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Khaled Abu – Rumman
Ala’ Eddin Abu – Shareb
------------------------------------Prof. Fouad Ammari

Bilirubin metabolism
Special investigations

What is jaundice


Jaundice is not a disease but
rather a sign that can occur in
many different diseases.
Jaundice is the yellowish
staining of the skin ,
sclerae (the whites of the
eyes) and other mucous
membranes that is caused
by high levels in blood of
the chemical bilirubin.
The color of the skin and
sclerae vary depending on the
level of bilirubin. When the
bilirubin level is mildly
elevated, they are yellowish.
When the bilirubin level is high,
they tend to be brown.

Normal serum total bilirubin is >>

5-17 μmol/L (< 1 mg/dL)
Jaundice is clinically evident when serum

total bilirubin > 2-3x normal (2.5 mg/dL)

Bilirubin metabolism .


cytochromes (20 to 25%) Hemoglobin (70 to 80%) Heme Heme oxygenase Biliverdin Biliverdin reductase Bilirubin albumin indirect unconjugate d pre-hepatic .Bilirubin Production Heme proteins myoglobin.


Bilirubin Excretion Bilirubin diglucuronide 2 glucuronate 90% liver Bacterial enzyme Bilirubin Bacterial enzyme intestines Urobilinogen --------> 10% kidneys 20% Bacterial enzymes 80% Stercobilinogen Urobilin Stercobilin urine feces .

Hyperbilirubinaemia  Disruption of bilirubin metabolism and excretion can cause hyperbilirubinaemia and subsequent jaundice  Hyperbilirubinaemia maybe unconjugated (indirect) or conjugated (direct) depending on the cause  Some inherited syndromes of bilirubin handling can result in hyperbilirubinaemia  Gilbert’s syndrome – reduced activity of glucuronyl transferase therefore reduced conjugated bilirubin therefore elevated unconjugated bilirubin  Criggler-Najjar – reduction in amount of glucoronyl transferase therefore elevated unconjugated bilirubin  Rotor’s/Dubin-Johnson syndrome – defective excretion of conjugated bilirubin into the biliary cannaliculi therefore elevated conjugated bilirubin .

Prehepatic jaundice Hemolytic disorders Thalassemias G6PD deficiency Hereditary spherocytosis Autoimmune hemolytic anemias Incompatible blood transfusion “A healthy liver can excrete 6x the normal load of bilirubin before unconjugated bilirubin starts to accumulate” Gilbert syndrome. Criggler-Najjar syndrome .

Alcohol. autoimmune.g. viral. primray biliary cirrhosis . Dubin-Johnson syndrome Can result in hepatocyte destruction and therefore unconjugated hyperbilirubinaemia or in bile cannaliculi destruction and therefore conjugated hyperbilirubinaemia or both . Primary sclerosing cholangiti haemochromatosis. wilsons. Druginduced. ) Rotor’s syndrome.Hepatocellular jaundice Intra-Hepatic Basically any acute or chronic liver disease!  Viral hepatitis Drug-induced hepatotoxicity Alcoholic and non- alcoholic liver disease (NASH) PBC PSC Autoimmune hepatitis Hemochromatosis Wilson’s disease Cirrhosis Liver tumors  All the causes of hepatitis/cirrhosis (e. alpha-1 antitrypsin deficiency .

.   4-TRAUMA 5-IDIOPATHIC 6-RADIOTHERAPY Malignant stricture: cholangiocarcinoma External compression:  pancreatitis . GASTRECTOMY. CHOLANGITIS . . PANCREATITIS. SCLEROSING CHOLANANGITIS. choledocal cyst . Mirizzi syndrome . hilar lymphadenopathy. hydatit cysts worms Wall pathologies: Intra-mural Benign stricture 1-BILIARY ATRESIA  2-IATROGENIC: BILIARY SURGERY . Pancreatic pseudocyst tumor of the ampulla of Vater. tumor of the head of the pancreas. HEPATIC RESECTION .LIVER TRANSPLANT  3-INFLAMMATORY.Obstructive jaundice: Post-hepatic Intraluminal obstruction: stones .oedema of head of pancreas.




MIRRIZI`s syndrome .




Some causes of Hepatic jaundice : result in hepatocellular destruction and therefore reduced re-excretion of re-absorbed urobilinogen (i. Reduction in entero-hepatic circulation of urobilinogen) resulting in elevated levels in urine  Post-Hepatic jaundice: Less bilirubin reaching intestine therefore reduction .Urine bilirubin Normally. tiny amount bilirubin (conjugated) excreted in urine * Pre-hepatic jaundice: Haemolysis causes rise in unconjugated bilirubin (water insoluble) and this is not excreted by the kidney therefore there is no rise in urine bilirubin * Some causes of Hepatic jaundice: result in damage to biliary cannaliculi and therefore result in poor biliary drainage and therefore elevated conjugated bilirubin levels in blood. excreted into urine (giving dark urine) * Post-Hepatic juandice: Obstruction to biliary drainage and so conjugated bilirubin (water soluble) levels in the blood increase and appear in the urine (giving dark urine) Urine urobilinogen Pre-hepatic jaundice: Haemolysis results in increased bilirubin production and subsequent increase bilirubin metabolism and urobilinogen in stool and therefore in the urine.e.

thalassemia)? DH any new medications that can cause jaundice? SH excess alcohol intake FH of jaundice (inherited disorders of bilirubin metabolism) . SCD. multiple sexual partners)? PMH of blood disorders (e. malaria)? Any risk factors for hepatitis (tattoos.g. blood transfusions. IVDU. high risk professions.Determining Aetiology of Jaundice: History           How long been jaundiced? Ever been jaundiced before? Any associated fevers or abdominal pain or weight loss? Pale stool and dark urine (suggests obstructive/post-hepatic jaundice)? Any recent foreign travel (hepatitis.

C If jaundice occuring on a background of alcohol abuse think alcoholic liver disease If jaundice is painless and family history of blood disorder think pre-hepatic jaundice .E) or malaria If jaundice occuring in patient with risk factors think hepatitis B.Determining aetiology of Jaundice: History       If jaundice associated with background of intermittent RUQ pains think gallstones and choledocholithiasis If jaundice associated with long history of upper abdominal pain and weight loss and patient elderly thing pancreatic cancer If jaundice associated with recent foreign travel think hepatitis (A.

Examination Jaundice Abdominal examination .

Skin 1.Mucous .Sclera 3.Jaundice 2.

Liver failure and liver cirrhosis Early signs : Finger clubbing Leukonychia Spider naevi Body hair loss Palmer erythema Duputyrens contracture Late signs : Jaundice Ill looking Teticular atrophy <<<>>> gynaecomastia Ascites Flapping tremor ( asterixis ) caput medusa Encephalopathy Intellectual change Convulsions Coma .

Early signs : Leukonychia Finger clubbing Palmer erythema .

Duputyrens contracture Spider naevi .

Late signs : caput medusa Ascite s .

Flapping tremor ( asterixis ) Gynecomastia .

palpable .. non tender + mild jaundie :::::: courvoisires signs :::: malignant CBD obstruction not stone Percussion: Auscultation. Hepatic Postgallbladder Pre-hepatic hepatic splenomegaly Present Present absent Gallbladder >>> enlarged ...Examination Abdominal examination :: Palpation: liver : enlarged or shrunken tenderness. liver span . ascites . .

angiography Biopsy .Investigations Labs Imaging: U/S . MRCP. nuclear medicine. CT. MRI. PTC. ERCP.

 Total bilirubin and its conjugated and unconjugated levels help to determine nature of jaundice Test Pre-hepatic Hepatic Post-hepatic Total bilirubin + ++ +++ Conjugated bilirubin Normal Increased Increased Unconjugated bilirubin Increased Increased Normal .

Determining aetiology of jaundice  Liver Enzymes  ALT/AST mainly present in hepatocytes  ALP/GGT mainly present in bile cannaliculi biliary tree Test Pre-hepatic Hepatic Post-hepatic ALT/AST Normal +++ raised + ALP/GGT Normal + +++ raised .

Test Pre-hepatic Hepatic Post-hepatic Urine colour Normal Normal Dark If Dark (urobilinogen + conjugated bilirubin ) (conjugated bilirubin ) Urine Bilirubin negative Negative Increased Urine urobilinogen Increased Normal present Decreased/negative Stool colour Normal Normal Pale .

..Alfa fetoprotein Primary Biliary Cirrhosis .Hepatitis serology -Antimitochondrial Ab .CBC and Reticulocyte count ( raised in Hemolysis ) -Test Albumin Prehepatic Hepatocellular Obstructive Blood glucose Normal Low if liver failure May be raised in pancreatic CA Haptoglobin Low Normal or low if liver failure Normal PT / INR Normal Prolonged Prolonged .

 2B. The same could be true of a tumour but usually by the time clinical jaundice is evident both intra and extraheptic bile ducts will be dilated. Ex : “medical” jaundice such as viral hepatitis. Ex as ductal gall stones and . drug induced cholestasis or hepatitis. Only the common bile duct is dilated(+10mm). The diagnosis that must be considered and excluded in this situation is hilar cholangiocarcinoma. noninvasive. the cause of the jaundice is at a cellular level or involving microspcopic bile ducts too small to visualize on a scan. autoimmune hepatitis. no radiation  1. Mirrizzi syndrome and gall bladder cancer.Imaging Ultrasound  Cheap. good sensitivity . metabolic disorders. All of the bile ducts inside the liver (intrahepatic) and outside of the liver (extrahepatic) are dilated. There is no duct dilatation either in the liver or in the extrahepatic bile ducts. .  3. primary biliary cirrhosis and so on. stricture secondary to pancreatitis or malignant distal bile duct cholangiocarcionoma or periampullary cancer.  2A.when a gallstone has blocked the lower end of the bile duct but there has not been sufficient time for the intrahepatic bile ducts to become dilated. The other less common alternative diagnoses include primary sclerosing cholangitis.Its rare and implies that the cause of obstruction is at the hilus of the liver. The level of obstruction must be at the lower end of the common bile duct. pancreatic cancer. The intrahepatic bile ducts are dilated (+4mm) but the extrahepatic bile duct is collapsed and non-dilated.

diagnosing and staging pancreatic and periampullary cancers.Gallstone cholangiocarcino ma Endoscopic U/S provides accurate imaging of stones in CBD. FNA can be used with the advantage of avoiding spillage of tumor cells into the peritoneal cavity .

g.CT computed tomography scan  Triple-phase spiral CT is the gold standard for liver imaging  Very useful for hepatic and pancreatic masses. may be used to guide biopsy  MRI may be a good alternative (e. patients who can’t take contrast) Liver mets .

.MRCP Magnetic resonance cholangiopancreatography Noninvasive visualization of biliary and pancreatic ducts Same quality of ERCP and PTC without the potential complications . Not therapeutic ...

g.ERCP Endoscopic retrograde cholangiopancreatography endoscopy and fluoroscopy Diagnostic Chronic pancreatitis Gallstones with dilated bile ducts on ultrasonography Bile duct tumors Suspected injury to bile ducts either as a result of trauma or iatrogenic Sphincter of Oddi dysfunction Pancreatic tumors Therapeutic Endoscopic sphincterotomy Removal of stones Insertion of stent Dilation of strictures (e. primary sclerosing cholangitis. anastomotic strictures after liver transplantation) .


If failed ERCP used to perform biliary drainage . metal stents can be placed across malignant biliary strictures to allow palliative drainage .PTC Percutaneous Transhepatic Cholangiography used to visualize the anatomy of the biliary tract.


Nuclear medicine HIDA (hepatobiliary iminodiacetic acid ) scan is used for gallbladder abnormalities Acute cholecystitis: GB will not take isotope in filling phase Biliary obstruction: failure/incomplete excretion of isoptope in secretory phase PET scan is useful for detecting primary and secondary liver malignancies .


PT should be corrected before biopsy . In the presence of jaundice.Biopsy U/S-guided needle biopsy of the liver may be warranted if no biliary dilation was found to demonstrate hepatic pathologies. Also useful for hepatic lesions.

antihistamines. ursodeoxcolic acid Fat-soluble vitamins Pre-operatively. make sure that the patient is wellhydrated and has no coagulopathy Surgical options Laparoscopic cholecystectomy Resection of neoplastic lesion Sphinctertomy .management Always manage the underlying cause Pruritis can be managed by cholestyramine. Stent insertion Liver trnasplant .