Liver Disorder

The liver CH.9.Liver Disorder 1 The liver - The liver is the largest organ in the human body; it weighs approximately 1.2 to 1.5 kg in the adult. - The liver has a dual blood supply; 1.the portal vein, which carries nutrient-rich blood from the capillary bed of the alimentary tract, 2. the hepatic artery, which carries well-oxygenated blood to the liver. Venous drainage from the liver occurs via the right and left hepatic veins. - The liver is of vital importance in - Intermediary metabolism - Detoxification - Elimination of toxic substances. Major functions of the liver …METABOLISM Carbohydrate metabolism: gluconeogenesis, glycogen synthesis & glycogenolysis Fat metabolism: fatty acid synthesis, cholesterol synthesis & excretion, lipoprotein synthesis, ketogenesis and bile & synthesis 25-hydroxylation of vitamin D Protein metabolism: synthesis of plasma proteins (including some coagulation factors but not immunoglobulins, urea synthesis Hormone metabolism: metabolism and excretion of steroid hormones, metabolism of polypeptide hormones Drugs and foreign compounds metabolism and excretion Storage: glycogen vitamin A vitamin B12 iron 2 Metabolism and excretion of bilirubin CH.9.Liver Disorder Excretion and detoxification function of the liver: 1. Bilirubin 2. Amino acids, which are deaminated in the liver. Amino groups, and the ammonia produced by intestinal bacterial action and absorbed into the portal vein are converted to urea. 3. Cholesterol, which is excreted in the bile either unchanged or after conversion to bile acids. 4. Steroidal hormones, which are metabolised and inactivated by conjugation with glucuronate or sulphate and excreted in the urine in these water-soluble forms. 5. Many drugs. 6. Toxins, the reticuloendothelial Kupffer cells in the hepatic sinusoids are well placed to extract toxic substances which have been absorbed from the GIT. Efficient excretion of the end-products of metabolism and of bilirubin depends on: 1. Normally functioning liver cells. 2. Normal blood flow through the liver. 3. Normal biliary ducts. CH.9.Liver Disorder 3 Damage to the organ may not obviously affect its activity since the liver has considerable functional reserve. - So simple tests of liver function (e.g., plasma bilirubin and albumin concentrations) are insensitive indicators of liver disease, -a fall in plasma albumin concentration could be attributed to advanced liver disease. - Tests reflecting liver damage (measurements of the activities of hepatic enzymes in plasma) are used. The most common disease processes affecting the liver are:  Hepatitis, with damage to liver cells.  Cirrhosis, in which increased fibrous tissue formation leads to shrinkage of the liver, decreased hepatocellular function and obstruction of bile flow.  Tumours, most frequently secondary; for example, metastases from cancers of the large bowel, stomach and bronchus. -Patients with liver disease often present with characteristic symptoms and signs, but the clinical features may be non-specific and in some patients, liver disease is discovered incidentally. - Extrahepatic biliary disease may present with clinical features suggestive of liver disease  may have secondary effects on the liver; for instance, obstruction to the common bile duct may cause jaundice and, if prolonged, a form of cirrhosis. CH.9.Liver Disorder 4 Hepatitis Tumour CH.9.Liver Disorder 5 Bilirubin metabolism CH.9.Liver Disorder -Bilirubin is derived from the haem moiety of the haemoglobin, myglobin and cytochrome molecules Haem & Pophyrins -Porphyrins: are cyclic compounds that bind metal ions usually Fe+2,Fe+3. -Heme: one ferrous ion coordinated in the center of porphyrins. -Heme is highly turned over: 6–7 gm is synthesized and destroyed daily Structure of porphorins -Ring structure of 4 pyrrole rings linked with methylenyl bridge. -Side chains: different porphyrins vary of the side chain that are attached to pyrrole rings. 6 CH.9.Liver Disorder Bilirubin metabolism - Iron is reutilized -RBC are taken up by liver and spleen and macrophages, and degraded by reticulo-endothelial system (RE) Formation of billirubin -Degradation is catalyzed by microsomal heme oxygenase enzyme of the ER cells. -The enzyme add the –OH to the methylen bridge oxidation CO and Fe+3 is released and the product is Billiverdin then it is reduced into Billirubin. Uptake of Billirubin by liver - Billirubin is slightly soluble in water transported in the blood through complexion to albumin, then taken by hepatocytes. Formation of Billirubin diglucuronide - In hepatocytes, the solubility of Billirubin is increased by addition of two molecules of Glucuronic acid catalyzed by “Billirubin glucuronyl transferase” using UDP-glucuronic acid. 7 CH.9.Liver Disorder Heme Degradation 8 A small fraction of unconjugated bilirubin circulates unbound, and this free portion is able to cross lipid-containing membranes, including the blood-brain barrier, leading to neurotoxicity 9 CH.9.Liver Disorder CH.9.Liver Disorder 10 Excretion of Billirubin into bile -Conjugated bilirubin is water-soluble and is secreted actively into the biliary canaliculi, eventually reaching the small intestine via the ducts of the biliary system. - Secretion into the biliary canaliculi is the rate limiting step in bilirubin metabolism -Billirubin diglucuronide is hydrolyzed and reduced by bacteria in the gut to yield urobillinogen. Urobillinogen Reabsorbed, go to kidneys and converted excreted as urobillinogen & urobillin (yellow color) Most are oxidized by bacteria to stercobillin (brown color) CH.9.Liver Disorder 11 CH.9.Liver Disorder Jaundice  Jaundice: The yellow discoloration of tissues skin and sclera due to bilirubin deposition, is a frequent feature of liver disease.  High level Bilirubin is toxic to CNS The bilirubin normally present in plasma is mainly (approximately 95%) unconjugated; since it is protein bound, it is not filtered by the renal glomeruli and, in health, bilirubin is not detectable in the urine.  Bilirubinuria: appearance of bilirubin in urine  reflects an increase in the plasma concentration of conjugated bilirubin, and is always pathological. Clinical jaundice may not be seen unless the plasma bilirubin concentration is more than two and half times the upper limit of normal.  Hyperbilirubinaemia can be caused by increased production of bilirubin, impaired metabolism, decreased excretion or 12 even combination. CH.9.Liver Disorder Jaundice can be classified to: 1.  An increased rate of bilirubin production exceeds normal excretory capacity of the liver (prehepatic jaundice)(Hemolytic jaundice: sickle cell anemia, or malaria). 2.  The normal load of bilirubin cannot be conjugated and/or excreted by damaged liver cells (hepatic jaundice). Hepatocellular Jaundice: liver damage, cirrhosis, hepatitis. 3.  The biliary flow is obstructed, so that conjugated bilirubin cannot be excreted into the intestine and is returned into the systemic circulation (posthepatic jaundice) Obstructive jaundice: bile duct obstruction. 13 CH.9.Liver Disorder 14 Biochemical assessment of liver function CH.9.Liver Disorder 1-Bilirubin A. Unconjugated hyperbilirubinaemia occurs if there is: 1-A marked increase in the bilirubin load  as a result of haemolysis, or of the breakdown of large amounts of blood after haemorrhage into the GIT. In haemolysis, hyperbilirubinaemia is due to increased production of bilirubin, which exceeds the capacity of the liver to remove and conjugate the pigment. 2-Impaired binding of bilirubin to ligand or impaired conjugation with glucuronate in the liver. Like in some liver disease. 3- Or it could be due to an inherited abnormality of bilirubin metabolism (defect in the conjugating enzyme) ’Gilbert’s syndrome’, 15 -Unconjugated hyperbilirubinaemia is also can be associated to high urobilinogen. Haemolytic disease  to more bilirubin is excreted in the bile  the amount of urobilinogen entering the hepatic circulation  increased and urinary urobilinogen is increased. - As a result of haemolytic disease  the plasma concentration of unconjugated bilirubin may be as high as 500 mol/L (30 mg/dl) and exceeds the plasma protein-binding capacity. -Unconjugated bilirubin is normally totally bound to albumin. -It is not water soluble and therefore cannot be excreted in the urine. - Patients with unconjugated hyperbilirubinaemia do not have bilirubinuria. CH.9.Liver Disorder 16 Jaundice in newborns - It is physiological jaundice is defined as: mild jaundice not present at birth, which develops during the first few days and continues during the first week of life, and for which there is no obvious pathological reason. - The transient ‘physiological’ jaundice of the new-borns reflects decrease in the activity of Billirubin glucuronyl transferase -The activity increases rapidly. -Jaundice during the first 24 hours of life is more likely to be pathological than physiological. - Proportionally more unconjugated bilirubin reaches the liver in the newborn infant than in the adult because: 1. The red cell half-life is shorter; the blood haemoglobin concentration falls rapidly during the first week of life, even in normal infants. 2. Delayed clamping of the umbilical cord may significantly increase red cell mass. 3. Damages may occur during birth  haemoglobin breakdown increases the 17 plasma bilirubin concentration. CH.9.Liver Disorder CH.9.Liver Disorder 18 - Newborns pathological Jaundice that diagnosed in during the first 24 hours of life could occur due: 1. With excessive haemolysis, as in Rhesus incompatibility, 2. A lack of enzyme activity, as occurs in prematurity and in Crigler-Najjar syndrome, there may be massive rise in plasma concentration of unconjugated bilirubin. In Crigler-Najjar patients the enzyme is either : inactive (type I) or severely reduced (type II). CH.9.Liver Disorder 19 CH.9.Liver Disorder 20 3. The high plasma level of unconjugated bilirubin leads to jaundice and kernicterus (bilirubin encephalopathy) If bilirubin levels exceed approximately 340 mol/L; its uptake into the brain may cause sever brain damage (kernicterus). Bilirubin is destroyed by ultraviolet light and lesser degrees of unconjugated hyperbilirubinaemia can be treated by phototherapy. Water loss from the skin may be high and fluid balance must be carefully monitored. 21 CH.9.Liver Disorder A. Unconjugated hyperbilirubinaemia CH.9.Liver Disorder 22 B-Conjugated hyperbilirubinaemia -Due to leakage of bilirubin from either hepatocytes or the biliary system into the bloodstream when its normal route of excretion is blocked. - The water-soluble conjugated bilirubin entering the systemic circulation is excreted in the urine, giving it a deep orange-brown colour. - In complete biliary obstruction, no bilirubin reaches the gut, no urobilin is formed and the stools are pale in colour. - Hyperbilirubinaemia can be due: to an excess of both conjugated and unconjugated bilirubin. - Bilirubinuria is always pathological. CH.9.Liver Disorder 23 CH.9.Liver Disorder Methods for the determination of bilirubin -The most widely used routine methods for bilirubin measurements are photometric methods based on diazo reaction. - The diazo reagent reacts with bilirubin to produce colorimetric dye. - The fraction of bilirubin that reacted with the diazo reagent in the absence of alcohol is called the direct bilirubin fraction (conjugated). -The indirect bilirubin (for Un-Conjugated) is used for the difference between total bilirubin (found after the addition of alcohol to the reaction mixture) and the direct bilirubin fraction. - Bilirubin levels in an adult in serum 0.3-1.2 mg/dl (5-21 mol/L), urine negative - Conjugated bilirubin (direct) in serum 0-0.2 mg/dl (0-3.4 mol/L) 24 PLASMA ENZYMES CH.9.Liver Disorder - Measurements of the activity of enzymes in plasma are of value in the diagnosis and management of a wide variety of diseases. - Most enzymes measured in plasma are primarily intracellular, being released into the blood when there is damage to cell membranes, -Small amounts of intracellular enzymes are present in the blood as a result of normal cell turnover. - When damage to cells occurs, increased amounts of enzymes will be released and their concentrations in the blood will rise. - However, such increases are not always due to tissue damage. - Other possible causes include: 1.increased cell turnover, 2.cellular proliferation (e.g. neoplasia), 3.increased enzyme synthesis (enzyme induction), 4.obstruction to secretion, 5.decreased clearance. Many other enzymes, for example renin, complement factors and coagulation factors, are actively secreted into the blood, where they fulfill their physiological function. 25 A major disadvantage in the use of enzymes for the diagnosis of tissue damage is their lack of specificity to a particular tissue or cell type. Many of these enzyme are not used as diagnostic tool but for monitoring the diseases Many enzymes are common to more than one tissue This problem may be prevented to some extent in two ways: A) First, different tissues may contain (and thus release when they are damaged) two or more enzymes in different proportions; e.g. alanine and aspartate aminotransferase are both present in cardiac muscle and hepatocytes, but there is relatively more alanine transaminase in the liver; B) Second, some enzymes exist in different forms (isoforms), termed isoenzymes. Individual isoforms are often characteristic of a particular tissue. So the pattern of increase of different enzymes can indicate the site of problem, e.g. high GGT and high ALP or AST indicates a problem in the liver While high ALT and CK-MB indicates MI CH.9.Liver Disorder 26 CH.9.Liver Disorder 1. 2. 3. 4. 5. 6. 7. Alanine aminotransferase (ALT) Aspartarte aminotransferase (AST) Alkaline phosphatase (ALP) Gamma glutamyl transferase (GGT or ‘Gamma GT’) Bilirubin Albumin Clotting studies, i.e. prothrombin time (PT) or international normalised ratio 27 Two important transferases: Alanine aminotransferas (ALT) called also Glutamate – Pyruvate transferase (GPT) or Serum ALT = SGPT, found in many tissues ,,,,catalyzes the transfer of amino group of alanine to produce pyruvate and glutamate. Aspartate aminotransferase (AST) called also Glutamate–Oxaloacetate transferase (GOT) or Serum AST = SGOT, - During the catabolism of amino acids AST takes amino group from glutamate to oxaloacetate forming aspartate. Which used as source of NH4 group in Urea synthesis Aspartate  source of amino group of the urea in the urea cycle. CH.9.Liver Disorder 28 1-Aspartate Transaminase (AST) AST (glutamate oxaloacetate transaminase GOT) is present in high concentrations in cells of cardiac and skeletal muscle, liver, kidney and erythrocytes. Damage to any of these tissues may increase plasma AST levels. AST can be used as indicator of muscle damage. Causes of Raised Plasma AST Activities * Artifact: due to in-vitro release from erythrocytes if there is haemolysis or if separation of plasma from cells is delayed. *Marked increase: circulatory failure with 'shock' and hypoxia; myocardial infarction; acute viral or toxic hepatitis. *Moderate increase: cirrhosis (may be normal, but may rise to twice the upper adult reference limit); infectious mononucleosis (due to liver involvement (type of viral infection “mononucleosis” refers to an increase in a special type of white blood cells (lymphocytes); cholestatic jaundice; malignant infiltration of the liver; skeletal muscle disease; after trauma or surgery (especially after cardiac surgery); severe hemolytic episodes (of erythrocyte origin). CH.9.Liver Disorder 29 CH.9.Liver Disorder 2-Alanin Transaminase (ALT) ALT (glutamate pyruvate transaminase, GPT) is present in high concentrations in liver and, to a lesser extent, in skeletal muscle, kidney and heart ALT is more specific for liver than muscle Causes of Raised Plasma ALT Activities *Marked increase: - acute viral or toxic hepatitis. - circulatory failure with 'shock' and hypoxia; *Moderate increase: -cirrhosis; -infectious mononucleosis (due to liver involvement); -liver congestion secondary to congestive cardiac failure; -cholestatic jaundice (up to 10 times the upper reference limit in adults); -surgery or extensive trauma and -skeletal muscle disease (much less affected than AST). 30 3-Gamma-glutamyl-transferase (GGT) GGT occurs mainly in the cells of liver, kidneys, pancreas and prostate. Plasma GGT activity is higher in men than in women. (5-L-glutamyl)-peptide + an amino acid peptide + 5-L-glutamyl amino acid It is very sensitive but unspecific indicator for liver dysfunction; Sensitive  anything wrong in the liver will elevate its activity non-specific  can’t indicate the reason of liver disease but Causes of raised plasma GGT activity -Induction of enzyme synthesis, without cell damage, by drugs or alcohol. *Many drugs most commonly the anticonvulsant phenobarbitone and phenytoin, *and alcohol induce proliferation of the endoplasmic reticulum. - Cholestatic liver disease (the flow of bile in the body is disrupted), when changes in GGT activity usually parallel those of alkaline phosphatase. -In biliary obstruction, plasma GGT activity may increase before that of alkaline phosphatase. - Hepatocellular damage, such as that due to infectious hepatitis; measurement of a plasma transaminase activities is a more sensitive indicator of such conditions. - Plasma GGT activity is frequently very high in patients with alcoholic liver disease but can be elevated, due to enzyme induction, in heavy alcohol drinkers in the absence of other evidence 31 of liver damage CH.9.Liver Disorder 4-Alkaline Phosphatase (ALP) -The alkaline phosphatases are a group of enzymes that hydrolyze organic phosphates at high pH. -They are present in most tissues but are in particularly high concentration in the osteoblasts of bone and the cells of the hepatobiliary tract, wall, renal tubules and intestinal placenta. -The exact metabolic function of ALP is unknown but it is probably important for calcification of bone. - In adults plasma ALP is derived mainly from bone and liver in approximately equal proportions; the proportion due to the bone fraction is increased when there is increased osteoblastic activity that may be physiological. CH.9.Liver Disorder 32 Causes of raised plasma ALP activity Bone disease: Rickets and osteomalacia; Paget's disease (may be very high); primary hyperparathyroidism with extensive bone disease (usually normal but may be slightly elevated) Liver disease: intra- or extrahepatic cholestasis, lesions, tumor. granulomas, and other causes of hepatic infiltration. Malignancy: bone or liver involvement or direct tumor production. CH.9.Liver Disorder 33 Diseases of the Liver CH.9.Liver Disorder 34 CH.9.Liver Disorder Diseases of the Liver 1.Cholestasis: is any condition in which bile excretion from the liver is blocked, which can occur either in the liver or in the bile ducts. Cholestasis may be either: *intrahepatic, in which bile secretion from the hepatocytes into the canaliculi is impaired, due to: viral hepatitis; drugs such as chlorpromazine or toxins such as alcohol; inflammation of the biliary tract; autoimmune disease (primary biliary cirrhosis); cystic fibrosis. *extrahepatic: due to obstruction to the flow of preformed bile through the biliary tract by: biliary stones; inflammation of the biliary tract; pressure on the tract from outside by malignant tissue, usually of the head of the pancreas. 35 Alkaline phosphatase activity is the most sensitive test for cholestasis. Increased synthesis of ALP in the affected ducts increases the activity of this enzyme in plasma. * Patients with prolonged cholestasis may present with :  severe jaundice  itching due to deposition of retained bile salts in the skin;  More rarely there is bleeding due to malabsorption of vitamin K,  with consequent prothrombin deficiency. -Cholesterol retention may cause hypercholesterolaemia. -Dark urine and pale stools suggest biliary retention of conjugated bilirubin 36 CH.9.Liver Disorder 2. Hepatitis: CH.9.Liver Disorder Hepatitis is the Latin word for liver inflammation. It is characterized by the  • destruction of a number of liver cells • the presence of inflammatory cells in the liver tissue. a. Acute Hepatitis: Acute hepatitis is most frequently caused by infectious agents, particularly viruses, and toxins. -Many toxins and drugs can also cause acute hepatitis, including alcohol, carbon tetrachloride. paracetamol and -The viruses primarily associated with hepatitis are hepatitis A, non-B’ (principally hepatitis C virus) and B ‘non-A, -Most cases of viral hepatitis resolve completely. -In severe cases, hepatic failure may develop, but most patients who survive the acute illness eventually recover completely, transaminase activities falling to normal in ten to twelve weeks. Infection with hepatitis A never leads to chronic disease. - Patients may present with jaundice but this is often not apparent early in the course of the disease. - The biochemical findings in acute hepatitis are associated with those of cell membrane damage with an increase in plasma ALT activity greater than that of AST. 37 Hepatitis A (infectious hepatitis), an RNA enterovirus, spread by contact with faecal matter, most often through ingestion of contaminated food. - Rarely fatal, it cannot be treated except by bed rest for 1–4 weeks, during which time no alcohol should be consumed. - It may recur after 3 months. Hepatitis B (serum hepatitis): Hepatitis B ranks as the ninth leading killer in the world - is shed through blood, semen, vaginal secretions, and approximately 4–6 weeks after symptoms develop. saliva - the virus may take up to 6 months to incubate, and people may also become asymptomatic carriers. - Hepatitis B may heal slowly, and is a leading cause of chronic liver disease and cirrhosis. - Effective vaccines exist, Hepatitis C: remains in the blood for years and accounts for a large percentage of cirrhosis, liver failure, and liver cancer cases. Its main mode of transmission is through blood transfusion, and possibly sexual intercourse CH.9.Liver Disorder 38 b. Chronic hepatitis CH.9.Liver Disorder 39 b. Chronic hepatitis : hepatic inflammation persisting without improvement for six months. Causes include: 1. autoimmune liver damage, 2. chronic infection with hepatitis B or C, 3. alcohol 4. drugs. *Chronic active hepatitis (is caused by active hepatocellular destruction with episodes of relapses and remissions, hepatitis usually progresses to cirrhosis. *Chronic persistent hepatitis (a form of chronic hepatitis that is usually benign, not progressing to cirrhosis, and usually asymptomatic without physical findings but with continuing abnormalities of tests of liver status). Chronic persistent hepatitis has good prognosis; chronic active hepatitis may respond to treatment with immunosuppresive or antiviral agents, according to its etiology, but the natural history is of progression to cirrhosis, which may be present at the time of diagnosis. -Plasma transaminase activities are elevated in all types,  reflecting the continuing hepatocellular damage. -ALP activity is usually normal. -Indices of synthetic function (albumin, prothrombin time) are often abnormal in chronic active hepatitis but not in chronic persistent hepatitis. 40 CH.9.Liver Disorder 3. Cirrhosis - Progressive disease of the liver characterised by 1.diffuse damage to hepatic parenchymal cells, 2.with nodular regeneration, 3.fibrosis, 4.disturbance of normal architecture; -associated with: 1. failure in the function of hepatic cells and 2.frequently resulting in and jaundice, interference with blood flow in the liver, portal hypertension, ascites, ultimately hepatic failure. - Cirrhosis is the end result of many inflammatory and metabolic diseases involving the liver, including prolonged toxic damage due to alcohol. - Causes of cirrhosis include: 1.chronic excessive alcohol intake, 2.autoimmune disease, 3.persistence of hepatitis B or C virus 4.various inherited metabolic diseases, such as Wilson’s disease, haemochromatosis and  -antitrypsin deficiency. 41 CH.9.Liver Disorder CH.9.Liver Disorder 42 •Cirrhosis can be the cause of biochemical abnormalities  that reflect specific alterations in metabolism i.e.,: •decreased albumin synthesis, •increased prothrombin time, •decreased cholesterol synthesis •insulin resistance. * Most of clotting factors are synthesized in the liver (Factor VII is an important one) clotting factors are plasma proteins include, so if there is any liver problem  clotting time will be increased  Acute diseases Factor VII is vit K dependent so in certain cases, the high prothrombine time is not due to liver diseases but due to vit K deficiency •Due to the great functional capacity of the liver, metabolic and clinical abnormalities may not become apparent until late in the course of the disease; until this time, the cirrhosis is said to be ‘compensated’. •There are no reliable, disease. simple biochemical tests  to diagnose subclinical 43 CH.9.Liver Disorder CH.9.Liver Disorder 3. Tumors -The liver is a common site for tumor metastasis. - Primary liver tumors are -rare -associated with cirrhosis, -persistence of serological markers for hepatitis B and C, and various carcinogens, including aflatoxins. Plasma -fetoprotein is -elevated at diagnosis in approximately 70-80% of patients with primary hepatocellular carcinomas  a valuable marker for this tumor although it can be increased, usually to a 44 lesser extent, in acute and chronic hepatitis and in cirrhosis. CH.9.Liver Disorder Liver Function Tests and Diseases Liver function Tests 1) Testing of Bilirubin which indicates the excretory capacity of the liver: prehepatic, hepatic, posthepatic jaundice 2) Testing of enzymes (ALT, AST, ALP and GGT) ALT is more specific for liver, ALP can indicate the Cholestasis, GGT is sensitive to liver diseases but non-specific 3) Testing of plasma proteins, which indicates the synthetic capacity of the liver  Measurement of albumin conc chronic diseases  Prothrombin time, clotting time  acute diseases  Polyclonal response in the Ig mainly IgG. When there is liver cirrhosis of autoimmune origin  high level of IgG 45 Typical Liver Function Test : Result Unit Reference AP (Alk Phos)............................................................... 30 to 120 U/L GGT (Gamma GT)........................................................ 5 to 35 U/L LD Lactate Dehydrogenase......................................... 100 to 225 U/L AST (Aspartate aminotransferase)............................... 5 to 45 U/L ALT (Alanine aminotransferase).................................. 5 to 45 U/L Albumin....................................................................... 38-55 g/L Total Bilirubin-Normal range is 3 - 18 umol/L.............. 0.174 - 1.04mg/dL Clotting Studies (Prothrombin Time)........................... 1 to 13.5 Seconds CH.9.Liver Disorder 46 CH.9.Liver Disorder 47