Dr Imran.
• Largest organ in the body
• Wt – 1500 to 1600gms
• Reddish brown triangular pyramid shaped, in
rt. Hypochondrium and mos...
Cystic artery
sole supply to bile
duct
liver
pancreas
spleen
Portal vein: 80%
Hepatic artery: 20%
Dual Blood Supply of Liver
Liver has dual blood
supply:
80% por...
 For anatomically divided into 2 left and right
lobes with right being bigger.
 Functionally divided into lobes by the p...
 The biliary system rt and lt hepatic ducts which
combine to form common hepatic duct drains
to the gall bladder by cysti...
It is connected to the diaphragm and abdominal
walls by five ligaments:
the membranous falciform (also separates the
rig...
 Anatomically the liver is divided into a
Right and a Left lobe by the falciform
ligament
 The Right lobe also has two m...
 The Liver receives around 1500 ml of blood/min
 The blood supply of the Liver is derived from The
Portal Vein (80%) and...
12
 The blood leaves the sinusoids via a
central vein , which drains in the hepatic vein.
Claude Couinad
A French surgeon &
anatomist who made
significant contribution in
the field of hepatobiliary
surgery ,he w...
 Middle hepatic vein divides the liver
into right and left lobes (or right and
left hemiliver). This plane runs from the
...
 Liver lobules – hexagonal structures consisting of
hepatocytes
 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 t...
Zone 1-
Rich in Oxygen, mitochondria
•Concerned with Oxidative metabolism and synthesis of
glycogen
Zone 2- transition
...
Hepatic Micro Circulatory Cone
Regulation of Hepatic Blood Flow
Intrinsic Regulation
• Hepatic Arterial Buffer Response -HABR
• Pressure flow Autoregula...
 With an intact HABR, changes in portal venous flow
cause reciprocal changes in hepatic arterial flow.
Portal venous flow...
 Various disorders (e.g., endotoxemia, splanchnic
hypo perfusion) may decrease or even abolish the
HABR and render the li...
 Hepatic pressure auto-regulation keeps constant blood flow
despite wide fluctuation in systemic BP. The mechanism
involv...
 Decrease in oxygen tension or the pH , ↑ Pco2 of
portal venous blood ,typically lead to increase in
hepatic arterial flo...
 Fibres of the vagus, phrenic and splanchnic nerves
(postganglionic sympathetic fibres from T6 to
T11)enter the liver at ...
 Gastrin, Glucagon, Secretin, Bile
salts, Angiotensin
II, Vasopressin, Catecholamines.
Cytokines, Interleukins, and other...
INCREASE IN HEPATIC
BLOOD FLOW
DECREASE IN HEPATIC
BLOOD FLOW
 Hypercapnia
 Acute hepatitis
 Supine posture
 Food in...
 Liver is supplied by sympathetic nerve fibres (
T6 to T11).
 Parasympathetic fibres – Rt & Lt Vagus.
 Fibres from Rt P...
1. Vascular functions
2. Metabolic functions
3. Bile formation & Excretion
 Normal Blood flow – 1500ml/min
 25 to 30% from Hepatic Artery
 70 – 75% from Portal veins.
 Hepatic Artery supplies 4...
 Portal vein pressure only about 7 – 10mmHg but
the low resistance of hepatic sinusoids allows rel.
large blood flow thro...
Hemorrhage
↓
Decrease in hep. Venous tone
↓
Blood shifts from hep. Veins & sinusoids into
central venous circulation & aug...
 Kupffer cells lining sinusoids are part of monocyte –
macrophage system.
 Func – phagocytosis, processing Ag, release o...
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 fru...
 All cells utilize glucose to produce energy in form
of ATP via glycolysis or citric acid cycle
 Liver can also utilize ...
 Only liver and muscle can store significant amount
of glycogen.
 Liver and kidney are unique in their capacity to
form ...
 When carbohydrate stores are saturated liver converts the
excess ingested carbohydrates into fat.
 Fatty acids thus for...
Liver performs an important function in protein
metabolism
Steps include-
1. Deamination from amino acids
2. Formation of ...
 Necessary for conversion of excess amino acids to
carbohydrates & fats
 Enzymatic processed convert amino acids to thei...
 Ammonia formed from deamination is highly
toxic to tissue
 2 molecules of ammonia + CO2 – Urea
 Urea thus formed readi...
 Hepatic transamination of appropriate keto acid
allows formation of non essential amino acids &
compensates for any diet...
Nearly all plasma proteins with notable exceptions
of Ig are formed by liver.
 Quantitatively the most important of these...
 All coagulation factors which exception of
factor VIII & vonWille Brand factor are
produced in liver.
 Vit K is necessa...
 Protease inhibitors (antithrombin III, α1 –
antitrypsin)
 Transport proteins (Transferrin, Haptoglobin,
Ceruloplasmin)
...
 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
super family.
 These ...
 Grapefruit juice.
 erythromycin,
 isoniazid,
 sulfonamides,
 ketoconazole
 Conjugation with the endogenous hydrophilic
molecules.
 It involves several processes such as
glucuronidation, sulphati...
 These are susceptible to enzyme induction.
 Heavy smoking, phenytoin admistration seen to
increase glucuronidation in h...
 It is a energy mediated transport/ elimination by
ATP- binding cassette transport proteins.
 Facilitates excretion of x...
• Genetic factors
• Diet
• Environment
• Age
• Enzyme Induction/Inhibition
• Liver disease
• Cardiac disease
 Factors : rate of hepatic blood flow, protein binding,
hepatic intrinsic clearance.
 Drug elimination – is volume of bl...
 Anesthetics significantly alter extraction by
reducing hepatic blood flow.
 Inhalational agents may influence drug clea...
High hepatic extraction
ratio
Low hepatic extraction
ratio
Lignocaine Diazepam
Propranolol Thiopentone
Meperidine Theophyl...
 Liver plays an important role in hormone, vitamin &
mineral metabolism
 Normal thyroid function is dependent on hepatic...
 Hepatocytes make most of the pro-coagulants
with exceptions of Factors III, IV, VIII.
 Liver also makes protein regulat...
 Main site.
 Hemoglobin is heme and globulin, with heme
containing ferrous and porphyrin IX.
 20% approx, heme synthesi...
 Source is from the Heme metabolism.
 Approx 300mg of bilirubin formed everyday.
 80% by the phagosytosis of scenecent ...
FUNCTIONS OF THE LIVER:
 Carbohydrate metabolism
Glycogenesis
Glycogenolysis
Gluconeogenesis
 Fat metabolism -
ketoge...
 Anesthesia & anaesthetic drugs affects the
hepatic function by following mechanisms :
 Alteration in the hepatic blood ...
Effect of volatile agents on hepatic
blood flow :
Halothane: Causes hepatic arterial constincton,
microvascular vasoconst...
 KETAMINE: Little effect on hepatic blood flow
 PROPOFOL: Significant splanchnic vasodilator
increases both hepatic arte...
 Vecuronium, rocuronium, mivacur
ium:
• Reduced elimination and Prolong duration of
action specially with infusion & repe...
 Reduction in hepatic blood flow in high spinal &
epidural anesthesia
 Secondary to hypotension
 Reversed by vasopresso...
 It is immunologically mediated, as it induces both
neoantigens & auto antigens. The incidence of fulminant
hepatic necro...
ISOFLURANE- Isoflurane metabolism yields highly reactive
intermediates (TF-acetyl chloride; acyl ester) that bind covalen...
Desflurane ↓hepatic blood flow ,it markedly reduce oxygen
delivery to the liver and small intestine without producing
com...
NITROUS OXIDE-
it produces a mild increase in sympathetic nervous
system tone leads to mild vasoconstriction of the
splan...
 Etomidate and thiopental at larger doses (>750 mg)
may cause hepatic dysfunction by ↓ hepatic blood
flow, either from ↑ ...
 Opioids have little effect on hepatic function, provided they
do not impair hepatic blood flow and oxygen supply. All
op...
 The volume of distribution of muscle relaxants,
may increase due to ↓ albumin an increase in γ-
globulin or the presence...
 Vecuronium-it is a steroidal muscle relaxant It
undergoes hepatic elimination by acetylation.
Decreased clearance, a pro...
 Atracurium & Cisatracurium
• Elimination half-lives and clinical durations of action
are similar in cirrhotic.82%to Boun...
 Altered protein binding
 Altered volume of distribution
 Altered drug metabolism due to hepatocyte
dysfuction
 Opioids: exaggerated sedative & respiratory
depressant effect and Half life is almost doubled
 Benzodiazepines : Durati...
 Splanchnic traction and exploratory laparotomy
can reduce blood flow to the intestines and the
liver
 Upper abdominal s...
 Liver major organ of metabolism
 Live dysfuction affects pharmacokinetics of
anesthetic drugs
 Anesthetic drugs affect...
 No one test reflects overall hepatic
function.
 Each test generally reflects one aspect of
hepatic function and must be...
 Normal total bilirubin - <1.5mg/dl
 Reflects balance between production &
biliary excretion.
 Jaundice is usually clin...
 These enzymes are released into circulation
as a result of hepatocellular injury or death.
 AST is present in many tiss...
 Is produced by liver, bone, small bowel,
kidneys & placenta.
 Excreted into bile
 Normal level – 25 to 85IU/L
 Most o...
SGOT/SGPT BILIRUBIN ALKPO4
BILIARY OBS + ++ +++
HEPATITIS +++ + +
ALCOHOL/DRUGS N/+ ++ N
 Normal level – 3.5 to 5.5g/dl
 Albumin level may be normal with Acute
Liver Disease
 Albumin values <2.5g/dl are gener...
 Significant increase of blood ammonia
levels usually reflect disruption of hepatic
urea synthesis.
 Normal whole blood ...
 Normal level is 11 to 14secs. (Measures the
activity of fibrinogen & factors V, VII & X)
 Relatively short half time of...
 Elevated serum LDH levels -
hepatocellular injury, extrahepatic
disorders or both.
 Extreme increases – massive liver d...
 Targeted testing is used to identify specific
hepatic or biliary diseases.
 Examples include –
1. Serologic testing to ...
 Identifying viral markers – antibodies,
antigens and genetic material – is the key
for diagnosis of hepatitis from hepat...
 CBC- Hb may show anemia esp with the target
cells in jaundiced patients due to macrocytosis.
 Leucopenia- complicates p...
 Child-Pugh Score
 Model of End-Stage Liver Disease
Score(MELD)
 Child-Turcotte-Pugh (CTP) score
 initially designed to stratify the risk of portacaval shunt
surgery in cirrhotic patie...
 M&M for pts undergoing intra-abd
surgery
 Incorporates three
biochemical(PT, albumin, bilirubin)
 Incorporates three c...
Points Assigned 1 2 3
Laboratory value
Bilirubin (mg/adL) < 2 2-3 > 3
Albumin (g/dL) > 3.5 2.8-3.5 < 2.8
PT or
INR
< 4 s
<...
 Created in 1999 to predict 3 month
mortality in pts with chronic dz.
 Prioritizes those on transplat list
 Looks at bi...
 >8: predictive of poor
 >24: qualifies for transplantation
Hepatic physiology & liver function tests
Hepatic physiology & liver function tests
Hepatic physiology & liver function tests
Hepatic physiology & liver function tests
Hepatic physiology & liver function tests
Hepatic physiology & liver function tests
Hepatic physiology & liver function tests
Hepatic physiology & liver function tests
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Hepatic physiology & liver function tests

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Hepatic physiology & liver function tests

  1. 1. Dr Imran.
  2. 2. • Largest organ in the body • Wt – 1500 to 1600gms • Reddish brown triangular pyramid shaped, in rt. Hypochondrium and most of epigastrium.
  3. 3. Cystic artery sole supply to bile duct
  4. 4. liver pancreas spleen Portal vein: 80% Hepatic artery: 20% Dual Blood Supply of Liver Liver has dual blood supply: 80% portal vein 20% hepatic artery
  5. 5.  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.
  6. 6.  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.
  7. 7. 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).
  8. 8.  Anatomically the liver is divided into a Right and a Left lobe by the falciform ligament  The Right lobe also has two minor lobes- The caudate lobe and The quadrate lobe
  9. 9.  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.
  10. 10. 12
  11. 11.  The blood leaves the sinusoids via a central vein , which drains in the hepatic vein.
  12. 12. Claude Couinad A French surgeon & anatomist who made significant contribution in the field of hepatobiliary surgery ,he was the first to describe segmental anatomy of the liver
  13. 13.  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 segments  Left hepatic vein divides the left lobe into a medial and lateral part.
  14. 14.  Liver lobules – hexagonal structures consisting of hepatocytes  At each of the six corners of a lobule is a portal triad
  15. 15. 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
  16. 16. Zone 1- Rich in Oxygen, mitochondria •Concerned with Oxidative metabolism and synthesis of glycogen Zone 2- transition Zone 3- • lowest in Oxygen, anaerobic metabolism, •Biotransformation of drugs, chemicals, and toxins •Most sensitive to damage due to ischemia, hypoxia, congestion
  17. 17. Hepatic Micro Circulatory Cone
  18. 18. Regulation of Hepatic Blood Flow Intrinsic Regulation • Hepatic Arterial Buffer Response -HABR • Pressure flow Autoregulation • Metabolic control Extrinsic Regulation • Neural Control • Humoral Control
  19. 19.  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. 
  20. 20.  Various disorders (e.g., endotoxemia, splanchnic hypo perfusion) may decrease or even abolish the HABR and render the liver more vulnerable to hypoxic injury.  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, Hypocapnia, Vasopressin.
  21. 21.  Hepatic pressure auto-regulation keeps constant blood flow despite wide fluctuation in systemic BP. The mechanism involves myogenic responses of vascular smooth muscle to stretch.  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
  22. 22.  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 state.  The underlying metabolic and respiratory status (e.g., hypercapnia, alkalosis, arterial hypoxemia) also modulates the distribution of blood flow within the liver.
  23. 23.  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.
  24. 24.  Gastrin, Glucagon, Secretin, Bile salts, Angiotensin II, Vasopressin, Catecholamines. Cytokines, Interleukins, and other inflammatory mediators have been implicated in the alteration of normal splanchnic and hepatic blood flow.
  25. 25. INCREASE IN HEPATIC BLOOD FLOW DECREASE IN HEPATIC BLOOD FLOW  Hypercapnia  Acute hepatitis  Supine posture  Food intake  Drug: Beta Agonist Phenobaritone  Enzyme inducers  IPPV  Hypocapnia  Hyhpoxia  Cirrhosis  alpha Stimulation  Beta blocker  Halothane, volatile & anesthetics  Vasopressin
  26. 26.  Liver is supplied by sympathetic nerve fibres ( T6 to T11).  Parasympathetic fibres – Rt & Lt Vagus.  Fibres from Rt Phrenic nerve.  Some autonomic fibres synapse first with Celiac Plexus whereas others reach the liver directly via splanchnic nerves & vagal branches before forming Hepatic Plexus
  27. 27. 1. Vascular functions 2. Metabolic functions 3. Bile formation & Excretion
  28. 28.  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 requirement  Portal veins supplies the remaining 50 – 55%  The total blood flow from this dual supply represents 25 – 30% of cardiac output
  29. 29.  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.
  30. 30. Hemorrhage ↓ Decrease in hep. Venous tone ↓ Blood shifts from hep. Veins & sinusoids into central venous circulation & augments circulating blood vol upto 300ml.
  31. 31.  Kupffer cells lining sinusoids are part of monocyte – macrophage system.  Func – phagocytosis, processing Ag, release of various proteins, enzymes, cytokines & other chem. Mediators.  Phagocytic activity is responsible for removing colonic bacteria & endotoxin entering bloodstream from portal circulation.  Cellular debris, viruses, proteins & particulate matter in blood are phagocytosed
  32. 32. 1. Carbohydrate Metabolism 2. Protein Metabolism 3. Fat Metabolism 4. Drug Metabolism 5. Other Metabolic functions
  33. 33.  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 carbohydrates.
  34. 34.  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 fatty acids.  Most of glucose absorbed from meal is stored as Glycogen in liver.  When glycogen storage is exceeded in liver, glucose is stored as fat.
  35. 35.  Only liver and muscle can store significant amount of glycogen.  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 concentration.  Glucocorticoids, catecholamines, glucagon & thyroid hormone greatly enhance gluconeogenesis – whereas insulin inhibits it.
  36. 36.  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.
  37. 37. Liver performs an important function in protein metabolism Steps include- 1. Deamination from amino acids 2. Formation of urea 3. Interconversion between non essential amino acids 4. Formation of plasma proteins
  38. 38.  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 hepatic gluconeogenesis.  Liver normally deaminates most of amino acids derived from dietary proteins  Branched chain amino acids are primarily metabolised by skeletal muscle.
  39. 39.  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
  40. 40.  Hepatic transamination of appropriate keto acid allows formation of non essential amino acids & compensates for any dietary deficiency in these amino acids
  41. 41. 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 proteases/elastases Proteins produced by liver  Albumin – maintains normal plasma oncotic pressure and is principal binding & transport protein for fatty acids & large no of hormones & drugs.
  42. 42.  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
  43. 43.  Protease inhibitors (antithrombin III, α1 – antitrypsin)  Transport proteins (Transferrin, Haptoglobin, Ceruloplasmin)  Complement  α1 – acid glycoprotein  C – reactive Protein  Serum Amyloid - A
  44. 44.  It is divided into 1. Phase I reaction. 2. Phase II reaction. 3. Phase III reaction.
  45. 45.  It is oxidative hydrolysis & reduction reactions  It is mainly microsomal oxidases, CYP isozymes super family.  These CYP isozymes are concentrated in the centrilobular zone.  It needs NADPH for its reactions and hence formation of superoxides and reactive free radicals, more chance of injury to these cells, necrosis.
  46. 46.  Grapefruit juice.  erythromycin,  isoniazid,  sulfonamides,  ketoconazole
  47. 47.  Conjugation with the endogenous hydrophilic molecules.  It involves several processes such as glucuronidation, sulphation, methylation, acetylation .  Glucuronidation is the common type.  Hepatic microsomal uridine diphosphate glucuronyl transferase mediates the reaction.
  48. 48.  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.
  49. 49.  It is a energy mediated transport/ elimination by ATP- binding cassette transport proteins.  Facilitates excretion of xenobiotics and endogenous compounds.  These proteins use ATP hydrolysis to drive molecular transport.  These resides on the canalicular surfaces of hepatocytes and enables biliary excretion of cationic compounds, including anticancer drugs.
  50. 50. • Genetic factors • Diet • Environment • Age • Enzyme Induction/Inhibition • Liver disease • Cardiac disease
  51. 51.  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.  Extraction ratio(E): amt of drug removed from the blood during a simple pass through the liver.
  52. 52.  Anesthetics significantly alter extraction by reducing hepatic blood flow.  Inhalational agents may influence drug clearance by altering drug-metabolizing ability or intrinsic clearance  Inhalational agents have been shown both in vitro and in vivo to alter drug metabolism at clinically relevant concentrations.  They are competitively inhibiting p-450, and phase II reactions.
  53. 53. High hepatic extraction ratio Low hepatic extraction ratio Lignocaine Diazepam Propranolol Thiopentone Meperidine Theophylline Verapamil Digitoxin Phenytoin Pancuronium
  54. 54.  Liver plays an important role in hormone, vitamin & mineral metabolism  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 hemostasis.
  55. 55.  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, & antithrombin III
  56. 56.  Main site.  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 synthetase.
  57. 57.  Source is from the Heme metabolism.  Approx 300mg of bilirubin formed everyday.  80% by the phagosytosis of scenecent RBCs by the RE cells.  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 excreted.  Enterohepatic circulation ensures some of these products to return to the liver.
  58. 58. FUNCTIONS OF THE LIVER:  Carbohydrate metabolism Glycogenesis Glycogenolysis Gluconeogenesis  Fat metabolism - ketogenesis  Protein metabolism anabolism deamination urea formation  Secretion of bile  Detoxification  Metabolism of vitamins A,D,K,E &  Clotting factors, esp prothrombin  Storage  Blood store
  59. 59.  Anesthesia & anaesthetic drugs affects the hepatic function by following mechanisms :  Alteration in the hepatic blood flow n HABR.  Metabolic function.  Drug metabolism.  Billiary function.
  60. 60. Effect of volatile agents on hepatic blood flow : Halothane: Causes hepatic arterial constincton, microvascular vasoconstriction Enflurane: Increase in hepatic vascular resistance Isoflurane: Increase in microvascular blood velocity Sevoflurane & Desflurane: Preservation of hepatic blood flow & function
  61. 61.  KETAMINE: Little effect on hepatic blood flow  PROPOFOL: Significant splanchnic vasodilator increases both hepatic arterial & portal venous blood flow  THIOPENTONE & ETOMIDATE: Hepatic arterial blood flow reduction, reducedf cardiac output
  62. 62.  Vecuronium, rocuronium, mivacur ium: • 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
  63. 63.  Reduction in hepatic blood flow in high spinal & epidural anesthesia  Secondary to hypotension  Reversed by vasopressors like dopamine, ephedrine
  64. 64.  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.
  65. 65. ISOFLURANE- Isoflurane metabolism yields highly reactive intermediates (TF-acetyl chloride; acyl ester) that bind covalently to hepatic proteins. For this isoflurane most likely causes hepatitis. 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 administration.
  66. 66. 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 small intestine. 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.
  67. 67. NITROUS OXIDE- 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 arterial system. N2O is a known inhibitor of the enzyme methionine synthase, which could potentially produce toxic hepatic effects.
  68. 68.  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
  69. 69.  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
  70. 70.  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.
  71. 71.  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.
  72. 72.  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 (Hoffmann's elimination). • 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
  73. 73.  Altered protein binding  Altered volume of distribution  Altered drug metabolism due to hepatocyte dysfuction
  74. 74.  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
  75. 75.  Splanchnic traction and exploratory laparotomy can reduce blood flow to the intestines and the liver  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 nonabdominal procedures
  76. 76.  Liver major organ of metabolism  Live dysfuction affects pharmacokinetics of anesthetic drugs  Anesthetic drugs affects liver function  Neuroaxial blocks: reduction in hepatic blood flow due to hypotension  Intropetative hypotension, hypoxia, hypocapnia, use of hepatotoxic drugs in perioperative period can cause postoperative hepatic dysfunction
  77. 77.  No one test reflects overall hepatic function.  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 substances 2. Parenchymal – result in generalised hepatocellular dysfunction
  78. 78.  Normal total bilirubin - <1.5mg/dl  Reflects balance between production & biliary excretion.  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 obstruction.  >50% unconj. Hyperbilirubinemia may be seen with hemolysis or cong. Or acquired defects in bilirubin conjugation
  79. 79.  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 fulminant hepatitis.
  80. 80.  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 bone.  Biliary Obstruction – more hepatic alkaline phosphatase is synthesized and released into circulation.  Increased levels indicate intrahepatic cholestasis & biliary obstruction.  Increased levels in pregnancy & Paget’s disease
  81. 81. SGOT/SGPT BILIRUBIN ALKPO4 BILIARY OBS + ++ +++ HEPATITIS +++ + + ALCOHOL/DRUGS N/+ ++ N
  82. 82.  Normal level – 3.5 to 5.5g/dl  Albumin level may be normal with Acute Liver Disease  Albumin values <2.5g/dl are generally indicative of CLD, acute stress or severe malnutrition.  Increased losses of albumin in urine is suggestive of Nephrotic syndrome.
  83. 83.  Significant increase of blood ammonia levels usually reflect disruption of hepatic urea synthesis.  Normal whole blood ammonia levels are 47 to 65mmol/L  Increase usually reflect severe hepatocellular damage.
  84. 84.  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 considered significant.  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 disease
  85. 85.  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 ecclampsia)
  86. 86.  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 metabolic disorders. 3. Tumor marker assays to detect hepatic malignancies
  87. 87.  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 phenotype analysis.  Markers for hepatic malignancy – AFP, des – γ – carboxylated prothrombin.
  88. 88.  CBC- Hb may show anemia esp with the target cells in jaundiced patients due to macrocytosis.  Leucopenia- complicates portal HTN and hypersplenism.  Leucocytosis- in hepatic abscess, alcoholic hepatitis, cholangitis.  Thrombocytopenia- in cirrhosis, due to dec in thrombopoetin in liver, and hypersplenism.
  89. 89.  Child-Pugh Score  Model of End-Stage Liver Disease Score(MELD)
  90. 90.  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 encephalopathy  good predictor of outcome in patients with complications of portal hypertension
  91. 91.  M&M for pts undergoing intra-abd surgery  Incorporates three biochemical(PT, albumin, bilirubin)  Incorporates three clinical features(Nutrition, +/- ascites, encephalopathy
  92. 92. Points Assigned 1 2 3 Laboratory value Bilirubin (mg/adL) < 2 2-3 > 3 Albumin (g/dL) > 3.5 2.8-3.5 < 2.8 PT or INR < 4 s < 1.7 4-6 s 1.7-2.2 > 6 s > 2.2 Signs 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.
  93. 93.  Created in 1999 to predict 3 month mortality in pts with chronic dz.  Prioritizes those on transplat list  Looks at bilirubin,INR,and serum creatinine
  94. 94.  >8: predictive of poor  >24: qualifies for transplantation

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