Niemann Liver

Niemann-Pick disease Sphingomyeiinase Cer-i-P—choline Sphingomyelin Enlarged liver and spleen, mental retardation fatal in early life. 

For example, Niemann-Piclc disease is caused by a rare genetic defect in the enzyme sphingomyelinase, which cleaves phosphocholine from sphingomyelin. Sphingomyelin accumulates in the brain, spleen, and liver. The disease becomes evident in infants, and causes mental retardation and early death. More common is Tay-Sachs disease, in which ganglioside GM2 accumulates in the brain and spleen (Fig. 2) owing to lack of the enzyme hexosaminidase A. The symptoms of Tay-Sachs disease are progressive retardation in development, paralysis, blindness, and death by the age of 3 or 4 years. 

Proca DM, Niemann TH, Porcell AI, DeYoung BR. MOC31 immunoreactivity in primary and metastatic carcinoma of the liver report of findings and review of other utilized markers. Appl Immunohistochem Mol Morphol 2000 8 120-5. 

Niemann-Pick disease Liver and spleen enlargement Mental retardation About 30% with red spot in retina... 

Amyloidosis, fatty liver, glycogenoses, Wolman s syndrome, hyperchylomicronaemia, Wilson s disease, Zellweger s cerebrohepato renal syndrome, Niemann-Pick disease, mucopolysaccharidoses, etc. 

Putterman, C, Zelingher, X, Shouval, D. Liver failure and the sea-blue histiocyte/adult Niemann-Pick disease. Case report and review of the literature. J. Clin. Gastroenterol. 1992 15 146-149... 

Smanik, E.J., Tavill, A.S., Jacobs, G.H., Schafer, I.A., Farquhar, L., Weher, F.L., Mayes, J.T., Schnlaik, JA., Petrelli, M., Zirzow, G.C., Oliver, K.L., Miller, S-PJ ., Brady, R.O. Orthotopic liver transplantation in two adults with Niemann-Pick and Gaucher s disease implications for the treatment of inherited metabolic disease. Hepatology 1993 17 42-49... 

Zhou, H., Linke, R.R, Schaefer, H.E., Miibius, W., Pfeifer, U. Progressive liver failure in a patient with adult Niemann-Pick disease associated with generalized AL amyloidosis. Virchows Arch. 1995 426 635-639... 

Of the four subtypes of Niemann-Pick disease, type A is the most severe. It is inherited as a recessive disorder (i.e., a defective copy of the gene must be inherited from each parent) that results in an absence of the enzyme sphingomyelinase. The absence of this enzyme causes the storage of large amounts of sphingomyelin and cholesterol in the brain, bone marrow, liver, and spleen. 

Acid SMase-deficient mice have been generated (K. Horinouchi, 1995) and have been useful both as models for Niemann-Pick disease and to study the roles of acid SMase in cell signaling (P. Santana, 1996 D.J. Sillience, 2001). Cer derived from aberrantly high acid SMase activity also appears to play a role in disease because activation of acid SMase and generation of Cer has been found to play a key role in the liver cirrhosis and anemia in Wilson disease, which is caused by accumulation of Cu(2+) in cells (P.A. Lang, 2007). 

There are conflicting data on whether the availability of cholesterol and/or cholesteryl esters directly influences apo B secretion. Several studies have suggested that cholesterol supply can regulate VLDL secretion. For example, VLDL production in animals and man is decreased by statin treatment, and inhibition of cholesterol synthesis by a statin, an inhibitor of the rate-limiting step of cholesterol biosynthesis (Chapter 14), reduced VLDL secretion in perfused rat livers (M. Heimberg, 1990) and primary hepatocytes. However, this effect of statins can perhaps be ascribed to increased expression of LDL receptors rather than to a reduction in cholesterol synthesis (Section 7.1). Depletion of cholesterol in rodent hepatocytes by the ABCAl-dependent lipidation of apo A1 (Chapter 19) also decreases VLDL secretion (R. Lehner, 2004). Furthermore, the secretion of apo BlOO-containing VLDLs is increased in primary hepatocytes derived from Niemann-Pick Cl-deficient mice. Niemann-Pick Cl-deficiency causes a severe defect in trafficking of unesterified cholesterol out of the lysosomal/endosomal pathway and consequently, Niemann-Pick Cl-deficient hepatocytes accumulate 5- to 10-fold more unesterified cholesterol than do wild-type hepatocytes. In hepatocytes from Niemann-Pick Cl-deficient mice, cholesterol synthesis is increased and the rate of cholesterol esterification and the amount of the transcriptionally active form of SREBP-1 are also increased (J.E. Vance, 2007). However, because of multiple alterations in lipid metabolism in these hepatocytes, increased VLDL secretion cannot be attributed specifically to increased synthesis of cholesterol or cholesteryl esters. 

Tay-Sachs Gaucher s Niemann-Pick Brain Spleen, Uver Several, particularly liver and spleen Glycolipid (gangUoside G t) Cerebrosides containmg glucose Sphingomyelins... 

Fig. 3-38. Enlarged liver in patient with Niemann-Pick disease...

Partial answers to the pathogenesis of Niemann-Pick disease have been obtained recently. An enzyme, sphingomyelinase, which hydrolyzes sphingomyelin to yield phosphorylcholine and ceramide has been found and partially purified from liver. Drastic reduction in the activity of this enzyme has been found in at least some patients with Niemann-Pick disease (see Fig. 3-40). In other cases the biochemical defect remains unknown [125], especially in those forms of the disease in which cholesterol accumulates (Nova Scotia variant). 

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