Pathology of Fabry disease and iatrogenic chloroquine-induced lipidosis mimicking Fabry disease...

Pathology of Fabry disease and Pathology of Fabry disease and iatrogenic chloroquine-induced iatrogenic chloroquine-induced

lipidosis mimicking Fabry lipidosis mimicking Fabry diseasedisease

Dusan Ferluga

Institute of Pathology, Faculty of Medicine University of Ljubljana, Ljubljana, Slovenia

Fabry disease• Inherited lysosomal storage disease• Mutations of X-chromosome-linked gene for lysosomal

enzyme -galactosidase A• Progressive harmful intralysosomal accummulation of

glycosphingolipid residua• Variability in clinical presentation, histopathology and

course with regard to family-specific mutation, sex and age• In hemizygous men neurological, cardiac, and renal failure

in the fifth decade or even before • In heterozygous women a wide range of presentations

from asymptomatic carrier, slow or even severe progressive course

• Fabry disease – a hot topic of today medicine with the promising enzyme replacement therapy with recombinant human -galactosidase A

Renal pathology in Fabry disease

• Long assumed to be unique and distinguishable from other lysosomal storage diseases by characteristic cell distribution of electron dense and particularly lamellated, concentric myeloid or perpendicular zebra cytoplasmic inclusions in association with progressive sclerosing involvement of all nephron compartments

• The specificity of the Fabry renal histopathology has been questioned after few case reports on Fabry disease mimicking renal involvement by iatrogenic chloroquine-induced lipidosis

• The aim of our study was to explore systematically the incidence of chloroquine-induced lipidosis in our kidney biopsy files and to compare their biopsy findings with those of Fabry disease in hemizigous male and heterozygous female patients

Fabry disease patients from two familiesFabry disease patients from two families

PatientSex/Age

Gene mutation

-Gal A (serum)

NephrosclerosisGlom(%) Tu-int(%) Vasc

Lamellar bodies

U-prot (g/d)

S-Creat (mol/L)

M / 40 Arg363Pro 2.5% N 100 / 19 seg 95 +++ +++ dif 3.8 630

M / 26 Arg363Pro 1.4% N 12 / 8 seg 15 +

+++ dif 0.34 N

F / 46 Arg363Pro 22.9% N 32 / 14 seg 35 ++ +/++ foc 0.63 N

F / 45 Arg363Pro 4.6% N 48 / 32 seg 30 ++ ++ irreg 1.79 N

F / 58 Asn272Ser 16.1% N 6 / 0 seg 15 ++ +/++ foc 0.63 N

F / 44 Asn272Ser 25.6% N 0 15 + ++/+ irreg 0.12 N

M, 40 yrs


PatientSex/Age

Gene mutation

-Gal A (serum)


Lamellar bodies

U-prot (g/d)

S-Creat (mol/L)

M / 40 Arg363Pro 2.5% N 100 / 19 seg 95 +++ +++ dif 3.8 630

M / 26 Arg363Pro 1.4% N 12 / 8 seg 15 +

+++ dif 0.34 N




F / 44 Asn272Ser 25.6% N 0 15 + ++/+ irreg 0.12 N

M, 26 yrs


PatientSex/Age

Gene mutation

-Gal A (serum)


Lamellar bodies

U-prot (g/d)

S-Creat (mol/L)

M / 40 Arg363Pro 2.5% N 100 / 19 seg 95 +++ +++ dif 3.8 630

M / 26 Arg363Pro 1.4% N 12 / 8 seg 15 +

+++ dif 0.34 N




F / 44 Asn272Ser 25.6% N 0 15 + ++/+ irreg 0.12 N

F, 46 yrs


PatientSex/Age

Gene mutation

-Gal A (serum)


Lamellar bodies

U-prot (g/d)

S-Creat (mol/L)

M / 40 Arg363Pro 2.5% N 100 / 19 seg 95 +++ +++ dif 3.8 630

M / 26 Arg363Pro 1.4% N 12 / 8 seg 15 +

+++ dif 0.34 N




F / 44 Asn272Ser 25.6% N 0 15 + ++/+ irreg 0.12 N

F, 45 yrs


PatientSex/Age

Gene mutation

-Gal A (serum)


Lamellar bodies

U-prot (g/d)

S-Creat (mol/L)

M / 40 Arg363Pro 2.5% N 100 / 19 seg 95 +++ +++ dif 3.8 630

M / 26 Arg363Pro 1.4% N 12 / 8 seg 15 +

+++ dif 0.34 N




F / 44 Asn272Ser 25.6% N 0 15 + ++/+ irreg 0.12 N

F, 44 yrs

Chloroquine - historical milestonesChloroquine - historical milestones World War II – antimalarial agentDecades – antirrheumatic agent, widely used (RA, SLE)Side-effects (experimental animals, humans)1948 – myotoxicity on exp. rats (Nelson AA, Filzhugh GG)1959 – irreversible retinopathy in humans (Hobbs HE et al)1963 – chloroquine neuromyopathy in humans (Whisnant

JP et al)1971 – drug-induced lipidosis by amphiphilic catonic

drugs (Yamamota et al), chloroquine best known and most thoroughly investigated so far

1974 – lysosomotropic agents (de Duve C et al)1977 – chloroquine cardiomyopathy (Magnussen I, de Fine

Olivarius B)2003 – Chloroquine-induced phospholipidosis of the

kidney mimicking Fabry's disease – case report (Müller-Höcker J et al)

Literature on cLiterature on chloroquine-inducedhloroquine-induced renal renal lipidlipidosisosis

Case reports

Underlying

Disease

Chloroquine Time Cumm

Lamellar bodies

Curvilin bodies

Prot (g/d)

S-Creat (mg/dL)

Müller-Hocher J et al, 2003

Sjögren syndrome

11 mo 51 g +++/+ + cell type?

0 1.0-2.1

Albay D et al, 2005

Rheumat arthritis

18 mo 130 g +++/+ 0(muscle biopsy+)

traces 2.2

Bracamonte ER et al, 2006

Undefined autoimm

10 yrs intermitent

+++/+ 0 1.2 1.3

PatientsPatients (Kidney biopsy files 1987-2007)(Kidney biopsy files 1987-2007)

25 pts, mostly SLE, on chloroquine 250 mg/d (1day – 8yrs)

___________________________________________ Chloroquine treatment

Renal lipidosis

No. of

pts

Duration Cummulative Withdrawn before biopsy

Yes 6 (24%)

11 days – 4.5 yrs 5.3 – 413 g 0

Suspected 3 (12%)

37 days – 10 mo 11.7 – 79 g 0

No 2 (8%)

1 day – 2 days 0.5 – 1.0 g 0

No 14 (56%)

27 days – 5 yrs 9.3 – 460 g 3 mo – 8 yrs

CChloroquine-inducedhloroquine-induced lipidlipidosis mimicking osis mimicking Fabry diseaseFabry disease

Patients/Biopsies

Cumm dose

Biopsy dg Lamellar bodies

Curvilin bodies

Prot (g/d)

S-Creat (mol/L)

35/04 5.3 g LN II +/ 0 0.7 norm

49/01 60 g Lupus-like sy (Chr Tu-Int N)

++ + 0.3 128

95/07 140 g Lupus-like sy (Ac Tu-Int N)

++ + 0.1 220

99/97 0 LN I 0 0 0 norm

49/07 103 g LN III (C) ++ /+ 1.7 norm

142/99 25 g LN III (A) /+ 0 0.7 norm

50/03 33 g LN III (A) + 0 1.1 norm

109/04 0 LN IV-G (A) 0 2.6 norm

142/83 0 LN I 0 0 1.1 norm

184/06 413 g FSGS ++/+++ + 0.5 152

LB 35/04


Patients/Biopsies

Cumm dose


Curvilin bodies

Prot (g/d)

S-Creat (mol/L)

35/04 5.3 g LN II +/ 0 0.7 norm


++ + 0.3 128


++ + 0.1 220

99/97 0 LN I 0 0 0 norm

49/07 103 g LN III (C) ++ /+ 1.7 norm

142/99 25 g LN III (A) /+ 0 0.7 norm

50/03 33 g LN III (A) + 0 1.1 norm

109/04 0 LN IV-G (A) 0 2.6 norm

142/83 0 LN I 0 0 1.1 norm

184/06 413 g FSGS ++/+++ + 0.5 152

LB 95/07


Patients/Biopsies

Cumm dose


Curvilin bodies

Prot (g/d)

S-Creat (mol/L)

35/04 5.3 g LN II +/ 0 0.7 norm


++ + 0.3 128


++ + 0.1 220

99/97 0 LN I 0 0 0 norm

49/07 103 g LN III (C) ++ /+ 1.7 norm

142/99 25 g LN III (A) /+ 0 0.7 norm

50/03 33 g LN III (A) + 0 1.1 norm

109/04 0 LN IV-G (A) 0 2.6 norm

142/83 0 LN I 0 0 1.1 norm

184/06 413 g FSGS ++/+++ + 0.5 152

LB 142/99 – first kidney biopsy

LB 184/06 – second kidney biopsy

DB 6047/06 – first skeletal muscle biopsy

MBK 1/08 – second skeletal muscle biopsy

Mechanisms of inherited and chloroquine-induced Mechanisms of inherited and chloroquine-induced inhibition of lysosomal phospholipidinhibition of lysosomal phospholipid catabolismcatabolism

Disease Mechanism

Fabry disease X-chromosome-linked genetic defect of α-galactosidase A with consequent progressive intralysosomal accumulation of glycosphingolipid residues

Chloroquine-induced lipidosis

- Adsorption to plasma membrane and accumulation of lysosomotropic drug within lysosomes - Formation of amphiphilic cationic drug–polar lipid complexes resistant to digestion- Key role of drug-induced strong but reversible inhibition of lysosomal phospholipases A and C

ConclusionsConclusions

1. Chloroquine-induced lipidosis in the kidney is not so rare as it appears according to limited literature.

2. Lamellar and dense cytoplasmic inclusions by EM involving nearly all renal cells, particularly podocytes, are identical to those in inherited Fabry disease. To avoid wrong biopsy diagnosis pathologist must closely collaborate with clinicians and carefully search for curvilinear inclusions, which are not present in Fabry disease.

ConclusionsConclusions

3. The intensity of kidney involvement appears to be dose-dependant, but individual susceptibility has to be considered.

ConclusionsConclusions4. It appears that initial changes may develop in

less than a month of drug consumption. They remain for a long time focal and become only gradually after years widespread like in hemizygous male patients with Fabry disease.

The kidney lesion is principally reversible as confirmed by clinical improvements and disappearance of the cytoplasmic inclusions from kidney and skin biopsies. However, the significance of apparently persisting curvilinear bodies in repeat skeletal muscle biopsy more than a year after discontinuation of the chloroquine therapy remains to be clarified.

CollaboratorsCollaborators

Asta Hvala (EM)

Alenka Vizjak (IH)

Blaz Rozman (rheumatologist)

Jelka Lindic (nephrologist)

Pathology of Fabry disease and iatrogenic chloroquine-induced lipidosis mimicking Fabry disease...

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