Pathobiochemistry of liver

portal vein

hepatic artery

bile duct

sinusoids

bile canaliculi

central vein

LIVER STRUCTURELIVER STRUCTURE

LIVER FUNCTIONSLIVER FUNCTIONS

•Distribution of nutrients•All types of metabolism (protein, lipid, carbohydrate, vitamin, mineral)•Excretory (bile acids, urea synthesis)•Destruction of toxic substances•Depot of iron, vitamins

METABOLISM OF CARBS IN METABOLISM OF CARBS IN LIVERLIVER

glycolisis metabolism of fructose and galactose gluconeogenesis release of glucose into blood (maintain the stable glucose concentration in blood) conversion of pyruvate into acetyl CoA tricarboxylic acid cycle pentose phosphate pathway glycogenolysis, glycogenogenesis

METABOLISM OF LIPIDS IN METABOLISM OF LIPIDS IN LIVERLIVER

synthesis of lipoproteins synthesis of triacylglyserols synthesis of phospholipids synthesis of fatty acids, elongation of fatty acids chain, desaturation synthesis of cholesterol ketone bodies formation lipolysis fatty acids oxidation

METABOLISM OF PROTEINS IN METABOLISM OF PROTEINS IN LIVERLIVER

protein synthesis, including blood plasma proteins protein decomposition; urea synthesis conversion of proteins into carbs and lipids interconversion of aminoacids conversion of proteins into low molecular weight nitrogen containing substances

• Formation of active form of vitamin D

• Formation of vitamin A from carotins

• Depo of cyanocobalamine and folic acid

• Depo of vitamin E• Phosphorilation of vitamins B,

formation of coenzyme forms

VITAMIN METABOLISM IN LIVER

DETOXIFICATION OF TOXIC DETOXIFICATION OF TOXIC SUBSTANCES IN LIVERSUBSTANCES IN LIVER

Phase I and phase II.

Phase I: hydrolysis, reduction, oxidation.

These reactions introduce functional group (—OH, —NH2, —SH, or —COOH) and usually result in a little increase of hydrophylic properties

Phase II includes: glucuronation, sulfation, acetylation, methylation, conjugation with glutathione, conjugation with aminoacids (glycin, taurin, glutamic acid)

Phase II results in the marked increase of hydrophylic properties of xenobiotic.

REACTION ENZYME LOCALIZATION

PHASE I

Hydrolysis

Reduction

Oxidation

EsterasePeptidase Epoxide hydrolase

Azo- and nitro-reduction Carbonyl reductionDisulfide reductionSulfoxide reduction

Alcohol dehydrogenaseAldehyde dehydrogenaseAldehyde oxidaseXanthine oxidaseMonoamine oxidaseDiamine oxidaseFlavin-monooxygenasesCytochrome P450

Microsomes, cytosol, lysosomes, blood lysosomes Microsomes, cytosol

Microflora, microsomes, cytosolCytosol, blood, microsomesCytosolCytosol

CytosolMitochondria, cytosolCytosolCytosolMitochondriaCytosolMicrosomesMicrosomes

PHASE II

Glucuronide conjugationSulfate conjugationGlutathione conjugationAmino acid conjugationAcetylationMethylation

MicrosomesCytosol, microsomesCytosolMitochondria, cytosolMitochondria, microsomesCytosol, microsomes, blood

General ways of xenobiotics biotransformation and their localization in cell

PHASE I

Hydrolysis

Esterases (carboxyesterases, cholinesterases, phosphatases) Peptidases

ReductionMetals and xenobiotics containing aldehyde, keto, disulfide, alkyn, azo, or nitro group are often reduced

Reducing agents:Reduced glutathione, FADH2, FMN,NADH NADPH.

OxidationAlcohol dehydrogenase

Aldehyde dehydrogenase

Oxidizes aldehydes to carbonic acids

Xanthine dehydrogenase-Xanthine oxidase

Monoaminooxidase

Oxidative deamination of amines (serotonin) and many xenobiotics

Cytochrom P450

The highest concentration – in endoplasmic reticulum of hepatocytes (microsomes).

Hem containing protein.

Catalyzes monooxigenation of oxygen atom into substrate; another oxygen atom is reduced to water

Electrons are transferred from NADPH to cytochrome P450 through flavoprotein NADPH-cytochrome P450 reductase.

SCHEME OF MONOOXYGENASE SYSTEM

The example of reaction that is catalyzed by cytochrome P450: hydroxylation of aliphatic carbon

The example of reaction that is catalyzed by cytochrome P450: hydroxylation of aromatic carbon

JAUNDICES

NORMAL METABOLISM OF BILE PIGMENTS

CELLS OF RESIndirect bilirubin

NADP+

NADPH2

Biliverdin reductase

Biliverdin

Iron

Globin

Verdoglobin

NADP+

Hemoxi-genase

NADPH2

Hemoglobin ERYTHROCYTES

KIDNEYS

Stercobilinogen

URINE

Stercobilin

Indirect bilirubin 1,7-20,5 mkmol/l

albumin

albumin

Indirect bilirubin

UDP-glucoronil-transferase

Direct bilirubin 0.8-4.3 mkmol/l

BLOOD

LIVER

Bilirubin mono-glucoronid, 20 %

Bilirubin di-glucoronid, 80 %

Dipyrols

-glucoro-nidase

Glucoronic acid

Direct bilirubin

BILE

INTESTINE

Mesobilirubin

Mesobilirubin (urobilinogen)

Stercobilinogen

Stercobilin

STOOL

METABOLISM OF BILE PIGMENTS IN HEMOLYTIC JAUNDICE

CELLS OF RES

Indirect bilirubin

Indirect bilirubin

albumin

albumin

Indirect bilirubin

Biliverdin reductase

UDP-glucoronil-transferase

Direct bilirubin

NADP+

NADPH2

Biliverdin

Iron

Globin

Verdoglobin

NADP+

NADPH2

Hemoglobin

Hemoxi- genase

BLOOD

LIVER

Bilirubin mono-glucoronid, 20 %

Bilirubin diglucoronid, 80 %

-glucoro- nidase

Glucoronic acid

Direct bilirubin

BILE

ERYTHROCYTES

KIDNEYS

INTESTINE

STOOL

Stool hypercholic

URINEUrine dark

Mesobilirubin

Mesobilinogen (urobilinogen)

Stercobilinogen

Stercobilin

Stercobilinogen

StercobilinUrobilin

METABOLISM OF BILE PIGMENTS IN HEPATIC JAUNDICE

CELLS OF RES

Indirect bilirubin

Indirect bilirubin

albumin

albumin

Indirect bilirubin

Biliverdin reductase

UDP-glucoronil-transferase

Direct bilirubin

NADP+

NADPH2

Biliverdin

Iron

Globin

Verdoglobin

NADP+

NADPH2

Hemoglobin

Hemoxi- genase

BLOOD

LIVER

Bilirubin mono-glucoronid, 20 %

Bilirubin diglucoronid, 80 %

-glucoro- nidase

Glucoronic acid

Direct bilirubin

BILE

ERYTHROCYTES

KIDNEYS

Urobilinogen INTESTINE

STOOL

Stool hypocholic

URINEUrine dark

Stercobi-linogen

StercobilinBilirubinUrobilin

Mesobilirubin

Mesobilinogen (urobilinogen)

Stercobilinogen

Stercobilin

METABOLISM OF BILE PIGMENTS IN OBSTRUCTIVE JAUNDICE

CELLS OF RESIndirect bilirubin

Indirect bilirubin

albumin

albumin

Indirect bilirubin

Biliverdin reductase

UDP-glucoronil-transferase

Direct bilirubin

NADP+

NADPH2

Biliverdin

Iron

Globin

Verdoglobin

NADP+

NADPH2

Hemoglobin

Hemoxi- genase

BLOOD

LIVER

Bilirubin mono-glucoronid, 20 %

Bilirubin diglucoronid, 80 %

Bile acids

-glucoro- nidase

Glucoronic acid

Direct bilirubin

BILE

Direct bilirubin

ERYTHROCYTES

KIDNEYS

Direct bilirubinINTESTINE

STOOL

Stool acholic, steatorhea

URINE Direct bilirubin Bile acids

Urine dark, foaming

Etiology and pathogenesis of liver insufficiency

• Infectious agents (hepatitis B virus, tuberculosis bacillus, helmints)• Hepatotropic poison (drugs - tetracycline, sulfonamides, industrial poisons - carbon tetrachloride, arsenic, chloroform, vegetable poisons - aflatoxin, muscarine)• Physical impacts (ionizing radiation)• Biological drugs (vaccines, serums)• Violation of blood circulation (thrombosis, embolism, venous congestion)• Endocrine pathology (diabetes mellitus, hyperthyroidism)• Tumors• Hereditary ensymopathy

Causes of Liver Failure

Consequences of Liver Failure

Fibrosis and Cirrhosis of the Liver

Fibrosis and Cirrhosis of the Liver

Clinical syndromes in liver injury

Lack of liver disorders manifested its functions lesion:• metabolic (involved in carbohydrate, fat, protein metabolism, metabolism of vitamins, hormones, biologically active substances)• protection (phagocytic and antitoxic)• digestive and excretory (the formation and release of bile)• hemodynamic (involved in maintaining systemic circulation).

Cholelithiasis: Abnormal Cholesterol to Bile Salt Ratio

Clinical syndromes of jaundice• Acholia associated with non-receipt of bile in the

intestine due to violations of the formation and outflow of bile. Acholia manifested disorders of digestion and absorption of fats, hypovitaminosis A, E, K, decreased intake of unsaturated fatty acids of phospholipids to build cell membranes, intestinal motility violation, increasing decay and fermentation.

• Dyscholia - violation of the physical-chemical properties of bile, causing it acquires the ability to form stones (due to genetic predisposition, poor nutrition, metabolic disorders, infectious-inflammatory processes, cholestasis).

Cholelithiasis: Abnormal Cholesterol to Bile Salt Ratio

Etiology and pathogenesis of jaundice

• Jaundice - a syndrome caused by an increase in blood bilirubin (hemolytic, parenchymal, mechanical).

• In hemolytic jaundice due to destruction of a large number of red blood cells accumulate indirect, protein bound bilirubin.

• When parenchymal jaundice disturbed capture, and excretion of bilirubin in hepatocytes due to their injuries.

• In mechanical jaundice occurs outflow obstruction of bile, compression of biliary tract tumor or scar, closing within a stone, worms, thick bile.

Mechanisms and Consequences of Cholestasis

Methods of experimental study of liver pathology

• hepatic-cell failure simulating full or partial removal of the liver, the introduction of poisons (carbon tetrachloride, chloroform, trinitrotoluene);• cholestatic model obtained by squising bile ducts by ligature;• hepatic vascular insufficiency simulating by overlapping portocaval anastomosis, ligation portal vein, hepatic vein, hepatic artery.