7. Biochemistry of Exceptional Situations

Content:

1. Metabolism of newborn
2. Metabolism in stress
3. Energy metabolism of obese

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Metabolism of newborn

Adaptation to a new environment

The term newborn denotes a child from the moment of its birth until a completed 28th postnatal day. It is a period of extensive adaptations of organs systems and functions of the child’s body caused by a forced change of the environment. Compared to the rest of the childhood, it is also characterized by higher death rate (mortality). These are the reasons why we treat the first 28 days of child’s life as a separate phase with its own medical field called neonatology.

In the course of development, a fetus finds itself in a thermoneutral environment of the uterus. Through placenta, it gets all the substances necessary for its growth and at the same time gets rid of the waste products of metabolism. The placenta thus replaces function of many organs, which have to adapt to new requirements after the birth. Among the most important adaptations are those of cardiovascular and respiratory systems, water and acid-base homeostasis, thermoregulation and energy metabolism.

The fetal cardiovascular system is adapted to a state, when the blood exchanges the blood gases in the placenta and rather avoids the lungs instead of flowing though them. There are special shunts in the circulation connecting the right and left atrium (so-called foramen ovale) and aorta and pulmonary artery (ductus arteriosus). Another bypass (ductus venosus) enables the oxygenated blood from placenta to circumvent the liver (that would not be able to hold the whole amount of blood flowing in) and flow directly to the heart. After the birth, as the child starts to breath spontaneously and the fluid filling the respiratory tract gets either squeezed out the airways or resorbed in the lung tissue, the above-mentioned shunts close and a normal lung blood flow establishes.

Energy metabolism and thermoregulation

Basic energy sources of a newborn are glucose and freefattyacids. Liver glycogen is used in the process of glycogenolysis providing the bloodstream with glucose – a process taking place particularly in the first 24 hours after the birth. Enzymatic systems of liver slowly mature and during the adaptation to external environment an up-regulation and increase in their activity occur, including the activity of enzymes of glucose metabolism.

The level of glycaemia in newborns reaches considerably lower levels compared to adults. A normal level ranges between 1.7-4.2 mmol/l in full-term newborns and around 1.3-3.3 mmol/l in prematurely born children (according to Tietz). Typically, the concentration of glucose decreases after birth, reaching its minimum approximately 2-4 hours after delivery, followed by a slow steady increase. Glycaemia thus rises back to its birth’s level only after several days.

It is also important to realize that the ratio of brain weight to the weight of the whole body is higher in newborns than in adults (brain constitutes a great proportion of body mass). The primary source of brain’s energy is glucose and its requirements are therefore higher in newly born children.

Except for degradation of liver glycogen, the glucose production takes place via gluconeogenesis as well, especially during prolonged fasting, when the glycogen reserves are depleted. Gluconeogenesis uses amino acids released during the degradation of muscles and glycerol made available during lipolysis of fat reserves. In order to prevent excessive loss of muscle tissue during fasting, the body of newborn (similarly to adult individuals) switches to triacylglycerols. Activated lipolysis thus becomes the source of free fatty acids that may be used in ketogenesis to produce ketone bodies (available as an energy source for brain as well). In general, the ability of newborns to withstand starvation is much worse compared to adults and they require a regular and frequent food intake.

The amount of energy reserves (glycogen and subcutaneous fat) significantly depends on the maturity of a fetus. In prematurely born children the low energy reserves pose a risk from developing a life threatening hypoglycaemia. In addition, the immature hormonal and enzymatic regulatory system are not able to react adequately when the level of glucose in blood starts to decrease.

Quite specific reservoir of energy in the body of a newly born child is a brown fat. It a type of adipose tissue consisting of cells containing more fat vacuoles and mitochondria (that give it the brown color) and having richer vasculature than white fat. It is located in the area between shovels and around large blood vessels. Although the view that the brown adipose tissue is not found in the bodies of adults is overcome, its importance is essential especially during the neonatal period and early childhood.

Thanks to its ability to uncouple the electron transport chain and oxidative phosphorylation, the cells of brown tissue shift the accumulated protons back to the mitochondrial matrix without ATP synthesis. The efficiency of the chain decreases and the energy (normally incorporated to the phosphate bounds of ATP) is released in the form of heat. The process takes place via an incorporation of a special group of proteins (e.g. thermogenin, also called UCP-1uncoupling protein 1) into the inner mitochondrial membrane. Some of these uncoupling proteins form channels enabling the protons to flow through, bypassing the ATP-synthases. The uncoupling takes place in other types of cells as well; the brown adipose tissue is, however, especially adapted to this process due to the high content of mitochondria.

Thermoregulation poses a challenge for the body of newly born child, as it consumes large quantities of energy and oxygen. Even full-term children are not able to maintain a stable body temperature (between 36.3 and 37°C) during the first 2 hours after the birth. Prematurely born children and newborns with low birth weight are therefore particularly prone to hypothermia mainly during the early postnatal period.

Internal environment of newborns

Newborns and children in general are characterized by higher proportion of water to the body weight. The younger the child is, the more water per kg of weight does it have. In case of fetus, the water constitutes as much as 90 % of the body weight. This share decreases to 75 % in newborns and at approximately one year the fraction of total body water (TBW) drops to 60 % of body weight.

The distribution of water within the organism changes as well. In adults, 2/3 of total body water is found inside the cells (the so-called intracellular fluid – ICF) and only 1/3 makes up the extracellular fluid (ECF – which includes interstitial fluid, blood plasma etc.). In newborns, this ratio is reversed and the amount of extracellular fluid is higher. The reason lies in the fact that newborns have smaller volume of organs and musculature, both high in ICF content. The ratio of ICF/ECF slowly increases and at around one year it reaches the values found in adults.

For an illustration, let’s compare the ECT turnover in 70kg adult male and 7kg infant:

1) In case of adult male with above-mentioned weight, the amount of TBW in organism is approximately 42 liters (60 % of his weight). Of this, the 1/3 or 14 liters is the ECT. The usual loss of body water (through perspiration, urination, etc.) is around 2.5 liters per day, thus representing approximately 18 % of the extracellular fluid.

2) In 7kg infant, the amount of ECT might be around 1.5 liters. Then the daily water losses of 700 ml represent almost 50 % of the total amount of extracellular fluid.

Neonatal jaundice

Jaundice (icterus), characterized by a yellow coloring of skin, mucosae and sclerae, affects up to 2/3 of full-term newborns and even more of the prematurely born ones. Generally, the icterus is caused by an accumulation of bilirubin, the degradation product of heme metabolism (see Subchapter 6/4).

For the yellow coloring to develop, the binding capacity of albumin has to be exceeded, as it normally binds and transports the unconjugated bilirubin to the liver. When the capacity is insufficient, the bilirubin accumulates in blood and diffuses into the tissues. The usual concentration of indirect bilirubin at which this happens is 35 μmol/l, but there are many other contributing factors (among them the concentration of albumin or other substances that bind to albumin).

The majority of newborns „suffer” from a so-called physiological jaundice. It develops due to a disintegration of fetal erythrocytes containing fetal hemoglobin (HbF). In contrast to erythrocytes in adults that usually survive around 120 days in the circulation, the fetal erythrocytes have an average length of survival only 70 days. Until they are replaced by adult erythrocytes, a higher rate of hemolysis occurs. Another factor contributing to a higher content of hemoglobin degradation products is immature enzymatic systems in liver (especially glucuronyl transferase, catalyzing the conjugation of indirect bilirubin to a more soluble direct bilirubin). These systems are not yet able to handle the surplus of the degradation products. Other factors include the loss of body water after the birth and underdeveloped intestinal microflora. Bacteria normally participate in metabolizing and eliminating the bilirubin in faeces and when their amount is low, less bilirubin gets excreted leading to higher rate of enterohepatic absorption.

The jaundice peaks around 3rd and 4th postnatal day and fades during the next two weeks. There are however many pathological conditions (including infections, congenital disorders of enzymatic systems or Rh incompatibility between the mother and child) that may complicate the course of the jaundice or even lead to a life-threatening condition of bilirubin toxicity.

Unconjugated, free bilirubin has an ability to cross the hematoencephalic barrier and enter the CNS, all thanks to its lipophilic nature. As a consequence, a toxic damage to the brain (hyperbilirubinemic toxic encephalopathy) called kernicterus may occur. The name is derived from a characteristic yellow coloring of some brain nuclei (mostly thalamic, cerebellar and nuclei of basal ganglia) revealed during the autopsies of death newborns. There is yet no consensus on the exact mechanism of bilirubin toxicity. It is assumed that an inhibition of enzymatic systems and neuron regulatory mechanisms (e.g. inhibition of protein phosphorylation) are at least partially responsible. Unconjugated bilirubin readily binds to cellular membranes and can damage membrane-bound organelles (such as mitochondria). The rate of oxidative phosphorylation and photosynthesis decreases, the rate of glycolysis increases. Affected neurons die and the condition may (depending on its the severity) lead to different degree of mental retardation, cerebral palsy or even death.

Therapy of neonatal jaundice uses a blue light (phototherapy) of a 450 nm wavelength. It triggers two processes: photoisomerisation, producing less lipophilic isomers (that may be excreted to bile even without glucuronidation) and photooxidation, degrading bilirubin to less toxic derivatives, which are excreted via urine. Other approaches include the administration of phenobarbital that induces a multiplication of enzymatic systems metabolizing the bilirubin or exchange blood transfusion, when the blood of the newborn is taken away and simultaneously replaced by a transfusion.

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Metabolism in stress

The term stress denotes an unspecific response of organism to a variety of challenging stimuli (stressors), which endanger the integrity and homeostasis of the body. The purpose of the reaction is to prevent or minimize the damage to the body and to cope with the situation.

The stress response consists of 3 phases (see Subchapter 11/8).

The changes in metabolism due to stress hormones

During the first (alarm) phase of the stress response, the metabolism is under the influence of catecholamines. The body tries to mobilize the energy reserves in order to give a maximal performance and to overcome the stressful situation (fight-or-flight reaction). Glycogenolysis in liver is activated, releasing glucose into the bloodstream even in cases, when the level of glucose is normal – a state often leading to hyperglycaemia. Apart from liver, activation of glycogenolysis and the adjoining glycolysis occur in muscles as well. Their purpose is to provide enough substrates for ATP synthesis that enables the muscles to work extensively (for example to escape the stressor).

Another source of energy substrates is the adipose tissue. Catecholamines activate lipolysis and the released free fatty acids are utilized in tissues (mainly muscles) as sources of energy. Glycerol released during lipolysis can be converted to glucose in the process of gluconeogenesis.

Resistance phase of the stress response is characterized by the activation of POMC and CRH-ACTH-cortisol systems. Cortisol turns on the protein catabolism. Proteins thus become the main source of the carbon skeleton necessary for the synthesis of glucose in the gluconeogenesis. Increased breakdown of proteins causes more bound nitrogen to be released and metabolized in the activated pathway of ornithine cycle. Growing production of urea presents a burden for kidneys.

In general, cortisol has anti-insulin (diabetogenic) effects leading to an increase of glucose level in blood, even causing hyperglycaemia. Contributing to this, it is its ability to increases the insulin resistance of peripheral tissues. As a result, the periphery does not take much glucose from the blood, potentiating the state of hyperglycaemia.

Other effects of cortisol during the stress reaction include the ability to enhance the effect of catecholamines, immunosuppressive effects (decreasing the synthesis of antibodies, amount of lymphocytes in circulation, suppressing the immune and inflammatory reaction etc.), effect of decreasing the collagen synthesis and fibroblast proliferation (both associated with impaired wound healing).

From a long-term point of view, a protracted, chronic stress accompanied by an increased cortisol concentration is harmful to the organism and leads to an exhaustion due to the shortage of the energy sources, catabolism of proteins and immune function failures.

Stress-induced and simple starvation

A stress-induced starvation is a specific state of an organism, during which the adaptation mechanisms, normally taking place during a simple starvation, do not develop. Instead, a state of catabolism initiated by stress hormones (catecholamines and cortisol) persists.

Under normal circumstances, the insufficient caloric intake (the so-called caloric malnutrition or marasmus) leads to a state of simple starvation. The body soon depletes the glycogen reserves in the liver, which serve, at the beginning, as a main source of glucose molecules released into the bloodstream. Subsequently, a proteolysis is activated and the glucogenic amino acids serve as a substrate for glucoses formation in the process of gluconeogenesis.

If the shortage of food lasts longer, the body activates mechanisms that save the proteins and direct the metabolism towards other source of energy – fatty acids and ketone bodies. The secretion of insulin drops, accompanied by an increase in the production of contra-regulatory hormonesglucagon, catecholamines and cortisol. Lipolysis is stimulated and its products (fatty acids and glycerol) are released into the blood circulation. Glycerol serves as a source of glucose molecules. Tissues that can benefit from the fatty acid metabolism stop (due to effects of the hormones) to utilize glucose that is thus saved for cells that strictly depend on it (such as neurons and erythrocytes).

During prolonged shortage of energy substrates, synthesis of thyroid hormones and stress hormones decreases. The result is a decrease in basal metabolic rate (up to 40 %) to reduce the demand for energy intake. Protein catabolism is restricted also, but lipolysis is stimulated conversely. Fatty acids become a source of ketone bodies synthesized by the liver cells, which are subsequently used as an alternative energy substrate for a variety of peripheral tissues (e.g. brain that covers a considerable part of the energy consumption by their utilization – need for glucose decreases).

People, who undergo this type of starvation, develop a significant loss of storage fat, but storage proteins (in the form of skeletal muscle) are saved for a long time. Simple starvation can be reversed simply by supplying nutrients, cascade of adaptation mechanisms stops and the body begins to accumulate energy reserves again.

Stress starvation arising in severe conditions (among other severe trauma, sepsis or extensive burns) is characterized by a significant mobilization of energy reserves in an attempt to supply vital organs with energy sources. In particular, glucose molecules – its blood concentration reaches hyperglycaemic levels. Neither increased secretion of insulin is able to alleviate hyperglycaemia due to the effects of stress hormones that inhibit peripheral glucose utilization (leads to a state of insulin resistance). Intensified gluconeogenesis and glycogenolysis participate in the development of hyperglycaemia – the main sources of carbon skeleton are amino acids obtained by protein catabolism of skeletal muscles. Body can lose 0.5 to 1 kg of the skeletal muscles per day during this condition of fully-activated proteolysis.

Consumption of amino acids leads to a decrease of plasma albumin (hypoalbuminaemia) accompanied by a decline in oncotic pressure. The result is the formation of ascites and generalized edemas. Adipose tissue is relatively saved and its catabolism is not increased to a high extent. Energy for the body comes from glucose molecules.

Recovery from a stress starvation is quite difficult process. Neither the delivery of energy, nor the supply of amino acids stop the stress response usually. Administered amino acids can not be used for proteins synthesis (due to metabolic situation), they may even harm the body due to an increased nitrogen load. Therapy should thus focus first on eliminating the underlying condition and subsequently on realimentation.

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Energy metabolism of an obese individual

Obesity is a nutritional disorder in which the individual’s caloric intake exceeds its energy expenses and excess energy is stored in a storage TAG. WHO defines obesity based on the body mass index (BMI) – for obesity is determining BMI greater than 30.

Metabolism in obese people runs most of the time in the „satietymode with activated anabolic pathways that generate energy reserves. Insulin released after meals is a factor stimulating lipogenesis in the liver. Synthesized triacylglycerols are secreted into the circulation in the form of VLDL that are subsequently degraded by lipoprotein lipase and incorporated into adipocytes of adipose tissue. Fatty acids are formed from the excess saccharides.

A long-term rise in insulin level leads to a state of insulin resistance that decreases the response of the insulin receptor. The state is initially compensated by a higher insulin production in the pancreas. When the resistance persists the pancreatic insulin production is insufficient to produce sufficient amount of insulin to overcome the resistance and type 2 diabetes mellitus develops.

Reduced entry of glucose molecules into peripheral tissues (insulin receptors do not respond to its presence) results in hyperglycaemia. Increased synthesis of FA, TAG and VLDL causes accompanying hyperlipoproteinemia. Unlike type 1 diabetes ketoacidosis usually does not develop, since insulin, which circulates in a relatively large amount, is still capable of inhibiting the hormone-sensitive lipase (that would otherwise activate lipolysis and release of FA).

Adipose tissue is a potent producer of various hormones in addition. In obese people both quantitative (depending on the volume of adipose tissue) and qualitative changes in their secretion occurs. Secretion of adiponectin decreases and body loses its protective effect (e.g. against the development of atherosclerosis). Conversely, resistin secretion increases, which promotes insulin resistance and the development of type 2 diabetes. Leptin levels rise proportionally to the amount of adipose tissue, but concomitantly emerged leptin resistance reverses its anorexigenic effect in obese people. Adipose tissue possesses a significant activity of aromatase also, thus serving as an important producer of estrogens obese people exhibit higher amount of these hormones.

Metabolically active is particularly the abdominal fat (stored in the abdominal cavity). Its accumulation leads to the so-called android type of obesity (narrow hips and a big belly), which is more common in men. It is associated with an increased cardiovascular risk and the risk of developing type 2 diabetes mellitus.

The second type of obesity is called gynoid (relatively narrow waist, wide hips) with a characteristic storage of fat in the hips, buttocks and thighs. It occurs more in women and is not accompanied with a metabolic risk because adipose tissue in this localization is only little metabolically and hormonally active.

Subchapter Authors: Petra Lavríková and Josef Fontana

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