A 56-year-old man is evaluated for progressive visual impairment. The patient works as part of the grounds crew at an airport, and says he has trouble identifying aircraft at a distance and with filling out paperwork at the end of his shift. His medical history includes poorly controlled diabetes mellitus, hypertension, and gout. A year ago, the patient underwent an uncomplicated repair of a right inguinal hernia. Physical examination shows bilateral clouding of the lens. The remainder of the examination is unremarkable. Which of the following metabolic conversions is most likely contributing to this patient's current condition?

Question

A 56-year-old man is evaluated for progressive visual impairment.  The patient works as part of the grounds crew at an airport, and says he has trouble identifying aircraft at a distance and with filling out paperwork at the end of his shift.  His medical history includes poorly controlled diabetes mellitus, hypertension, and gout.  A year ago, the patient underwent an uncomplicated repair of a right inguinal hernia.  Physical examination shows bilateral clouding of the lens.  The remainder of the examination is unremarkable.  Which of the following metabolic conversions is most likely contributing to this patient's current condition?

Quizplus · Accepted Answer

11ec160b_36c5_8c1a_9249_8d7f584bb8d0_MD0001_00 This patient has cataracts, an opacification of the lens of the eye that can lead to blindness, likely a result of long-standing hyperglycemia due to poorly controlled diabetes mellitus. Certain cells (eg, retinal, endothelial, lens, renal mesangial, Schwann) are more vulnerable to hyperglycemia-induced damage because they are unable to regulate glucose transport when circulating levels are high. Multiple metabolic pathways are involved in the pathogenesis of hyperglycemia-induced tissue damage: Advanced glycosylation end-products (AGEs): Glucose can nonenzymatically attach to proteins and lipids, forming reversible glycosylation products that slowly stabilize into irreversible products. Under hyperglycemic conditions, AGEs accumulate and facilitate deposition of LDL in blood vessel walls and inflammatory cell invasion that causes atherosclerosis and microangiopathic complications. High glucose levels in the aqueous humor may also induce nonenzymatic glycation of lens proteins, which contributes to cataract formation. Polyol pathway overactivity: The enzyme aldose reductase converts glucose to sorbitol, which is then oxidized to fructose by the enzyme sorbitol dehydrogenase. With hyperglycemia, formation of sorbitol occurs faster than its metabolism to fructose, resulting in its accumulation. Sorbitol increases the osmotic pressure in tissues and stimulates the influx of water, leading to osmotic cellular injury. In addition, oxidative stress resulting from the depletion of NADPH (aldose reductase consumes NADPH) also contributes to cataract formation and other diabetic complications such as retinopathy, peripheral neuropathy, and nephropathy. (Choices A and B) Aldose reductase also catalyzes the conversion of galactose (obtained from dietary lactose) to galactitol, but sorbitol dehydrogenase is incapable of oxidizing galactitol to its corresponding keto sugar (tagatose, a food sweetener). In galactosemia (galactose 1-phosphate uridyltransferase deficiency), excess galactitol is produced, which causes cataracts in newborns. (Choice D) In the hexose monophosphate shunt, glucose-6-phosphate is converted to 6-phosphogluconolactone by the enzyme glucose-6-phosphate dehydrogenase (G6PD), generating the reducing equivalent NADPH. G6PD deficiency results in hemolytic anemia during times of increased oxidative stress. (Choice E) Lactate dehydrogenase catalyzes the conversion of pyruvate to lactate under anaerobic conditions. Excess lactate forms in hypoxic states, causing metabolic acidosis. Educational objective: In hyperglycemic states, aldose reductase converts glucose to sorbitol at a rate faster than sorbitol can be metabolized. Sorbitol accumulates in certain cells such as lens cells, causing an influx of water and resulting in osmotic cellular injury. Depletion of NADPH by aldose reductase also increases oxidative stress, which accelerates development of cataracts and diabetic microvascular complications (eg, neuropathy, retinopathy). __________ References: The pathobiology of diabetic complications: a unifying mechanism. (http://www.ncbi.nlm.nih.gov/pubmed/15919781)

A 56-Year-Old Man Is Evaluated for Progressive Visual Impairment