Clinical Biochemistry Lec 4+5 Liver Disorders PDF

Clinical Biochemistry Lec 4 +5 Dr. Rasha Khalaf 5th stage 1st semester 2024-2025 Liver disorders and gallstones  FUNCTIONS OF THE LIVER 🠶 The liver has essential synthetic and excretory functions an can be thought of as a large metabolic factory...

Clinical Biochemistry Lec 4 +5 Dr. Rasha Khalaf 5th stage 1st semester 2024-2025 Liver disorders and gallstones  FUNCTIONS OF THE LIVER 🠶 The liver has essential synthetic and excretory functions an can be thought of as a large metabolic factory. It also detoxifie and, like the kidneys, excretes the end products of metabolism. 1. General metabolic function 2. Synthetic function 3. Excretion and detoxification function 1. General metabolic functions  2. Synthetic functions 🠶 Hepatocytes synthesize: ✓ Plasma proteins, excluding immunoglobulins and complement, ✓ most coagulation factors, including fibrinogen and factors II (prothrombin), V, VII, IX, X, XI, XII and XIII – of these, prothrombin (II) and factors VII, IX and X cannot be synthesized without vitamin K. ✓ Primary bile acids. ✓ The lipoproteins, such as VLDL and high-density lipoprotein (HDL)  Synthetic functions 🠶 Deficiencies in synthetic function can be detected only if liver disease is extensive. 🠶 Before a fall in plasma albumin concentration is attributed to advanced liver disease, extrahepatic causes must be excluded, such as the loss of protein through the kidney, gut or skin, or across capillary membranes into the interstitial space, as in even mild inflammation or infection. 🠶 Prothrombin levels, assessed by measuring the prothrombin time, may be reduced because of impaired hepatic synthesis, whether due to failure to absorb vitamin K or to hepatocellular damage. If hepatocellular function is adequate, parenteral administration of vitamin K may reverse the abnormality.  3. Excretion and detoxification 🠶 Substances that are inactivated and excreted by the liver include the following: ✓🠶 Cholesterol – excreted in the bile either unchanged or after conversion to bile acids. ✓ 🠶 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. ✓ 🠶 Steroid hormones – which are metabolized and inactivated by conjugation with glucuronate and sulphate and excreted in the urine in these water soluble forms. ✓ 🠶 Many drugs – which are metabolized and inactivated by enzymes of the endoplasmic reticulum system; some are excreted in the bile. ✓ 🠶 Toxins – the reticuloendothelial Kupffer cells in the hepatic sinusoids are well placed to extract toxic substances that have been absorbed from the gastrointestinal tract. Excretion and detoxification Efficient excretion of the end products of metabolism and of bilirubin depends on: 🠶 normally functioning liver cells, 🠶 normal blood flow through the liver, 🠶 patent biliary ducts.  Formation and excretion of bilirubin 🠶 At the end of their lifespan, red blood cells are broken down by the reticuloendothelial system, mainly in the spleen. 🠶 The released hemoglobin is split into globin, which enters the general protein pool, and haem, which is converted to bilirubin after the removal of iron, which is reused. 🠶 About 80% of bilirubin is derived from haem within the reticuloendothelial system. 🠶 Other sources include the breakdown of immature red cells in the bone marrow and of compounds chemically related to hemoglobin, such as myoglobin and the cytochromes. 🠶 Less than 300 μmol of bilirubin is produced daily from the breakdown of erythrocytes, while the normal liver is able to conjugate up to about 1 mmol/day, and therefore hyperbilirubinemia is an insensitive index of parenchymal hepatic disease. Formation and excretion of bilirubin 🠶 Bilirubin is normally transported to the liver bound to albumin. In this form it is called unconjugated bilirubin, which is lipid soluble and therefore, if not protein bound, can cross cell membranes, including those forming the blood–brain barrier. In this form it is potentially toxic; however, at physiological concentrations it is all protein bound. 🠶 In the adult, about 300 µmol per day of bilirubin reaches the liver, where it is transferred from plasma albumin, through the permeable vascular sinusoidal membrane. albumin is bound to ligandin (Y protein).From there it is actively transported to the smooth endoplasmic reticulum, where it is conjugated with glucuronate by a process catalyzed by uridine diphosphate glucuronyl transferase.  Formation and excretion of bilirubin 🠶 Bilirubin monoglucuronide passes to the canalicular surfaces of the hepatocytes, where, after the addition of a second glucuronate molecule, it is secreted by active processes into the bile canaliculi. This process is largely dependent on the active secretion of bile acids from hepatocytes. 🠶 These energy-dependent steps are the ones most likely to be impaired by :- ❑ liver damage (hypoxia and septicemia) ❑ increased pressure in the biliary tract. ❑ Other anions, including drugs, may compete for binding to ligandin, thus impairing bilirubin conjugation and excretion. ❑ Novobiocin inhibits glucuronyl transferase, thus exacerbating unconjugated hyperbilirubinaemia.  Formation and excretion of bilirubin  🠶 Bilirubin is often assayed by the Van den Bergh reaction, which allows conjugated (direct-reacting) and unconjugated (indirect-reacting) bilirubin to be distinguished. 🠶 Conjugated bilirubin enters the gut lumen in bile; it is broken down by bacteria in the distal ileum and the colon into a group of products known as stercobilinogen (faecal urobilinogen). 🠶 Some is absorbed into the portal circulation, most of which is re-excreted in bile (enterohepatic circulation). 🠶 A small amount enters the systemic circulation and is excreted in the urine as urobilinogen, which can be oxidized to a coloured pigment, urobilin. Formation and excretion of bilirubin Bilirubin metabolism and jaundice 🠶 Jaundice usually becomes clinically apparent when the plasma bilirubin concentration reaches about 50 μmol/L (hyperbilirubinaemia), about twice the upper reference limit. It occurs when bilirubin production exceeds the hepatic capacity to excrete it. This may be because: 1. 🠶An increased rate of bilirubin production exceeds normal excretory capacity of the liver (prehepatic jaundice). 2. 🠶The normal load of bilirubin cannot be conjugated and/or excreted by damaged livercells (hepatic jaundice). 3. 🠶The biliary flow is obstructed, so that conjugated bilirubin cannot be excreted into the intestine and is regurgitated into the systemic circulation (post hepatic jaundice).  Retention of bilirubin in plasma: jaundice Unconjugated hyperbilirubinaemia occurs if there is: 🠶 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 gastrointestinal tract or, for example, under the skin due to extensive bruising; in cases of haemolysis, plasma bilirubin rarely exceeds 75μmol/L. 🠶 Impaired binding of bilirubin to ligandin or impaired conjugation with glucuronatein the liver. Retention of bilirubin in plasma: jaundice 🠶 In some pathological conditions,: plasma unconjugated bilirubin levels may increase so much that they exceed the protein-binding capacity. The lipid-soluble, unbound bilirubin damages brain cells (kernicterus). This is most likely to occur in newborn, particularly premature, infants in whom the hepatic conjugating mechanisms are immature. 🠶 In addition, the proportion of unbound, unconjugated bilirubin, and therefore the risk of cerebral damage, increases if: plasma albumin concentration is low, 🠶 unconjugated bilirubin is displaced from binding sites, for example by high levels of free fatty acids or drugs such as salicylates or sulphonamides. Retention of bilirubin in plasma: jaundice 🠶 Unconjugated bilirubin is normally all protein bound and is not water soluble and therefore cannot be excreted in the urine. 🠶 Patients with unconjugated hyperbilirubinaemia do not have bilirubinuria (‘acholuric jaundice’) such as Gilbert’s syndrome. Retention of bilirubin in plasma: jaundice 🠶 Conjugated bilirubinaemia is one of the earliest signs of impaired hepatic excretion. 🠶 In most cases of jaundice in adults, both conjugated and unconjugated fractions of bilirubin are increased in plasma but conjugated bilirubin predominates. 🠶 Conjugated bilirubin is water soluble and is less strongly protein bound than the unconjugated form, and therefore can be excreted in the urine (choluric jaundice). 🠶 Bilirubinuria is always pathological. Dark urine may be an early sign of some forms of hepatobiliary disease. Urobilinogen 🠶 Urobilinogen, unlike bilirubin, is often detectable in the urine of normal people by testing with commercial strip tests, particularly if the urine, and therefore the urobilinogen, is concentrated. 🠶 Urinary urobilinogen concentration is increased in the following situations: 1. When haemolysis is very severe: large amounts of bilirubin enter the intestinal lumen and are converted to stercobilinogen. An increased amount of urobilinogen is formed and absorbed. If the hepatic capacity to re-secrete it is exceeded, it is passed in the urine. 2. When liver damage impairs re-excretion of normal amounts of urobilinogen into the bile. 🠶 The colourless, unabsorbed stercobilinogen is oxidized to stercobilin, a pigment that contributes to the brown colour of faeces. Pale stools may, therefore, suggest biliary obstruction associated with an absence of urinary urobilinogen.  Quize ( A2,4) 1.. main cause of Chylomicron syndrome---------------- - 2. Corneal arcus associated with ---------- 3. In heterozygote FH there is more likely to be an increased amount of -------- 4. The Fredrickson’s phenotypes seen in FCH----------- --------------------------------  Quize(B6,8,10) 1. in Type III hyperlipoproteinemia, the lipoprotein increased is -------------- 2. FH associated with ------------------------ xanthomata 3. Plasma lipoprotein electrophoresis can show the classic type III picture with --------- 4. chylomicron syndrome cause by mutation in ----- ----------------------- BIOCHEMICAL TESTS FOR LIVER DISEASE Tests indicate Hepatocyte damage changes in plasma enzyme activity[Aminotransferases (alanine and aspartate)] generally indicate liver cell membrane damage rather than hepatic function capacity. Because these enzymes are also present in other tissues, changes in plasma activities may reflect damage to those tissues rather than to the liver. A rise in plasma aminotransferase activities is a sensitive indicator of damage to cytoplasmic and/or mitochondrial membranes. Liver cells contain more (AST) than (ALT), but ALT is confined to the cytoplasm, in which its concentration is higher than that of AST. While AST confined in mitochondria  In inflammatory or infective conditions, such as viral hepatitis, the cytoplasmic membrane sustains the main damage; causes a relatively greater increase in plasma ALT than AST activities. [ viral hepatitis ALT>AST) In infiltrative disorders in which there is damage to both mitochondrial and cytoplasmic membranes, there is greater increase in plasma AST than ALT activity [In infiltrative disorders AST>ALT] ALT more specific for hepatic disease; AST may be present in skeletal muscle and other A plasma AST:ALT ratio if: > 2 is suggestive but not diagnostic of alcoholic liver disease < 1 suggests chronic viral hepatitis or hepatic steatosis Tests indicate Hepatic synthetic function Albumin Hypoalbuminaemia is such a common finding in many severe illnesses that it is a less specific indicator of impaired synthetic capacity than a prolonged prothrombin time. Prothrombin time The prothrombin time may be prolonged by: by cholestasis: fat-soluble vitamin K cannot be absorbed normally if fat absorption is impaired due to intestinal bile salt deficiency. The abnormality is then corrected by parenteral administration of the vitamin. A prolonged prothrombin time may also result from severe impairment of synthetic ability if the liver cell mass is greatly reduced; in such cases it is not corrected by parenteral administration of vitamin K. Tests indicate Hepatic excretory function A high plasma conjugated bilirubin concentration indicates impaired hepatic excretory function but as this is also raised in hepatocellular disease it is not specific for cholestasis. This may be accompanied by a high plasma alkaline phosphatase (ALP) activity [In cholestasis increase bilirubin +ALP] Other tests for liver 1. Alkaline phosphatase disease is derived from a number of different tissues, including the liver, the osteoblasts in bone and the placenta. Plasma activities rise in cholestatic liver disease. A raised ALP concentration in the presence of a raised g-glutamyl transferase (GGT) concentration implies that the ALP is of hepatic origin. 2. ᵞ-Glutamyl transferase (GGT) is an enzyme derived from the endoplasmic reticulum of the cells of the hepatobiliary tract. As this reticulum proliferates, for example in response to the prolonged intake of alcohol and of drugs such as phenobarbital and phenytoin, synthesis of the enzyme is induced and plasma GGT activity increases. 3. Bile acid measurement in obstetric cholestasis Raised total plasma bile acid concentrations in the third trimester of pregnancy associated with pruritus are suggestive of obstetric cholestasis, which can lead to both maternal and fetal morbidity and mortality. Elevation of plasma ALT concentration may follow the increase in the concentration of plasma bile salts DISEASES OF THE LIVER 1- Cholestasis Cholestasis is defined as a decrease in bile flow due to impaired secretion by hepatocytes or to obstruction of bile flow through intra-or extrahepatic bile ducts It is essential to distinguish between intrahepatic and extrahepatic causes of cholestasis, as surgery may be indicated for the latter but is usually contraindicated for intrahepatic lesions. 1- Cholestasis  The biochemical and clinical findings Alkaline phosphatase(ALP) activity is a sensitive test severe jaundice in patient with prolonged and widespread cholestasis pruritus due to the deposition of retained bile salts in the skin More rarely, there is bleeding due to malabsorption of vitamin K Cholesterol retention may cause hypercholesterolaemia. Dark urine and pale stools suggest biliary retention of conjugated bilirubin The jaundice caused by extrahepatic obstruction due to malignant tissue is typically painless and progressive, but there may be a history of vague persistent back pain and weight loss, lasma aminotransferase activities may increase. Unless the cause is clinically obvious, evidence of dilated ducts due to extrahepatic obstruction should be sought using tests such as ultrasound, computerized tomography (CT) scanning or cholangiography Acute hepatitis The biochemical findings in acute hepatitis are predominantly those of cell membrane damage: an increase in plasma ALT activity greater than that of AST in very severe cases, impaired prothrombin synthesis. Caused by Viral hepatitis Alcoholic hepatitis Drugs and other toxins Viral hepatitis Hapatitis A: (‘infectious hepatitis’) transmitted by the faecal–oral route as a food-borne infection is relatively common in schools and other institutions Relapses may occur, but it rarely progresses to chronic hepatitis Hepatitis B: (‘serum hepatitis’) is transmitted by blood products and other body fluids; it occurs more sporadically than hepatitis Some patients may be anicteric; some may develop chronic active hepatitis and later cirrhosis and hepatocarcinoma. They may become asymptomatic carriers of the disease. Hepatitis C:(non-A, non-B hepatitis), may be the result of sexual transmission or the transfusion of blood products may progress to cirrhosis. Viral hepatitis In all types there may be a 3- to 4-day history of anorexia, nausea and tenderness or discomfort over the liver before the onset of jaundice. Some patients remain anicteric. Biochemical finding ✓Plasma aminotransferase activities are very high ✓jaundice becomes remain elevated for several months. Once jaundice appears, some of the initial symptoms improve. ✓ALP moderate raise ✓If hepatocellular damage is severe and extensive, the prothrombin time may be increased and, in patients with cholestasis, malabsorption of vitamin K may be a contributory factor.  ◆ Cirrhosis : ✓ End result of many inflammatory and metabolic disease in liver, including prolong toxic damage usually due to alcohol. ✓ In early stage may no abnormal finding. ✓ In advance cases, plasma AST↑ , ALT slight raised , ✓ reduce function cell mass(reduce albumin, prothrombin time), ✓ ascited(accumulation of fluid in peritoneal cavity due to impair lymphatic drainage. ✓ β-γ fusion on protein electrophoresis.  JAUNDICE Haemolytic jaundice : There are many causes of haemolysis, including sickle cell anaemia, thalassaemia and spherocytosis, and it can also be drug or autoimmune induced. The biochemical finding: ✓ abnormal blood film ✓Urinary bilirubin concentration is usually not raised in haemolysis (acholuric jaundice). ✓Jaundice in the newborn infant  1. Pigment stones: found in such chronic haemolytic. The stones consist mostly of bile pigments, with variable amounts of calcium. Rarely, they contain enough calcium to be radio-opaque. They are small, hard and dark green or black, and are usually multiple  2. Cholesterol gallstones ✓Cholesterol precipitate if bile is supersaturated with it. precipitation on a nucleus of crystals causes progressive enlargement. ✓The stones may be single or multiple ✓They are described as mulberry-like and are either white or yellowish; the cut surface appears crystalline ✓more common in obese individuals ✓may be an increased incidence in patients taking some lipid-lowering drugs, such as the fibric acid derivatives. 3. Mixed stones Most gallstones contain a mixture of bile constituents, usually with a cholesterol nucleus as a starting point. They are multiple-faceted, dark-brown stones with a hard shell and a softer centre and may contain enough calcium to be radio-opaque