Review Article
Porphyrias in Japan: Compilation of All Cases Reported through 2002
Masao Kondo,a Yuzo Yano,b Masuo Shirataka,c Gumpei Urata,a Shigeru Sassad aDivision of Applied Nutrition, National Institute of Health and Nutrition, Tokyo; bDepartment of Internal Medicine, Tokyo Metropolitan Otsuka General Hospital, Tokyo; cDepartment of Medical Informatics, Kitazato University School of Medicine, Kanazawa; dYamanouchi Pharmaceutical Co, Ltd, Tokyo, Japan Received September 11, 2003; received in revised form March 4, 2004; accepted March 5, 2004 Abstract
The first case of porphyria on record in Japan was a patient with congenital erythropoietic porphyria (CEP) reported by Sato and Takahashi in 1920. Since then until the end of December 2002, 827 cases of porphyrias have been diagnosed fromcharacteristic clinical and/or laboratory findings (463 males, 358 females, and 6 of unknown sex). Essentially all inherited por-phyrias have been found in Japan, with the incidences and clinical symptoms generally being similar to those reported for othercountries. The male-female ratio was approximately 1:1 for CEP, whereas it was higher for erythropoietic protoporphyria. Incontrast, preponderances of female patients exist with acute hepatic porphyrias, such as acute intermittent porphyria (AIP),variegate porphyria (VP), and hereditary coproporphyria (HCP), and with undefined acute porphyria. Although porphyriacutanea tarda (PCT) is believed to be increasing recently in women in other countries because of smoking and the use of con-traceptives, it is still by far more prominent in males in Japan than in females. The recent increasing contribution of hepatitis Cvirus infection to PCT in Japan has also been recognized, but there have been no PCT cases in Japan with HFE gene muta-tions. Familial occurrence and consanguinity were high for CEP, as expected; however, significant consanguinity was also notedin families where CEP, AIP, HCP, VP, or PCT occurred as a single isolated case without a family history of disease. This surveyalso revealed that as many as 71% of acute hepatic porphyria cases were initially diagnosed as nonporphyria and later revisedor corrected to porphyria, indicating the difficulty of diagnosing porphyria in the absence of specific laboratory testing for por-phyrins and their precursors in urine, stool, plasma, and erythrocyte samples.
Int J Hematol. 2004;79:xxx-xxx. doi: 10.1532/IJH97.031272004 The Japanese Society of Hematology Key words: Porphyria; Hepatic porphyria; Erythropoietic porphyria; Cutaneous porphyria; Chronic porphyria 1. Introduction
tent porphyria (AIP). Porphyrias have been recognizedessentially in all populations and regions of the world, but Porphyrias are a group of disorders caused by inherited there seems to be some predilection for porphyria types, deficiencies in the activities of the enzymes of the heme depending on race and district [1,2]. In addition to the con- biosynthetic pathway [1]. Affected patients have neurologic genital porphyrias, some porphyrias, such as porphyria disturbances, cutaneous photosensitivity, or both. Although cutanea tarda (PCT), occur as an acquired disease induced these symptoms may be general in nature, porphyrias can be by exposure to chemicals used in modern chemistry [3,4].
definitively diagnosed by demonstrating the presence of spe- Thus, there is also a new trend of porphyrias that did not exist cific metabolites, such as excessive excretion of ␦-aminole- many years ago. There has been, however, no historical or vulinic acid (ALA), porphobilinogen, or porphyrins, in the regional compilation of the reports of porphyrias occurring urine, stool, and plasma [2]. The most definitive diagnosis of in a single country, let alone the world. To better appreciate porphyrias is the demonstration of a specific enzyme defect these aspects of porphyrias, we compiled all identifiable por- in cells from the patient, but this approach remains largely a phyria cases in Japan, either in published reports or in pub- tool for research rather than for general clinical use, except lished abstracts, and examined if there is any specific aspect for the erythrocyte porphobilinogen deaminase assay, which is commercially available for the diagnosis of acute intermit- 2. Results and Discussion
Correspondence and reprint requests: Masao Kondo, Division of Applied Nutrition, National Institute of Health and Nutrition, Our survey was based on abstracts on porphyrias that 1-23-1, Toyama Shinjuku-ku, Tokyo 162-8636, Japan; 81-3-3203- have been published in Igaku Chuo Zasshi. This journal pub- 5721 (ext 4303); fax: 81-3-3205-9536 (e-mail: kondo@nih.go.jp).
lishes abstracts of all medical articles published in Japan. It Kondo et al / International Journal of Hematology 79 (2004) xx-xx was founded in 1903 and uses the style of Centralblatt für dieGesamte Medicin. Igaku Chuo Zasshi currently uses 2459journals (2296 Japanese journals and 163 Western journals)and entered 282,784 abstracts in 2002. The first recorded case of porphyria in Japan was one of congenital erythropoietic porphyria (CEP) reported by Sato and Takahashi [5]. Allcases of porphyrias since then until the end of 2002 havebeen retrieved by using porphyria as a key word, and every record has been carefully reviewed. The number of medical journals that listed porphyrias was 234, and the number of porphyria cases in our survey was 1434. The cases of patientswho had clinical symptoms suggestive of porphyrias but whohad no other definitive laboratory findings characteristic ofporphyrias (eg, increased ALA, porphobilinogen, or por- phyrin levels in the urine) were eliminated. Apparently redundant reports of original cases have also been excluded.
This survey left us with 827 cases of porphyrias, 776 cases of which were definitively classified or reported as a specific type of porphyria. Fifty-one cases were likely to have been acute hepatic porphyria, but it was not possible to assign them to AIP, hereditary coproporphyria (HCP), or variegate porphyria (VP) (Table 1). CEP and AIP have been found in Japan since the 1920s, and their rates do not seem to have changed with time. In contrast, erythropoietic protopor- phyria (EPP), ␦-aminolevulinate dehydratase porphyria(ADP), HCP, PCT, VP, and hepatoerythropoietic porphyria (HEP) were not found before 1957, reflecting the fact that the first case of PCT was recognized in 1957 [6] and the firstreports of other porphyrias were made thereafter. The male- female ratio was approximately 1:1 for CEP. There were more male patients with EPP than female patients (98 versus 56). In contrast, there were preponderances of female patients with acute hepatic porphyrias such as AIP, VP, and HCP, as well as with undefined acute porphyria (AP)(Table 1). This trend appears to be similar for these porphyr- ias in other populations [2]. Although PCT was believed to have increased recently in women in other countries becauseof smoking and the use of contraceptives [2], our data indi-cate that it is still more prominent by far in males in Japanthan in females (35 males versus 3 females between 1996 and 2002, and 278 males versus 23 females for all cases to date).
Patients were also classified according to their age at the time of their first medical examination (Table 2). Ideally speaking, this classification should have been made on the basis of age at the onset of the disease; however, such infor-mation was missing from many records except for ADP, CEP, and HEP. Thus in most cases we had to use patient age at thetime of the first medical examination or hospital admission.
Similar to other populations, CEP in Japan was seen pre- dominantly in young patients within 5 years of birth; how- ever, its incidence extended beyond the age of 30 years, and the disease of some patients in fact had a late onset in life.
Most EPPs were found from birth to the third decade of life.
In contrast, most acute hepatic porphyrias, such as AIP, HCP, essed as the total (males:females:sex unknown). CEP indicates congenital erythr and VP, occurred at ages ranging from 16 to 40 years. OneHCP case was found at birth. This patient had a very rare early-onset HCP and was heterozygous for the copropor- phyrinogen oxidase gene defect with exon 6 skipping.
Abnormalities of steroid metabolism apparently contributed , ‰-aminolevulinate dehydratase porphyria; AIP to the early manifestation of porphyria [7]. PCT occurred Table 2.
Age of Patients on Hospital Admission*
*Abbreviations are expanded in the footnote to Table 1.
later in life, peaking in the age range between 41 years and 50 and ALAD activity was substantially higher in this patient years. Geographical classification of these cases showed the than in the other ADP patients. It is unclear whether the ubiquitous distribution of porphyrias in all parts in Japan, 10% ALAD activity was responsible for the porphyria-like and no particular trend was apparent (data not shown).
symptoms in this patient, because a Swedish girl who had an To date, 4 cases of ADP have been reported in the world ALAD activity level 12% of normal because of an F12L literature [8-11]. These cases comprised 2 German males mutation of the ALAD gene was reported to be perfectly [8,9], 1 Belgian male [10] and 1 Swedish baby boy [11]. The healthy [18]. Whether the disease of this Japanese patient disease in all of these patients was characterized by severe was bona fide ADP was not established as no further studies abdominal pain, neuropathy, markedly decreased erythro- were made because of her “private wishes” [16].
cyte ALA dehydratase (ALAD) activity (2% of normal), With respect to familial occurrence and consanguinity, pos- markedly increased urinary excretion of ALA, and increased itive consanguinity was confirmed in 18% of CEP cases, 1% of erythrocyte protoporphyrin concentrations. In addition, the EPP cases, 4% of AIP cases, and 3% of HCP cases but in none molecular defects in the ALAD have been defined in all of of the cases of other porphyrias (Table 3). However, a signifi- these patients, because the mutant ALADs in the patients cant number of consanguineous cases were also found in fam- were confirmed to have little enzyme activity when ilies where CEP, AIP, HCP, VP, or PCT occurred as a single expressed in a heterologous system and were thus clearly isolated case without a family history of the disease (Table 3).
responsible for the porphyria symptoms in the patients [12- The hematologic findings of porphyria patients are sum- 15]. It should be noted that a Japanese woman was described marized in Table 4. The mean counts of red blood cells as the fifth ADP patient [16]. This patient was a 69-year-old decreased in CEP cases but not in other porphyrias. In con- woman who had certain clinical symptoms, such as vomiting, trast, hematocrit values decreased in most porphyrias except abdominal pain, facial numbness, and paresis of the extremi- for PCT. The reasons for this finding and the discrepancy in ties with gait disturbance, that resembled those of acute red blood cell counts are unclear. Hemoglobin values were hepatic porphyria. In addition, she became comatose with similar to those for hematocrits. There were no significant hyponatremia, and laboratory findings showed signs compat- differences in all porphyrias for mean corpuscular hemoglo- ible with the syndrome of inappropriate secretion of antidi- bin, mean corpuscular volume, and mean corpuscular hemo- uretic hormone, which often occurs in association with the globin concentration. Reticulocytosis was reported in 3 of acute attacks of hepatic porphyrias [1,2,17]. The patient had the 4 cases of CEP where its record was found, as expected decreased erythrocyte ALAD activity (approximately 10% for the hemolytic anemia attendant with this disease. There of the mean normal level), slightly increased coproporphyrin was no record of reticulocytosis or hemolytic anemia in HEP excretion in the urine, and a normal level of erythrocyte pro- cases, suggesting that Japanese patients with HEP may have toporphyrin. Thus, the findings in this case were somewhat a milder form of the disease. Other findings are unremark- different from those of the 4 well-documented ADP cases in able except for erythrocyte protoporphyrin levels, which that the urinary excretion of ALA was normal on 1 occasion, were extremely elevated in EPP cases, as expected. Bone the erythrocyte protoporphyrin concentration was normal, marrow findings were available only for EPP cases and Table 3.
Familial Occurrence and Consanguinity*
*Abbreviations are expanded in the footnote to Table 1. Percentages are of all cases.
Kondo et al / International Journal of Hematology 79 (2004) xx-xx Table 4.
Hematologic Findings*
2500-20,000 3100-23,100 4400-45,900 3900-18,400 1800-11,700 *RBC indicates red blood cells; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; MCHC, mean corpuscular hemoglobin concentration; WBC, white blood cells; TIBC, total iron-binding capacity; UIBC, unbound iron-binding capacity; G/E, granulocyte/erythroid. Otherabbreviations are expanded in the footnote to Table 1.
Table 5.
Clinical Symptoms of Cutaneous Porphyrias*
(nose, fingernails, pinnas, phalanges, and so on) *Abbreviations are expanded in the footnote to Table 1.
showed occasional sideroblasts in some patients. There have This patient was more likely to have had either CEP or HEP been also a few reports in the world literature of the associ- than EPP, but the information available in the published ation of EPP with sideroblastic anemia [19-22].
abstract was insufficient for a definitive diagnosis. Ery- Clinical symptoms of cutaneous porphyrias are summa- throdontia was almost exclusively found in CEP cases but rized in Table 5. As expected, there were many photosensi- was also found in 1 case of EPP [24]. Anemia and tive dermatologic symptoms, such as light-induced erythema, splenomegaly are known to occur with CEP, but they were blisters, erosion, ulcers, crusting, scars, hyperpigmentation, also observed in a few cases of EPP. Liver dysfunction was a and hypopigmentation of the skin, in cutaneous porphyrias.
characteristic feature of both EPP and PCT.
Most instances of liver dysfunction were observed in PCT Histologic findings of liver biopsy specimens were also cases. Dark urine was a characteristic feature of CEP and reviewed (Table 6). Liver biopsy was done predominantly for PCT but not of EPP, although 1 patient with EPP was patients with PCT. Of 123 patients with PCT who underwent reported to have had dark urine [23]. Because protopor- liver biopsy, 116 patients (94.3%) were found to have some phyrin cannot be excreted into the urine, this finding of black form of liver abnormality, such as liver cirrhosis (12.2%), urine casts doubt on the diagnosis of EPP for this patient.
chronic hepatitis (57.7%), or fatty liver (14.6%).Twelve cases Table 6.
Histologic Findings of Liver Biopsy Specimens from Patients with Porphyria Cutanea Tarda (PCT)*
Hepatitis C Virus Antibody (n = 50), n (%) Kondo et al / International Journal of Hematology 79 (2004) xx-xx Table 7.
Clinical Symptoms of Acute Hepatic Porphyrias*
*Abbreviations are expanded in the footnote to Table 1.
(9.8%) were associated with hepatoma, confirming the later revised or corrected to porphyria, indicating the diffi- increased association of PCT with hepatoma [25]. Twenty- culty of the initial diagnosis of porphyria. Diagnosis is more five patients (20.3%) had liver abnormalities but of an difficult for acute hepatic porphyrias than for cutaneous “undefined nature.” Chronic hepatitis in PCT was notably porphyrias, as 145 cases (77.1%) of AIP, 25 cases (46.3%) of associated with a marked increase in positive test results for VP, 30 cases (81.1%) of HCP, and 35 cases (68.6%) of AP hepatitis C virus antibody (86.0%). This trend is similar to had initially been diagnosed as nonporphyric disorders.
that reported in other countries [26,27].
These findings suggest that the difficulty of initial porphyria The clinical symptoms presented at the time of hospital diagnosis may be partly due to the presentation of complex admission for acute hepatic porphyria are summarized in symptoms but may also be due to the relative unawareness Table 7. Various gastrointestinal and neurologic symptoms have been reported for AIP, VP, HCP, and AP. Dermatologic The factors that had precipitated acute hepatic porphyrias findings were also reported for VP and HCP. These trends and the factors that were found in association with PCT are are similar to those reported for other populations. Very few also summarized (Table 9). Precipitating factors were demon- dermatologic findings were found for AP, suggesting that strated in many cases of AIP but in fewer cases of VP, HCP, and most AP patients were AIP patients who lacked photocuta- AP. Many of these patients, however, also developed porphyria in the absence of identifiable precipitating factors. Alcohol use Many porphyrias were not diagnosed properly at the is a predominant precipitating factor found in PCT cases, first medical examination or hospital admission. The initial although alcohol use most likely underscores rather than pre- diagnoses of these porphyria cases summarized in Table 8 cipitates the disease. The frequencies of mutations in the HFE include various neurologic, gastrointestinal, and dermato- gene have also been reported to be elevated in PCT patients logic disorders. The results showed that 235 (71%) of the in several populations [28,29], but such mutations have not 331 cases of acute hepatic porphyrias had originally been been found in PCT cases in Japan [30], reflecting the fact that diagnosed as nonporphyria diseases. These diagnoses were HFE gene mutations are rare in the Japanese population.
Table 8.
Initial Diagnoses of Acute Hepatic Porphyrias*
*Abbreviations are expanded in the footnote to Table 1.
Table 9.
Aggravating Factors in Hepatic Porphyrias*
*Abbreviations are expanded in the footnote to Table 1.
The types of drugs and treatments used for cutaneous The treatment of acute hepatic porphyrias is summarized porphyrias are summarized in Table 10. Except for phle- in Table 11. Glucose infusion remained the mainstay of treat- botomy and chloroquine for the treatment of PCT, there ment, whereas very few patients in Japan with acute hepatic were no specific treatments for any given porphyria. Cimeti- porphyrias were treated with hematin or heme arginate. The dine, which had originally been shown to be effective for relatively few uses of heme compounds (5 cases) may reflect treating AIP [31,32], was also tried in 2 cases of PCT with the difficulty in obtaining these compounds in Japan but may also suggest the unawareness of this treatment modality.
Table 10.
Treatment Used in Cutaneous Porphyrias*
*Abbreviations are expanded in the footnote to Table 1.
Kondo et al / International Journal of Hematology 79 (2004) xx-xx Table 11.
Treatment Used in Acute Hepatic Porphyrias*
*ATP/AMP, adenosine triphosphate/adenosine monophosphate; ACTH, adrenocorticotropic hormone. Other abbreviations are expanded in the Table 12.
Clinical Courses of Porphyrias after Patient Admission*
*Percentages are of all cases. Abbreviations are expanded in the footnote to Table 1.
The clinical courses after hospital admission of patients Acknowledgments
with porphyrias are also summarized (Table 12). Morepatients showed an improvement than a worsening in their This work has been supported in part by grants from the acute hepatic porphyria. The 3 erythropoietic porphyrias (ie, Japan Porphyria Foundation (M.K.), USPHS DK-32890 CEP, EPP, and particularly HEP), however, showed a signifi- (S.S.), and the American Porphyria Foundation (S.S.).
cant incidence of poor outcomes, which resulted in death in80% of the 5 reported cases. Among the hepatic porphyrias, References
the death rate was highest for AIP (25.0%), followed by VP(16.7%) and AP (19.6%), and was low for HCP (2.7%) and 1. Sassa S. The hematological aspects of porphyrias. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligson D, eds. Williams Hematology. 6th ed. New York, NY: McGraw-Hill; 2001:703-720.
In summary, essentially all known inherited porphyrias 2. Anderson KE, Sassa S, Bishop DF, Desnick RJ. Disorders of heme were also found in Japan with incidences and clinical symp- biosynthesis: X-linked sideroblastic anemia and the porphyrias. In: toms similar to those reported in other countries [2]. In con- Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and trast to the known high incidences of VP in South Africa Molecular Bases of Inherited Disease. 8th ed. New York, NY: [34,35] and AIP in Lapland [36,37], there is no particular trend for porphyria occurrences in Japan. The recent increas- 3. Daniell WE, Stockbridge HL, Labbe RF, et al. Environmental chemical exposures and disturbances of heme synthesis. Environ ing contribution of hepatitis C virus infection to PCT patho- Health Perspect. 1997;105(suppl 1):37-53.
genesis in Japan is also clear [38]. Human immunodeficiency 4. Jung D, Konietzko J, Reill-Konietzko G, et al. Porphyrin studies in virus (HIV) has also been reported in the PCT cases of TCDD-exposed workers. Arch Toxicol. 1994;68:595-598.
patients of other races [39,40], but there have not been any 5. Sato A, Takahashi H. Family anemia of a certain kind or an anemia PCT cases associated with HIV in Japan. There is a clear of hemoglobinuria which is not yet reported. Acta Paediatr Jpn.
male predominance for PCT in Japan (male-female ratio, 6. Nishiura M, Takeda K, Tani T, Akasawa M. Porphyria cutanea 12:1), and this trend continues. In contrast to the reported tarda. Acta Dermatol. 1960;55:566-575.
association of HFE mutations with PCT in various other 7. Takeuchi H, Kondo M, Daimon M, et al. Neonatal-onset hereditary populations, there have been no HFE mutations in cases of coproporphyria with male pseudohermaphrodism. Blood. 2001;98: PCT in Japan [30]. Many porphyrias were originally diag- nosed as nonporphyric disorders, suggesting that the initial 8. Doss M, von Tiepermann R, Schneider J, Schmid H. New type of diagnosis based on the physical examination of patients is hepatic porphyria with porphobilinogen synthase defect and inter-mittent acute clinical manifestation. Klin Wochenschr. 1979;57: unsatisfactory and that careful analyses of metabolites char- acteristic of porphyrias, such as ALA, porphobilinogen, and 9. Doss M, von Tiepermann R, Schneider J. Acute hepatic porphyria porphyrins, from urine, stool, and blood samples should be syndrome with porphobilinogen synthase defect. Int J Biochem.
made to establish the correct porphyria diagnosis.
10. Hassoun A, Verstraeten L, Mercelis R, Martin J-J. Biochemical 25. Kordac V. Frequency of occurrence of hepatocellular carcinoma in diagnosis of an hereditary aminolaevulinate dehydratase defi- patients with porphyria cutanea tarda in long-term follow-up. Neo- ciency in a 63-year-old man. J Clin Chem Clin Biochem. 1989;27: 26. English JC, Peake MF, Becker LE. Hepatitis C and porphyria 11. Thunell S, Holmberg L, Lundgren J. Aminolaevulinate dehydratase cutanea tarda. Cutis. 1996;57:404-408.
porphyria in infancy: a clinical and biochemical study. J Clin Chem 27. Lamoril J, Andant C, Bogard C, et al. Epidemiology of hepatitis C and G in sporadic and familial porphyria cutanea tarda. Hepatol- 12. Ishida N, Fujita H, Fukuda Y, et al. Cloning and expression of the defective genes from a patient with ␦-aminolevulinate dehydrataseporphyria. J Clin Invest. 1992;89:1431-1437.
28. Sampietro M, Fiorelli G, Fargion S. Iron overload in porphyria 13. Akagi R, Nishitani C, Harigae H, et al. Molecular analysis of cutanea tarda. Haematologica. 1999;84:248-253.
␦-aminolevulinate dehydratase deficiency in a patient with an 29. Bulaj ZJ, Phillips JD, Ajioka RS, et al. Hemochromatosis genes and unusual late-onset porphyria. Blood. 2000;96:3618-3623.
other factors contributing to the pathogenesis of porphyria 14. Akagi R, Shimizu R, Furuyama K, Doss MO, Sassa S. Novel molec- cutanea tarda. Blood. 2000;95:1565-1571.
ular defects of the ␦-aminolevulinate dehydratase gene in a patient 30. Furuyama K, Kondo M, Hirata K, Fujita H, Sassa S. Extremely rare with inherited acute hepatic porphyria. Hepatology. 2000;31: association of HFE mutations with porphyria cutanea tarda in Japanese patients. Hepatology. 1999;30:1532-1533.
15. Maruno M, Furuyama K, Akagi R, et al. Highly heterogeneous 31. Horie Y, Udagawa M, Hirayama C. Clinical usefulness of cimeti- nature of ␦-aminolevulinate dehydratase (ALAD) deficiencies in dine for the treatment of acute intermittent porphyria: a prelimi- ALAD porphyria. Blood. 2001;97:2972-2978.
nary report. Clin Chim Acta. 1987;167:267-271.
16. Muraoka A, Suehiro I, Fujii M, Murakami K. ␦-Aminolevulinic acid dehydratase deficiency porphyria (ADP) with syndrome of 32. Horie Y, Norimoto M, Tajima F, Sasaki H, Nanba E, Kawasaki H.
inappropriate secretion of antidiuretic hormone (SIADH) in a 69- Clinical usefulness of cimetidine treatment for acute relapse in year-old woman. Kobe J Med Sci. 1995;41:23-31.
intermittent porphyria. Clin Chim Acta. 1995;234:171-175.
17. Sassa S. Diagnosis and therapy of acute intermittent porphyria.
33. Horie Y, Tanaka K, Okano J, et al. Cimetidine in the treatment of porphyria cutanea tarda. Int Med. 1996;35:717-719.
18. Akagi R, Yasui Y, Harper P, Sassa S. A novel mutation of ␦-amino- 34. Eales L, Day RS, Blekkenhorst GH. The clinical and biochemical laevulinate dehydratase in a healthy child with 12% erythrocyte features of variegate porphyria: an analysis of 300 cases studied at enzyme activity. Br J Haematol. 1999;106:931-937.
Groote Schuur Hospital, Cape Town. Int J Biochem. 1980;12: 19. Lim HW, Cooper D, Sassa S, Dosik H, Buchness MR, Soter NA.
Photosensitivity, abnormal porphyrin profile, and sideroblasticanemia. J Am Acad Dermatol. 1992;27:287-292.
35. Kirsch RE, Meissner PN, Hift RJ. Variegate porphyria. Semin Liver 20. Romslo I, Brun A, Sandberg S, Bottomley SS, Hovding G, Talstad I.
Sideroblastic anemia with markedly increased free erythrocyte 36. Goldberg A, Rimington C. Diseases of Porphyrin Metabolism.
protoporphyrin without dermal photosensitivity. Blood. 1982;59: Springfield, Ill: Charles C. Thomas; 1962.
37. Lee JS, Anvret M. Identification of the most common mutation 21. Rothstein G, Lee R, Cartwright GE. Sideroblastic anemia with der- within the porphobilinogen deaminase gene in Swedish patients mal photosensitivity and greatly increased erythrocyte protopor- with acute intermittent porphyria. Proc Natl Acad Sci U S A. 1991; phyrin. N Engl J Med. 1969;280:587-590.
22. Scott AJ, Ansford AJ, Webster BH, Stringer HC. Erythropoietic 38. Kondo M, Horie Y, Okano J, et al. High prevalence of hepatitis C protoporphyria with features of a sideroblastic anaemia terminat- virus infection in Japanese patients with porphyria cutanea tarda.
ing in liver failure. Am J Med. 1973;54:251-259.
23. Hashimoto K, Kanie T, Mibu K, Okumura E. Protoporphyria ery- thropoietica: on blood cell abnormality in an autopsied patient [in 39. Mansourati FF, Stone VE, Mayer KH. Porphyria cutanea tarda and Japanese] [abstract]. Rinsho Ketsueki. 1966;7:33.
HIV/AIDS: a review of pathogenesis, clinical manifestations and 24. Takasaki H. Symposium on clinical aspects on porphyrias, 2: epi- management. Int J STD AIDS. 1999;10:51-56.
demiologic and clinical studies on hepatic porphyria [in Japanese].
40. O’Connor WJ. Porphyria cutanea tarda and HIV: two cases associ- Nippon Naika Gakkai Zasshi. 1967;56:956-959.
ated with hepatitis C. AIDS Patient Care STDS. 1998;12:341-346.

Source: http://dp47253191.lolipop.jp/porphyria/Porphyria%20in%20Japan.pdf

Microsoft word - rx_bs_for_hsa_plan

YOUR BENEFITS Benefit Summary Outpatient Prescription Drug Missouri 10/30/50 Plan 0H9 Modified Your Copayment and/or Coinsurance is determined by the tier to which the Prescription Drug List Management Committee has assigned the Prescription Drug Product. All Prescription Drug Products on the Prescription Drug List are assigned to Tier 1, Tier 2 or Tier 3. Find individuali

Understand more about your current level of fitness by having a vitality fitness assessment with a personal trainer at any true fitness centre

Vitality Fitness Assessment Benefit Guide | 1 Vitality Fitness Assessment Partner Benefit Guide Overview AIA Vitality members can understand more about their current level of fitness by having a Vitality Fitness Assessment with a personal trainer at any True Fitness centre. Members are awarded up to 1,500 Vitality Points for each assessment. AIA Vitality members can also earn Vit

Copyright © 2014 Medical Pdf Articles