3. Liver Flashcards
What makes the liver a notable organ?
Largest solid organ w/ large reserve capacity
Capable of regeneration
Receives 25% of cardiac output
How is blood supplied to the liver?
Nutrient rich blood from PORTAL VEIN
- drains intestinal tract (sup. mesenteric + splenic veins)
O2 rich blood from HEPATIC ARTERY
Describe the microanatomy of the liver
Histological structural unit = liver lobule
- hexagonal prism of tissue
Filled with rows of hepatocytes;
- radiate from central vein
- separated by vascular sinusoids
Sinusoids lined sporadically with kuppfer cells;
- hepatic macrophages - phagocytic
- part of RES, remove gut bacteria in venous circ
Portal tracts at corners;
- branches of hepatic artery
- portal vein
- bile duct
Describe blood + nutrient flow through the liver lobule
Blood flow: portal tracts > central hepatic vein
- toxins not requiring metabolism damage portal tract periphery 1st
- toxin + hypoxia metabolites damage central vein area first
Nutrients from GI (except fat micelles): sinusoidal spaces > systemic circulation
What happens to the microanatomy of the liver during damage e.g. cirrhosis?
Damage leads to distortion of lobule architecture
- blood skips directly to central hepatic portal vein then hepatic vein
- this bypasses hepatocytes = significantly decreased detox
What are the broad functions of the liver?
~500 functions
Categories;
- synthetic e.g. circulating proteins, bile + bile acids, storage
- metabolic e.g. hormone, protein, carbohydrate, lipid
- detox e.g. drug, immunological
- excretion of metabolic end products e.g. bilirubin
Describe the synthetic functions of the liver
Primary site for synthesis of all circulating proteins -hepatocytes synthesise;
Plasma proteins:
- albumin (oncotic pressure/TP of water insoluble substances e.g. iron)
- Igs
- complement
Binding proteins for hormones
Lipoproteins:
- VLDL
- HDL
Most coag factors:
- fibrinogen
- prothrombin, FVII, IX, X (synth reqs vit K)
- FV, XI, XII, XIII
Also the site of bile + bile acid formation;
- water, electrolytes, bile acids, cholesterol, phospholipids, bilirubin
- bile acid metabolites synthesised in liver cells from cholesterol
Describe the general metabolic functions of the liver
When there is high glucose conc in the portal vein it is converted to;
- glycogen
- carbon skeletons of fatty acids (stored in adipose tissues as VLDL)
When fasting, systemic plasma glucose is maintained by; glycogenolysis + GNG
What is GNG?
Gluconeogenesis
The synthesis of glucose from substrates - glycerol, lactate, amino acids
Describe the excretory + detox functions of the liver
Excretes;
- bilirubin
- amino acids: deaminated in liver
- cholesterol: excreted in bile
- steroid hormones: metabolised + inactivated by conjugation with gluconate + sulphate
- many drugs: metabolised + inactivated by ER enzymes
- toxins: kuppfer cells extract toxins absorbed at GI tract
What are the markers of the livers synthetic function + how are they tested?
Albumin;
- major product of liver
- may be normal in acute liver injury (long t1/2)
- decreased albumin = chronic liver disease > oedema
Prothrombin;
- clotting factor (req vit K)
- increased prothrombin = liver injury (sensitive)
- failure to absorb vit K or hepatocellular damage? retest after vit K supplementation
What is the problem with liver tests involving metabolic markers for liver disease?
Liver has large functional reserve;
- extensive disease required for detectable deficiencies
= consider non hepatic factors first
Tests for metabolic (synth + secretory) function relatively insensitive for liver disease
Describe liver bilirubin metabolism
Bilirubin = yellow compound produced during catabolism of heme from RBCs
- RBC lifespan ~ 120 days
- aged/damaged RBCs removed from circ in spleen
- degraded by splenic macrophages (part of RES)
Degradation of hemoglobin > heme + globin;
- globin broken into a acids for reuse
- heme > biliverdin by heme oxygenase (iron released as Fe2+)
- biliverdin > bilirubin by bilverdin reductase
Bilirubin TPed to liver by fac diffusion bound to serum albumin protein
- taken up by ligandin at sinusoidal membrane
Conjugated with glucuronic acid x2 in liver = water soluble
- catalysed by UDP-glucuronosyl transferase
Conjugated bilirubin excreted from liver in bile;
- excretion of bilirubin from liver > bile canaliculi = active energy dependent + rate limiting process
Intestinal bacteria deconjugate bilirubin-diglucuronide > urobilinogens
- some absorbed by intestinal cells + TPed to kidneys = excreted as urobilin in urine (yellow)
- some taken up via enterohepatic circulation + reexcreted as bile
- most travels down digestive tract + converted to stercobilinogen = oxidised to stercobilin + excreted in faeces (brown)
What is jaundice and how is it characterised?
Jaundice aka icterus is raised bilirubin concentration in plasma causing yellow discoloration of skin + eyes;
- normal = <1.0mg/dL
- jaundice = >2-3mg/dL
What are the signs + symptoms of jaundice?
Yellowish discolouration of skin + conjunctival membranes of eyes;
- presence = @ least 3mg/dL serum bilirubin
- eyes one of first tissues to change colour
Dark urine
Commonly assoc with itchiness (pruritis)
May be pale faeces
Kernicterus - newborns
What are the types of bilirubin + causes of their excess in plasma?
Unconjugated/indirect bilirubin;
- excess RBC breakdown
- large bruises
- genetic conditions e.g. Gilbert’s syndrome
- prolonged fasting
- newborn jaundice
- thyroid problems
Conjugated/direct bilirubin;
- liver disease, e.g. cirrhosis/hepatitis
- infections common in developing world (viral hep, leptospirosis, schistosomiasis, malaria)
- medications (common in developed)
- blockage of bile duct (common in developed): gallstones, cancer, pancreatitis
What are the 3 types of jaundice causes (broadly)?
Pre-hepatic - excess RBC breakdown
Hepatic - failure of conj system in liver (liver disease)
Post-hepatic - obstruction in flow of bile
How is jaundice classified?
Based on part of physiological mechanism affected;
- PREHEPATIC/HEMOLYTIC;
- pathology prior to liver
- upstream of conjugation
- intrinsic defects in RBCs/extrinsic causes external to RBCs - HEPATIC/HEPATOCELLULAR;
- pathology within liver
- failure of conjugation
- disease of parenchymal cells of liver - POSTHEPATIC/CHOLESTEROL;
- pathology after conjugation in liver
- obstruction of biliary passage
Describe pre-hepatic jaundice
Anything causing increased hemolysis
Increased unconjugated bilirubin in blood: deposition = blood
Increased bilirubin production = increased urobilinogen in urine
- no bilirubin in urine: unconjugated not water soluble
Describe causes of pre-hepatic jaundice
Tropical: severe malaria
Genetic;
- sickle cell
- spherocytosis
- thalassemia
- pyruvate kinase deficiency
- G6PD deficiency
Diseases of kidney;
- hemolytic uremic syndrome
What are the lab findings in pre-hepatic jaundice?
Urine:
- no bili (unconj insoluble
- increased bili = increased urobilinogen >2 units
Serum:
- increased unconj bili
Kernicterus:
- increased unconj not albumin bound + lipid soluble
- newborns increased permeability of BBB = neurotoxic
Describe hepatic jaundice
Due to failure of conj system;
Liver disease/hepatocellular jaundice;
- cell necrosis = decreased metabolic/excretory function
- buildup of unconj bili in blood
Describe primary biliary cirrhosis (a type of hepatic jaundice)
Primary biliary cirrhosis;
- increased plasma conj bili (impairment of excretion into bile)
- increased bile salts in blood excreted in urine (dark)
Usually interference at all steps of bili metabolism;
- UPTAKE: TP across hepatocyte impaired = no uptake into cell or TP into biliary canaliculi
- CONJUGATION: decreased metabolic function
- EXCRETION: swelling/edema of cells (inflamm) = obstruction of intrahepatic biliary tree but unconj still enters = rupture/backflow via lymph = increased unconj + conj bili in blood
Excretion is the rate limiting step = greatest impaired = conj hyperbilirubinemia predominates;
- conj bili doesn’t enter intestine
- not converted to urobilinogen = excreted as conj bili = dark urine
What are the causes of hepatic jaundice?
Acute/chronic hepatitis Hepatotoxicity Cirrhosis Drug induced hep Alcoholic LD Primary biliary cirrhosis Newborns: immature hepatic mechanisms Leptospirosis Defects in bili metabolism: Gilbert's (5% pop) or Crigler-Najjar
What are the lab findings in hepatic jaundice?
Depends on cause
Urine:
- conj bili present
- urobilinogen = dark (>2 units, variable)
No associated kernicterus
Plasma protein characteristic changes;
- decreased plasma albumin
- increased plasma globulins (increased Ab formation)
Serum;
- increased conj + unconj bili
Describe post-hepatic jaundice
Due to obstruction of bilirubin from liver (cholestatic obstructive jaundice)
Mainly increased conj bilirubin (backflow)
Complete obstruction = no no access to intestine for conversion to uro/stercobilinogen+ partial reabsorption/urine excretion;
- pale stools
- dark urine (conj bili but no urobilin)
Describe the causes of post-hepatic jaundice
Gallstones in common bile duct Pancreatic cancer (head) Drugs Parasites (liver fluke) in common bile duct Strictures of duct Biliary atresia (absence/narrowing) Cholangiocarcinoma Pancreatitis Cholestasis of pregnancy Pancreatic pseudocysts Mirizzi's syndrome
What are the common lab findings in post-hepatic jaundice?
Serum;
- increased conj bili
- increased cholesterol
Urine;
- no urobilin
- conj bili = dark
- characteristic but not distinguishing as present in other illnesses
Pale stool: no uro/stercobilinogen
Severe itching: deposition of bile salts in skin
List the common causes of liver injury
Infection - viral hep
Drugs - paracetamol
Toxins - alcohol
Tumours
Metabolic disease - hemochromatosis, Wilson’s
Autoimmune disease
Vascular disorders - clots (thrombosis), heart failure
How is liver disease classified?
May be classified by site of damage;
- hepatocellular damage
- cholestatic obstructive disease
Describe hepatocellular disease + its causes
Direct damage to liver cells
Causes;
- alcohol
- hepatitis (many forms: most common = viral)
- toxins
- drugs
Describe cholestatic (obstructive) liver disease + its causes
Obstruction: bile cannot flow liver> duodenum
Causes;
- Within liver = intrahepatic
- secretion: hepatocytes > canaliculi impaired
- or impairment of bile formation
- e.g. viral hep, drugs (chlorpromazapine), autoimmune, e.g. primary biliary cirrhosis, toxins (alcohol), cystic fibrosis - Outside liver = extrahepatic
- obstruction of bile through biliary tract/bile duct
- gallstones, strictures, tumours (pancreas head), inflammation of biliary tract
What is liver cirrhosis?
Replacement of normal liver tissue with fibrous scar tissue
- loss of functional hepatocytes
- due to long term damage (chronic)
- typically slow development: months > years
Describe the signs + symptoms of liver disease
Tired/weak Itchy Lower leg swelling Yellow skin Easy bruising Ascites with spontaneous infection Spider like blood vessels
What are the possible complications of liver cirrhosis?
Hepatic encephalopathy = confusion + unconsciousness
Bleeding from dilated veins (oesophagus/stomach)
Liver cancer
What are the causes of liver cirrhosis?
Alcohol abuse (most common)
Hep B + C
NAFLD (obesity, diabetes, high blood fats, high BP)
Uncommon causes; Hep autoimmune PBC (primary biliary cholangitis) Hemochromatosis Medications Gallstones
What is the treatment for cirrhosis?
Depends on cause
Goal often to prevent complications/worsening;
- avoid alcohol in all cases
- hep B + C = antivirals
- autoimmune = steroids
- bile duct blockage = ursodiol
- severe = liver transplant
Describe the pathophysiology of cirrhosis
Often preceeded by hepatitis + FLD (steatosis) independent of cause;
- if cause removed at this stage = fully reversible
Pathological hallmark of cirrhosis = scar/fibrous tissue replacing normal parenchyma;
- blocks portal flow of blood through organ
- increases BP + disturbs normal function
What does recent research say regarding cirrhosis pathophysiology?
Shows pivotal role of STELLATE CELL in development of cirrhosis (normally stores vit A)
Inflammation;
- activates stellate cells
- increases fibrosis by production of of myofibroblasts = obstruction of hepatic blood flow
Stellate cells secrete;
- TGF-B = fibrotic response + proliferation of CT
- TIMP1 + 2 = inhibitors of MMP = can’t breakdown fibrotic material of ECM
Cascade of processes leads to fibrous tissue bands (septa) separating hepatocyte nodules
- replaces entire liver architecture = decreased bloodflow throughout
What is the purpose of liver function tests (LFTs)?
Measurements of the presence, extent + type of liver disease
Can also be used to monitor treatment
What components of the blood can be measured in an LFT?
Plasma proteins;
- Prothrombin time (PT/INR)
- aPTT
- albumin (functionality)
Bilirubin (direct/indirect + total)
Ammonia
Liver enzymes; Liver transaminases: - aspartate transaminase (AST) - alanine transaminase (ALT) - assess cellular integrity
Gammaglutamyltranspeptidase (GGT)
Alkaline phosphatase (ALP)
- both assess biliary tract
Describe the use of the bilirubin LFT
Total = unconj (indirect) + conj (direct)
Total bili:
- liver disease >17umol/L
- deposition + jaundice >40umol/L
Increased unconj bili;
- overproduction
- decreased uptake
- decreased conj
Increased conj;
- directly proportional to degree of hepatocyte injury
- backward leakage
NOT a sensitive indicator of hepatic dysfunction due to reserve capacity of liver;
- max daily excretion = >10x greater than average daily production
Why are liver enzymes used to test LF?
Liver cell damage typified by release of enzymes from damaged liver cells which causes their activity levels to rise in plasma
Describe the use of aminotransferases as LFTs
AST: aspartate aminotransferase
ALT: alanine aminotransferase
Increased activity = cell damage
- high levels = hepatocellular disease
- also rise in cholestatic (obstructive) disease
ALT more specific to liver than AST;
- ALT = highest conc in liver
- AST = highest conc in liver but decreasing concentrations in cardiac/ skeletal muscle/ kidneys/ brain/ pancreas/ lungs/ leukocytes /RBCs
How have recent studies proposed to increase the specificity of AST as an LFT?
Studies have shown 2 isotypes of AST;
- ~80% AST activity in liver = mitochondrial isotype
- healthy pop have predominantly cytosolic isotype circulating
- distinguishable by assay
Describe the use of ALP as an LFT
ALP: alkaline phosphatase
Liver not only source of ALP activity;
- when associated with increased GGT suggests liver origin
Usually = cholestasis (intra/extra) but also rises in hepatocellular
Describe the use of GGT as an LFT
GGT: gamma glutamyl transpeptidase
Enzyme produced in bile ducts
Sensitive indicator of liver disease;
- raised in any liver disease (cholestasis/hepatocellular)
NOT SPECIFIC;
- inducible enzyme: may be increased by alcohol intake + drugs
Describe the use of ammonia as an LFT
Elevated in severe acute or chronic LD
Due to impaired breakdown of nitrogenous waste
Elevated levels cause lethargy + confusion
What can LFTs help differentiate between and how?
Acute hepatocellular damage
- greatly increased AST + ALT
- ALP normal or increased
- bilirubin normal/greatly increased
Obstruction of biliary tract/cholestatic LD
- greatly increased ALP + GGT
- increased AST + ALT
- bilirubin increased (may be normal if cholestasis v localised, e.g. with liver secondaries)
Reduced functioning tissue mass/chronic LD/cirrhosis;
- decreased albumin
- prolonged PT
