Doc. MUDr. Jana Plevková PhD Ústav patologickej fyziológie JLF UK 2009

1. Metabolic disorders (faty molecules, proteins, aminoacids, purines, pyrimidines) Pathophysiology of nutrition and obesity Doc. MUDr. Jana Plevková PhD Ústav patologickej fyziológie JLF UK 2009

2. Metabolism Appropriate amount of energy inside the cells affects the activity of the body as a complex structure, it's performance, resistance against overload /diseases, stress reactions/ - metabolism is also a source of substrates necessary for the structure and function of the individual compartments and subunits within the human organism Evaluation of nutrition from the qualitative and quantitative stand points – that means • optimal energy content • appropriate composition of individual nutrients and essential molecules Metabolic disorders could lead to the depletion of energy and/or substrates and also to the accumulation of some products, molecules with potential hazards for the body /ketonbodies/ anabolism vs catabolism

3. Regulation of metabolic processes • Inzulin – predominantly anabolic action,  transport of glucose into the muscle cells, fatty tissue cells, stimulates proteosynthesis, inhibits lipolysis, also causes the transport of K together with glucose into the cells, increases appetite • Glucagon –  plasma glucose level /glycogenolysis a gluconeogenesis in liver cells/,  lipolysis, its level increases during the starvation • STH – proteoanabolic action, some effects are mediated via IGF– 1, increases plasma glucose level, high level of STH may lead to insulin resistance /acromegalia + impaired glucose tolerance/

4. Regulation of metabolic processes • Glucocorticoids - plasma glucose /gluconeogenesis/, proteocatabolic effect in peripheral tissues, in spite proteosynthesis in liver is stimulated, they belong to stress hormones responsible for metabolic effects such is insulin resistance, have mineralocorticoid effect • T3 a T4 –  basal metabolism,  oxygen consumption and heat production, sensitize tissues for KA effects, increase glucose reabsorbing from he gut, normal concentration has proteoanabolic effect, while increased level has proteocatabolic effect – the most dangerous is proteocatabolism in myocardium • Reproductive hormones – anabolic effect – androgens /muscles, positive nitrogen balance, estrogens – subcutaneous distribution of fatty tissue, Na retention, interfere with metabolism of cholesterol, progesterone  thermogenesis

5. The role of different organs in metabolic processes • Liver – inclusion into portal circulation – contact with substrates reabsorbed in the gut, regulation of plasma glucose level, synthesis of proteins, origin of urea, lipid particles stock, synthesis of lipoproteins, bile acids, vitamins stock .... • Muscles mass – approx. 40% body weight, important tissue with respect to energy consumption, reservoir of proteins • Fatty tissue – storage of energy, lipolysis and subsequent transportation of FA into the muscles, liver, turnover of steroid hormones

6. The role of different organs in metabolic processes • GIT – processes of digestion and reabsorbing of nutrients, synthesis of chylomicrones, strong proliferative activity of intestinal mucosa – enterocytes turnover • Bones – calcium storage, puffer activity • Skin – change of the vit. D, thermoregulation, deposition of subcutaneous fatty tissue • Kidneys – activation of vit D, reabsorbing of glucose, AA, tubular transporting systems require a lot of energy • RS and CVS – the main role of these both systems is to secure optimal oxygen and substrates supply to the tissues optimal for their metabolic rate – to produce energy but both systems need energy for function too

7. Sources of energy in the human body • There is a hierarchy in the substrate utilization • Glucose – promptly available source, precise regulation, replenished with the glucose from the food and gluconeogenesis, its level is well balanced in spite of long lasting food starvation • Depletion of the glucose, or inability to utilize glucose /not available glucose/ IR leads to the changes in the energy pathways – energy is predominantly obtained from fat and proteins • Lipolysis due to lack of glucose or if glucose is not available for the mat. pathway leads to the formation of keton bodies, which may replace the energy sources for the myocardium, muscles, while glucose is saved for the CNS, formation of keton bodies, and its utilization protects proteins against excessive breaking down

8. Disorders of nutrition and their consequences • Water, proteins, carbohydrates, fat, micronutirents – all of these mentioned food components have to follow the guideliness for „normal – determined“ requirement with respect to qualitative and quantitative standpoints • Serious, long lasting starvation could lead to – malnutrition, catabolism, hypovitaminosis, or avitaminosis • Increased intake of some food components could lead to disease caused by increased content of these components in the body – hypervitaminosis A, D • Increased imbalanced intake of food /energy – obesity • Long lasting inappropriate food composition – civilization diseases, ATS, malignant tumors

9. Decreased nutrition Hyponutrition – the intake of food as a complex is decreased Malnutrition – inappropriate composition of food with respect to QUALITY – amount of energy could be guaranteed, but the food is missing some of the essential factors / essential AA, proteins/ which depletion could lead to a serious health problems Kwashiorkor – this is specific type of malnutrition, when food is missing proteins,  hypoalbuminaemia  decrease of the oncotic pressure  disorders of Starling balance on the capillary wall  edema - steatosis of the liver – because of excessive turnover of lipids - changes in the nourishment of the skin - anemia, hypothermia, neurologic disorders, bradycardia, changes of the homeostasis - characteristics for the less developed countries - old persons during extreme catabolism and simultaneous inappropriate food intake /stay in hospital/

12. Decreased nutrition • Deficiency disease – due to decreased intake of concrete food components, which could lead to health problems – deficiency of iron – anemia, in young girls /period, avoid meat/ • Marasm – this kind of hyponutrition is caused due to lack of all food components – proportional lack of nutrients /starvation, mental anorexia/ - reduction of subcutaneous fatty tissue - decrease of metabolic rate • The difference between marasm and kwashiorkor – this one is no proportional lack of nutrients, cause of the lack of proteins only (C, F – might be OK/ • Better prognosis is for marasm - after the supplementation of food the patients clinical course gets better soon

14. Simple starvation limited, not completely lacked intake of food the change of metabolic pathways is a physiologic response to the starvation - the general idea is the most economic use of energy /to save energy/ - long lasting starvation leads to depletion of energy and substrates, as well as depletion of vitamins and micronutrients • in the first order the glycogen storage is utilized /12 – 24 hours/ • in the second order the plasma glucose level is optimized via gluconeogenesis, this stage is linked with  level of insulin and  level of contra regulatory hormones • this processes are followed with  lipolysis and B oxidation of FA • formation of Kenton bodies • after the beginning of ketogenesis the processes of gluconeogenesis and proteocatabolism are suppressed – adaptation – this is a protection against excessive braking down of proteins to AA and their use for GNG • manifestation -  body weight, slimming, with possibly character of marasm

15. Secondary malnutrition The difference between second. And simple starvation is that secondary malnutrition is caused by an underlying conditions – diseases which leads to inadequate nutrition via different mechanisms • Decreased food intake – anorexia, nausea, disease of GIT, disorders of digestion, absorption, intestinal inflammation, pancreas, disorders of bile secretion etc. • Increased loss of nutrients – exudative gastro and enteropathy, bleeding, diarrhoea • Increased requirements – fever, infections, tumors, surgical procedures In this type of malnutrition the regulatory mechanisms are disturbed, and proteocatabolism is present – the proteins are not protected and are taken as a possible substrates for the gluconeogenesis

16. Catabolic processes • Caused by disturbances in metabolism - in regulatory mechanism • Simple starvation – better prognosis, in secondary malnutrition the prognosis is worse • Negative protein and energetic balance develops quickly • Pathomechanism involved: • effects of inflammatory mediators • effects of activate d axis hypothalamusx pit. gland x adrenal gland • Malignant tumors – long lasting breaking down processes –lipids, proteins with gluconeogenesis in liver, tumor is producing molecules strongly affecting metabolism /TNF  - kachectin/ • Extensive trauma, burns, SIRS, FUO, extreme stress ?

17. Systemic changes – affection of the whole body caused by malnutrition • weight loss – reduction of the adipocytes size, tissue atrophy • ECC – volume is relatively stabile, protein loss leads to decrease of oncotic pressure of plasma • myocardium –  stroke volume,  contractility,  glycogen content with atrophy of myofibrils, changes are reversible • RS – minimal affection, changes of the respiratory muscles power,  VC, abnormal finding in spirometry,  min. ventilation • GIT – decrease of motility and secretion, atrophy of the mucosa, loss of the intestinal microvilli and decreased turnover of enterocytes • pancreas – exocrine function is  , while endocrine function is not affected

18. Systemic changes – affection of the whole body caused by malnutrition • kidneys – reduction of capsaula adiposa renis, atrophy,  possibility to concentrate urine due to decrease of the osmotic medullar gradients • liver – atrophy of hepatocytes,  reduction of the cell volume,  glycogen content, suppressed proteosynthesis in kwash., but hepatomegalia due to steatosis • endocrine system –  of hormone production, testosterone, FSH/LH in women, disturbed conversion of T3 to T4 • immune system – all components of immune system are affected, both cellular and humoral processes • barrier impairment – atrophy of skin, GIT mucosa • Worse, long lasting healing of the wounds

20. Obesity More than 7% world population suffer from obesity • Incidence of overweight and obesity has increased during the last two decades  „epidemic of obesity“ • Frequency of obesity is increasing significantly especially in countries with high % of pauperised inhabitants for a prolonged period, when the accesibility of food suddenly improved • There is increased incidence of obesity in children • Negative influence of obesity on men health is now convincingly proven

21. Obesity Obese person – person with body weight noticeably exceed the upper interval of physiological values and this weight increase is caused by accumulation of fatty tissue in men more than 25% and in woman more than 30% of total body weight is represented by fatty tissue Obesity is a chronic disease possibly leading to multiple organ dysfunction and other complications Obesity is caused by a complex action of several factors –multifactorial disease

22. Obesity hazards • CVS – atherosclerosis, IHD, heart failure, varices, deep venous thrombosis with complications • endocrine – PCO, irregular period, infertility • GIT – GERD, liver statuses, bile stones, hernia, colorectal Ca • genitourinary – erectile dysfunction, hypogonadism in men, Ca of breast and uterus, premature labour, incontinence, • skin and skin adnex – lymphedema, celulitis, skin infection • musculosceletal – gouty arthritis, immobility, osteoarthritis, sacral back pain • neurologic – cerebral ischemia, carpal tunnel syndrome • respiratory – Pickwick sy, OSA • psychologic – depression, low self retting, social stigmatization

23. Methods for assessing obesity 1) body mass index – BMI body weight ( v kg) BMI = height ( v m)2 normal value: BMI =19 – 25, overweight: BMI =26 – 30 obesity: BMI > 30 „malignant“ obesity: BMI > 40 2) weistline:hippline ratio normal value: 0,7 – 0,95 3) meassurement of the skin folds 4) weist circumference: men < 95cm; women- < 81cm • Technically demending methods: CT, densitometry diluting methods

24. Classification of obesity • Etiopathogenetic 1. Primary 2. Secondary B. Pathological anatomy - 1. Hypertrophic 2. Hypertrophic+ hyperplastic C. According the fat distribution 1. Android type (men) – apple shape - risk of DM, AMI, cerebral ischemia, other CVS diseases 2. Gynoid type (women) – pear shape - risk of disorder of musculosceletal system (hip joins, knees)

25. Main causes and mechanism involved in pathogenesis of obesity Genetic determinants – approx. 33% of obese patients have genetic background monogenic diseases – mutation of the gene encoding the synthesis of leptin, or mutation of leptin receptor polygenic disorders – mutation of several genes, which combination and simultaneous effects of external factors leads to onset of obesity These disorders might be related to  receptors with metabolic effects, genes for uncoupling proteins or LDL receptors

26. Main causes and mechanism involved in pathogenesis of obesity The most common factors leading to overweight and obesity are: genetic predisposition food containing too much energy limited body movement and lack of physical exercise consequence of other disease /hypotyreosis/ disorders of food intake and its regulation psychic stress side effects of some drugs

27. Main causes and mechanism involved in pathogenesis of obesity The most common pathomechanism involved is that intake of food /energy exceeds the energy requirements or consumption, and this"energy“ is then stored as a fatty tissue. I. primary increased intake of energy/food, which organism is not able to utilize in spite of normal speed of metabolic processes /overeating/ II. primary decrease of the energy consumption to the level of possible storage of fatty tissue in spite of normal food intake metaboliced metaboli rate – different kind of diets, hypotyreosis/ III. combination of both mechanisms

28. The role of the CNS Regulation of food intake, consumption of energy and mass of fatty tissue Based on the afferent inputs into the CNS and via humoral signaling molecules - insulin, CCK, glucose, leptin, ghrelin Short lasting regulation of food intake(meal to meal via the changes of the glucose plasma level and the fluctuation of ATP in the hypothalalmic neurones Medium regulation ghrelin – humoral factor, which level is increased after emptying of the stomach – via release of NPY in hypothalamus – stimulates the food intake – when the stomach is empty Long lasting regulation - leptin – humoral factor created in the fatty tissue, sufficient fatty storage leads to release of leptin which suppress the food intake and consumption of more energy, because body has enough of fatty tissue, lack or inappropriate storage leads to stimulation of food intake via leptin release block Now there is known several problems of this regulatory pathway possibly causing obesity- example – mutation of leptin receptor

29. The role of the CNS The centre for the food intake regulation is located within the ventromedial hypothalamus – experimental damage to the c. arcuatus leads to  hyperfagia  increased food intake and setpoint for the body weight  obesity VMH – two types of neurons with reciprocal activity first /anorexigenic/ – leptin sensitive (mediator is  MSH) suppress the apetite and suppress the food intake, responsible for the stimulus „STOP EATING“ second /orexigenic/ - (mediator is NPY) – stimulus „EAT“ Abnormal function of SNS -  activity of SNS in pancreas, heart, fatty tissue – abnormal thermoregulation -  activity of SNS and  activity of PSNS  abnormal thermoregulation,  production of insulin  IR  obesity

30. The role of the CNS

31. Content of the fat in food – relation to obesity  amount of fat in food  tendency for the increased intake of energy Mechanisms  feeding effect of the fat is less effective than the feeding effect of carbohydrates and proteins  passive overeat  increased concentration of energy in the food unit  fat has positive effects on the taste receptors – therefore his content in the food enhance fat intake itself  late inhibitory effects of the feeding signals after fat intakeenhances intake of the food as a whole

32. Fat paradox Fat induced feeding signals vs over intake of fat Fat in the intestinal system represents strong pre - absorbtion signal mediated - mainly CCK, glucose, bombesine, SST - enterostatine (pentapeptid from pro-kolipasis) - products of the fat ingestion Fat enters the intest. with a time shift /long stay in stomach/  is mixed with other nutrients – less effective feeding signals with time shift Fat in the mouth  stimulation of the taste receptors  facilitation of intake, therefore the natura feeding potential is obsolete • density of energy in fat food  intake of  amount of energy, because the feeding signals have no effects yet

33. Short lasting vs long lasting reduction of body weight The total amount of the fatty tissue within the body is regulated consequence: any reduction of the fatty mass leads to activation of compensatory mechanisms  to get the fatty storage into the former status Is there a possibility to reduce body weight in obese people effectively in spite the mass of fatty tissue is regulated? Is there a possibility to reduce body fat content in spite of these regulations?

34. The mass of fatty tissue which is „protected“ can be effectively reduced, therefore it s not possible to talk about a stabile „set point“ for the fat stores Mass of fatty tissue can be  due to internal factors - changes of emotive status - level of BMR external factors - the taste and availability of the food - increased content of fat in food Mass of fatty tissue can be  due to - intake of low calorie diet at libitum - increased physical activity and it's maintenance during the long time

35. Visceral obesity Strong relationship between the visceral obesity and onset of metabolic complication Example: 2 groups of patients with the same BMI - 1. gr. – fatty tissue in subcutaneous location - 2. sk – fatty tissue within the abdominal cavity Different metabolic parameters were found in those groups 2. nd group has impaired PGTT test and higher level of TAG in the plasma Increased content of visceral fat leads to IR, no matter what ´s the BMI -  level of FFA in blood - insulin resistance - dyslipidaemia -  TAG,  LDL,  HDL cholesterol, predisposition to ATS

36. Visceral obesity

37. Mechanisms responsible for visceral obesity Aging Hormonal profile Indirect evidences: - less frequent in female before menopause than in male - it is supposed that estrogens stimulate deposition of fatty tissue in the gluteal region and hips (gluteofemoral distribution) - progestagens „are competing“ with glucocorticoids with respect to binding sites on glucocorticoids receptors  suppressed accumulation of fat within the abdominal cavity Visceral fat – high lipolytic activity  FFA and glycerol in blood – due to stimulation of  adrenoreceptors

38. Disorders of lipid metabolism • The role of the lipid molecules within the body • 1. source and storage of energy • 2. structure of cells, tissues, organs • 3. component of operating molecules B. General types of disorders 1. Hyperlipoproteinemia 2. Hypolipoproteinemia

39. Lipoproteíny (LP) – spheric molecules transporting apolar liipids within the blood Composition of characteristics - inside the spheric particle – apolar lipids • surface is constituted from polar chains, allowing the transport in the plasma • phospholipids, cholesterol, TAG • apolipoproteins (apo) – important for the metabolic pathways of LP • those particles differ with density, size, amount of the lipids transported, amount and type of apo, site of origin, metabolism and other parameters

40. Chylomicrons (CM) –the largest one LP with lowest density • VLDL – smaller than CM, more dense, transport – endogenous • TAG synthetized in the liver • IDL – (intermediate – density LP) • LDL – containing cholesterol esters and apo (B100) • HDL – the smallest one and highest density from all LP • ( reverse transport of cholesterol) • Lipoprotein (a) – lipoprotein particle, a part of LDL molecule, • on its surface is present a molecule very similar to plasminogene • Important risk of atherosclerosis

41. Enzymes metabolizning LP • •Lipoproteine lipase (LPL) • - release of FFA from TAG in CM and VLDL • - located in endothelial cells • - is activated by C II(present both in CM and VLDL) • Hepatic lipase • hydrolysis of TAG in liver • activated by apo E • LCAT = lecitín : cholesterol acyl transferase • CETP = cholesterol ester transfer protein

42. LDL receptor – pick up of LDL (IDL), localized in cells of different • tissues, mainly on hepatocytes • ! predisposed persons •  intake of cholesterol  down regulation of LDLr • in liver, therefore the pick up of LDL is  • HDL receptor – cleavage of HDL from the plasma • - localised within the tissues with steroid turnover • (adrenal glands, ovaria, hormonal stimulation of these glands • stimulates its expression) • Scavenger receptors (SR) • - pick up of LDL, which were not trapped by LDL receptors • - important role in scavenging of oxidated LDL particles • - present in macrophages, smooth muscles cells - atherogenesis

43. Hyperlipoproteinemia Pathologic process characterized by increased level of one or more LP in the plasma • Hyperlipidemia -  level, concentration of lipids ( usually TAG + CH) in plasma • Dyslipoproteinemia (dyslipidemia) - disorder of the proportionality of lipids plasma content usually with HDL cholesterol level

44. a) Hypercholesterolemia • increased cholesterol in the blood • 75 % of cholesterol in the blood is represented by LDL cholesterol • LDL cholesterol has atherogenic hazards • atherogenity of LDL cholesterol  with the degree of its oxidation and glycation • oxidated and glycated LDL cholesterol is cleaved SR on macrophages and smooth muscles cells  turn into he foam cells b) Hypertriacylglycerolemia c) Combination of a and b

45. Classification of hyperlipoproteinemias ( Nečas et al., 2000)

46. Major types of hyperlipoproteinemias (HLP) • Primary • 1.Familiar combined HLP • Is the most common genetically determined type HLP • (autosomal dominant type – ADD) • manifested with phenotypes 2a, 2b or 4 • Component of metabolic X syndrome •  risk of ATS and subsequent complications • 2. Familiar hypercholesterolemia (ADD) • Cause: mutation of LDL receptor • manifested with a phenotype 2a • exaggerated acceleration of ATS • MI in about 40 yrs of age • xantomatosis of the tendons and arcus lipoides corneae

47. 3. Polygenic hypercholesterolemia • the most common hypercholesterolemia ( type 2a ) • Mechanisms involved: • genetic predisposition  change of the reabsorbtion and endogenne cholesterol synthesis, change of the LDL pathways • external factors – alcohol, diabetes,  carbohydrates intake, • fat intake • The difference between 2 and 3 – in this case the person lack • xantomas, ATS is less accelerated than in homozygot form of 2 4. Familiarna dyslipoproteinemia • Polygenic disorder • manifested with phenotype 3 HLP • severe xantomatosis and ATS acceleration

48. 5. Familiar hypertriacyglycerolemia • ADD disorder • common disorder similar to combined HLP /1/ • manifested with phenotype 4 HLP • chol. level is not elevated, only TAG are  • manifestation is also affected with external factors • 6. Familiar defect of LPL and apo C II • rare AR genetic disorder • homozygote form  deposition of TAG within tissues • xantomas, hepatosplenomegalia, increased risk of pancreatitis • manifested with phenotype 1 (defect LPL) or 5 (defect apo CII ) • 7. Familiar hyperalfaliporoteinemia •  HDL  slightly risk of ATS • small doses of alcohol -  HDL • estrogens  HDL

49. B. Secondary HLP • Are caused by other disease • The most common diseases linked with HLP: • diabetes mellitus • nephrotic syndrome, chronic renal failure • hypotyreosis • primary biliary cirrhosis • alcoholism HLP may be also a consequence side effects of drugs – contraceptive pills