Glomerular mesangiolipidosis in Alagille syndrome (arteriohepatic dysplasia)

Abstract

Alagille syndrome is characterized by the association of chronic cholestasis with a paucity of interlobular bile ducts and a distinctive facies together with cardiovascular, skeletal and eye abnormalities. We examined the kidneys of 26 patients with this syndrome; 22 were under 3 years of age and 4 were 4, 6, 12 and 17 years old, respectively. Eighteen showed glomerular lesions of variable severity characterized by a mesangiolipidosis. In the 8 lesser affected patients light microscopy (LM) disclosed a fibrillar appearance of the mesangium, and electron microscopy (EM) showed lipid vacuoles widespread in the mesangial matrix. In the 10 patients who were affected to a greater degree LM and EM showed, in addition to the mesangial matrix changes, the presence of mesangial foam cells. Clinical signs of renal involvement were mild in all patients except for one who died from chronic renal failure at 8 months of age. The extent of mesangiolipidosis was not related to age but to the degree of cholestasis, the most severe lesions being observed in patients aged 3, 6, 8, and 14 months. The glomerular lesions observed in Alagille syndrome are strikingly similar to those observed in adults with lecithin-cholesterol acyl transferase deficiency and other conditions characterized by an increase in plasma lipoproteins rich in free cholesterol and in phospholipids. We conclude that glomerular involvement should be added to the characteristic features of Alagille syndrome. Also we found that the lipid deposition in the glomeruli of patients with Alagille syndrome is related to an abnormal lipid metabolism, which is the consequence of severe cholestasis. The most striking feature of our study is the early detection of the glomerular lesions, contrasting with the lack of overt clinical renal disease. Renal failure may be a major complication for patients with this syndrome in adulthood.

Features of alagille syndrome in 92 patients: Frequency and relation to prognosis

“…42,43 Recent data presented here and elsewhere document that renal and pancreatic (exocrine and endocrine) disease should routinely be considered during the evaluation of an AGS patient. [44][45][46][47][48][49] The presence of renal disease did not correlate with increased mortality in our patients and only rarely is it the cause of death in AGS patients. The diversity of manifestations within each organ system is intriguing.…”

Ectopic Notch Activation in Developing Podocytes Causes Glomerulosclerosis

“…Glomerular mesangiolipidosis, the glomerular lesion in Alagille syndrome (OMIM# 118450), a multisystem disorder featuring severe cholestasis caused by JAG1 or NOTCH2 mutations, 37 is characterized by lipid deposits within mesangial cells and matrix 38 and bears little resemblance to glomerular lesions demonstrated in Notch2 del1/ϩ ; Jag1 ϩ/Ϫ mice, which exhibit extrarenal phenotypes observed in humans with Alagille syndrome. 39 Because glomerular mesangiolipidosis is reported in conditions of abnormal lipid metabolism, 38 glomerulopathy in humans with Alagille syndrome is more likely to be an effect of cholestasis rather than a primary glomerular defect in Notch signaling.…”

Oncogenic role of the Notch pathway in primary liver cancer

“…The disease is a multi-organ disorder most commonly diagnosed by liver abnormalities, which lead to hepatic bile duct paucity and cholestasis at birth (18). Cardiac, skeletal and ophthalmological abnormalities, and less frequently renal or vascular deficiencies, are also observed in patients with AGS (19). Numerous renal abnormalities are observed in patients with AGS, including renovascular disease, renal tubular acidosis, tubulointerstitial nephritis and renal dysplasia/hypoplasia (20).…”