For anatomically divided into 2 left and right
lobes with right being bigger.
Functionally divided into lobes by the portal
vein into 8 lobes.
Each lobe having a portal vein, branch of
hepatic artery and a bile canaliculi.
The biliary system rt and lt hepatic ducts which
combine to form common hepatic duct drains
to the gall bladder by cystic ducts.
Gall 9cm in length, capacity of 50ml, bld supply
from cystic artery, branch of hepatic artery.
Sphincter of ODDI is at the duodenal opening.
It is connected to the diaphragm and abdominal
walls by five ligaments:
the membranous falciform (also separates the
right and left lobes),
coronary, right and left triangular ligaments,
and the fibrous round ligament (which is
derived from the embryonic umbilical vein).
Anatomically the liver is divided into a
Right and a Left lobe by the falciform
The Right lobe also has two minor lobes-
The caudate lobe and The quadrate lobe
The Liver receives around 1500 ml of blood/min
The blood supply of the Liver is derived from The
Portal Vein (80%) and The Hepatic Artery (20%)
Terminal branches of the hepatic portal vein and
hepatic artery empty together and mix as they enter
sinusoids in the liver.
Sinusoids are distensible vascular channels lined
with highly fenestrated endothelial cells and
bounded circumferentially by hepatocytes.
The blood leaves the sinusoids via a
central vein , which drains in the hepatic vein.
A French surgeon &
anatomist who made
significant contribution in
the field of hepatobiliary
surgery ,he was the first to
anatomy of the liver
Middle hepatic vein divides the liver
into right and left lobes (or right and
left hemiliver). This plane runs from the
inferior vena cava to the gallbladder
fossa (Cantlie's line)
Right hepatic vein divides the right
lobe into anterior and posterior
Left hepatic vein divides the left
lobe into a medial and lateral part.
Liver lobules – hexagonal structures consisting of
At each of the six corners of a lobule is a portal triad
Portal Triads: Branches of two vessels: portal vein,
hepatic artery, along with bile drainage ductules all run
together to infiltrate all parts of liver.
Zonal Flow of Blood
Rich in Oxygen, mitochondria
•Concerned with Oxidative metabolism and synthesis of
Zone 2- transition
• lowest in Oxygen, anaerobic metabolism,
•Biotransformation of drugs, chemicals, and toxins
•Most sensitive to damage due to
ischemia, hypoxia, congestion
Regulation of Hepatic Blood Flow
• Hepatic Arterial Buffer Response -HABR
• Pressure flow Autoregulation
• Metabolic control
• Neural Control
• Humoral Control
With an intact HABR, changes in portal venous flow
cause reciprocal changes in hepatic arterial flow.
Portal venous flow reduced then there is reduction in
hepatic artery resistance.
But not vice versa.
The HABR mechanism involves the synthesis and
washout of adenosine from periportal regions.
Various disorders (e.g., endotoxemia, splanchnic
hypo perfusion) may decrease or even abolish the
HABR and render the liver more vulnerable to
Factors increasing hepatic blood flow: feeding,
glucagon, hypercapnia, recumbent position,
hepatocellular enzyme induction, ac. Hepatitis.
Factors decreasing: Anesthetic agents, surgical
trauma, IPPV, PEEP, bet adrenergic blockade,
Hepatic pressure auto-regulation keeps constant blood flow
despite wide fluctuation in systemic BP. The mechanism
involves myogenic responses of vascular smooth muscle to
The hepatic artery exhibits pressure-flow auto regulation in
metabolically active liver (postprandial) but not in the fasting
state. Thus, hepatic flow autoregulation is not likely to be an
important mechanism during anesthesia.
Pressure-flow autoregulation is nonexistent in the portal
circulation.Thus, decrease in systemic blood pressure—as
often occurs during anesthesia—typically lead to proportional
decrease in portal venous flow
Decrease in oxygen tension or the pH , ↑ Pco2 of
portal venous blood ,typically lead to increase in
hepatic arterial flow.
Postprandial hyperosmolarity increases hepatic
arterial and portal venous flow but not in the fasting
The underlying metabolic and respiratory status
(e.g., hypercapnia, alkalosis, arterial hypoxemia) also
modulates the distribution of blood flow within the
Fibres of the vagus, phrenic and splanchnic nerves
(postganglionic sympathetic fibres from T6 to
T11)enter the liver at the hilum
When sympathetic tone decreases, splanchnic
reservoir increases whereas sympathetic
stimulation,translocates blood volume from the
splanchanic reservoir to the central circulation.
Vagal stimulation alters the tone of the
presinusoidal sphincters, the net effect is a
redistribution of intrahepatic blood flow without
changing total hepatic blood flow.
Gastrin, Glucagon, Secretin, Bile
II, Vasopressin, Catecholamines.
Cytokines, Interleukins, and other
inflammatory mediators have been implicated
in the alteration of normal splanchnic and
hepatic blood flow.
Normal Blood flow – 1500ml/min
25 to 30% from Hepatic Artery
70 – 75% from Portal veins.
Hepatic Artery supplies 45 – 50% of liver’s oxygen
Portal veins supplies the remaining 50 – 55%
The total blood flow from this dual supply represents
25 – 30% of cardiac output
Portal vein pressure only about 7 – 10mmHg but
the low resistance of hepatic sinusoids allows rel.
large blood flow through portal vein.
Small changes in hepatic venous tone thus can
result in large changes in hepatic blood vol.,
allowing liver to act as a blood resevoir.
Decrease in hep. Venous tone
Blood shifts from hep. Veins & sinusoids into
central venous circulation & augments
circulating blood vol upto 300ml.
Kupffer cells lining sinusoids are part of monocyte –
Func – phagocytosis, processing Ag, release of
various proteins, enzymes, cytokines & other chem.
Phagocytic activity is responsible for removing
colonic bacteria & endotoxin entering bloodstream
from portal circulation.
Cellular debris, viruses, proteins & particulate matter
in blood are phagocytosed
1. Carbohydrate Metabolism
2. Protein Metabolism
3. Fat Metabolism
4. Drug Metabolism
5. Other Metabolic functions
The final products of carbohydrate metabolism are
glucose, fructose & galactose.
With exception of large amount of fructose that is
converted by liver to lactate, hepatic conversion of
fructose & galactose into glucose makes glucose
metabolism final common pathway for most
All cells utilize glucose to produce energy in form
of ATP via glycolysis or citric acid cycle
Liver can also utilize the phosphogluconate
pathway which not only provides energy but also
produces an imp. Cofactor in the synthesis of
Most of glucose absorbed from meal is stored as
Glycogen in liver.
When glycogen storage is exceeded in liver,
glucose is stored as fat.
Only liver and muscle can store significant amount
Liver and kidney are unique in their capacity to
form lactate, pyruvate, amino acids & glycerol.
Hepatic gluconeogenesis is vital in the
maintainence of a normal blood glucose
Glucocorticoids, catecholamines, glucagon &
thyroid hormone greatly enhance gluconeogenesis
– whereas insulin inhibits it.
When carbohydrate stores are saturated liver converts the
excess ingested carbohydrates into fat.
Fatty acids thus formed can be used immediately and stored
in adipose tissue or the liver for later consumption.
Only RBCs and renal medulla can utilize only glucose.
Neurons normally utilize only glucose but after a few days of
starvation they can switch to breakdown products of fatty
acids that have been made by liver as an energy source.
Liver performs an important function in protein
1. Deamination from amino acids
2. Formation of urea
3. Interconversion between non essential amino
4. Formation of plasma proteins
Necessary for conversion of excess amino acids to
carbohydrates & fats
Enzymatic processed convert amino acids to their
respective keto acids & produce ammonia.
Deamination of alanine plays an important role in
Liver normally deaminates most of amino acids
derived from dietary proteins
Branched chain amino acids are primarily
metabolised by skeletal muscle.
Ammonia formed from deamination is highly
toxic to tissue
2 molecules of ammonia + CO2 – Urea
Urea thus formed readily diffuses out of liver and
can be excreted by kidneys
Hepatic transamination of appropriate keto acid
allows formation of non essential amino acids &
compensates for any dietary deficiency in these
Nearly all plasma proteins with notable exceptions
of Ig are formed by liver.
Quantitatively the most important of these proteins
are albumin, α1 – antitrypsin & other
Proteins produced by liver
Albumin – maintains normal plasma oncotic
pressure and is principal binding & transport
protein for fatty acids & large no of hormones &
All coagulation factors which exception of
factor VIII & vonWille Brand factor are
produced in liver.
Vit K is necessary co factor in synthesis of
Prothrombin, factor VII, IX & X
Liver also produces plasma cholinesterase, an
enzyme that hydrolyses esters, including Local
anesthetics & Sch
Protease inhibitors (antithrombin III, α1 –
Transport proteins (Transferrin, Haptoglobin,
α1 – acid glycoprotein
C – reactive Protein
Serum Amyloid - A
It is divided into
1. Phase I reaction.
2. Phase II reaction.
3. Phase III reaction.
It is oxidative hydrolysis & reduction reactions
It is mainly microsomal oxidases, CYP isozymes
These CYP isozymes are concentrated in the
It needs NADPH for its reactions and hence
formation of superoxides and reactive free
radicals, more chance of injury to these
Conjugation with the endogenous hydrophilic
It involves several processes such as
glucuronidation, sulphation, methylation, acetylation
Glucuronidation is the common type.
Hepatic microsomal uridine diphosphate glucuronyl
transferase mediates the reaction.
These are susceptible to enzyme induction.
Heavy smoking, phenytoin admistration seen to
increase glucuronidation in humans.
In some drugs the conjugation ends up with a
metabolite more potent than the parent drug. Eg:
morphine- becomes morpine 6- glucuronide a potent
byproduct which is responsible for some of the
analgesia produced by morphine.
It is a energy mediated transport/ elimination by
ATP- binding cassette transport proteins.
Facilitates excretion of xenobiotics and endogenous
These proteins use ATP hydrolysis to drive
These resides on the canalicular surfaces of
hepatocytes and enables biliary excretion of cationic
compounds, including anticancer drugs.
Factors : rate of hepatic blood flow, protein binding,
hepatic intrinsic clearance.
Drug elimination – is volume of blood from which the
drug is completely removed per unit of time.
Is equal to the product of hepatic blood flow and the
Extraction ratio(E): amt of drug removed from the
blood during a simple pass through the liver.
Anesthetics significantly alter extraction by
reducing hepatic blood flow.
Inhalational agents may influence drug clearance
by altering drug-metabolizing ability or intrinsic
Inhalational agents have been shown both in vitro
and in vivo to alter drug metabolism at clinically
They are competitively inhibiting p-450, and phase
High hepatic extraction
Low hepatic extraction
Liver plays an important role in hormone, vitamin &
Normal thyroid function is dependent on hepatic
formation of the more active T3 from T4
Liver is also mojor site of degradation for insulin,
steroid hormones, glucagon & ADH
Hepatocytes are principal storage sites for Vit A, B12,
E, D & K.
Hepatic production of transferrin & Haptoglobin is
important because proteins are important in iron
Hepatocytes make most of the pro-coagulants
with exceptions of Factors III, IV, VIII.
Liver also makes protein regulators of
coagulation & the fibrinolytic pathways.
Such regulators include protein
C, S, Z, Plasminogen Activator Inhibitor, &
Hemoglobin is heme and globulin, with heme
containing ferrous and porphyrin IX.
20% approx, heme synthesised in the liver.
Rate limiting step is synthesis of 5-
aminolevulinic acid catalysed by ALA
Source is from the Heme metabolism.
Approx 300mg of bilirubin formed everyday.
80% by the phagosytosis of scenecent RBCs by the RE
The extracted heme is converted to bilirubin, this is the
rate limiting step.
This is then bound to albumin and liver processes the
molecules into conjugated bilirubin in 2 steps, and then
Enterohepatic circulation ensures some of these
products to return to the liver.
FUNCTIONS OF THE LIVER:
Fat metabolism -
Secretion of bile
vitamins A,D,K,E &
Anesthesia & anaesthetic drugs affects the
hepatic function by following mechanisms :
Alteration in the hepatic blood flow n HABR.
Effect of volatile agents on hepatic
blood flow :
Halothane: Causes hepatic arterial constincton,
Enflurane: Increase in hepatic vascular resistance
Isoflurane: Increase in microvascular blood velocity
Sevoflurane & Desflurane: Preservation of hepatic
blood flow & function
Vecuronium, rocuronium, mivacur
• Reduced elimination and Prolong duration of
action specially with infusion & repeated doses
Atracurium & cisatracrium:
• Nondependant of hepatic metabolism and can
be used without modification of doses in end
stage liver disease
Reduction in hepatic blood flow in high spinal &
Secondary to hypotension
Reversed by vasopressors like dopamine,
It is immunologically mediated, as it induces both
neoantigens & auto antigens. The incidence of fulminant
hepatic necrosis terminating in death associated with
halothane was found to be 1 per 35,000.
Demographic factors ; It’s a idiosyncratic reaction,
susceptible population include Mexican Americans
,Obese women, , Age >50 yrs, , Familial predisposition,
Severe hepatic dysfunction while Children are resistant.
Prior exposure to halothane is a important risk factor &
multiple exposure increases the chance of hepatitis.
ISOFLURANE- Isoflurane metabolism yields highly reactive
intermediates (TF-acetyl chloride; acyl ester) that bind covalently
to hepatic proteins. For this isoflurane most likely causes
It undergoes minimal biodegradation, preserves microvascular
blood flow & oxygen delivery more than halothane or enflurane .
DESFLURANE- it is similarly biotransformed to trifluoroacyl
metabolites, appears even less likely than isoflurane to cause
immune injury because only 0.02 to 0.2% of this agent is
metabolized (1/1,000th that of halothane). Desflurane metabolites
are usually undetectable in plasma, except after prolonged
Desflurane ↓hepatic blood flow ,it markedly reduce oxygen
delivery to the liver and small intestine without producing
comparable reductions of hepatic oxygen uptake or hepatic and
mesenteric metabolism. Therefore, desflurane anesthesia may
decrease the oxygen reserve capacity of both the liver and the
SEVOFLURANE - It is metabolized more extensively than
isoflurane or desflurane,but slightly less than enflurane, and much
less than halothane.
The metabolism of sevoflurane is rapid (1.5 to 2 times faster than
enflurane), and produces detectable plasma concentrations of
fluoride and hexafluoroisopropanol (HFIP) within minutes of
initiating the anesthesia.
The liver conjugates most of the HFIP with glucuronic acid, which
is then excreted by the kidney.
it produces a mild increase in sympathetic nervous
system tone leads to mild vasoconstriction of the
splanchnic vasculature, leading to a decrease in portal
blood flow, and mild vasoconstriction of the hepatic
N2O is a known inhibitor of the enzyme methionine
synthase, which could potentially produce toxic
Etomidate and thiopental at larger doses (>750 mg)
may cause hepatic dysfunction by ↓ hepatic blood
flow, either from ↑ hepatic arterial vascular resistance
or from reduced cardiac output and blood pressure.
Ketamine has little impact on hepatic blood
flow, even with large doses
Propofol increases Blood Flow in both the hepatic
arterial and portal venous circulation, suggesting a
significant splanchnic vasodilator effect
Opioids have little effect on hepatic function, provided they
do not impair hepatic blood flow and oxygen supply. All
opioids increase tone of the common bile duct and the
sphincter of Oddi, as well as the frequency of phasic
contractions, leading to increases in biliary tract pressure
and biliary spasm.
Morphine undergoes conjugation with glucoronic acid at
hepatic & extra hepatic site (kidney). The significantly
reduced metabolism of morphine in patients with
advanced cirrhosis leads to a prolonged elimination half-
life, markedly increased bioavailability of orally
administered morphine, decreased plasma protein
binding, and potentially exaggerated sedative and
respiratory-depressant effects. The oral dose of the drug
should be reduced because of increased bioavailability
The volume of distribution of muscle relaxants,
may increase due to ↓ albumin an increase in γ-
globulin or the presence of edema.so the initial
dose requirements of these medications are
increased in cirrhotic patients and subsequent
dose requirements may be ↓, and drug effects
prolonged, owing to ↓ in hepatic blood flow and
impaired hepatic clearance, and possible
concurrent renal dysfunction.
Vecuronium-it is a steroidal muscle relaxant It
undergoes hepatic elimination by acetylation.
Decreased clearance, a prolonged elimination half-
life, and prolonged neuromuscular blockade in
patients with cirrhosis .
Rocuronium- another steroidal muscle relaxant
with a faster onset of action than vecuronium, also
undergoes hepatic metabolism and elimination.
Hepatic dysfunction can increase the volume of
distribution of rocuronium, thereby prolonging its
elimination half-life and producing a longer clinical
recovery profile and return of normal twitch tension.
Atracurium & Cisatracurium
• Elimination half-lives and clinical durations of action
are similar in cirrhotic.82%to Bound albumin they
undergo clearance by organ-independent elimination
i.e. spontaneous non-enzymatic degradation
• Laudanosine, a metabolite of both atracurium and
cisatracurium, is eliminated primarily by the liver; and
although its concentration may increase in patients
undergoing liver transplantation, clinically relevant
neurotoxicity has not been reported
Altered protein binding
Altered volume of distribution
Altered drug metabolism due to hepatocyte
Opioids: exaggerated sedative & respiratory
depressant effect and Half life is almost doubled
Benzodiazepines : Duration of action increased
Thiopentone, Etomidate, Propofol, Ketamine:
Repeated doses & prolong infusion causes
accumulation of drugs
Increases risk of hepatic encephalopathy
Splanchnic traction and exploratory laparotomy
can reduce blood flow to the intestines and the
Upper abdominal surgery is associated with the
greatest reduction in hepatic blood flow
Elevation of liver chemistry tests is more likely
to occur after biliary tract procedures than after
Liver major organ of metabolism
Live dysfuction affects pharmacokinetics of
Anesthetic drugs affects liver function
Neuroaxial blocks: reduction in hepatic blood flow
due to hypotension
hypotension, hypoxia, hypocapnia, use of
hepatotoxic drugs in perioperative period can cause
postoperative hepatic dysfunction
No one test reflects overall hepatic
Each test generally reflects one aspect of
hepatic function and must be interpreted
in conjunction with other tests alone with
clinical assessment of patient.
Liver abnormalities can be divided into
1. Obstructive – affect biliary excretion of
2. Parenchymal – result in generalised
Normal total bilirubin - <1.5mg/dl
Reflects balance between production &
Jaundice is usually clinically obvious
when total bilirubin exceeds 2mg/dl
>50% conj. Hyperbilirubinemia is ass. with
urinary urobilinogen & may reflect
hepatocellular dysfunction, intrahep.
Cholestasis or extrahepatic biliary
>50% unconj. Hyperbilirubinemia may be
seen with hemolysis or cong. Or acquired
defects in bilirubin conjugation
These enzymes are released into circulation
as a result of hepatocellular injury or death.
AST is present in many tissues – liver, heart,
skeletal, muscle & kidneys.
ALT is primarily located in liver & more
specific for hepatic dysfunction
Normal – 35 to 45U/L
Mild elevation can be seen in cholestasis or
metastatic liver disease.
Abs. levels correlate poorly with degree of
hepatic injury in chronic conditions, but are
of great importance in acute liver disease. Eg-
drug overdose, ischaemic injury and
Is produced by liver, bone, small bowel,
kidneys & placenta.
Excreted into bile
Normal level – 25 to 85IU/L
Most of circulating enzymes are derived from
Biliary Obstruction – more hepatic alkaline
phosphatase is synthesized and released into
Increased levels indicate intrahepatic
cholestasis & biliary obstruction.
Increased levels in pregnancy & Paget’s
Normal level – 3.5 to 5.5g/dl
Albumin level may be normal with Acute
Albumin values <2.5g/dl are generally
indicative of CLD, acute stress or severe
Increased losses of albumin in urine is
suggestive of Nephrotic syndrome.
Significant increase of blood ammonia
levels usually reflect disruption of hepatic
Normal whole blood ammonia levels are 47
Increase usually reflect severe
Normal level is 11 to 14secs. (Measures the
activity of fibrinogen & factors V, VII & X)
Relatively short half time of factor VII (4 to
6Hrs)make PT useful in evaluating hepatic
synthesis function of pt with ALD or CLD.
Prologation of PT >3 to 4s from control are
Only 20 to 30% of normal factor activity is
required for normal coagulation, prolongation
of PT reflects severe liver disease unless Vit K
deficiency is +
Failure of PT to correct following parenteral
administration of Vit K implies severe liver
Elevated serum LDH levels -
hepatocellular injury, extrahepatic
disorders or both.
Extreme increases – massive liver damage
– fulm. Viral hepatitis, drug induced
failure or hypoxic hepatitis.
Prolonged concurrent elevation –
malignant infiltration of liver.
Notable hep disorders – hemolysis,
rhabdolysis, tumor necrosis, renal
infarction, acute CVA or MI. (severe
Targeted testing is used to identify specific
hepatic or biliary diseases.
Examples include –
1. Serologic testing to identify viral, microbial
& autoimmune causes.
2. Genetic testing to diagnose heritable
3. Tumor marker assays to detect hepatic
Identifying viral markers – antibodies,
antigens and genetic material – is the key
for diagnosis of hepatitis from hepatotropic
viruses (A, B, C, E) and herpesviruses
such as CMV & EBV.
Special tests – serum α1 – AT and
Markers for hepatic malignancy – AFP, des
– γ – carboxylated prothrombin.
CBC- Hb may show anemia esp with the target
cells in jaundiced patients due to macrocytosis.
Leucopenia- complicates portal HTN and
Leucocytosis- in hepatic abscess, alcoholic
Thrombocytopenia- in cirrhosis, due to dec in
thrombopoetin in liver, and hypersplenism.
Model of End-Stage Liver Disease
Child-Turcotte-Pugh (CTP) score
initially designed to stratify the risk of portacaval shunt
surgery in cirrhotic patients
based upon five parameters: serum bilirubin, serum
albumin, prothrombin time, ascites and
good predictor of outcome in patients with
complications of portal hypertension
M&M for pts undergoing intra-abd
biochemical(PT, albumin, bilirubin)
Incorporates three clinical
Points Assigned 1 2 3
Bilirubin (mg/adL) < 2 2-3 > 3
Albumin (g/dL) > 3.5 2.8-3.5 < 2.8
< 4 s
> 6 s
Ascites None Slight Moderate
Encephalopathy None Stages 1-2 Stages 3-4
Child class A = 5-6 points; Child class B = 7-9 points; Child class C = 10-15 points
Child CG, Turcotte JG. Surgery and portal hypertension. In: The
Liver and Portal Hypertension. Child CG, ed. Philadelphia:
Saunders; 1964:50-64. Pugh RNH, et al. Br J Surg. 1973;60:648-652.
Created in 1999 to predict 3 month
mortality in pts with chronic dz.
Prioritizes those on transplat list
Looks at bilirubin,INR,and serum
>8: predictive of poor
>24: qualifies for transplantation