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Metabolic disorders (faty molecules, proteins, aminoacids, purines, pyrimidines) Pathophysiology of nutrition and obesity

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Title: Metabolic disorders (faty molecules, proteins, aminoacids, purines, pyrimidines) Pathophysiology of nutrition and obesity


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/

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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

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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 hypothalamus x 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

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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 gt 30
  • malignant obesity BMI gt 40
  • 2) weistlinehippline ratio
  • normal value 0,7 0,95
  • 3) meassurement of the skin folds
  • 4) weist circumference men lt 95cm
    women- lt 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 ?set
    point 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 intake enhances 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 (
Necas et al., 2000)
Type ? lipoprotein ? lipid
1 CM TAG
2a LDL cholesterol
2b LDL,VLDL cholesterol, TAG
3 IDL,CM - remnants TAG, cholesterol
4 VLDL TAG
5 VLDL,CM TAG, cholesterol
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
50
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51
Hypolipoproteinemia Very rare diseases
genetically determined Examples Familiar
abetalipoproteinemia defect in synthesis of
apoproteine ? lack of lipoproteins
CM, VLDL, LDL, decreased concentrations of
cholesterol in blood, ? TAG in
blood Manifestation - impaired fat reabsorbtion
in GIT - disorders of
the CNS/PNS function
  • Tangier disease lack of HDL in blood
  • neuropathy, ATS is not accelerated !
  • deposition of cholesterol esters i macrophages
  • . big orange colored lymphatic tissue of the
    Waldayer ring

52
  • Other lipid metabolism related disorders
  • consequences of enzymes mutations
  • disorders of metabolism ? lipidosis
  • deposition of lipids within organs - (
    tezaurisomes )
  • Types of lipidosis
  • a) Nieman Pick s disease sphingomyelinosis
  • accumulation of sphingomyeline in liver
    macrophages, in spleen and lymphatic nodes
  • Consequence severe impairment of CNS
  • b) Gauchers disease - cerebrosidosis,
    cerebrosidolipidosis
  • deposition of glucocerebrozide
  • Consequence severe retardation of the CNS
    development at early age

53
Disorders of protein and AA metabolism
  • Disorders of nitrogen balance
  • a) Positive nitrogen balance growth,
    recuperation,
  • pregnancy, sportsmen, physical /manual work
  • b) Negative nitrogen balance - catabolic
    processes
  • ( cancer, fever, malnutrition, SIRS....
    )

2. Disorders of the protein blood composition
a) ? production of monoclonal Ig
Waldenströms macroglobulinemia ? hyper viscosity
of the blood Mechanism ? production of
IgM, hematological malignances
54
Myeloma multiplex ? hyper viscosity of
blood Mechanism ? production of IgA b)
? production of kryoglobulins ? disorders in
microcirculation due to precipitation of
kryoglobulins because of the
temperature drop in peripheral circulation
c) hyperfibrinogenemia, kryofibirinogenemia Fibrin
ogen is ? due to reactive processes /acute phase/
d) hypoalbuminemia Inappropriate production of
albumin in liver, or increased loss of albumin
due to nephrotic syndrome decrease of the
oncotic pressure of plasma impairment of
Starling's powers - edema
55
3. Disorders of AA metabolism
  • Phenylketonuria ARP
  • Phe esential AA, conversion to Tyr via enzyme
    Phe hydroxylase

Mechanism mutation of phenylalaninhydroxylase Con
sequence accumulation of phenylalanine ?
onset of abnormal metabolic products
phenylpyruvate, fenylacetate
severe disorder of the CNS
hypopigmentation due to inhibitory effect of
Phe on melanine production eczema -
mechanism of action of these abnormal metabolites
is not completely known.
56
  • b) Albinoism ? level or complete lack of
    melanine in the
  • skin, skin adnexes,
    eye
  • Mechanism defect of enzyme tyrozinase, which
    converts
  • Tyr to DOPA
  • Manifestation oculocutaneous albinoism (most
    common)
  • ? sensitivity of skin to UV light ?
    basocelular carcinomas
  • hypopigmentation of the skin
  • photophobia, and sight impairment

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  • c) Alcaptonuria (ochronosis)
  • - ARP
  • Mechanism defect of oxidize of homogentis
    acid
  • in the metabolic pathway of Phe rsp. Tyr
  • Consequences
  • accumulation of brow- red sometimes blue/black
    pigment in connective tissue - ochronosis
  • damage of the join cartilage ? arthrosis
  • damage of the heart valves ? valvular disorders
  • elimination of the pigment via urination,
    sweating
  • colored ear, eye sclera

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  • d) Homocystinuria
  • Mechanisms impaired metabolic pathways of
    sulphur containig AA ( cystein, metionin )
  • type I homocysteinuria
  • is caused by defect enzyme cystationsyntase
  • ( its co factor is vit B6 pyridoxin)
  • ?? concentration of homocysteine in blood
  • vision impairment
  • vessel complication (accelerated ATS,
    thrombosis)

typ II homocystinuria
is caused by defect resynthesis of met from
homocysteine In the process of resynthesis
participate folic acid and vit B12 Homocysteine
is able to cause a vessel endothelial damage
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Disorders of purine and pyrimidine metabolism
  • heterocyclic molecules, a component of NA and
    nucleotides
  • Disorders of those metabolic pathways are
    manifested as hyperuricaemia and gout
  • Hyperuricaemia increased concentration of uric
    acid the end stage metabolite of the purine
    turnover in the body, its level in the blood is
    influenced by exogenous intake and endogenous
    production
  • Normal level of uric acid is ? 340 ?mol/l in
    women and ? 420 ?mol/l in men
  • 1. primary cause not completely known
  • 2. secondary causes are known diseases leading
    to increased breakdown of NA - catabolism of NA,
    cytostatic drugs, tumor therapy, ? elimination of
    UA in renal failure

60
Gout arthritis
  • Disease caused by impaired purine metabolism
    and accumulation of uric acid in the blood
  • Pathogenesis
  • Formation of microcrystal of uric acid in the
    connective tissues, synovial membrane,
    periarticular structures ? fagocytosis of the
    crystals by PMN leucocytes ? activation of local
    inflammatory cascade activation of lysosomal
    enzymes, activation of complement, kinine system
    tissue damage
  • joints - gout arthritis
  • kidneys gout nephritis chronic renal failure
  • vessels acceleration of atherosclerosis

61
Disorders of porphyrine metabolism
  • Porphyrines are heterocyclic molecules
    precursors for biosynthesis of HEM cycle of 4
    subunits with cental atom /iron, cuprum, zinc/
  • hemoglobin, myoglobin binding and transport
    of oxygen
  • cytochromes energy pathway inside the cells
  • transport of electron
    in oxidative phosphorylation
    within mitochondria
  • cytochrome P- 450 hydroxylation, detoxicating
  • katalase, peroxidase metabolism of oxygen
    radicals
  • synthesis of NO

62
Disorders of porphyrine metabolism
Normal metabolism a) precursos is delta
aminolevulic acid and syntase of ? ALA is the
first enzyme in this pathway b) ? ALA is
then turned into porphyrinogenes (URO, KOPRO a
PROTO) and then finally to final product
porphyrine c) last one enzyme is
ferochelatase, binding central iron atom into the
molecule
Types of porphyrines - uroporphyrines
- koproporphyrines -
protoporphyrine ?
hem
63
Disorders of porphyrine metabolism
64
Porphyria disease caused by impaired HEM
synthesis and accumulation of HEM precursors
porphyrines in the body Classification
a) hepatal b) erytropoetic
General causes a) congenital b)
acquired Mechanism mutation and subsequent
dysfunction of one of the 8 enzymes participating
in the pathway of HEM synthesis
65
  • Acute porphyria (AP)
  • Acute intermittent porphyria
  • Characteristics no photosensitivity
  • Signs
  • due to accumulation of porphyrine precursors, ?
    ALA, porphobilinogene
  • due to ? HEM protein s in neurons
  • due to synthesis of false neuromediators
  • due to abnormal NO synthesis
  • - acute abdomen, paresis, psychic problems
  • - changes of homeostasis (hyponatremia,
    hypochloremia)
  • - systemic hypertension
  • factors provoking AP steroid hormones, (?
    morbidity in women befor menopause, contraceptive
    pills, stress, starvation, fever

66
Chronic porphyria (CHP) Porphyria cutanea tarda
(PCT)- the most common in SR
Characteristics PCT - photosensitivity
- onset of the water blisters on the
skin exposed
to sun
  • Mechanisms of photosensitivity
  • porfyrines contain system of doubled conjugated
    bindings ?
  • Exposition to sun leads to production of ORS ?
    oxygen radical damage the structure of the skin -
    blisters

Acquired porphyrias exposition to poisons like
polyhalogenated carbohydrates, griseofulvinu, lead
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