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Alimentary system > Liver failure and jaundice > Flashcards

Liver failure and jaundice Flashcards

1
Q

Is Liver failure the only cause of jaundice

A

No

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2
Q

List the functions of bile

A

Cholesterol homeostasis

Dietary lipid (bile salts solubilise lipids and vit A/D/E/K) / vitamin absorption

Removal of xenobiotics/ drugs/ endogenous waste products

e. g. 
- cholesterol metabolites
- adrenocortical 
- other steroid hormones
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3
Q

Describe the composition of human bile

A 
Water- 97%
Bile salts- 0.7%
Inorganic salts- 0.7%
Bile pigments (Bilirubin, Bilverdin)- 0.2%
Fatty acids- 0.15%
Lecitihin- 0.1%
Cholesterol- 0.06%
Drug metabolites- higher molecular weight- ones that can't be filtered
Trace metals- Fe, Zn, Mn, Pb, Cu
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4
Q

What other substances may be secreted into bile

A

Adrenocortical and other steroid hormones
Drugs/Xenobiotics- for excretion in faeces with bilirubin
Cholesterol- to fine tune serum concentrtions
Alkaline Phosphatase (ALP)

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5
Q

Summarise the composition of bile

A

Bile is 97% water and exists in an alkaline solution

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6
Q

How much bile is produced each day

A

500ml produced/secreted daily

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7
Q

What is the colour of bile

A

Green/yellow colour due to glucoronides of bile pigments

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8
Q

Where is bile produced

A

Bile is produced from 2 distinct areas:
o 60% by hepatocytes.
o 40% by Cholangiocytes (biliary epithelial cells) in the biliary tree.

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9
Q

Where does bile drain

A

Bile drains from liver, through bile ducts, into duodenum at duodenal papilla

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10
Q

Explain the role of the biliary tree in bile production

A

Alters pH, fluidity and modifies bile as it flows through

H20 drawn INTO bile (osmosis through paracellular junctions)

Luminal glucose and some organic acids also reabsorbed

HCO3- and Cl- actively secreted INTO bile by CFTR mechanism (Cystic Fibrosis Transmembrane Regulator)

Cholangiocytes contribute IgA by exocytosis

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11
Q

What governs bile flow

A

Bile flow closely related to concn of bile acids and salts in blood

Biliary excretion of bile salts and toxins performed by transporters on apical surface of hepatocytes + cholangiocytes

These biliary transporters also govern rate of bile flow

Dysfunction of the transporters is a cause of cholestasis

Pump bile acids in and out of tree changing pH, HCO3- and cl- facilitating flow of bile

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12
Q

What are the main transporters of the biliary tree

A

Bile Salt Excretory Pump (BSEP)
MDR related proteins (MRP1 & MRP3)
products of the familial intrahepatic cholestasis gene (FIC1) and multidrug resistance genes (MDR1 & MDR3).

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13
Q

Describe the role of BSEP

A

BSEP (ABCB11 gene): active transport of bile acids across hepatocyte canalicular membranes into bile, and secretion of bile acids is a major determinant of bile flow

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14
Q

Describe the role of MDR1

A

MDR1: mediates canalicular excretion of xenobiotics, cytotoxins

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15
Q

Describe the role of MDR3

A

MDR 3: encodes a phospholipid transporter protein that translocates phosphatidylcholine from inner to outer leaflet of canalicular membrane

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16
Q

Describe the importance of these transporters

A

if they stop working (genetic mutations)- abnormal bile flow- too thick- cholestasis

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17
Q

What are bile salts produced from

A

Na and K salts of bile acids (conjugated in liver) to glycine and taurine (cysteine derivative)

Bile acids synthesised from cholesterol

Four bile acids in humans:

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18
Q

Describe how secondary bile acids are produced from primary bile acids

A

§ There are 4 bile salts in humans:
o 2 Primary Acids: 2 Secondary Acids: Cholic Acid à Deoxycholic Acid
Chenodeoxycholic Acid à Lithocholic Acid
§ The conversion of primary (formed in the liver) to secondary occurs via colonic bacteria.

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19
Q

Describe the functions of bile acids

A

Reduce surface tension of fats
Emulsify fat preparatory to its digestion/absorption
Remember bile is watery and fats are insoluble in water- bile salts envelope around them to allow them to be carried in bile

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20
Q

Describe bile salt micelles

A

Bile salts amphipathic
One surface has hydrophilic domains, facing OUT
2nd has hydrophobic domains, facing IN
free Fatty Acids and Cholesterol INSIDE
thus transported to GIT epithelial cells for absorption

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21
Q

What is the danger of high concs of bile salts

A

Detergent-like actions make bile salts potentially cytotoxic in high concentrations

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22
Q

What is the ampulla of the bile duct controlled by

A

The sphincter of oddi

This is normally closed- so the bile produced from the liver is stored in the gall bladder

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23
Q

Describe the anatomy of the biliary tree

A

Each hepatocyte is apposed to several bile canaliculi

these drain into intralobular bile ducts, coalesce
interlobular ducts —– Right/Left Hepatic Ducts
join outside liver to form Common Hepatic Duct

Cystic Duct drains the gall bladder

Cystic Duct unites with Common Hepatic Duct to form COMMON BILE DUCT (CBD)

CBD joined by Pancreatic Duct prior to entering duodenal papilla

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24
Q

What happens in response to eating

A

Between meals duodenal orifice closed, therefore bile diverted into gall bladder for storage

Eating causes sphincter of Oddi to relax

Gastric contents (F.As, A.As > CHOs) enter duodenum causing release of cholecystikinin, CCK (Gut mucosal hormone)

Cholecystikinin causes gall bladder to contract and to relax sphincter of oddi

25
Q

Describe the roles of the enterohepatic circulation in prolonging drug action

A

Liver cells transfer various substances, including drugs, from plasma to bile
Many hydrophilic drug conjugates (esp. glucoronide) are concentrated in bile – GUT
Glucoronide hydrolysed in gut — active drug released — reabsorbed- - cycle repeated
“reservoir” of re-circulating drug
can prolong action e.g. morphine
therefore we need to adjust dose- but not all the compound enters the enterohepatic circulation

26
Q

Describe the enterohepatic circulation of bile salts

A

o 95% of bile salts reabsorbed in the terminal ileum by Na+/bile-salt co-transport. (Na+/K+ ATPase system )
§ Terminal ileum disease/resection – less resorption = more fatty stool as less bile salt excreted (liver cannot sustain production) and malabsorption of fat-soluble vitamins (A, D, E, K).
o 5% are converted to secondary bile acids in the colon by colonic bacteria:
§ Deoxycholate absorbed.
§ Lithocholate excreted in stool (99% of it).
o Reabsorbed salts go via the portal veins, back to the liver to be re-excreted in bile.
o 3g of bile salts at any one time, secreted 2x a meal.
0.2 g excreted each day

27
Q

How many times is bile released a day

A

3g bile salt pool re-cycles repeatedly in enterohepatic circulation (2x/meal; 6 – 8x/day)

28
Q

Describe the consequence of Terminal Ileal Resection/Disease

A

bile salt reabsorption and stool [fat] (because
decreased bile reabsorption and increased stool (fat)
enterohepatic circulation interrupted and liver can’t increase rate of bile salt production enough to make it up)
could be chron’s disease or an abscess
sometimes misdiagnosed as I.B.S

29
Q

What happens if bile is stopped from entering the gut

A

If bile stopped from entering Gut:
Up to 50% ingested fat appears in faeces
malabsorption fat soluble vitamins (A,D,E,K)

30
Q

Describe the functions of the gall bladder

A

Stores bile (50ml), released after meal for fat digestion

Acidifies bile

Concentrates bile by H20 diffusion following net absorption of Na+, Cl-, Ca2+, HCO3 (decreasing intra-cystic pH)

- Gall bladder can reduce volume of its stored bile by 80 – 90%
31
Q

Compare hepatic duct bile to gallbladder bile

A

Gallbladder bile- greater percentage of solids
Greater conc of bile salts
lower pH

32
Q

What are the effects of cholecystectomy

A

Periodic discharge of bile from GB aids digestion BUT is NOT ESSENTIAL

Normal health and nutrition exist with continuous slow bile discharge into duodenum

Avoid foods with high fat content

33
Q

Summarise bilirubin conjugation

A

Bilirubin is derived predominantly from haemoglobin breakdown in the spleen and carried in the blood, bound to albumin.
BR-albumin in blood dissociates at the liver and free BR enters the hepatocyte and joins to P protein (intracellular binding proteins) to form bilirubin P
Bilirubin P joins to UPGDA (uridine diphospho-glucoronic acid)
this is broken down:
Glucuronyl transferase catalyses production of bilirubin diglucuronide and UDP
transported ACROSS concentration gradient into
bile canaliculi GIT

34
Q

What is the total BR in the blood equal to

A

TOTAL BR = FREE BR (UNCONJUGATED) + CONJUGATED BR

35
Q

What are urobilinogens

A

Urobilinogens = H2O-SOLUBLE, colourless derivatives of BR formed by action of GIT bacteria

36
Q

What can happen to urobilinogens

A 
urobilinogen is formed mainly in the intestines by bacterial action on bilirubin glucoronides . About half of the urobilinogen formed is reabsorbed and taken up via the portal vein to the liver, enters circulation and is excreted by the kidney.
GIT mucosa (relatively) IMpermeable to CONJUGATED BR
but is PERMEABLE to UNCONJUGATED BR and Urobilinogens

Therefore some UNCONJUGATED BR enters enterohepatic circulation; and some forms urobilinogens

20% urobilinogens reabsorbed into gen.circulation urine excretn

37
Q

What can urobilinogen be converted into

A

Some urobilinogen is reabsorbed and excreted by the kidneys in urine. Urobilinogen is also converted by bacteria in the gut to stercobilinogen . Most of the stercobilinogen is oxidized to stercobilin (responsible for the brown colour of faeces) within the gastrointestinal tract. Roughly 10% of the stercobiliogen is reabsorbed and returned to the liver via the portal circulation - enterohepatic circulation

38
Q

How are urobilinogens passed in stool

A

Some urobilinogens passed in stool as Stercobilinogen

39
Q

How much urobilinogen is reabsorbed

A

§ Half of urobilinogen (UBR) formed is reabsorbed –portal vein to liver – circulation– kidney – excreted.
o 50% formed is reabsorbed from the gut, 50% is excreted in stool.
§ 20% of the 50% reabsorbed into the general circulation is excreted in urine.
§ 50% of urobilinogen is passed in the stool as Stercobilinogen.
· Faeces are brown as Stercobilinogen is oxidised to stercobilin

40
Q

What is cholestasis

A

Cholestasis: slow/cessation of bile flow

41
Q

What is meant by jaundice

A

Jaundice: Excess BR in blood (> 34 – 50microM/L)
Normal BR <21 microM/L
(yellow tinge to skin, sclerae, mucous membranes)

42
Q

Describe the relationship between cholestasis and jaundice

A

Cholestasis normally results in jaundice

Jaundice does not necessarily mean there is cholestasis

43
Q

Describe pre-hepatic jaundice

A 
Increased quantity of BR:
 Haemolysis
 Massive Transfusion
 Haematoma resorption
 Ineffective erythropoiesis

RBCs dying quicker than 120 days due to haemolysis (drugs, leukaemia, sepsis, infection)
BR goes up faster than downstream path can deal with

44
Q

What is pre-hepatic jaundice characterised by

A

§ Hb drop without overt bleeding.
Haemolytic anaemias eg sickle cell disease.
↑ breakdown of red blood cells → ↑ production of bilirubin → jaundice.
Remember this is unconjugated bilirubin, which is not water soluble, therefore does not pass into the urine.
↑ serum urobilinogen but otherwise normal liver biochemistry.

45
Q

Describe the investigations for pre-hepatic jaundice

A

Blood film: haptoglobins, LDH.

46
Q

Describe intra-hepatic jaundice

A

Normal BR entering liver
Defective uptake

Defective conjugation

Defective BR excretion
due to disease killing hepatocytes
high unconjugated bilirubin

47
Q

What can cause hepatic jaundice

A 
Liver Failure:
 Acute/Fulminant- sudden- often due to paracetamol overdose 
 Acute on Chronic
 Viral hepatitis, EtOH (ethanol)
, Autoimmune disease etc.

Intrahepatic cholestasis:
sepsis, TPN (total parenteral nutrition- I.V nutrition), Drugs

48
Q

Describe post-hepatic/obstructive jaundice

A

Defective Transport of BR by Biliary duct system e.g. common bile duct stones, HepPancBil malignancy, local LNpathy, cholangiocarcinoma (cancer of bile duct)

Look out for sepsis (cholangitis)

Dilated bile ducts on scans

49
Q

What is post-hepatic/obstructive jaundice characterised by

A

§ Very usually by cholangitis.
§ Stool pale – as less stercobilin.
§ Urine dark as more BR sent to kidneys.
Predominately conjugated BR

50
Q

How is post-hepatic/obstructive jaundice caused

A

Blockage blocks bile duct- above blockage- bile duct dilates

less enters colon and duct- less stercobilin- faeces will be pale

51
Q

Describe Gilbert’s syndrome

A

Commonest hereditary cause of increased bilirubin
Up to 5% of the population
Autosomal recessive inheritance
Elevated unconjugated bilirubin in bloodstream

52
Q

What causes Gilbert’s syndrome

A

Cause: 70%-80% reduction in glucuronidation activity of the enzyme Uridine-diphosphate-glucuronosyltransferase isoform 1A1 (UDPGT-1A1).
Converts bilirubin to bilirubin diglucuronide more slowly- especially under stress

53
Q

When is Gilbert’s syndrome symptomatic

A

No serious consequences
Mild jaundice may appear under:
exertion, stress, fasting, infections
otherwise usually asymptomatic

54
Q

How is Gilbert’s syndrome diagnosed

A

Raised unconjugated hyperbilirubin .
Otherwise normal liver biochemistry.
Normal full blood count, smear and reticulocyte count (thus excluding haemolysis)
Absence of signs of liver disease

55
Q

Describe the management for Gilbert’s syndrome

A

Reassure the patient that no further investigation or treatment is necessary

56
Q

List some other congenital abnormalities that can result in Jaundice

A

Crigler-Najjar, Dubin Johnson, Rotor’s syndromes are rare.

57
Q

What are the investigations for obstructive jaundice

A

§ CT or MRCP, ultrasound etc.

MRCP = magnetic resonance cholangiopancreatography

58
Q

Describe cholestatic jaundice

A

Cholestatic jaundice is caused by the failure of bile secretion by the liver or bile duct obstruction. This is divided into intrahepatic and extrahepatic cholestasis.
Intrahepatic cholestasis is caused by hepatocellular swelling or abnormalities at cellular lever of bile excretion.
Extrahepatic cholestasis results from the obstruction of bile flow at any point distal to the bile canaliculi.

It is important to differentiate between intrahepatic and extrahepatic cholestatic jaundice as management is quite different.

59
Q

How does the liver balance the loss of bile salts

A

Bile salts may be recycled up to 10 times per day with loss of only 5% into the faeces. To balance the loss, the liver produces 0.1-0.5mg per day of new (primary) bile salts.
95% recycled and 5% made in pool

Alimentary system (15 decks)

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