7 Liver Failure and Jaundice Flashcards
Q: Why do we produce bile? (3)
A: Cholesterol homeostasis
Dietary lipid / vitamin absorption (particularly fat soluble ones: ADEK)
Removal of xenobiotics (foreign to body)/ drugs/ endogenous waste products (normal from within)
Q: Give 3 examples of endogenous waste products.
A: - cholesterol metabolites
- adrenocortical
- other steroid hormones
Q: What is the main composition of bile? %? 3 other components. What type of solution?
A: water 97%
- bile salts and inorganic salts
- bile pigments bilirubin (BR) and bilivirdin (smaller)
- fatty acids
in an alkaline electrolyte solution
Q: Name 4 other substances excreted into bile.
A: Adrenocortical and other steroid hormones
Drugs/Xenobiotics
Cholesterol
Alkaline Phosphatase (ALP)
Q: How much bile is secreted/produced daily? What colour is it and why? What produces it? (2) Percentages?
A: 500mL
Green/yellow colour because of glucoronides of bile pigments
60% bile secreted by hepatocytes (liver cells)
Up to 40% secreted by cholangiocytes (biliary epithelial cells that line biliary tree)
Q: Where does bile go from the organ of production and how?
A: Bile drains from liver, through bile ducts, into duodenum at duodenal papilla
Q: What is the role of the biliary tree in bile production? (6)
A: (40% bile secreted by cholangiocytes (biliary epithelium))
modifies bile as it flows through
- Alters pH
- alters fluidity
- H20 drawn out of 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 into bile
Q: What can a mutation in CFTR affect?
A: 1/3 those with CF have mutation in this
bile does not flow easily through liver and they get cholestasis (slow flow of bile)
Q: Draw a diagram showing a hepatocyte, cholangiocyte and bile flow.
A: REFER
Q: What is bile flow closely related to? Which structures govern the rate of bile flow? Dysruption causes?
A: conc 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
Q: What are the main transporters in cells that produce bile? (4-6 names)
A: Bile Salt Excretory Pump (BSEP)
MDR related proteins (MRP1 and MRP3)
products of the familial intrahepatic cholestasis gene (FIC1)
multidrug resistance genes (MDR1 and MDR3)
Q: What’s the role of BSEP? (2) What codes for it?
A: (important for bile acids)
active transport of bile acids across hepatocyte canalicular membranes into bile, and secretion of bile acids is a major determinant of bile flow
ABCB11 gene
Q: What’s the role of MDR1?
A: excretion of xenobiotics, cytotoxins into bile
Q: What’s the role of MDR3?
A: phosphatidylcholine movement
Q: What are bile salts? Synthesised from?
A: Bile acids are conjugated with taurine or glycine (cysteine derivative) in the liver, and the sodium and potassium salts of these conjugated bile acids are called bile salts (conjugated in liver)
Bile acids synthesised from cholesterol
Q: What are the 4 main bile acids in humans?
A: 2 PRIMARY Acids (formed in liver)
-Cholic acid -Chenodeoxycholic acid
converted by colonic bacteria
-Deoxycholic acid -Lithocholic acid
SECONDARY Acids
Q: What are the 2 main roles of bile? How can it do this? What property allows them to do this? Describe (3). Then what happens to them?
A: -Reduce surface tension of fats
-Emulsify fat preparatory to its digestion/ absorption in gut
Bile Salts form Micelles
- Bile salts amphipathic
- One surface has hydrophilic domains, facing OUT (can be carried by water in the bile)
- 2nd has hydrophobic domains, facing IN
- free Fatty Acids and Cholesterol INSIDE
thus transported to GI tract epithelial cells for absorption
Q: What can the action of bile salts be in high concentrations? potentially? How does present? explain.
A: Detergent-like actions make bile salts potentially cytotoxic in high concentrations
condition: ‘bile acid malabsorption’ where bile acid circulation doesn’t work-> too high a bile acid concentration in bile and therefore in the gut which can irritate colon -> gut irritation eg diarrhoea
Q: In terms of bile, what exits the 2 main lobes of the liver and what do they become when they connect? where? What structure connects to them after? followed by? in? ends? Movement is controlled by?
A: right and left hepatic duct (contain bile)
form hepatic duct
join at hilum just outside liver
gall bladder joins to it via its cystic duct to form common bile duct just before it goes to pancreas and joins pancreatic duct
enter duodenum via the ampulla of the bile duct (controlled by sphincter of Oddi)
Q: What happens to bile that enters the bile duct? why?
A: once meets cystic gut of gall bladder, usually the bile is diverted so that it goes to the gall bladder for storage
sphincter of oddi is closed between meals
Q: When does bile enter the duodenum? how?
A: 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 SoO to relax
Q: What is each hepatocyte apposed to in terms of the biliary system? What happens to the structures they appose?
A: several bile canaliculi
drain-> intralobular bile ducts, coalesce-> interlobular ducts -> R and L hepatic ducts -> join outside liver to form Common Hepatic Duct
Q: What is the structure of enterhepatic circulation? What enters it?
A: blood travelling between small intestine and liver
exit from liver: bile-> enter SI -> reabsorbed into terminal ileum -> transported to enterocytes-> enter portal blood-> taken up by hepatocytes -> excreted into canaliculis -> continue
liver: cells transfer various substances, including drugs, from plasma to bile
bile salts and some drugs
Q: Describe the enterhepatic circulation of drugs. What type? What does it become? allows?
A: Many hydrophilic drug conjugates (esp. glucoronide)
are concentrated in bile -> GUT -> glucoronide hydrolysed -> active drug re released -> reabsorbed -> cycle repeats
“reservoir” of re-circulating drug
can prolong action e.g. morphine
Q: What percentage of bile salts enter enterohepatic circulation? How? What happens to them? (4)
A: -95% bile salts absorbed from small (terminal) ileum - mainly
-by Na+/bile salt co-transport Na+-K+ ATPase system at cell surface
- 5% converted to secondary bile acids in colon:
- deoxycholate absorbed
- lithocholate 99% excreted in stool
-absorbed B.salts –portal vein–> back to liver -> re-excreted in bile
Q: What quantity of bile salt recycles in enterohepatic circulation? How often? (2) What would happen if bile stopped entering the gut? (2)
A: 3g (2x/meal; 6 – 8x/day)
- Up to 50% ingested fat appears in faeces
- malabsorption fat soluble vitamins (A,D,E,K)
Q: What does terminal ileal resection/disease cause? 2 examples.
A: decreased bile salt reabsorption and increased stool [fat] (because enterohepatic circulation interrupted and liver can’t increase rate of bile salt production enough to make it up)
cancer and crohns
Q: What are the functions of the gall bladder? (3) What can it do to bile? by? (2)
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 (intra-cystic pH)
Gall bladder can reduce volume of its stored bile by 80 – 90% by concentrating- removing water and not contents
Q: Complete table:
hepatic bile duct | gall bladder bile
% solids - bile salts mM/L - pH
A: 2-4………10-12
10-20……….50-100
7.8-8.6……..7-7.4
Q: What is a cholecystectomy? reasons? (2) How does this affect a person? What should they avoids?
A: surgical removal of gall bladder
- gall stones
- cancer
Normal health and nutrition exist with continuous slow bile discharge into duodenum
-Periodic discharge of bile from GB aids digestion BUT is NOT ESSENTIAL
Avoid foods with high fat content
Q: What is bilirubin? 3 sources?
A: water insoluble yellow pigment
75% BR from Hb breakdown in spleen
22% from catabolism of other haem proteins
2-3% from ineffective bone marrow erythropoiesis
Q: How is bilirubin excreted? Include the struggle with excreting BR in bile? Draw diagram to show.
A: is bound to albumin (protein made in liver) and carried in the blood -> in the liver most dissociates
BR is water insoluble while bile is mainly water
Free BR enters hepatocyte, binds cytoplasmic proteins -> conjugated to glucoronic acid (UDPGT enzyme from smooth ER)
=> becomes diglucoronide-BR (more soluble > free BR) via E: glucoronyl transferase
transported ACROSS concentration gradient into bile canaliculi -> enter GIT= gastro interstinal tract
REFER
Q: What makes up total BR? What’s the normal amount of BR in blood?
A: FREE BR (UNCONJUGATED) + CONJUGATED BR (smaller amount)
20microM/L
Q: What are urobilinogens? Where is it mainly formed? by? What happens to it? (3)
A: H2O-SOLUBLE, colourless derivatives of BR
mainly in the intestines by bacterial action on bilirubin
- 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.
- 20% urobilinogens reabsorbed into gen. circulation urine excretn
- Some urobilinogens passed in stool as Stercobilinogen
Q: What it the permeability of the GIT mucosa to conjugated BR, unconjugated BR and urobilinogens?
A: GIT mucosa (relatively) IMpermeable to CONJUGATED BR
but is PERMEABLE to UNCONJUGATED BR and Urobilinogens
Q: Why is faeces brown?
A: in colon= BR is reduced by gut bacteria action to stercobilinogen ->
Oxidation of stercobilinogen to stercobilin which is brown
Q: What causes jaundice? (3) How does it present? Relationship?
A: -Cholestasis: cessation of bile flow or problem in the pathway of BR metabolism and excretion
- Excess BR in blood (> 34 – 50microM/L)
- deposits in sclera of eyes and mucosal tissue
(yellow tinge to skin, sclerae, mucous membranes)
Cholestasis normally results in jaundice
Jaundice does not necessarily mean there is cholestasis
Q: What are the 3 main cause types of jaundice?
A: pre hepatic= before liver
hepatic
post hepatic
Q: What can cause pre hepatic jaundice? (4) How does conjugated and unconjugated BR vary? Look for? Tests? (3)
A: Increased quantity of BR being produced
- Haemolysis (destruction of RBC)
- Massive Transfusion
- Haematoma resorption (large blood clot= resolved)
- Ineffective erythropoiesis
majority unconjugated (normally 50/50)
Look for: Hb drop without overt bleeding; BR»>LFTs (lung function tests)
If you think it’s haemolysis-> Blood film; haptoglobins, LDH
Q: What can cause hepatic jaundice? (3) 2 examples.
A: defective hepatocytes
- Defective uptake
- Defective conjugation
- Defective BR excretion
Liver Failure:
Intrahepatic cholestasis
Q: What are the types of liver failure? (5) What can cause Intrahepatic cholestasis? (3) What can both these cause?
A: Acute/Fulminant Chronic Viral hep EtOH (alcohol) AID (autoimmune)
sepsis, Drugs, cirrhosis
hepatic jaundice
Q: What can post hepatic jaundice also be called? How is it caused? examples? (2) Look out for? Stool?
A: obstructive
Defective Transport of BR by Biliary duct system = get build up of BR e.g. common bile duct stones (gall stones that have moved), HepPancBil malignancy
Look out for sepsis (cholangitis)
pale stool: less BR, less stercobilinogen, less stercobilin = less brown
Q: What is Gilbert’s syndrome? Jaundice type? How many people does it affect? How?
What does it lead to? Consequences? When does jaundice appear?
A: Commonest hereditary cause of increased unconjugated bilirubin in blood stream (hepatic jaundice)
- Up to 5% of the population
- Autosomal recessive inheritance
Cause: 70%-80% reduction in glucuronidation activity of the enzyme UDPGT-1A1= slow enzyme= slow conjugation of BR
No serious consequences
Mild jaundice may appear under:
exertion, stress, fasting, infections
otherwise usually asymptomatic
Q: What is liver failure in simple terms? Broad mechanisms? (2) Clinical result?
A: hepatocyte destruction > regen
combination of apoptosis and/or necrosis
catastrophic illness…can rapidly lead to coma/death due to multi-organ failure
Q: Describe apoptosis as a cause of liver failure. (2) Eg cause?
A: Apoptosis (e.g. Acetaminophen= Paracetamol):
- nuclear shrinkage but no cell membrane rupture - therefore no release of intracellular content, no 2ndary inflammn
Q: Describe necrosis as a cause of liver failure. (2) Eg cause?
A: Necrosis (Ischaemia):
- assoc. with ATP exhaustion resulting in swollen cell - eventually lyses...release of intracellular content…2ndary inflammn
Q: What triggers the apoptosis of liver cells? example? Which is activated by? example?
What else regulated the pathways of hepatocyte death? (3)
A: activation of caspases (cysteine proteases) triggered e.g. after oxidative mitochondrial damage
Caspase cascade activated by cytokines e.g. TNF-alpha
- cellular nitric oxide (NO)
- antioxidants
- various pro- and anti-inflammatory cytokines e.g. IFN, IL-10, IL-12, natural killer cell-derived IL-5
Q: Any insult which can induce apoptosis may also lead to? especially if?
A: cell death by necrosis, esp if level of mitochondrial damage depletes ATP stores
Q: What is fulimant hepatic failure? Most common cause in west? east? What is Sub-fulminant hepatic failure?
A: rapid development (< 8wks) of severe acute liver injury with impaired synthetic function (INR/PT, albumin) + encephalopathy in person with previously normal liver or well-compensated liver disease
drug/paracetamol OD
hep B/E
longer (<6 months)
Q: What are the 2 clinical differences between fulimant and sub hepatic failure?
A: cerebral oedema common in fulminant, rare in subfulminant
Renal failure + portal hypertension more frequent in subfulminant
Q: What are the 3 classifications of fulimant hepatic failure?
A: Hyperacute Hepatic Failure (0-7 days)
Acute Hepatic Failure (8-28 days)
Subacute Hepatic Failure (29 days to 12 weeks)
after the onset of jaundice
Q: 3 toxin based causes of ALF?
A: Paracetamol (Severe toxicity certain > 25g) Amanita phalloides (fungus) Bacillus cereus (bacteria)
Q: Vascular cause of ALF?
Metabolic?
Pregnancy? (2)
A: Ischaemic hepatitis
Wilson’s disease
hepatic infarction, HEV
Q: How does hepatic failure affect:
- detoxification?
- glycogen storage?
- production of clotting factors?
- immunological function and globulin production?
- maintenance of homeostasis?
A: Encephalopathy (confusion and possible coma caused by cerebral oedema) and cerebral oedema (astrocyte swelling due to toxins in brain)
hypoglycaemia
coagulopathy and bleeding
increased susceptibility to infection (globulins make antibodies)
albumin produced by liver maintains oncotic pressure so without water leaves= reduced bp= circulatory collapse, renal failure
Q: Name 3 symptoms of acute liver failure.
A: Initially non-specific – malaise, nausea, lethargy
Jaundice
After a variable time period, encephalopathy
Q: What can cause death in ALF? (5)
A: Cerebral Oedema
Renal failure
Respiratory failure
Acid-base and electrolyte disturbance
Coagulopathy
Q: How can ALF be treated? What is crucial? Downsides if given to wrong patient? (3)
A: Emergency liver transplant is the only therapeutic intervention of proven benefit
Timing/selection of pts is crucial
Unnecessary transplant carries < 20% 1-year mortality
commits pt to lifelong immunosuppression
is expensive wastes a precious graft
Q: Survival rates of liver transplants?
A: 5 year survival rate ranges between 60-80%
Q: Enterohepatic circulation. Benefits? (2) Downside?
A: -This can be a healthy (and beneficial) process, for example in the recycling of bile salts (sometimes so efficiently that the same salts can be used twice to digest the same meal).
-This improves the digestion and absorption of fats.
One way the liver processes some drugs is to excrete them via bile (to avoid them going into circulation), and eventually the faeces. However they may get reabsorbed in the small intestine and re-enter the portal circulation cyclically, significantly increasing their half-life.
Q: What are the 3 major categories of jaundice?
A: haemolytic jaundice
jaundice caused by congenital hyperbilirubinamias
cholestatic jaundice
Q: What’s haemolytic jaundice?
A: 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
Q: What are the early signs of liver disease? (5) Later? (5)
A: Early stage symptoms tend to be generalised:
Lethargy Anorexia Malaise Pruritus – itchy skin Right upper quadrant pain
As disease progresses, the patient may notice:
Peripheral swelling Abdominal bloating Bruising Vomiting of blood Confusion and somnolence (drowsy)
Q: Various signs are caused by the reduced capacity of the liver to metabolise oestrogens. What are they? (5)
A: spider naevi – telangiectases (swollen blood vessels) consist of a central arteriole with radiating small vessels, found in the distribution of the superior vena cava.
loss of body hair
gynaecomastia - enlargement of the male breast with firm tissue extending concentrically beyond the nipple.
testicular atrophy
palmar erythema - ‘liver palms’ - reddening of palms at the thenar and hypothenar eminences – a non-specific change of hyperdynamic circulation
Q: What is cirrhosis? Characterised by? (3) Leads to? (3)
A: Cirrhosis is the final common pathway for liver disease.
It is characterised by necrosis of liver cells, followed by progressive fibrosis and nodule formation
which leads to the impairment of liver cell function and gross distortion of the liver architecture leading to portal hypertension and deterioration of liver function.
Q: What are the 2 types of cirrhosis? Often caused by?
A: Micronodular cirrhosis: uniform, small nodules up to 3 mm in diameter. This type is often caused by ongoing alcohol damage or biliary tract disease.
Macronodular cirrhosis: nodules of variable size. This type is often seen following chronic viral hepatitis.
Q: When does chronic hepatic failure occur? Time scale? AKA?
A: Chronic hepatic failure occurs where there is a deterioration in liver function superimposed on chronic liver disease.
The actual deterioration in the patient’s state may occur very rapidly - the patient may progress through confusion and stupor into coma in a matter of hours.
This sort of hepatic failure is also called decompensation, referring to the fact that previous problems with liver function had been well compensated
