Introduction

Humans are endotherms, animals that keep their body temperature within a stable range using heat production and heat dissipation. The ability to produce heat from calories is an essential mechanism required for life-sustaining cellular reactions that need a sufficient intake of calories. The molecules in food contain energy, or calories, stored in chemical bonds. Metabolic reactions can extract energy from these chemical bonds and use them to power various metabolic reactions that maintain the body's homeostasis. Energy metabolism is a highly regulated process to meet the energy demands of our body under variable conditions at rest and during work or exercise. [1]

Fundamentals

Calories are a measure of energy. The lowercase “c” calories (cal) is the amount of energy to raise the temperature of one gram of water by one degree Celsius at one atmospheric pressure. Likewise, the uppercase “C” Calories (Cal or Kcal) is the amount of energy needed to raise the temperature of one kilogram of water by one degree Celsius.

1 Cal or 1 Kcal = 1000 cal

When referring to food, the Calorie (Kcal) is used. Proteins and carbohydrates both contain 4 Kcal/g. Fats provide 9 kcal/g. According to the U.S. Dietary Guidelines, 45-65% of calories should come from carbohydrates, 20-35% from fats, and 10-35% from proteins.

The total energy expenditure (TEE) includes the total daily energy expenditure (DEE), active energy expenditure (AEE includes exercise and non-exercise related), and the thermic effect of feeding (TEF). The Basal Metabolic Rate (BMR) measures the total daily energy expenditure per day by the body at rest or basal level and accounts for up to 60% of total energy expenditure, with active energy expenditure ~30% and remaining ~10% accounts for thermic effect of feeding. BMR measures the amount of energy required for vital activities such as respiration and maintaining circulation. Thermic effect of feeding accounts for the energy required to digest and absorb food. BMR can be calculated by Direct or Indirect calorimetry and is measured under controlled conditions. Thermoneutral conditions are important while measuring BMR to eliminate the inclusion of any activity that may contribute to BMR. Direct calorimetry measures the total heat generated over a certain period of time, while indirect calorimetry calculates BMR by measuring the total quantity of oxygen consumed in a defined time. Resting metabolic rate (RMR) is yet another way to measure the metabolic rate and is essentially similar to BMR but is measured under less restrictive conditions[2][3]. Adult human females and males have an average BMR of 1300-1500 kcal/day and 1600-1800 kcal/day, respectively. With stress, activity, and energy expenditure the metabolic rate rises, but the BMR remains the same. On average, the daily metabolic rate is 150 percent of one’s BMR, 1950-2250 kcal/day for adult females and 2400-2700 kcal/day for adult males[4][5]. Another quick simple way to estimate the BMR is through the following equations:

Women: BMR = 655 + ( 4.35 x weight in pounds ) + ( 4.7 x height in inches ) - ( 4.7 x age in years )

Men: BMR = 66 + ( 6.23 x weight in pounds ) + ( 12.7 x height in inches ) - ( 6.8 x age in years )

Cellular

The mitochondria control cellular metabolism and produce most of the heat in the body. This control is implemented with the help of the tricarboxylic acid cycle (TCA cycle) and the Electron Transport Chain. The TCA cycle, also known as the Kreb’s Cycle or Citric Acid cycle, is a central driver of cellular respiration and takes place in the matrix of the mitochondria. The TCA cycle begins with its substrates, Acetyl-CoA, and oxaloacetate derived from pyruvate, the end product of glycolysis. Besides glucose, the beta-oxidation of fats is another major source of Acetyl CoA. These two substrates are funneled into the TCA cycle, and undergo a series of redox reactions producing various intermediates and result in the formation of high energy bonds in the form of NADH and FADH2. NADH and FADH2 undergo oxidation at the Complex I and II of electron transport chain respectively and participate in the oxidative phosphorylation process to generate ATP molecules. The process of oxidative phosphorylation occurs at the inner mitochondrial membrane, consumes oxygen, and phosphorylates ADP to form ATP molecules. Finally, this ATP is then used to power various molecular reactions throughout the body which creates heat. ATP hydrolysis is an exergonic process where the phosphate bonds are broken to release energy in the form of heat. The inner mitochondrial membrane also contains a unique uncoupling protein (UCP-1), also known as thermogenin that is involved in regulating the inner membrane permeability and the resultant generation of heat [6][7].

Pathophysiology

Body temperature is tightly regulated by a process called thermoregulation, controlled by a master regulator, the hypothalamus that modulates the heat gain or loss by the body. Up to 60% of the heat generated during metabolic processes is used to maintain body temperature. Accordingly, dysregulation of thermoregulatory mechanisms can result in hypothermia or hyperthermia [8].

Hypothermia: If the heat produced by these reactions is exceeded by total body heat loss, the body is in a state of hypothermia. Hypothermia is defined as a core body temperature below 35 degrees Celsius (C) or 95 degrees Fahrenheit (F). Hypothermia can be classified as mild, moderate, or severe. Mild hypothermia is characterized by substantial shivering and behavior changes. It is defined as a core temperature between 32-35 degrees C (89.6-95 degrees F). A core body temperature between 28-32 degrees C (82.4-89.6 degrees F) is defined as moderate hypothermia. It is characterized by dilation of pupils, cardiac arrhythmias, confusion, possible loss of consciousness, and lack of shivering. Severe hypothermia is defined as a core temperature below 28 degrees C (82.4 degrees F). Severe bradycardia and ventricular fibrillation can occur at this stage. Cardiac arrest becomes more likely as the body becomes colder. To counteract hypothermia, the hypothalamus can increase the body’s overall metabolic rate generating more heat.

Shivering is an involuntary response to cold temperatures that uses muscle contractions to generate heat. It can increase the basal metabolic rate by as much as 5 to 6 times. The intensity of shivering depends on the core temperature and a person’s BMI. Studies show that decreased shivering is correlated with increased body fat.  Additionally, peripheral vessels can undergo vasoconstriction keeping blood centrally and minimizing heat loss to the environment. The outer body then acts as a barrier between the body’s core and the environment. Frostbite risk increases as peripheral vasoconstriction increases. The treatment of mild to moderate hypothermia is the removal of cold, wet clothing and rapid-rewarming with a hot bath at 37-39 degrees C. If the hypothermia is severe, active internal rewarming is indicated. The treatment process is often painful and may require pain medication [9][10].

Hyperthermia: Hyperthermia is the state of increased core body temperature resulting from the body creating more heat than it can dissipate. A temperature higher than 37.5–38.3 °C (99.5–100.9 °F) classifies as hyperthermia in humans. Causes of hyperthermia encompass a wide range of factors such as drugs, toxins, as a compensatory immune reaction to certain infections, and malignant hyperthermia. Normally, the core body temperature is maintained by thermoregulatory mechanisms such as sweating, shivering, and vasoconstriction that are controlled by the hypothalamus. The breakdown of these thermoregulatory mechanisms in the body can cause elevation of temperature, ranging from mild to dangerously high levels and can be life life-threatening.

Clinical Significance

Malignant Hyperthermia (MH) occurs in response to certain triggers such as volatile anesthetics (e.g. isoflurane) and muscle relaxants (e.g. succinylcholine) that are often used during surgical procedures. At-risk individuals may experience hyperthermia, an increase in heart rate, respiration, and muscle rigidity. This can also lead to rhabdomyolysis, acidosis, and myoglobinuria.

Certain muscle disorder caused by mutations in genes such as RYR1 (ryanodine receptor1) and CACNA1S (Calcium voltage-gated channel subunit alpha1S) can predispose affected individuals to malignant hyperthermia susceptibility. The majority of these cases are caused by an autosomal dominant mutation in the RYR1gene that encodes the ryanodine receptor resulting in an uncontrolled release and abnormal accumulation of intracellular calcium in the skeletal muscle. This triggers the activation of other cellular processes involved in the generation of heat and sustained muscle contraction for a  prolonged duration resulting in muscle rigidity. Besides addressing the symptoms and triggers, dantrolene sodium is used to treat malignant hyperthermia. Dantrolene is a hydantoin derivative that binds to the ryanodine receptor to inhibit the release of calcium and thus interfering with muscle contraction. However, calcium channel blockers such as Verapamil are contraindicated for the treatment of MH can interact with dantrolene, and result in hyperkalemia and cardiac depression. The patient should also be observed for at least 24 hours in an intensive care unit. In the 1970s, the mortality rate of Malignant Hyperthermia was 80%. Because of increased knowledge and understanding, it is below 5% [11][12][13].

Hyperthermia caused by uncouplers: While UCP-1 is a physiological uncoupler, other non-physiological compounds such as Aspirin in high doses and 2,4-dinitrophenol can uncouple of the oxidative phosphorylation producing excessive heat resulting in hyperthermia[7][14][15].

Non-shivering Thermogenesis: In contrast to adults, heat production by shivering is not functional in newborns. Here, another mechanism known as non-shivering thermogenesis plays an important role in temperature regulation in neonates. Fat from brown adipose tissue contains an abundance of mitochondria and is used along with a specific physiological uncoupling protein called thermogenin or uncoupling protein (UCP-1). UCP-1 protein is present in the inner mitochondrial membrane and when activated, increases the membrane permeability of the inner mitochondrial membrane. The fat from brown adipose tissue is broken down and activates the UCP-1 causing the pores to open, uncoupling the oxidative phosphorylation, thus disrupting the proton gradient. This allows the protons to diffuse into the mitochondrial matrix, releasing heat in the process [7][16][17].