Metabolic disorders (faty molecules, proteins, aminoacids, purines, pyrimidines)

Pathophysiology of nutrition and obesity

Doc. MUDr. Jana Plevková PhDÚstav patologickej fyziológie JLF UK

2009

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

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/

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

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

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

The role of different organs in metabolic processes

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

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

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/

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

Decreased nutrition

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

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

1. Decreased food intake – anorexia, nausea, disease of GIT, disorders of digestion, absorption, intestinal inflammation, pancreas, disorders of bile secretion etc.

2. Increased loss of nutrients – exudative gastro and enteropathy, bleeding, diarrhoea

3. 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

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 ?

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

• 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

Systemic changes – affection of the whole body caused by malnutrition

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

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

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

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

A. 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)

Classification of obesity

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

The most common factors leading to overweight and obesity are:genetic predispositionfood containing too much energylimited body movement and lack of physical exerciseconsequence of other disease /hypotyreosis/disorders of food intake and its regulationpsychic stressside effects of some drugs

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

Main causes and mechanism involved in pathogenesis of obesity

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 regulationghrelin – 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

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

The role of the CNS

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

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

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?

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

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

Visceral obesity

Mechanisms responsible for visceral obesity

AgingHormonal 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

Disorders of lipid metabolism

A. 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 General types of disorders

1. Hyperlipoproteinemia

2. Hypolipoproteinemia

Lipoproteíny (LP) – spheric molecules transporting apolar liipids within the blood

- those particles differ with density, size, amount of the lipids those particles differ with density, size, amount of the lipids transported, amount and type of apo, site of origin, metabolism and transported, amount and type of apo, site of origin, metabolism and other parametersother parameters

- surface is surface is cconstituonstitutedted from polar chains, allowing the transport in the from polar chains, allowing the transport in the plasmaplasma­ phospholipids, cholesterol, TAG apolipoproteins (apo) – important for the metabolic pathways of LP

- inside the spheric particle – apolar lipids

Composition of characteristics

• 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

Enzymes metabolizning LPEnzymes metabolizning LP

•• Lipoproteine lipase (LPL)Lipoproteine lipase (LPL) - release of FFA from TAG in- 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 lipaseHepatic lipase hydrolysis of TAG in liver

activated by apo E

• LCAT = lecitín : cholesterol acyl transferase

• CETP = cholesterol ester transfer protein

• 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

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

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

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

Major types of hyperlipoproteinemias (HLP)

A. Primary1. 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

33. . 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 The difference 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

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

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

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

Other lipid metabolism related disorders • consequences of enzymes mutationsconsequences of enzymes mutations• disorders of metabolism lipidosis • deposition of lipids within organs - ( tezaurisomes )

Types of lipidosisa) Nieman – Pick ´s disease – sphingomyelinosis accumulation of sphingomyeline in liver macrophages, in spleen and

lymphatic nodes Consequence: severe impairment of CNS

b) Gaucher´s disease - cerebrosidosis, cerebrosidolipidosis• deposition of glucocerebrozideConsequence: severe retardation of the CNS development at early age

Disorders of protein and AA metabolism

1. 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 • Waldenström´s macroglobulinemia hyper viscosity of the blood Mechanism: production of IgM, hematological malignances

•• Myeloma multiplexMyeloma 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

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

c) hyperfibrinogenemia, kryofibirinogenemia

Fibrinogen is due to reactive processes /acute phase/

3. Disorders of AA metabolism

a) Phenylketonuria – ARP

Phe = esential AA, conversion to Tyr via enzyme Phe hydroxylase

Mechanism: mutation of phenylalaninhydroxylase

Consequence: • accumulation of phenylalanine onset of

abnormal metabolic products phenylpyruvate, fenylacetate

• severe disorder of the CNS

• hypopigmentation: due to inhibitory effect of Pheon melanine production

• eczema

- mechanism of action of these abnormal metabolites

is not completely known.

b) Albinoism – level or complete lack of melanine in the skin, skin adnexes, eye

Mechanism: defect of enzyme tyrozinase, which convertsTyr to DOPA

Manifestation: • oculocutaneous albinoism (most common)

• sensitivity of skin to UV light basocelular carcinomas • hypopigmentation of the skin• photophobia, and sight impairment

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

d) Homocystinuria

Mechanisms: impaired metabolic pathways of sulphur containig AA

( cystein, metionin )

type I homocysteinuria is caused by defect enzyme cystationsyntase

( it´s co factor is vit B6 – pyridoxin)• concentration of homocysteine in blood• vision impairment• vessel complication (accelerated ATS, thrombosis)

• • is caused by defect resynthesis of met from homocysteine In the process of resynthesis participate folic acid and vit B12Homocysteine – is able to cause a vessel endothelial damage

typ II homocystinuria

Disorders of purine and pyrimidine metabolism

heterocyclic molecules, a component of NA and nucleotidesDisorders 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

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 arthritiskidneys – gout nephritis – chronic renal failure vessels – acceleration of atherosclerosis

Porphyrines are heterocyclic molecules – precursors for biosynthesis of HEM – cycle of 4 subunits with cental atom /iron, cuprum, zinc/

Disorders of porphyrine metabolism

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

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

Disorders of porphyrine metabolism

Disorders of porphyrine metabolism

General causesGeneral causes

a) congenital

b) acquired

Mechanism: mutation and subsequent dysfunction of one of the 8

enzymes participating in the pathway of HEM synthesis

Porphyria – disease caused by impaired HEM synthesis and accumulation of HEM precursors – porphyrines in the body

Classification a) hepatal

b) erytropoetic

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

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