Starvation versus Stress

-the metabolic response to critical illness is very different from simple or uncomplicated starvation, in which loss of muscle is much slower in an adaptive
response to preserve lean body mass
-stored glycogen, the primary fuel source in early starvation, is depleted in 24 hours. After the depletion of glycogen, glucose is available from the
breakdown of protein to amino acids
-the depressed glucose levels lead to decreased insulin secretion and increased glucagon.
-during the adaptive state of starvation, protein catabolism is reduced, and hepatic gluconeogenesis decreases
-lipolytic activity is also different in starvation and in stress
-after 1 week of fasting or food starvation, a state of ketosisin which ketone bodies supply the bulk of energy needs, thus reducing the need for
gluconeogenesis and conserving body protein to the greatest possible extentdevelops.
-In late starvation, as in stress, ketone body production is increased, and fatty acids serve as a major energy source for all tissues except the brain,
nervous system, and RBCs
-starvation is characterized by decreased energy expenditure, diminished gluconeogenesis, increased ketone body production, and decreased
ureagenesis
-conversely, energy expenditure in stress is markedly increased, as are gluconeogenesis, proteolysis, and ureagenesis
-as discussed, the stress response is activated by hormonal and cell mediatorscounter-regulatory hormones such as catecholamines, cortisol, and
growth hormone (this mediator activation doesnt occur in starvation)
Systemic inflammatory response syndrome and multiple organ dysfunction syndrome
PATHOPHYSIOLOGY
-sepsis- patient has a documented infection and an identifiable organism. Bacteria and their toxins lead to a stronger inflammatory response. Other
microorganisms that lead to an inflammatory response include viruses, fungi, and parasites
-SIRS- widespread inflammation that can occur in infection, pancreatitis, ischemia, burns, multiple trauma, hemorrhagic shock, or immunologically
mediated organ injury
-the inflammation is usually present in areas remote from the primary injury, affecting otherwise healthy tissue
-each condition leads to release of cytokines, proteolytic enzymes, or toxic oxygen species (free radicals) and activation of the complement cascade
-A common complication of SIRS is MODS- syndrome generally begins with lung failure and is followed by failure of the liver, intestines, and kidney in no
particular order
-hematologic and Myocardial failures usually manifest later however CNS changes can occur at any time
-MODS can be primary as the direct result of injury to an organ from trauma (EX: pulmonary contusion, renal failure caused by rhabdomyolysis, or
coagulopathy from multiple blood transfusions)
-Secondary MODS occurs in the presence of inflammation or infection in organs remote from the initial injury
-Patients with SIRS and MODS are clinically hypermetabolic and exhibit high cardiac output, low O2 consumption, high venous O2 saturation, and lactic
academia (they generally have a strong positive fluid balance assoc. with massive edema and a decrease in plasma protein concentrations
-The gut hypothesis suggests that the trigger is injury or disruption of the gut barrier function, with corresponding translocation of enteric bacteria into
mesentery lymph nodes, liver and other organs
-unique gut-derived factors carried in the intestinal lymph but not the portal vein usually lead to acute injury- and shock- induced SIRS and MODS
-shock results in gut hypoperfusion (source of proinflammatory mediators)
-early guy hypoperfusion causes an ileus or lack of peristalsis in both the stomach and small bowel, and late infections cause further worsening of this gut
dysfunction
-early enteral feeding is thought to restore gut function and influence the clinical course (mech. Due to the enhanced functional and structural integrity of
the gut
-enteral feeding may have a role in maintaining tight junctions between the intraepithelial cells, stimulating blood flow and inducing the release of trophic
factors
-maintenance of villous height supports the secretory immunocytes that make up the gut-associated lymphoid tissue
-with central parenteral nutrition, mucosal atrophy and a loss of epithelial barrier function may occur (EBF)
-a rise in interferon gamma and decline in IL-10 contribute to the loss of EBF in animal models along with a dramatic decline in the expression of tight
junction and adherens junction proteins
-studies in animals suggest that glutamine added to the parenteral solution may protect the EBF
SUPPLEMENTAL READING
-surgery or other trauma causes metabolic changes that induce catabolism
-in critically ill patients, metabolic stress results in significant changes in metabolism
-malnutrition results from (decreased intake/anorexia, maldigestion/malabsorption, altered transport and storage of nutrients, hypermetabolism,
increased losses/excretion of nutrients)
-this is quite different from the situation of starvation without metabolic stress
METABOLIC EFFECTS OF STARVATION
STRESS RESPONSE
Stages include (Alarm stage- fight of flight- CNS alerted and bodys defenses mobilized- SNS and hypothalamus are stimulated) (Adaptation- allows
fight or flight- actions of cortisol, NE, EPI, and other mediators) (Exhaustion- continuous stress results in progressive breakdown of ability of body to
compensate to maintain homeostasis- assoc. with development of chronic disease or death)
-stress response occurs when presence of injured tissue from hypoxia (low O2 level), inflammation, burns, trauma, etc. exists or is PERCEIVED TO EXIST.
-this is catabolic response and is same for all of these stressors, incl. thermal burns, injury from automobile accident or psychological stress, such as
taking exam (degree and duration of response vary)
-A. HORMONES AND CATECHOLAMINS OF THE STRESS RESPONSE
-in response to a stressor, the CNS through the hypothalamus responds through hormone and catecholamine release
1. SNS produces NE (catechol and hormone)increased BP, decreased gastric secretion, dilated bronchial airways, etc.
SNSEPI (catechol and hormone)
-heart- increased BPincreased CO and vascular contraction (vasoconstriction)
-adipose tissue- increased lipolysis (breakdown of fat) and free fatty acids in blood
-pancreasproduced less insulin, more GLUCAGON (hormone that interferes with insulin action)more blood GLUCOSE
-liverless glycogen synthesis, more glycogenolysis (breakdown of glycogen), more gluconeogenesis (formation of new
glucose)increased blood glucose
2. corticotropin-releasing hormone (CRH)anterior pituitarybeta endorphins (less pain sensation)
GROWTH HORMONE lipolysis, increased protein synthesis, gluconeogenesis, less glucose uptake by muscle and adipose tissue; blocks insulin
actionsincreased blood glucose
Adrenocorticotropic hormone (ACTH)adrenal cortexCORTISOL
-liver- more protein synthesis, increased gluconeogenesisincreased blood glucose
-muscle more protein catabolism in skeletal protein and blood amino acids
-immune system- some function decreased anti-inflammatory
-lipolysis in extremities and lipogenesis in face and trunk
3. CRHposterior pituitaryvasopressin (hormone previously antidiuretic homeone) more Na and Water retention (makes you not need to pee)
B. EBB (fight or flight phase) AND FLOW PHASES
1. Ebb phase- first 24-48 hours post injury with high levels of catecholamines, cortisol, and glucagon (the body is trying to survive the injury. This is a
period of hypovolemia, possibly shock, and tissue hypoxia. Blood flow goes to the brain, heart, lungs, and muscle and little goes to GI tract. Body temp is
lower. Insulin levels fall and glucagon rises hepatic glucose production begins)
2. Flow Phases- period of increased energy expenditure (hypermetabolism), high N excr. And total body protein catabolism. Substrates are provided for
gluconeogenesis, acute phase proteins, immune factors, and wound healing
A. Acute phase-hypermetabolismmarked catabolism-peaks 3-6 days after insult & subsides 2-3 week(acute phase proteins synth. in liver that change
metabolism. Cytokines stimulate their synthesis
B. Adaptive Phase- transition from acute phase after 2-3 weeks (Catabolism begins to subside. The patient feels better (corticoid-withdrawal phase).
Diuresis (increased urinary flow) occurs. N excr. Decreases (means less protein breakdown. Overtime, muscle mass increases and weight gain occurs.
Perhaps 6 weeks later body comp returns to normal (has been termed the fat gain phase)
C. Mediators of flow phase (cytokines and hormones)
1. glucagon- inhibits insulin actioninsulin resistance so blood glucose increases (COUNTERREGULATORY HORMONE)
2. cortisol (glucocorticoid)- lipolysis, amino acid mobilization, glucagon and growth hormone release; inhibition of protein synthesis and insulin action
(COUNTERREGULATORY HORMONE)
3. GH- lipolysis, increased protein synthesis, gluconeogenesis, less glucose uptake by muscle and adipose tissue; blocks insulin action increased blood
glucose)
4. Catecholamines- (EPI and NE)- hepatic glycogenolysis, fat lipolysis, gluconeogenesis
5. Vasopressin- Na and water retention- restore blood volume
6. cytokines-
a. IL-1acute phase response- fever, leukocytosis
acute phase protein synthesis- fibrinogen, complement, globulins, C reactive protein, alpha 1 acid glycoprotein, ceruloplasmin (lower
serum Zn and Fe)
more O2 and substrates for metabolically active tissues
hypermetabolism- hyperglycemia, increased urea production, large urinary N losses
lean body mass wasting far more that simple starvation; cell catabolism
loss of K, PO4, Mg (cell catabolism- loss of these electrolytes which are inside cells)
b. IL-6
c. tumor necrosis factor (TNFa)- anorexia and protein synthesis
-metabolic stress is a time when nutritional status is greatly affected, and nutrition is needed in adequate but not excessive amounts for survival
METABOLIC EFFECTS OF STARVATION
-when Simple Starvation is present, the response of the body is to adapt to survive for as long as possible. Glucose is a limited commodity in starvation
so that only cells that are requisite for glucose for energy- nervous tissue, bone marrow, renal medulla, erythrocytes, and some immune factors- use
glucose almost exclusively. That results in the need for approx. 100-200g CHO/day
A. Early Starvation
1. Muscle- in early starvation, the sequence of use of sources of energy is as follows:
-glycogen from the liver is used gone after about 24 hours
-then body protein (muscle) is converted to amino acids and then branched chain amino acids (BCAA) BCAA= leucine, valine, isoleucine
-BCAA transported to liver used for energy (TCA cycle).BCAA also converted to alanine in muscle that is transported to liver and converted to
glucose for glucose-requisite cells
-Net result is loss of skeletal muscle- estimated 75g body protein/day (because of water content of body protein -> 360g lean body mass/day)
2. Body Fat- adipose tissue is catabolized daily
-trigylceridesglycerol + 3 Fatty acids
-glycerol- converted to glycerol-3-PO4 (part of glycolysis so can be used by glucose-requisite cells)
-free fatty acids (and ketones from fatty acid catabolism- beta oxidation) used by non-glucose requiring cells
-FFAs and ketones produced from fatty acid catabolism (beta oxidation) are used for energy by non-glucose-requiring tissues (some ketones
produced by catabolism of BCAAs in liver also)
-Net result is loss of body fat- estimated 160g adipose tissue/day
B. Prolonged Starvation > 1 week- gradually the amount of glucose used by all tissues decreases and is replaced by ketones (BCKA and ketones from beta
oxidation)
protein catabolism drops to 20 g/day100 g lean body mass
most energy comes from adipose tissue (95% from fat/ketones)
-Body size (BMI) and thus energy use falls. The individual becomes less active and sleeps more
-Further adaptation includes reduced body core temp and metabolic rate
-loss of intercostal muscle needed for respiration makes it harder to clear pulmonary secretions (person may die of respiratory failure or
pneumonia)
-life continues for a surprisingly long time because of adaptation