How Energy Shifts Lead to Systemic Illness

For overall redirection of energy-rich substrates to the activated immune system, this program has the following significance: 1) Anemia is accompanied by reduced energy expenditure for erythropoiesis (events during sickle-cell anemia depict how much energy is needed for red blood cell production³²); 2) lower oxygen-transport capacity and lower oxygen tension leads to decreased physical activity; 3) reduced iron levels are followed by decreased myoglobin levels in skeletal muscle (lower muscular work); and 4) absorbed iron is used in activated macrophages (necessary for peroxide- and nitric oxide–generating enzymes [usually for killing microbes], and used for cytochromes in the respiratory chain complex to handle necessary protons for adenosine triphosphate production). From this point of view, mild CID-related anemia is an adaptive program.

Osteopenia

Calcium as well as phosphorus are essential for energy consumption.³³ To meet metabolic demands during CIDs, both elements need to be provided from bone (internal store) because the fatigue, anorexia, and malnutrition that accompany inflammatory disease lead to reduced calcium and phosphorus uptake in the gut (think of the starvation program).

Several important factors contribute to osteopenia in CIDs: 1) vitamin D and K deficiency (see the above section on anorexia); 2) magnesium deficiency (see the above section on anorexia); 3) upregulation of proinflammatory cytokines supporting osteoclast activity via RANKL; 4) increased SNS activity³⁴; 5) increased cortisol levels³⁵; and 6) decreased gonadal hormones. Together, these changes can promote osteoclastic bone resorption while osteoblastic bone generation is inhibited.

Recently, the role of osteocalcin, an osteoblast hormone, has been revisited.³⁶ Studies have shown that this hormone increases insulin sensitivity, indicating that bone-sparing factors such as osteocalcin can support glucose uptake and fuel storage. Although these metabolic changes may occur in CIDs and influence pathogenesis, they likely have been evolutionarily conserved for transient inflammatory episodes.

click for large version

Figure 4: Summary of disease sequelae in CIDs. During transient inflammatory episodes, the mentioned programs, in green, represent activities to support the short-lived immune response, in red. However, during prolonged infinite inflammation, such as in CIDs, the continuous use of these programs leads to unwanted systemic disease sequelae.

Conclusion

In the past, several notable features of CIDs were considered independent phenomena in the absence of a unifying model to explain both their prominence and coexistence. As a common denominator, the redirection of energy-rich fuels from energy stores to the activated immune system can explain systemic disease sequelae (see Figure 4, above). This theory also can explain the observed disturbances of the neuroendocrine immune regulation in CIDs. In this conceptualization, the induction of systemic responses results from an appeal for energy-rich substrates, called the energy appeal reaction. The theory states that the energy appeal reaction has been positively selected for transient inflammatory episodes, but prolonged use of adaptive programs can become pathogenic. Thus, one can add the “systemic response” to the list of classical etiologic factors of CIDs (see Table 2, p. 26). Hopefully, recognition of the importance of energy fluxes during both acute and chronic inflammation can provide a new perspective of disease pathogenesis and lead to better approaches for diagnosis and treatment.

Acknowledgments

The theory demonstrated in this paper was developed by the author during the last 10 years in individual steps that have been published previously.^1,9,17,37