covers extensive and authentic information regarding physiology of liver and liver function tests. text is collected from standard text books

1. Dr. Anil babu Swarna (Jr. Resident)Dr. Anil babu Swarna (Jr. Resident)
Dept. of AnesthesiologyDept. of Anesthesiology
Mamata medical collegeMamata medical college

2. The liver lies in the right upper quadrant of the abdominal cavity and is attached to the
diaphragm.
It is the largest organ in the body, weighing approximately 1,500 g and representing 2% of
body weight.
In the neonate, the liver accounts for approximately 5% of body weight.
Hepatocytes represent approximately 80% of the cytoplasmic mass within the liver.

3.  The liver is divided into four lobes
consisting of 50,000 to 100,000 individual
hepatic lobules. Blood flows past
hepatocytes via sinusoids from branches
of the portal vein and hepatic artery to a
central vein.
 There is usually only one layer of
hepatocytes between sinusoids so the
total area of contact with plasma is great.
 Central veins join to form hepatic veins,
which drain into the inferior vena cava.

4.  Each hepatocyte is also located adjacent
to bile canaliculi, which coalesce to form
the common hepatic duct. This duct and
the cystic duct from the gallbladder join
to form the common bile duct, which
enters the duodenum at a site
surrounded by the sphincter of Oddi
 The main pancreatic duct also unites with
the common bile duct just before it enters
the duodenum.

5. Endothelial cells that line the hepatic
lobules contain large pores, permitting easy
diffusion of certain substances, including
plasma proteins, into extravascular spaces
of the liver that connect with terminal
lymphatics.
The extreme permeability of the lining of
endothelial cells allows large quantities of
lymph to form, which contain protein
concentrations that are only slightly less
than the protein concentration of plasma.
Indeed, approximately one-third to one-
half of all the lymph is formed in the liver

6. PORTAL TRIADPORTAL TRIAD
Branches of the two vessels-
portal vein, hepatic artery, along
with bile drainage ductules all
run together to infiltrate all parts
of liver

7. Zone 1 (Periportal)Zone 1 (Periportal)
Rich in Oxygen, mitochondria
Concerned with Oxidative metabolism
and synthesis of glycogen
Zone 2-Zone 2- transition
Zone 3-Zone 3- lowest in Oxygen, anaerobic
metabolism,
Biotransformation of drugs, chemicals,
and toxins. Hence hypoxic insult to the
Liver first effects biotransformation of
drugs
Most sensitive to damage due to
ischemia, congestion (apart from hypoxia)

8.  The liver receives a dual afferent blood
supply from the hepatic artery and portal
veins. Total hepatic blood flow is
approximately 1,450 mL per minute or
approximately 29% of the cardiac output.
 Of this amount, the portal vein provides
75% of the total flow but only 50% to 55%
of the hepatic oxygen supply because this
blood is partially deoxygenated in the pre-
portal organs and tissues (gastrointestinal
tract, spleen, pancreas).

9.  The hepatic artery provides only 25% of
total hepatic blood flow but provides 45%
to 50% of the hepatic oxygen
requirements.
 Hepatic artery blood flow maintains
nutrition of connective tissues and walls of
bile ducts. For this reason, loss of hepatic
artery blood flow can be fatal because of
ensuing necrosis of vital liver structures.
 An increase in hepatic oxygen
requirements is met by an increase in
oxygen extraction rather than a further
increase in the already high hepatic blood
flow.

10.  The liver offers modest resistance to blood flow
from the portal venous system. As a result, the
pressure in the portal vein averages 7 to 10 mm
Hg, which is considerably higher than the almost
zero pressure in the inferior vena cava.
 Cirrhosis of the liver, is characterized by
increased resistance to portal vein blood flow
due to replacement of hepatic cells with fibrous
tissue that contracts around the blood vessels.
 The gradual increase in resistance to portal vein
blood flow produced by cirrhosis causes large
collateral vessels to develop between the portal
veins and the systemic veins.

11.  The most important of these collaterals are from the splenic veins to the
esophageal veins.
 These collaterals may become so large that they protrude into the lumen of the
esophagus, producing esophageal varices. The esophageal mucosa overlying
these varices may become eroded, leading to life-threatening hemorrhage.
 In the absence of the development of adequate collaterals, sustained increases in
portal vein pressure may cause protein-containing fluid to escape from the
surface of the mesentery, gastrointestinal tract, and liver into the peritoneal
cavity.
 This fluid, known as ascites, is similar to plasma, and its high protein content
causes an increased colloid osmotic pressure in the abdominal fluid.
 This high colloid osmotic pressure draws additional fluid from the surfaces of the
gastrointestinal tract and mesentery into the peritoneal cavity.

13. HEPATIC ARTERIAL BUFFER RESPONSE (HABR)HEPATIC ARTERIAL BUFFER RESPONSE (HABR)
The HABR mechanism involves the synthesis and washout of adenosine- a vasodilating
substance from peri-portal regions
With an intact HABR, changes in portal venous flow cause reciprocal changes in hepatic
arterial flow. If portal venous flow reduced then there is reduction in hepatic artery resistance.
But not vice versa. i.e., a decrease in portal vein blood flow is accompanied by an increase in
hepatic artery blood flow by as much as 100%.
Various disorders (e.g., endotoxemia, splanchnic hypo perfusion) may decrease or even
abolish the HABR and render the liver more vulnerable to hypoxic injury.

14.  Portal HypertensionPortal Hypertension: Fibrotic constriction characteristic of hepatic cirrhosis can increase
resistance to portal vein blood flow, as evidenced by portal venous pressures of 20 to 30 mm
Hg.
 The resulting increased resistance to portal vein blood flow may result in development of
shunts (varices) to allow blood flow to bypass the hepatocytes.
 Conversely, congestive heart failure and positive pressure ventilation of the lungs impair
outflow of blood from the liver because of increased central venous pressure, which is
transmitted to hepatic veins

15. PRESSURE FLOW AUTO REGULATIONPRESSURE FLOW AUTO REGULATION
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 non-existent in the portal circulation. Thus, decrease in
systemic blood pressure—as often occurs during anesthesia—typically lead to proportional
decrease in portal venous flow

16. METABOLIC CONTROLMETABOLIC CONTROL
Decrease in oxygen tension or the pH , ↑ Pco2 of portal venous blood ,typically lead to
increase in hepatic arterial flow.
Postprandial hyper-osmolarity 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.

17. NEURAL CONTROLNEURAL CONTROL
Sympathetic nervous system innervation is from T3 to T11 and is mediated via adrenergic
receptors. This innervation is principally responsible for resistance and compliance of hepatic
venules.
Changes in hepatic venous compliance play an essential role in overall regulation of cardiac
output and the reservoir function of the liver
When sympathetic tone decreases, splanchnic reservoir increases whereas sympathetic
stimulation translocates blood volume from the splanchnic reservoir to the central circulation
Vagal stimulation alters the tone of the pre-sinusoidal sphincters, the net effect is a
redistribution of intrahepatic blood flow without changing total hepatic blood flow

18. HUMORAL CONTROLHUMORAL CONTROL
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

19. INCREASE IN HEPATIC BLOOD FLOWINCREASE IN HEPATIC BLOOD FLOW
Hypercapnia
Acute hepatitis
Supine/ recumbent posture
Food intake
Glucagon
Drugs: Beta Agonists, Phenobaritone
Enzyme inducers
DECREASE IN HEPATIC BLOOD FLOWDECREASE IN HEPATIC BLOOD FLOW
IPPV, PEEP
Hypocapnia
Hypoxia
Cirrhosis
alpha Stimulation
Beta blockers
Halothane, Volatile anesthetics
Surgical trauma
Vasopressin

20. VOLATILE AGENTSVOLATILE AGENTS
Halothane: causes hepatic arterial constriction, microvascular vasoconstriction
Halothane decreases hepatic oxygen supply more than isoflurane, enflurane, desflurane, or
sevoflurane when administered in equal potent doses. In contrast to the other volatile
anesthetics, halothane preserves autoregulation of hepatic blood flow only to a limited extent
and only when used in doses that do not decrease systemic blood pressure more than 20%.

21.  Enflurane: causes the same effects of halothane but with lesser intensity
 Isoflurane: causes Increase in microvascular blood velocity
 Sevoflurane: Preservation of hepatic O2 delivery and hepatic blood flow & function. Superior
to isoflurane in maintaining hepatic blood flow
 Desflurane: decreases hepatic blood flow
 HBF:HBF: SEVO > ISO > DES > HALO
NITROUS OXIDENITROUS 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.

22. IV ANESTHETIC AGENTSIV ANESTHETIC AGENTS
KETAMINE: Little effect on hepatic blood flow even with large doses
PROPOFOL: Significant splanchnic vasodilator increases both hepatic arterial & portal venous
blood flow
THIOPENTONE & ETOMIDATE: 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
REGIONAL ANESTHESIAREGIONAL ANESTHESIA
Reduction in hepatic blood flow in high spinal & epidural anesthesia secondary to hypotension
(decrease in MAP). Further reduced by an infusion of norepinephrine
Reversed by vasopressors like dopamine, ephedrine

23. OpiodsOpiods
Morphine and Meperidine reduces HBF. Fentanyl is the preferred agent but Remifentanil is ideal.
SedativesSedatives
Diazepam- prolonged metabolism in liver disease.
Lorazepam- eliminated by glucuronidation without hepatic metabolism. So preferred agent
Neuromuscular Blocking DrugsNeuromuscular Blocking Drugs
The volume of distribution of muscle relaxants, may increase due to ↓ albumin and 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 the drug effects are prolonged owing to ↓ in
hepatic blood flow and impaired hepatic clearance, and possible concurrent renal dysfunction

24.  Hypoxia:Hypoxia:
 Hypoxia decreases HBF
 Effects of hypoxia depends on duration & degree & of anesthetic used
 PaCoPaCo22::
 Hypocapnea causes vasoconstriction - causing decrease in HBF
 Hypercapnea causes
 pCo2 is maintained between 35 – 40 mm of Hg during surgery
Vasodilation - causing increase in HBF
Sympathetic stimulation - causes
decrease in HBF (due to decrease
in portal blood flow)

25.  Surgical stimulation may further decrease hepatic blood flow, independent of the anesthetic
drug administered.
 The greatest decreases in hepatic blood flow occur during intra-abdominal operations,
presumably due to mechanical interference of blood flow produced by retraction in the
operative area, as well as the release of vasoconstricting substances such as catecholamines.
 Upper abdominal surgery is associated with the greatest reduction in hepatic blood flow
 Elevation of liver biochemical tests is more likely to occur after biliary tract procedures than
after nonabdominal procedures

26. Factors : 1) rate of hepatic blood flow
2) protein binding
3) 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): amount of drug removed from the blood during a simple pass through
the liver.
Anesthetic agents significantly alter extraction ratio by reducing hepatic blood flow.
Inhalational agents may influence drug clearance by altering drug-metabolizing ability or
intrinsic clearance
They competitively inhibit p-450, and phase II reactions

27. Few drugs with high and low hepatic extraction ratio
High hepatic extraction ratio Low hepatic extraction ratio
Lignocaine Diazepam
Propranolol, Labetolol Thiopentone
Meperidine, Morphine, Fentanyl Theophylline
Verapamil Digitoxin
Propofol Phenytoin
Pancuronium

28.  Altered protein binding
 Altered volume of distribution
 Altered drug metabolism due to hepatocyte dysfunction
 Opioids: exaggerated sedative & respiratory depressant effect and Half life is almost doubled
 Benzodiazepines : Duration of action increased
 Thiopentone, Etomidate, Propofol, Ketamine: Repeated doses & prolonged infusion causes
accumulation of drugs
 Increases risk of hepatic encephalopathy
 Presence of liver disease does not increase the adverse effect of anaesthesia on liver function
and that surgical trauma is more important than anaesthesia in producing liver dysfunction

29.  Reservoir function
 Blood cleansing functions
 Metabolic functions
 Bile formation & Excretion

30.  The liver normally contains approximately 500 mL of blood or approximately 10% of the total
blood volume.
 An increase in central venous pressure causes back pressure, and the liver, being a distensible
organ, may accommodate as much as 1 L of extra blood. As such, the liver acts as a storage
site when blood volume is excessive, as in case of congestive heart failure, and is capable of
supplying extra blood when hypovolemia occurs.

31.  Kupffer cells lining sinusoids are part of monocyte – macrophage system.
 Functions – phagocytosis, processing of Antigens, release of various proteins, enzymes,
cytokines & other chemical mediators.
 Phagocytic activity is responsible for removing colonic bacteria & endotoxins entering the
bloodstream from portal circulation.
 Cellular debris, viruses, proteins & particulate matter in blood are phagocytosed

32.  CARBOHYDRATE METABOLISMCARBOHYDRATE METABOLISM
 In carbohydrate metabolism, the liver performs the following functions:
1. Storage of large amounts of glycogen
2. Conversion of galactose and fructose to glucose
3. Gluconeogenesis
4. Formation of many chemical compounds from intermediate products of carbohydrate
metabolism
 The liver is especially important for maintaining a normal blood glucose concentration.
Storage of glycogen allows the liver to remove excess glucose from the blood, store it, and
then return it to the blood when the blood glucose concentration begins to fall too low,
which is called the glucose buffer function of the liver

33.  In a person with poor liver function, blood glucose concentration after a meal rich in
carbohydrates may rise two to three times as much as in a person with normal liver function.
 Gluconeogenesis in the liver is also important in maintaining a normal blood glucose
concentration because gluconeogenesis occurs to a significant extent only when the glucose
concentration falls below normal.
 Large amounts of amino acids and glycerol from triglycerides are then converted into
glucose, thereby helping to maintain a relatively normal blood glucose concentration.
 The final products of carbohydrate metabolism are glucose, fructose & galactose.

34.  All cells utilize glucose to produce energy in form of ATP via glycolysis or citric acid cycle
 Liver can also utilize the Phospho-gluconate pathway which not only provides energy but also
produces an important 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
 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 maintenance of a normal blood glucose concentration.
 Glucocorticoids, catecholamines, glucagon & thyroid hormone greatly enhance
gluconeogenesis – whereas insulin inhibits it

35.  FAT METABOLISMFAT METABOLISM
 Although most cells of the body metabolize fat, certain aspects of fat metabolism occur
mainly in the liver. In fat metabolism, the liver performs the following specific functions:
1. Oxidation of fatty acids to supply energy for other body functions
2. Synthesis of large quantities of cholesterol, phospholipids, and most lipoproteins
3. Synthesis of fat from proteins and carbohydrates
 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.
 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

36.  PROTEIN METABOLISMPROTEIN METABOLISM
 The most important functions of the liver in protein metabolism are the following:
 1. Deamination of amino acids
 2. Formation of urea for removal of ammonia from the body fluids
 3. Formation of plasma proteins
 4. Interconversions of the various amino acids and synthesis of other compounds from amino
acids
Deamination
 Necessary for conversion of excess amino acids to carbohydrates & fats
 Enzymatic processes convert amino acids to their respective keto acids & produce ammonia.
 Deamination of alanine plays an important role in hepatic gluconeogenesis.

37.  Liver normally deaminates most of amino acids derived from dietary proteins
 Branched chain amino acids are primarily metabolised by skeletal muscle.
Formation of Urea
 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
Interconversion between non essential amino acids
 Hepatic transamination of appropriate keto acid allows formation of non essential amino
acids & compensates for any dietary deficiency in these amino acids

38. Formation of plasma proteins
 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 the principal binding & transport
protein for fatty acids & large number of hormones & drugs.
 All coagulation factors with the exception of factor VIII & VonWille Brand factor are produced
in liver.
 Vitamin 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 & Scholine

39. Other important proteins produced are
Protease inhibitors (antithrombin III, α1 – antitrypsin)
Transport proteins (Transferrin, Haptoglobin, Ceruloplasmin) Hepatic production of transferrin
& Haptoglobin is important because proteins are important in iron hemostasis
Complement protiens
α1 – acid glycoprotein
C – reactive Protein
Serum Amyloid - A

40. Other metabolic functions:
 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 major site of degradation for insulin, steroid hormones, glucagon & ADH
 Hepatocytes are principal storage sites for Vit A, B12, E, D & K.
Coagulation
 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

41.  Hepatocytes continually form bile (500 mL
daily) which ultimately reach the common bile
duct
 Gallbladder has a capacity of 35 to 50 mL.
 The most potent stimulus for emptying the
gallbladder is the presence of fat in the
duodenum, which evokes the release of the
hormone cholecystokinin by the duodenal
mucosa.
 When adequate amounts of fat are present,
the gallbladder empties in approximately 1
hour.
 The principal components of bile are bile salts,
bilirubin, and cholesterol.

42. BILE SALTS: Bile salts combine with lipids in the duodenum to form water-soluble complexes
(micelles) that facilitate gastrointestinal absorption of fats (triglycerides) and fat-soluble
vitamins.
Once absorbed, bile salts return to the liver via the portal vein and enter back into
hepatocytes (enterohepatic circulation). In the absence of bile secretion, steatorrhea and
deficiency of vitamin K develop with in a few days

43. BILE SALTS: Bile salts combine with lipids in the duodenum to form water-soluble complexes
(micelles) that facilitate gastrointestinal absorption of fats (triglycerides) and fat-soluble
vitamins.
Once absorbed, bile salts return to the liver via the portal vein and enter back into
hepatocytes (enterohepatic circulation). In the absence of bile secretion, steatorrhea and
deficiency of vitamin K develop with in a few days
CHOLESTEROL: Cholesterol is an important component of cell walls synthesized in tissues and
is transported from the periphery to the liver as high-density lipoproteins (HDL). Once
cholesterol has reached the liver, it is excreted in the bile in association with bile acids.
Cholesterol in the bile may precipitate as gallstones if there is excess absorption of water in
the gallbladder or the diet contains too much cholesterol. 85% of gall stones are cholesterol
stones

44.  After RBC lysis the released hemoglobin is
converted to bilirubin in reticuloendothelial
cells
 It enters the circulation & transported in
combination with albumin to the liver. In
hepatocytes, bilirubin conjugates principally
with glucuronic acid.
 Unconjugated bilirubin may be neurotoxic and
may even cause a rapidly fatal
encephalopathy.
 In the gastrointestinal tract, bilirubin is
converted by bacterial action mainly into
urobilinogen.
 Urobilinogen in the intestine is converted into
stercobilinogen

45.  Better term is liver biochemical tests
 Liver tests have shortcomings. They can be normal in patients with
serious liver disease and abnormal in patients with diseases that do
not affect the liver.
 Liver tests rarely suggest a specific diagnosis; rather, they suggest a
general category of liver disease, such as hepatocellular or cholestatic,
which then further directs the evaluation
 Many tests, such as the aminotransferases or alkaline phosphatase, do
not measure liver function at all !!! Rather, they detect liver cell
damage or interference with bile flow.

46.  TESTS BASED ON DETOXIFICATION AND EXCRETORY FUNCTIONSTESTS BASED ON DETOXIFICATION AND EXCRETORY FUNCTIONS
 Bromsulphthalein test
 Serum bilirubin
 Urine Bilirubin
 Blood Ammonia
 Serum enzymes
 Enzymes that reflect damage to hepatocytes
Aminotransferases- AST (SGOT) and ALT (SGPT)
 Enzymes that reflect cholestasis
 Alkaline phosphatase, 5ʹ-nucleotidase, and γ-glutamyl transpeptidase (GGT)
 TESTS THAT MEASURE BIOSYNTHETIC FUNCTION OF THE LIVERTESTS THAT MEASURE BIOSYNTHETIC FUNCTION OF THE LIVER
 Serum Albumin
 Serum Globulins
 Coagulation factors

47.  Bromsulphthalein is a dye used to assess the excretory function of the Liver
 It’s a non-toxic compound almost exclusively excreted by the Liver through bile
 BSP is administered intravenously (5mg/ kg) and the serum concentrations of the dye are
measured at 45 minutes and 2 hours
 In normal individuals less than 5% of the dye is retained at the end of 45 minutes
 Any impairment in liver function causes an increased retention of the dye
 This test is quite sensitive to assess the liver function with reference to excretory function
 Now its obsolete

48.  It is a specific test for identificaion of increased serum bilirubin levels.
 Normal serum gives a negative van den Bergh reaction.
 Mechanism of the reaction:
 Van den Bergh reagent is a mixture of equal volumes of sulfanilic acid (in dilute HCI) &
sodium nitrite
 Principle: Diazotised sulfanilic acid reacts with bilirubin to form a purple coloured
azobilirubin.
 Direct and indirect reactions:
 Bilirubin as such is Insoluble in water while the conjugated bilirubin is soluble
 Van den Bergh reagent reacts with conjugated bilirubin & gives a purple colour immediately
(normally within 30 seconds).
 This is direct positive van den Bergh reaction

49.  Addition of methanol (or alcohol) dissolves the unconjugated bilirubin & gives the van den
Bergh reaction (normally within 30 minutes) positive.
 This is indirect positive.
 lf the serum contains both unconjugated and conjugated bilirubin in high concentration, the
purple colour is produced immediately (direct positive) which is further intensified by the
addition of alcohol (indirect positive).
 This type of reaction is known as biphasic.

50. SERUM BILIRUBINSERUM BILIRUBIN
When measured by modifications of the original van den Bergh method, normal values of
total serum bilirubin are reported between 1 and 1.5 mg/dL with 95% of a normal population
falling between 0.2 and 0.9 mg/dL.
If the plasma bilirubin level exceeds 1mg/dl, the condition is called hyperbilirubinemia.
Levels between 1 & 2 mg/dl are indicative of latent jaundice
When the bilirubin level exceeds 2 mg/dl, it diffuses into tissues producing yellowish
discoloration of sclera, conjunctiva, skin & mucous membrane resulting in jaundice.
Icterus is the Greek term for jaundice
>50% conjugated Hyperbilirubinemia is associated with urinary urobilinogen & may reflect
hepatocellular dysfunction, intra hepatic Cholestasis or extrahepatic biliary obstruction.
>50% unconjugated Hyperbilirubinemia may be seen with hemolysis or acquired defects in
bilirubin conjugation

51. I. Indirect hyperbilirubinemia
A. Hemolytic disorders
1. Inherited
a. Spherocytosis, elliptocytosis, glucose-6-
phosphate dehydrogenase and pyruvate
kinase deficiencies
b. Sickle cell anemia
2. Acquired
a. Microangiopathic hemolytic anemias
b. Paroxysmal nocturnal hemoglobinuria
c. Spur cell anemia
d. Immune hemolysis
e. Parasitic infections
(1) Malaria
(2) Babesiosis
B. Ineffective erythropoiesis
1. Cobalamin, folate, and severe iron
deficiencies
2. Thalassemia
C. Increased bilirubin production
1. Massive blood transfusion
2. Resorption of hematoma

52.  D. Drugs
 1. Rifampin
 2. Probenecid
 3. Ribavirin
 E. Inherited conditions
 1. Crigler-Najjar types I and II
 2. Gilbert’s syndrome
 II. Direct hyperbilirubinemia (inherited conditions)
A. Dubin-Johnson syndrome
B. Rotor syndrome

53.  Viral hepatitis
Hepatitis A, B, C, D, and E
Epstein-Barr virus
Cytomegalovirus
Herpes simplex virus
 Alcoholic hepatitis
 Drug toxicity
Predictable, dose-dependent
(e.g., acetaminophen)
Unpredictable, idiosyncratic
(e.g., isoniazid)
 Environmental toxins
 Vinyl chloride
 Jamaica bush tea—pyrrolizidine alkaloids
 Kava Kava
 Wild mushrooms—Amanita phalloides, A.
verna
 Wilson’s disease
 Autoimmune hepatitis

54.  I. IntrahepaticI. Intrahepatic
 A. Viral hepatitis
1. Fibrosing cholestatic hepatitis—hepatitis B and C
2. Hepatitis A, Epstein-Barr virus infection,
cytomegalovirus infection
 B. Alcoholic hepatitis
 C. Drug toxicity
1. Pure cholestasis—anabolic and contraceptive
steroids
2. Cholestatic hepatitis—chlorpromazine,
erythromycin
3. Chronic cholestasis—chlorpromazine and
prochlorperazine
 D. Primary biliary cirrhosis
 E. Primary sclerosing cholangitis
 F. Vanishing bile duct syndrome
1. Chronic rejection of liver transplants
2. Sarcoidosis
3. Drugs
 G. Congestive hepatopathy and ischemic
hepatitis
 H. Inherited conditions
1. Progressive familial intrahepatic cholestasis
2. Benign recurrent cholestasis
 I. Cholestasis of pregnancy
 J. Total parenteral nutrition

55.  K. Nonhepatobiliary sepsis
 L. Benign postoperative cholestasis
 M. Paraneoplastic syndrome
 N. Veno-occlusive disease
 O. Graft-versus-host disease
 P. Infiltrative disease
 1. Tuberculosis
 2. Lymphoma
 3. Amyloidosis
 Q. Infections
 1. Malaria
 2. Leptospirosis
 II. ExtrahepaticII. Extrahepatic
 A. Malignant
 1. Cholangiocarcinoma
 2. Pancreatic cancer
 3. Gallbladder cancer
 4. Ampullary cancer
 5. Malignant involvement of the porta hepatis lymph nodes
 B. Benign
 1. Choledocholithiasis
 2. Postoperative biliary strictures
 3. Primary sclerosing cholangitis
 4. Chronic pancreatitis
 5. AIDS cholangiopathy
 6. Mirizzi’s syndrome
 7. Parasitic disease (ascariasis)

56.  Unconjugated bilirubin always binds to albumin in the serum and is not filtered by the kidney.
Therefore, any bilirubin found in the urine is conjugated bilirubin.
 The presence of bilirubinuria implies the presence of liver disease.
 BLOOD AMMONIABLOOD AMMONIA: The liver plays a role in the detoxification of ammonia by converting it
to urea, which is excreted by the kidneys. Striated muscle also plays a role in detoxification of
ammonia
 Normal whole blood ammonia levels are 47 to 65 mmol/L
 However there is a poor correlation of the blood serum ammonia and hepatic function. The
ammonia can be elevated in patients with severe portal hypertension and portal blood
shunting around the liver even in the presence of normal or near normal hepatic function.
 Elevated arterial ammonia levels correlate with fulminant hepatic failure.

57. SERUM AMINO TRANSFERASES – SGOT & SGPTSERUM AMINO TRANSFERASES – SGOT & SGPT
These enzymes are released into circulation as a result of hepatocellular injury or death.
AST (SGOT)AST (SGOT)
is present in many tissues – liver > heart muscle > skeletal muscle > kidneys > brain >
pancreas > lung > leucocytes > erythrocytes
so less specific for liver disease
Normal range: 10-45 U/L
ALT (SGPT):ALT (SGPT):
ALT (SGPT) is primarily located in liver & more specific for hepatic dysfunction
Normal – 5 to 40 U/L
Mild elevation can be seen in cholestasis or metastatic liver disease.

58.  De Ritis ratio (AST:ALT)De Ritis ratio (AST:ALT)
 Elevations in serum levels of ALT and AST are nonspecific indicators of hepatocellular damage
 In most acute hepatocellular disorders, the ALT is higher than or equal to the AST. Whereas
the AST:ALT ratio is typically <1 in patients with chronic viral hepatitis and non-alcoholic fatty
liver disease
 AST/ALT ratio becomes greater than 2 as cirrhosis develops
 Ratio >3:1 is highly suggestive of alcoholic liver disease.
 The AST in alcoholic liver disease is rarely >300 IU/L, and the ALT is often normal. A low level
of ALT in the serum is due to an alcohol-induced deficiency of pyridoxal phosphate

59. ALT > AST
HEPATIC CAUSES
α1-antitrypsin deficiency
Autoimmune hepatitis
Chronic viral hepatitis (B, C,
and D)
Hemochromatosis
Steatosis and steatohepatitis
Wilson disease
medication and toxins
NON HEPATIC CAUSES
Celiac disease
Hyperthyroidism
( Acute severe >20 fold )
Acute bile duct
obstruction
Acute Budd-Chiari
syndrome
Acute viral hepatitis
Autoimmune hepatitis
Ischemic hepatitis
Medications/toxins
Wilson disease
( Chronic, Mild < 5 fold )

60. ALT > AST AST > ALT
HEPATIC CAUSES
α1-antitrypsin deficiency
Autoimmune hepatitis
Chronic viral hepatitis (B, C,
and D)
Hemochromatosis
Steatosis and steatohepatitis
Wilson disease
medication and toxins
NON HEPATIC CAUSES
Celiac disease
Hyperthyroidism
(Chronic, Mild < 5 fold)( Acute severe >20 fold )
Acute bile duct
obstruction
Acute Budd-Chiari
syndrome
Acute viral hepatitis
Autoimmune hepatitis
Ischemic hepatitis
Medications/toxins
Wilson disease
( Acute severe>20 fold )( Chronic, Mild < 5 fold )
Hepatic Causes
Alcohol-related liver injury
Cirrhosis.
Nonhepatic Causes
Hypothyroidism
Myopathy
Strenuous exercise
Hepatic Cause
Medications or toxins in a
patient with underlying
alcoholic liver injury
Nonhepatic Cause
Acute rhabdomyolysis

61.  SERUM ALKALINE PHOSPHATASESERUM ALKALINE PHOSPHATASE
 Is produced by liver, bone, small bowel, kidneys & placenta. Excreted into bile
 Normal level – 25 to 95 IU/L
 ALP is a hydrolase enzyme responsible for removing phosphate groups from many types of
molecules, including nucleotides & proteins.
 Most effective in an alkaline environment.
 Physiological rise in ALP seen in…
1) Age > 60 years ( 1 – 1.5 times)
2) For blood group types O & B ( after eating a fatty meal, due to influx of intestinal ALP into
the blood
3) Growing children and adolescents
4) Lately in normal pregnancy (placental ALP)

62.  SERUM ALKALINE PHOSPHATASESERUM ALKALINE PHOSPHATASE
 ALP can be < 3 times elevated in any liver disease
 ALP > 4 times elevated in…
1) Cholestatic liver disease
2) Infiltrative liver disease – Cancer, Amyloidosis
3) Paget’s disease of bone – due to rapid bone turnover

63.  5ʹ-5ʹ-nucleotidasenucleotidase
 Normal range: 2-15 U/L
 The serum activity of 5'-nucleotidase is elevated in hepatobiliary disease & this parallels ALP.
 The 5'-nucleotidase is not altered in bone disease (as is the case with ALP)
 GGT (GGT (γ-γ-glutamyl transpeptidase)glutamyl transpeptidase)
 Normal range: 7 - 48 U/L (varies with age)
 Serum GGT is highly elevated in biliary obstruction & alcoholism and is the most sensitive test
 GGT elevation in serum is less specific for cholestasis when compared to alkaline
phosphatase or 5ʹ-nucleotidase
 Some have advocated the use of GGT to identify patients with occult alcohol use. But its lack
of specificity makes its use in this setting questionable.
 Phenytoin and enzyme inducers increase this enzyme in circulation

64.  Serum AlbuminSerum Albumin
 Serum albumin is synthesized exclusively by hepatocytes. Daily production is nearly 15 g/ day
and there is 300 – 500 g of albumin distributed in the body fluids. It has a long half-life: 18–20
days. Hence un-reliable to measure it in acute liver disease
 Normal level – 3.5 to 5.5 g/dl
 Albumin level may be normal with Acute Liver Disease
 Values <2.5g/dl are generally indicative of CLD, acute stress or severe malnutrition.
 Hypoalbuminemia is not specific for liver disease and may occur in protein malnutrition of
any cause, as well as protein-losing enteropathies, nephrotic syndrome, and chronic
infections that are associated with prolonged increases in levels of serum interleukin 1 and
tumor necrosis factor, cytokines that inhibit albumin synthesis
 Increased losses of albumin in urine is suggestive of Nephrotic syndrome

65.  Serum GlobulinsSerum Globulins
 Serum globulins are a group of proteins made up of γ-globulins (immunoglobulins) produced
by B lymphocytes and α and β globulins produced primarily in hepatocytes
 γ globulins are increased in chronic liver disease, such as chronic hepatitis and cirrhosis.
 Increases in the concentration of specific isotypes of γ globulins are often helpful in the
recognition of certain chronic liver diseases.
 Diffuse polyclonal increase in IgG levels are common in autoimmune hepatitis; increases
>100% should alert the clinician to this possibility.
 Increase in the IgM levels are common in primary biliary cirrhosis
 whereas increase in the IgA levels occur in alcoholic liver disease
 Cirrhosis of the liver causes a reversal of albumin/globulin ratio (A/G ratio)

66.  Prothrombin Time:Prothrombin Time:
 Normal level is 11 to 14secs. (Measures the activity of factors II, V, VII & X)
 Relatively short half life of factor VII (4 to 6Hrs) makes PT useful in evaluating Acute hepatic
failure. (Fibrinogen has a half life of 5 days)
 Prologation of PT >3 to 4 seconds from control are considered significant.
 Regional anesthesia is contraindicated if PT >2.5 s above control, platelet count is less than
50,000/cu.mm, bleeding time >12 m
 Only 20 to 30% of normal factor activity is required for normal coagulation, prolongation of
PT reflects severe liver disease unless Vitamin K deficiency is present.
 PT is not an accurate measure of bleeding risk in cirrhotic patients because it assess the
activity of only pro-coagulant factors, not the anti-coagulants such as protein C and anti-
thrombin whose production is also reduced in cirrhosis

67.  Prothrombin Time:Prothrombin Time:
 Failure of correction of prolonged PT > 5 seconds above control following parenteral
administration of Vitamin K implies severe liver disease and is a poor prognostic sign (in both
acute and chronic liver failure)
 INR is a better indicator than PT because it is a standardized value and is not subjected to lab
variability as PT
 The international normalized ratio (INR) is used to express the degree of anticoagulation on
warfarin therapy.
 International sensitivity index (ISI): INR standardize PT measured according to thromboplastin
reagent used in any Lab expressed as ISI

69.  Lactate dehydrogenase:Lactate dehydrogenase:
 Normal range is 140 – 280 U/L
 LDH is extensively present in the body tissues such as- blood cells, lungs, kidneys, liver,
muscles, heart muscle and tumor cells. Released during tissue damage- common marker for
injury
 Elevated serum LDH levels may not only due to hepatocyte injury but also due to extra-
hepatic causes
 Extreme increases may be seen in massive liver damage – fulminant Viral hepatitis, drug
induced failure or hypoxic hepatitis.
 Prolonged concurrent elevation may be seen in malignant infiltration of liver.
 Apart from notable hepatic disorders increased levels are seen in hemolysis, rhabdolysis,
tumor necrosis, renal infarction, acute CVA, acute MI, severe eclampsia etc.

70.  liver biopsy is the standard for the assessment of hepatic fibrosis.
 Need has arrived to go for non invasive tests.
 Single serum biochemical marker that potentially reflect the activity level of hepatic
fibrogenesis - Hyaluronan
 Hyaluronan is a glucosaminoglycan produced in mesenchymal cells and widely distributed in
the extracellular space.
 Typically degraded by hepatic sinusoidal cells
 A fasting hyaluronan levels greater than 100 mg/L (sensitivity83% & specificity78%) helpful
for the detection of cirrhosis in patients due to a variety of chronic liver diseases like chronic
hepatitis C, chronic hepatitis B, alcoholic liver disease, and non-alcoholic steatohepatitis.

71.  FIBRO TEST: ( MULTIPLE PARAMETER TEST)FIBRO TEST: ( MULTIPLE PARAMETER TEST)
 It is the best evaluated among multiparameter blood tests.
 The test incorporates..
Haptoglobin
Bilirubin
GGTP
Apolipoprotein A-I
Alpha2-macroglobulin
 FIBRO Spect IIFIBRO Spect II assay incorporates
Hyaluronate
Tissue inhibitor of metalloproteinase 1
Alpha 2-macroglobulin