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Pathophysiology of liver

prepared by M.D., PhD Marta R. Gerasymchuk

prepared by M.D., PhD 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. Structure 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  Sinusoids  Central vein  Hepatic Veins  IVC 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. 1 0. 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 .
  • P ediatric 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 μ mol/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
  •   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 Pathophysiology of liver Presentation Transcript

  • Actuality 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.
  • CONTENT1. Microscopic architecture of the liver parenchyma.2. The liver is a big chemical laboratory.Carbohydrate, Protein, and Lipid Metabolism.1. The cases of liver pathology.2. Carbohydrate metabolism disorder in liver.3. Fat metabolism disorder. Liver fatty infiltration.4. Protein metabolism infringement.5. Microelements metabolism disorder in liver.6. Methods of experimental design of violations of function of liver.7. Functional insufficiency of liver, its etiology, pathogenesis, basic displays.8. A metabolic disturbance is at the diseases of liver. Antitoxic liver function disorder.9. An exchange of bilirubin in an organism in a norm.10. Jaundices: classification, etiology, pathogenesis, basic clinical displays of separate kinds.11. Enzymopathic jaundices (Gilberts syndrome, Crigler - Nagar syndrome, Dubin- Johnson syndrome).12. Differential diagnostics of separate types of jaundices is on the basis of information of laboratory researches of physiology liquids of organism.13. Hepatocerebral coma: pathogenesis of basic displays, medical measures14. Cirrhosis of the liver.15. Disorders of the gallbladder and extrahepatic bile ducts.
  • Liver• 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
  • Blood Supply of the LiverHepatic Arterial Autoregularity Vasodilatation
  • The following processes take place in the liver:1. The creation of bile pigments synthesis of cholesterol, synthesisand secretion of bile.2. The detoxication of toxic products, coming from gastrointestinaltract.3. The synthesis of proteins (proteins of plasma of blood amongthem), their deposition, transamination and desamination ofaminoacids, 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 (ketonebodies).6. The deposition and exchange of vitamins (А, В, D), the depositionof iron, copper, zinc ions.7. The regulation of the balance between coagulant andanticoagulant blood system, the formation of heparine.8. The destruction of some microorganisms, bacterial and othertoxins.9. The deposition of plasma of blood, the regulation of a total amountof blood.10. Hemopoiesis in the fetus.
  • Functions of the LiverType FunctionMetabolicAbsorptive 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 Produces glucose from glycogen (glycogenolysis) and fatty acids and Period amino acids (glyconogenesis). Converts fats to ketones (accelerated if fasting). Produces urea from protein catabolism.Immunologic Macrophages filter blood. Metabolic Detoxifies or conjugates waste products, hormones, drugs. TransformationClotting Functions Produces several essential clotting factors.Plasma Proteins Synthesizes albumin and other plasma proteins.Exocrine Synthesizes bile salts. FunctionsEndocrine Involved in activation of vitamin D. Produces angiotensinogen. Secretes Functions insulin-like growth factors (somatomedin).
  • 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
  • Disorders Liver Function Hepatic Test Jaundice Biliary Tract Disease  Cholelithiasis-Choledocholithiasis  Cholecystitis-Cholangitis  Biliary tract obstruction Hepatic Disease  Hepatitis Acute & Chronic A/B/C/D/E, ETOH/drug  Cirrhosis  Hepatic Failure Neoplasm (later section)
  • ETHIOLOGY ETHIOLOGYInfectious agents – hepatitis virus, Koch’s bacillus, pale Spirochaeta, Actynomyces, Echinococcuses, Ascarides;1. Hepatotropic poisons, including medicines – tetracycline, PASA (paraaminosalycil acid), sulphanilamides, industrial poisons (CCl4, arsenic, chloroform); plants poisons (aphlatoxine, muscarine);2. Physical influences – ionizing radiation;3. Biological substances – vaccines, serums;4. Blood flow violations – thrombosis, embolism, venous hyperemia;5. Endocrine pathology – diabetes mellitus, hyperthyroidism;6. Tumors;7. Hereditary enzymes pathology.
  • 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.
  • Liver diseases pathogenesis is characterized by two main mechanisms:- the direct hepatocytes affection:a) dystrophy,b) necrosis;- autoimmune injury of hepatocytes by autoantibodies, which are formed in response to hepatocytes antigens structure changed. Liver affection by any of the above described etiologic factors may lead to such state, when the liver becomes not capable to execute its functions and to provide the homeostasis. That state is called the liver insufficiency. It may be total, when all functions are suppressed; or partial, when only some functions suffer, e.g., the bile-forming one.
  • Metabolic function failure Liver is the central organ of the chemical homeostasis. It is placed between the collar vein from one side, and the systemic circulation from the other. Its placement should be recognized as the optimal one for the execution of the metabolic function. All substances coming with food, excluding only those, which are transported via mesentery lymphatic vessels into the breast blood stream, must go through the liver. Only in such way, with liver participation, food is either decomposed, or expelled, or deposited. The metabolic liver function means liver participation in the chemical elements metabolism of almost all classes – carbons, fats, proteins, enzymes, vitamins. Hepatocytes affection negatively influences each of those metabolisms.
  • Carbohydrate  metabolism disorder Glycogen synthesis and its splitting are the main regulatory processes, with the help of which liver keeps glucose homeostasis, particularly its level in blood. The slowing-down of glycogen synthesis may happen at any hepatocytes affection. That leads to the simultaneous limitation of glucuronic acid formation, which is indispensable in disintoxication of many exogenic poisons (industrial toxins) and final metabolites (cadaverine, putrescine) and unconjugated bilirubin. The slowing-down of glycogen splitting in liver is conditioned by corresponding enzymes defect or their total absence. The diseases belonging to that group are called glycogenosises, all being of inheritable origin. They are manifested by glycogen accumulation in liver, by hepatomegalia and hypoglycemia. Several forms are distinguished among them, depending which enzymes is not synthesized.
  • Carbohydrate metabolism disorder1. The slowing-down of glycogen synthesis (limitation ofglucuronic acid formation, which leads to accumulation of manyexogenic poisons (industrial toxins) and final metabolites(cadaverine, putrescine) and unconjugated bilirubin.2. Slowing-down of glycogen dissociation (glycogenosis –hereditary diseases, which is due to enzymes abnormality andlead to deposit of glycogen and carbohydrate liver dystrophyExamples:Glycogenosis I type (Hirke’s disease) – defect of glucose-6-phosphataseGlycogenosis III type (Korry’s disease, Forbs’s disease) – deficitof amilo-1,6-glucosidaseGlycogenosis VI type (Gers’s disease) – deficit of liverphosphorilase complex – proteinkinase, phosphorilase kinaseand phosphorilaseManifestations: hepatomegalia and hypoglycemia
  • Glycogenosis of type I• Type 1= Von Gierke’s: – Shortly after birth: Severe lifethreatening Hypoglycemia – Lactic acidosis –due to isolated glycolysis of glucose-6-phosphate (G-6-Ph). – Hyper-uricemia, hyper lipidemia – Increased association with epistaxis – *Hepatomegaly – **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.
  • Glycogenosis of type III Glycogenosis of type III (Korri disease, Forbs disease, so called debrancher enzyme defect) is the deficit of amilo-1,6-glucosidase, the enzymes, which breaks the connections in the places of glycogen molecule branching. Glycogen in the Liver (left stained That is why the branched to show glycogen, right normal) molecule does not turn into a direct chain of glucose monomers. In response to the decrease of glucose level in blood, glycogen is rended only to the branching areas. In the result of that, a lot of unsplitted Glycogen in Muscle Cells glycogen accumulates in hepatocytes. Hepatomegalia, hypoglycemia and cramps take place. However, some part of glucose does come into blood.
  • Type VІ  glycogenosis – Hers’ disease Illness arises as result of insufficiency of hepatic phosphorilase complex. Glycogen accumulates in liver. Typical sign is hepatomegalia.
  • 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.
  • Obesity Diabetes ToxicFATTYLIVER
  • 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.
  • 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.
  • Protein 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).
  • 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.
  • Wilson’s Disease• Pathogenesis: – a rare treatable genetic disorder of copper metabolism. – There is an abnormal accumulation of copper in the hepatocytes. – This is a metabolic disorder affecting basal ganglia, eyes, & kidney. – The defect is in the ceruloplasm which carries the copper. – The serum ceruloplasm & copper are both low (copper low b/c it can’t be carried)
  • 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 coma.
  • Hepatocerebral coma• 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, blood flowand  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.
  • 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.
  • Bile Secretion• 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.
  • 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.
  • Disor der s of bile for mationDisor der s of bile for mationand bile excretionand bile excretion   Clinical syndromes Clinical syndromes1. Jaundice (icterus) --means yellowish of skin, mucous 1. Jaundice (icterus) means yellowish of skin, mucous membranes and sclera in the result of bile membranes and sclera in the result of bile pigments deposit; pigments deposit;2. Cholemia - appears at obstructive and2. Cholemia - appears at obstructive and parenchimatous jaundices, when bile comes into parenchimatous jaundices, when bile comes into the blood. It is caused by bile acids and the main the blood. It is caused by bile acids and the main symptoms are bradycardia, arterial hypotension, symptoms are bradycardia, arterial hypotension, excitability, skin itch; excitability, skin itch;3. Steatorea --syndrome, which occurs due to violation3. Steatorea syndrome, which occurs due to violation of digestion and fats absorption. Fats are excreted of digestion and fats absorption. Fats are excreted with faeces. The fat-like vitamins А, D, Е, K are with faeces. The fat-like vitamins А, D, Е, K are being lost together with fat being lost together with fat
  • Jaundice Jaundice is the yellowish discoloration of  the skin and sclera of the eyes seen as a  result of excess bilirubin in the blood  (greater than 1.2 mg/dL or <20,5 mcM/L).  Jaundice (icterus) is detectable clinically  when the serum bilirubin is greater than 50  μmol/L (3 mg/dL).  Bilirubin is a product of red blood cell  breakdown. Jaundice is also referred to as  icterus.  There are three main types of jaundice: 1) hemolytic jaundice, 2) intrahepatic jaundice, 3) extrahepatic obstructive jaundice.
  • 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:
  • Hemolytic jaundice• 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.
  • Inheritable hepatic jaundice The basis of inheritable hepatic jaundice is the violations of the unconjugated bilirubin capture by hepatocytes, its insufficient conjugation or its insufficient isolation of the conjugated bilirubin from the hepatocyte. The insufficient capture of the unconjugated bilirubin brings forward Jilbert’s syndrome. The genetic defect means the blockage of ligandin (γ-albumin) synthesis, which transports unconjugated bilirubin through the membrane to the inside of the
  • Differential Diagnosis of Hereditary Jaundice with Normal Liver  Chemistries & No Signs or Symptoms of Liver Disease Unconjugated Hyperbilirubinemia Crigler-Najjar Syndrome Gilbert’s Type I Type IIIncidence <7% of pop’n Very rare UncommonInheritance mode AD AR ADSerum bilirubin <3; <6 >20 <20 usual total (mg/dL) Mostly B1; inc. All indirect All indirect with fastingDefect Hepatic UDP-glucuronyl transferase activity Decreased Absent Marked dec.Age at onset of Adolescence Infancy Childhood, jaundice adolescence
  • Differential Diagnosis of Hereditary Jaundice with Normal Liver Chemistries & No Signs or Symptoms of  Liver Disease Unconjugated Hyperbilirubinemia Crigler-Najjar Syndrome Gilbert’s Type I Type IIUsual clinical Appear in early Jaundice, Asymptomatic features adulthood; kernicterus in jaundice, often 1st re- infants, kernicterus cognized w/ young adults rare fastingLiver biopsy Normal Normal NormalTreatment Not needed Liver transplant Phenobarbital
  • Inheritable hepatic jaundice The low intensity of conjugation depends on the defecit of UDP-glucuroniltranspherasa of hepatocytes.  Krigler-Nayar syndrome takes place.  At the total absence of the enzymes (type I), the classic  bilirubinous encephalopathy develops; at autopsy the  nucleus jaundice is found out. The majority of sick  children die, and those, who don’t, suffer with  choreoathetosis. Child’s brain is especially disposed to  the development of bilirubinous encephalopathy within  the first weeks or months of life.  At type II the conjugative ability of hepatocytes increases  after phenobarbital introduction. The introduction this  substance within 2-3 weeks normalizes bilirubin level in  blood.
  • Differential Diagnosis of Hereditary Jaundice with NormalLiver Chemistries & No Signs or Symptoms of Liver Disease Conjugated Hyperbilirubinemia Dubin-Johnson Rotor’s SyndromeIncidence Uncommon RareInheritance mode AR ARSerum bilirubin usual 2-7; < 25 2-7; < 20 total (mg/dL) Direct ~ 60% Direct ~ 60%Defect Impaired biliary Impaired biliary excretion excretionUrine total coproporphyrin Normal IncreasedAge at onset of jaundice Childhood, Adolescence, early adolescence adulthoodUsual clinical features Asymptomatic Asymptomatic jaundice in young jaundice adultsOral cholecystogram GB not visualized NormalLiver biopsy Charac. pigment No pigmentTreatment Not needed None
  • Inheritablehepatic jaundice The laboured discard of the conjugated bilirubin from the hepatocyte into the bile is  clinically displayed by two syndromes: Dubin- Johnson and Rotor. 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.
  • Parenchymatous jaundice is  conditioned by endogenic  (inheritable) and outside  influences.Parenchymatous jaundice is  jaundicecharacterized 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.
  • 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 
  • Comparison of Jaundice  (Cholestatic & Hepatocelllular) Hepatocellular Cholestasis InfiltrationDisease example Acute viral hep. CBD stone Metastatic tumorSerum bilirubin 4 – 8 6 – 20* Usually <4, often (mg/dL) normalAST, ALT (U/mL) Markedly inc.,  May be sl. Inc., <  May be slightly  often 500-1,000 200 inc., < 100Serum ALP 1-2x normal 3-5x normal 2-4x normalPT Inc. in severe  Inc. in chronic  Normal disease casesResponse to No Yes parenteral vit. K*Serum bilirubin > 10 mg/dL is rarely seen with CBD stone andusually indicates carcinoma.
  • Liver Function Tests: Normal Values & Changes Tests Normal Values Hepatocellular Uncomplicated Jaundice Obstructive JaundiceBilirubin   Direct 0.1-0.3 mg/dL Increased Increased   Indirect 0.2-0.7 mg/dL Increased Increased Urine bilirubin None Increased IncreasedSerum albumin/  Alb, 3.5-5.5 g/dL Albumin  Unchangedtotal protein Tot, 6.5-8.4 g/dL decreasedAlk phos 30-115 IU/L Increased (+) Increased (++++)Prothrombin time INR of 1.0-1.4; 10%  No response to  Prolonged but  inc. after vit K in 24  parenteral vit. K;  responds to  hrs prolonged parenteral vit. KALT, AST ALT: 5-35 IU/L Inc. in hepato-  Minimally increased AST: 5-40 IU/L cellular damage,  viral hepatitis
  • What is Hepatitis? Inflammation of the liver Caused by viruses, alcohol, medications, and other toxins This training will focus on viral hepatitis  Hepatitis A Virus (HAV)  Hepatitis B Virus (HBV)  Hepatitis C Virus (HCV)  Hepatitis D Virus (HDV)  Hepatitis E Virus (HEV)  Hepatitis F  Hepatitis G (not confirmed yet). These viruses all affect the liver but otherwise are unique
  • Acute 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
  • 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 persons infected with hepatitis A virus HAV is usually spread by “fecal-oral transmission” – Putting something in the mouth (food, water, hands) that has been contaminated with the stool of a person with hepatitis A – Most infections come from contact with a household member or sex partner who has hepatitis A Highly infectious and stable in environment for months
  • Signs and Symptoms of HAV Adults have signs and symptoms more often than children jaundice  nausea fatigue  diarrhea abdominal pain  fever loss of appetite Incubation Period: 15-50 days (average 28 days)
  • Hepatitis B (HBV)Type B hepatitis was at one time referred to as "serum hepatitis," because it wasthought that the only way hepatitis B virus (HBV) could spread was through bloodor serumAbout 6-10% of patients with hepatitis B develop chronic HBV infection (infectionlasting at least six months and often years to decades) and can infect others aslong as they remain infected. Patients with chronic hepatitis B infection also are atrisk of developing cirrhosis, liver failure and liver cancer. HBV is spread through  unprotected sex with an infected person  by sharing drugs, needles, or "works" when using drugs  through needlesticks or sharps exposures on the job  from an infected mother to her baby during birth The best way to protect against HBV is vaccination
  • HBV Structure & Antigens Dane particleHBsAg = surface (coat) protein ( 4 phenotypes : adw, adr, ayw and ayr)HBcAg = inner core protein (a single serotype)HBeAg = secreted protein; function unknown
  • Open Reading FramesThere are 4 open reading frames derived from the same strand (theincomplete + strand)• S - the 3 polypeptides of the surface antigen (preS1, preS2 and S -produced from alternative translation start sites.• C - the core protein• P - the polymerase• X - a transactivator of viral transcription (and cellular genes?).HBx is conserved in all mammalian (but not avian) hepadnaviruses.Though not essential in transfected cells, it is required for infectionin vivo.
  • Hepatitis C (HCV)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, liverfailure, and liver cancer.The hepatitis C virus (HCV) usually is spread by shared needles among drugabusers, blood transfusion, hemodialysis, and needle sticks. Approximately 90% oftransfusion-associated hepatitis is caused by hepatitis CPreventing HCV Infection There is no vaccine Best prevention is behavior change  Do not shoot drugs  Do not share personal items such as razors or toothbrushes  Avoid tattoos or body piercing
  • Symptoms of HCV 80% of persons have no signs or symptoms jaundice  abdominal pain  fatigue  loss of appetite dark urine  nausea Incubation Period: 14-180 days (average 45 days)Potential Co-Infection Effect of HCV on HIV Disease• HCV disease does not appear to accelerate HIV disease• Higher toxicity from Highly Active Antiretroviral Therapy(HAART)• As people live longer with HIV, many more HIV deaths arecaused by HCV-related end stage liver disease• There is still a lot of research to be done on these effects
  • Types 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 Overview Caused by hepatitis D virus (HDV) Coined “Delta Hepatitis” Rarely seen in the United States Found only in persons infected with HBVand has similar routes of transmission as HBV Prevention is vaccination for HBVHepatitis E Overview Caused by hepatitis E virus Primarily a disease of import Very similar to hepatitis A with fecal-oral transmission Transmitted like HAV with the same symptoms No vaccination available
  • HbsA Anti- Anti- HBe Anti- Interpretation g H H Ag H Bs Bc Be + - IgM + - Acute HBV, high infectivity + - IgG + - Chronic HBV, high infectivity + - IgG - + Late-acute or chronic HBV infection, low infectivity + + + +/- +/- Heterotypic anti-HBs with HBsAg; usually indicates chronic HBV carrier state - - IgM +/- +/- Acute HBV infection (anti-HBc window) - + IgG - +/- Recovery from HBV infection - - IgG - +/- Low-level HBsAg carrier or remote past infection - + - - - Immunization for HBV (with HBsAg)
  • Alcoholic Hepatitis An acute or chronic illness involving the liver with necrosis, inflammation & scarring 95% develop a fatty liver which is a reversible process Encephalopathy & death 20% 30% go on to cirrhosis within 6 mo 50% of those abstaining for 6 mo recover completely
  • Alcoholic Hepatitis Symptoms Most patients are symptomatic. The most common complaints are:  Anorexia, nausea, vomiting  Abdominal pain (RUQ)  Fever (due to infection or inflammation of liver)  Weight loss due to anorexia  Jaundice is usually mild  Diarrhea which is due to portal hypertension
  • Alcoholic Liver Disease Alcoholic Hepatitis • Characteristics: 1. Hepatocyte swelling & necrosis  ballooning due to accumulation of fat, water & proteins 2. Mallory bodies – eosinophilic cytoplasmic inclusions in degenerating hepatocytes 3. Neutrophilic reaction – accumulate around degenerating hepatocytes (“satellitosis”) 4. Fibrosis – (+) activation of sinusoidal stellate cells & portal tract fibroblasts
  • Histological features ofalcoholic hepatitis.(B) (Black arrows) Mallorybodies are irregulareosinophilic cytoplasmicstructures with a rope-likeappearance. (Openarrow) Ballooningdegeneration ofhepatocytes.
  • Alcoholic HepatitisPhysical Findings• Jaundice• Spider angiomas• Palmar erythema• Clubbing of fingers• Gynecomastia• Hepatomegaly• Splenomegaly• Pruritis• Ascites• Edema• Caput medusa• Testicle atrophy• Dark urine, light
  • Alcoholic Hepatitis Damage to liver causesHepatic insufficiency: Hyperestrinism: whichwhich is responsible is responsible for:for the following: – Spider nevi– Coma – Alopecia– Jaundice – Gynecomastia– Ascites – Palmar erythema– Anemia – Testicle atrophy– Hemorrhagic tendency– Ankle edema
  • Alcoholic Liver Disease Alcohol Effects 1. Alcohol through action of alcohol DH & acetaldehyde DH  excess NADH + H+  increased lipid biosynthesis 2. Impaired assembly & secretion of lipoproteins + increased peripheral fat catabolism  fatty liver 3. Impaired hepatic methionine catabolism  dec. intrahepatic glutathione (GSH) levels  inc. sensitivity to oxidative injury
  • Alcoholic Liver Disease Alcohol Effects 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 5. Impaired microtubular and mitochondrial function 6. Alcohol  acetaldehyde  (+) lipid peroxidation  disrupt cytoskeletal and membrane function
  • Alcoholic Liver Disease Alcohol Effects 7. Become a major caloric source  displace other nutrients  (+) malnutrition and vitamin deficiencies 8. Lead to chronic gastritis, intestinal mucosal damage and pancreatitis  impaired digestive function 9. Induce release of bacterial endotoxin into portal circulation from gut  (+) liver inflammation 10. Induce release of endothelins from sinusoidal endothelial cells  (+) vasoconstriction & contraction of stellate cells  dec. hepatic sinusoidal perfusion  regional hypoxia
  • Metabolic Disorders Non-alcoholic Fatty Liver Disease (NAFL) • Occurs in patients who are not heavy drinkers • Strong association with obesity, dyslipidemia and insulin resistance, and overt type 2 DM • Presents only with elevated serum amino- transferases and/or GGT • (+) accumulation of triglycerides within hepatocytes • Progress to non-alcoholic steatohepatitis (NASH)  CIRRHOSIS
  • Chronic Hepatitis► Forms:  A. Chronic Active Hepatitis: ►Refers to the form of CH were the liver test & histology are compatible with active & progressive inflammation & necrosis  B. Chronic Persistent Hepatitis: ►Refers to the mild & histological non progressive CH where the inflammation is confirmed only to the portal tracts. The enzymes are normal or only moderately elevated.
  • Inherited Chronic LiverDisorders A. Wilson’s disease B. Hemachromatosis C. Alpha 1-antitrypsin deficiency D. Reye syndrome
  • Haemochromatosis Pathogenisis: A group of disorders with excessive absorption of iron. The iron is layed down in liver, heart, pancrease, kidney, & skin (bronze diabetes)  Primary cause unknown  Secondary- Iron overload : • anemias • cirrhosis • Dietary  Diagnosis: • Lethargy, weakness in men 40-60 yo • Skin hyperpigmentation • Diabetes 30-60% of pt’s • arthopathy
  • Alpha 1-AntitrypsinDeficiency In children associated liver disease In teenagers & adults, a progressive liver disease with pulmonary manifestations Pathogenesis: Alpha 1-trypsin is a potent protease inhibitor found in the serum, body fluids, & tissues It is synthesized by the liver to protect from tissue injury resulting from protease like trypsin
  • Reye’s Syndrome An illness seen in the pediatric age group associated with the flu Symptoms: Nausea, vomiting, hyperactivity, confusion, seizures, & coma, Increasing drowsiness, Belly Pains On liver biopsy there are fatty infiltration Chemistry: elevated liver enzymes, NH3***NEVER give Aspirin to children with varicella infection (chicken pox), or during flu sx.***
  • Occurs in young children with viralillness (Varicella or influenza) treatedwith AspirinMechanism: unknown, butmitochondrial injury and dysfunctionplay an important role
  • REYES SYNDROME• only happens in kids less than 15 years old.• The cause is unknown, but it is strongly associated with Aspirin use during flus.• The liver becomes inflamed and destroyed for unknown reasons.• It is important because Reyes 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.
  • Hepatic (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
  • 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
  • Hepatic Failure• Complications: 1. Hepatic encephalopathy  associated with increased blood ammonia levels  reversible if underlying hepatic condition can be corrected  features: (a) change in consciousness (b) fluctuating neurologic signs – rigidity, hyperreflexia, asterixis 2. Hepatorenal syndrome  renal failure in patients with chronic liver disease  main renal functional abnormalities: (a) sodium retention (b) impaired free water excretion (c) decreased renal perfusion (d) decreased GFR
  • Hepatic Failure• Hepatic encephalopathy: – A metabolic disorder of the CNS system & neuromuscular system with slight changes in the brain (edema) – Clinical Features: • Confusion • Flapping tremor (asterixis) • Drowsiness • Coma death Caused by elevated levels of NH3 (ammonia)
  • Cirrhosis • 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
  •  Etiology: triad Cirrhosis  1. necrosis  2. regenerating nodules  3. fibrosis Categories:  Major • Alcoholic (#1 cause in western world) • Post necrotic  Minor • Wilson’s disease • Haemochromatosis • Biliary • Chronic hepatic congestion  Budd-Chiari syndrome • uncommon condition induced by thrombotic or nonthrombotic obstruction to hepatic venous outflow  Cardiac • Right sided heart failure • Tricuspid insufficiency
  • • Pathogenesis: Progressive fibrosis & re-organization of vascular micro-architecture of liverCollagen deposition Loss of fenestration of New vascular(types I & III) in the sinusoidal endothelial channels in the lobule cells septaeCreate delicate or Impaired hepatocellular Shunting of bloodbroad septal tracts protein secretion around the (albumin, clotting factors, parenchyma lipoproteins)
  • Pathophysiology of Cirrhosis FibrosisIntrahepatic resistance Splanchnic BFPortal HPN Systemic Hyperkinetic Circulation and HypotensionSBP PS-Shunts Activ. Neurohumoral factorsVariceal formationHepatic Enceph Sodium/Water retentionPulmonary HPNHepatorenal Syn Ascites Didier Lubrec MD, AASLD, 2001
  • Mechanism of fibrosis andcirrhosis of the liver
  • Blind Man’s DiagnosisThe characteristic diffusenodularity of the surface reflectsthe interplay between nodularregeneration and scarring. Thegreenish tint of some nodules isdue to bile stasis.
  • • Complications associated with cirrhosis: 1. Hepatic 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
  • • Complications associated with cirrhosis: 2. Portal hypertension a) Ascites b) Congestive splenomegaly c) Esophageal varices d) Hemorrhoids, periumbilical collateral circulation
  • Cirrhosis • Complications associated with cirrhosis: 3. Hepatorenal syndrome due to decreased renal blood flow 4. Hyperestrinism in males a) Gynecomastia b) Spider angiomas c) Female distribution of hair
  • Portal hypertensionIncreased pressure in Portosystemic Splenomegaly peritoneal capillaries shunting of blood Anemia Development of Ascites collateral channels Shunting of ammonia Leukopenia and toxins from the intestine into the general circulation Caput Esophageal medusae varices Thrombocytopenia Hepatic encephalopathy Hemorrhoids Bleeding Mechanisms of disturbed liver function related to portal hypertension .
  • Portal hypertensionDevelopment of portal hypertension Characterized by, that displays by triad sign:1) ascites , (abdominal [peritoneal] dropsy),2) capute medusae – varicose veins of front wall of abdomen, veins of gullet (esophagus), and rectal veins,3) splenome galy .
  •  Pathophysiology: Ascites  Alteration of hepatic blood flow causing portal hypertension.  Reduction in liver function:  Reduction in synthesis of albumin & coagulation proteins  Reduction in detoxification of bilirubin, ammonia, & drugs Complications of ascites: Dyspnea vomiting Decreased cardiac output hydrothorax Anorexia scrotal edema Reflux esophagitis Treatment:  Improve hepatic function  Restrict sodium & fluid intake  Aldactone which inhibits aldosterone  Paracentesis (removal of fluid with addition of IV albumin)  Shunts  Abstain from alcohol  Diuretics  Aldactone  Lasix
  • LFT’s/Transaminases Transaminases Aspartate-AST (SGOT) & Alanine- ALT (SGPT): – AST (SGOT)  is normally found in a diversity of tissues including liver, heart, muscle, kidney, and brain. It is released into serum when any one of these tissues is damaged. – For example, its level in serum rises with heart attacks and with muscle disorders.  It is therefore not a highly specific indicator of liver injury. – ALT (SGPT)  is, by contrast, normally found largely in the liver.  This is not to say that it is exclusively located in liver but that is where it is most concentrated.  It is released into the bloodstream as the result of liver injury.  It therefore serves as a fairly specific indicator of liver
  • AST/ALT status.released into the circulation following hepatocyte injury or death.The ratio of AST:ALT can be helpful AST:ALT > 2:1 suggesting alcoholic liver disease AST:ALT < 1:1 suggesting viral hepatitis. They are sensitive, but non-specific for liver damage. Need isoenzymes The normal range of values for AST (SGOT) is from 5 to 40 units per liter of serum (the liquid part of the blood). The normal range of values for ALT (SGPT) is from 7 to 56 units per liter of serum. Normal range can vary according to a number of factors, including age and gender.
  • AST/ALT  status.released into the circulation following hepatocyte injury or death. The ratio of AST:ALT can be helpful  AST:ALT > 2:1 suggesting alcoholic liver disease  AST:ALT < 1:1 suggesting viral hepatitis.  They are sensitive, but non-specific for liver damage.  Need isoenzymes  The normal range of values for AST (SGOT) is from 5 to 40 units per liter of serum (the liquid part of the blood).  The normal range of values for ALT (SGPT) is from 7 to 56 units per liter of serum. • Normal range can vary according to a number of factors, including age and gender.
  • AST/ALT The highest levels of AST and ALT are found with disorders that cause the death of numerous liver cells (extensive hepatic necrosis).  Although, the precise levels of these enzymes do not correlate well with the extent of liver damage or the prognosis This occurs in such conditions as acute viral hepatitis A or B, pronounced liver damage inflicted by toxins as from an overdose of acetaminophen (Tylenol), and prolonged collapse of the circulatory system (shock) when the liver is deprived of fresh blood bringing oxygen and nutrients
  • Serum Alkaline Phosphatase- (Alk Phos)  Derived from liver, intestines, bones & placenta.  Released causing high levels during  liver damage, particularly necrosis,  cholestasis/ bile duct obstruction,  neoplastic,  infiltrative & granulomatous liver disease.  Need isoenzymes
  • Pathophysiology Underlying the Symptoms and Signs of Liver Disease Symptoms/Signs Pathophysiologic MechanismWeakness, fatigue, anorexia, weight loss, muscle Failure of multiple metabolic functions wastingFever Liver inflammation, decreased reticuloendothelial function with increased risk of infectionBruising, increased bleeding Thrombocytopenia secondary to splenic enlargement, decreased synthesis of clotting factors 1,11, V, VII, VIII, IX. And XPalmar erythema, cutaneous spider Altered metabolism of sex hormones, chronic telangiectases, irregular menses, debilitation gynecomastia, impotence, female body hair distribution in men, testicular atrophyHepatic encephalopathy Abnormal protein metabolismFetor hepaticus Decreased detoxificationPruritus Decreased bile salt excretionCyanosis Arteriovenous shunts in lungs, liverJaundice Biliary obstruction, decreased bilirubin synthesis, decrease bilirubin excretionHyperdynamic circulation, wide pulse pressure, Generalized vasodilation (? Hormonally mediated) tachycardiaAscites, peripheral edema Portal hypertension, sodium and water retention, low serum albumin secondary to decreased hepatic synthesisSplenomegaly Portal hypertension
  • Pathophysiology Underlying the Symptoms and Signs of Liver Disease Symptoms/Signs Pathophysiologic MechanismHepatomegaly 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) Portal hypertension with collateral blood flow or abnormal abdominal vascular pattern around hepatic blockage (caput medusae, umbilical bruit)Osteomalacia, hypocalcemia, night Fat-soluble vitamin malabsorption and loss of fat- blindness, coagulopathy 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 sequestrationLeukopenia Hypersplenism secondary to portal hypertensionHypoglycemia Altered glycogenosis, gluconeogenesisHyperglycemia Portosystemic shunting with delayed hepatic uptake of absorbed glucoseHypercholesterolemia Obstructive jaundice with decreased cholesterol excretion
  • References1. General and clinical pathophysiology / Edited by Anatoliy V. Kubyshkin – Vinnytsia: Nova Knuha Publishers – 2011. – P. 546–566.2. Essentials of Pathophysiology: Concepts of Altered Health States (Lippincott Williams & Wilkins), Trade paperback (2003) / Carol Mattson Porth, Kathryn J. Gaspard – Сhapter 28. – P. 494–516.3. Symeonova N.K. Pathophysiology / N.K. Symeonova // Kyiv, AUS medicine Publishing. – 2010. – P. 434–459.4. Russell J. Greene. Pathology and Therapeutics for Pharmacists. A basis for clinical pharmacy practice / Russell J. Greene, Norman D. Harris // Published by the Pharmaceutical Press An imprint of RPS Publishing 1 Lambeth High Street, London SE1 7JN, UK 100 South Atkinson Road, Suite 200, Greyslake, IL 60030-7820, USA. – Chapter 2. – P. 138–165.5. Gozhenko A.I. General and clinical pathophysiology / A.I. Gozhenko, I.P. Gurcalova // Study guide for medical students and practitioners. Edited by prof. Zaporozan, OSMU. – Odessa. – 2005. – P. 248–259.6. Silbernagl S. Color Atlas of Pathophysiology / S. Silbernagl, F. Lang // Thieme. Stuttgart. New York. – 2000. – P. 162–175.7. Copstead Lee-Ellen C. Pathophysiology / Lee-Ellen C. Copstead, Jacquelyn L. Banasik // Elsevier Inc, 4th edition. – 2010. – P. 854–903.8. Robbins and Cotran Pathologic Basis of Disease 8th edition / Kumar, Abbas, Fauto 2007. – Chapter 15. – P. 600–630.9. Corwin Elizabeth J. Handbook of Pathophysiology / Corwin Elizabeth J. – 3th edition. Copyright В. – Lippincott Williams & Wilkins – 2008. – Chapter 17. – P. 574 – 602.10. Pathophysiology, Concepts of Altered Health States, Carol Mattson Porth, Glenn Matfin. – New York, Milwaukee. – 2009. – P. 949–974.