Jaundice and liver failure

Question 1

what is the function of bile

Answer 1

cholesterol homeostasis - increase/decrease conc
absorption and digestion - of lipids by emulsification and solubisation, and vitamins ADEK
toxin excretion - eliminated in faeces, endogenous/exogenous eg cholesterol metabolites, adrenocortical, steroid hormones

Question 2

how much of bile is water

Answer 2

97%

Question 3

substances that are secreted into bile

Answer 3

adrenocortical and other steroids
drugs/xenobiotics
cholesterol
alkaline phosphatase

Question 4

where does bile come from

Answer 4

secret 1/2L/day
hepatocytes secrete primary bile - reflective of conc of blood in sinosoids - 60%
cholangiocyts - modify bile, reabsorb as required of sugar and acid, secretion of HCO3- and cl-, IgA exocytosed into bile -mmune func - 40%

Question 5

describe the pathway of the biliary tree

Answer 5

starts in bile canaliculi exit to hepatocytes - prouce biule
drain into suctiles
drain into small bile ducts - intralobular
drain into interlobular bile ducts
merge to form L and R hepatic ducts
convege to common hepatic duct
connects to cystic duct
connects to gall bladder (not part of tree)
merge of common hepatic duct and cystic duct form common bile duct which extend to duodenum
at distal end pancreatic duct joins and vessel is called ampulla of Vater
opens to medial wall of duodenum at duodenal papilla

Question 6

what happens to the bile as it goes through the biliary tree

Answer 6

alters pH
H2O drawn in to bile - osmosis paracellularly
luminal glucose and organic acids are reabsorbed
HCO3- and Cl- actively secreted into bile by CFTR
cholangiocytes contribute IgA by exocytosis into bile

Question 7

what governs the rate of the bile flow

Answer 7

biliary transporters on apical surface of hepatocytes and cholangiocytes
they perform the excretion of bile salts and toxins
pump bile acid in and out of bile
change cl, H and pH -> make bile more fluid
genetic - dysfunction = cholestasis

Question 8

what are the main bile transporters

Answer 8

bile salt excretory pump (BSEP)
MDR related proteins (MRP1, MRP3)
products of the familial intrahepatic cholestasis gene (F1C1) and multidrug resistant genes (MDR1 MDR3)

Question 9

describe the bile salt excretory pump

Answer 9

controlled by ABCB1 gene
AT of bile acids into bile across canalicular membrane
secretion of acids

Question 10

describe MDR1

Answer 10

mediate canalicular excretion of xenobiotics and cytotoxins

Question 11

describe MDR3

Answer 11

encodes phospholipid transporter

that translocates phosphatidylcholine from inner to outer leaflet of canalicular membrane

Question 12

what are bile salts

Answer 12

component of bile
cholic acid and chenodeoxycholic converted to deoxycholic acid and lithocolic acid (secondary acids) by colonic bacteria
amphipathic = hydophobic and philic region

Question 13

function of gut bacteria on bile salts

Answer 13

convert primary bile salts to secondary
cholic - deoxycholic acid
chenodeoxyxholic - lithocolic acid

Question 14

function of bile salts

Answer 14

reduce fat surface tension
emulsify fat for digestion/absorption
micelles = larger surface area

Question 15

structure of micelles

Answer 15

amphiphilic
philic - out
phobic - in
FFA and chol - in

Question 16

problem with bile salts

Answer 16

detergent like -> cytotoxic in high conc
= not reabsorbed = gut irritation = diarrhoea
OR intrahepatic cholestasis of pregnancy = damage foetus - cardiac

Question 17

describe the actions of the sphincter of Oddi

Answer 17

when don’t eat - closed - bile goes to cystic duct to gall bladder
when eat - gastric contents entering duodenum trigger release of cholecystokinin - sphincter relax - gall bladder squeeze - bile inter duodenum

Question 18

describe the enterohepatic circulation

Answer 18

from liver in bile -> gut -> intestine -> liver

substances cycle between gut and liver by cont reabsorption in gut - carriage in portal to liver and hepatic secetion inyo bile canaliculi
recycle bile salts - reabsorbed from the portal circulation into liver by active transport
drugs might get reabsorbed - increasing their half life

Question 19

describe the enterohepatic circulation of bile salts

Answer 19

absorbed bile salts go to liver via portal vein -> liver -> re-excreted as bile
95% reabsorbed from terminal ileum
by Na/bile salt co-transport Na/K ATPase system
5% converted to secondary bile acids in colon - deoxycholate absorbed, 99% lithocholate excreted

Question 20

comparison between gall bladder bile and hepatic duct bile

Answer 20

gall bladder bile - more acidic, higher % solids and conc of bile salts

Question 21

importance of gall bladder

Answer 21

aids digestion but not essential

basal level anyway if have cholecystectomy

Question 22

what is bilirubin, and what is it made of

Answer 22

water insoluble, yellow pigment

from Hb breakdown in blood
catabolism of other haem proteins
ineffective erythropoiesis

Question 23

describe the excretion of bilirubin

Answer 23

BR bound to albumin -> dissociate in liver -> free BR enter hepatocyte -> bind to cytoplasmic proteins -> is conjugated to glucuronic acid by glucuronyl transverase -> BR-diglucuronide and UDP -> active transport into canaliculi -> GI tract

Question 24

total BR =

Answer 24

unconjugated (free) BR + conjugated BR

Question 25

why is bile conjugated

Answer 25

it is more soluble

Question 26

describe urobilinogens

Answer 26

water soluble derived from bile by GI bacteria half reabsorbed -> liver -> kidney -> excretion some urobilinogens passed as stool as stercobilinogeen

Question 27

why is faeces brown

Answer 27

stercobilinogen from urobilinogen is oxidised to stercobilin - brown

Question 28

what is jaundice

Answer 28

yellow discolouration of sclerae and skin because of rasied bilrubin detecatble when bilrubin is >40umol/L

Question 29

how does cholestasis cause jaundice

Answer 29

less bile enters intestine - flow is slowed/stopped = less excreted failure of bile secretion or bile duct obstruction intrahepatic cholestasis - hepatocellular swelling/ abnormalities at cellular level extrahpatic cholestasis - obstruction of bile flow distal to canaliculi

Question 30

describe pre-hepatic jaundice

Answer 30

``` cause: increased quality of BR from: haemolysis transfusion haematoma resorption - road accident where cells die quickly ineffective erythropoiesis ``` problem: more BR than downstream path can cope with, increase urobilinogen type of BR: problem before reach liver = unconjugated

Question 31

describe hepatic/hepatocellular jaundice

Answer 31

cause: defective uptake, defective conjugation, defective BR excretion - because of liver failure: acute/fulminant from paracetamol OD, acute on chronic from Hep B/C, alcohol, autoimmune disease type of BR - unconjugated

Question 32

describe post hepatic/obstructive jaundice

Answer 32

problem: defective transport of BR by biliary duct system eg biliary duct stones, HepPancBil malignancy, local LNpathy BR increase - it is not taken to the gut = less stercobilinogen = less stercobilin = pale faeces some bilirubin diverted to kidney to try and get rid of it - dark urine type of BR - conjugated confirm with MRI scan - see blockage

Question 33

summarise Gilbert's syndrome

Answer 33

commonest congenital autosomal recessive # 2-7% population

Question 34

type of BR in Gilbert's syndrome

Answer 34

unconjugated

Question 35

cause of Gilbert's syndrome

Answer 35

mutation coding for UDP-glucuronsyltransferase isoform 1A, reduce glucuronidation activity, reduce conjugation

Question 36

consequence of Gilbert's syndrome

Answer 36

benign can cause jaundice under triggers: dehydration, fasting, exertion and iral illnss

Question 37

consequence of liver disease

Answer 37

lead to coma/death - multiorgan failure

Question 38

what is fulminant hepatic failure

Answer 38

``` rapid development <8wks acute injury impaired sympathetic function encephalopathy previously normal liver or well compensated liver disease ```

Question 39

time frame for sub-fulminant hepatic failure

Answer 39

<6months

Question 40

cause of chronic liver failure

Answer 40

``` Hep B or C alcohol fatty liver autoimmune genetic - Wilson's, haemachromatosis drug - methotrexate ```

Question 41

cause of acute liver failure

Answer 41

``` paracetamol OD amanita phalloides bacillus cereus acute fatty liver disease of pregnancy hepatic infarction HEV Budd-chiari Single Agent: Isoniazid, NSAID’s, valproate Drug combinations: Amoxicillin/clavulanic acid, trimethoprim/sulphamethoxazole, rifampicin/isoniazid Vascular Diseases Ischaemic hepatitis, post-OLT hepatic artery thrombosis, post-arrest, VOD Metabolic causes Wilson’s disease, Reye’s syndrome ```

Question 42

results of liver disease

Answer 42

``` encephalopathy (astrocyte) and cerebral oedema hypoglycaemia coagulopathy and bleeding increased suseptibilty to infection circulatory collapse renal failure ```

Question 43

causes of death in ALF

Answer 43

``` Bacterial and fungal infections Circulatory instability Cerebral Oedema Renal failure Respiratory failure Acid-base and electrolyte disturbance Coagulopathy ```

Question 44

liver transplant

Answer 44

``` for ALF - only useful intervention timing crucial dangerous expensive immunosuppression ```

Question 45

how does alcohol cause liver disease

Answer 45

hepatotoxin fatty change, alc hepatitis, cirrhosis genetic and immunological mech

Question 46

early stage symptoms - liver failure (LF)

Answer 46

``` Lethargy Right upper quadrant pain Pruritus – itchy skin Malaise Anorexia ```

Question 47

later symptoms

Answer 47

``` Peripheral swelling Confusion and somnolence Vomiting of blood Bruising Abdominal bloating ```

Question 48

signs of liver disease

Answer 48

jaundice spider naevi - because unable to met oestrogen = telangiectases: central arteriole ith radiating small vessels - distribution of SVC loss of body hair - unable to met oestrogen gynaecomastia - unable to met oestrogen - enlargement of male breast testicular atrophy - unable to met oestrogen palmar erythema - unable to met oestrogen - liver palms, at thena and hypothemar eminences xanthelasma - sharply demarcated yellowish deposit of cholesterol under skin around eyelids finger clubbing puritis - itchy skin dupuytren's contracture - sign of alcoholic liver disease ascites and dilated veins of abdomen hepatomegaly hepoatosplenomegaly caput medusa - portal hypertension, distended and engorged paraumbilical veins - radiate from umbilicus across abdomen to join systemic veins

Question 49

cirrhosis

Answer 49

necrosis of liver cells followed b progressive fibrosis and nodle formation imapirment of func distortion of the liver = portal hypertension

Question 50

aetiology of cirrhosis

Answer 50

alcohol hep B and C in response to chronic liver injury liver biopsy to confirm disease

Question 51

micronodular cirrhosis

Answer 51

uniform, small noules 3mm | ongoing alcohol damage/bilary tract disease

Question 52

macronodular cirrhosis

Answer 52

nodules of variable size | following viral hepatitis

Question 53

hyperacute liver failure

Answer 53

encephalopathy occurs within 7 days of jaundice

Question 54

acute liver failure - encephalopathy

Answer 54

after 8-28 days of jaundice.

Question 55

subacute liver failure

Answer 55

encephalopathy occurs 5-12 weeks after the onset of jaundice.

Question 56

clinical features of acute liver failure

Answer 56

``` jaundice CNS complications coagulopathy renal failure sepsis CV complications metabolic complications ```

Question 57

sepsis

Answer 57

bacterial infection in 90% cases, fungal in 32% cases present within 3 days of hospital admission fever and high white cell count absent

Question 58

way to reduce sepsis

Answer 58

prophylactic IV antibiotic therapy in acute hepatic failure

Question 59

CV

Answer 59

reduction in peripheral resistance reflec increase in CO to maintain bp cardiac failure and hypotesion

Question 60

metabolic effects of LF

Answer 60

Hypoglycaemia and Hypoxia

Question 61

CNS effects of LF

Answer 61

hepatic encephalopathy - inevitable | accumulation of toxins induces cerebral oedema and reduced consciousness -> coma

Question 62

renal

Answer 62

hepatorenal syndrome - unexplained failure when undergoing surgery for biliary tract obstruction or with liver disease reduced renal flow because of cortical vasoconstriction - perhaps because of accumulation of endotoxin, normally cleared in liver irreversible and fatal only survive if have liver transplant

Question 63

coagulopathy

Answer 63

liver plays an important role: synth of coagulation factors I, II, V, VII, IX, X. vitamin K dependant factors - 2, 7, 9, 10 and factor V 1st affected factor VII 1st to decline- short half life factor I only affected in severe disease inhibition of fibrinolysis/coagulation - liver responsible for synthesising anticoagulant proteins - protein C, S, antithrombin III clearance of activated cogulation factors - fibrin and tissue plasminogen activator tPA are removed by livers reticuloendothelial system absorption of vitamin K impairment of any of this = bleeding

Question 64

suggestions of a coagulation defect

Answer 64

bleeding at any site oozing at venepuncture sites bruising

Question 65

function of gall bladder

Answer 65

store bile - released after a meal for fat absorption acidify bile concentrate bile by water diffusion followed by net absorption of Na/Cl/Ca/HCO3 reduce vol of stored bile by 80-90%