Regulation of lipid metabolism.Classes of lipoproteins.Hyperlipidemias.Atherosclerosis.Complications of atherosclerosis.ObesityGenetic disordersFat-soluble vitamins

The knowledge of the reasons and mechanisms of atherosclerosis development is necessary for the doctors of various profession for prophylaxis and treatment of this disease. According to modern notions, main etiological factors of atherosclerosis is dyslipoproteinemia and increased permeability arterial wall for lipoproteins. Atherosclerosis exceptionally widespread disease. On data WHO, mortality of the patients in the age 35-44 years for damages of heart and vessels connected with atherosclerosis, increased lately by 60%.

Metabolic Rate - the amount of energy liberated per unit of time. The amount of energy liberated by the catabolism of food in the body is the same as the amount liberated when food is burned outside the body. The energy liberated by catabolic processes in the body is used for maintaining body functions, digesting and metabolizing food, thermoregulation, and physical activity. It appears as external work, heat, and energy storage: = + + Isotonic muscle contractions perform work at a peak efficiency approximating 50%: = / Calories The standard unit of heat energy is the calorie (cal), defined as the amount of heat energy necessary to raise the temperature of 1 g of water 1 degree, from 15 C to 16 C. This unit is also called the gram calorie, small calorie, or standard calorie. The unit commonly used in physiology and medicine is the Calorie (kilocalorie; kcal), which equals 1000 cal.

Essentially all of the energy of isometric contractions appears as heat, because little or no external work (force multiplied by the distance that the force moves a mass) is done. Energy is stored by forming energy-rich compounds. The amount of energy storage varies, but in fasting individuals it is zero or negative. Therefore, in an adult individual who has not eaten recently and who is not moving (or growing, reproducing, or lactating), all of the energy output appears as heat. Calorimetry

The energy released by combustion of foodstuffs outside the body can be measured directly (direct calorimetry) by oxidizing the compounds in an apparatus such as a bomb calorimeter, a metal vessel surrounded by water inside an insulated container. The food is ignited by an electric spark. The change in the temperature of the water is a measure of the calories produced. Similar measurements of the energy released by combustion of compounds in living animals and humans are much more complex, but calorimeters have been constructed that can physically accommodate human beings. The heat produced by their bodies is measured by the change in temperature of the water in the walls of the calorimeter.

The caloric values of the common foodstuffs, as measured in a bomb calorimeter, are found to be 4.1 kcal/g of carbohydrate, 9.3 kcal/g of fat, and 5.3 kcal/g of protein. In the body, similar values are obtained for carbohydrate and fat, but the oxidation of protein is incomplete, the end products of protein catabolism being urea and related nitrogenous compounds in addition to CO2 and H2O (see below). Therefore, the caloric value of protein in the body is only 4.1 kcal/g. Indirect Calorimetry

Energy production can also be calculated by measuring the products of the energy-producing biologic oxidationsie, CO2, H2O, and the end products of protein catabolism producedbut this is difficult. However, O2 is not stored, and except when an O2 debt is being incurred, the amount of O2 consumption per unit of time is proportionate to the energy liberated by metabolism. Consequently, measurement of O2 consumption (indirect calorimetry) is used to determine the metabolic rate. Respiratory Quotient (RQ)

The respiratory quotient (RQ) is the ratio in the steady state of the volume of CO2 produced to the volume of O2 consumed per unit of time. It should be distinguished from the respiratory exchange ratio (R), which is the ratio of CO2 to O2 at any given time whether or not equilibrium has been reached. R is affected by factors other than metabolism. RQ and R can be calculated for reactions outside the body, for individual organs and tissues, and for the whole body. The RQ of carbohydrate is 1.00, and that of fat is about 0.70. This is because H and O are present in carbohydrate in the same proportions as in water, whereas in the various fats, extra O2 is necessary for the formation of H2O.

Determining the RQ of protein in the body is a complex process, but an average value of 0.82 has been calculated. The approximate amounts of carbohydrate, protein, and fat being oxidized in the body at any given time can be calculated from the RQ and the urinary nitrogen excretion. RQ and R for the whole body differ in various conditions. For example, during hyperventilation, R rises because CO2 is being blown off. During severe exercise, R may reach 2.00 because CO2 is being blown off and lactic acid from anaerobic glycolysis is being converted to CO2 (see below). After exercise, R may fall for a while to 0.50 or less. In metabolic acidosis, R rises because respiratory compensation for the acidosis causes the amount of CO2 expired to rise. In severe acidosis, R may be greater than 1.00. In metabolic alkalosis, R falls.

The O2 consumption and CO2 production of an organ can be calculated at equilibrium by multiplying its blood flow per unit of time by the arteriovenous differences for O2 and CO2 across the organ, and the RQ can then be calculated. Data on the RQ of individual organs are of considerable interest in drawing inferences about the metabolic processes occurring in them. For example, the RQ of the brain is regularly 0.97-0.99, indicating that its principal but not its only fuel is carbohydrate. During secretion of gastric juice, the stomach has a negative R because it takes up more CO2 from the arterial blood than it puts into the venous blood *

Measuring the Metabolic Rate In determining the metabolic rate, O2 consumption is usually measured with some form of oxygen-filled spirometer and a CO2-absorbing system. The spirometer bell is connected to a pen that writes on a rotating drum as the bell moves up and down. The slope of a line joining the ends of each of the spirometer excursions is proportionate to the O2 consumption. The amount of O2 (in milliliters) consumed per unit of time is corrected to standard temperature and pressure and then converted to energy production by multiplying by 4.82 kcal/L of O2 consumed.

The metabolic rate determined at rest in a room at a comfortable temperature in the thermoneutral zone 12-14 hours after the last meal is called the basal metabolic rate (BMR). This value falls about 10% during sleep and up to 40% during prolonged starvation. The rate during normal daytime activities is, of course, higher than the BMR because of muscular activity and food intake. The maximum metabolic rate reached during exercise is often said to be ten times the BMR, but trained athletes can increase their metabolic rate as much as 20-fold. The BMR of a man of average size is about 2000 kcal/d.

Large animals have higher absolute BMRs, but the ratio of BMR to body weight in small animals is much greater. One variable that correlates well with the metabolic rate in different species is the body surface area. This would be expected, since heat exchange occurs at the body surface. The actual relation to body weight (W) would be

However, repeated measurements by numerous investigators have come up with a higher exponent, averaging 0.75.

Thus, the slope of the line relating metabolic rate to body weight is steeper than it would be if the relation were due solely to body area. The cause of the greater slope has been much debated but remains unsettled. *

LipoproteinComposition (%)Size (nm)ProteinFree CholesterolCholesteryl EstersTriglyceridePhospholipidOriginChylomicrons75-1000223903IntestineChylomicron remnants30-80. . .. . .. . .. . .. . .CapillariesVery low density lipoproteins (VLDL)30-8084165517Liver and intestineIntermediate-density lipoproteins (IDL)25-40105254020VLDLLow-density lipoproteins (LDL)2020746621IDLHigh-density lipoproteins (HDL)7.5-1050416525Liver and intestine

Transports diet-derived triglyceride (TG) in the blood Composition:(1) Protein (2%); (2) TG (87%); (3) Cholesterol (CH;3%); (4) Phospholipid (8%) Synthesized in intestinal epithelium(1) Requires apolipoprotein (apo) B-48 for assembly and secretion(2) Nascent chylomicrons in the circulation obtain apo C-Il and apo E from high density lipoprotein (HDL) Absent during fasting If increased, it forms a creamy supranate.1) Test tube must be left upright in a refrigerator overnight,2) Chylomicron floats on top of plasma because it has very little protein (low density).

Source of fatty acids and glycerol Used to synthesize TG in the liver and adipose Hydrolysis by capillary lipoprotein lipase (CPL) leaves a chylomicron remnant, Chylomicron remnants arc removed by apo E receptors in the liver.

LipoproteinFunctionsApoproteinsFunctionsChylomicronsTransport dietary triglyceride and cholesterol from intestine to tissuesapoB-48apoC-IIapoESecreted by intestineActivates lipoprotein lipaseUptake of remnants by the liverVLDLTransports triglyceride from liver to tissuesapoB-100apoC-IIapoESecreted by liverActivates lipoprotein lipaseUptake of remnants (IDL) by liverIDL(VLDL remnants)Picks up cholesterol from HDL to become LDLPicked up by liverapoEapoB-100Uptake by liverLDLDelivers cholesterol into cellsApoB-100Uptake by liver and other tissues via LDL receptor (apoB-100 receptor)HDLPicks up cholesterol accumulating in blood vesselsDelivers cholesterol to liver and steroidogenic tissues via scavenger receptor (SR-B1)Shuttles apoC-II and apoE in bloodapoA-1Activates lecithin cholesterol acyltransferase (LCAT) to produce cholesterol esters

Transports liver-synthesized TG in the bloodRequires apolipoprotein B-100 for assembly and secretion Composition:(1) Protein (9%); (2) TG (55%); (3) CH (17%); (4) Phospholipid (19%).

Source of fatty acids and glycerol1) Used to synthesize TG in the adipose tissue2) Hydrolysis by CPL produces intermediate-density lipoprotein (IDL) and low density lipoprotein (LDL).3) Some of the IDL is removed from blood by apo E receptors in the liver.

Cholesterol ester transport protein (CETP)(1) Transfers CH from HDL to VLDL;(2) Transfers TG from VLDL to HDL;(3) An increase in VLDL always causes a decrease in HDL-CH. If increased, it forms a creamy infranate. Note that the protein is greater in VLDL than in chylomicrons, so it sinks rather than floats in plasma. TG levels(1) Optimal level < 150 mg/dL(2) Borderline high level 150 to 199 mg/dL(3) High level 200 to 499 mg/dL,(4) Very high level > 500 mg/dL

Transports cholesterol in the blood Derives from continued hydrolysis of IDL by CPL Removed from blood by LDL receptors in peripheral tissue Composition: 1) Protein (22%); 2) TG (10%); CH (47%); (4) Phospholipid (21%) Calculated LDL = CH - HDL - TG/51) Presence of chylomicrons falsely lowers calculated LDL by increasing diet-derived triglyceride; hence, fasting is required for an accurate calculated LDL.2) To reduce the chance for a falsely low calculated LDL, LDL is directly measured if the serum TG > 400 mg/dL. Functions of cholesterol:1) Component of the cell membrane.2) Synthesis of vitamin D, adrenal cortex hormones, bile salts and acids. Ranges of LDL:1) Optimal level < 100 mg/dL. Risk for coronary heart disease (CHD) markedly reduced

2) Near optimal level is 100 to 129 mg/dL.3) Borderline high level is 130 to 159 mg/dL.4) High level is 160 to 189 mg/dL.5) Very high level > 190 mg/dL.Greatest risk for CHD

Fasting is not required for an accurate serum CH. Note that the CH content in chylomicrons is

Good cholesterol Increased by exercise, wine, estrogen Composition: 1) Protein (50%); 2) TG (3%; unless VLDL is increased); 3) CH (20%); 4) Phospholipid (27%) Synthesized by the liver and small intestine Functions of HDL1) Source of apolipoproteins for other lipoprotein fractions2) Removes cholesterol from atherosclerotic plaquesa) Delivers CH from peripheral tissue to the liverb) CH is either excreted into bile or converted into bile acids/salts.Measured in the laboratory as HDL-CH1) Inverse association of levels of HDL-CH and incidence and prevalence of CHD2) Decreased if VLDL is increased3) Ranges of HDL-CH(a) High level (optimal) 60 g/dL(b) Low level (suboptimal) < 40 mg/dL

4) Fasting is not required for an accurate serum HDL-CH.Same reason as for serum CH.

In the body, fatty acids are broken down to acetyl-CoA, which enters the citric acid cycle. The main breakdown occurs in the mitochondria by -oxidation. Fatty acid oxidation begins with activation of the fatty acid, a reaction that occurs both inside and outside the mitochondria. Medium- and short-chain fatty acids can enter the mitochondria without difficulty, but long-chain fatty acids must be bound to carnitine in ester linkage before they can cross the inner mitochondrial membrane. Carnitine is -hydroxy--trimethylammonium butyrate, and it is synthesized in the body from lysine and methionine. A translocase moves the fatty acid-carnitine ester into the matrix space in exchange for free carnitine. In the matrix space, the ester is hydrolyzed, making the activated fatty acid molecule available for -oxidation and providing free carnitine for further exchange. -Oxidation proceeds by serial removal of two carbon fragments from the fatty acid. The energy yield of this process is large.

For example, catabolism of 1 mol of a six-carbon fatty acid through the citric acid cycle to CO2 and H2O generates 44 mol of ATP, compared with the 38 mol generated by catabolism of 1 mol of the six-carbon carbohydrate glucose. *

Deficient -oxidation of fatty acids can be produced by carnitine deficiency or genetic defects in the translocase or other enzymes involved in the transfer of long-chain fatty acids into the mitochondria. This causes cardiomyopathy. In addition, it causes hypoketonemic hypoglycemia with coma, a serious and often fatal condition triggered by fasting, in which glucose stores are used up because of the lack of fatty acid oxidation to provide energy, and ketone bodies are not formed in normal amounts because of the lack of adequate CoA in the liver.

In many tissues, acetyl-CoA units condense to form acetoacetyl-CoA. In the liver, which (unlike other tissues) contains a deacylase, free aceto-acetate is formed. This -keto acid is converted to -hydroxybutyrate and acetone, and because these compounds are metabolized with difficulty in the liver, they diffuse into the circulation. Acetoacetate is also formed in the liver via the formation of 3-hydroxy-3-methylglutaryl-CoA, and this pathway is quantitatively more important than deacylation. Acetoacetate, -hydroxybutyrate, and acetone are called ketone bodies (KB). Tissues other than liver transfer CoA from succinyl-CoA to acetoacetate and metabolize the "active" acetoacetate to CO2 and H2O via the citric acid cycle. There are also other pathways whereby ketone bodies are metabolized.Acetone is discharged in the urine and expired air. The normal blood ketone level in humans is low (about 1 mg/dL) and less than 1 mg is excreted per 24 hours, because the ketones are normally metabolized as rapidly as they are formed. However, if the entry of acetyl-CoA into the citric acid cycle is depressed because of a decreased supply of the products of glucose metabolism, or if the entry does not increase when the supply of acetyl-CoA increases, acetyl-CoA accumulates, the rate of condensation to acetoacetyl-CoA increases, and more acetoacetate is formed in the liver. The ability of the tissues to oxidize the ketones is soon exceeded, and they accumulate in the bloodstream (ketosis).

Acetone breath KB in urine

KETONURIA KB in the blood

KETONEMIA pH - AcidosisDehydra-tationAre osmotic!

Two of the three ketone bodies, acetoacetate and -hydroxybutyrate, are anions of the moderately strong acids acetoacetic acid and -hydroxybutyric acid. Many of their protons are buffered, reducing the decline in pH that would otherwise occur. However, the buffering capacity can be exceeded, and the metabolic acidosis that develops in conditions such as diabetic ketosis can be severe and even fatal. Three conditions lead to deficient intracellular glucose supplies: starvation, diabetes mellitus, and a high-fat, low-carbohydrate diet. In diabetes, glucose entry into cells is impaired. When most of the caloric intake is supplied by fat, carbohydrate deficiency develops because there is no major pathway for converting fat to carbohydrate. The liver cells also become filled with fat, which damages them and displaces any glycogen that is formed. In all of these conditions, ketosis develops primarily because the supply of ketones is overabundant. The acetone odor on the breath of children who have been vomiting is due to the ketosis of starvation. Parenteral administration of relatively small amounts of glucose abolishes the ketosis, and it is for this reason that carbohydrate is said to be antiketogenic.

*

Atherosclerosis is a form of arteriosclerosis in which thickening and hardening of the vessel are caused by the accumulation of lipid-laden macrophages within the arterial wall, which leads to the formation of a lesion called a plaque. Atherosclerosis is not a single disease but rather a pathologic process that can affect vascular systems throughout the body, resulting in ischemic syndromes that can vary widely in their severity and clinical manifestations. It is the leading contributor to coronary artery and cerebrovascular disease.

*

The mummified Egyptians, were likely to have been wealthy, and therefore probably consumed a lot of saturated fat. This is in fact not the first time that hardened arteries were identified in Egyptian mummies. And yet the Unangans, of the Aluetian Islands in Alaska, subsisted almost entirely on marine life. They, and the other mummies, were preserved naturally through climate factors, not because they had attained any special status that would have privileged them with extra-rich foods. But that ancient people, too, had calcified arteries, "suggests that the disease is an inherent component of human aging and not necessarily associated with any specific diet or lifestyle." Indeed, the mummies with signs of calcification tended to be older, or what in those days counted as age: they died at around 43 years as opposed to 32. For each decade of life the mummies survived before being mummified, the risk of severe atherosclerosis increased by 69 percent.Hatiay, a male Egyptian scribe who lived during the New Kingdom (1570-1293 BCE), enters the CT scanner. [The Lancet]Evidence of carotid artery disease in HatiayAnd yet ancient people of Egypt, Peru, southwest America, and Alaska commonly suffered from hardened arteries, too. Using CT scans, researchers examined the remaining arteries of 137 mummies, and found signs of probable or definite atherosclerosis in 34 % of them.

http://www.theatlantic.com/health/archive/2013/03/study-mummies-have-atherosclerosis-too/273863/http://blogs.unimelb.edu.au/sciencecommunication/2013/08/13/mummies-return-is-a-reality-we-need-more-mummy-hunters/Put more colorfully, "We found that heart disease is a serial killer that has been stalking mankind for thousands of years," one of the study's lead authors, Randall Thompson, said in a statement.In modern men and women over the age of 50, the condition's prevalence is as high as 82 and 68 percent, respectively. And certain behaviors certainly increase this risk -- these findings in fact emphasize the importance of controlling for those factors, like diet, that are indeed controllable. As with last summer's counter-intuitive findings that sedentary office workers burnas many calories in a dayas modern hunter-gatherers, this should at the very least make us question whether the good old days of pre-modern living were as ideal as wetend to imagine them.*

Role of blood monocytes. Though blood monocytes do not possess receptors for normal LDL, LDL does appear in the monocyte cytoplasm to form foam cell. Plasma LDL on entry into the intima undergoes oxidation. The oxidised LDL formed in the intima performs the following all-important functions on monocytes and endothelium: For monocytes: Oxidised LDL acts to attract, proliferate,

immobilise and activate them as well as is readily taken up by scavenger receptor on the monocyte to transform it to a lipid-laden foam cell.For endothelium: Oxidised LDL is cytotoxic.Death of foam cell by apoptosis releases lipid to form lipid core of plaque.

PATHOPHYSIOLOGY1. Injured endothelial cells become inflamed and cannot make normal amounts of antithrombotic and vasodilating cytokines.2. Numerous inflammatory cytokines are released, including tumor necrosis factor-alpha (TNF-), interferongamma (IFN-), interleukin-1 (IL-1), toxic oxygen radicals, and heat shock proteins.3. Macrophages adhere to injured endothelium by way of adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1).4. These macrophages then release enzymes and toxic oxygen radicals that create oxidative stress, oxidize LDL, and further injure the vessel wall.5. Growth factors also are released, including angiotensin II, fibroblast growth factor, and platelet-derived growth factor, which stimulate smooth muscle cell proliferation in the affected vessel.

Once injury has occurred, endothelial dysfunction and inflammation lead to the following pathophysiologic events:

Endothelial Dysfunction in AtherosclerosisRoss R. N Engl J Med 1999; 340:115126.

Fatty-Streak Formation in Atherosclerosis Ross R. N Engl J Med 1999; 340:115126.

Formation of an Advanced, Complicated Lesion in Atherosclerosis Ross R. N Engl J Med 1999; 340:115126.

THROMBOSIS (due to endothelium damage)

2. Ulceration(necrosis of and releasing of lisosomal enzymes causes damage of plaque wall)

3. Calcinations(deposit of insoluble calcium salts)4 stage - COMPLICATIONS

Clinical EffectsMajor sites of atherosclerosis (serially numbered) in descending order of frequency.The clinical effects of atherosclerosis depend upon the size and type of arteries affected. In general, the clinical effects result from the following:1. Slow luminal narrowing causing ischaemia and atrophy.2. Sudden luminal occlusion causing infarction necrosis.3. Propagation of plaque by formation of thrombi and emboli.4. Formation of aneurysmal dilatation and eventual rupture.Accordingly, the symptomatic atherosclerotic disease involves most often the heart, brain, kidneys, small intestine and lower extremitiesThe effects pertaining to these organs are:

1) AortaAneurysm formation, thrombosis and embolisation to other organs.2) HeartMyocardial infarction, ischaemic heart disease.3) BrainChronic ischaemic brain damage, cerebral infarction.4) Small intestineIschaemic bowel disease, infarction.5) Lower extremitiesIntermittent claudication, gangrene.

It is estimated that nearly half of the U.S. population has some form of dyslipidemia, especially among white and Asian populations. These abnormalities are the result of a combination of genetic and dietary factors. Primary or familial dyslipoproteinemias result from genetic defects that cause abnormalities in lipid-metabolizing enzymes and abnormal cellular lipid receptors. Secondary causes of dyslipidemia include several common systemic disorders, such as diabetes, hypothyroidism, pancreatitis, and renal nephrosis, as well as the use of certain medications such as certain diuretics, beta-blockers, glucocorticoids, interferons, and antiretrovirals.

or dyslipoproteinemia refers to abnormal concentrations of serum lipoproteins

Optimal Near Optimal Desirable Low Borderline High Very HighTotal cholesterol

a) Cholestyramine (Questran), anion exchange resin; binds bile acids; enhances cholesterol excretion.b) Colestipol (Colestid), same as cholestyramine.c) Lovastatin, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor; decreases cholesterol synthesis in the liver.d) Nicotinic acid (niacin), decreases release of free fatty acids from adipose tissue; increases lipogenesis in liver; decreases glucagon release; most effective for type V disorder.e) Neomycin, experimental medication; questionable mode of action; decreases LDLs.f) Clofibrate (Atromid-S), decreases release of free fatty acids from adipose tissue; decreases hepatic secretion of VLDL and increases catabolism of VLDL.g) Gemfibrozil (Lopid), similar to clofibrate but increases HDLs more.

Name Laboratory Findings Clinical Features TherapyType I: exogenous hyperlipidemia;fat-induced hypertriglyceridemiaCholesterol normalTriglycerides increased three timesChylomicrons increasedAbdominal painHepatosplenomegalySkin and retinal lipid depositsUsual onset: childhoodLow-fat dietType IIa: hypercholesterolemiaTriglycerides normalLDL increasedCholesterol increasedPremature vascular diseaseXanthomas of tendons and bony prominencesCommonOnset: all agesLow-saturated-fat and low-cholesterol dietCholestyramine (a); Colestipol (b); Lovastatin (c); Nicotinic acid (d) ;Neomycin (e).Intestinal bypassType IIb: combined hyperlipidemia;carbohydrate-induced hypertriglyceridemiaLDL, VLDL increasedCholesterol increasedTriglycerides increasedSame as IIaSame as IIa; plus carbohydrate restrictionClofibrate (f); Gemfibrozil (g) Lovastatin

(h) Estrogens, decrease IDL levels in type III disorders; experimental.(i) Progesterone, decreases plasma triglycerides in type V disorders; experimental.

Name Laboratory Findings Clinical Features TherapyType III: dysbetalipoproteinemiaIDL or chylomicron remnants increasedCholesterol increased

Triglycerides increasedPremature vascular diseaseXanthomas of tendons and bony prominencesUncommonOnset: adulthoodWeight controlLow-carbohydrate, low-saturated-fat, andlow-cholesterol dietAlcohol restrictionClofibrate; Gemfibrozil; Lovastatin; Nicotinic acid; Estrogens (h)Intestinal bypassType IV: endogenous hyperlipidemia;carbohydrate-induced hypertriglyceridemiaGlucose intoleranceHyperuricemiaCholesterol normal or increasedVLDL increasedTriglycerides increasedPremature vascular diseaseSkin lipid depositsObesityHepatomegalyCommon onset: adulthoodWeight controlLow-carbohydrate dietAlcohol restrictionClofibrate; Nicotinic acidIntestinal bypassType V: mixed hyperlipidemia;carbohydrate and fat-induced hypertriglyceridemiaGlucose intoleranceHyperuricemiaChylomicrons increasedVLDL increasedLDL increasedCholesterol increasedTriglycerides increased three timesAbdominal painHepatosplenomegalySkin lipid depositsRetinal lipid depositsOnset: childhoodWeight controlLow-carbohydrate and low-fat dietClofibrate; Lovastatin;Nicotinic acid; Progesterone (i)Intestinal bypass

a. Epidemiology1) Autosomal recessive2) Rare childhood diseaseb. Pathogenesis1) Deficiency of CPL or2) Deficiency of apo C-llc. Clinical findings1) Chylomicrons are primarily increased in early childhood.2) VLDL increases later in life.3) Presents with acute pancreatitis Pancreatic vessels filled with chylomicrons rupture.d. Laboratory findings1) Increase in serum TG > 1000 mg/dL (primarily chylomicrons)2) Turbid supranate (chylomicrons) and clear infranate (early childhood)3) Normal (usual case) to moderately increased serum CH

Physical signs of heterozygous familial hypercholesterolemia (HeFH), which result from cholesterol deposited within macrophages in specific sites. Tendinous xanthomas, for example, manifest first as thickening of, and later as deposits within, extensor tendons. A: Lateral borders of thickened Achilles' tendons are shown with arrows. B: Tendinous xanthomas can also occur in the extensor tendons of the hands (shown), feet, elbows and knees. C: Xanthelasmas are cholesterol deposits in the eyelids. D: Arcus cornealis results from cholesterol infiltration around the corneal rim (arrow). Deposits in and around the eye tend to be more specific for HeFH in people younger than 45 years; in elderly people, they are less likely to be associated with blood lipoprotein abnormalities, for instance in the case of arcus senilis. Some patients may report having observed cutaneous cholesterol deposition in response to a functional enquiry. People with HeFH have been known to undergo cosmetic eyelid surgery to remove xanthelasmas even repeatedly, for lesions that continued to recur without ever having had their plasma lipoprotein profiles determined. *

a. Laboratory findings1) Serum LDL > 190 mg/dL2) Serum CH > 260 mg/dLa) Serum TG < 300 mg/dL (called type IIa)b) Serum TG > 300 mg/dL (called type lIb)b. Pathogenesis Decreased synthesis of LDL receptors.c. Acquired causes of hypercholesterolemia1) Primary hypothyroidism Decrease in LDL receptor synthesis or function2) Nephrotic syndrome Increase in LDL correlates with the degree of hypoalbuminemia3) Extrahepatic cholestasis (obstruction of bile)Bile contains CH for excretion

d. Familial hypercholesterolemia1) Autosomal dominant (AD) disorder2) Deficiency of LDL receptors3) Clinical findings

a) Premature coronary- artery- disease and strokeb) Tendon xanthomas Cholesterol deposit located over tendons (e.g. Achilles) and extensor surfaces of joints

c) XanthelasmaYellow, raised plaque on the eyelid

e. Polygenic hypercholesterolemia (type Ila)1) Most common hereditary cause (85% of cases)2) Multifactorial (polygenic) inheritance3) Alteration in regulation of LDL levels4) Normal serum TGf. Familial combined hypercholesterolemia (type lIb)1) AD inheritance.2) Serum CH and TG begin to increase around puberty.3) Associated with metabolic syndrome.4) Increase in CH and TG and decrease in HDL.

Familial dysbetalipoproteinemia ("remnant disease")

1) AD inheritance2) Deficiency of apo E3) Decreased liver uptake of chylomicron remnants and IDLClinical findings

1) Palmar xanthomas in flexor creases2) Increased risk for coronary artery disease3) Increased risk for peripheral vascular disease (unlike type II disorders)Laboratorv findings

1) Serum CH and TG > 300 mg/dL2) Serum CH 250 to 500 mg/dL3) LDL< 190 mg/dL4) Confirm diagnosis with ultracentrifugation to identify remnants Lipoprotein electrophoresis and identification of apo E gene defect are other studies that can be used.Treatment Fibric acid derivatives

Laboratory findings1) Serum TG > 300 mg/dL; 2) Serum CH 250 to 500 mg/dL; 3) Serum LDL < 190 mg/dL; 4) Turbid infranate after refrigerationIncrease in VLDL - due to increase in synthesis or decrease in catabolismAcquired causes of hypertriglyceridemia1) Excess alcohol intake2) Oral contraceptives - estrogen increases synthesis of VLDL3) Diabetes mellitus - decreased muscle and adipose CLP4) Chronic renal failure - increased synthesis of VLDL5) Thiazides, -blockers - possible inhibition of CPLFamilial hypertriglyceridemia1) Autosomal dominant disorder2) Clinical findingsa) Eruptive xanthomas - yellow, papular lesions(b) Increased risk for coronary artery- and peripheral vascular diseaseTubero-eruptive xanthoma

a. Pathogenesis1) Increase in chylomicrons and VLDL2) Due to decreased activation and release of CPLb. Familial hypercholesterolemia (type IV) + exacerbating disorder Exacerbating disorders diabetic ketoacidosis (DKA: most common), alcoholc. Increased serum TG > 1000 mg/dL; normal CH and LDL.d. Turbid plasma1) Supranate after refrigeration, due to increased chylomicrons2) Infranate after refrigeration, due to increased VLDL.e. Hyperchylomicronemia syndrome1) Eruptive xanthomas2) Increased incidence of acute pancreatitis3) Lipemia retinalis - retinal vessels look like milk: blurry vision4) Dyspnea and hypoxemia - impaired gas exchange in pulmonary capillaries5) Hepatosplenomegaly6) Increase in serum TG (usually >1000 mg/dL)7) Normal serum CH and LDL8) Turbid supranate and infranate after refrigerationf. Treatment(1) Treat exacerbating disorder (e.g.. DKA)(2) Nicotinic acid or fibric acid derivatives

Apolipoprotein B deficiency (abetalipoproteinemia)a. Autosomal recessiveb. Deficiency of apolipoprotein B-48 and B-100(1) Deficiency of chylomicrons, VLDL and LDL(2) Decrease in serum CH and TG

c. Clinical findings1) Malabsorptiona) Chylomicrons accumulate in villi and prevent reabsorption of micelles.b) Marked decrease in vitamin E2) Ataxia (spinocerebellar degeneration), hemolytic anemia with thorny RBCs (acanthocytes) related to vitamin E deficiency.d. Treatment - vitamin E

Obesity an excess of adipose tissue that imparts health risk; a body weight of 20% excess over ideal weight for age, sex and height is considered a health risk.

1. Body mass index (BMI) > 30kg/m2 (normal, 19.5-24.9kg/m2)1) Excess fat in the waist and flanks is more important than an excess in the thighs and buttocks.2) Excess visceral fat in the abdominal cavity has greater significance than excess subcutaneous fat.Magnetic resonance imaging is used to access the amount of visceral fat.Body mass index (BMI) which is equal to weight in kg/height in m2

ETIOLOGY Obesity results when caloric intake exceeds utilisation.The imbalance of these two components can occur in the following situations:

1. Inadequate pushing of oneself away from the dining table causing overeating.2. Insufficient pushing of oneself out of the chair leading to inactivity and sedentary life style.3. Genetic predisposition to develop obesity.4. Diets largely derived from carbohydrates and fats than protein-rich diet.5. Secondary obesity may result following a number of underlying diseases such as hypothyroidism, Cushings disease, insulinoma and hypothalamic disorders.

Obesity is a problem because of its complications. It is associated with accelerated atherosclerosis and an increased incidence of gallbladder and other diseases. Its association with type 2 diabetes is especially striking. As weight increases, insulin resistance increases and frank diabetes appears. At least in some cases, glucose tolerance is restored when weight is lost.The causes of the high incidence of obesity in the general population are probably multiple. Studies of twins raised apart show that there is a definite genetic component. It has been pointed out that through much of human evolution, famines were common, and mechanisms that permitted increased energy storage as fat had survival value. Now, however, food is plentiful in many countries, and the ability to gain and retain fat has become a liability. As noted above, the fundamental cause of obesity is still excess of energy intake in food over energy expenditure. If human volunteers are fed a fixed high-calorie diet, some gain weight more rapidly than others, but the slower weight gain is due to increased energy expenditure in the form of small, fidgety movements (nonexercise activity thermogenesis; NEAT). Body weight generally increases at a slow but steady rate throughout adult life. Decreased physical activity is undoubtedly a factor in this increase, but decreased sensitivity to leptin may also play a role.

*

LeptinSatiety (hunger/appetite suppression) and regulation of eating behavior by hypothalamusSympathoactivationInsulin sensitizingModulating role in reproduction, angiogenesis, immune response, blood pressure control, and osteogenesis

AdiponectinInsulin sensitizingAnti-inflammatoryAnti-atherogenic

ResistinPromotes insulin resistance and increased blood glucose levelsInhibits adipocyte differentiation and may function as a feedback regulator of adipogenesis

Visfatin (from visceral fat)Mimics insulin and binds to insulin receptors in rats

Vaspinmay be insulin sensitizingLipoprotein lipaseApolipoprotein ECholesterol ester transfer protein

Regulators of Lipoprotein MetabolismInflammatory CytokinesTumor necrosis factor-alphaInterleukins (IL-6, IL-8, IL-10)Plasminogen activator inhibitor-1Monocyte chemoattractant protein-1

Other Hormones and CytokinesEstrogenAngiotensinogenTissue factorTransforming growth factor-betaInsulin-like growth factorNitric oxide synthaseAcylation stimulating proteinAdipophilinAdipoQMonobutyrinAgouti protein

Regulation of appetite and satiety occurs through neuroendocrine regulation of eating behavior, energy metabolism, and body fat mass. The system is complex and controlled by a dynamic circuit of signaling molecules from the periphery acting on central controls including the brain stem, hypothalamus, and autonomic nervous system. An imbalance in this system is usually associated with excessive caloric intake in relation to exercise with the consequence of weight gain and obesity.The arcuate nucleus (ARC) in the hypothalamus has two sets of neurons with opposing effects that interact to regulate and balance food intake and energy metabolism. One set of neurons produces neuropeptide Y (NPY) and agoutirelated protein (AGRP), which stimulates eating and decreases metabolism (anabolic). Another set of neurons synthesizes pro-opiomelanocortin (POMC)-producing peptide and cocaineand-amphetamine-regulated transcript (CART), collectively known as POMC/CART neurons. They inhibit eating and increase metabolism (catabolic). Both sets of neurons express their effects by activating second-order neurons in the hypothalamus, which increases or decreases appetite and energy metabolism.

Fat cell mass [Leptin/insulin] expression[Leptin/insulin] action in hypothalamusArcuate nucleusParaventricularnucleus

Ghrelin is produced by the stomach in response to hunger and stimulates food intake and induces metabolic changes leading to an increase in body weight and body fat mass. Ghrelin also stimulates release of growth hormone (GH) from anterior pituitary cells, the release of gastric acid and gastric motility, and affects pancreatic functions. It has vasodilatory, cardioprotective, and antiproliferative effects.Adiponectin has insulin-sensitizing properties and plasma levels decrease with visceral obesity, contributing to insulin resistance, cardiovascular disease, and metabolic syndrome.Obese individuals, particularly those with expansion of visceral adipose tissue, are at increased risk for coronary artery disease resulting from hyperlipidemia, hypertension, and factors that promote thrombosis and inflammation.Decreased adiponectin levels are associated with increased levels of inflammatory markers, such as IL-6 and TNF-. Adiponectin may serve as an anti-inflammatory and anti-atherogenic plasma protein and may have an important role in vascular remodeling that is limited with obesity.Obesity is associated with insulin resistance, which predisposes an individual to type 2 diabetes mellitus. The insulin resistance may be related to an insulin receptor defect or to postreceptor effects with alteration in glucose transporter functions. Excess insulin also may be a response to excessive caloric intake. Resistin is greatly increased in those with obesity and may be an antagonist to insulin action and a mediator of inflammation.

Pathogenesis

a. Genetic factors account for 50% to 80% of eases. Examplesdefects in the leptin gene, syndrome X (obesity, hypertension, diabetes)b. Acquired causes(1) Endocrine disordershypothyroidism, Cushing syndrome(2) Hypothalamic lesions, menopausec. Leptin1) Leptin is a hormone. a) Secreted by adipose tissue b) Maintains energy balance (intake and output)2) Leptin increases when adipose stores are adequate. a) Decreases food intake (inhibits satiety center) b) Increases energy expenditure (stimulates (-oxidation of fatty- acids)3) Leptin decreases when adipose stores are inadequate. a) Increases food intake (stimulates the satiety center) b) Decreases energy expenditure (inhibits -oxidation of fatty acids)4) Obesity related to leptin dysfunction may be caused by the following; a) Resistance to leptin effects b) Mutations resulting in inhibition of leptin release

PATHOGENESIS. The lipid storing cells, adipocytes comprise the adipose tissue, and are present in vascular and stromal compartment in the body. Besides the generally accepted role of adipocytes for fat storage, these cells also release endocrine-regulating molecules. These molecules include: energy regulatory hormone (leptin), cytokines (TNF- and interleukin-6), insulin sensitivity regulating agents (adiponectin, resistin and RBP4), prothrombotic factors (plasminogen activator inhibitor), and blood pressure regulating agent (angiotensingen).Adipose mass is increased due to enlargement of adipose cells due to excess of intracellular lipid deposition as well as due to increase in the number of adipocytes. The most important environmental factor of excess consumption of nutrients can lead to obesity. However, underlying molecular mechanisms of obesity are beginning to unfold based on observations that obesity is familial and is seen in identical twins. Recently, two obesity genes have been found: ob gene and its protein product leptin, and db gene and its protein product leptin receptor.*

1. Hyperinsulinaemia. Increased insulin secretion is a feature of obesity. Many obese individuals exhibit hyperglycaemia or frank diabetes despite hyperinsulinaemia. This is due to a state of insulin-resistance consequent to tissue insensitivity.

2. Type 2 diabetes mellitus. There is a strong association of type 2 diabetes mellitus with obesity. Obesity often exacerbates the diabetic state and in many cases weight reduction often leads to amelioration of diabetes.

3. Hypertension. A strong association between hypertension and obesity is observed which is perhaps due to increased blood volume. Weight reduction leads to significant reduction in systolic blood pressure.

Obesity is the most common and most expensive nutritional problem in the USA. A convenient and reliable indicator of body fat is the body mass index (BMI), which is the body weight (in kilograms) divided by the square of the height (in meters). Values above 25 are abnormal. Individuals with values of 25-30 are overweight, and those with values > 30 are obese. In the USA, 55% of the population are overweight and 22% are obese. The incidence of obesity is also increasing in other countries. Indeed, the Worldwatch Institute has estimated that although starvation continues to be a problem in many parts of the world, the number of overweight people in the world is now as great as the number of underfed. *

4. Hyperlipoproteinaemia. The plasma cholesterol circulates in the blood as low-density lipoprotein (LDL) containing most of the circulating triglycerides. Obesity is strongly associated with VLDL and mildly with LDL. Total blood cholesterol levels are also elevated in obesity.5. Atherosclerosis. Obesity predisposes to development of atherosclerosis. As a result of atherosclerosis and hypertension, there is increased risk of myocardial infarction and stroke in obese individuals.6. Nonalcoholic fatty liver disease (NAFLD). Obesity contributes to development of NAFLD which may progress further to cirrhosis of the liver.7. Cholelithiasis. There is six times higher incidence of gallstones in obese persons, mainly due to increased total body cholesterol.

8. Hypoventilation syndrome (Pickwickian syndrome). This is characterised by hypersomnolence, both at night and during day in obese individuals along with carbon dioxide retention, hypoxia, polycythaemia and eventually right-sided heart failure. (Mr Pickwick was a character, the fat boy, in Charles Dickens Pickwick Papers. The term pickwickian syndrome was first used by Sir William Osler for the sleepapnoea syndrome).9. Osteoarthritis. These individuals are more prone to develop degenerative joint disease due to wear and tear following trauma to joints as a result of large body weight.10. Cancer. Diet rich in fats, particularly derived from animal fats and meats, is associated with higher incidence of cancers of colon, breast, endometrium and prostate.

http://www.blogadao.com/as-10-pessoas-mais-pesadas-do-mundo/*

CLINICAL FINDINGCOMMENTSCancerIncreased incidence of estrogen-related cancers (e.g., endometrial, breast) because of increased aromatization of androgens to estrogens in adipose tissueCholelithiasisIncreased incidence of cholecystitis and cholesterol stones: bile is supersaturated with cholesterolDiabetes mellitus, type 2Increased adipose downregulates insulin receptor synthesis Hyperinsulinemia increases adipose storesWeight reduction upregulates insulin receptor synthesisHepatomegalyFatty change accompanied by liver cell injury and repair by fibrosisHypertensionHyperinsulinemia increases sodium retention, leading lo increase in plasma volumeLeft venlricular hypertrophy and stroke complicate hypertensionHypertriglyceridemiaHypertriglyceridemia decreases serum high-density lipoprotein levels, increasing risk of coronary artery diseaseIncreased low-density lipoprotein levelsHypercholesterolemia predisposes lo coronary artery diseaseObstructive sleep apneaWeight of adipose tissue compresses upper airways causing respiratory acidosis and hypoxemiaPotential for developing cor pulmonale (pulmonary hypertension and right ventricular hypertrophy)OsteoarthritisDegenerative arthritis in weight-bearing joints (e.g., femoral heads)

Prader-Willi syndrome (PWS) is a single gene imprinting disorder (Psora/ Syphilis) caused by defects in chromosome 15. These defects may be of two types:1. Paternally inherited deletion or disruption of genes in the proximal arm of chromosome 15. (Syphilis)2. Maternal disomy in the proximal arm of chromosome 15. (Psora)Related wordsCryptorchidism-dwarfism-subnormal mentality; hypogenital dystrophy with diabetic tendency; hypotonia-hypomentia-hypogonadism-obesity syndrome; Labhart-Willi syndrome; Prader-Labhart-Willi Fancone syndrome; Willi-Prader syndrome.Historical BackgroundThe first patient with Prader-Willi syndrome was described by Langdon-Down In 1887 as an adolescent girl with mental impairment (Psora), short stature (Psora), hypogonadism (Psora), obesity (Psora). He called these symptoms to polysarcia.In 1956, Prader et al reported some patients with similar phenotypes.In 1981, Ledbetter et al identified microdeletions (Syphilis) within chromosome 15 and determined it to be the site for Prader-Willi syndrome.

PathophysiologyPrader-Willi syndrome is the first human disorder recognized to genomic imprinting. In such disorders, genes are expressed differentially based on the parent of origin. It results from the loss of imprinted genomic material within the paternal 15q11.2-13 locus. The loss of maternal genomic material (Syphilis) at the 15q11.2-13 locus results in Angelman syndrome.Most cases of Prader-Willi syndrome that involve deletions (Syphilis), unbalanced translocations (Psora), and uniparental (maternal) disomy (Psora) are sporadic.

Children Hyperphagia (Psora) with progressive development of obesity (Psora). Short stature (Psora) with lack of pubertal growth shot (Syphilis). Sleep disturbances (Psora), obstructive sleep apnea and narcolepsy (Psora). Growth hormone deficiency (Psora). Premature growth of pubic and axillary hair (Psora) but other features of Prader-Willi syndrome are usually delayed or incomplete.

Testicular descent late (Psora) ; menarche may occur as late as age 30 (Psora). Features of psychosis and behavioural problems- temper outbursts (Psora), stubborn (Psora), and obsessive-compulsive behaviour (Psora), eating garbage (Psora) and frozen food (Psora), and stealing resources to obtain food (Psora) leading to gastric complications, gastric necrosis (Psora/Syphilis) and even death. Mild mental retardation (Psora). Obesity complications- sleep apnoea (Psora), cor pulmonale (Psora/Sycosis), diabetes mellitus (Pseudopsora), atherosclerosis (Sycosis).

SPINGOLIPIDS. DISORDERSClasses of sphingolipids and their hydrophilic groups include:Sphingomyelin: phosphorylcholineCerebrosides: galactose or glucoseGangliosides: branched oligosaccharide chains terminating in the 9-carbon sugar, sialic acid (N-acetylneuraminic acid, NANA)Sphingolipids released when membrane is degraded are digested in endosomes after fusion with lysosomes. Lysosomes contain many enzymes, each of which removes specific groups from individual sphingolipids. Genetic deficiencies of many of these enzymes are known, and the diseases share some of the characteristics of I-cell disease.

DiseaseLysosomal Enzyme MissingSubstrate Accumulating in Inclusion BodySymptomsTay-SachsHexosaminidase AGanglioside GM2Cherry red spots in macula; blindnessGaucherGlucocerebrosidaseGlucocerebrosideType 1: AdultHepatosplenomegaly Erosion of bones, fractures; Pancytopenia or thrombocytopenia; Characteristic macrophages (crumpled paper inclusions)Niemann-PickSphingomyelinaseSphingomyelinCherry red spot in maculaHepatosplenomegaly, Microcephaly, severe mental retardation; Zebra bodies in inclusions; Characteristic foamy macrophages; Early death

The bright light at right enters through the pupil of the eye; at left, the red spot in diagnosis of Tay-Sachs diseaseAdult onset Niemann-Pick disease type C presenting with psychosis

VitaminEFFECTS OF DEFICIENCYEFFECTS OF TOXICITYARetinolOcular lesions: night blindness, xerophthalmia - dry and scaly scleral conjunctiva; keratomalacia - corneal ulcers may occur which may get infected; Bitots spots - focal triangular areas of opacities due to accumulation of keratinised epithelium; blindness - squamous metaplasia of corneal epithelium)Cutaneous lesions: xeroderma - the skin develops papular lesions giving toad-like appearance, due tofollicular hyperkeratosis and keratin plugging in thesebaceous glands; Other lesions: squamous metaplasia of respiratory epithelium, pneumonia; urothelium and pancreatic ductal epithelium, subsequent anaplasia; retarded bone growth; renal calculiPapilledema and seizures (due to an increase In intracranial pressure), hepatitis, bone pain (due to periosteal proliferation)DCalcitriolPathologic fractures, excess osteoid, bow legsChildren: rickets; craniotabes (soft skull bones); rachitic rosary (defective mineralization and overgrowth of epiphyseal cartilage in ribs)Adults: called osteomalaciaContinuous muscle contraction (hypocalcaemic tetany)Hypercalcemia with metastatic calcification, renal calculi

VitaminEFFECTS OF DEFICIENCYEFFECTS OF TOXICITYE-Tocophe-rolHemolytic anemia (damage to RBC membrane), reduced red cell lifespan;Peripheral neuropathy, degeneration of posterior column (poor joint sensation) and spinocerebellar tract (ataxia), retinal pigments, degeneration axons of peripheral nerves; denervation of musclesSterility in male and female animalsDecreased synthesis of vitamin K-dependent procoagulant factors;synergistic effect with warfarin anticoagulationKNewborns: Hypoprothrombinaemia in hemorrhagic disease of newborn (CNS bleeding, ecchymoses); Adults: gastrointestinal bleeding, ecchymoses; prolonged prothrombin time and partial thromboplastin time biliary obstruction - bile is prevented from entering the bowel due to biliary obstruction which prevents the absorption of this fat-soluble vitamin. Surgery in patients of obstructive jaundice, therefore, leads to marked tendency to bleeding. malabsorption of fat develop vitamin K deficiency e.g. coeliac disease, sprue, pancreatic disease, hypermotility of bowel etc. anticoagulant therapy - patients on warfarin group of anticoagulants have impaired biosynthesis of vitamin K-dependent coagulation factors.antibiotic therapy - the use of broad-spectrum antibiotics and sulfa drugs reduces the normal intestinal flora. diffuse liver disease - (e.g. cirrhosis, amyloidosis of liver, hepatocellular carcinoma, hepatoblastoma) have hypoprothrombinaemia due to impaired synthesis of prothrombin. Administration of vitamin K to such patients is of no avail since liver, where prothrombin synthesis utilising vitamin K takes place, is diseased.Hemolytic anemia and jaundice in newborns if mother receives excessvitamin K

Copstead Lee-Ellen C. Pathophysiology / Lee-Ellen C. Copstead, Jacquelyn L. Banasic // Elsevier Inc. 2010. ROBBINS BASIC PATHOLOGY / [edited by] Vinay Kumar, Abul K. Abbas, Jon C. Aster. 9th ed. 2013.Kathryn L. McCance . Pathophysiology: the biologic basis for disease in adults and children / [edited by] Kathryn L. McCance, Sue E. Huether; section editors, Valentina L. Brashers, Neal S. Rote - 6th ed. 2010.Pathophysiology, Concepts of Altered Health States, Carol Mattson Porth, Glenn Matfin. New York, Milwaukee. 2009. Essentials of Pathophysiology: Concepts of Altered Health States (Lippincott Williams & Wilkins), Trade paperback (2003) / Carol Mattson Porth, Kathryn J. Gaspard. Chapters 15, 29. General and clinical pathophysiology. Edited by prof. A.V. Kubyskin. Simferopol. 2011.Silbernagl S. Color Atlas of Pathophysiology / S. Silbernagl, F. Lang // Thieme. Stuttgart. New York. 2000.

Essentially all of the energy of isometric contractions appears as heat, because little or no external work (force multiplied by the distance that the force moves a mass) is done. Energy is stored by forming energy-rich compounds. The amount of energy storage varies, but in fasting individuals it is zero or negative. Therefore, in an adult individual who has not eaten recently and who is not moving (or growing, reproducing, or lactating), all of the energy output appears as heat. Calorimetry

The energy released by combustion of foodstuffs outside the body can be measured directly (direct calorimetry) by oxidizing the compounds in an apparatus such as a bomb calorimeter, a metal vessel surrounded by water inside an insulated container. The food is ignited by an electric spark. The change in the temperature of the water is a measure of the calories produced. Similar measurements of the energy released by combustion of compounds in living animals and humans are much more complex, but calorimeters have been constructed that can physically accommodate human beings. The heat produced by their bodies is measured by the change in temperature of the water in the walls of the calorimeter.

The caloric values of the common foodstuffs, as measured in a bomb calorimeter, are found to be 4.1 kcal/g of carbohydrate, 9.3 kcal/g of fat, and 5.3 kcal/g of protein. In the body, similar values are obtained for carbohydrate and fat, but the oxidation of protein is incomplete, the end products of protein catabolism being urea and related nitrogenous compounds in addition to CO2 and H2O (see below). Therefore, the caloric value of protein in the body is only 4.1 kcal/g. Indirect Calorimetry

Energy production can also be calculated by measuring the products of the energy-producing biologic oxidationsie, CO2, H2O, and the end products of protein catabolism producedbut this is difficult. However, O2 is not stored, and except when an O2 debt is being incurred, the amount of O2 consumption per unit of time is proportionate to the energy liberated by metabolism. Consequently, measurement of O2 consumption (indirect calorimetry) is used to determine the metabolic rate. Respiratory Quotient (RQ)

The respiratory quotient (RQ) is the ratio in the steady state of the volume of CO2 produced to the volume of O2 consumed per unit of time. It should be distinguished from the respiratory exchange ratio (R), which is the ratio of CO2 to O2 at any given time whether or not equilibrium has been reached. R is affected by factors other than metabolism. RQ and R can be calculated for reactions outside the body, for individual organs and tissues, and for the whole body. The RQ of carbohydrate is 1.00, and that of fat is about 0.70. This is because H and O are present in carbohydrate in the same proportions as in water, whereas in the various fats, extra O2 is necessary for the formation of H2O.

Determining the RQ of protein in the body is a complex process, but an average value of 0.82 has been calculated. The approximate amounts of carbohydrate, protein, and fat being oxidized in the body at any given time can be calculated from the RQ and the urinary nitrogen excretion. RQ and R for the whole body differ in various conditions. For example, during hyperventilation, R rises because CO2 is being blown off. During severe exercise, R may reach 2.00 because CO2 is being blown off and lactic acid from anaerobic glycolysis is being converted to CO2 (see below). After exercise, R may fall for a while to 0.50 or less. In metabolic acidosis, R rises because respiratory compensation for the acidosis causes the amount of CO2 expired to rise. In severe acidosis, R may be greater than 1.00. In metabolic alkalosis, R falls.

The O2 consumption and CO2 production of an organ can be calculated at equilibrium by multiplying its blood flow per unit of time by the arteriovenous differences for O2 and CO2 across the organ, and the RQ can then be calculated. Data on the RQ of individual organs are of considerable interest in drawing inferences about the metabolic processes occurring in them. For example, the RQ of the brain is regularly 0.97-0.99, indicating that its principal but not its only fuel is carbohydrate. During secretion of gastric juice, the stomach has a negative R because it takes up more CO2 from the arterial blood than it puts into the venous blood *Large animals have higher absolute BMRs, but the ratio of BMR to body weight in small animals is much greater. One variable that correlates well with the metabolic rate in different species is the body surface area. This would be expected, since heat exchange occurs at the body surface. The actual relation to body weight (W) would be

However, repeated measurements by numerous investigators have come up with a higher exponent, averaging 0.75.

Thus, the slope of the line relating metabolic rate to body weight is steeper than it would be if the relation were due solely to body area. The cause of the greater slope has been much debated but remains unsettled. *For example, catabolism of 1 mol of a six-carbon fatty acid through the citric acid cycle to CO2 and H2O generates 44 mol of ATP, compared with the 38 mol generated by catabolism of 1 mol of the six-carbon carbohydrate glucose. *Two of the three ketone bodies, acetoacetate and -hydroxybutyrate, are anions of the moderately strong acids acetoacetic acid and -hydroxybutyric acid. Many of their protons are buffered, reducing the decline in pH that would otherwise occur. However, the buffering capacity can be exceeded, and the metabolic acidosis that develops in conditions such as diabetic ketosis can be severe and even fatal. Three conditions lead to deficient intracellular glucose supplies: starvation, diabetes mellitus, and a high-fat, low-carbohydrate diet. In diabetes, glucose entry into cells is impaired. When most of the caloric intake is supplied by fat, carbohydrate deficiency develops because there is no major pathway for converting fat to carbohydrate. The liver cells also become filled with fat, which damages them and displaces any glycogen that is formed. In all of these conditions, ketosis develops primarily because the supply of ketones is overabundant. The acetone odor on the breath of children who have been vomiting is due to the ketosis of starvation. Parenteral administration of relatively small amounts of glucose abolishes the ketosis, and it is for this reason that carbohydrate is said to be antiketogenic.

*

*http://www.theatlantic.com/health/archive/2013/03/study-mummies-have-atherosclerosis-too/273863/http://blogs.unimelb.edu.au/sciencecommunication/2013/08/13/mummies-return-is-a-reality-we-need-more-mummy-hunters/Put more colorfully, "We found that heart disease is a serial killer that has been stalking mankind for thousands of years," one of the study's lead authors, Randall Thompson, said in a statement.In modern men and women over the age of 50, the condition's prevalence is as high as 82 and 68 percent, respectively. And certain behaviors certainly increase this risk -- these findings in fact emphasize the importance of controlling for those factors, like diet, that are indeed controllable. As with last summer's counter-intuitive findings that sedentary office workers burnas many calories in a dayas modern hunter-gatherers, this should at the very least make us question whether the good old days of pre-modern living were as ideal as wetend to imagine them.*Dyslipidemia (or dyslipoproteinemia) refers to abnormal concentrations of serum lipoproteins as defined by the Third Report of the National Cholesterol Education Program. It is estimated that nearly half of the U.S. population has some form of dyslipidemia, especially among white and Asian populations. These abnormalities are the result of a combination of genetic and dietary factors. Primary or familial dyslipoproteinemias result from genetic defects that cause abnormalities in lipid-metabolizing enzymes and abnormal cellular lipid receptors. Secondary causes of dyslipidemia include several common systemic disorders, such as diabetes, hypothyroidism, pancreatitis, and renal nephrosis, as well as the use of certain medications such as certain diuretics, beta-blockers, glucocorticoids, interferons, and antiretrovirals.*Physical signs of heterozygous familial hypercholesterolemia (HeFH), which result from cholesterol deposited within macrophages in specific sites. Tendinous xanthomas, for example, manifest first as thickening of, and later as deposits within, extensor tendons. A: Lateral borders of thickened Achilles' tendons are shown with arrows. B: Tendinous xanthomas can also occur in the extensor tendons of the hands (shown), feet, elbows and knees. C: Xanthelasmas are cholesterol deposits in the eyelids. D: Arcus cornealis results from cholesterol infiltration around the corneal rim (arrow). Deposits in and around the eye tend to be more specific for HeFH in people younger than 45 years; in elderly people, they are less likely to be associated with blood lipoprotein abnormalities, for instance in the case of arcus senilis. Some patients may report having observed cutaneous cholesterol deposition in response to a functional enquiry. People with HeFH have been known to undergo cosmetic eyelid surgery to remove xanthelasmas even repeatedly, for lesions that continued to recur without ever having had their plasma lipoprotein profiles determined. *Obesity is a problem because of its complications. It is associated with accelerated atherosclerosis and an increased incidence of gallbladder and other diseases. Its association with type 2 diabetes is especially striking. As weight increases, insulin resistance increases and frank diabetes appears. At least in some cases, glucose tolerance is restored when weight is lost.The causes of the high incidence of obesity in the general population are probably multiple. Studies of twins raised apart show that there is a definite genetic component. It has been pointed out that through much of human evolution, famines were common, and mechanisms that permitted increased energy storage as fat had survival value. Now, however, food is plentiful in many countries, and the ability to gain and retain fat has become a liability. As noted above, the fundamental cause of obesity is still excess of energy intake in food over energy expenditure. If human volunteers are fed a fixed high-calorie diet, some gain weight more rapidly than others, but the slower weight gain is due to increased energy expenditure in the form of small, fidgety movements (nonexercise activity thermogenesis; NEAT). Body weight generally increases at a slow but steady rate throughout adult life. Decreased physical activity is undoubtedly a factor in this increase, but decreased sensitivity to leptin may also play a role.

*PATHOGENESIS. The lipid storing cells, adipocytes comprise the adipose tissue, and are present in vascular and stromal compartment in the body. Besides the generally accepted role of adipocytes for fat storage, these cells also release endocrine-regulating molecules. These molecules include: energy regulatory hormone (leptin), cytokines (TNF- and interleukin-6), insulin sensitivity regulating agents (adiponectin, resistin and RBP4), prothrombotic factors (plasminogen activator inhibitor), and blood pressure regulating agent (angiotensingen).Adipose mass is increased due to enlargement of adipose cells due to excess of intracellular lipid deposition as well as due to increase in the number of adipocytes. The most important environmental factor of excess consumption of nutrients can lead to obesity. However, underlying molecular mechanisms of obesity are beginning to unfold based on observations that obesity is familial and is seen in identical twins. Recently, two obesity genes have been found: ob gene and its protein product leptin, and db gene and its protein product leptin receptor.*Obesity is the most common and most expensive nutritional problem in the USA. A convenient and reliable indicator of body fat is the body mass index (BMI), which is the body weight (in kilograms) divided by the square of the height (in meters). Values above 25 are abnormal. Individuals with values of 25-30 are overweight, and those with values > 30 are obese. In the USA, 55% of the population are overweight and 22% are obese. The incidence of obesity is also increasing in other countries. Indeed, the Worldwatch Institute has estimated that although starvation continues to be a problem in many parts of the world, the number of overweight people in the world is now as great as the number of underfed. *http://www.blogadao.com/as-10-pessoas-mais-pesadas-do-mundo/*