN Porphyrias Consortium. Presented at the Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias, Lucerne, Switzerland, May 16-18, 2013.
84.  Bishop DF, Tchaikovskii V, Nazarenko I, Desnick RJ. Molecular Expression and Characterization of Erythroid-Specific 5-Aminolevulinate Synthase Gain-of-Function Mutations Causing X-Linked Protoporphyria. Presented at the Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias, Lucerne, Switzerland, May 16-18, 2013.
85.  Gou EW, Singh A, Pierson KS, Wilkinson GS, Anderson KE. Frequency of Porphyria Testing in a National Health Care Database. Presented at the Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias, Lucerne, Switzerland, May 16-18, 2013.
86.  Larion S, Caballes FR, Hwang S-I, Lee J-G, Rossman WE, Parsons J, Steuerwald N, Li T, Maddukuri V, Yazici C, Groseclose G, Finkielstein CV, Bonkovsky HL.  Circadian rhythms in acute intermittent porphyria—a pilot study. Presented at the Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias, Lucerne, Switzerland, May 16-18, 2013.
87.  Mittal S, Yasuda M, Desnick RJ, Anderson KE. Metabolic Analysis in Transgenic Mouse Models of Acute Intermittent Porphyria (AIP). Presented at the Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias, Lucerne, Switzerland, May 16-18, 2013.
88.  Naik H, Balwani M, Doheny D, Liu L, Desnick RJ. Experience with a Pilot Skype Internet Support Group for Symptomatic Patients with Acute Intermittent Porphyria. Presented at the Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias, Lucerne, Switzerland, May 16-18, 2013.
89.  Ludtke A, Yasuda M, Gan L, Clavero-Villarrub S, Nazarenko I, Kim J, Doheny D, Balwani M, Desnick RJ. Acute Intermittent Porphyria: Identification of 19 Novel Hydroxymethylbilane Synthase Mutations and Functional Characterization of Four Novel Missense Mutations. Presented at the Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias, Lucerne, Switzerland, May 16-18, 2013.
90.  Maddukuri VC, Yazici C, Anderson KE, Bissell DM, Bloomer JR, Desnick RJ, Phillips JD, Naik H, Gandolfo L, Light C, Bonkovsky HL.  Acute intermittent porphyria [AIP] in the United States:  features of the first 82 cases enrolled in the longitudinal study of the porphyria consortium [PC].  Presented at the Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias, Lucerne, Switzerland, May 16-18, 2013.
91.  Phillips JD, Warby C, Bergonia H, Marcero J, Parker C, Franklin M. Porphyria studies in Cyp1A2-/- and wild type mice suggest that heme regulation of ALA-synthase transcription and mitochondrial membrane translocation can be separated based on heme supply-and-demand. Presented at the Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias, Lucerne, Switzerland, May 16-18, 2013.
92.  Singal AK, Jampana SC, Kormos-Hallberg C, Anderson KE. Low-dose hydroxychloroquine to treat or prevent relapse of porphyria cutanea tarda during hepatitis C treatment. Presented at the Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias, Lucerne, Switzerland, May 16-18, 2013.
93.  Singal AK, Gou EW, Albuerne M, Kormos-Hallberg C, Anderson KE. Relapse of porphyria cutanea tarda after achieving remission with phlebotomy or low dose hydroxychloroquine. Presented at the Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias, Lucerne, Switzerland, May 16-18, 2013.
94.  Yazici C, Maddukuri VC, Anderson KE, Bissell DM, Bloomer JR, Desnick RJ, Phillips JD, Naik H, Gandolfo L, Light C, Bonkovsky HL.  Hereditary coproporphyria [HCP] and variegate porphyria [VP] in the United States:  Initial results from the longitudinal study of the porphyria consortium [PC].  Presented at the Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias, Lucerne, Switzerland, May 16-18, 2013.
95.  Wang B, Bissell DM, Lai J, Cimino T, Porphyrias Consortium. A Combined Clinical Index for the Diagnosis of Acute Porphyria. Presented at the Annual Assembly of the Swiss Society of Clinical Chemistry & International Congress of Porphyrins and Porphyrias, Lucerne, Switzerland, May 16-18, 2013.
96.  Ludtke A, Yasuda M, Balwani M, Liu L, Arvelakis A, Naik H, Clavero S, Bishop D, Phillips J, Ramanujam S, Anderson K, Yu C, Florman SS, Desnick RJ. First US Orthotopic Liver Transplant for Intractable Acute Intermittent Porphyria. Presented at The American Society of Human Genetics 63rd Annual Meeting, Boston, MA, October 22-26, 2013.
97.  Gou E , Weng C, Phillips JD, Balwani M, Bissell DM, Bloomer JR, Bonkovsky HL, Desnick RJ, Naik H, Anderson KE. Variability in erythrocyte and plasma porphyrin levels in erythropoietic protoporphyria and x-linked protoporphyria. Presented at the American College of Gastroenterology Annual Meeting, Philadelphia, PA, October 20-22, 2014.


Thursday, December 17, 2015

EPP Patient Letter Writing Campaign Update

EPP Patient Letter Writing Campaign Update

Dear EPP Family,
As you all know, we are collecting EPP patient experiences in letter-form so that we can take them collectively to the FDA to ask them for the accelerated approval of the drug Afamelanotide. To date we have collected 214 patient letters with a few more on the way.
Please take a minute to write a letter today. You can scan or/and send it to us by replying to this email. You can also fax it to us at 713.840.9552. Today is the very last chance to make a difference!
Your contributions to previous letter campaigns worked.  They convinced the FDA to approve Phase III of the drug trials in the USA, and our American letters helped convince the European Medicines Agency to grant approval of the drug in the European Union.  Now it is our turn to seek approval for Afamelanotide by the FDA in the USA!
If you have any questions, please reach out to the APF 713.266.9617.  Let's make this happen.  Patient advocacy works. THANK YOU FOR PARTICIPATING!

"Remember....Research is the key to your cure!"

Wednesday, December 16, 2015

Patient Education Meeting in Orlando Florida a huge success

Patient Education Meeting in Orlando Florida a huge success

The Patient Educational Meeting that we held last weekend in Orlando Florida in conjunction with the ASH convention, was a huge success. We had a great turn out there was standing room only! A special thank you to Dr’s Phillips, Parker and Silver, and the Recordati Company for coming to the meeting. The questions asked by the members were excellent, showing that the more you ask and the more you learn then the better equipped you are to care for yourself! We would like to thank the doctors who presented at the meeting as well as our long-term APF member Amy Chapman for helping us to organize it. Also, special thanks to everyone who attend with their families and friends.
Watch the APF E-news for the announcements about the upcoming meetings. Make sure your membership is up to date, so you receive all news.

Please get involved and take action now and sign up for research so that we can learn more and ultimately find a cure!  

“Research….is the key to your cure!”



Monday, December 14, 2015

An update of clinical management of acute intermittent porphyria

An update of clinical management of acute intermittent porphyria


Acute intermittent porphyria (AIP) is a rare inherited metabolic disease due to a deficiency of the hydroxymethylbilane synthase (HMBS) in heme biosynthesis. AIP manifests after the puberty with occasional neuropsychiatric crises associated with accumulation of porphyrin precursors such as δ-aminolevulinic acid (ALA) and porphobilinogen (PBG) which are released from the liver into the circulation, (Figure 1). The diagnosis is often delayed, because clinical manifestations are unspecific and commonly mimic acute encephalopathy or abdominal crisis of other origin.
Figure 1
Precipitating factors and pathogenesis of an acute attack in AIP.
AIP is the most common type of acute porphyrias in most of the countries worldwide. The major clinical manifestation of AIP is an acute attack, which is clinically indistinguishable from those caused by other acute porphyrias: variegate porphyria (VP) and hereditary coproporphyria (HCP). The management of an acute attack in each disease is similar, and thus, more specific classification of an acute porphyria can be done in remission. Photosensitivity and skin fragility found in patients with cutaneous porphyrias, VP and HCP, occur independently of acute attacks and do not occur in AIP.,
When acute porphyria is suspected, biochemical plasma or urinalyses of porphyrin precursors are mandatory to confirm the diagnosis of an acute porphyric attack. More than five-fold elevation of urinary PBG excretion together with typical symptoms of an acute attack is sufficient to start a treatment, but in each case other causes of abdominal crisis must be excluded before a specific treatment of an acute attack is administered. Plasma porphyrin spectrum is a valuable tool to confirm the diagnosis in the early phase and helps to identify different subtypes of acute porphyrias during an acute attack. In AIP emission peak is only transient, and if taken late, may be negative leading to misdiagnosis. AIP and HCP cannot be distinguished by plasma analysis. Mutation screening can be done at the quiescent phase of the disease (Table 1).
Table 1
The laboratory investigations to confirm AIP and other acute porphyrias
Currently, the prognosis of patients with AIP is good even in severe attacks,, but physicians should be aware of a potentially fatal outcome of the disease. During remission the majority of the patients experience no clinical symptoms. Hypertension, chronic kidney insufficiency, chronic pain syndromes, and hepatocellular carcinoma (HCC) may be long-term complications of AIP.,,
The management of patients with AIP include following strategies:
  1. During an acute attack: 1) treatment with heme preparations, if an acute attack is severe or moderate; 2) symptomatic treatment of autonomic dysfunctions, sensorimotor neuropathy and encephalopathy; 3) exclusion of precipitating factors; and 4) adequate nutrition and fluid therapy.
  2. During remission: 1) exclusion of precipitating factors (education of patients and family doctors), 2) information about on-line drug lists, and 3) mutation screening for family members and education about precipitating factors in mutation-positive family members which can diminish mortality and prevent subsequent attacks among them.
  3. Management of patients with recurrent attacks: 1) evaluation of the lifestyle, 2) evaluation of hormonal therapy in women, 3) prophylactic heme therapy, and 4) liver transplantation in AIP patients with severe recurrent attacks.
  4. Follow-up of the AIP patients for long-term complications: chronic hypertension, chronic kidney insufficiency, chronic pain syndrome, and HCC.

Clinical manifestations and pathogenesis of an acute attack

The majority of acute attacks manifest as a combination of abdominal pain, mild mental symptoms, and autonomic dysfunction., Both acute peripheral neuropathy and severe encephalopathy may develop, if an acute attack proceeds,, (Figure 2). It is usually iatrogenic, mainly due to administration of porphyrinogenic drugs when the diagnosis of acute porphyria is delayed.,, Both endogenous and exogenous factors, such as certain medications, alcohol, infections, low caloric intake, or changes in sex hormone balance during the menstrual cycle or pregnancy, can provoke clinical manifestations in AIP, (Figures 1 and and2).2). All these factors induce heme synthesis either directly or indirectly via activation of ALA synthase in the liver resulting in accumulation of porphyrins and their precursors in the tissues and circulation.
Figure 2
Staging of an acute attack in connection with precipitating factors and recommendations of heme therapy.
Excess of ALA is the most potential candidate to cause neuronal damage and could be responsible for autonomic and peripheral neuropathy and encephalopathy via multiple mechanisms. Results from both the experimental and clinical data support the direct neurotoxicity of ALA, but also modification of γ-aminobutyric acid (GABA)-ergic system due to the structural similarity of ALA and GABA/glutamate, as well as formation of free radicals and reactive oxygen species from ALA may play a role in the pathogenesis of an acute attack.
Heme preparations, in the current treatment, lead to a rapid decrease of synthesis of porphyrin precursors via negative feedback (Figure 1). Reduced transcription of ALA synthase in the liver achieved by heme results in cessation of an acute attack within few days. Dose-dependent administration of glucose has also been shown to downregulate ALA synthase in experimental conditions via peroxisome-proliferator-activated receptor γ coactivator 1α (PGC-1α), a protein which directly induces transcription of ALA synthase 1.Subsequently, glucose infusions have been used to prevent fasting and may be sufficient in mild attacks. Despite the fact that recombinant human-HMBS-enzyme (rh-HMBS) therapy decreased the plasma level of PBG rapidly, it had no effect on the ALA level or the patients’ acute symptoms. In contrast, liver transplantation immediately corrects porphyrin metabolism to normal demonstrating the dominant role of liver as a source of ALA.
The exact mechanism of cyclic attacks in women is unknown. Despite the level of sex hormones is at the highest during the second and third trimester, acute attacks are rare during pregnancy.,,, Although, especially, progesterone is known to be a potent inducer of ALA synthase, the direct role of sex hormones as sole precipitating factors is unlikely. Moreover, cyclical attacks occur mainly in premenstruum when the levels of estrogen and progesterone fluctuate the most, and usually are resolved during early menstruation., Individual variation in the progesterone metabolism may play a role in clinical manifestations of AIP. Cytochrome-P450 activities in the liver also vary individually and can result in an abnormal level or ratio of sex hormones affecting the feedback mechanism to hypothalamus. Several neurotransmitters control the menstrual cycle through the regulation of pulsatile release of gonadotropin-releasing hormone (GnRH) and other clock mechanisms in the hypothalamus. This interaction may activate abnormal liver metabolism, and consequently precipitate acute attacks by the central mechanism making AIP a central nervous system disorder in addition to a liver disease.

Diagnosis of AIP

The clinical criteria of an acute attack include the paroxysmal nature of the symptoms with abdominal or back pain associated with one or more signs of autonomic dysfunction, hyponatremia, muscle weakness, or mental symptoms (Table 2).
Table 2
The key symptoms indicating acute porphyria
The biochemical criteria of an acute attack include more than a fivefold increase of urinary PBG excretion (Table 1), which can be detected by a simple Watson-Schwartz or Hoesch qualitative test. The results should be confirmed by a quantitative measurement of urinary PBG, since false positive results in these screening tests are possible, especially, if perchloric acid instead of amyl alcohol is used as an extract.If the urine samples are not sheltered from the light, urinalysis may become false negative.
Urinary excretion of PBG is elevated in 88% of the patients with AIP in remission. During an acute attack PBG excretion increases commonly at least two- to fourfold from the values found in remission. Urinary ALA is always increased during an acute attack but remains elevated only in 61% of AIP cases in remission. In AIP, urinary excretion of uroporphyrins is increased, including both I and III isomers, and exceeds that of coproporphyrins I and III.
Of note, abnormal metabolism of porphyrin and their precursors may also be detected in patients with hepatopathy or heavy metal intoxications., The clinical manifestations may even resemble AIP, but biochemically only a mild to moderate coproporphyrinuria is present, and porphyrin precursors are commonly only transiently elevated., If urinary ALA level exceeds that of PBG significantly, lead intoxication should be excluded.
In AIP, plasma porphyrin emission spectrum test with excitation wave length of 405 nm shows a peak at 615–620 nm during an acute attack similar to HCP but it can be less frequently found in remission.,Emission peak is due to porphyrins’ ability to absorb light at wave length around 400 nm and their emission as red fluorescence, at around 600 nm. Plasma emission spectrum test is used mainly to exclude symptomatic V P, since it has a unique 624–627 nm spectrum due to protein-associated plasma porphyrins.,, Of note, emission peak is commonly negative at the asymptomatic phase of VP.
Around 20% of the patients with AIP have moderately increased excretion of fecal protoporphyrin, which is less prominent than that of VP patients., Since fecal coproporphyrin level is usually normal in AIP,more than tenfold excretion of coproporphyrin (isoform III:I >2) in feces together with protoporphyrin suggests HCP.
In 84%–95% of patients with AIP,, erythrocyte HMBS (Erc-HMBS) activity has been lower than normal. In the variant form of AIP (5%–16% of all patients),, Erc-HMBS activity was normal due to an alternative splicing of the HMBS gene in erythroid cells. HMBS activity should be assayed in remission, since erythropoiesis may be enhanced during an attack as well as in hypochromic or hemolytic anemias and hepatopathy., In contrast, it can be decreased in non-porphyric individuals with sideropenia.
DNA analysis is the most reliable method to confirm AIP in the patients and their symptom-free relatives., The direct sequencing of the HMBS gene is used to identify a mutation in the proband and the asymptomatic gene carriers among the family members. The sensitivity of the mutation analysis is 90%–100%.,, To date, 391 mutations have been reported in the HMBS gene, and therefore DNA testing in an index case of a family is perhaps more laborious and time consuming, but afterward mutation analysis may easily reveal several family members at risk.

Treatment of an acute attack

Current treatment options include heme preparations during an acute attack, which may be life-saving, especially if encephalopathy or polyneuropathy develop. The treatment should be started immediately during a severe or moderate acute attack after the demonstration of typical symptoms of acute porphyria and more than fivefold elevation of urine PBG shown by qualitative tests. Other causes of abdominal crises and neuropsychiatric symptoms often demanding other specific and rapid interventions should always be excluded.
Only around 30%–50% of the patients with a mutation in the HMBS gene have mild or moderate clinical symptoms of AIP during their life span.,, Less commonly, around 3%–5% of the patients with AIP, have recurrent severe attacks, and no time for neuronal recovery. These patients are at a high risk for chronic pain syndrome. The onset and clinical outcome of an attack is commonly influenced by several exogenous factors simultaneously, and endogenous factors, such as the residual activity of a mutated protein, individual differences in other metabolic pathways in the liver and in neuronal protection capacity, may modify the clinical outcome.,


Heme preparations have been used for acute attacks for more than three decades without tolerance.,,,Hemin is isolated and purified from human red cell concentrates. In Europe, Asia, and South Africa, hemin is commercially available as heme arginate (Normosang®, Orphan Europe SARL, Puteaux, France) and in Northern America as lyophilized hematin (Panhematin®, Ovation Pharmaceuticals Inc., Deerfield, IL, USA).
In an open series of 22 patients, the patients treated with heme arginate recovered more rapidly in comparison with those treated with glucose infusions in the earlier series. Safety and efficiency of lyophilized hematin has also been demonstrated in six open-labeled studies involving over 200 AIP patients. The only study using a placebo-controlled series found insignificant benefit of heme arginate for the analgesic requirement, pain score, and duration of the hospital stay. The validity of the trial has been questioned due to small number of patients (eleven patients treated with heme and ten with a placebo), a high proportion of the patients with peripheral neuropathy in this series (43%), delayed administration of preparation (>2 days after admission), and difficulties in arranging a placebo, which resembles heme arginate.
Heme arginate and lyophilized hematin are usually infused daily (3–4 mg/kg) into a large peripheral vein or venous access port for 3–4 consequent days, but a repetitive course may be required if porphyric symptoms are still progressing, (Table 3). Concentrated solution of heme arginate is mixed with 100 mL physiological saline, and lyophilized hematin is reconstituted with sterile water before infusion.,,Lyophilized hematin should be used immediately after reconstitution. Heme arginate should also be used soon after dilution, since it becomes unstable and may aggregate. In both cases, addition of human serum albumin may be beneficial in order to diminish the risk of phlebitis at the site of infusion. After infusion, the vein should be washed with saline for 10–15 minutes. For the long-term use of heme, a central access catheter (tunneled catheter or portacat) may be useful. Low molecular weight heparin can be used subcutaneously to prevent or treat thrombophlebitis.
Table 3
Clinical manifestations and treatment of an acute attack
The treatment with heme preparations should be started without delay, but even in the late stage of progressing motor neuropathy, it is efficient. If a patient’s neurological condition has stabilized (plateau phase, Figure 2), an additional treatment with heme is rarely necessary but other causes such as infections may deteriorate the patient’s clinical condition and should be treated properly.
The reported side effects include mild coagulopathy, thrombophlebitis, and anaphylactic shock in one case.

High carbohydrate loading and supportive treatment

The treatment of acute attacks with high carbohydrate diet or infusions (300–500 g/day) has been in use in order to downregulate the activity of ALA synthase and prevent fasting. High dose of glucose should be infused continuously 24 hours per day with an automatic syringe, and blood sugar level should be monitored regularly to avoid hyper- or hypoglycemia causing additional neurological complications. If a patient is able to eat, carbohydrate rich meals may similarly have a beneficial effect.
Currently, the use of glucose is limited only to mild attacks (ie, mild pain, no paresis, seizures, or hyponatremia) according to the guidelines for the treatment of an acute attack in the USA and South Africa, or if heme arginate or hematin are not available locally, (Table 3). In mild cases, the dose of glucose can be lower than discussed earlier. If glucose infusions do not result in clinical remission within a day or two, or if an acute attack is severe at the onset, heme preparations should be used. Mild or clearly resolving attacks with minor pain or anxiety may be treated symptomatically.
Low to moderate dose of glucose and saline infusions should be used as supportive treatment to prevent dehydration and during fasting if the patient is unable to drink. The amount of daily fluids may vary from restricted fluid intake in a case of inappropriate antidiuretic hormone secretion to rapid restoration of intravascular volume and correction of electrolyte disturbances in rhabdomyolysis-induced renal failure.Thus, fluid restoration must be tailored individually and careful monitoring of water and electrolyte balance, including sodium, potassium, and magnesium, and renal function should be done (Table 4). Mild to severe hyponatremia is a rather common phenomenon (25%–60%) during an acute attack,,, and should be corrected slowly (<12 mmol/L/24 h), because of potential pontine myelinolysis, a condition also described in a patient with AIP.
Table 4
Signs, symptoms, and metabolites followed during an acute attack
Rhabdomyolysis during an acute attack is often neglected, but can be easily diagnosed by measurement of plasma myoglobin or creatinine kinase level and should be treated according to the guidelines. Acute kidney insufficiency is a rare but a severe complication of an acute attack, and may proceed to hemodialysis.,,

Elimination of precipitating factors

All potentially precipitating factors such as drugs, smoking, and alcohol should be eliminated during an acute attack. Infections should be treated promptly and caloric intake of a patient should be sufficient to avoid fasting.,, Administration of porphyrinogenic drugs commonly results in proceeding of an acute attack to neuropathy or encephalopathy (Figure 2). Several lists of potentially safe and unsafe drugs are available on the Internet.
Some drugs, such as barbiturates and sulfonamides, are strictly forbidden since their use has been associated with several severe attacks. Most of the drugs, however, are classified as potentially porphyrinogenic, since clinical data about their safety in acute porphyria is lacking. The majority of the patients, especially asymptomatic, tolerate many drugs well; thus, total avoidance of drugs for the safety reasons leads to inappropriate treatment of patients’ other diseases. Antibiotics excluding sulfonamides, drugs for cardiovascular diseases, and pain killers are usually well tolerated in addition to preparations used in oncology. The follow-up of urinary excretion of porphyrin precursors may elucidate the effect of a drug on the heme biosynthesis but increased excretion of porphyrin metabolites without clinical symptoms should not solely determine its use. In each case the potential risk and advantage of a drug should be evaluated by a clinician.

Symptomatic therapy

Symptomatic therapy for pain, hypertension, tachycardia, nausea, and vomiting is commonly required (Table 3)., Abdominal pain is usually intensive (visual analog scale, VAS >7 cm, scale from 0 to 10 cm) and opiates are needed. Morphine, pethidine, oxycodone, tramadol, and fentanyl have been used without complication. Paracetamol and anti-inflammatory drugs can be used in mild cases.
Beta blockers are commonly used for tachycardia and to prevent arrhythmia. If a hypertensive crisis develops, it can be treated with beta blockers or clonidine or other drugs recommended by the current guidelines. Nausea and vomiting can be controlled by olanzapine, lorazepam, or prochlorperazine.,Domperidone has been used during an acute attack, but interactions with opiates and other drugs increasing the risk for arrhythmias may prevent its use. Metoclopramide has been associated with neuropathy and encephalopathy during a few acute attacks, but some patients have used it without complications.Urinary retention is quite common and can be treated with catheterization. Blood pressure, heart rate, pain score by visual analog scale, and severity of the muscle weakness should be evaluated daily at the bed side. Bulbar paresis, proceeding muscle weakness, and arrhythmia are signs of progression of an acute attack and the patient should be transferred to the intensive care unit. Respiratory insufficiency as a sign of motor neuropathy increases risk of pneumonia and may require early mechanical ventilation. Patients with paresis due to neuropathy or encephalopathy require rehabilitation therapy even in the early phase.
Epileptic seizures, which are usually generalized, can be treated with intravenous diazepam, gabapentin, levetiracetam, or propofol if status epilepticus develops.,, Usually there is a single or few transient seizures, which associate with acute encephalopathy visualized as posterior reversible syndrome in brain magnetic resonance imaging (MRI) and does not require anticonvulsive treatment in the follow-up.Correction of hyponatremia may be beneficial in patients with seizures (Tables 3 and and4).4). Insomnia and anxiety are usually mild and do not require additional medications but can be treated with benzodiazepines, such as lorazepam. Hallucinations are also signs of acute encephalopathy and should be treated with phenothiazine or olanzapine.

Prognosis of an acute attack

Duration of the diagnostic delay of an acute attack correlates with a fatal outcome mainly due to the administration of drugs known to precipitate AIP for a misdiagnosed attack. The causes of death are related to complications of prolonged ventilation and cardiac arrest.,,,, The majority of patients display full functional recovery even after a severe attack.
The mortality has decreased dramatically during the last decades among diagnosed AIP patients by 5%–20% during an acute attack,, but it is still a potentially fatal disease.

Prevention of acute attacks

Avoidance of precipitating factors

In remission, patients may tolerate medications classified as potentially unsafe and alcohol, but if porphyric symptoms appear their use should be restricted.,, The education of patients and their family doctors about precipitating factors, including the information of safe and unsafe drugs, necessity of prompt treatment of infections, healthy lifestyle with regular normocaloric diet, avoidance of alcohol, if porphyric symptoms occur, and smoking, reduction of excessive stress are essential for patients’ prognosis.,, In the treatment of obesity, the patients with AIP should include carbohydrates into their diet, and the weight reduction should be done slowly.
DNA diagnostics among family members is recommended before the adulthood, since it decreases the likelihood of an acute attack to 5% in patients diagnosed at the presymptomatic phase. The prenatal screening in families with AIP is not recommended because of a low risk of severe attacks among mutation carriers and good therapy options even if acute attacks would develop.

Prevention of cyclical recurrent attacks

In women with AIP, the menstrual cycle is the most common precipitating factor (10%–39%) manifesting usually with 1–3 months interval in premenstruum., In the majority cases, these attacks are mild and do not require hospitalization. Irregular cycles due to hormonal imbalance may predispose to cyclical attacks. However, in 3%–5% of the women cyclical attacks are severe and frequent (up to 2–4 weeks interval),,which disable their lives. If the patient has recurrent attacks preventive therapy is needed.

Evaluation of the lifestyle

Usually these women have several precipitating factors simultaneously. It is important to first correct lifestyle, indicating cessation of smoking and use of alcohol or any medication or homeopathic drug which may be porphyrinogenic. Since body mass index (BMI) is commonly at the low or low normal level among women with recurrent attacks, gaining weight, at least a few kilos, may be beneficial to balance energy metabolism. Patients should avoid fasting and potential hypoglycemia by regular eating habits.

Evaluation of hormonal therapy in women

The exogenous hormonal therapy can be used, if lifestyle changes are insufficient to prevent attacks. Contraceptive pills have been used for prophylaxis of recurrent acute attacks for many years,, but not all women respond to this therapy even after 3 months of use. We have used ethinyl estradiol-levonorgestrel preparation successfully, and the responders have tolerated them well, even for years. About 46%–58% of the Finnish and Swedish women with AIP and VP have used hormonal pills for contraception,, and the majority of them have had no complications in remission despite use of various progesterone compounds in combination with estrogen preparations. Intrauterine devices including levonorgestrel have not been reported to cause porphyric symptoms. Based on our results, we have let our patients use hormonal contraception under supervision.
Of note, contraceptive pills can also provoke acute attacks in 5%–14% of the women with both latent and manifest AIP (24% of selected women with previously manifest AIP),, and as such many guidelines recommend not to use them.,, Tolerance to progesterone preparations may vary individually but estrogen preparations, especially used for menopausal symptoms, do not usually precipitate porphyric symptoms., Thus, it is important that the risk for potential complications and benefits of hormonal therapy are evaluated individually by a clinician. Excretion of porphyrin precursors should be controlled and hormonal preparations should be stopped, if symptoms suggestive for acute porphyria occur during their use.
In contrast, GnRH analogs inducing ovarian suppression are not porphyrinogenic and have been reported to diminish the severity and frequency of attacks in 60%–80% of the women. The responders have more frequently had regular menstrual cycles and pronounce decrease in the estradiol level after the treatment with GnRH analogs when compared to the women who have been nonresponders or have responded only to a high dose of the preparation., Drug-induced menopause decreased the excretion of porphyrin precursors to 60% of the previous values in both groups.
The treatment should first be continued up to a few months, and thereafter its efficiency should be evaluated. If a longer period for treatment is needed, GnRH agonist can be combined with estrogen preparations to avoid osteopenia and other menopausal symptoms. Estrogen patches are preferred to avoid the first passage metabolism in the liver. Progesterone should be administered regularly to avoid increased risk of endometrial cancer during the postmenopausal estrogen therapy, but they may also induce acute attacks during the combination treatment. Intrauterine device with levonorgestrel has been used without complications in this compound hormonal therapy, and another option is to lower the dose of GnRH analogs to sustain natural sex-hormone level, which could prevent the long-term side effects of the GnRH agonist., The patients should be followed carefully and efficiently, and side effects and need for the combination therapy should be evaluated at regular intervals. Women with cyclical attacks may also become asymptomatic after their natural menopause. Screening of urinary excretions of PBG and ALA may elucidate the biochemical activity of the disease, and maybe useful to follow.

Prophylactic heme therapy

Regular heme infusions commonly alleviate the severity and frequency of recurrent attacks.,, The aim of this treatment is to decrease substantially the level of porphyrin precursors in plasma. The majority of patients respond well but the long-term treatment may induce dependence on the exogenic heme. As a result, a patient may have increased need for heme from monthly to twice a week infusions and withdrawal of the treatment is difficult due to severe porphyric symptoms. Frequent administrations of heme preparations may lead to thrombotic complications of superficial veins, and assessment of a permanent central venous catheter may be necessary. Moreover, long-term treatment of heme may lead to iron overload and organ damage due to hemosiderosis. Progressing hepatopathy, heart failure, and endocrinopathies may develop. Follow-up of plasma ferritin and transferrin saturation levels is necessary, and computed tomography (CT) or MRI reveal iron load in organs. Venesections are usually poorly tolerated but iron chelates may be used.

Liver transplantation in AIP patients with severe recurrent attacks

If the standard treatment is unsuccessful or quality of life is unbearable, liver transplantation is an option for severely affected patients., Currently, more than ten AIP patients have undergone liver (or liver-kidney) transplantation since 2004.,, It has been successful in the majority of cases resulting in immediate correction of abnormal porphyrin metabolism and cessation of attacks and chronic pain syndrome.Immunosuppressive drugs have been tolerated well by the patients, and their quality of life has improved dramatically. A few patients have died soon after liver transplantation mainly due to infections. Timing is also important in the liver transplantation. Patients should not wait too long in a too poor condition since the recovery from the operation and immunosuppression may associate with early complications such as infections or thromboembolic complications. If chronic motor neuropathy and encephalopathy have been present for years, the full recovery of neuronal damage may not be reached even after total normalization of porphyrin metabolism. Of note, partial liver transplantation has not corrected biochemical abnormalities or clinical manifestations permanently and should not be done. Moreover, transplantation of the HMBS deficient liver induced an abnormal porphyrin metabolism in a recipient.

Management of pregnancies

Previously, pregnancies were commonly complicated by acute attacks mainly during the first trimester and postpartum, and women with AIP were advised to avoid pregnancy. Currently, overall prognosis for pregnancy in AIP is good, especially if the diagnosis is known in advance and no porphyrinogenic drugs are used.,,
Cyclical attacks do not predict attacks during pregnancy, and pregnancy nowadays seldom precipitates acute attacks.,, Heme preparations have been used during pregnancy without fetal or maternal complications.,,, In some women, who have experienced cyclical attacks for many years, recurrent attacks have stopped after the first trimester of pregnancy, and these women have been asymptomatic thereafter., Thus, pregnancy may act as a hormonal therapy and could be even considered as an option for the women with cyclical attacks.

Long-term complications of AIP

Hypertension and renal insufficiency

The prevalence of hypertension is significantly higher in patients with manifest AIP than in general population.,,, Thus, early monitoring of blood pressure and efficient treatment with antihypertensive drugs is mandatory to avoid organ complications. This is especially crucial if renal failure is already present.
Monitoring of creatinine level in the follow-up of patients with manifested AIP shows mild to moderate elevation in 10%–50% of the cases.,, This is significantly more common than in general population.,,,, Tubulointerstitial kidney disease has been the main presentation in a biopsy of the investigated cases.,, It has been commonly associated with recurrent acute attacks, hypertension, and use of anti-inflammatory drugs.,,, The main recommendation for renal protection include adequate drinking regimen, blood pressure control, and avoidance of anti-inflammatory or other nephrotoxic drugs according to the general guidelines. Patients with AIP and nephropathy, even mild, have an increased risk of deterioration of renal functions during an attack, and should be treated carefully with fluid therapy and hemodialysis if necessary.
Chronic hemodialysis may induce cutaneous symptoms in patients with AIP mimicking porphyria cutanea tarda (PCT). Since mainly ALA and PBG but not porphyrins have been filtered during dialysis, recurrent attacks were transformed to cutaneous manifestations in one patient. Use of high-flux hemodialysis and erythropoietin substitution might be of help since they remove plasma porphyrins and have alleviated clinical manifestation in PCT patients with end-stage renal failure., Kidney transplantation or combined liver and kidney transplantation have been done successfully and should be done whenever needed. The patients who have undergone kidney or liver transplantation should be followed up regularly because of increased risks of renal failure, hypertension, and cardiovascular complications. Metabolic changes and osteoporosis may also develop. Skin cancers and lymphomas are more common than in the general population and thus, extensive exposure to the sunlight and smoking should be avoided. Long-term complications are often multifactorial but commonly related to immunosuppressive drugs in use.

Hepatocellular carcinoma

Several population-based studies of AIP patients have shown an evidence of a significantly increased incidence of HCC in AIP compared to general population.,, The highest incidence of HCC (23%–27%, more than 60-fold increased risk compared to general population) was shown in the Finnish and Swedish patients with AIP.,, In contrast to renal insufficiency, HCC has developed in patients with both symptomatic and asymptomatic AIP, although the patients with manifested AIP are likely at higher risk. Only in one-third of the cases, HCC has coexisted with liver cirrhosis or well-known risk factors for HCC, such as viral hepatitis or heavy alcohol consumption.,,, Hepatoma should always be considered if a patient develops acute attacks or an abdominal pain after long-term remission or abnormally high porphyrin excretion pattern even at the old age. Hepatomas can be solitary or multiple in AIP patients,, and should be treated according to current guidelines (ie, hepatic resection, local ablation therapies, multikinase inhibitors) whenever possible.,,
Since 10% of the patients with AIP die of hepatoma, the patients with AIP most likely benefit from regular screening for HCC after 50 years of age. Early diagnosis of HCC is crucial for the prognosis and can be achieved only by accurate radiological imaging.

Chronic pain

Among AIP patients with recurrent acute attacks, chronic neuropathic, myalgic, or abdominal pain usually accompanied by fatigue is common (18%–22%)., This could be due to repetitive autonomic and peripheral nerve damage during acute attacks, and the long-term hypocaloric nutrition inducing catabolic stage and muscle atrophy. The mouse model of AIP, which is in contrast to human autosomal-dominant AIP caused by compound heterozygous mutations in HMBS gene (HMBS -/-) and severe deficiency of HMBS enzyme, has developed chronic axonal motor neuropathy even in the absence of acute attacks and elevated ALA levels. In humans, a homozygous AIP patient has developed a chronic sensorimotor neuropathy associated with severe neurodegenerative encephalopathy and mental retardation at his early childhood but no chronic pain syndrome has been present.
The treatment options include prevention of acute attacks as described earlier and prolonged treatment with gabapentin or antidepressants, such as fluoxetine. Prophylactic heme infusions commonly alleviate the chronic pain syndrome., Regular use of opiates induces tolerance to these drugs and high doses may increase the risk of side effects such as addiction, somnolence, and apnea.

Future therapies

rh-HMBS preparation has been shown to lower plasma PBG levels in symptom-free patients with increased excretion of urinary PBG. The similar biochemical effect of rh-HMBS therapy was demonstrated in theHMBS (−/−) mouse model. The rh-HMBS-enzyme replacement therapy, however, had no effect on the patients’ symptoms during acute attacks mainly due to constantly high plasma ALA levels. This may be due to the fact that the rh-HMBS included only the erythroid specific form of the enzyme and was not targeted to the liver, the main site of ALA overproduction. The potential development of rh-HMBS-enzyme replacement therapy should be focused on the delivery of an active enzyme into the liver restoring the normal HMBS activity and heme biosynthesis.
Both adenoviral-mediated and nonviral HMBS gene transfers corrected the metabolic defect in the cell lines of AIP patients and HMBS (−/−) mice. Only virus-mediated DNA transfer into the liver was successful and corrected metabolic defect in HMBS (−/−) mice at least for a month., Adenoviral cytotoxicity, especially, for hepatocytes, the immunological response to viral antigens, and only transient transduction of the therapeutic gene limit potential applications of this method. Adeno-associated viral (AAV) vector encoding HMBS and driven by liver-specific regulatory elements, such as α1-microglobulin enhancer and α1-antitrypsin promoter, is a promising alternative to the first-generation adenoviral vectors, since it demonstrated long-term transgene expression of HMBS in the liver with reduced risk of side effects.AAV vector encoding HMBS (recombinant AAV serotype 5-codon-optimized human HMBS, rAAV5-cohHMBS) has been used in macaques. The safety and efficiency of AAV vector containing the HMBSgene is currently investigated in the clinical trial (Phase I).
Small interfering RNA targeting liver ALA synthase results in reduction of ALA synthase mRNA and prevents acute attacks in AIP mouse model, and it is under development for human studies. This demonstrates that downregulation of liver heme biosynthesis via direct ALA synthase inhibitor could result in a promising future therapy.


Before the glucose and hematin treatment of an acute attack has been introduced, the mortality rate during an acute attack of AIP was up to 66%. Currently, the improved diagnostics, the early and effective treatment with heme preparations, and the prevention of acute attacks have decreased the mortality substantially. However, the morbidity and mortality (5%–20%) of an acute attack is still significant if the diagnosis of AIP is delayed.,,, Thus, it is important that AIP patients are treated in the experienced centers with facilities that enable monitoring of their clinical and biochemical profile.
Current options to prevent acute attack include patients and family doctor education and family screening forHMBS mutation carriers. In patients with recurrent attacks, ovarian suppression using hormonal interventions, prophylactic heme therapy, or liver transplantation should be considered to improve the prognosis and quality of their lives. Future therapies, such as enzyme or gene delivery, should demonstrate clinical efficiency and safety before they can be applied to the clinical use. In the long-term follow-up, impaired renal function and hypertension should be treated carefully, and screening for hepatomas should be considered after 50 years of age.


The authors have participated in clinical trials organized by Zymenex, Alnylam, Clinuvel, and Boehringer Ingelheim, and as speakers in seminars organized by Orphan Europe. The authors report no other conflicts of interest in this work.


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What is δ-Aminolevulinic Acid Dehydratase Porphyria (ADP)?

What is δ-Aminolevulinic Acid Dehydratase Porphyria (ADP)? ADP is more severe than the other acute porphyrias and can present in childhoo...