Nephropathology
   
Case 95
Diagnosis
 
     
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Diagnosis: Lecithin-Cholesterol Acyltransferase Deficiency

Lecithin-cholesterol acyltransferase (LCAT) is a key enzyme involved in reverse cholesterol transport from the peripheral tissues to the liver. LCAT deficiency, in which this enzyme is congenitally absent, is a genetic disease that impairs the esterification of free cholesterol in the plasma, leading to accumulation of phospholipids, including lecithin, in the organs of the body; the main clinical manifestations are corneal opacities, normochromic anemia and renal disorder.

There are two forms of the disease: familial LCAT deficiency in which there is complete LCAT deficiency, and fish eye disease in which there is a partial deficiency. Both are autosomal recessive disorders caused by mutations of the LCAT gene. Symptoms of the familial form include diffuse corneal opacities, target cell hemolytic anemia and proteinuria with renal failure. Fish eye disease only causes progressive corneal opacification. Renal failure is the major cause of morbidity and mortality in complete LCAT deficiency, while in partial deficiency (fish eye disease) major cause for morbidity is visual impairment due to corneal opacity. The patients have very low HDL cholesterol and high triglyceride level. Definitive diagnosis rest on LCAT gene analysis for mutation and studies of enzyme activity (Modified from Wikipedia - [Link]).

Laboratory findings in familial LCAT deficiency: Normochromic normocytic anemia with anisopoikilocytosis, target cells, stomatocytes, and hematologic evidence of hemolysis may be present; proteinuria is commonly detected during the second or third decade of life; less common findings include hyaline and granular casts and red blood cells; progressive renal insufficiency; low concentrations of HDL cholesterol (generally < 10mg/dL), high concentrations of plasma unesterified cholesterol, low concentrations of plasma cholesterol ester, elevated very low-density lipoprotein (VLDL) and triglyceride levels, negligible plasma LCAT activity (Raghavan V. Lecithin-Cholesterol Acyltransferase Deficiency. In: eMedicine. Consulted: January 2014 [Link to the website]).

Renal biopsy shows glomerular changes: lipid deposition with prominent accumulation of foam cells, peculiar thrombus-like deposits (Figures 3, 4, 7, 9 of the case), capillary walls are thickened with bubbly, vacuolated or honeycomb appearance. Silver stained sections show craters and vacuolization of the GBM resembling late-stage membranous GN; double contours are often noted. Mesangium is often expanded, with vacuolated appearance, and contains acellular, eosinophilic matrix that accumulates in areas of segmental sclerosis. Tubules and interstitium show unspecific changes. IF is negative or there are entrapment of IgM and/or C3. Electron microscopy is very useful for diagnosis: glomerular epimembranous, intramembranous, subendothelial, and mesangial lipid deposits. The lipids are partly deeply osmiophilic, with cross-striated curvilinear serpinginous fibrils, rounded lamellar densities, and granular densities. Densely osmiophilic GBM deposits have resembled the glomerular alterations of dense deposit desease. The renal abnormality, although easily recognizable, is not exactly specific, because similar lipid deposits occur in kidney of patients with chronic liver disease, who also have elevated serum lipoproteins (Heptinstall's Pathology of the Kidney, 6° ed. Wolters Kluwer / Lippincott Williams & Wilkins, 2007).

Our patient had corneal opacities and he had not family history of renal disease. Laboratory tests revealed an extremely low level of serum HDL and undetectable serum LCAT activity.

Inhibitory anti-LCAT antibodies that can lead to glomerular lesions similar to those observed in LCAT deficiency have been described: non familiar forms (Takahashi S, et al. Nephrotic syndrome caused by immune-mediated acquired LCAT deficiency. J Am Soc Nephrol. 2013;24:1305-12. [PubMed link]; Simonelli S, et al. Severe high-density lipoprotein deficiency associated with autoantibodies against lecithin-cholesterol acyltransferase in non-Hodgkin lymphoma. Arch Intern Med. 2012;172:179-81. [PubMed link]).

Images of corneal opacities and electron microscopy: Link 1; Link 2.

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References

  • Raghavan V. Lecithin-Cholesterol Acyltransferase Deficiency. In: eMedicine. Consulted: January 2013 [Link to the website]
  • Hirashio S, Ueno T, Naito T, Masaki T. Characteristic kidney pathology, gene abnormality and treatments in LCAT deficiency. Clin Exp Nephrol. 2013 Oct 31. [Epub ahead of print] [PubMed link]
  • Takahashi S, Hiromura K, Tsukida M, Ohishi Y, Hamatani H, Sakurai N, Sakairi T, Ikeuchi H, Kaneko Y, Maeshima A, Kuroiwa T, Yokoo H, Aoki T, Nagata M, Nojima Y. Nephrotic syndrome caused by immune-mediated acquired LCAT deficiency. J Am Soc Nephrol. 2013;24(8):1305-12.  [PubMed link]
  • Simonelli S, Gianazza E, Mombelli G, Bondioli A, Ferraro G, Penco S, Sirtori CR, Franceschini G, Calabresi L. Severe high-density lipoprotein deficiency associated with autoantibodies against lecithin:cholesterol acyltransferase in non-Hodgkin lymphoma. Arch Intern Med. 2012;172(2):179-81. [PubMed link]
  • Strøm EH, Sund S, Reier-Nilsen M, Dørje C, Leren TP. Lecithin: Cholesterol Acyltransferase (LCAT) Deficiency: renal lesions with early graft recurrence. Ultrastruct Pathol. 2011;35(3):139-45. [PubMed link]
  • Palmiero PM, Sbeity Z, Liebmann J, Ritch R. In vivo imaging of the cornea in a patient with lecithin-cholesterol acyltransferase deficiency. Cornea. 2009;28(9):1061-4. [PubMed link]

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