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• W2061994459 abstract "A 71-year-old African-American female was admitted to the hospital with hemoptysis, interstitial pneumonia, pleural and pericardial effusions, and mediastinal lymphadenopathy. There was a history of hypertension and chronic kidney disease, but her serum creatinine had been relatively stable at 1.6 mg/100 ml (141 mmol/l) for the past year. She was treated initially with ethambutol and azithromycin for possible mycobacterium avium intracellulare, but these were subsequently discontinued when no definite mycobacteria were identified on lung biopsy. She also received linezolid for possible staphylococcal pneumonia. Bronchoscopic biopsy and examinations of pleural and pericardial fluid were nondiagnostic. During her hospital course, she developed cardiac arrhythmia and was treated with amiodarone. She was discharged 3 weeks after admission with a diagnosis of interstitial pneumonia of unclear etiology. Her serum creatinine at discharge was 2.4 mg/100 ml (212 mmol/l), but over the next 4 months, it slowly increased to 3.5 mg/100 ml (309 mmol/l). She was re-admitted for further evaluation. Past medical history was significant for hypertension, positive antinuclear antibody (first detected before hydralazine treatment), positive tuberculin skin test, hemoptysis, interstitial lung disease and mediastinal lymphadenopathy from unclear etiologies, hypertrophic cardiomyopathy, mitral regurgitation, and aortic insufficiency. Home medications included amiodarone, calcium acetate, iron, furosemide, potassium, hydralazine, prednisone, pantoprazole, sodium bicarbonate, clonidine, glargine insulin, and nifedipine. During questioning, it was discovered that the patient had been mistakenly taking a high dose of amiodarone (200 mg three times a day) for the past 4 months. The dosage was decreased to 200 mg/day and subsequently discontinued a few days later. Family history was remarkable for a deceased brother with end stage renal disease presumed to be due to diabetic nephropathy. Review of systems was significant for dyspnea, but otherwise was negative for burning sensation in her extremities, chronic abdominal pain, stroke, skin rash, or foamy urine. On admission, her physical examination revealed an obese female with a blood pressure of 162/76 mm Hg and a heart rate of 76. She was afebrile. There was a systolic murmur, but the rest of the examination was unremarkable. Specifically, there was no evidence of angiokeratoma, bluish-gray skin discoloration, or neurological abnormality. Laboratory values are illustrated inTable 1. Her perinuclear anti-neutrophil cytoplasmic antibody was positive at 32 a.u./ml (normal <19 a.u./ml), and an antinuclear antibody was positive at 1:160 (homogeneous). She underwent diagnostic renal biopsy.Table 1Laboratory valuesSerum/blood (reference range) Blood urea nitrogen (mg/100 ml)62 (7–17) Creatinine (mg/100 ml)3.5 (0.7–1.2)Urine (reference range) UrinalysispH 7, specific gravity 1.014, 30 mg protein/100 ml Microscopy5–20 white blood cells/high power field1–4 red blood cells/high power fieldNo castsSerologic tests (reference range) Antinuclear antibody1:160 (negative) Anti-neutrophil cytoplasmic antibody myeloperoxidase32 a.u./ml (<19 a.u./ml) Serine protease38 a.u./ml (<20 a.u./ml) C3135.7 mg/100 ml (90–180) C424 mg/100 ml (16–38) DNA antibodyNegative Hepatitis B antigenNonreactive HCVNonreactive Aspartate aminotransferase737 (14–36 U/l) Alanine aminotransferase584 (9–52 U/l) Rheumatoid factor16 IU/ml (<10 IU/ml) Open table in a new tab There were six glomeruli in the sections for light microscopy. Two were globally sclerotic, and the remaining glomeruli showed segmental mildly increased mesangial matrix with mild mesangial hypercellularity. Some of the capillary lumina were dilated and filled with vacuolated cells (Figure 1). No vacuolation was identified in the visceral epithelial cells with the periodic acid-Schiff hematoxylin and silver stains. There was patchy mild interstitial fibrosis. Some of the tubules were quite dilated and contained hyaline casts. There was no significant interstitial inflammation. The arterioles were unremarkable. One medium-sized artery at the corticomedullary junction showed moderate intimal fibrous thickening. Sections for immunofluorescence contained four glomeruli. There was no staining for IgG, IgM, IgA, C1q, C3, albumin or light chains in the glomeruli, vessels, or tubular basement membranes. Examination of the semi-thin sections by light microscopy revealed small inclusions in visceral epithelial and mesangial cells, as well as occasional proximal tubular epithelial cells. No inclusions were noted in parietal epithelial or endothelial cells. Ultrastructural examination of two glomeruli revealed mildly increased mesangial matrix. The capillary basement membranes showed moderate thickening due to widening of the lamina densa as well as focal expansion of the subendothelial space. In some capillary loops, the subendothelial zone was lucent and contained fluffy material. Many glomerular capillaries were occluded by vacuolated cells (Figure 2). The foot processes were focally effaced. Numerous lamellated lipid inclusions (‘myeloid bodies’) were noted, primarily in visceral epithelial cells, but also occasionally in mesangial cells and tubular epithelial cells (Figure 3a). No inclusions were identified in endothelial cells.Figure 3Comparison of ultrastructural findings in amiodarone-induced phospholipidosis and Fabry disease. (a) Electron micrograph showing enlarged visceral epithelial cells with numerous large lipid inclusions. The capillary wall is mildly thickened, and there is focal effacement of the foot processes (original magnification × 12,600). (b) Lipid inclusions in visceral epithelial cells from a patient who has Fabry disease. Note that inclusions may be relatively sparse (original magnification × 12,600).View Large Image Figure ViewerDownload (PPT) The biopsy was interpreted as showing features suggestive of Fabry disease, with superimposed mild interstitial fibrosis and moderate arteriosclerosis. In light of the kidney biopsy findings in association with her underlying cardiac disease and positive family history of renal disease, an assay for plasma α-galactosidase A was performed at Mt. Sinai School of Medicine. The plasma α-galactosidase A level was low at 2.2 U/ml (normal range 6.2–18.6 U/ml). Assay of leukocyte α-galactosidase A was not performed. Subsequently, DNA sequencing for mutations in the α-galactosidase gene was also performed at Mt. Sinai School of Medicine. No mutation was identified in the coding regions or adjacent intron/exon boundaries of the patient's α-galactosidase gene. Independent slit-lamp examination by two ophthalmologists revealed cornea verticillata, which are golden-brown or gray opacities that branch out from a central whorl, usually across the inferior cornea (Figure 4). This finding supports a diagnosis of systemic lipidosis, but it does not differentiate Fabry disease from drug-induced phospholipidosis. Because of the negative α-galactosidase gene mutation studies and lack of explanation for the cause of the relatively sudden decline in her renal function, we explored alternative explanations for renal phospholipidosis. Gentamycin, chloroquine, and hydroxychloroquine are cationic amphiphilic drugs that have been reported as causes of drug-induced phospholipidosis with renal biopsy findings similar to those in Fabry disease,1.Albay D. Adler S.G. Philipose J. et al.Chloroquine-induced lipidosis mimicking Fabry disease.Mod Pathol. 2005; 18: 733-738Crossref PubMed Scopus (61) Google Scholar,2.Müller-Höcker J. Schmid H. Weiss M. et al.Chloroquine-induced phospholipidosis of the kidney mimicking Fabry's disease: case report and review of the literature.Hum Pathol. 2003; 34: 285-289Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar,3.Bracamonte E.R. Kowalewska J. Starr J. et al.Latrogenic phospholipidosis mimicking Fabry disease.Am J Kidney Dis. 2006; 48: 844-850Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar,4.Woywodt A. Hellweg S. Schwarz A. et al.A wild zebra chase.Nephrol Dial Transplant. 2007; 22: 3074-3077Crossref PubMed Scopus (18) Google Scholar but the patient had never received any of those medications. However, amiodarone is also a cationic amphiphilic drug, and it is well known to cause lamellated phospholipid inclusions in lung biopsies from patients with amiodarone pulmonary toxicity.5.Jessurun G.A.J. Crijns H.J.G.M. Amiodarone pulmonary toxicity.Br Med J. 1997; 314: 619-620Crossref PubMed Google Scholar Moreover, amiodarone and other cationic amphiphilic drugs are known to cause cornea verticillata indistinguishable from that of Fabry disease.6.Hauser A.C. Lorenz M. Sunder-Plassmann G. The expanding clinical spectrum of Anderson–Fabry disease: a challenge to diagnosis in the novel era of enzyme replacement therapy.J Intern Med. 2004; 255: 629-636Crossref PubMed Scopus (25) Google Scholar Therefore, we suspected that amiodarone was the cause of her phospholipidosis. As there are data showing that antioxidants such as silymarin and vitamin E may reduce lysosomal phospholipidosis in amiodarone toxicity in animals,7.Agoston M. Orsi F. Feher E. et al.Silymarin and vitamin E reduce amiodarone-induced lysosomal phosphoplipidosis in rats.Toxicology. 2003; 190: 231-241Crossref PubMed Scopus (45) Google Scholar she was empirically placed on vitamin E treatment. Following discontinuation of amiodarone, her creatinine slowly decreased. Her serum creatinine 2 and 3 months after discontinuation of amiodarone declined to 2.7 (239 mmol/l) and 2.4 mg/100 ml (212 mmol/l), respectively. Repeat measurement of her plasma α-galactosidase A level 3 months after discontinuation of amiodarone was 0.148 U/l (normal range 0.016–0.200 U/l; performed by ARUP Laboratories, Salt Lake City, UT, USA). It is worth noting that her aspartate aminotransferase and alanine aminotransferase were also elevated on admission and gradually improved after the withdrawal of amiodarone. These abnormal values probably represented amiodarone hepatotoxicity, although liver biopsy was not performed. In retrospect, the patient's positive perinuclear anti-neutrophil cytoplasmic antibody may have been secondary to treatment with hydralazine. The final diagnosis was amiodarone-associated renal and corneal phospholipidosis mimicking Fabry disease. Intracellular phospholipid accumulation as concentric lamellar bodies (zebra bodies or myelin figures) in kidney biopsy specimens is a well-recognized finding in Fabry disease, which is an X-linked lysosomal storage disorder secondary to α-galactosidase A deficiency, resulting in accumulation of glycosphingolipids (particularly globotriaosylceramide) in various tissues. However, phospholipidosis can also be induced by cationic amphiphilic drugs, which are compounds that contain an aromatic or aliphatic ring structure and a hydrophilic region that is positively charged at physiologic pH.8.Reasor M.J. Kacew S. Drug-induced phospholipidosis: are there functional consequences?.Exp Biol Med. 2001; 226: 825-830PubMed Google Scholar For example, gentamycin has long been known to cause ‘myelin bodies’ in kidney biopsy specimens that are similar to those of Fabry disease, although in the case of gentamycin toxicity, the deposits are confined to tubular epithelium. Hydroxychloroquine and chloroquine, which are potent inhibitors of lysosomal phospholipase A and C, are additional examples of amphiphilic drugs that cause lamellated phospholipid inclusions in kidneys mimicking Fabry disease.1.Albay D. Adler S.G. Philipose J. et al.Chloroquine-induced lipidosis mimicking Fabry disease.Mod Pathol. 2005; 18: 733-738Crossref PubMed Scopus (61) Google Scholar,2.Müller-Höcker J. Schmid H. Weiss M. et al.Chloroquine-induced phospholipidosis of the kidney mimicking Fabry's disease: case report and review of the literature.Hum Pathol. 2003; 34: 285-289Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar,3.Bracamonte E.R. Kowalewska J. Starr J. et al.Latrogenic phospholipidosis mimicking Fabry disease.Am J Kidney Dis. 2006; 48: 844-850Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar,4.Woywodt A. Hellweg S. Schwarz A. et al.A wild zebra chase.Nephrol Dial Transplant. 2007; 22: 3074-3077Crossref PubMed Scopus (18) Google Scholar As noted above, amiodarone is also a cationic amphiphilic drug, and its ability to produce similar inclusions in various tissues is not surprising. However, although it is a well-known cause of pulmonary and hepatic toxicity, significant renal toxicity has not been described. In particular, there have not been any previous reports of myelin bodies in amiodarone-induced nephrotoxicity in humans. Electron microscopic studies in amiodarone-induced pulmonary toxicity have shown lamellated phospholipid inclusions similar to those observed in Fabry disease.9.Liu F.L. Cohen R.D. Downar E. et al.Amiodarone pulmonary toxicity: functional and ultrastructural evaluation.Thorax. 1986; 41: 100-105Crossref PubMed Scopus (60) Google Scholar On the other hand, the occlusion of glomerular capillary lumina by vacuolated histiocytes in our patient is not typical of Fabry disease. Similar findings were noted by Albay et al.1.Albay D. Adler S.G. Philipose J. et al.Chloroquine-induced lipidosis mimicking Fabry disease.Mod Pathol. 2005; 18: 733-738Crossref PubMed Scopus (61) Google Scholar in a patient with chloroquine-induced lipidosis, and they suggested that they might be a distinguishing feature unique to chloroquine cell injury. Müller-Höcker et al.2.Müller-Höcker J. Schmid H. Weiss M. et al.Chloroquine-induced phospholipidosis of the kidney mimicking Fabry's disease: case report and review of the literature.Hum Pathol. 2003; 34: 285-289Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar did not mention these changes in their report of a patient with chloroquine toxicity, but one of the figures in their paper shows a capillary luminal cell with similar features. In conjunction with the findings in our case, it is reasonable to suggest that this abnormality is a common feature of cationic amphiphilic drugs. However, it should be mentioned that Bracamonte et al.3.Bracamonte E.R. Kowalewska J. Starr J. et al.Latrogenic phospholipidosis mimicking Fabry disease.Am J Kidney Dis. 2006; 48: 844-850Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar specifically noted that such histiocytes were not present in their case of hydroxychloroquine renal toxicity, nor did Woywodt et al.4.Woywodt A. Hellweg S. Schwarz A. et al.A wild zebra chase.Nephrol Dial Transplant. 2007; 22: 3074-3077Crossref PubMed Scopus (18) Google Scholar mention this finding. There are several mechanisms by which cationic amphiphilic drugs induce phospholipidosis, and they may not be exactly the same for each drug. In general, these drugs inhibit the activity of lysosomal phospholipases, resulting in the accumulation of one or more classes of phospholipids in lysosomes.8.Reasor M.J. Kacew S. Drug-induced phospholipidosis: are there functional consequences?.Exp Biol Med. 2001; 226: 825-830PubMed Google Scholar This inhibition may occur when cationic amphiphilic drugs bind to hydrophobic and hydrophilic moieties of phospholipids, resulting in complexes that are undigestible by lysosomal phospholipases.8.Reasor M.J. Kacew S. Drug-induced phospholipidosis: are there functional consequences?.Exp Biol Med. 2001; 226: 825-830PubMed Google Scholar However, there is also evidence that cationic amphiphilic drugs directly inhibit lysosomal phospholipases. Studies in an in vitro cell culture model showed inhibition of phospholipases A1 and A2 by amiodarone, which prevented lysosomal phospholipid degradation and thus led to accumulation in various cell types.10.Martin W.J. Kachel D.L. Vilen T. et al.Mechanism of phospholipidosis in amiodarone pulmonary toxicity.J Pharmacol Exp Ther. 1989; 251: 272-278PubMed Google Scholar Similarly, chloroquine is known to inhibit a number of lysosomal phospholipases.11.Fredman P. Klinghardt G.W. Svennerholm L. Effect of chloroquine on the activity of some lysosomal enzymes involved in ganglioside degradation.Biochem Biophys Acta. 1987; 917: 1-8Crossref PubMed Scopus (20) Google Scholar,12.Shaikh N.A. Downar E. Butany J. Amiodarone, an inhibitor of phospholipase activity: a comprehensive study of the inhibitory effects of amiodarone, chloroquine and chlorpromazine.Mol Cell Biochem. 1987; 76: 163-172Crossref PubMed Scopus (65) Google Scholar On the basis of the above observations, the decrease in α-galactosidase A level in our patient noted just after the biopsy was performed is probably not surprising. In vitro studies of chloroquine have shown a specific inhibitory action on α-galactosidase activity.13.Inagaki M. Katsumoto T. Nanba E. et al.Lysosomal glycosphingolipid storage in chloroquine-induced alpha-galactosidase-deficient human endothelial cells with transformation by simian virus 40: in vitro model of Fabry disease.Acta Neuropathol. 1993; 85: 272-279Crossref PubMed Scopus (14) Google Scholar Although a specific effect on α-galactosidase A has not been shown for amiodarone, it is certainly not unreasonable to expect that it might occur. As the patient's plasma α-galactosidase A level returned to the normal range within several months after stopping amiodarone therapy, we suspect that the temporary decrease was secondary to amiodarone toxicity. Lipidosis-inducing drugs such as amiodarone, chloroquine, amodiaquine, benoquin, tilorone, and gentamycin may also cause intraepithelial corneal deposits in a verticillate pattern (cornea verticillata) similar to Fabry disease.14.D’Amico D.J. Kenyon K.R. Drug-induced lipidoses of the cornea and conjunctiva.Int Ophthalmol. 1981; 4: 67-76Crossref PubMed Scopus (31) Google Scholar,15.Chew E. Ghosh M. McCulloch C. Amiodarone-induced cornea verticillata.Can J Ophthalmol. 1982; 17: 96-99PubMed Google Scholar However, in only one of the reports of renal toxicity associated with hydroxychloroquine or chloroquine were corneal lesions described.4.Woywodt A. Hellweg S. Schwarz A. et al.A wild zebra chase.Nephrol Dial Transplant. 2007; 22: 3074-3077Crossref PubMed Scopus (18) Google Scholar In one case report of chloroquine toxicity, there is no specific mention of corneal involvement, but the authors state that no clinical features of Fabry disease were identified.1.Albay D. Adler S.G. Philipose J. et al.Chloroquine-induced lipidosis mimicking Fabry disease.Mod Pathol. 2005; 18: 733-738Crossref PubMed Scopus (61) Google Scholar In the other two reports, the authors specifically state that there was no corneal involvement.2.Müller-Höcker J. Schmid H. Weiss M. et al.Chloroquine-induced phospholipidosis of the kidney mimicking Fabry's disease: case report and review of the literature.Hum Pathol. 2003; 34: 285-289Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar,3.Bracamonte E.R. Kowalewska J. Starr J. et al.Latrogenic phospholipidosis mimicking Fabry disease.Am J Kidney Dis. 2006; 48: 844-850Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar On the other hand, corneal involvement in patients who are taking amiodarone appears to be quite common. In one study, 35 of 37 patients who were taking amiodarone developed cornea verticillata.15.Chew E. Ghosh M. McCulloch C. Amiodarone-induced cornea verticillata.Can J Ophthalmol. 1982; 17: 96-99PubMed Google Scholar Cornea verticillata have been shown to be reversible after discontinuation of amiodarone.15.Chew E. Ghosh M. McCulloch C. Amiodarone-induced cornea verticillata.Can J Ophthalmol. 1982; 17: 96-99PubMed Google Scholar In our patient, follow-up ophthalmologic examination performed 4 months after discontinuation of amiodarone showed improvement but persistence of cornea verticillata. Induction of lipidosis by cationic amphiphilic drugs is dose dependent, and discontinuation of these drugs can lead to reversal of phospholipidosis.8.Reasor M.J. Kacew S. Drug-induced phospholipidosis: are there functional consequences?.Exp Biol Med. 2001; 226: 825-830PubMed Google Scholar However, in humans, there is a paucity of data on the rate of reversal. In one case report of hydroxychloroquine renal toxicity, the primary renal abnormality was increasing proteinuria with only mild elevation of the serum creatinine.3.Bracamonte E.R. Kowalewska J. Starr J. et al.Latrogenic phospholipidosis mimicking Fabry disease.Am J Kidney Dis. 2006; 48: 844-850Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar Six months after the renal biopsy, proteinuria had improved slightly (decreasing from a high of 3.38 g/24 h to 2.16 g/24 h), and serum creatinine had returned to baseline levels. In the other report of hydroxychloroquine toxicity, the patient presented with new-onset proteinuria, and 15 months after renal biopsy, her proteinuria still ranged between 1.8 and 5 g/day.4.Woywodt A. Hellweg S. Schwarz A. et al.A wild zebra chase.Nephrol Dial Transplant. 2007; 22: 3074-3077Crossref PubMed Scopus (18) Google Scholar In the two cases of chloroquine toxicity,1.Albay D. Adler S.G. Philipose J. et al.Chloroquine-induced lipidosis mimicking Fabry disease.Mod Pathol. 2005; 18: 733-738Crossref PubMed Scopus (61) Google Scholar,2.Müller-Höcker J. Schmid H. Weiss M. et al.Chloroquine-induced phospholipidosis of the kidney mimicking Fabry's disease: case report and review of the literature.Hum Pathol. 2003; 34: 285-289Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar parameters of renal function had recovered to pretreatment levels after 9 and 12 months. In our patient, the serum creatinine has declined from a high of 3.5 mg/100 ml (309 mmol/l) to 2 mg/100 ml (176 mmol/l) 5 months after discontinuation. This is still 25% higher than her baseline level before amiodarone therapy, but based on the length of recovery time for the patients with hydroxychloroquine or chloroquine toxicity, it is possible that additional recovery of renal function will occur with longer follow-up. In summary, phospholipidosis can be induced by a number of cationic amphiphilic drugs, including amiodarone, which cause renal and corneal morphological findings mimicking Fabry disease. A high index of suspicion is warranted if a renal biopsy is suggestive of Fabry disease, because these patients and their family members may benefit from enzyme replacement therapy.16.Warnock D.G. Fabry disease: diagnosis and management, with emphasis on renal manifestations.Curr Opin Nephrol Hypertens. 2005; 14: 87-95Crossref PubMed Scopus (47) Google Scholar As the genetic and iatrogenic conditions cannot be distinguished on morphological criteria alone, the diagnosis must be confirmed by measurement of enzymatic activity and/or mutational analysis of the α-galactosidase A gene. We gratefully acknowledge the help of Dr Balamurali Ambati and Michael Stanley from Medical College of Georgia, who took the photograph of cornea verticillata." @default.
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• W2061994459 title "Progressive renal insufficiency associated with amiodarone-induced phospholipidosis" @default.
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