Jaundice Flashcards
What is jaundice?
- yellow discoloration of skin + sclera
- as a result of hyperbilirubinaemia
- normal range of bilirubin = 3.4-20 umol/L
- jaundice may not be clinically evident until serum levels >50umol/L
- sclera tend to be first to become jaundiced
Describe the metabolism of haemoglobin after red cell breakdown
- bilirubin is a product of metabolism of Hb (80%) and other haem containing proteins (eg. myoglobin, C P450) (20%)
- degradation of Hb into bilirubin takes place in macrophages
- bilirubin is then excreted into plasma and binds w/ albumin
What happens next to the unconjugated bilirubin and how is it excreted?
- uptake of unconjugated bilirubin into hepatocyte
- unconj bilirubin converted to conjugated bilirubin by glucuronyl transferase (makes bilirubin water soluble)
- bilirubin secreted (as component of bile) into small intestine
- bacterial enzymes deconjugate bilirubin and convert it into urobilinogen
- 90% urobilinogen broken down further into stercobilinogen + stercobilin and excreted in faeces
- 10% urobiliniogen absorbed via portal vein
- majoriy of absorbed urobilinogen re-enters hepatocyte + re-excreted in bile (eneterohepatic circulation)
- rest of absorbed urobilinogen bypasses liver and is excreted by kidneys in urine
What can disruption of bilirubin metabolism and excretion lead to?
- hyperbilirubinaemia
- subsequent jaundice
- hyperbilirubinaemia may be unconjugated or conjugated depending on cause
What are examples of unconjugated hyperbilirubinaemias?
- Haemolytic
- Gilbert’s syndrome - UDP-glucuronyl transferase deficiency causing defective conjugation therefore increased unconjugated bilirubin, autosomal recessive, benign
- Crigler-Najjar syndrome - autosomal recessive, deficiency of UDP-glucuronosyl transferase, do not survive to adulthood (T1), type 2 is slightly more common and less severe and may improve w phenobarbital
What are examples of conjugated hyperbilirubinaemias?
- Dubin-Johnson + Rotor syndromes - defective excretion of conjugated bilirubin into biliary cannaliculi therefore elevated conjugated bilirubin
Both are autosomal recessive and benign, get a grossly black liver in Dubin-Johnson syndrome
How is jaundice classified?
- pre-hepatic
- intra-hepatic/hepatocellular
- post-hepatic/obstructive
What are pre-hepatic causes of jaundice?
- Haemolysis
- Gilbert’s syndrome
- Crigler-Najjar syndrome
What are causes of hepatocellular jaundice?
- Alcoholic liver disease
- NAFLD/NASH
- Viral hepatitis
- Autoimmune hepatitis
- Cirrhosis
- Haemochromotosis
- Autoimmune cholangitis
- Wilson’s disease
- Alpha-1-antitrypsin deficiency
- Drug-induced
- Pregnancy
- Malignancy
What are causes of post-hepatic jaundice?
- gallstones
- carcinoma (bile duct, head of panc, ampulla)
- biliary stricture
- sclerosing cholangitis
- pancreatic pseudocyst
- alcohol
- drugs
- cystic fibrosis
What questions are important to ask a jaundiced patient in the history?
- how long? happened before?
- associated symps: fevers? abdo pain? weight loss?
- pale stool, dark urine? (-> obstructive)
- recent foreign travel? country of origin?
- tattoos, IVDU, profession, piercings, blood transfusions, sexual partners?
- alcohol and drug history/intake
- medications?
- family history of jaundice?
- recent surgery?
What clinical features might you look/ask for with a jaundiced patient (examination)?
- hepatomegaly + texture
- splenomegaly
- hepatic encephalopathy
- chronic liver disease stigmata
- lymphadenopathy
- ascites
- palpable gallbladder
- pale stools + dark urine (=cholestatic)
What are differentials for jaundice?
- alcoholic liver disease
- choledocholithiasis
- Hep A, B, C, E
- NASH
- drug-induced
- ascending cholangitis
- autoimmune hep
- pancreatic carcinoma
- haemochromatosis
- pregnancy
- post-op stricture
- haemolysis
- Gilbert’s syndrome
What might be some accompanying symptoms of a patient with jaundice?
- fatigue
- abdominal pain
- weight loss
- vomiting
- fever
- pale stools
- dark urine
How can liver function tests help determine the type of jaundice - specifically conjugated and unconjugated bilirubin?
- Bilirubin (conjugated vs unconj levels) (urine bilirubin and urobilinogen levels)
Total bilirubin and its conjugated and unconjugated levels help to determine nature of jaundice
What other liver function tests apart from bilirubin are useful in determining aetiology of jaundice?
- ALT/AST mainly present in hepatocytes
- ALP/GGT mainly present in biliary tree
- derangement of particular liver enzymes in associated w/ jaundice can determine nature of jaundice
How does excretion of urine bilirubin change among pre-hepatic, hepatic and post-hepatic jaundice?
normally, tiny amount bilrubin (conjugated) excreted in urine
- pre-hepatic: hameolysis causes rise in unconj bilirubin (water insoluble) and this is not excreted by kidney therefore no rise in urine bilirubin
- hepatic: some causes result in damage to biliary tree + therefore result in poor biliary drainage + therefore elevated conjugated bilirubin levels in blood, excreted into urine (giving dark urine)
- post-hepatic: obstruction to biliary drainage so conjugated bilirubin (water soluble) levels in blood increase and appear in urine (dark urine)
How is urine urobilinogen levels different across pre-hepatic, hepatic and post-hepatic jaundice?
- pre-hepatic: haemolysis results in increased bilirubin prod and subsequent increased bilirubin metabolism and urobilinogen in stool + therefore in urine
- hepatic: some causes result in hepatocellular destruction and therefore reduced re-excretion of re-absorbed urobilinogen (ie. reduction in entero-hepatic circulation of urobilinogen) resulting in elevated levels in urine
- post-hepatic: less bilirubin reaching intestine therefore reduction in urobilinogen therefore reduction in urine urobilinogen
What other bedside and blood investigations apart from LFTs are important?
-
Bloods:
- FBC (low Hb -> haemolysis)
- LFTs, conjugated/unconj bilirubin
- Clotting (INR)
- U+Es (hepatorenal syndrome)
-
Urine:
- Bilirubin
- Urobilinogen
What specific tests can be done to look for pre-hepatic jaundice causes?
- sickle cell test
- serum electrophoresis
- blood film
What investigations can be done to look for hepatic causes of jaundice specifically?
- serum iron, ferritin, copper, a1-antitrypsin
- auto-antibody screen
- hepatitis screen
- Liver USS
What are obstructive causes of jaundice?
- luminal: gallstone
-
intra-mural:
- benign stricture (eg. as complication of cholecystectomy or due to pancreatitis)
- malignant stricture: cholangiocarcinoma
-
extra-mural:
- head of pancreas cancer
- pancreatitis (oedema of head of panc)
- pancreatic pseudocyst
- compression by malignant lymph nodes at porta hepatis
If a USS shows dilation of the CBD, then ERCP/MRCP or PTC can be done. How is an ERCP useful for jaundice investigations?
- used to assess biliary tree anatomy + determine cause of obstruction
- furthermore, obstruction can be relieved (diagnostic + therepeutic, but invasive)
- stone extraction w/ balloon trawel
- sphincterotomy
- biliary stent (if stricture)
- brushings for cytology
Many drugs impair liver function and should always be considered when there are mildly abnormal LFTs. Damage is usually classified as dose and non-dose dependent.
What are the possible mechanisms of damage by drugs to the liver?
- disruption of Ca<strong>2</strong>+ homeostasis
- disruption of canalicular transport mechanisms
- formation of non-functioning enzyme drug complexes
- complexes may present as antigens
- induction of apoptosis
- inhibition of mitochondrial function preventing fatty acid metabolism, and lactate and ROS accumulation
How does paracetamol impair liver function?
- normally paracetamol conjugated w/ glucuronide + sulphate
- a small portion is metabolised to highly reactive NAPQI, immediately conjugated w/ glutathione + secreted as cysteine + mercapturic conjugates
- xs paracetamol doses result in saturation of sulphate conjugation pathway
- so excess diverted into oxidation
- leads to excess prod of toxic NAPQI metabolite as glutathione stores depleted
- this binds to hepatocyte membranes -> liver necrosis
- IV N-acetylcysteine replenishes cellular glutathione, reducing NAPQI toxicity
How does halothane and volatile liquid anaesthetics cause liver impairment?
- repeated exposure causes hepatitis; thought to be hypersensitivity rxn
- unexplained fever occurs 10 days after ≥2 administrations followed by jaundice
- most recover, however there is high mortality in severe cases
- enflurane and isoflurane are hepatotoxic in sensitised individuals, but have lower risk than halothane
How do steroids impact on the liver?
- natural + synthetic oestrogens interfere w/ canalciular biliary flow -> pure cholestasis
- rare in contraceptive pill, but associated w/ inc gallstones, hepatic adenomas, Budd-Chiari and peliosis hepatis
- anabolic steroids also cause peliosis hepatis where there is dilation of hepatic sinusoids, forming blood filled lakes
How do phenothiazines (eg. cholorpromazine) impact the liver?
- can produce cholestatic condition owing to hypersensitivity rxn
- occurs in 1%, usually within first 4 weeks
- associated w/ fever + eosinophilia
How does Anti-TB chemotherapy impact on the liver?
- isoniazid causes elevated aminotransferases in 10-20% w/ hepatic necrosis and jaundice in smaller %
- hepatotoxicity of isoniazid is thought to be due to its metabolites from acetylation
- rifampicin causes hepatitis, usually within weeks, esp high doses
- pyrazinamide causes abnormal LFTs + rarely liver necrosis
How does amiodarone impact on the liver?
- leads to steatohepatitis + liver failure if drug not stopped in time
