Caveolin-1 associates with the endo/lysosomal machinery of cells in culture, suggesting that it functions at these organelles independently of its contribution to cell surface caveolae. Here we explored mice lacking caveolin-1 specifically in the retinal pigment epithelium (RPE Support of the neural retina generally and of adjacent photoreceptor neurons specifically by the retinal pigment epithelium (RPE) 5 is essential for vision (1). A major function of the RPE is its contribution to photoreceptor outer segment renewal, a continuous and life-long rejuvenation process that involves the formation of new membrane disks at the proximal end of the outer segment and diurnal shedding of distal spent outer segment tips (2). Outer segment renewal is critical for photoreceptor function and survival, and any abnormality is thought to impair vision. RPE cells participate in outer segment renewal by clearing shed photoreceptor outer segment fragments (POS) by receptor-mediated phagocytosis (3).Mechanistically, RPE phagocytosis belongs to a family of conserved non-inflammatory clearance phagocytosis pathways that other cell types use to remove apoptotic cells and debris. These pathways have in common that their failure to efficiently clear debris contributes to human disease. However, unlike other forms of phagocytosis, RPE clearance of POS occurs in a strict diurnal rhythm that is regulated by light and circadian mechanisms (4). This is a unique advantage for RPE phagocytosis studies because all steps of the synchronized phagocytic process may be quantified precisely in situ in the intact, undisturbed retinas of experimental animals. Content in the RPE of engulfed rod POS phagosomes peaks shortly after light onset and declines characteristically within several hours as RPE cells complete digestion of their phagocytic load before the next burst of intake (5).Like other phagocytic pathways, ingested phagosomes in the RPE fuse with lysosomal vesicles to form phagolysosomes. In POS phagolysosomes, degradation of opsin, which constitutes ϳ85% of POS protein, requires the aspartic protease cathepsin D and phagosomal acidification (6, 7). Because RPE cells are post-mitotic in the mammalian eye and ingest numerous POS daily, prompt and complete POS engulfment is essential to prevent gradual buildup of undigested debris in the RPE (8). Inefficient RPE lysosomal function causes accumulation of debris in human and experimental animal RPE that can be toxic and
Introduction Glycogenic hepatopathy (GH) is an infrequently described complication of predominantly type 1 diabetes characterized by liver dysfunction and hepatomegaly. This condition is different from the more common nonalcoholic fatty liver disease (NAFLD) which is clinically indistinguishable. Liver biopsy is currently the only way to differentiate the two conditions. We present a 19 year old female with persistent transaminasemia secondary to glycogenic hepatopathy associated with poorly controlled type 1 diabetes. Case Description A 19 year old female was admitted with DKA secondary to facial cellulitis. She had a past history of poorly controlled type 1 DM since age 9, proteinuria, and transaminasemia since age 14. Initial labs showed elevated plasma glucose 365 mg/dL, bicarbonate 15 mEq/L, anion gap 22, positive betahydroxybutyrate, AST 208 mmol/L, ALT 136 mmol/L, and HbA1c 12. 0%. She was successfully resuscitated from DKA. Repeat liver function tests showed further elevation of AST 819 mmol/L and ALT 346 mmol/L. Ultrasound of liver showed increased echotexture reported as steatosis. Further history revealed significant financial difficulty due to which patient was using different kinds of basal and bolus insulins interchangeably. She would sometimes use bolus insulin to cover for lack of basal insulin. Prior gastroenterology workup showed ANA positivity in a speckled pattern but was otherwise unrevealing for infective, autoimmune, or alcoholic hepatitis. Liver biopsy was therefore recommended by inpatient gastroenterology. Liver biopsy revealed spotty mild lobular hepatitis and focal portal fibrosis consistent with glycogenic hepatopathy. Features of autoimmune hepatitis were not seen in liver biopsy. Discussion Glycogen hepatopathy seems to represent an acquired form of glycogen storage disorder. Pathophysiology is suspected to be a combination of hyperglycemia and hyperinsulinemia leading to increased glycogen accumulation in hepatocytes while glycogenolysis is suppressed. This mechanism seems to correlate with our patient who reported use of large doses of short acting insulin followed by glucose administration to counteract hypoglycemia. Abnormal glucagon activity or enzymes deficiencies in glycogenolysis pathway (as reported with congenital glycogenstorage disorders) have not been elucidated. Recent data has also questioned reversibility and long term safety as liver biopsies of patients with glycogenic hepatopathy have demonstrated varying degrees of fibrosis. Newer MRI protocols seem to be able to distinguish GH from NAFLD, and this is important as these are pathophysiologically distinct and will have different management strategies. This case highlights glycogenic hepatopathy as an underrecognized complication of diabetes that will require improved recognition and further investigation to evaluate long term consequences. Presentation: No date and time listed
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