MACRONUTRIENT CATABOLISM IN THE FASTED STATE The body has a remarkable ability to withstand food deprivation, allowing humans to survive cycles of feast and famine. Adaptive changes allow the body to access stored macronutrients to provide for routine activities. Individuals with protein-energy malnutrition (PEM) or protein-calorie malnutrition (PCM) can have varying symptoms, determined by the cause of the malnutrition. Starvation of both protein and calories leads to marasmus at one end of the PEM continuum. At the opposite end is protein deprivation that occurs in individuals who are consuming carbohydrates almost entirely. Kwashiorkor is the Ghanaian word for the disease that develops when a mother's first child is weaned from protein-rich breast milk to a protein-poor carbohydrate food source. The condition is caused by severe protein deficiency and hypoalbuminemia. In adults, the correct term is protein-energy malnutrition, not the pediatric term, kwashiorkor. Glucose is an obligate nutrient for the brain and nervous system, red and white blood cells, and other glucose requiring tissues. To maintain function, the blood glucose level must be maintained within a normal range at all times. During early fasting, glucose is obtained from glycogen by the action of the hormones glucagon and epinephrine; these stores are depleted in 18 to 24 hours. At this point, new glucose must be synthesized using protein as a substrate. The catabolic hormones epinephrine, thyroxine, and glucagon stimulate the release of muscle protein and other available substrates for gluconeogenesis. The most common amino acid substrate for gluconeogenesis is alanine; when its nitrogen is removed, alanine becomes pyruvate. Note that glycogen is never totally depleted, even during long-term starvation. A small amount of preformed glycogen is carefully guarded as a primer for glycogen resynthesis. As fasting is prolonged and the body adapts to starvation conditions, liver gluconeogenesis decreases from producing 90% of the glucose to less than 50%, with the remainder being supplied by the kidney. . Thus, during starvation, glucose production by the kidney increases while production by the liver decreases. In addition to glucose, a reliable energy source is required during fasting. The best source is fat that is stored in adipocytes and used primarily by muscles, including the heart muscle, to make ATP. Fatty acid release and use require low insulin levels and an increase of the anti-insulin hormones glucagon, cortisone, epinephrine, and growth hormone. Anti-insulin hormones activate the hormone-sensitive lipase enzyme on the adipocyte membrane. This enzyme cleaves stored triglycerides, releasing fatty acids and glycerol from fat cells. Fatty acids travel to the liver bound to serum albumin and easily enter the liver cells. Once inside the cell, fatty acids enter the liver mitochondria via the carnitine acyltransferase transport system, which carries fatty acid carnitine esters across the mitochondrial membrane. Once inside the mitochondria, acetyl CoA is formed from fatty acid CoA via the process of α-oxidation. During starvation, excess acetyl CoA molecules accumulate in the liver because the liver is able to obtain all necessary energy from the process of α-oxidation and form ketones, which then enter the bloodstream and act as a source of energy for the muscles, thus sparing protein. Adaptation to starvation depends on ketone production. As the blood ketone level rises during fasting, the brain and nervous system, although obligate glucose consumers, begin to use ketones as an energy source. Because the brain is using a fuel other than glucose, the demand on muscle protein for gluconeogenesis declines, thereby reducing the rate of muscle catabolism. Reduced muscle catabolism reduces the amount of ammonia received by the liver. Liver synthesis of urea decreases precipitously, reflecting the slower rate of muscle protein deamination. If the fast extends for weeks, the rate of urea synthesis and excretion is minimized. In an individual who has adapted to starvation, urea is excreted from the kidney at approximately the same rate as uric acid. Thus, in an individual who is adapting to starvation, protein losses are minimized and lean body mass spared. Although fat cannot be converted into glucose, it does provide fuel for the muscle and brain as ketones. As long as water is available, a normal-weight individual can fast for a month. Relatively normal nutritional indices, immune function, and other system function are maintained. However, when fat stores are exhausted, protein is used, and death is the ultimate consequence. In certain cases of trauma and sepsis, the individual is not able to adapt to fasting or starvation. If an individual who is fasting develops an infection, inflammatory mediators such as interleukin-l and tumor necrosis factor stimulate insulin secretion and prevent the development of mild ketosis. Without ketones the brain and other tissues continue to depend on glucose, thereby limiting the person's ability to adapt to starvation Muscle mass erodes to provide glucose substrates. A fasting person with an infection rapidly develops a negative nitrogen balance. When 50% of the protein stores is exhausted, recovery from infection is poor. Adaptation to starvation is also not possible for those with protein malnutrition because the carbohydrate intake stimulates insulin production. Insulin is a storage hormone that prevents fat stores from being accessed for fuel. It also inhibits fat from being formed into ketones, thereby limiting adaptation to starvation. Insulin secretion inhibits muscle breakdown. Protein cannot be used to make albumin and other visceral proteins. Edema results because albumin exerts osmotic pressure in the vessels. If the albumin concentration is low, fluid remains in the extracellular spaces and causes edema. Compromised neural function or GI absorption, decreased cardiac output, immune function, fatigue, and other symptoms of malnutrition result from inadequate protein synthesis, inadequate ATP production, and fluid accumulation in the tissues. Nonadapted malnutrition is dangerous. Not only can unremitting protein loss become life threatening by compromising the muscles of the heart and respiratory system, but it also compromises the immune system. The individual becomes susceptible to a vicious cycle of infections, diarrhea, additional nutrient loss, an even weaker immune system, and finally opportunistic infections and death. Iatrogenic, or "physician-induced," malnutrition was recognized long ago as a danger for hospitalized patients and remains so to this day.