Detection of Urinary Mulberry Bodies Leads to Diagnosis of Fabry Cardiomyopathy
2017; Lippincott Williams & Wilkins; Volume: 10; Issue: 12 Linguagem: Inglês
10.1161/circheartfailure.117.004538
ISSN1941-3297
AutoresToshiyuki Yano, Ryo Takahashi, Tomohisa Yamashita, Nobutaka Nagano, Aki Ishikawa, Akihiro Sakurai, Hiroki Maruyama, Tetsuji Miura,
Tópico(s)Trypanosoma species research and implications
ResumoHomeCirculation: Heart FailureVol. 10, No. 12Detection of Urinary Mulberry Bodies Leads to Diagnosis of Fabry Cardiomyopathy Free AccessCase ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessCase ReportPDF/EPUBDetection of Urinary Mulberry Bodies Leads to Diagnosis of Fabry CardiomyopathyA Simple Clue in the Urine Sediment Toshiyuki Yano, MD, PhD, Ryo Takahashi, MD, Tomohisa Yamashita, MD, PhD, Nobutaka Nagano, MD, Aki Ishikawa, MD, PhD, Akihiro Sakurai, MD, PhD, Hiroki Maruyama, MD, PhD and Tetsuji Miura, MD, PhD Toshiyuki YanoToshiyuki Yano From the Department of Cardiovascular, Renal and Metabolic Medicine (T.Y., R.T., T.Y., N.N., T.M.) and Department of Medical Genetics, Liberal Arts and Science (A.I., A.S.), Sapporo Medical University School of Medicine, Japan; and Department of Clinical Nephroscience, Niigata University Graduate School of Medical and Dental Sciences, Japan (H.M.). , Ryo TakahashiRyo Takahashi From the Department of Cardiovascular, Renal and Metabolic Medicine (T.Y., R.T., T.Y., N.N., T.M.) and Department of Medical Genetics, Liberal Arts and Science (A.I., A.S.), Sapporo Medical University School of Medicine, Japan; and Department of Clinical Nephroscience, Niigata University Graduate School of Medical and Dental Sciences, Japan (H.M.). , Tomohisa YamashitaTomohisa Yamashita From the Department of Cardiovascular, Renal and Metabolic Medicine (T.Y., R.T., T.Y., N.N., T.M.) and Department of Medical Genetics, Liberal Arts and Science (A.I., A.S.), Sapporo Medical University School of Medicine, Japan; and Department of Clinical Nephroscience, Niigata University Graduate School of Medical and Dental Sciences, Japan (H.M.). , Nobutaka NaganoNobutaka Nagano From the Department of Cardiovascular, Renal and Metabolic Medicine (T.Y., R.T., T.Y., N.N., T.M.) and Department of Medical Genetics, Liberal Arts and Science (A.I., A.S.), Sapporo Medical University School of Medicine, Japan; and Department of Clinical Nephroscience, Niigata University Graduate School of Medical and Dental Sciences, Japan (H.M.). , Aki IshikawaAki Ishikawa From the Department of Cardiovascular, Renal and Metabolic Medicine (T.Y., R.T., T.Y., N.N., T.M.) and Department of Medical Genetics, Liberal Arts and Science (A.I., A.S.), Sapporo Medical University School of Medicine, Japan; and Department of Clinical Nephroscience, Niigata University Graduate School of Medical and Dental Sciences, Japan (H.M.). , Akihiro SakuraiAkihiro Sakurai From the Department of Cardiovascular, Renal and Metabolic Medicine (T.Y., R.T., T.Y., N.N., T.M.) and Department of Medical Genetics, Liberal Arts and Science (A.I., A.S.), Sapporo Medical University School of Medicine, Japan; and Department of Clinical Nephroscience, Niigata University Graduate School of Medical and Dental Sciences, Japan (H.M.). , Hiroki MaruyamaHiroki Maruyama From the Department of Cardiovascular, Renal and Metabolic Medicine (T.Y., R.T., T.Y., N.N., T.M.) and Department of Medical Genetics, Liberal Arts and Science (A.I., A.S.), Sapporo Medical University School of Medicine, Japan; and Department of Clinical Nephroscience, Niigata University Graduate School of Medical and Dental Sciences, Japan (H.M.). and Tetsuji MiuraTetsuji Miura From the Department of Cardiovascular, Renal and Metabolic Medicine (T.Y., R.T., T.Y., N.N., T.M.) and Department of Medical Genetics, Liberal Arts and Science (A.I., A.S.), Sapporo Medical University School of Medicine, Japan; and Department of Clinical Nephroscience, Niigata University Graduate School of Medical and Dental Sciences, Japan (H.M.). Originally published4 Dec 2017https://doi.org/10.1161/CIRCHEARTFAILURE.117.004538Circulation: Heart Failure. 2017;10:e004538IntroductionFabry disease is an X-linked lysosomal storage disease characterized by globotriaosyceramide accumulation because of genetic loss/deficiency of α-galactosidase A (α-Gal A) activity. Clinical symptoms of classic Fabry disease, such as acroparethesia and neuropathic pain, typically become apparent in childhood and adolescence. Clinical manifestations in adulthood include cardiac and renal diseases, which are the main causes of death. Life expectancy of untreated Fabry males is ≈50 years. Myocardial involvement in Fabry disease is potentially misdiagnosed as hypertrophic cardiomyopathy unless careful workup of the patient, including pathological and genetic tests, is performed. The presence of chronic kidney disease with proteinuria in patients with ventricular hypertrophy leads to further analyses for diagnosis of Fabry disease. Although deterioration of renal function, leading to end-stage renal disease, is a typical manifestation of classical Fabry disease, a cardiac variant of Fabry disease, often accompanied by mild proteinuria, has also been reported.A 52-year-old man with ventricular hypertrophy and a history of acroparethesia during childhood was referred to our hospital (Figure A). He had no history of hypertension and no evidence of valvular diseases or chronic kidney disease (estimated glomerular filtration rate of 101.7 mL/min per 1.73 m2). Urinalysis showed no proteinuria (0.05 g/g Cr), but characteristic fat bodies with a whorl-like appearance, called mulberry bodies, in urinary sediments were detected by microscopic examination (Figure B). Cardiac magnetic resonance imaging showed concentric left ventricular hypertrophy and late gadolinium enhancement within the postero-lateral wall of the basal portion of the left ventricle (Figure C), typical findings of myocardial involvement in Fabry disease. In endomyocardial biopsy samples, most of the cardiomyocytes showed vacuolar changes (Figure D) and accumulation of myelin bodies (Figure E), evidence of Fabry cardiomyopathy. The levels of α-Gal A activity in leukocytes and plasma were low at 1.5 nmol/h per mg protein (normal range: 49.8–116.4) and 0.5 nmol/h per mL (normal range: >4.0 in males), respectively, and gene analysis demonstrated a known mutation of the α-Gal A gene (p.W340X), leading to the final diagnosis of Fabry disease.Download figureDownload PowerPointFigure. A, Twelve-lead electrocardiography. B, Mulberry bodies in the urine sediment. C, Late gadolinium-enhanced cardiac magnetic resonance imaging. D, Histological analysis of cardiac biopsy samples (hematoxylin and eosin staining; original magnification ×200). E, Electromicroscopic analysis. Numerous myelin bodies were easily observed in cardiomyocytes (magnification ×10 000).Measurement of plasma α-Gal A activity as a first-line screening for Fabry disease in males has a sensitivity of 100% when using a cutoff value of <4 nmol/h per mL, but its specificity is not necessarily high because level of α-Gal A activity is modestly reduced in the patients who have nonpathogenic mutations.1 It is also widely used to differentiate Fabry cardiomyopathy from hypertrophic cardiomyopathy in patients with ventricular hypertrophy but is not necessarily performed as a routine laboratory test. In addition, females with Fabry disease may have normal to low-normal plasma/leukocyte α-Gal A activity.2 Thus, there is a limitation in the usefulness of an assay for α-Gal A activity as a screening test for Fabry disease. Ultrastructual analysis of endomyocardial biopsy specimens is a gold standard technique to diagnose Fabry cardiomyopathy except for cases being treated with chloroquine or amiodarone,3 but this technique has a serious adverse event rate (0.12%–2%).Mulberry bodies are distal tubular epithelial cells with accumulated globotriaosyceramide and are frequently detected in urine sediment of Fabry patients.4–6 Selvarajah et al4 examined the diagnostic potential of detection of urinary mulberry bodies in 35 male and female Fabry patients with various clinical spectrums and in 21 controls with other renal diseases, such as glomerular nephritis or acute tubular injury.4 The presence of urinary mulberry bodies had a sensitivity of 100% (95% confidential interval: 85.4%–100%) and specificity of 100% (80.8%–100%) for diagnosis of Fabry disease although repeated and careful examination of urine sediments is required for its detection in our experience. In addition, excretion of urinary mulberry bodies was reported to be increased in Fabry patients with renal involvement in a severity-dependent manner.4 Importantly, mulberry bodies can be detected even in heterozygous Fabry disease females with normal renal function and no albuminuria.4 In our patient with ventricular hypertrophy who had no evidence of proteinuria or chronic kidney disease, careful examination of urinary sediments for mulberry bodies provided a clue for diagnosis of Fabry cardiomyopathy, leading to genetic and histological analysis, although further analysis is needed to demonstrate the sensitivity of detection of urinary mulberry bodies in a cardiac variant of Fabry disease. In conclusion, microscopic examination of urinary sediment should be routinely performed as a first-line screening for Fabry disease, even for patients with ventricular hypertrophy who have no evidence of proteinuria or chronic kidney disease.DisclosuresDr Maruyama received research support from Sanofi. The other authors report no conflicts.FootnotesCirc Heart Fail is available at http://circheartfailure.ahajournals.org.Correspondence to: Toshiyuki Yano, MD, PhD, Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-ku, Sapporo 060-8543, Japan. E-mail [email protected]References1. Maruyama H, Takata T, Tsubata Y, Tazawa R, Goto K, Tohyama J, Narita I, Yoshioka H, Ishii S. Screening of male dialysis patients for fabry disease by plasma globotriaosylsphingosine.Clin J Am Soc Nephrol. 2013; 8:629–636. doi: 10.2215/CJN.08780812.CrossrefMedlineGoogle Scholar2. Linthorst GE, Poorthuis BJ, Hollak CE. Enzyme activity for determination of presence of Fabry disease in women results in 40% false-negative results.J Am Coll Cardiol. 2008; 51:2082; author reply 2082–2083. doi: 10.1016/j.jacc.2008.02.050.CrossrefMedlineGoogle Scholar3. Smid BE, van der Tol L, Cecchi F, Elliott PM, Hughes DA, Linthorst GE, Timmermans J, Weidemann F, West ML, Biegstraaten M, Lekanne Deprez RH, Florquin S, Postema PG, Tomberli B, van der Wal AC, van den Bergh Weerman MA, Hollak CE. Uncertain diagnosis of Fabry disease: consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance.Int J Cardiol. 2014; 177:400–408. doi: 10.1016/j.ijcard.2014.09.001.CrossrefMedlineGoogle Scholar4. Selvarajah M, Nicholls K, Hewitson TD, Becker GJ. Targeted urine microscopy in Anderson-Fabry disease: a cheap, sensitive and specific diagnostic technique.Nephrol Dial Transplant. 2011; 26:3195–3202. doi: 10.1093/ndt/gfr084.CrossrefMedlineGoogle Scholar5. Honda T, Komatsu E, Furuse S, Mise N. Fabry disease diagnosed based on the detection of urinary mulberry bodies.Intern Med. 2016; 55:2903. doi: 10.2169/internalmedicine.55.7084.CrossrefMedlineGoogle Scholar6. Shimohata H, Ogawa Y, Maruyama H, Hirayama K, Kobayashi M. A renal variant of fabry disease diagnosed by the presence of urinary mulberry cells.Intern Med. 2016; 55:3475–3478. doi: 10.2169/internalmedicine.55.7367.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Fogazzi G, Garigali G, Pieruzzi F, Corbelli A, Fiordaliso F, Consonni D and Messa P (2021) A morphological classification of the fat particles found in the urinary sediment of patients with Fabry disease, Clinical Chemistry and Laboratory Medicine (CCLM), 10.1515/cclm-2021-0079, 59:11, (1832-1843), Online publication date: 26-Oct-2021., Online publication date: 1-Oct-2021. Yonishi H, Namba-Hamano T, Hamano T, Hotta M, Nakamura J, Sakai S, Minami S, Yamamoto T, Takahashi A, Kobayashi W, Maeda I, Hidaka Y, Takabatake Y, Sakai N and Isaka Y (2020) Urinary mulberry bodies as a potential biomarker for early diagnosis and efficacy assessment of enzyme replacement therapy in Fabry nephropathy, Nephrology Dialysis Transplantation, 10.1093/ndt/gfaa298, 37:1, (53-62), Online publication date: 31-Dec-2022. Martínez-Figueroa C, Cortés-Sarabia K, Catalán-Nájera H and Martínez-Alarcón M (2020) Mulberry bodies in the urine sediment of a patient with chronic kidney disease, Advances in Laboratory Medicine / Avances en Medicina de Laboratorio, 10.1515/almed-2020-0028, 1:3, Online publication date: 6-Oct-2020., Online publication date: 1-Sep-2020. Martínez-Figueroa C, Cortés-Sarabia K, Catalán-Nájera H and Martínez-Alarcón M (2020) Cuerpos de mora en sedimento urinario de una paciente con enfermedad renal crónica, Advances in Laboratory Medicine / Avances en Medicina de Laboratorio, 10.1515/almed-2019-0039, 1:3, Online publication date: 6-Oct-2020., Online publication date: 1-Sep-2020. Kato Y, Ishikawa A, Aoki S, Sato H, Ojima Y, Kagaya S and Nagasawa T (2019) Fabry Disease with Pacemaker Implantation as the Initial Event, Internal Medicine, 10.2169/internalmedicine.2468-18, 58:20, (2993-3000), Online publication date: 15-Oct-2019. Onishi R, Kanaoka K, Sugiura J, Tokunaga M, Takemoto Y, Onoue K, Yamamoto Y, Horii M and Saito Y (2018) A Cardiac Variant of Fabry Disease Diagnosed with Chance Urinary Mulberry Cells, Internal Medicine, 10.2169/internalmedicine.1177-18, 57:23, (3385-3388), Online publication date: 1-Dec-2018. December 2017Vol 10, Issue 12 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.117.004538PMID: 29203563 Originally publishedDecember 4, 2017 KeywordsFabry diseaseglomerular filtration ratehypertrophic cardiomyopathyhypertrophy, left ventricularmulberry bodyurinalysismutationPDF download Advertisement SubjectsCardiomyopathyHypertrophy
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