Effects of Immune Responses on Nutritional Status

5. Effects of Immune Responses on Nutritional Status

Immune responses to infection, neoplasia, or as the result of immune-mediated disease, can affect the nutritional status of the patient (Table 4).

Anorexia

An almost universal finding in significant inflammatory disease states is a disturbance in food intake that ranges from a suppressed appetite to complete anorexia. This loss of appetite is considered part of the acute phase response. Inflammatory cytokines are important mediators of the suppression of food intake, particularly IL-1, IL-6, and TNF-α (Langhans, 2000). The site of action of cytokines can be on central nuclei (hypothalamus) or on peripheral nerves that then produce ascending signals through sensory afferent pathways to central feeding centers.

The fact that anorexia of infection is an almost universal effect in all mammalian species, suggests that it might have a benefit. In support of this notion is the observation that force feeding of anorexic septic mice increases mortality, and in those that survive, the time to survival is increased (Murray & Murray, 1979). This deleterious effect of over-nutrition in sepsis and other systemic inflammatory responses has been confirmed in other species, including humans (see below).

These findings suggest that in seriously ill septic patients, consideration should be given to the risks of overfeeding, as well as what might constitute an ideal dietary composition. Thus although it is not suggested that starvation is preferable to supportive nutrition in severe infection, it is important that one considers how the evolved response of anorexia and the associated metabolic derangements might be instructive in formulating ideal diets for sepsis.

The Acute Phase Response

The acute phase response (APR) is a prominent systemic reaction of the organism to local or systemic disturbances in its homeostasis caused by infection, trauma or surgery, neoplasia, or immune mediated diseases. Cytokines activate receptors on different target cells leading to a systemic reaction resulting in activation of the hypothalamic-pituitary-adrenal axis, reduction of growth hormone secretion and a number of physical changes clinically characterized by fever, anorexia, negative nitrogen balance and catabolism of muscle cells (Gruys et al., 2005). Other effects on endocrine and nutritional parameters include a decrease in HDL and LDL, increased ACTH and glucocorticoids, decreased serum levels of calcium, zinc, iron, vitamin A and of a-tocopherol, and a change in concentration of several plasma proteins (Table 5) (Gruys et al., 2005).

The acute-phase response to injury or infection is associated with alteration in dynamics of many trace elements, particularly iron, zinc and copper. The fall in serum iron and zinc, and rise in serum copper, is brought about by changes in the concentration of specific tissue proteins controlled by cytokines, especially IL-1, TNF-α, and IL-6. These are generally believed to be beneficial aspects of the early acute phase response.

In addition to the decrease of serum zinc, iron and albumin, a decrease of transferrin, cortisolbinding globulin, transthyretin (TTR) and retinol-binding protein have been described. The resulting disturbance in vitamin A metabolism that occurs in chronic infestation and inflammatory states worsens the vitamin A deficiency that is seen in children and pregnant mothers in developing countries from malnutrition (Stephensen, 2001). Vitamin A deficiency has a wellknown negative feedback effect on immunity, producing one of the best described immunosuppressive effects of malnutrition.

Cachexia

Starvation (simple energy deprivation) is accompanied by metabolic adaptations to ensure essential nutrients are available for vital organs. Starvation results in decreased insulin secretion and a moderate increase in cortisol, leading to muscle catabolism and lipolysis. Lipolysis liberates fatty acids which are picked up by the liver, packaged into lipoproteins (VLDL), and exported back out into the circulation along with ketone bodies for utilization as fuel by the majority of cells in the body. Amino acids released from muscle are used by the liver for the synthesis of essential proteins (e.g., clotting proteins), and by the kidney and liver to synthesize glucose for those tissues dependant upon it (e.g., leukocytes, erythrocytes). As tissues (e.g., the brain) adapt to utilizing ketones in preference to glucose, the release of amino acids from muscle slows, and lean body mass is preserved. All of the metabolic adaptations can be reversed with feeding.

Severe inflammatory responses also induce a collection of metabolic derangements that result in accelerated lipolysis and muscle catabolism, producing wasting that is not explained solely by a decrease in food intake (Table 6). The defining difference between starvation and cachexia, is that in cachexia, forced feeding will not reverse the derangements, will not preserve the loss in lean body mass, and results only in fat accumulation. Cachexia has been shown to occur in association with sepsis, non-septic inflammatory disease, neoplasia, and cardiac failure. Cachexia accounts for 30 - 80% of cancer-related deaths in humans (diaphragmatic failure, edema, immune compromise) (Kotler 2000).

Inflammatory cytokines, particularly IL-6, TNF-α, and IL-1, are largely responsible for the derangements, and produce both local effects at the site of inflammation, but also endocrine effects (IL-6).

For instance, in severe infection, circulating TNF-α is an important inducer of accelerated lipolysis, and by up-regulating the ubiquitin-proteosome system, is largely responsible for the disproportionate muscle catabolism associated with cachexia (Camps et al., 2006). In addition to generalized muscle catabolism, the metabolism of individual amino acids can be deranged. In FIV infected cats, similar to human HIV-AIDS patients, the IFN-γ produced in response to the infection stimulates accelerated tryptophan catabolism and a decrease in serum tryptophan concentrations (Kenny et al., 2007). The exact consequences of this metabolic response are uncertain so far, although it does raise the possibility that supplementation with tryptophan metabolites such as niacin or melatonin might have some therapeutic benefit in FIV-infected cats.

In inflammatory diseases, there is an exaggerated secretion of insulin in response to feeding, but most cells in the body (especially the liver) are resistant to the effects. This resistance prevents utilization of precious glucose and preserves blood glucose for essential tissues (brain, erythrocytes, leukocytes). There is a massive increase in cortisol which induces a large breakdown of fat and muscle, increasing the delivery of free fatty acids and amino acids to the liver, and greatly increasing muscle and visceral protein breakdown. Since the liver is resistant to insulin, feeding does little to prevent it from continuing to produce glucose, and hyperglycemia results (Andersen et al., 2004).

Risks of Over Feeding and Hyperglycemia

Hyperglycemia – More Than a Number?

Therefore, any serious acute illness can result in:

• Hyperglycemia
• Insulin resistance
• Increased hepatic glucose production.

This has been termed the "Diabetes of injury". Previously this insulin resistance and hyperglycemia was thought to be an adaptive response promoting glucose uptake by essential tissues and prevention of uptake by muscle. Thus moderate hyperglycemia has been tolerated by veterinary and medical clinicians.

In 2001, a study of 1548 human intensive care patients was instigated to determine if there was any benefit to tightly controlling blood glucose in severe illness (van den Berghe et al., 2001). Blood glucose was controlled with intensive insulin therapy to less than 6 mmol/L (110 mg/dL). Amazingly there was a 43% reduction in mortality in all patients, and even in "long stay" patients, mortality was reduced by 10.6%. In addition there was:

• Shortened hospitalization
• Reduced nosocomial infections
• Reduced acute renal failure
• Reduced anemia
• Fewer cases of liver failure
• Less multiple organ dysfunction
• Reduced muscle weakness.

Although no similar studies have been performed in feline patients, a "stress-hyperglycemia" is a very common finding in seriously ill cats. In critically ill dogs, hyperglycemia is also common, and hyperglycemia at presentation is associated with increased duration of hospitalization, and the occurrence of sepsis was more frequent in hyperglycemia dogs than normoglycemic dogs (Torre et al., 2007). Finally, canine patients not surviving hospitalization had a higher median glucose concentration compared with those surviving to discharge (Torre et al., 2007).

Is Glucose Toxic?

Hyperglycemia is not normally toxic in the short term. Normally, cells are relatively protected from hyperglycemia by down-regulation of glucose transporters. However, although the insulin secreted in inflammatory states does not result in reducing blood glucose, it does lead to other signaling effects within cells (Figure 10). Thus hyperglycemia stimulates continued insulin release which signals to many cell types to undergo metabolic changes associated with the post-prandial state, that are inappropriate in a diseased state. These alterations have been confirmed in canine sepsis.

Figure 10. Metabolic effects of insulin on the cells.

In addition, although there is a relative insulin resistance, some glucose is forced into some cells leading to cellular glucose overload in neurons, endothelium, alveoli, vascular smooth muscle, and renal tubule cells.

This combination of exaggerated insulin signaling and glucose overload leads to:

• Acute renal failure
• Accelerated removal of erythrocytes and anemia
• Polyneuropathy, brain edema, depression, seizures
• Immunosuppression, decreased phagocytosis and killing
• Increased sepsis
• Increased vascular permeability, decreased responsiveness, activation, coagulation, disseminated intravascular coagulation.

Recommendations for Feeding in Severe Inflammatory Diseases

Clearly feeding excessive carbohydrate will exacerbate hyperglycemia and increase morbidity, whilst feeding excessive fat exacerbates hepatic load and leads to fatty liver development and liver dysfunction. The recommendations for feeding in severe inflammatory diseases are presented in Table 7.