Bile and Jaundice GIHEP 2023-24

Bile & Jaundice Year 2 Medicine GIHEP Module Dr. Stephen Keely  Learning Outcomes By the end of this lecture you should be able to: 1. Describe the composition and function of bile, and how it is released 2. Discuss the pathways for haem transport, metabolism (as bilirubin) a...

Bile & Jaundice Year 2 Medicine GIHEP Module Dr. Stephen Keely  Learning Outcomes By the end of this lecture you should be able to: 1. Describe the composition and function of bile, and how it is released 2. Discuss the pathways for haem transport, metabolism (as bilirubin) and excretion 3. Define jaundice and describe its clinical presentation 4. Classify jaundice according to the location of the bilirubin-handling defect 5. Discuss potential causes and clinical differences between each type of jaundice (pre-, intra-, post-hepatic) 6. Identify the causes and treatments of certain hyperbilirubinemias  What is bile? Fluid that is made and secreted by liver – ~500mL produced daily by adults – Usually a yellow-green colour – Alkaline pH (7.5 – 8) After synthesis bile is stored in the gallbladder Released in response to cholecystokinin (CCK) after eating a meal – Nutrients induce release of CCK from I cells in the duodenum – CCK induces gallbladder contraction Principal functions – Facilitate fat digestion & absorption – Excretion of excess cholesterol and metabolites – Neutralisation of stomach acid  Excretory functions of bile Principal excretory products include: Bile acids Bile pigments – degradation of haem Cholesterol Drugs and their metabolites Particulate matter – Removed from blood stream by Kupffer cells of Liver Composition of bile  Bile and Fat Digestion - Bile acids act as detergents – solubilise and Hydrophobic emulsify fats in food. - Are amphipathic molecules (i.e.) charged (hydrophillic) on one side and uncharged Hydrophillic (hydrophobic) on the other side - Enables them to aggregate around droplets of fat to form micelles, https://upload.wikimedia.org/wikipedia/commons/thumb/f/f7/Lipid_and_bile_salts.svg/295px-Lip - hydrophobic sides face towards the fat droplet and hydrophilic sides face outwards. - Pancreatic amylase can enter micelles and digest triglycerides into monoglycerides and FAs  Image:Cholesterol.svg Bile Acid Metabolism Cholesterol Cyp7A1 Cholic Acid Chenodeoxycholic Acid (Primary Bile Acids) Conjugation Taurocholic Acid Taurochenodeoxycholic Acid (Conjugated Primary Liver Glycocholic Acid Glycochenodeoxycholic Acid Bile Acids) Storage in Gallbladder CCK Duodenum (Fat digestion & absorption) 95% Reabsorbed in the ileum Intestine 5% Enter Colon Bacterial Metabolism Secondary Bile Acids Excreted in faeces  Summary – Bile Acids - Primary BAs are synthesised in the liver from cholesterol, conjugated to glycine or taurine and stored in the gallbladder - Released from the gallbladder in response to a meal to facilitate fat digestion and absorption - Primary bile acids are converted to secondary bile acids by bacteria in the colon - Provide a pathway for excess cholesterol excretion from the body  What is bilirubin? Bilirubin = a natural degradation product of haem Erythrocytes (RBCs) have a finite lifespan in the bloodstream (~60-120 days Most senescent RBCs get destroyed extra-vascularly by phagocytosis and/or lysis of the RBCs. (in the liver, spleen or bone marrow) Intravascular haemolysis also occurs but is more rare Usually as a consequence of disease - eg., antibody mediated lysis of RBCs Released haem is toxic and must be metabolised Fe2+ is very reactive and causes tissue damage & inflammation – particularly in kidneys, liver & CNS Haem is therefore detoxified in a 2-step process by metabolism to bilirubin - 75% of the bilirubin in the body is derived from RBCs (~250-300mg/day) - Remainder comes from other heme containing proteins (eg., myoglobin, cytochromes etc.) Formation of bilirubin Red blood cell Phagocytosis & Hemolysis (spleen, liver) Haemoglobin Globin (protein) Haem Bilirubin Fe2+ Amino acids Recycled Excreted for erythropoesis  Handling of free (intra-vascular) haemoglobin - Free haem in the blood is toxic - Detoxification is achieved by binding to serum proteins. Haptoglobin: haemoglobin-haptoglobin complex metabolized in liver and spleen forming iron-globin complex and bilirubin – Prevents loss of iron in urine Haemopexin: binds free haem – Haem-hemopexin complex taken up by liver – iron stored bound to ferritin Albumin: complex of oxidized haem and albumin (known as Met-haemalbumin)  Degradation of haem to bilirubin - Occurs mostly in the spleen and requires 2 enzymes - Heme Oxygenase - Biliverdin reductase Haem HMOX (high activity in the spleen) Biliverdin BVRA Bilirubin Metabolism of bilirubin Liver takes up bilirubin by carrier-mediated facilitated diffusion (Transporter = OATP, high binding capacity) Binds to cytoplasmic proteins in hepatocytes - Ligandin - Protein Y (prevents efflux back into blood) Bilirubin is conjugated with glucuronic acid, catalysed by UDP-glucuronyl transferase (UDP-glucuronosyltransferase) (makes bilirubin water-soluble) Metabolism of bilirubin (cont’d) Conjugated bilirubin secreted into bile ducts (active transport via Multidrug Resistant-like Protein, MRP-3) Bile excreted from liver into gut - glucoronidases in colonic bacteria de-conjugate bilirubin to urobilinognen (colourless) Oxidation by Reabsorption to bacteria (85%) portal blood 5% 10% Stercobilin Kidneys Liver Oxidation Urobilin Feces Bile Urine  Summary - Formation and Fate of Bilirubin Hemolysis of RBCs Haem Bilirubin formation (primarily in the spleen) Transported in bloodstream (bound to albumin) Taken up by liver Conjugated with glucuronic acid (for water solubility) Re-absorbed; excreted from kidney as urinary urobilin Excreted into bile Excreted as faecal stercobilin Urobilinogen formed in intestinal tract  Jaundice Definition: A condition in which the skin, whites of the eyes and mucous membranes turn yellow because of high bilirubin levels (hyperbilirubinemia) Typically indicates the presence of underlying disease involving abnormal heme metabolism, liver dysfunction, or biliary tract obstruction Occurs when levels of serum bilirubin are > 35M/L (normal = 17uM/L) Rare in adults (< 1:1000) but common in babies (~ 80% of newborns) Associated symptoms include urticara, abdominal pain, pale feces, & dark urine. Severe cases can lead to neurological damage (kernicterus) Treatment depends on the underlying cause  Classification of Jaundice Jaundice is classified into 3 categories: - based on which part of the physiological mechanism the pathology affects Pre-hepatic (haemolytic) jaundice – Bilirubin production exceeds uptake capacity of liver Intra-hepatic (hepatocellular) jaundice – Bilirubin cannot be taken up, conjugated and/or excreted due to hepatocellular damage Post-hepatic (cholestatic) jaundice – Obstruction to biliary flow - conjugated bilirubin ‘regurgitated’ back into systemic circulation  Pre-hepatic jaundice Also called haemolytic jaundice or hematogenous jaundice Excess production of bilirubin following haemolysis Excess RBC lysis is commonly due to autoimmune disease – haemolytic disease of newborn (Rh- or ABO- incompatibility) – structurally abnormal RBCs (sickle cell disease) – breakdown of extravasated blood High plasma levels of unconjugated bilirubin – normal level ~17μmol/L  Intra-hepatic jaundice Also called hepatocellular jaundice Impaired uptake, conjugation or secretion of bilirubin Reflects generalized liver cell (hepatocyte) dysfunction (newborns, cirrhosis, hepatitis, genetic abnormalities etc.) Hyperbilirubinaemia usually accompanied by other abnormal biochemical markers of liver function (eg. elevated AST, ALT)  Post-hepatic jaundice Also called obstructive jaundice or choleostatic jaundice Caused by obstruction to biliary tract (e.g. gallstones, cancer) Plasma bilirubin conjugated Other bile constituents (e.g., bile acids) also accumulate in plasma Characterised by:- – pale stools (absence of faecal bilirubin or stercobilin) – dark urine (increased conjugated bilirubin) In complete obstruction, urobilin absent from urine  Differential diagnosis of jaundice Pre-hepatic Intra-hepatic Post-hepatic Conjugated bilirubin *Present Increased Increased ALT or AST Normal Increased Normal Alkaline phosphatase Normal Normal Increased (ALP) Urine bilirubin Absent Present Present Urine urobilinogen Present Present Absent *to discuss in lecture  Newborn jaundice Common, particularly in premature infants - characterized by yellowing of the skin and eyes - occurs 2-4 days after birth - due to immaturity of enzymes involved in bilirubin conjugation - accumulation of unconjugated bilirubin in the blood - usually transient, resolving within first 10 days of life Complications: – Free (unbound) unconjugated bilirubin may be deposited in brain Can cause encephalopathy leading to Kernicterus (rare form of brain damage) – Aggravating factors Haemolysis (infants have an increased turnover of RBCs) Breast feeding (dehydration can increase RBC lysis) Sulphonamides - displaces bilirubin from albumin Antibiotics – can inhibit glucuronyltransferase  Newborn jaundice Treatment: – Usually requires no treatment and resolves over first 10 days of life – Phototherapy (UV light) converts bilirubin to water-soluble, non-toxic form – Phenobarbitone administration (induces synthesis of UDP-glucuronyl transferase) – Exchange blood transfusion to remove excess bilirubin Jaundice within first 24 hrs of birth or which takes longer than 10 days to resolve is usually pathological – maternal/fetal incompatability of blood types – Bacterial/viral infection – Liver disease  Gilbert’s Syndrome most common inherited disorder of bilirubin conjugation Characterized by mild, fluctuating unconjugated hyperbilirubinaemia – often correlated with dehydration, fasting or illness Onset of symptoms is typically during adolescence – changes in sex hormones can affect bilirubin metabolism Caused by – reduced activity of UDP-glucuronyl transferase (UDP-glucuronosyltransferase) prevents in bilirubin conjugation in the liver Can be treated with phenobarbitone to stimulate UDP– glucuronyl transferase  Crigler-Najjar Syndrome Extremely rare autosomal recessive disorder presenting with severe unconjugated hyperbilirubinaemia usually present from birth Caused by mutation in gene coding for UDP-glucuronyl transferase (UDP- glucuronosyltransferase) – Type l - complete absence – Type ll - marked reduction in enzyme activity Affected individuals at high risk for kernicterus Treatment – Type l by liver transplant (in some cases) by 5 yrs of age – Type ll with phenobarbitone or phototherapy (10-12 hrs/day)  Dubin-Johnson Syndrome Benign genetic disorder presenting with conjugated hyperbilirubinaemia Most patients have lifelong, recurrent mild symptoms of jaundice Characterized by impaired biliary secretion of conjugated bilirubin (ie, intrahepatic jaundice) - mutation in gene coding for MRP-2 Jaundice may worsen with aggravating factors e.g., other illnesses, pregnancy and oral contraceptives Treatment not usually necessary Causes of jaundice  Case study I – NEWBORN ?? JAUNDICE 10 day old premature infant, born at 34 weeks gestational age, was clinically jaundiced. Plasma content Reference range – Bilirubin – total 166 μmol/L