1 / 117

Liver MSc Clinical Biochemistry

Liver MSc Clinical Biochemistry. Dr Sarah Mapplebeck Consultant Clinical Biochemist. Lecture structure. Session 1 Liver structure and function Liver investigations Session 2 Liver cases. Session 1. STRUCTURE AND FUNCTION. Structure of liver. Largest internal organ

kisha
Télécharger la présentation

Liver MSc Clinical Biochemistry

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. LiverMSc Clinical Biochemistry Dr Sarah Mapplebeck Consultant Clinical Biochemist

  2. Lecture structure • Session 1 • Liver structure and function • Liver investigations • Session 2 • Liver cases

  3. Session 1 STRUCTURE AND FUNCTION

  4. Structure of liver • Largest internal organ • Situated in right hypochnodrium • Divided into right and left lobes by middle hepatic vein • Subdivided into eight segments by divisions of the right, middle and left hepatic vein

  5. Blood supply • Blood supply to liver constitutes 25% of resting cardiac output via two main vessels • Hepatic artery • Branch of coeliac axis • Supplies 25% of total blood flow • Autoregulation of blood flow by hepatic artery ensure a constant total liver blood flow • Portal vein • Drains most of the GI tract and spleen • Supplies 75% of blood flow

  6. Functions of the liver • Metabolic • Protein metabolism • Carbohydrate metabolism • Lipid metabolism • Formation of bile • Metabolism and excretion of bilirubin • Hormone and drug inactivation

  7. Protein metabolism • Synthesis • Principal site of synthesis of most circulating proteins • Receives amino acids from intestine and muscle and regulates plasma levels • Plasma contains approx 60-80 g/L (albumin, globulin, fibrinogen) • Transport proteins e.g transferrin, caeruloplasmin produced in liver • Coagulation factors and complement components • Degradation (nitrogen excretion) • Amino acids degraded by transamination and oxidative deamination to ammonia • Ammonia converted to urea and is renally excreted • Failure of excretion occurs in severe liver disease

  8. Carbohydrate metabolism • Glucose homeostasis and maintenance of blood sugar major function of liver • Stores approx 80g glycogen • Immediate fasting state • Blood glucose maintained by glucose released from glycogen breakdown (glycogenolysis) or by newly synthesized glucose (gluconeogensis) • Sources for gluconeogensis are lactate, pyruvate, amino acids from muscle (alanine and glutamine) • Prolonged starvation • Ketone bodies and fatty acids are used as alternative sources of fuel • Body adapts to lower glucose requirement

  9. Lipid metabolism • Fats transported in plasma as lipoproteins (protein-lipid complexes) • Liver has major role in metabolism of lipoproteins • VLDL and HDL synthesised by liver • Triglycerides (come from diet) also synthesised in liver from circulating free fatty acids and glycerol • Cholesterol comes from diet but mainly synthesised in liver from acetyl CoA

  10. Formation of bile • Bile secretion • Bile acid metabolism • Bilirubin metabolism

  11. Bile secretion • Bile consists of water, electrolytes, bile acids, cholesterol, phospholipids and conjugated bilirubin • Two processed involved in bile acid secretion • Bile salt dependent • Bile salt independent • Bile salt dependent • Uptake of bile acids (and other organic/inorganic ions) across the basolateral (sinusoidal) by transport proteins – driven by Na-K-ATPase in basolateral membrane • Sodium and water follow passage of bile acids • Bile salt independent • Water flow is due to other osmotically active solutes e.g glutathione, bicarbonate

  12. Bile acid metabolism • Bile acids are synthesised in hepatocytes from cholesterol • Excreted into the bile and pass into duodenum • Primary bile acids • Cholic acid and chenodeoxycholic acid are conjugated with glycine or taurine which increases their solubility • Secondary bile acids • Primary bile acids converted by intestinal bacteria into deoxycholic and lithocholic acid • Bile acids act as detergents – main function lipid solubilisation • Have both hydrophobic and hydrophilic end and in aq solution aggregate forming micelles

  13. Bile acid metabolism

  14. Hormone and drug inactivation • Major site for metabolism of drugs and alcohol • Fat soluble drugs are converted to water soluble substances facilitating excretion in bile or urine • Liver catabolises hormones e.g insulin, glycogen, oestrogens, growth hormone, glucocorticoids, parathyroid hormone • Prime target organ for hormones e.g insulin

  15. Bilirubin metabolism • Produced mainly from breakdown of mature red cells in Kupffer cells of liver and reticuloendothelial cells • 15% bilirubin comes from catabolism of other haem containing proteins (myoglobin, cytochromes, catalases) • Typically 250-300mg bilirubin produced daily • Iron and globulin removed from the haem and reused • Biliverdin is formed from the haem and is reduced to form bilirubin • Bilirubin produced is unconjugated

  16. Bilirubin metabolism • Uncongugated bilirubin • Not water soluble • Transported to liver bound to albumin • Dissociates from albumin and taken up by hepatic cell membrane and transported to ER • In ER is conjugated with glucuronic acid by bilirubin-uridyl diphosphate (UDP)

  17. Bilirubin metabolism • Conjugated bilirubin • Water soluble • Secreted into biliary canaliculi reaching small intestine • In gut bilirubin converted into urobilinogen (colorless) • Most urobilinogen oxidised in colon to brown pigment stercobilin excreted in stool • Some urobilinogen is absorbed from gut into portal blood and small amount excreted in urine

  18. Bilirubin metabolism

  19. LIVER INVESTIGATIONS

  20. Investigations • Blood tests • Liver function tests • Serum albumin • Prothrombin time • Liver biochemistry • ALT/AST – reflecting hepatocellular damage • ALP and GGT – reflecting cholestasis • Total protein • Viral markers • Additional blood investigations; haematological, biochemical, immunological and genetic • Urine tests • For bilirubin and urobilinogen • Imaging techniques • To define gross anatomy • Liver biopsy • For histology

  21. Liver function tests • Serum albumin • Marker of synthetic function • Guide to severity of chronic liver disease • Falling serum albumin is poor prognostic sign • In acute liver disease albumin may be normal • Prothrombin time (PTT) • Marker synthetic function • Short half life so sensitive indicator of both acute and chronic liver disease • Vit K def should be excluded as cause of prolonged PTT • Vit K def commonly occurs in biliary obstruction as low intestinal concentration of bile salts results in poor absorption of vit K • INR often used as PTT varies in laboratories

  22. Hypoalbuminaemia

  23. Causes of hypoalbuminaemia • Haemodilution • Pregnancy, iv therapy, cirrhosis, antidiuretics • Decreased synthesis • Severe liver disease (chronic hepatitis, cirrhosis) • Malabsorption, malnutrition • Altered distribution • Liver failure/cirrhosis • Malignancy • Loss from the body • Skin (burns, exudative lesions) • Gut (protein loosing enteropathy) • Increased catabolism • Malignancy • Misc • Acute/chronic illness, malignancy

  24. Hyperalbuminaemia • Increased albumin • Dehydration/haemoconcentration • Venous stasis • Healthy young adult

  25. Liver biochemistry • Bilirubin • Aminotransferases • alanine amino transferase (ALT) and asparate amino transferase (AST) • Alkaline phosphatase (ALP) • Gamma glutamly transpeptidase • Total protein

  26. Bilirubin and jaundice • Yellow discoloration of tissues due to bilirubin deposition • Clinical jaundice may not be clear until plasma bilirubin >50 umol/L • First observed in sclera of the eye

  27. Laboratory investigation of Jaundice • Classified on basis of other LFTs • Isolated hyperbilirubinaemia • High serum bilirubin only abnormality • Unconjugated • Conjugated • Hepatobiliary disease • High bilirubin accompanies other abnormalities in LFTs

  28. Laboratory investigation of jaundice

  29. Isolated hyperbilirubinaemia • Increased production • Haemolytic anaemias, hypersplenism, mechanical heart valves, resorption of haematomas, • Decreased hepatic uptake • Gilbert’s syndrome • Drugs- Rifampicin, Testosterone, Sulphasalazine • Decreased conjugation • Gilbert’s syndrome • Gallstones

  30. Further investigation • Bilirubin fractionation • Conjugated, unconjugated or mixed hyperbilirubinaemia • FBC • Haemolytic disease and pernicious anaemia (megaloblastic anaemia) • Associated with mild isolated hyperbilirubinaemia • Reticulocytes • Haemolytic disease does not always produce low Hb • High retic indicated high red cell production rate seen in haemolytic disease • Lactate dehydrogenase • Elevated in haemolysis, pernicious anaemia and hepatitis • Haptoglobulin • Bind to haemoglobin released in intravascular haemolysis causing low levels

  31. Gilberts syndrome • Autosomal dominant (7% population) • Bilirubin between 20 and 60 μmol/L • Decreased conjugation especially during intercurrent illness or starvation • Elevation <100 umol/L • Measure Conjugated and unconjugated bilirubin • Reflexed in lab on all GP requests when total bilirubin is over 30 umol/L and no other abnormalities • >75 % unconjugated is consistent with Gilberts Syndrome • Become jaundiced when unwell or fasting • Reassure that no further tests are required

  32. Cholestatic jaundice • Extrahepatic cholestasis • Due to large duct obstruction of bile flow at any point in the biliary tract distal to the bile canaliculi • Intrahepatic cholestasis • Failure of bile secretion • Pale stools and dark urine with conjugated serum bilirubin

  33. Transaminases • ALT and AST are present in hepatocytes and leak into blood with liver cell damage • Indicate hepatocellular damage • AST • Mainly mitochondrial and also present in heart, muscle, kidney and brain • High levels seen in hepatic necrosis, MI, muscle injury and CCF • ALT • Cytosol enzyme • More liver specific rise only in liver disease • Released early in liver damage and remain elevated for weeks • In hepatocelluar disease ALT rises before jaundice • Cholestatic disease ALT may not rise • Many labs only measure ALT as more specific than AST

  34. Levels of ALT • Minor elevations (<100 U/L) • Chronic hepatitis B and C • Haemochromatosis • Fatty liver • Moderate elevations (100-300 U/L) • Alcoholic hepatitis • Autoimmune hepatitis • Wilson’s disease • Major elevations (>300 U/L) • Drug toxins e.g. paracetamol • Acute viral hepatitis • Ischaemic liver

  35. Non-hepatic causes of elevated ALT • Coeliac disease • Muscle disease • Strenuous exercise

  36. Alkaline phosphatase (ALP) • Present in canalicular and sinusoidal membranes of liver • Present in other tissues • Bone, intestinal, placenta • Normal situations bone and liver are the major isoenzymes • If required, origin determined by electrophoretic separation of isoenzymes • If elevated GGT, ALP can be presumed to come from liver

  37. Alkaline phosphatase (ALP) • Raised in cholestasis from any cause (intra or extra hepatic) • Synthesis of ALP is increased and realsed into blood • Cholestatic jaundice levels may be 4XURL • Raised levels also in conditions with infiltration of liver e.g metastases and cirrhosis often in absence of jaundice • Highest levels due to liver disease seen with hepatic metastases and primary bilary cirrhosis

  38. Isolated mild rise in Alkaline Phosphatase • Bone disease • Paget’s disease • Osteomalacia • Healing fractures • Metastases • Hyperparathyroidism • Vitamin D deficiency • Drugs • Anti epileptics • Pregnancy • Growth • Children and teenage growth spurt • Biliary disease • Primary biliary cirrhosis (AMA positive)

  39. Other investigations with elevated ALP • Further investigation may include • Calcium and phosphate • VitD and PTH • Liver enzymes • PSA • Electrophoresis • Isoenzymes • Radiology

  40. GGT • Microsomal enzyme present in many tissues as well as liver • Activity can be induced by drugs e.g phenytoin and alcohol • If ALP normal a raised GGT good guide to alcohol intake • Mild elevations in GGT is common even with small alcohol consumption and doesn’t mean liver damage if other liver biochemistry normal • In cholestasis GGT rises in parallel with ALP

  41. Isolated rise in Gamma GT • Only measure to clarify raised alkaline phosphatase or DVLA fitness to drive • Alcohol (although not always) • Drugs • Anticonvulsants, NSAIDs, antibiotics, antifungals, cytotoxics, testosterone • Non alcoholic fatty liver • Congestive cardiac failure • Afro-Caribbeans have higher reference range • Main use to identify source of ALP cheaper the ALP isoenzymes

  42. Other liver function tests • Total proteins • Measurement alone is of little value • Globulin fraction calculated • Elevated globulin fraction is liver disease is usually polyclonal due to increased circulating immunoglobins (rather than monoclonal in myeloma) • Viral markers • Viruses are major cause of liver diease • Virology investigations are often key in diagnosis e.g. hepatitis

  43. Additional blood investigations - Biochemical • Alpha1 antitrypsin • Deficiency can produce cirrhosis • Alpha fetoprotein • Normally produced by fetal liver • Reappearance in high conc indicates hepatocellular carcinoma • Serum and urine copper • Wilsons disease

  44. Additional blood investigations - Immunoglobulins • Increased serum immunoglobulins • Due to reduced phagocytosis by sinusoidal and Kupffer cells of antigen from the gut • Antigens then stimulate antibody production • Immunoglobulins (not produced by liver) • Polyclonal elevations in chronic liver disease • IgM elevated in primary biliary cirrhosis (PBC) • IgA elevated in alcoholic liver disease • IgG increased in autoimmune liver disease

  45. Additional blood investigations - Autoantibodies • Anti mitochondrial Antibodies (AMA) • Found in serum in >95% patients primary biliary cirrhosis • Nucleic, smooth muscle, liver/kidney microsomal antibodies • High titre in autoimmune hepatitis • Also in other autoimmune conditions e.g. SLE and liver disease

  46. Other tests • Genetic analysis • HFE in haemochromatosis • Copper transporting ATPast in Wilsons disease • Urine tests • Bilirubin not found in urine in health • Bilirubinuria is due to presence of conjugated (soluble) bilirubin • Found in jaundiced patient with hepatobilary disease • Absence implies that jaundice is due to increased unconjuated bilirubin • Urobilinogen • Little value but suggests haemolysis or hepatic dysfunction of any cause

  47. Imaging techniques • Ultrasound (USS) • Computed tomography (CT) • Magnetic resonance imaging (MRI) • Plain X ray of abdomen • Endoscopy

  48. Liver biopsy • Histological examination of liver used in the differential diagnosis of diffuse or localised parenchymal disease • Can be done day case • Mortality rate <0.02% in good hands • Guided by US or CT when specific lesions need to be biopsied • Minor complications • Usually in first 2hrs • Abdominal or shoulder pain • Minor bleeding • Major complications • Major bleeding • Sepsis

More Related