Pathophysiology of liver


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prepared by M.D., PhD, Associate Professor Marta R. Gerasymchuk
Department of Pathophysiology
Ivano-Frankivsk National
Medical University

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  • Classical anatomic landmarks in the average 1400-1800 gram adult liver.
    The liver is encased in a fibroelastic capsule called Glisson's capsule and is grossly separated into right and left lobes. Glisson's capsule contains blood vessels, lymph vessels, and nerves. The two liver lobes consist of many smaller units called lobules. The lobules contain the liver cells (hepatocytes) that line up together in plates. The hepatocytes are considered to be the functional units of the liver. Liver cells are capable of cell division and readily reproduce when needed to replace damaged tissue.
  • The liver is nothing more than an array of cells between the portal and caval venous systems. This shows the direction of flow. The liver gets about 80% of its blood supply from the portal veins and 20% from the hepatic arterial system.
    The IDEAL three-dimensional diagram: Hexagonal Hepatic “LOBULE”
    From the point of view of anatomy, physiology, and pathology, you must clearly understand the DIRECTION is:
    Portal vein
    Central vein
    Hepatic Veins
    Crucially important concept worth repeating. KNOW the difference between an acinus and a lobule.
    The best tip to understanding liver disease is to understand the direction of blood flow. TOXIC injuries generally do more damage in the part of the liver closest to the PORTAL vein, and HYPOXIC injuries generally do more damage in the parts of the liver around the CENTRAL vein, i.e., centrolobular necrosis.
  • The classical view of liver tissue from a liver biopsy, H&E stained.
    The FIRST part of the lobule, i.e., portal triad is the FIRST to get blood flow, so it is also the FIRST to get the brunt of general toxic effects, and the LAST to get the brunt of ischemic effects.
    The LAST part of the lobule, central vein!
  • 1. The creation of bile pigments synthesis of cholesterol, synthesis and secretion of bile.
    2. The detoxication of toxic products, coming from gastrointestinal tract.
    3. The synthesis of proteins (proteins of plasma of blood among them), their deposition, transamination and desamination of aminoacids, the formation of urea, the synthesis of creatinine.
    4. The synthesis of glycogene from monosaccharides.
    5. The oxidation of fatty acids, the formation of acetone (ketone bodies).
    6. The deposition and exchange of vitamins (А, В, D), the deposition of iron, copper, zinc ions.
    7. The regulation of the balance between coagulant and anticoagulant blood system, the formation of heparine.
    8. The destruction of some microorganisms, bacterial and other toxins.
    9. The deposition of plasma of blood, the regulation of a total amount of blood.
    10. Hemopoiesis in the fetus.
  • Metabolic Biotransformation
    The liver has an important role in transforming biologic substances that may be toxic at high levels or that cannot be excreted from the body without transformation. Substances acted upon in this manner by the liver may include both those ingested by an individual as well as those produced by the body itself. Examples of substances that are transformed by the liver include bilirubin, various hormones, drugs, and toxins. Metabolic biotransformation is also referred to as metabolic detoxification.
  • Glucose Handling by the Liver
    After glucose is digested and absorbed into the bloodstream, it is delivered to all cells of the body to be used as an energy source. As discussed in Chapter 16, insulin is required for glucose to gain entry to most cells. If glucose is unnecessary for immediate energy, it can be stored in cells as glycogen. The liver is especially capable of storing large amounts of glucose as glycogen. Because the liver can store glycogen, it acts as a glucose buffer for the blood. When glucose levels rise in the blood, the liver's conversion of glucose to glycogen and the storage of glycogen increase. Glycogen formation, called glycogenesis, occurs in the absorptive phase of digestion, which is the period soon after a meal when glucose levels are high. Glycogenesis is insulin dependent. By increasing the conversion and storage of glucose in times of excess, the liver returns plasma glucose levels toward normal.
    In times of fasting or between meals, the breakdown of glucagon to glucose occurs in the liver, again serving to normalize circulating levels of glucose. The breakdown of glycogen is called glycogenolysis. In addition, when glucose levels decrease between meals, the liver initiates gluconeogenesis (the new formation of glucose) to keep blood glucose levels constant. Gluconeogenesis is accomplished in the liver by conversion of amino acids to glucose after deamination (removal of the amino group) and by conversion of glycerol, a product of fatty acid breakdown, to glucose. The breakdown of glycogen and the formation of glucose occur in the postabsorptive phase of digestion, the time between meals when external food sources are not readily available. The postabsorptive stage of digestion is under the control of the pancreatic hormone glucagon and other gastrointestinal hormones.
  • Pediatric Consideration
    Infants and children are particularly dependent on fatty acid oxidation during periods of fasting as a result of reduced glycogen storage, immature activity of enzymes involved in glycolysis and gluconeogenesis, and increased basal metabolic needs. Ketone bodies are produced and can serve as alternative fuel for cardiac and skeletal muscles. Excess ketones, however, can lower blood pH.
    Fatty Acid Handling by the Liver
    Nearly all digested fats are absorbed into the lymphatic circulation as chylomicrons—conglomerates of triglycerides, phospholipids, cholesterol, and lipoprotein. The chylomicrons are delivered by the lymph to the thoracic duct, where they join the systemic circulation. Triglycerides are subsequently changed back into fatty acids and glycerol by enzymes in the walls of all capillaries, especially the capillaries that serve the liver and the adipose tissue. From the capillaries, fatty acids and glycerol can diffuse into most cells.
    Once inside the liver and other cells, fatty acids and glycerol again combine to form triglycerides. Triglycerides are stored until needed during the postabsorptive stage. At this time they may be metabolized back to glycerol and free fatty acids. Glycerol and fatty acids can enter the Krebs cycle to produce ATP, so that cells are provided with energy. Elevations in the hormones glucagon, cortisol, growth hormone, and the catecholamines signal cells to break down stored triglycerides into free fatty acids and glycerol.
    Instead of directly entering the Krebs cycle, some glycerol and free fatty acids may be used by the liver to produce new glucose. This can result in the production of ketones when triglyceride breakdown is excessive. The brain itself cannot use free fatty acids directly for energy production. Therefore, the liver's conversion of fats to glucose (gluconeogenesis) is essential for supporting the energy needs of the brain when glucose levels are low.
  • Fat vacuoles are large enough to completely REPLACE the hepatocyte cytoplasm.
    Why is the differential diagnosis of MACRO vesicular steatosis the same as MICRO vesicular steatosis?
  • Pathways of Lipid Metabolism. Although most body cells can metabolize fat, certain aspects of lipid metabolism occur mainly in the liver. These include the oxidation of fatty acids to supply energy for other body functions; the synthesis of large quantities of cholesterol, phospholipids, and most lipoproteins; and the formation of triglycerides from carbohydrates and proteins. To derive energy from neutral fats (triglycerides), the fat must first be split into glycerol and fatty acids, and then the fatty acids split into acetyl-coenzyme A (acetyl-CoA). Acetyl-CoA can be used by the liver to produce adenosine triphosphate (ATP) or it can be converted to acetoacetic acid and released into the bloodstream and transported to other tissues, where it is used for energy. The acetyl-CoA units from fat metabolism also are used to synthesize cholesterol and bile acids. Cholesterol has several fates in the liver. It can be esterified and stored; it can be exported bound to lipoproteins; or it can be converted to bile acids.
  • Protein Synthesis and Conversion of Ammonia to Urea. Even though the muscle contains the greatest amount of protein, the liver has the greatest rate of protein synthesis per gram of tissue. It produces the proteins for its own cellular needs and secretory proteins that are released into the circulation. The most important of these secretory proteins is albumin. Albumin contributes significantly to the plasma colloidal osmotic pressure and to the binding and transport of numerous substances, including some hormones, fatty acids, bilirubin, and other anions. The liver also produces other important proteins, such as fibrinogen and the blood clotting factors.
    Proteins are made up of amino acids. Protein synthesis and degradation involves two major reactions: transamination and deamination. In transamination, the amino group (NH2) from an amino acid is transferred to α-ketoglutaric acid (a Krebs cycle keto acid) to form glutamic acid. The transferring amino acid becomes a keto acid and α-ketoglutaric acid becomes an amino acid (glutamic acid). The reaction is fully reversible. The process of transamination is catalyzed by aminotransferases, enzymes that are found in high amounts in the liver. Oxidative deamination involves the removal of an amino group from an amino acid. This occurs mainly by transamination, in which the amino group of glutamic acid is removed as ammonia, and α-ketoglutaric is regenerated. Because ammonia is very toxic to body tissues, particularly neurons, it is converted to urea in the liver and then excreted by the kidneys. The goal of amino acid degradation is to produce molecules that can be used to produce energy or be converted to glucose.
    Plasma Protein Synthesis
    The liver is responsible for synthesizing plasma proteins, including albumin. The albumin concentration in the plasma is the main source of plasma osmotic pressure, the primary force causing reabsorption of fluid from the interstitial space into the capillary (see Chapter 13). If the liver is incapable of making adequate amounts of plasma proteins, osmotic pressure in the capillary will be low, and plasma filtered out at the start of the capillary will not flow back in by the time the capillary reforms to a venule. Therefore, swelling and edema of the interstitial space will occur.
  • For example, without bile, a vitamin K deficit would occur and be apparent in less than a week. Without adequate vitamin K, blood coagulation would be impaired.
    The liver also functions in the handling of another component of bile, bilirubin. Bilirubin is formed as an end product of hemoglobin breakdown and must be metabolized by the liver for it to be excreted.
  • Bilirubin Biotransformation
    Bilirubin is a product of red blood cell breakdown. When a red blood cell has lived out its 120-day life span, the cell membrane becomes fragile and ruptures. Hemoglobin is released and is acted upon by circulating phagocytic cells to form free bilirubin. Free bilirubin binds to plasma albumin and circulates in the bloodstream to the liver.
    Free bilirubin is considered unconjugated in that, although it is bound to albumin, the binding is reversible. Once in the liver, bilirubin releases from albumin and, because free bilirubin is lipid soluble, moves easily into the hepatocytes. Once inside the hepatocytes, bilirubin is rapidly bound to another substance, usually glucuronic acid, and is now considered conjugated. Conjugated bilirubin is water soluble, not lipid soluble.
    Most conjugated bilirubin is actively transported into the bile canaliculi. From there it is delivered along with the other components of bile to the gallbladder or small intestine. A small amount of conjugated bilirubin does not go to the intestine as a bile component, however, but rather is absorbed back into the bloodstream. Therefore, in the bloodstream, there is always a small amount of conjugated bilirubin present, along with unconjugated bilirubin on its way to the liver.
    Once in the intestine, conjugated bilirubin is acted upon by bacteria and changed into urobilinogen. Most urobilinogen enters the bloodstream and is excreted by the kidneys in the urine, some is excreted in the stool, and some is recycled back to the liver in the enterohepatic (intestinal to liver) circulation. Figure shows the steps involved in the conjugation and excretion of bilirubin.
    The conjugation of bilirubin is essential for its excretion. Without conjugation, bilirubin cannot be excreted by either the kidneys or the intestines. The handling of bilirubin by the liver is a form of metabolic detoxification. Without conjugation, unconjugated bilirubin would build up in the bloodstream to toxic levels.
  • Jaundice (icterus) is detectable clinically when the serum bilirubin is greater than 50 μmol/L (3 mg/dL).
    The usual division of jaundice into prehepatic, hepatocellular and obstructive (cholestatic) is an oversimplification as in hepatocellular jaundice there is invariably cholestasis and the clinical problem is whether the cholestasis is intra­hepatic or extrahepatic.
  • - Coinfection with HIV and Hepatitis C is a significant problem, especially among injection drug users
    In the United States it estimated that 240,000 persons are infected with both HCV and HIV.
    Studies estimate that as many as 25-30% of HIV positive people in the United States are coinfected with HCV and up to 10% of HCV positive person are infected with HIV.
    In urban areas of the US, up to 90% of person who acquired HIV infection from injection drug use also have HCV.
    HCV accelerated in the setting of HIV: Increased risk for cirrhosis
    HCV frequently “drives prognosis” in co-infected pts: making treatment more difficult
  • HAART - Highly Active Antiretroviral Therapy
  • a.a. – amino acid
  •  In the final result, the metabolism violation in the liver may lead to cirrhosis. This is a complicated process, which results in abnormal connective tissue growth. The clue of understanding of this matter lies in anatomic connection of the liver lobe with the microcirculation unit – a blood capillary, a billary duct and a lymphatic vessel. The more stable to demage and capable to regenerate are the hepatocyte of 1-st zone, and the less stable to demage and capable to regenerate are the hepatocyte of 3-d zone more sensible, wich are localised afar to the microcirculation unit.
    The cirrhosis development depends on the nature, the level and the duration of the unfavourable influence onto the liver parenchyma. The liver has got a wonderful ability to regenerate. If a rat is ablated of 50-70 % of the liver, this organ regenerates its initial mass within quite a short period of time. In that case, however, the damage has only the quantitative and local character, and not the difuse one, when damage captures more sensible cells in the whole organ simultaneously. E.g., at Wilson’s disease hepatocytes are liable to chronic influence of the unphisiologically high copper concentrations. That damage is not local any more, it spreads over the whole liver. Hepatocytes of zone 3, which are the least capable to withstand a damage, die and are replaced with the more resistant hepatocytes of zones 2-nd and 1-st. That leads to the unorganized parenchyma regeneration that is characteristic for cirrhosis. Parallel, fibroblasts are activated, and the additional connective tissue starts to be synthesized. Its growth is a determinant process in the cirrhosis formation.
    Fibroblasts activation leads to the excess synthesis by them of glucosaminoglycanes, glycoproteides and collagen. Normally, collagen is adjusted to cellular surface, and its synthesis is restricted by the cellular surface. However, in the process of fibrosis, collagen is formed behind its connection with a cell, and is located chaotically. Anatomic correlations in a liver lobe alter. The lobe structure is distorted by the regenerating parenchyma nodules and the nodules of the fibrous connective tissue. The blood stream through the lobes is violated, and that leads to further death of hepatocytes, fibrosis spreading and the loss of hepatocytes ability to regenerate. The cell amount decreases. The decreased parenchyma does not correspond to the metabolism demands. The liver insufficiency takes place.
  • Pathophysiology of liver

    1. 1. ActualityActuality  The diseases of liver and bile excretory system take considerable specific weight in a general morbidity of the population, and last decade the further growth of them was increased.  Technological revolution and associated with it the negative ecological shifts have resulted in useful increase of frequency and spread spectrum of diseases of liver and cholic tracts. In connection with urbanisation of life, hypokinesia, and also such negative phenomenon as alcoholism, morbidity the hepatitis and cirrhosis of liver, cholelithiasis and cholecystitis considerably has increased.  The chemicalization of effecting, agriculture, mode of life activities and medicine promoted growth of frequency of toxic and medicamental damages of liver. Sharp increase of medical manipulations, blood transfusion have stimulated useful increase of morbidity by serumal hepatitis.  The main morphological types of damages of liver is hepatitis, cirrhosis, cancer. Etiological value in formation of the majority of acute and chronic diseases of liver have the agents many zymotic and infection diseases (viruses, bacteria, spirochetes, pathogenic fungi, elementary, helminths) and toxic substances - hepatotoxins, including alcohol and medicine drugs.  Therefore preventive maintenance encompasses them the broad audience of problems. The pathogenetic treatment of diseases of liver bases on knowledge of their mechanisms of disturbance of structure and function of liver, which one are revealed with the help biochemical, cytochemical, radioisotope and other method of testings.
    2. 2. CONTENTCONTENT 1.1. Microscopic architecture of the liver parenchyma.Microscopic architecture of the liver parenchyma. 2.2. The liver is a big chemical laboratory.The liver is a big chemical laboratory. Carbohydrate, Protein, and Lipid Metabolism.Carbohydrate, Protein, and Lipid Metabolism.  The cases of liver pathology.The cases of liver pathology.  Carbohydrate metabolism disorder in liver.Carbohydrate metabolism disorder in liver.  Fat metabolism disorder. Liver fatty infiltration.Fat metabolism disorder. Liver fatty infiltration.  Protein metabolism infringement.Protein metabolism infringement. 1.1. Microelements metabolism disorder in liver.Microelements metabolism disorder in liver. 2.2. Methods of experimental design of violations of function of liver.Methods of experimental design of violations of function of liver. 3.3. Functional insufficiency of liver, its etiology, pathogenesis, basic displays.Functional insufficiency of liver, its etiology, pathogenesis, basic displays. 4.4. A metabolic disturbance is at the diseases of liver.A metabolic disturbance is at the diseases of liver. Antitoxic liver function disorder.Antitoxic liver function disorder. 5.5. An exchange of bilirubin in an organism in a norm.An exchange of bilirubin in an organism in a norm. 6.6. Jaundices: classification, etiology, pathogenesis, basic clinical displays of separateJaundices: classification, etiology, pathogenesis, basic clinical displays of separate kinds.kinds. 7.7. Enzymopathic jaundices (Gilbert's syndrome, CriglerEnzymopathic jaundices (Gilbert's syndrome, Crigler -- Nagar syndrome, Dubin-Nagar syndrome, Dubin- Johnson syndrome).Johnson syndrome). 8.8. Differential diagnostics of separate types of jaundices is on the basis ofDifferential diagnostics of separate types of jaundices is on the basis of information of laboratory researches of physiology liquids of organism.information of laboratory researches of physiology liquids of organism. 9.9. Hepatocerebral comaHepatocerebral coma: pathogenesis of basic displays, medical measures: pathogenesis of basic displays, medical measures 10.10. Cirrhosis of the liver.Cirrhosis of the liver. 11.11. Disorders of the gallbladder and extrahepatic bile ducts.Disorders of the gallbladder and extrahepatic bile ducts.
    3. 3. LiverLiver • Largest internal organ • Weighs about 1400-1800 gram • Located on right side under ribcage • Ability to regenerate • Has over 500 vital functions • Involved in many digestive, vascular and metabolic activities
    5. 5. Blood Supply of the Liver Hepatic Arterial Autoregularity Vasodilatation Hepatic Arterial Autoregularity Vasodilatation
    6. 6. The following processes takeThe following processes take place in the liver:place in the liver: 1.1. The creation of bileThe creation of bile pigments synthesispigments synthesis of cholesterol,of cholesterol, synthesissynthesis and secretion of bileand secretion of bile.. 2.2. TheThe detoxicationdetoxication of toxic products, coming from gastrointestinalof toxic products, coming from gastrointestinal tract.tract. 3.3. TheThe synthesis of proteinssynthesis of proteins (proteins of plasma of blood among(proteins of plasma of blood among them), their deposition, transamination and desamination ofthem), their deposition, transamination and desamination of aminoacids, the formation of urea, the synthesis of creatinine.aminoacids, the formation of urea, the synthesis of creatinine. 4.4. TheThe synthesis of glycogenesynthesis of glycogene from monosaccharides.from monosaccharides. 5.5. TheThe oxidation of fatty acidsoxidation of fatty acids, the formation of acetone (ketone, the formation of acetone (ketone bodies).bodies). 6.6. TheThe deposition and exchangedeposition and exchange ofof vitaminsvitamins ((АА,, ВВ, D), the deposition, D), the deposition ofof iron, copper, zinc ionsiron, copper, zinc ions.. 7.7. TheThe regulationregulation of the balance betweenof the balance between coagulantcoagulant andand anticoagulant blood systemanticoagulant blood system, the formation of heparine., the formation of heparine. 8.8. TheThe destructiondestruction of someof some microorganisms, bacterialmicroorganisms, bacterial and otherand other toxinstoxins.. 9.9. TheThe deposition of plasma of blooddeposition of plasma of blood, the regulation of a total amount, the regulation of a total amount of blood.of blood. 110.0. HemopoiesisHemopoiesis in the the fetus.
    7. 7. Functions of the LiverFunctions of the Liver Type Function Metabolic Absorptive Period Converts glucose to glycogen and triglycerides; stores glycogen. Converts amino acids to fatty acids or stores amino acids. Makes lipoprotein from triglycerides and cholesterol. Postabsorptive Period Produces glucose from glycogen (glycogenolysis) and fatty acids and amino acids (glyconogenesis). Converts fats to ketones (accelerated if fasting). Produces urea from protein catabolism. Immunologic Metabolic Transformation Macrophages filter blood. Detoxifies or conjugates waste products, hormones, drugs. Clotting Functions Produces several essential clotting factors. Plasma Proteins Synthesizes albumin and other plasma proteins. Exocrine Functions Synthesizes bile salts. Endocrine Functions Involved in activation of vitamin D. Produces angiotensinogen. Secretes insulin-like growth factors (somatomedin).
    8. 8. Liver Damage Inflammation – immune response Fibrosis – development of scar tissue Cirrhosis – a process where liver cells are destroyed and replaced with scar tissue Hepatocellular Carcinoma – type of liver cancer
    9. 9. DisordersDisorders Liver FunctionLiver Function Hepatic TestHepatic Test JaundiceJaundice Biliary Tract DiseaseBiliary Tract Disease – Cholelithiasis-CholedocholithiasisCholelithiasis-Choledocholithiasis – Cholecystitis-CholangitisCholecystitis-Cholangitis – Biliary tract obstructionBiliary tract obstruction Hepatic DiseaseHepatic Disease – Hepatitis Acute & ChronicHepatitis Acute & Chronic A/B/C/D/E, ETOH/drugA/B/C/D/E, ETOH/drug – CirrhosisCirrhosis – Hepatic FailureHepatic Failure Neoplasm (later section)Neoplasm (later section)
    10. 10. ETHIOLOGYETHIOLOGYETHIOLOGYETHIOLOGY Infectious agentsInfectious agents – hepatitis virus, Koch’s bacillus, pale– hepatitis virus, Koch’s bacillus, pale Spirochaeta, Actynomyces, Echinococcuses,Spirochaeta, Actynomyces, Echinococcuses, Ascarides;Ascarides; 1.1. Hepatotropic poisons, including medicinesHepatotropic poisons, including medicines –– tetracycline, PASA (paraaminosalycil acid),tetracycline, PASA (paraaminosalycil acid), sulphanilamides, industrial poisons (CClsulphanilamides, industrial poisons (CCl44, arsenic,, arsenic, chloroform); plants poisons (aphlatoxine,chloroform); plants poisons (aphlatoxine, muscarine);muscarine); 2.2. Physical influencesPhysical influences – ionizing radiation;– ionizing radiation; 3.3. Biological substancesBiological substances – vaccines, serums;– vaccines, serums; 4.4. Blood flow violationsBlood flow violations – thrombosis, embolism,– thrombosis, embolism, venous hyperemia;venous hyperemia; 5.5. Endocrine pathologyEndocrine pathology – diabetes mellitus,– diabetes mellitus, hyperthyroidism;hyperthyroidism; 6.6. TumorsTumors;; 7.7. Hereditary enzymes pathologyHereditary enzymes pathology..
    11. 11. PATHOPHYSIOLOGY OF LIVER • Ethiology of liver functions violation • In the prevailing majority of cases, liver pathology is presented by two processes: 1) Hepatitis – liver inflammation; 2) Cirrhosis – the intensified diffuse growth of the new connective liver tissue (stroma) on the background of dystrophic and necrotic hepatocytes (parenchyma) damage.
    12. 12. Liver diseases pathogenesis is characterized by two main mechanisms: - the direct hepatocytes affection:the direct hepatocytes affection: a)a) dystrophy,dystrophy, b)b) necrosis;necrosis; -- autoimmune injury of hepatocytes byof hepatocytes by autoantibodies,, which are formed in response to hepatocyteswhich are formed in response to hepatocytes antigens structure changed.antigens structure changed.  Liver affection by any of the above described etiologicLiver affection by any of the above described etiologic factors may lead to such state, when the liverfactors may lead to such state, when the liver becomes not capable to execute its functions and tobecomes not capable to execute its functions and to provide the homeostasis. That state is called theprovide the homeostasis. That state is called the liver insufficiency..  It may beIt may be total, when all functions are suppressed;, when all functions are suppressed;  oror partial, when only some functions suffer, e.g., the, when only some functions suffer, e.g., the bile-forming one.bile-forming one.
    13. 13. Metabolic function failureMetabolic function failure  Liver is the central organ of the chemical homeostasis.Liver is the central organ of the chemical homeostasis. It is placed between theIt is placed between the collar veincollar vein from one side,from one side, and theand the systemic circulationsystemic circulation from the other. Itsfrom the other. Its placement should be recognized as the optimal oneplacement should be recognized as the optimal one for the execution of the metabolic function.for the execution of the metabolic function.  All substances coming with food, excluding only those,All substances coming with food, excluding only those, which are transported via mesentery lymphaticwhich are transported via mesentery lymphatic vessels into the breast blood stream, must go throughvessels into the breast blood stream, must go through the liver. Only in such way, with liver participation,the liver. Only in such way, with liver participation, food is either decomposed, or expelled, or is either decomposed, or expelled, or deposited.  TheThe metabolic liver functionmetabolic liver function means livermeans liver participation in the chemical elements metabolism ofparticipation in the chemical elements metabolism of almost all classes – carbons, fats, proteins, enzymes,almost all classes – carbons, fats, proteins, enzymes, vitamins.vitamins. HepatocytesHepatocytes affection negativelyaffection negatively influences each of those metabolisms.influences each of those metabolisms.
    14. 14. Carbohydrate  metabolism disorderCarbohydrate  metabolism disorder  GlycogenGlycogen synthesis and its splitting are the main regulatorysynthesis and its splitting are the main regulatory processes, with the help of which liver keeps glucoseprocesses, with the help of which liver keeps glucose homeostasis, particularly its level in blood. The slowing-downhomeostasis, particularly its level in blood. The slowing-down of glycogen synthesis may happen at any hepatocytesof glycogen synthesis may happen at any hepatocytes affection. That leads to the simultaneous limitation ofaffection. That leads to the simultaneous limitation of glucuronic acid formation, which is indispensable inglucuronic acid formation, which is indispensable in disintoxication of many exogenic poisons (industrial toxins)disintoxication of many exogenic poisons (industrial toxins) and final metabolites (cadaverine, putrescine) andand final metabolites (cadaverine, putrescine) and unconjugated bilirubin.unconjugated bilirubin.  TheThe slowing-down of glycogen splittingslowing-down of glycogen splitting in liver is conditionedin liver is conditioned by corresponding enzymes defect or their total corresponding enzymes defect or their total absence. The diseases belonging to that group are calledThe diseases belonging to that group are called glycogenosises, all being of inheritable origin. They areglycogenosises, all being of inheritable origin. They are manifested by glycogen accumulation in liver, bymanifested by glycogen accumulation in liver, by hepatomegaly and hypoglycemia. Several forms arehepatomegaly and hypoglycemia. Several forms are distinguished among them, depending which enzymes is notdistinguished among them, depending which enzymes is not synthesized.synthesized.
    15. 15. 1.1. The slowing-down of glycogenThe slowing-down of glycogen synthesissynthesis ((limitation oflimitation of glucuronic acid formationglucuronic acid formation,, which leads to accumulation of manywhich leads to accumulation of many exogenic poisons (industrial toxins) and final metabolitesexogenic poisons (industrial toxins) and final metabolites (cadaverine, putrescine) and unconjugated bilirubin.(cadaverine, putrescine) and unconjugated bilirubin. 2.2. Slowing-down of glycogenSlowing-down of glycogen dissociation (dissociation (glycogenosisglycogenosis –– hereditary diseaseshereditary diseases,, which is due towhich is due to enzymesenzymes abnormality andabnormality and lead to deposit oflead to deposit of glycogenglycogen and carbohydrate liver dystrophyand carbohydrate liver dystrophy ExamplesExamples:: Glycogenosis I typeGlycogenosis I type ((HirkeHirke’s’s diseasedisease) –) – defect of glucose-6-defect of glucose-6- phosphatasephosphatase Glycogenosis III typeGlycogenosis III type ((KorrKorry’sy’s disease, Forbsdisease, Forbs’s’s diseasedisease) –) – deficitdeficit of amilo-1,6-glucosidaseof amilo-1,6-glucosidase Glycogenosis VI type (Glycogenosis VI type (Gers’s diseaseGers’s disease)) –– deficit of liverdeficit of liver phosphorilase complex – proteinkinase, phosphorilase kinasephosphorilase complex – proteinkinase, phosphorilase kinase and phosphorilaseand phosphorilase Manifestations:Manifestations: hepatomegalia and hypoglycemiahepatomegalia and hypoglycemia Carbohydrate metabolism disorderCarbohydrate metabolism disorder
    16. 16. Glycogenosis of type I • Type 1= Von Gierke’s: – Shortly after birth: Severe lifethreatening Hypoglycemia – Lactic acidosis –due to isolated glycolysis of glucose-6-phosphateglucose-6-phosphate (G-6-Ph). – Hyper-uricemia, hyper lipidemiaHyper-uricemia, hyper lipidemia – Increased association with epistaxis – *HepatomegalyHepatomegaly – **Adverse response to Glucagon with worsening Lactic acidosis • Management requires IV glucose, and then as outpt, close NG corn-starch or glucose solution administration to achieve close to nl glucose homeostasis. • Frequent snacks and meals. Continuous nighttime glucose infusions up to the age of 2.
    17. 17. Glycogenosis of type IIIGlycogenosis of type III Glycogenosis of type IIIGlycogenosis of type III ((Korri disease, ForbsKorri disease, Forbs diseasedisease, so called debrancher, so called debrancher enzyme defect) is the deficit ofenzyme defect) is the deficit of amilo-1,6-glucosidase, theamilo-1,6-glucosidase, the enzymes, which breaks theenzymes, which breaks the connections in the places ofconnections in the places of glycogen molecule branching.glycogen molecule branching. That is why the branchedThat is why the branched molecule does not turn into amolecule does not turn into a direct chain of glucosedirect chain of glucose monomers.monomers.  In response to the decrease ofIn response to the decrease of glucose level in blood,glucose level in blood, glycogen is rended only to theglycogen is rended only to the branching areas. In the result ofbranching areas. In the result of that, a lot of unsplittedthat, a lot of unsplitted glycogen accumulates inglycogen accumulates in hepatocyteshepatocytes.. Hepatomegalia,Hepatomegalia, hypoglycemiahypoglycemia andand crampscramps take place. However, some parttake place. However, some part of glucose does come intoof glucose does come into blood.blood. Glycogen in the Liver (left stained to show glycogen, right normal) Glycogen in Muscle Cells
    18. 18. Type VІ  glycogenosis – Hers’ diseaseType VІ  glycogenosis – Hers’ disease  Illness arises as result of insufficiency ofIllness arises as result of insufficiency of hepatic phosphorilase complex. Glycogenhepatic phosphorilase complex. Glycogen accumulates in liver. Typical sign isaccumulates in liver. Typical sign is hepatomegalia.hepatomegalia.
    19. 19. Fat metabolism disorder. Liver fatty infiltration • One of the most striking liver functions is the critical evaluation of the correlation among food substances, which come to it from the stomach via the collar vein. If there is no balance in food ingredients, the liver reacts very peculiarly – it takes for a temporal depositing the surplus substances and stores them until the necessary product appears to construct macromolecules and to expel them into blood. At pathologic conditions, liver stores mainly fats. That phenomenon is called the fats liver infiltration. • Exogenic triglycerides are hydrolyzed in the intestines, and in enterocytes they are resynthesized and come into the liver as a part of hylomicrones. They come into hepatocytes and are decomposed to fatty acids and glycerin. Fatty acids are partly oxidized and partly participate in the formation of triglycerides, phospholipids and cholesterin ethers. The formed triglycerides are expelled by the liver into blood in the form of lipoproteides of very low and of low density. • The production of lipoproteides by the liver demands the close linkage of the processes of lipidic and albumin synthesizes. The availability of the starting products is also indispensable, but in the balance amount. The reason of fats infiltration can be any agent, which violates this balance in such way, that lipids amount become higher in the correlation to albumins amount. In the result of that it is impossible to involve the liver lipids into the synthesis of lipoproteides and to excreta them into blood. A part of lipids deposits in liver.
    20. 20. FATTY LIVER Obesity Diabetes Toxic
    21. 21. Liver fats infiltration becomes possible in such cases: a) The increased lipolysis in the fat tissue, most often – at the decompensated diabetes mellitus. The lipidic predecessors of lipoproteides (fatty acids) are so high at diabetes patients, that they have no time to start to participate in triglycerides synthesis and the last – in lipoproteides synthesis. b) Hypoglycemia (at starvation or glycogenosis) can provoke the liver fats infiltration. In the conditions of glucose deficit, the insulin production secondarily decreases and lipolysis is activated. The excess of free fat acids, which come into the liver, can exceed the abilities to join triglycerides into lipoproteides. The incompatibility between the delivery and synthesis processes provokes the fats infiltration. c) Lipoproteides production and fats expelling from the liver decrease in the conditions, when sources of aminoacids are restricted (e.g., at albumin starvation), thus apoproteines synthesis is decreased. Lipides, as raw material for lipoproteides synthesis, remain unused because the deficit of protein component.
    22. 22. Liver fats infiltration becomes possible in such cases: d) The fatty infiltration can be caused by the lipotropic aminoacids deficit (choline and metionine) in food. e) The same picture can be caused by B12 – hypovitaminosis and folic acid deficit, because it is caused by endogenic choline deficit. f) The fatty infiltration can be also conditioned by toxins influences, for example amanitotoxine, which blockes ß- oxidixation of fatty acids in mitochondrias. g) Hypoxia is believed to be one of the important pathogenic links of fatty infiltration. All factors, which cause the lasting hypoxia or suppress mitochondrias, the limit of hepatocytes energy synthezise, lead to the fatty distrophy of the liver.
    23. 23. Protein metabolism infringementProtein metabolism infringement • The main consequences of albumin metabolism infringement at the liver affection are as follows: a) Hypoproteinemia is the result of blood level decrease of albumins, α- and β-globulins, which are synthesized by hepatocytes. It leads to hypooncia and as the result edema develops. b) Hyper-gamma-globulinemiais the result of gamma- globulines synthesize increase by Kuffer’s cells and plasmocytes. c) Dysproteinemia is the result of macroglobulins and crioglobulins accumulation. d) Hemorrhagic syndrome in the result of the decreased synthesis of blood coagulation factors (besides VIII factor). e) The increase of blood RN (retarded nitrogen) in the result of the decreased urea synthesis and ammonia accumulation. That happens at 80% parenchyma affection. f) Increase of enzymes level in blood (aminotranspherases).
    24. 24. Microelements metabolism disorder • The well-known example is Wilson’s disease, when copper deposits in hepatocytes. Normally, the copper, which comes into a hepatocyte, is distributed among the cytoplasm and the subcellular organels. • There is a special albumin in the liver – metall-thionein, which binds copper. It functions as a temporal copper depositor. In some time, the deposited copper enters the metal-containing enzymes, or is withdrawn with bile. • Some persons have got metall-thionein with very high relation to copper, which is determined hereditary. That shifts of copper liver pool balance in such a way that leads to the drop of its secretion with bile and to the decrease of its joining the ceruloplasmin, an albumin that transports copper in blood. • At the long-term copper accumulation by abnormal metall-thionein, the binding centres satiate, and copper excess is absorbed by liver lysosomes. The metal is accumulated in hepatocytes and leads to hepatomegalia.
    25. 25. Wilson’s DiseaseWilson’s Disease • Pathogenesis:Pathogenesis: – a rare treatable genetica rare treatable genetic disorder of copperdisorder of copper metabolism.metabolism. – There is an abnormal accumulation of copper inThere is an abnormal accumulation of copper in the hepatocytes.the hepatocytes. – This is a metabolic disorder affecting basalThis is a metabolic disorder affecting basal ganglia, eyes, & kidney.ganglia, eyes, & kidney. – An autosomal recessive defect (ATP7B gene) inAn autosomal recessive defect (ATP7B gene) in ATP-mediated hepatocyte copper transport.ATP-mediated hepatocyte copper transport. – Results in lack of Cu incorporation intoResults in lack of Cu incorporation into ceruloplasminceruloplasmin.. – The serum ceruloplasm & copper are both lowThe serum ceruloplasm & copper are both low (copper low because it can’t be carried)(copper low because it can’t be carried)
    26. 26. Antitoxic function disorder •  The antitoxic liver function aggravation is connected to the  violation of certain reactions directed to rendering harmless  the toxic substances, which are formed in an organism or  come from outside:      a) Urea synthesis disorder resulting in ammonia  accumulations.      b) Conjugation disorder, i.e. the formation of pair compounds  with glucuronic acid, glycin, cystine, taurine. In such way  unconjugated bilirubin, scatol, indol, phenol, kadaverin,  thyramin, etc. become harmless.  c) Acetylization disorder leading to  sulphamides accumulation at their long- term usage.  d) Oxidization disorder leading to the  accumulation of aromatic carbons. Deep disorders of the antitoxic liver  function bring forward liver  encephalopathy and liver comaencephalopathy and liver coma.
    27. 27. • The Hepatocerebral coma is a syndrome developing in the result of the  liver insufficiency. It is characterized by the deep affection of the central  nervous system (consciousness loss, reflexes loss, cramps, bleeding and  breathing disorders). • The most frequent liver coma reasons are as follows:                viral hepatitis, toxic liver dystrophy, cirrhosis, portal hypertensia.  • The main mechanism of the central nervous system damage is the  accumulation of toxic neurotropic substances: • a) Ammonia. In liver mytochondria urea is synthesized from ammonia.  • At liver affection, ammonia does not join the urea cycle (ornitative cycle).  Ammonia binds with α-ketoglutaric acid and forms glutaminic acid.  • Exclusion of α-ketoglutaric acid from Krebs cycle slows down ATP and  decreases energy outcome in neurons, decreases their repolarization and  function. • b) Rotting products, which are absorbed from the large intestine – phenol,  indol, skatol, kadaverine, thyramine. • c) Low-molecular fatty acids – oleic, capronic, valeric. They interact with  lipids of neurons membranes and slow down the excitement transfer. • d) Pyroracemic acid derivatives – acetoine, butylenglicol.
    28. 28. Other pathogenic links: a) Aminoacid disbalance in blood –  -   the decrease of valine, leucine, isoleucine;  -   the increase of phenylalanine, thyrosine, thryptophane,  metionine.  In the result of that, false mediators are synthesized –  oktopamine, β-phenilethyramine, which displace  noradrenaline and dophamine from synaptosomes and  block synaptic transfer to the central nervous system. b) Hypoglycemia resulting from gluconeogenesis or  glycogenolysis weakening in hepatocytes that  additionally restricts ATP synthesis in the brain. c) Hypoxia of haemic type in connection with the  blockage of the breathing surface of erythrocytes by  toxic substances. d) Hypopotassiumia as the result of the secondary  aldosteronism. e) Disorder of the acid-basic balance in neurones and  in intercellular liquid.
    29. 29. • Bile is made by all hepatocytes and consists of water, bile salts, bilirubin, cholesterol, fatty acids, lecithin, and electrolytes. Except for water, the most abundant substance in bile is bile salt. • Bile salts are synthesized in the liver from cholesterol that either has been delivered to the liver from the small intestine or synthesized directly by the liver in the process of fat metabolism. • All hepatic cells participate in making bile and each secretes bile into the small bile canaliculi that surround all liver cells. • The canaliculi empty into progressively larger ducts that ultimately join into the hepatic duct and common bile duct. These ducts deliver bile either to the gallbladder for storage or into the intestine directly. • Bile salts function in the digestion of fat and are normally recycled after use in the small intestine. • Without bile, as much as 40% of fats in the diet would not be absorbed across the intestine and so would be lost in the stool. The absorption of fat-soluble vitamins across the small intestine would be similarly affected.
    30. 30. Disorders of bile formation and secretion • Liver cells secret bile. It consists of water, bile acids, bile pigments, cholesterine,  phospholipids, fat acids, mucin and other ingredients.  • The main indicator of bile formation and bile secretion is the secretion of bile  pigments, i.e. bilirubin and its derivatives. Bilirubin is formed in SMP cells (liver,  spleen, red bone marrow) from the gem by chipping-off iron by means of  hemoxygenase (biliverdin) and further renovation by biliverdin-reductase  (unconjugated bilirubin). Its paradoxical, but the transformation of biliverdin into  bilirubin decreases the substance solutability, and its secretion becomes problematic.   • Unmconjugated bilirubin is not soluble in water. In blood, 75 % of it binds with albumin and circulates in such form. Unconjugated bilirubin approaches the  hepatocyte and binds with lipandin, the albumin placed on its surface, or with γ- albumin, which might be identical to glutation-5-transpherase. Ligandin transports  unconjugated bilirubin to microsomes, where it binds with glucuronic acid  (conjugation). The reaction is catalized by microsomic UDP-glucuroniltranspherase  (uridine-dyphosphate- glucuroniltranspherase).  • Monoglucuronide and bilirubin dyglucuronide are formed. The conjugated bilirubin is secreted into the duodenum and is removed from the organism as  stercobilin with feces and urine. A part of the conjugated bilirubin is restored up to  urobilinogen in liver ducts, gallbladder and small intestines under the influence of  microflore enzymes.  • Urobilinogen does not enter the general blood flow and normally is not excreted. It  is absorbed into the liver vein and is splitted by the liver to pirolites. • The violation of bile formation and bile excretion is manifested by characteristic syndromes: jaundice, cholemia and steatorrhea.
    31. 31. Disorders of bile formation and bile excretion Disorders of bile formation and bile excretion  Clinical syndromes 1. Jaundice (icterus) - means yellowish of skin, mucous membranes and sclera in the result of bile pigments deposit; 2. Cholemia - appears at obstructive and parenchimatous jaundices, when bile comes into the blood. It is caused by bile acids and the main symptoms are bradycardia, arterial hypotension, excitability, skin itch; 3. Steatorea - syndrome, which occurs due to violation of digestion and fats absorption. Fats are excreted with faeces. The fat-like vitamins А, D, Е, K are being lost together with fat  Clinical syndromes 1. Jaundice (icterus) - means yellowish of skin, mucous membranes and sclera in the result of bile pigments deposit; 2. Cholemia - appears at obstructive and parenchimatous jaundices, when bile comes into the blood. It is caused by bile acids and the main symptoms are bradycardia, arterial hypotension, excitability, skin itch; 3. Steatorea - syndrome, which occurs due to violation of digestion and fats absorption. Fats are excreted with faeces. The fat-like vitamins А, D, Е, K are being lost together with fat
    32. 32. JaundiceJaundice  Jaundice is the yellowish discoloration of Jaundice is the yellowish discoloration of  the skin and sclera of the eyes seen as a the skin and sclera of the eyes seen as a  result of excess bilirubin in the blood result of excess bilirubin in the blood  (greater than 1.2 mg/dL(greater than 1.2 mg/dL or <20,5 mcM/L or <20,5 mcM/L). ).   Jaundice (icterus) is detectable clinically Jaundice (icterus) is detectable clinically  when the serum bilirubin is greater than 50 when the serum bilirubin is greater than 50  μμmol/L (3 mg/dL). mol/L (3 mg/dL).   Bilirubin is a product of red blood cell Bilirubin is a product of red blood cell  breakdown. Jaundice is also referred to as breakdown. Jaundice is also referred to as  icterus. icterus.   There are three main types of jaundice: There are three main types of jaundice:  1) 1) hemolytic jaundice, hemolytic jaundice,  2) 2) intrahepatic jaundice, intrahepatic jaundice,  3) 3) extrahepatic obstructive jaundice.extrahepatic obstructive jaundice.
    33. 33. Jaundice (icterus) • This means yellowishing of skin, mucous membranes and sclera in the result of bile pigments depositing in them. There are three types of jaundice: A. Hemolytic jaundice, conditioned by the surplus formation of unconjugated bilirubin or by the violation of its transportation. B. Parenchimatous jaundice, conditioned by hepatocytes pathology. C. Obstructive jaundice, which takes place on the basis of the insufficient bile outflow. • The normal plasma concentration of bilirubin is maximally 17 μmol/L  (1,2 mg/dL). If it rises to more than 30 μmol/L, the sclera become yellow; if  the concentration rises further, the skin turns yellow as well (jaundice [icterus]). Several forms can be distinguished:
    34. 34. • Appears, as a rule, in the result  of the excess erythrocytes haemolysis. Its reasons are  the same as for the haemolytic anaemia.  • The special features of bile  pigments exchange at this  jaundice are as follows:  1) in the blood – high level of  unconjugated bilirubin;  2) in the feaces – stercobilin  concentration is increased;  3) in the urine – stercobilin  concentration is increased too,  4)  no cholemia.
    35. 35. Inheritable hepaticInheritable hepatic jaundicejaundice  The basis ofThe basis of inheritable hepatic jaundiceinheritable hepatic jaundice is theis the violations of theviolations of the unconjugated bilirubinunconjugated bilirubin capture bycapture by hepatocytes, its insufficient conjugation or itshepatocytes, its insufficient conjugation or its insufficientinsufficient isolation of the conjugated bilirubin fromisolation of the conjugated bilirubin from the hepatocytethe hepatocyte..  The insufficient capture of the unconjugated bilirubinThe insufficient capture of the unconjugated bilirubin brings forwardbrings forward Jilbert’s syndromeJilbert’s syndrome. The genetic. The genetic defect means the blockage of ligandin (defect means the blockage of ligandin (γ-albuminγ-albumin)) synthesis, whichsynthesis, which transports unconjugated bilirubintransports unconjugated bilirubin through the membrane to thethrough the membrane to the inside of theinside of the
    36. 36. Differential Diagnosis of Hereditary Jaundice with Normal Liver Differential Diagnosis of Hereditary Jaundice with Normal Liver  Chemistries & No Signs or Symptoms of Liver DiseaseChemistries & No Signs or Symptoms of Liver Disease Unconjugated HyperbilirubinemiaUnconjugated Hyperbilirubinemia Crigler-Najjar Syndrome Gilbert’s Type I Type II Incidence Inheritance mode Serum bilirubin usual total (mg/dL) Defect Age at onset of jaundice <7% of pop’n Very rare Uncommon AD AR AD <3; <6 >20 <20 Mostly B1; inc. All indirect All indirect with fasting Hepatic UDP-glucuronyl transferase activity Decreased Absent Marked dec. Adolescence Infancy Childhood, adolescence
    37. 37. Differential Diagnosis of Hereditary Jaundice with Differential Diagnosis of Hereditary Jaundice with  Normal Liver Chemistries & No Signs or Symptoms of Normal Liver Chemistries & No Signs or Symptoms of  Liver DiseaseLiver Disease Unconjugated HyperbilirubinemiaUnconjugated Hyperbilirubinemia Crigler-Najjar Syndrome Gilbert’s Type I Type II Usual clinical features Liver biopsy Treatment Appear in early Jaundice, Asymptomatic adulthood; kernicterus in jaundice, often 1st re- infants, kernicterus cognized w/ young adults rare fasting Normal Normal Normal Not needed Liver transplant Phenobarbital
    38. 38. InheritableInheritable hepatichepatic jaundicejaundiceThe low intensity of conjugationThe low intensity of conjugation depends on the defecit of UDP-depends on the defecit of UDP- glucuroniltranspherasa ofglucuroniltranspherasa of hepatocytes.hepatocytes. Krigler-NayarKrigler-Nayar syndromesyndrome takes place.takes place. At theAt the total absence of the enzymestotal absence of the enzymes ((type Itype I)), the classic, the classic bilirubinousbilirubinous encephalopathy developsencephalopathy develops; at autopsy the nucleus; at autopsy the nucleus jaundice is found out. Thejaundice is found out. The majority of sick children diemajority of sick children die, and, and those, who don’t,those, who don’t, suffer with choreoathetosissuffer with choreoathetosis.. Child’s brainChild’s brain is especially disposed to the development ofis especially disposed to the development of bilirubinous encephalopathybilirubinous encephalopathy within the first weeks orwithin the first weeks or months of life.months of life. AtAt type IItype II thethe conjugative ability of hepatocytesconjugative ability of hepatocytes increasesincreases afterafter phenobarbitalphenobarbital introduction. Theintroduction. The introduction this substance within 2-3 weeksintroduction this substance within 2-3 weeks normalizes bilirubin level in blood.normalizes bilirubin level in blood.
    39. 39. Differential Diagnosis of Hereditary Jaundice with NormalDifferential Diagnosis of Hereditary Jaundice with Normal Liver Chemistries & No Signs or Symptoms of Liver DiseaseLiver Chemistries & No Signs or Symptoms of Liver Disease Conjugated HyperbilirubinemiaConjugated Hyperbilirubinemia Dubin-Johnson Rotor’s Syndrome Incidence Inheritance mode Serum bilirubin usual total (mg/dL) Defect Urine total coproporphyrin Age at onset of jaundice Usual clinical features Oral cholecystogram Liver biopsy Treatment Uncommon AR 2-7; < 25 Direct ~ 60% Impaired biliary excretion Normal Childhood, adolescence Asymptomatic jaundice in young adults GB not visualized Charac. Pigment (black liver → metabolites of catecholamines) Not needed Rare AR 2-7; < 20 Direct ~ 60% Impaired biliary excretion Increased Adolescence, early adulthood Asymptomatic jaundice Normal No pigment None
    40. 40. Inheritable hepatic jaundice  The laboured discard of the conjugated bilirubin from the hepatocyte into the bile is  clinically displayed by two syndromes:   The acquired liver jaundice is connected with the  hepatocytes affection by virus, toxic and other  agents.   Its pathogenic mechanism is the decrease of  conjugation processes. Dubin-JohnsonDubin-Johnson RotorRotor
    41. 41. Parenchymatous jaundice is  conditioned by endogenic  (inheritable) and outside  influences. Parenchymatous jaundiceParenchymatous jaundice is  characterized by the following  violations of bile pigments  metabolism:  A) in the blood – the  unconjugated bilirubin  concentration is increased and the  conjugated bilirubin appears;  B) in the feces – stercobilin  drops;  C) in the urine – stercobilin drops,  the appearance of urobilin and  conjugated bilirubin.
    42. 42. Cholelithiasis (pigmental stones) • Obstructive jaundice is connected with the  obstruction for bile outflow (tumour, cholelithiasis). • Peculiarities of bile pigments metabolism at this type  of jaundice are as follows:  • in the blood – the conjugated bilirubin usually are          elevated; Blood levels of bile acids often are elevated  in obstructive jaundice. • Feces – clay colored because of the lack of                                   bilirubin in the bile;  • Urine - is dark. • Cholemic syndrome appears at obstructive and  parenchimatous jaundices, when bile comes into blood. It is caused by bile acids and the main  symptoms are: 1. bradycardia,  2. hypotension,  3. excitability,  4. skin itch. • Steatorea is a syndrome, which is based on the  violation of digestion and fats absorption. Fats  are excreted with feces. The fat-like vitamins are 
    43. 43. Comparison of Jaundice Comparison of Jaundice  (Cholestatic & Hepatocelllular)(Cholestatic & Hepatocelllular) Hepatocellular Cholestasis Infiltration Disease example Acute viral hep. CBD stone Metastatic tumor Serum bilirubin (mg/dL) 4 – 8 6 – 20* Usually <4, often  normal AST, ALT (U/mL) Markedly inc.,  often 500-1,000 May be sl. Inc., <  200 May be slightly  inc., < 100 Serum ALP 1-2x normal 3-5x normal 2-4x normal PT Inc. in severe  disease Inc. in chronic  cases Normal Response to parenteral vit. K No Yes  *Serum bilirubin > 10 mg/dL is rarely seen with CBD stone and usually indicates carcinoma.
    44. 44. Liver Function Tests: Normal Values & Changes TestsTests Normal ValuesNormal Values HepatocellularHepatocellular JaundiceJaundice UncomplicatedUncomplicated ObstructiveObstructive JaundiceJaundice BilirubinBilirubin       DirectDirect       IndirectIndirect 0.1-0.3 mg/dL0.1-0.3 mg/dL 0.2-0.7 mg/dL0.2-0.7 mg/dL IncreasedIncreased IncreasedIncreased IncreasedIncreased Increased Increased  Urine bilirubinUrine bilirubin NoneNone IncreasedIncreased IncreasedIncreased Serum albumin/ Serum albumin/  total proteintotal protein Alb, 3.5-5.5 g/dLAlb, 3.5-5.5 g/dL Tot, 6.5-8.4 g/dLTot, 6.5-8.4 g/dL Albumin Albumin  decreaseddecreased UnchangedUnchanged Alk phosAlk phos 30-115 IU/L30-115 IU/L Increased (+)Increased (+) Increased (++++)Increased (++++) Prothrombin timeProthrombin time INR of 1.0-1.4; 10% INR of 1.0-1.4; 10%  inc. after vit K in 24 inc. after vit K in 24  hrshrs No response to No response to  parenteral vit. K; parenteral vit. K;  prolongedprolonged Prolonged but Prolonged but  responds to responds to  parenteral vit. Kparenteral vit. K ALT, ASTALT, AST ALT: 5-35 IU/LALT: 5-35 IU/L AST: 5-40 IU/LAST: 5-40 IU/L Inc. in hepato- Inc. in hepato-  cellular damage, cellular damage,  viral hepatitisviral hepatitis Minimally increasedMinimally increased
    45. 45. What is Hepatitis?What is Hepatitis?  Inflammation of the liverInflammation of the liver  Caused by viruses, alcohol, medications, andCaused by viruses, alcohol, medications, and other toxinsother toxins  This training will focus on viral hepatitisThis training will focus on viral hepatitis  Hepatitis A Virus (HAV)Hepatitis A Virus (HAV)  Hepatitis B Virus (HBV)Hepatitis B Virus (HBV)  Hepatitis C Virus (HCV)Hepatitis C Virus (HCV)  Hepatitis D Virus (HDV)Hepatitis D Virus (HDV)  Hepatitis E Virus (HEV)Hepatitis E Virus (HEV)  Hepatitis F  Hepatitis G (not confirmed yet). These viruses all affect the liver but otherwise are unique
    46. 46. Acute HepatitisAcute Hepatitis  Hepatitis can be defined as a constellation of signs & symptoms resulting from inflammation & hepatic cell necrosis  In a previously asymptomatic individual the term “acute” is applied  Virus is the most common cause of hepatitis.  Only occasionally can bacterial infections like syphilis or TB be considered  Most cases of acute hepatitis are sub-clinical & usually undiagnosed
    47. 47. Hepatitis A (HAV)Hepatitis A (HAV) At one time, hepatitis A was referred to as "infectious hepatitis" because it could be spread from person to person like other viral infections. Infection with hepatitis A virus can be spread through the ingestion of food or water, especially where unsanitary conditions allow water or food to become contaminated by human waste containing hepatitis  Found in the stool (feces) of personsFound in the stool (feces) of persons infected with hepatitis A virusinfected with hepatitis A virus  HAV is usually spread by “fecal-oralHAV is usually spread by “fecal-oral transmission”transmission” – Putting something in the mouth (food,Putting something in the mouth (food, water, hands) that has beenwater, hands) that has been contaminated with the stool of acontaminated with the stool of a person with hepatitis Aperson with hepatitis A – Most infections come from contactMost infections come from contact with a household member or sexwith a household member or sex partner who has hepatitis Apartner who has hepatitis A  Highly infectious and stable inHighly infectious and stable in environment for monthsenvironment for months
    48. 48. Signs andSigns and Symptoms of HAVSymptoms of HAV  jaundicejaundice  fatiguefatigue  abdominal painabdominal pain  loss of appetiteloss of appetite  nauseanausea  diarrheadiarrhea  feverfever Adults have signs and symptomsAdults have signs and symptoms more often than childrenmore often than children Incubation Period: 15-50 days (average 28 days)
    49. 49. Hepatitis B (HBV)Hepatitis B (HBV) Type B hepatitis was at one time referred to as "serum hepatitis," because it was thought that the only way hepatitis B virus (HBV) could spread was through blood or serum About 6-10% of patients with hepatitis B develop chronic HBV infection (infection lasting at least six months and often years to decades) and can infect others as long as they remain infected. Patients with chronic hepatitis B infection also are at risk of developing cirrhosis, liver failure and liver cancer.  HBV is spread throughHBV is spread through  unprotected sex with an infectedunprotected sex with an infected personperson  by sharing drugs, needles, orby sharing drugs, needles, or "works" when using drugs"works" when using drugs  through needlesticks or sharpsthrough needlesticks or sharps exposures on the jobexposures on the job  from an infected mother to herfrom an infected mother to her baby during birthbaby during birth  The best way to protect against HBVThe best way to protect against HBV isis vaccinationvaccination
    50. 50. HBV Structure & AntigensHBV Structure & Antigens Dane particleDane particle HBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr) HBcAg = inner core protein (a single serotype) HBeAg = secreted protein; function unknown
    51. 51. There are 4There are 4 open reading framesopen reading frames derived from the same strand (thederived from the same strand (the incomplete + strand)incomplete + strand) • SS - the 3 polypeptides of the surface antigen (- the 3 polypeptides of the surface antigen (preS1, preS2 and SpreS1, preS2 and S -- produced from alternative translation start sites.produced from alternative translation start sites. • CC - the core protein- the core protein • PP - the polymerase- the polymerase • XX - a transactivator of viral transcription (and cellular genes?).- a transactivator of viral transcription (and cellular genes?). HBx is conserved in all mammalian (but not avian) hepadnaviruses.HBx is conserved in all mammalian (but not avian) hepadnaviruses. Though not essential in transfected cells, it is required for infectionThough not essential in transfected cells, it is required for infection in vivo. Open Reading Frames
    52. 52. Type C hepatitis was previously referred to as "non-A, non-B hepatitis, Patients with chronic hepatitis C infection are at risk for developing cirrhosis, liver failure, and liver cancer. The hepatitis C virus (HCV) usually is spread by shared needles among drug abusers, blood transfusion, hemodialysis, and needle sticks. Approximately 90% of transfusion-associated hepatitis is caused by hepatitis C Hepatitis C (HCV) Preventing HCV InfectionPreventing HCV Infection  There isThere is nono vaccinevaccine  Best prevention is behaviorBest prevention is behavior changechange  Do not shoot drugsDo not shoot drugs  Do not share personal itemsDo not share personal items such as razors or toothbrushessuch as razors or toothbrushes  Avoid tattoos or body piercingAvoid tattoos or body piercing
    53. 53. Symptoms of HCVSymptoms of HCV  jaundicejaundice  fatiguefatigue  dark urinedark urine  abdominal pain abdominal pain   loss of appetiteloss of appetite  nauseanausea 80% of persons have no signs or symptoms80% of persons have no signs or symptoms Incubation Period: 14-180 days (average 45 days)Incubation Period: 14-180 days (average 45 days) • HCV disease does not appear to accelerate HIV diseaseHCV disease does not appear to accelerate HIV disease • Higher toxicity fromHigher toxicity from Highly Active Antiretroviral TherapyHighly Active Antiretroviral Therapy ((HAART)HAART) • As people live longer with HIV, manyAs people live longer with HIV, many more HIV deaths aremore HIV deaths are caused by HCV-related end stage liver diseasecaused by HCV-related end stage liver disease • There is still a lot of research to be done on these effectsThere is still a lot of research to be done on these effects Potential Co-Infection Effect ofPotential Co-Infection Effect of HCVHCV on HIV Diseaseon HIV Disease
    54. 54. Types D, E, F, and G HepatitisTypes D, E, F, and G Hepatitis There also are viral hepatitis types D, E, F (not confirmed yet), and G. The most important of these at present is the hepatitis D virus (HDV), also known as the delta virus or agent. It is a small virus that requires concomitant infection with hepatitis B to survive. HDV cannot survive on its own because it requires a protein that the hepatitis B virus makes (the envelope protein, also called surface antigen) to enable it to infect liver cells. Hepatitis D OverviewHepatitis D Overview Caused by hepatitis D virus (HDV)Caused by hepatitis D virus (HDV) Coined “Delta Hepatitis”Coined “Delta Hepatitis” Rarely seen in the United StatesRarely seen in the United States FoundFound onlyonly in persons infected with HBVin persons infected with HBV and has similar routes of transmission as HBVand has similar routes of transmission as HBV Prevention is vaccination for HBVPrevention is vaccination for HBV Hepatitis E OverviewHepatitis E Overview Caused by hepatitis E virusCaused by hepatitis E virus Primarily a disease of importPrimarily a disease of import Very similar to hepatitis A with fecal-oral transmissionVery similar to hepatitis A with fecal-oral transmission Transmitted like HAV with the same symptomsTransmitted like HAV with the same symptoms No vaccination available
    55. 55. HbsAHbsA gg Anti-Anti- HH BsBs Anti-Anti- HH BcBc HBeHBe AgAg Anti-Anti- HH BeBe InterpretationInterpretation ++ -- IgMIgM ++ -- Acute HBV, high infectivityAcute HBV, high infectivity ++ -- IgGIgG ++ -- Chronic HBV, high infectivityChronic HBV, high infectivity ++ -- IgGIgG -- ++ Late-acute or chronic HBV infection, lowLate-acute or chronic HBV infection, low infectivityinfectivity ++ ++ ++ +/-+/- +/-+/- Heterotypic anti-HBs with HBsAg;Heterotypic anti-HBs with HBsAg; usually indicates chronic HBV carrierusually indicates chronic HBV carrier statestate -- -- IgMIgM +/-+/- +/-+/- Acute HBV infection (anti-HBc window)Acute HBV infection (anti-HBc window) -- ++ IgGIgG -- +/-+/- Recovery from HBV infectionRecovery from HBV infection -- -- IgGIgG -- +/-+/- Low-level HBsAg carrier or remote pastLow-level HBsAg carrier or remote past infectioninfection -- ++ -- -- -- Immunization for HBV (with HBsAg)Immunization for HBV (with HBsAg)
    56. 56. Alcoholic HepatitisAlcoholic Hepatitis  An acute or chronic illness involving the liverAn acute or chronic illness involving the liver with necrosis, inflammation & scarringwith necrosis, inflammation & scarring  95% develop a fatty liver which is a reversible95% develop a fatty liver which is a reversible processprocess  Encephalopathy & death 20%Encephalopathy & death 20%  30% go on to cirrhosis within 6 month30% go on to cirrhosis within 6 month  50% of those abstaining for 6 month recover50% of those abstaining for 6 month recover completelycompletely
    57. 57. Alcoholic HepatitisAlcoholic Hepatitis SymptomsSymptoms  Most patients are symptomatic.Most patients are symptomatic.  The most common complaints are:The most common complaints are:  Anorexia, nausea, vomitingAnorexia, nausea, vomiting  Abdominal pain (RUQ)Abdominal pain (RUQ)  Fever (due to infection or inflammation of liver)Fever (due to infection or inflammation of liver)  Weight loss due to anorexiaWeight loss due to anorexia  Jaundice is usually mildJaundice is usually mild  Diarrhea which is due to portal hypertensionDiarrhea which is due to portal hypertension
    58. 58. Alcoholic Liver DiseaseAlcoholic Liver Disease Characteristics:Characteristics: 1.1. Hepatocyte swelling & necrosisHepatocyte swelling & necrosis  ballooning due toballooning due to accumulation of fat, water &accumulation of fat, water & proteinsproteins 2.2. Mallory bodiesMallory bodies – eosinophilic– eosinophilic cytoplasmic inclusions incytoplasmic inclusions in degenerating hepatocytesdegenerating hepatocytes 3.3. Neutrophilic reactionNeutrophilic reaction –– accumulate around degeneratingaccumulate around degenerating hepatocytes (“satellitosis”)hepatocytes (“satellitosis”) 4.4. FibrosisFibrosis – (+) activation of– (+) activation of sinusoidal stellate cells & portalsinusoidal stellate cells & portal tract fibroblaststract fibroblasts Alcoholic HepatitisAlcoholic Hepatitis
    59. 59. Histological features of alcoholic hepatitis. (B) (Black arrows) Mallory bodies are irregular eosinophilic cytoplasmic structures with a rope-like appearance. (Open arrow) Ballooning degeneration of hepatocytes.
    60. 60. Alcoholic Hepatitis Physical Findings • Jaundice • Spider angiomas • Palmar erythema • Clubbing of fingers • Gynecomastia • Hepatomegaly • Splenomegaly • Pruritis • Ascites • Edema • Caput medusa • Testicle atrophy • Dark urine, light
    61. 61. Alcoholic HepatitisAlcoholic Hepatitis Damage to liver causesDamage to liver causes Hepatic insufficiency:Hepatic insufficiency: which is responsiblewhich is responsible for the following:for the following: – ComaComa – JaundiceJaundice – AscitesAscites – AnemiaAnemia – Hemorrhagic tendencyHemorrhagic tendency – Ankle edemaAnkle edema Hyperestrinism:Hyperestrinism: whichwhich is responsible for:is responsible for: – Spider neviSpider nevi – AlopeciaAlopecia – GynecomastiaGynecomastia – Palmar erythemaPalmar erythema – Testicle atrophyTesticle atrophy
    62. 62. Alcoholic Liver DiseaseAlcoholic Liver Disease 1.1. Alcohol through action of alcohol DH & acetaldehydeAlcohol through action of alcohol DH & acetaldehyde DHDH  excess NADH + Hexcess NADH + H++  increased lipidincreased lipid biosynthesisbiosynthesis 2.2. Impaired assembly & secretion of lipoproteins +Impaired assembly & secretion of lipoproteins + increased peripheral fat catabolismincreased peripheral fat catabolism  fatty liverfatty liver 3.3. Impaired hepatic methionine catabolismImpaired hepatic methionine catabolism  dec.dec. intrahepatic glutathione (GSH) levelsintrahepatic glutathione (GSH) levels  inc. sensitivityinc. sensitivity to oxidative injuryto oxidative injury 4. Induction of cytochrome P450 (a) CYP2E1  inc. alcohol catabolism in ER & inc. conversion of other drugs to toxic metabolites (b) production of reactive O2 species  damage membrane hepatocellular dysfunction
    63. 63. Alcoholic Liver DiseaseAlcoholic Liver Disease 5. Impaired microtubular and mitochondrial function 6. Alcohol  acetaldehyde  (+) lipid peroxidation  disrupt cytoskeletal and membrane function 7.7. Become a major caloric sourceBecome a major caloric source  displace other nutrientsdisplace other nutrients  (+) malnutrition and vitamin deficiencies(+) malnutrition and vitamin deficiencies 8.8. Lead to chronic gastritis, intestinal mucosal damage andLead to chronic gastritis, intestinal mucosal damage and pancreatitispancreatitis  impaired digestive functionimpaired digestive function 9.9. Induce release of bacterial endotoxin into portal circulationInduce release of bacterial endotoxin into portal circulation from gutfrom gut  (+) liver inflammation(+) liver inflammation 10.10. Induce release ofInduce release of endothelinsendothelins from sinusoidal endothelialfrom sinusoidal endothelial cellscells  (+) vasoconstriction & contraction of stellate cells(+) vasoconstriction & contraction of stellate cells  dec. hepatic sinusoidal perfusiondec. hepatic sinusoidal perfusion  regional hypoxiaregional hypoxia Alcohol EffectsAlcohol Effects
    64. 64. • Occurs in patients who are not heavy drinkersOccurs in patients who are not heavy drinkers • Strong association withStrong association with obesity, dyslipidemiaobesity, dyslipidemia and insulin resistance, and overt type 2 DMand insulin resistance, and overt type 2 DM • Presents only with elevated serum amino-Presents only with elevated serum amino- transferases and/or GGTtransferases and/or GGT • (+) accumulation of triglycerides within(+) accumulation of triglycerides within hepatocyteshepatocytes • Progress toProgress to non-alcoholic steatohepatitisnon-alcoholic steatohepatitis (NASH)(NASH)  CIRRHOSISCIRRHOSIS
    65. 65. Chronic HepatitisChronic Hepatitis ►Forms:Forms:  A.A. Chronic Active HepatitisChronic Active Hepatitis:: ►Refers to the form of CH were the liver test & histologyRefers to the form of CH were the liver test & histology are compatible with active & progressive inflammation &are compatible with active & progressive inflammation & necrosisnecrosis  B.B. Chronic Persistent HepatitisChronic Persistent Hepatitis:: ►Refers to the mild & histological non progressive CHRefers to the mild & histological non progressive CH where the inflammation is confirmed only to the portalwhere the inflammation is confirmed only to the portal tracts. The enzymes are normal or only moderatelytracts. The enzymes are normal or only moderately elevated.elevated.
    66. 66. Inherited Chronic LiverInherited Chronic Liver DisordersDisorders A. Wilson’s diseaseA. Wilson’s disease B. HemachromatosisB. Hemachromatosis C. Alpha 1-antitrypsinC. Alpha 1-antitrypsin deficiencydeficiency D. Reye syndromeD. Reye syndrome
    67. 67. HaemochromatosisHaemochromatosis  PathogenisisPathogenisis: A group of: A group of disorders withdisorders with excessiveexcessive absorption of iron.absorption of iron.  The iron is layed down inThe iron is layed down in liver, heart, pancrease,liver, heart, pancrease, kidney, & skin (bronzekidney, & skin (bronze diabetes)diabetes)  Primary is due to mutationPrimary is due to mutation in the HFE gene, usuallyin the HFE gene, usually C282YC282Y (cystein is replaced by(cystein is replaced by tyrosine at amino acid 282)tyrosine at amino acid 282)  Secondary - Iron overloadSecondary - Iron overload :: • Anemias; Cirrhosis;Anemias; Cirrhosis; • DietaryDietary  DiagnosisDiagnosis:: • Lethargy, weakness inLethargy, weakness in men 40-60 40-60 y.o. • Skin hyperpigmentationSkin hyperpigmentation • Diabetes 30-60% of pt’sDiabetes 30-60% of pt’s • arthopathyarthopathy Treatment - phlebotomy
    68. 68. Alpha 1-AntitrypsinAlpha 1-Antitrypsin DeficiencyDeficiency In children associated liver diseaseIn children associated liver disease In teenagers & adults, aIn teenagers & adults, a progressive liver disease withprogressive liver disease with pulmonary manifestationspulmonary manifestations Pathogenesis:Pathogenesis: Alpha 1-trypsin is aAlpha 1-trypsin is a potent protease inhibitor found inpotent protease inhibitor found in the serum, body fluids, & tissuesthe serum, body fluids, & tissues It is synthesized by the liver toIt is synthesized by the liver to protect from tissue injury resultingprotect from tissue injury resulting from protease like trypsinfrom protease like trypsin
    69. 69. Reye’s SyndromeReye’s Syndrome  An illness seen in the pediatric age groupAn illness seen in the pediatric age group associated with the fluassociated with the flu  Symptoms: Nausea, vomiting, hyperactivity,Symptoms: Nausea, vomiting, hyperactivity, confusion, seizures, & coma, Increasingconfusion, seizures, & coma, Increasing drowsiness, Belly Painsdrowsiness, Belly Pains  On liver biopsy there are fatty infiltrationOn liver biopsy there are fatty infiltration  Chemistry: elevated liver enzymes, NH3Chemistry: elevated liver enzymes, NH3 ******NEVERNEVER givegive AspirinAspirin to children withto children with varicella infection (chicken pox), orvaricella infection (chicken pox), or during flu sx.!!!!!!!!!!during flu sx.!!!!!!!!!!
    70. 70. Occurs in young children with viralOccurs in young children with viral illness (Varicella or influenza) treatedillness (Varicella or influenza) treated with Aspirinwith Aspirin Mechanism: unknown, butMechanism: unknown, but mitochondrial injury and dysfunctionmitochondrial injury and dysfunction play an important roleplay an important role
    71. 71. REYE'S SYNDROME • only happens in kids less than 15 years old. • The cause is unknown, but it is strongly associated with Aspirin use during flu's. • The liver becomes inflamed and destroyed for unknown reasons. • It is important because Reye's syndrome kills about half of kids who get it. • NEVER give aspirin containing medications to your kids under 15 years old for fever control. • Use Acetaminophen/ Ibuprofen instead.
    72. 72. Hepatic (Liver) FailureHepatic (Liver) Failure  May result from:  A. Slow deterioration as part of a chronic progress  B. Rapid worsening after repeated injuries  C. catastrophic event such as massive necrosis  Causes:  1. Functional liver failure without overt necrosis  Reye’s syndrome, tetracycline toxicity  2. Chronic liver disease  Chronic active hepatitis  Cirrhosis  3. Fulminate failure: refers to acute severe impairment of liver function with encephalopathy & coma in patients who have had liver disease for less than 8 weeks
    73. 73. Hepatic Failure • Clinical features: 1. Jaundice 2. Hypoalbuminemia  peripheral edema 3. Hyperammonemia  cerebral dysfunction 4. Fetor hepaticus  “musty” or “sweet & sour” body odor due to mercaptan formation by action of GI bacteria on methionine (sulfur-containing) 5. Impaired estrogen metabolism  hyperestrogenemia (a) palmar erythema – 2º to local vasodilatation (b) spider angiomas – central, pulsing, dilated arteriole from which small vessels radiate (c) hypogonadism & gynecomastia in males 6. Multi-organ system failure - respiratory failure with pneumonia, sepsis + renal failure  cause of death 7. Coagulopathy - impaired synthesis of factors II, VII, IX and X  (+) bleeding tendency
    74. 74. Hepatic FailureHepatic Failure • Complications:Complications: 1.1. Hepatic encephalopathyHepatic encephalopathy  associated with increased blood ammonia levelsassociated with increased blood ammonia levels  reversible if underlying hepatic condition can be correctedreversible if underlying hepatic condition can be corrected  features:features: (a)(a) change in consciousnesschange in consciousness (b)(b) fluctuating neurologic signs – rigidity, hyperreflexia,fluctuating neurologic signs – rigidity, hyperreflexia, asterixisasterixis 2.2. Hepatorenal syndromeHepatorenal syndrome  renal failure in patients with chronic liver diseaserenal failure in patients with chronic liver disease  main renal functional abnormalities:main renal functional abnormalities: (a)(a) sodium retentionsodium retention (b)(b) impaired free water excretionimpaired free water excretion (c)(c) decreased renal perfusiondecreased renal perfusion (d)(d) decreased GFRdecreased GFR
    75. 75. Hepatic FailureHepatic Failure • Hepatic encephalopathyHepatic encephalopathy:: – A metabolic disorder of theA metabolic disorder of the CNS system &CNS system & neuromuscular system withneuromuscular system with slight changes in the brainslight changes in the brain (edema)(edema) – Clinical FeaturesClinical Features:: • ConfusionConfusion • Flapping tremorFlapping tremor (asterixis)(asterixis) • DrowsinessDrowsiness • ComaComa deathdeath Caused by elevated levels ofCaused by elevated levels of NH3 (ammonia)NH3 (ammonia)
    76. 76. CirrhosisCirrhosis • Most common cause is alcoholic liver disease • Key features: 1. The parenchymal injury & consequent fibrosis are diffuse. 2. The nodularity is part of the diagnosis  reflects balance between regeneration and scarring. 3. Vascular architecture is re-organized by the parenchymal damage and scarring  formation of abnormal interconnections
    77. 77.  Etiology: triadEtiology: triad  1. necrosis1. necrosis  2. regenerating nodules2. regenerating nodules  3. fibrosis3. fibrosis  Categories:Categories:  MajorMajor • Alcoholic (#1 cause in western world)Alcoholic (#1 cause in western world) • Post necroticPost necrotic  MinorMinor • Wilson’s diseaseWilson’s disease • HaemochromatosisHaemochromatosis • BiliaryBiliary • Chronic hepatic congestionChronic hepatic congestion  Budd-Chiari syndromeBudd-Chiari syndrome • uncommon conditionuncommon condition Induced by thromboticInduced by thrombotic or nonthromboticor nonthrombotic obstruction to hepatic venous outflowobstruction to hepatic venous outflow  CardiacCardiac • Right sided heart failureRight sided heart failure • Tricuspid insufficiencyTricuspid insufficiency CirrhosisCirrhosis
    78. 78. • Pathogenesis: Progressive fibrosis & re-organization of vascular micro-architecture of liver Collagen deposition (types I & III) in the lobule Loss of fenestration of sinusoidal endothelial cells New vascular channels in the septae Create delicate or broad septal tracts Impaired hepatocellular protein secretion (albumin, clotting factors, lipoproteins) Shunting of blood around the parenchyma
    79. 79. Pathophysiology of CirrhosisPathophysiology of Cirrhosis Intrahepatic resistanceIntrahepatic resistance Splanchnic BFSplanchnic BF Portal HPNPortal HPN Systemic HyperkineticSystemic Hyperkinetic Circulation and HypotensionCirculation and Hypotension SBPSBP PS-ShuntsPS-Shunts Activ. NeurohumoralActiv. Neurohumoral factorsfactors Variceal formationVariceal formation Hepatic EncephHepatic Enceph Sodium/Water retentionSodium/Water retention Pulmonary HPNPulmonary HPN Hepatorenal SynHepatorenal Syn AscitesAscites Didier Lubrec MD, AASLD, 2001 Fibrosis
    80. 80. Mechanism ofMechanism of fibrosis andfibrosis and cirrhosis of thecirrhosis of the liverliver
    81. 81. The characteristic diffuseThe characteristic diffuse nodularity of the surface reflectsnodularity of the surface reflects the interplay between nodularthe interplay between nodular regeneration and scarring. Theregeneration and scarring. The greenish tint of some nodules isgreenish tint of some nodules is due to bile stasis.due to bile stasis. Blind Man’sBlind Man’s DiagnosisDiagnosis
    82. 82. • Complications associated withComplications associated with cirrhosis:cirrhosis: 1.1. Hepatic failureHepatic failure a) Multiple coagulation defects b) Hypoalbuminemia due to decreased albumin synthesis  pitting edema and ascites c) Hepatic encephalopathy d) Increased serum ammonia due to defective urea cycle
    83. 83. • Complications associated with cirrhosis: 2.Portal hypertension a) Ascites b) Congestive splenomegaly c) Esophageal varices d) Hemorrhoids, periumbilical collateral circulation
    84. 84. CirrhosisCirrhosis ComplicationsComplications associated withassociated with cirrhosis:cirrhosis: 3.3. HepatorenalHepatorenal syndromesyndrome due todue to decreased renaldecreased renal blood flowblood flow 4.4. HyperestrinismHyperestrinism inin malesmales a)a) GynecomastiaGynecomastia b)b) Spider angiomasSpider angiomas c)c) FemaleFemale distribution of hairdistribution of hair
    85. 85. Portal hypertension Increased pressure in peritoneal capillaries Portosystemic shunting of blood Splenomegaly Ascites Development of collateral channels Caput medusae Esophageal varices Hemorrhoids Shunting of ammonia and toxins from the intestine into the general circulation Hepatic encephalopathy Anemia Leukopenia Bleeding Thrombocytopenia Mechanisms of disturbed liver function relatedMechanisms of disturbed liver function related to portal hypertensionto portal hypertension.
    86. 86. Portal hypertensionPortal hypertension DDevelopment of portal hypertensionevelopment of portal hypertension Characterized by, that displays byCharacterized by, that displays by triad signtriad sign:: 1)1) ascitesascites, (abdominal [peritoneal], (abdominal [peritoneal] dropsy),dropsy), 2)2) capute medusaecapute medusae – varicose veins– varicose veins of front wall of abdomen, veins ofof front wall of abdomen, veins of gullet (esophagus), and rectal veins,gullet (esophagus), and rectal veins, 3)3) splenomegalysplenomegaly..
    87. 87. AscitesAscites Pathophysiology:Pathophysiology:  Alteration of hepatic blood flow causing portal hypertension.Alteration of hepatic blood flow causing portal hypertension.  Reduction in liver function:Reduction in liver function:  Reduction in synthesis of albumin & coagulation proteinsReduction in synthesis of albumin & coagulation proteins  Reduction in detoxification of bilirubin, ammonia, & drugsReduction in detoxification of bilirubin, ammonia, & drugs  Complications of ascites:Complications of ascites: DyspneaDyspnea vomitingvomiting Decreased cardiac outputDecreased cardiac output hydrothoraxhydrothorax Anorexia scrotal edemaAnorexia scrotal edema Reflux esophagitisReflux esophagitis  Treatment:Treatment:  Improve hepatic functionImprove hepatic function  Restrict sodium & fluid intakeRestrict sodium & fluid intake  Aldactone which inhibits aldosteroneAldactone which inhibits aldosterone  Paracentesis (removal of fluid with addition of IV albumin)Paracentesis (removal of fluid with addition of IV albumin)  ShuntsShunts  Abstain from alcoholAbstain from alcohol  DiureticsDiuretics  AldactoneAldactone  LasixLasix
    88. 88. LFT’s/TransaminasesLFT’s/Transaminases  Transaminases Aspartate-Transaminases Aspartate-ASTAST (SGOT) & Alanine-(SGOT) & Alanine- ALTALT (SGPT)(SGPT):: – AST (SGOT)AST (SGOT)  is normally found in a diversity of tissues including liver, heart,is normally found in a diversity of tissues including liver, heart, muscle, kidney, and brain. It is released into serum when any onemuscle, kidney, and brain. It is released into serum when any one of these tissues is damaged.of these tissues is damaged. – For example, its level in serum rises with heart attacks and with muscleFor example, its level in serum rises with heart attacks and with muscle disorders.disorders.  It is therefore not a highly specific indicator of liver injury.It is therefore not a highly specific indicator of liver injury. – ALT (SGPT)ALT (SGPT)  is, by contrast, normally found largely in the, by contrast, normally found largely in the liver.  This is not to say that it is exclusively located in liver but that isThis is not to say that it is exclusively located in liver but that is where it is most concentrated.where it is most concentrated.  It is released into the bloodstream as the result of liver injury.It is released into the bloodstream as the result of liver injury.  It therefore serves as a fairlyIt therefore serves as a fairly specific indicator of liverspecific indicator of liver
    89. 89. AST/ALTAST/ALT   released into the circulation following hepatocyte injury orreleased into the circulation following hepatocyte injury or death.death. The ratio of AST:ALT can be helpfulThe ratio of AST:ALT can be helpful  AST:ALT > 2:1AST:ALT > 2:1 suggestingsuggesting alcoholic liver diseasealcoholic liver disease  AST:ALT < 1:1AST:ALT < 1:1 suggestingsuggesting viral hepatitisviral hepatitis..  They are sensitive, but non-specific for liver damage.They are sensitive, but non-specific for liver damage.  Need isoenzymesNeed isoenzymes  The normal range of values for AST (SGOT) is from 5 to 40The normal range of values for AST (SGOT) is from 5 to 40 units per liter of serum (the liquid part of the blood).units per liter of serum (the liquid part of the blood).  The normal range of values for ALT (SGPT) is from 7 to 56The normal range of values for ALT (SGPT) is from 7 to 56 units per liter of serum.units per liter of serum. Normal range can vary according to a number of factors, includingNormal range can vary according to a number of factors, including age and gender.age and gender.
    90. 90. AST/ALTAST/ALT  TheThe highest levels of AST and ALThighest levels of AST and ALT are found withare found with disorders that cause the death of numerous liver cellsdisorders that cause the death of numerous liver cells (extensive(extensive hepatic necrosishepatic necrosis).).  Although, the precise levels of these enzymes do notAlthough, the precise levels of these enzymes do not correlate well with the extent of liver damage or thecorrelate well with the extent of liver damage or the prognosisprognosis  This occurs in such conditions asThis occurs in such conditions as acute viral hepatitisacute viral hepatitis A or BA or B, pronounced liver damage inflicted by, pronounced liver damage inflicted by toxinstoxins as from anas from an overdose of acetaminophenoverdose of acetaminophen (Tylenol), and(Tylenol), and prolonged collapse of the circulatory systemprolonged collapse of the circulatory system (shock)(shock) when the liver is deprived of fresh blood bringingwhen the liver is deprived of fresh blood bringing oxygen and nutrientsoxygen and nutrients
    91. 91. Serum Alkaline Phosphatase-Serum Alkaline Phosphatase- (Alk Phos)(Alk Phos)  Derived from liver, intestines, bones &Derived from liver, intestines, bones & placenta.placenta.  Released causing high levels duringReleased causing high levels during liver damage, particularly necrosis,liver damage, particularly necrosis, cholestasis/ bile duct obstruction,cholestasis/ bile duct obstruction, neoplastic,neoplastic, infiltrative & granulomatous liver disease.infiltrative & granulomatous liver disease.  Need isoenzymesNeed isoenzymes
    92. 92. Pathophysiology Underlying the Symptoms and Signs of Liver Disease Symptoms/SignsSymptoms/Signs Pathophysiologic MechanismPathophysiologic Mechanism Weakness, fatigue, anorexia, weight loss, muscle wasting Failure of multiple metabolic functions Fever Liver inflammation, decreased reticuloendothelial function with increased risk of infection Bruising, increased bleeding Thrombocytopenia secondary to splenic enlargement, decreased synthesis of clotting factors 1,11, V, VII, VIII, IX. And X Palmar erythema, cutaneous spider telangiectases, irregular menses, gynecomastia, impotence, female body hair distribution in men, testicular atrophy Altered metabolism of sex hormones, chronic debilitation Hepatic encephalopathy Abnormal protein metabolism Fetor hepaticus Decreased detoxification Pruritus Decreased bile salt excretion Cyanosis Arteriovenous shunts in lungs, liver Jaundice Biliary obstruction, decreased bilirubin synthesis, decrease bilirubin excretion Hyperdynamic circulation, wide pulse pressure, tachycardia Generalized vasodilation (? Hormonally mediated) Ascites, peripheral edema Portal hypertension, sodium and water retention, low serum albumin secondary to decreased hepatic synthesis Splenomegaly Portal hypertension
    93. 93. Pathophysiology Underlying the Symptoms and Signs of Liver Disease Symptoms/SignsSymptoms/Signs Pathophysiologic MechanismPathophysiologic Mechanism Hepatomegaly Cirrhosis (liver may be small), hepatitis, vascular congestion, bile duct obstruction, infection, benign infiltrative disease (e.g., fatty liver, amyloidosis, hemochromatosis), malignant infiltrative disease (e.g., metastatic cancer, 1ymphoma, large space-occupying lesions such as neoplasm, abscess) Varices (esophageal, gastric, rectal, ectopic) or abnormal abdominal vascular pattern (caput medusae, umbilical bruit) Portal hypertension with collateral blood flow around hepatic blockage Osteomalacia, hypocalcemia, night blindness, coagulopathy Fat-soluble vitamin malabsorption and loss of fat- soluble vitamine reserves A, D, and K; loss of vitamin К metabolis (a cofactors for I, II, VII, VIII, IX, and X) Anemia Multifactorial: blood loss, chronic disease, vitamin B12 deficiency splenic sequestration Leukopenia Hypersplenism secondary to portal hypertension Hypoglycemia Altered glycogenosis, gluconeogenesis Hyperglycemia Portosystemic shunting with delayed hepatic uptake of absorbed glucose Hypercholesterolemia Obstructive jaundice with decreased cholesterol excretion
    94. 94. ReferencesReferences 1.1. Robbins and Cotran Pathologic Basis of DiseaseRobbins and Cotran Pathologic Basis of Disease 88th edition / Kumar, Abbas, Fautoth edition / Kumar, Abbas, Fauto 20020077.. – Chapter 15. – P. 600– Chapter 15. – P. 600––630.630. 2.2. Copstead Lee-Ellen C. Pathophysiology / Lee-Ellen C. Copstead, Jacquelyn L.Copstead Lee-Ellen C. Pathophysiology / Lee-Ellen C. Copstead, Jacquelyn L. Banasik // Elsevier Inc, 4th edition. – 2010. – P. 854–903.Banasik // Elsevier Inc, 4th edition. – 2010. – P. 854–903. 3.3. Corwin Elizabeth J. Handbook of Pathophysiology / Corwin Elizabeth J. – 3th edition.Corwin Elizabeth J. Handbook of Pathophysiology / Corwin Elizabeth J. – 3th edition. Copyright ВCopyright В.. – Lippincott Williams & Wilkins – 2008. –– Lippincott Williams & Wilkins – 2008. – Chapter 17. – P. 574 – 602.Chapter 17. – P. 574 – 602. 4.4. Pathophysiology, Concepts of Altered Health States, Carol Mattson Porth, GlennPathophysiology, Concepts of Altered Health States, Carol Mattson Porth, Glenn Matfin. – New York, Milwaukee. – 2009. – P. 949–974.Matfin. – New York, Milwaukee. – 2009. – P. 949–974. 5.5. General and clinical pathophysiology / Edited by Anatoliy V. Kubyshkin – Vinnytsia:General and clinical pathophysiology / Edited by Anatoliy V. Kubyshkin – Vinnytsia: Nova Knuha Publishers – 2011. – P.Nova Knuha Publishers – 2011. – P. 546546––566566.. 6.6. Essentials of Pathophysiology: Concepts of Altered Health States (Lippincott WilliamsEssentials of Pathophysiology: Concepts of Altered Health States (Lippincott Williams & Wilkins), Trade paperback (2003)& Wilkins), Trade paperback (2003) // Carol Mattson Porth, Kathryn J. GaspardCarol Mattson Porth, Kathryn J. Gaspard –– ССhapter 28. – P. 494–516.hapter 28. – P. 494–516. 7.7. Symeonova N.K. Pathophysiology / N.K. Symeonova // Kyiv, AUS medicineSymeonova N.K. Pathophysiology / N.K. Symeonova // Kyiv, AUS medicine Publishing. – 2010. – P. 434–459.Publishing. – 2010. – P. 434–459. 8.8. Russell JRussell J.. GreeneGreene.. Pathology and Therapeutics for Pharmacists. A basis for clinicalPathology and Therapeutics for Pharmacists. A basis for clinical pharmacy practicepharmacy practice // Russell JRussell J.. Greene, Norman DGreene, Norman D.. Harris // Published by theHarris // Published by the Pharmaceutical Press An imprint of RPS Publishing 1 Lambeth High Street, LondonPharmaceutical Press An imprint of RPS Publishing 1 Lambeth High Street, London SE1 7JN, UK 100 South Atkinson Road, Suite 200, Greyslake, IL 60030-7820, USASE1 7JN, UK 100 South Atkinson Road, Suite 200, Greyslake, IL 60030-7820, USA. –. – Chapter 2. – P. 138–165.Chapter 2. – P. 138–165. 9.9. SilbernaglSilbernagl S.S. Color Atlas of PathophysiologyColor Atlas of Pathophysiology / S./ S. SilbernaglSilbernagl, F., F. LangLang //// ThiemeThieme.. StuttgartStuttgart.. New YorkNew York. –. – 20002000. – P. 162–175.. – P. 162–175.