JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY HYDERABAD Pharm.D II Year PATHOPHYSIOLOGY Previous Question Paper (February - 2023 - R08)

Hypoxia or ischemia leads to a reduction in oxidative phosphorylation within the mitochondria, resulting in decreased ATP production. The depletion of ATP triggers a cascade of reversible cellular changes:

1. Failure of the Na+/K+-ATPase pump: Reduced ATP levels cause the pump to fail, leading to an intracellular accumulation of sodium and an efflux of potassium. This osmotic imbalance results in the influx of water, causing cellular swelling (hydropic change) and dilation of the endoplasmic reticulum.
2. Anaerobic glycolysis: To compensate for the lack of ATP, cells switch to anaerobic metabolism, increasing glycogen consumption and lactic acid production. This lowers intracellular pH, which causes clumping of nuclear chromatin and impairs the activity of various cellular enzymes.
3. Detachment of ribosomes: The swelling of the endoplasmic reticulum leads to the detachment of ribosomes from the rough endoplasmic reticulum, resulting in a decline in protein synthesis.
4. Structural alterations: Plasma membrane blebbing and the formation of myelin figures may occur, but these changes remain reversible if oxygen supply is restored and ATP production resumes.

Glycogen storage diseases (GSDs) are a group of inherited metabolic disorders caused by genetic deficiencies in enzymes responsible for the synthesis or degradation of glycogen. These deficiencies lead to either the accumulation of abnormal amounts of glycogen or the formation of glycogen with abnormal structures in tissues such as the liver and skeletal muscles.

Key examples include:

• Von Gierke disease (Type I GSD): Caused by a deficiency of glucose-6-phosphatase. It primarily affects the liver and kidneys, leading to severe fasting hypoglycemia, hepatomegaly, and growth retardation because the liver cannot release free glucose into the blood.
• Pompe disease (Type II GSD): Caused by a deficiency of lysosomal acid alpha-glucosidase (acid maltase). This leads to the accumulation of glycogen within lysosomes in all organs, but the heart is most severely affected, resulting in cardiomegaly and early-onset heart failure.
• Cori disease (Type III GSD): Caused by a deficiency of the glycogen debranching enzyme. This results in the accumulation of glycogen with short outer chains (limit dextrin) in the liver and muscles, causing hepatomegaly and mild hypoglycemia.
• McArdle disease (Type V GSD): Caused by a deficiency of muscle phosphorylase. This prevents the breakdown of glycogen in skeletal muscles, leading to exercise-induced muscle cramps, weakness, and myoglobinuria.