Jaundice and liver failure Flashcards
what is the function of bile
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
how much of bile is water
97%
substances that are secreted into bile
adrenocortical and other steroids
drugs/xenobiotics
cholesterol
alkaline phosphatase
where does bile come from
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%
describe the pathway of the biliary tree
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
what happens to the bile as it goes through the biliary tree
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
what governs the rate of the bile flow
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
what are the main bile transporters
bile salt excretory pump (BSEP)
MDR related proteins (MRP1, MRP3)
products of the familial intrahepatic cholestasis gene (F1C1) and multidrug resistant genes (MDR1 MDR3)
describe the bile salt excretory pump
controlled by ABCB1 gene
AT of bile acids into bile across canalicular membrane
secretion of acids
describe MDR1
mediate canalicular excretion of xenobiotics and cytotoxins
describe MDR3
encodes phospholipid transporter
that translocates phosphatidylcholine from inner to outer leaflet of canalicular membrane
what are bile salts
component of bile
cholic acid and chenodeoxycholic converted to deoxycholic acid and lithocolic acid (secondary acids) by colonic bacteria
amphipathic = hydophobic and philic region
function of gut bacteria on bile salts
convert primary bile salts to secondary
cholic - deoxycholic acid
chenodeoxyxholic - lithocolic acid
function of bile salts
reduce fat surface tension
emulsify fat for digestion/absorption
micelles = larger surface area
structure of micelles
amphiphilic
philic - out
phobic - in
FFA and chol - in
problem with bile salts
detergent like -> cytotoxic in high conc
= not reabsorbed = gut irritation = diarrhoea
OR intrahepatic cholestasis of pregnancy = damage foetus - cardiac
describe the actions of the sphincter of Oddi
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
describe the enterohepatic circulation
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
describe the enterohepatic circulation of bile salts
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
comparison between gall bladder bile and hepatic duct bile
gall bladder bile - more acidic, higher % solids and conc of bile salts
importance of gall bladder
aids digestion but not essential
basal level anyway if have cholecystectomy
what is bilirubin, and what is it made of
water insoluble, yellow pigment
from Hb breakdown in blood
catabolism of other haem proteins
ineffective erythropoiesis
describe the excretion of bilirubin
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
total BR =
unconjugated (free) BR + conjugated BR
why is bile conjugated
it is more soluble
describe urobilinogens
water soluble
derived from bile by GI bacteria
half reabsorbed -> liver -> kidney -> excretion
some urobilinogens passed as stool as stercobilinogeen
why is faeces brown
stercobilinogen from urobilinogen is oxidised to stercobilin - brown
what is jaundice
yellow discolouration of sclerae and skin because of rasied bilrubin
detecatble when bilrubin is >40umol/L
how does cholestasis cause jaundice
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
describe pre-hepatic jaundice
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
describe hepatic/hepatocellular jaundice
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
describe post hepatic/obstructive jaundice
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
summarise Gilbert’s syndrome
commonest congenital
autosomal recessive #
2-7% population
type of BR in Gilbert’s syndrome
unconjugated
cause of Gilbert’s syndrome
mutation coding for UDP-glucuronsyltransferase isoform 1A, reduce glucuronidation activity, reduce conjugation
consequence of Gilbert’s syndrome
benign
can cause jaundice under triggers:
dehydration, fasting, exertion and iral illnss
consequence of liver disease
lead to coma/death - multiorgan failure
what is fulminant hepatic failure
rapid development <8wks acute injury impaired sympathetic function encephalopathy previously normal liver or well compensated liver disease
time frame for sub-fulminant hepatic failure
<6months
cause of chronic liver failure
Hep B or C alcohol fatty liver autoimmune genetic - Wilson's, haemachromatosis drug - methotrexate
cause of acute liver failure
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
results of liver disease
encephalopathy (astrocyte) and cerebral oedema hypoglycaemia coagulopathy and bleeding increased suseptibilty to infection circulatory collapse renal failure
causes of death in ALF
Bacterial and fungal infections Circulatory instability Cerebral Oedema Renal failure Respiratory failure Acid-base and electrolyte disturbance Coagulopathy
liver transplant
for ALF - only useful intervention timing crucial dangerous expensive immunosuppression
how does alcohol cause liver disease
hepatotoxin
fatty change, alc hepatitis, cirrhosis
genetic and immunological mech
early stage symptoms - liver failure (LF)
Lethargy Right upper quadrant pain Pruritus – itchy skin Malaise Anorexia
later symptoms
Peripheral swelling Confusion and somnolence Vomiting of blood Bruising Abdominal bloating
signs of liver disease
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
cirrhosis
necrosis of liver cells
followed b progressive fibrosis and nodle formation
imapirment of func
distortion of the liver = portal hypertension
aetiology of cirrhosis
alcohol
hep B and C
in response to chronic liver injury
liver biopsy to confirm disease
micronodular cirrhosis
uniform, small noules 3mm
ongoing alcohol damage/bilary tract disease
macronodular cirrhosis
nodules of variable size
following viral hepatitis
hyperacute liver failure
encephalopathy occurs within 7 days of jaundice
acute liver failure - encephalopathy
after 8-28 days of jaundice.
subacute liver failure
encephalopathy occurs 5-12 weeks after the onset of jaundice.
clinical features of acute liver failure
jaundice CNS complications coagulopathy renal failure sepsis CV complications metabolic complications
sepsis
bacterial infection in 90% cases, fungal in 32% cases
present within 3 days of hospital admission
fever and high white cell count absent
way to reduce sepsis
prophylactic IV antibiotic therapy in acute hepatic failure
CV
reduction in peripheral resistance
reflec increase in CO to maintain bp
cardiac failure and hypotesion
metabolic effects of LF
Hypoglycaemia and Hypoxia
CNS effects of LF
hepatic encephalopathy - inevitable
accumulation of toxins induces cerebral oedema and reduced consciousness -> coma
renal
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
coagulopathy
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
suggestions of a coagulation defect
bleeding at any site
oozing at venepuncture sites
bruising
function of gall bladder
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%
