Case 5 -
Iatrogenic Phospholipidosis Mimicking Fabry's Disease
University of Washington Medical Center
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Light microscopic examination of the paraffin-embedded sections stained with, silver methenamine
counterstained with hematoxylin and eosin (one of which was provided to you) demonstrated medulla and
renal cortex containing up to 4 intact glomeruli. The glomerular visceral epithelial cells were
diffusely enlarged and contained abundant, finely vacuolated cytoplasm (Figure 1). The glomeruli were
without inflammation or segmental sclerosis. Some of the tubular epithelial cells showed evidence of
acute tubular injury, characterized by vacuolization and blebbing of the apical cytoplasm into the
tubular lumina. There was mild, patchy interstitial fibrosis, associated with mild tubular atrophy.
Muscular arteries demonstrated mild intimal sclerosis. Arteriolar segments showed no significant
sclerosis. There was no evidence of vasculitis.
Case 5 - Slide 1
Material submitted for immunofluorescence microscopy contained 2 intact glomeruli. The
glomeruli, tubular basement membranes, and interstitium showed no significant staining for IgG, IgA, IgM,
kappa or lambda light chains, complement, fibrinogen, or albumin. Arterial vessels were not prominent in
Methylene blue-stained thick sections cut at 1 µm were prepared from all tissue
submitted for electron microscopy and contained only one glomerulus. Light microscopic examination
revealed dense intracytoplasmic granules within the glomerular visceral epithelial cells (Figure 2).
Upon ultrastructural examination, the glomerular visceral epithelial cells contained prominent
membrane-bound electron dense bodies with a multilamellar appearance, characteristic of myelin figures or
zebra bodies (Figures 3 and 4). Similar structures were focally present within mesangial cells,
glomerular endothelial cells, interstitial cells, tubular epithelial cells, and vascular endothelium.
The foot processes of overlying epithelial cells showed patchy effacement. No immune type electron dense
deposits were present within the glomeruli, tubular basement membranes, interstitium, or peritubular
Interpretation and Initial Morphologic Diagnosis
Renal biopsy with features characteristic of Fabry's disease, with superimposed acute tubular
injury/acute tubular necrosis and mild arteriosclerosis.
Based on the renal biopsy results, a measurement of the patient's leukocyte α-galactosidase A
enzyme activity was immediately obtained in order to confirm the diagnosis of Fabry's disease. This
test, performed on leukocytes, revealed a decreased enzyme level of 21 nmoles/hr/mg protein (normal mean
47). However, repeat testing on leukocytes and plasma obtained approximately one week later and
performed in a different referral laboratory demonstrated normal enzyme activity. Since
hydroxychloroquine is known to inhibit lysosomal enzymes, including the α-galactosidase A enzyme,
this therapy was discontinued. Mutational analysis by denaturing high performance liquid chromatography
(DHPLC) performed at the second referral laboratory showed no abnormalities in the patient's
α-galactosidase A gene. The patient was placed on angiotensin converting enzyme (ACE) inhibitor
therapy. At follow-up, 6 months following the renal biopsy, the patient's proteinuria had improved
slightly, dropping to 2158 mg/24 hours from her previous measured high of 3384 mg/24 hours. Her serum
creatinine decreased to 1.1 mg/dl (97 µmol/dl), but her reduced creatinine clearance persisted at 58
mL/min (0.97 mL/s). A repeat analysis of the patient's α-galactosidase A enzyme activity was
performed 6.5 months after the initial test and was within normal limits.
Final Clinicopathological Diagnosis
The renal biopsy morphologic findings were re-evaluated in light of the patient's
α-galactosidase A enzyme activity tests results, the lack of a detectable mutation in the
α-galactosidase A gene, and the patient's medication history. A final diagnosis of iatrogenic
phospholipidosis due to hydroxychloroquine was made.
Fabry's disease is one of several well-characterized lipidoses with a renal phenotype. This X-linked
disease is due to the inactivation of the lysosomal enzyme, α-galactosidase A, which can result in
the intracellular accumulation of globotriaosylceramide within a variety of renal cells, including
podocytes, glomerular endothelial cells, mesangial cells, tubular epithelium, interstitial foam cells,
vascular myocytes, and vascular endothelium
First described approximately 50 years ago, the
renal biopsy features of classic Fabry's disease are well characterized
examination of glomeruli characteristically shows enlarged podocytes with abundant, finely-vacuolated
cytoplasm, due to accumulated globotriaosylceramide. Although podocytes are predominantly affected,
accumulation of this storage product can occur in a variety of renal cells, including parietal epithelial
cells, mesangial cells and glomerular endothelial cells, distal and proximal tubular epithelium,
interstitial foam cells, vascular endothelium and vascular myocytes. As the disease progresses,
mesangial expansion, segmental glomerulosclerosis, and global glomerulosclerosis can occur. Advanced
disease is marked by progressive tubular atrophy and interstitial fibrosis . Immunofluorescence
microscopic studies are generally non-contributory. Electron microscopy reveals enlarged lysosomes
filled with characteristic electron dense lamellated membrane structures (Zebra bodies, myelin figures).
Progressive proteinuria is often associated with increased podocyte foot process effacement.
The differential diagnosis of intrarenal lipid accumulation includes various lysosomal storage
diseases. The most useful feature in distinguishing Fabry's disease from other forms of renal lipidosis
is the ultrastructural appearance of accumulated lipid as electron dense, multi-lamellated myelin figures
All other primary renal lipidoses have morphologic features distinct from Fabry's disease, which
reflects differences either in the cellular distribution of accumulated lipid material or in the
appearance of the storage material at the electron microscopic level (See Table 1 in Ref 4). Lipid
accumulation primarily affecting glomerular podocytes, resulting in abundant foamy cytoplasm similar to
that seen in Fabry's disease, is commonly found in infantile nephrosialidosis, GM-1 gangliosidosis,
I-Cell disease (mucolipidosis, type 2), Hurler's syndrome, Niemann-Pick disease, and Farber's disease
Accumulation of lipid with predominant involvement of glomerular mesangial and endothelial cells
is seen in Gaucher's disease, and lecithin-cholesterol acyltransferase (LCAT)
Disorders such as Refsum's disease and Sandhoff's disease (GM-2 gangliosidosis) primarily involve the
tubular epithelium and are unlikely to be confused with Fabry's disease
None of the
above lipidoses demonstrate prominent and widespread whorled myelin figures upon ultrastructural
examination, although such figures are occasionally encountered in Niemann-Pick disease.
This biopsy illustrated classic renal pathologic features of Fabry's disease, including prominent
vacuolization of visceral epithelial cells by light microscopy and demonstration of characteristic
intracellular myelin figures by electron microscopy. Many pathologists (including me) would regard these
features as diagnostic of Fabry's disease until proven otherwise, and this was conveyed to the referring
nephrologist as soon as the electron microscopic findings were obtained. However, both we and the
referring nephrologist had concerns about this surprising and unsuspected diagnosis, given the lack of
other symptoms or family history of Fabry's disease. We sought confirmation of this interpretation.
Measurement of the patient's α-galactosidase A enzyme activity demonstrated depressed enzymatic
activity, a finding widely considered as definitive proof of the carrier state in a female suspected of
having Fabry's Disease, seemingly confirming the diagnosis. We then scored this as a triumph for the
superiority of diagnostic nephropathology, and its servant, the nephropathologist, over other diagnostic
modalities with their lack of such penetrating insight into the basis for a patient's disease.
Only a week later, clouds appeared on the horizon. A second study of enzyme activity in plasma and in
leukocytes performed in a different laboratory on specimens obtained only 1 week later was within normal
limits, as was a third study performed 6 and ˝ months after the initial test. This prompted a
reconsideration of this patient's previous diagnosis and medication history. The predominant alternate
diagnostic consideration to Fabry's disease was iatrogenic phospholipidosis of the kidney, which has
morphologic features identical to Fabry's disease. Iatrogenic phospholipidosis has been reported in
association with several drugs, the most common being chloroquine and amiodarone
a weak base that becomes concentrated within lysosomes and inhibits key lysosomal enzymes, including
Due to the similarities in chemical structure, it is reasonable to
assume that hydroxychloroquine causes iatrogenic phospholipidosis in a manner similar to chloroquine.
Given our patient's long-term treatment with hydroxychloroquine, lack of family history, and lack of
additional symptoms of Fabry's disease, we favored a diagnosis of iatrogenic phospholipidosis due to
reduced circulating α-galactosidase activity resulting from inhibition by hydroxychloroquine. This
interpretation was confirmed with the results of the DNA mutational analysis test, which demonstrated a
normal α-galactosidase A gene sequence in this patient, and excluded the possibility that the
patient was a female carrier of a mutant gene.
Most reports of iatrogenic phospholipidosis have described morphologic features identical to those of
classic Fabry's disease. Due to the inability to distinguish the genetic and iatrogenic conditions based
on morphologic grounds alone, as this case illustrates, a diagnosis of Fabry's disease must be confirmed
by the demonstration of depressed enzymatic activity and/or by mutational analysis of the
α-galactosidase A gene. Genetic analysis is necessary to ensure detection of female carriers, who
may demonstrate normal enzymatic activity due to unequal X-chromosome inactivation. Any history of
exposure to implicated drugs should prompt the pathologist to consider the possibility of iatrogenic
phospholipidosis. Several case reports of patients with iatrogenic phospholipidosis indicate that
removal of the offending agent may lead to complete recovery of renal function and resolution of
Although these reports are encouraging, our patient has not demonstrated similar
recovery. Six months after discontinuation of hydroxychloroquine, our patient continues to excrete
significant urinary protein (2158 mg/24 hours) and shows a decreased creatinine clearance of 58 mL/min
(0.97 mL/s). This may reflect the fact that our patient was treated with hydroxychloroquine
intermittently for 10 years, while the patients reported by Albay et al.  and Muller-Hocker et al.
were exposed to chloroquine for much shorter time periods (18 months and 17 months, respectively).
It is noteworthy that the studies which established the efficacy of enzyme replacement therapy leading
to its approval for treatment of patients with Fabry's disease in the United States was based on removal
of globotriaosylceramide from endothelial cells in biopsy samples obtained from treated patient and
controls . Similar efficacy in removal of lipid from podocytes was not achieved. It is not clear
why this therapy is less effective for podocyte accumulation. One possibility is that the exogenously
administered enzyme is less able to gain entrance to podocytes compared to endothelial cells. In our
patient, the predominant lipid accumulation was within podocytes, while the endothelium was much less
affected. It is possible that our patient's failure to demonstrate significant improvement in clinical
renal parameters may reflect a similar inability to achieve adequate α-galactosidase A activity
within podocytes. The level of α-galactosidase A expression in normal podocytes and the degree of
lipid removal from podocytes required for disease abatement is not known. If the endogenous enzyme
activity in podocytes is normally low or absent, the patient may still require exogenous enzyme to remove
the lipid. However, if the process of enzyme entry into the podocyte is normally slow or nonexistent,
some patients may recover slowly or incompletely when the offending drug is removed and normal measurable
circulating enzyme activity is restored and/or replacement therapy is instituted.
In summary, we present a case of iatrogenic phospholipidosis with renal biopsy features
morphologically identical to classic Fabry's disease. In this case, an atypical presentation with lack
of additional Fabry's symptoms and a history of exposure to hydroxychloroquine led to further laboratory
testing which confirmed the proper diagnosis. Removal of the offending agent may not be sufficient to
restore renal function in patients with acquired phospholipidosis.
Erika Bracamonte, MD contributed extensively to the evaluation of this patient during her tenure as a
renal pathology fellow at the University of Washington and authored a case report (ref 4) from which much
of this presentation was obtained.
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