Pathophysiology: Cachexia

Weight Loss in Cancer ✥Weight loss has been used as an indicator of poor prognosis in cancer patients ✵Nearly 1/3rd of cancer deaths can be attributed to cachexia ✥Correlated with adverse outcomes ✵Increased incidence and severity of treatment side effects and increased risk of infection, thereby reducing chances for survival ✥Weight loss is often used as a surrogate for malnutrition ✵Does not take into account the time course of the weight loss or the type of tissue loss ✵May be affected by fluid shifts and may represent changes in hydration status, edema, or ascites rather than actual changes in fat and lean body mass 67 Cachexia ✥Cancer anorexia cachexia ✥Loss of weight and muscle mass ✵ With or without loss of fatty mass ✥Muscle wasting and loss of appetite 68 Definitions ✥Anorexia ✵Loss of appetite or desire to eat ✥Cachexia ✵Condition marked by weakness, weight loss, fat, and muscle loss or t Asap aint ✥Sarcopenia I ✵Severe muscle depletion ✥Starvation ✵Severe deficiency of caloric intake 69 Cellular Respiration Mainsourceof no no 1 Glucose energy'intlebody 2 1 Glycolysis ATP 2 NADH + 2 H+ 2 Pyruvic acid 2 Formation of acetyl-coA 4 2 CO2 2 NADH + 2 H+ 2 Acetyl-coA 2 ATP 4 CO2 3 Krebs cycle 6 NADH + 6 H+ 2 FADH2 Electrons Electron transport chain 26 or 28 ATP e– e– e– 6 O2 6 H2 O 70 Glycolysis 3 ATE 1 Glucose 2 ATP 2 ADP + 2 P Dihydroxyacetone phosphate Glyceraldehyde 3-phosphate 2 NAD+ 4 ADP + 4 P 2 NADH + 2 H+ 4 ATP Pyruvic acid 71 Absentof Absentof oxygen are oxygen f 72 Source ATP Yield Per Glucose Molecule (Process) Glycolysis Oxidation of one glucose molecule to two pyruvic acid molecules 2 ATPs (substrate-level phosphorylation). Formation of two Molecules of Acetyl Coenzyme A Production of 2 NADH + H+ 3 or 5 ATPs (oxidative phosphorylation). 2 NADH + 2H+ 5 ATPs (oxidative phosphorylation). Krebs Cycle and Electron Transport Chain Oxidation of succinyl-CoA to succinic acid 2 GTPs that are converted to 2 ATPs (substrate-level phosphorylation). Production of 2 FADH2 3 ATPs (oxidative phosphorylation). Total 30 or 32 ATPs per glucose molecule. 73 Warburg Effect ✥Otto Warburg – German scientist (1931 Nobel Prize) ✥Described unusual energy expenditure by cancer cells ✵Cancer cells use only glycolysis to generate ATP from glucose ✵Even in presence of O2, do not complete the entire respiration process ✵Able to survive in hypoxic conditions ✥Cancer cells’ energy expenditure wastes a lot of energy ✵2 ATP generated from 1 molecule of glucose used 74 Normal cells: Cellular respiration – 3 step process to produce 32 molecules of ATP 75 Cancer cells: Do not use last 2 steps; Only glycolysis – to get enough energy they must use a lot more sugar to keep the 1st step running as fast as possible 76 Warburg Effect ✥ Abnormal dependence on glycolysis as the sole source of ATP creation, even in presence of oxygen – Warburg effect ✥ Hypoxia induces proteins involved in glycolysis, ✥ Attributed to mutations in the enzymes involved in energy generation ✵ Akt activated in response to hypoxia ✵ Ras and MYC activated in cancer – contribute to increased glycolysis ✵ Loss of p53 triggers Warburg effect 77 78 Riversible Cancer Cachexia a metopside ✥Cachexia versus starvation ✵ Weight loss observed in both ✵ Difference Mechanisms Reversal 79 FDG-PET imaging ✥Excessively high metabolic activity of cancer cells is utilized in locating them in the body using a whole-body PET scan ✵Fluoro-deoxy-glucose is phosphorylated to 6-phsohoFDG by hexokinase, which gets trapped inside the cells ✥Precautions: Arrive on time/be ready to wait – 18F has half-life of 2 hours 80