5.4 Phospholipidosis (M. Fabry-like lesion)

Definition: Phopholipidosis is a storage disorder characterized by an excessive accumulation of phopholipids and, morphologically, by the intracellular accumulation of myelin figures (myelinoid bodies) in various tissues.

Preliminary notes on myelin figures: The term “myelin” was coined by R.Virchow. Today, the term “myelinoid membranes” is used to describe markedly osmiophilic membranes and the term “myelin figures” is employed when such membranes show a stacked (“zebra bodies”), reticulated or whorled arrangement. Single membrane-bound myelin figures should be termed “myelinosomes”. They exhibit acid phosphatase activity, i.e. lysosomes.

Myelin figures are found in a wide variety of acquired metabolic disorders (including long-term treatment effects due to cationic amphiphilic drugs) and genetic disorders such as Gauchers, Niemann-Pick, Tay-Sachs disease and M. Fabry. In the latter glycosphingolipids -Globotriaosylceramide (Gb₃)- accumulate in the cells due to a alpha-galactosidase deficiency.

(F.N.Ghadially, Ultrastructual pathology of the cell and matrix. 3rd ed Butterworths (1988). U.Kodavanti, H.M.Mehendale: Pharmacological Reviews 42: 327-353)

Kidney:Only Fabry’s disease and cationic amphiphilic drugs play a role in the kidney as the cause of myelin figures. Rarely, individual myelin figures of unknown etiology are found. Well over 100 cationic amphiphilic drugs are potentially capable of inducing phospholipidosis, of these only a few have relevance for the kidney. Under physiological conditions (normal kidney), myelin figures are absent.

By light microscopy: The changes in the kidney due to drug-induced phospholipidosis are usually so discrete that they evade diagnosis. In particularly severe cases however, they may be so prominent that Fabry’s disease can be misdiagnosed. 

In classical cases of Fabry’s disease, foamy podocytes are evident. Vascular smooth muscle cells, as well as the tubular epithelium may also exhibit foam cell changes.  Foam cells reveal a positive reaction with fat staining (Sudan stain) in frozen sections and also reveal unspecific autofluorescence (lipids). After glutaraldehyde fixation, strong methylene blue staining inclusion bodies are seen in foam cells in semi-thin sections.

In the electron microscope, typical myelin figures are seen in foam cells.  In Fabry’s disease, as a rule, many podocytes are similarly affected. Endothelial and mesangial cells are only involved to a lesser extent.  Also the endothelium of arteries or peritubular capillaries, vascular smooth muscle cells, as well as the tubular epithelial cells can be affected to varying degrees.

With drug-induced phospholipidosis, cellular involvement is usually more discrete. Then, only scattered myelin figures are found in podocytes or tubular epithelium, less often the endothelium or smooth muscle cells are affected.

Chloroquine- induced phospholipidosis may be mistaken for Fabry’s disease in extreme cases. For this reason the diagnosis of Fabry’s disease must be confirmed by measurement of the alpha-galactosidase activity in serum. If myelin figures are found together with curvilinear bodies, Fabrys disease is unlikely because curvilinear bodies were never seen in Fabry`s disease . Curvilinear bodies must be systematically searched for, using magnifications of more than 15000 times. With all other genetic diseases that exhibit foam cells in glomeruli, these are either optically empty or reveal polymorphic inclusions (see table below).

The pathogenesis of drug related phopholipidosis is still unclear. Two possible mechanisms are discussed:

a), formation of indigestible complexes of cationic amphiphilic drugs and phospholipids, which accumulate and are stored as myelin figures in lysosomes

b), direct or indirect inhibition of phopholipases in lysosomes, resulting in accumulation and storage of phopholipids in form of myelin figures

(N. Anderson, J. Borlak Drug-induced phopholipidosis FEBS Letters 580,5533-5540 (2006).