The document discusses the many functions of the liver, including intermediary metabolism of proteins, carbohydrates, and lipids; production of coagulation factors; bilirubin metabolism; endocrine, immune, and drug metabolism functions. It then describes evaluation of liver function through tests of hepatocellular injury like ALT and AST, hepatic protein synthesis by measuring albumin and prothrombin time, and tests for cholestatic or specific liver diseases.

1. +
Functions of liver and its
evaluation.

2. +
FUNCTIONS:
 Intermediary Metabolism- a. Protein Metabolism
b. Carbohydrate Metabolism
c. Lipid Metabolism
 Coagulation Factors
 Erythropoiesis and erythrocytosis
 Bilirubin Metabolism
 Endocrine function
 Immune Function
 Drug metabolism and excretion

3. +
Protein Metabolism
 Deamination of amino acids
 Formation of urea by Krebs-Henseleit cycle (removal of
ammonia)
 Interconversion between non-essential amino acids
 Formation of plasma proteins

4. +
Plasma Proteins
 Albumin: 15% of total liver protein production. 12-15g albumin
is produced every day by healthy adults.
 Factors modulating synthesis of albumin: Plasma oncotic
pressure, dietary amino acids and hormones.
 Alfa Feto Protein (AFP): Main source is the yolk sac,
hepatocytes and enterocytes. Marker of hepatocellular
carcinoma.(HCC)
 Others: Pro coagulants, cytokines, chemokines,acute phase
reactants, and transport proteins.

5. +
Carbohydrate Metabolism
 Important homeostatic regulator of blood glucose.
 Factors controlling glucose production: Neuroendocrine(
insulin, catecolamines, glucagon) and glucose concentration in
sinusoidal blood.
 Fed state, hepatocytes polymerize glucose and store it as
glycogen.
 Unfed state, hepatocytes depolymerize glycogen to glucose.
 Regulation of glycogen metabolism is by :
1. Glycogen Synthase
2.Glycogen Phosphorylase

6. +
 Glycogen stores are depleted after 24hrs of fasting.
 Body then depends on hepatic gluconeogenesis to replenish
blood glucose.
 Substrates for gluconeogenesis:
1.Lactate
2.Glycerol from hydrolysis of triglycerides
3.Glucogenic amino acids such as alanine and glutamine

7. +
Regulation of gluconeogenesis
 Glucagon and catecholamines stimulate gluconeogenesis
 Glucagon via cAMP dependant protein kinases
 Insulin inhibits gluconeogenesis and blocks the stimulatory
effect of glucagon and catecolamines on this pathway.

8. +
Lipid Metabolism
 Retains releases and oxidizes fatty acids in accord with
nutritional and endocrine influences.
 Major source of intra hepatic fatty acids include:
1.Free fatty acids extracted from blood
2.de novo lipogenesis
3.hydrolysis of cytoplasmic triglycerides
4.hepatocellular uptake and metabolism of blood borne
lipoproteins.

9. +
 Acetyl coA is a building block for lipids and a product of the
oxidative breakdown of fatty acids and carbohydrates.
 Mitochondria oxidise acetyl groups to yield carbon dioxide,
water and ATP.
 The surplus is metabolized to ketone bodies- acetoacetate, b-
hydroxybutyrate and acetone.
 Hepatocytes lack ketoacyl CoA transferase so they cannot
extract energy from ketones.
 Insulin modulates ketogeneis by inhibiting lipolysis in
adipocytes.

11. +
Bile Metabolism
 Daily production of bile is 600-800ml.
 Composition of bile:
97% water
<1% bile salts
Lipids-Cholestrol
Fatty Acids,
Pigments, Inorganic salts, Lecithin,Alkaline Phosphatase

12. +
Functions of bile salts
 Activate lipases
 Promote micelle formation
 Intestinal uptake of fat soluble vitamins, cholestrol and other
lipids
 Excretion of numerous lipophilic substances, exogenous and
endogenous.

14. +
Coagulants and Procoagulants
 Hepatocytes make most of the procoagulants with the
exception of factor III, IV and VII.
 It also makes protein regulators of coagulation and the
fibrinolytic pathway such as protein S, protein C, protein Z,
plasminogen activator inhibitor and antithrombin III.

15. +
Vitamin K Cofactor andCarboxylation

16. + Heme Metabolism

17. + Bilirubin Metabolism

18. +
Endocrine Functions
 Hepatocytes produce a wide variety of endocrine substances :
Angiotensinogen
Thrombopoeitin
Insulin-like-growth factor (IGF-1)
 They take up thyroxine T4 and may activate it to T3 or
inactivate it.
 The liver also inactvates aldosterone, ADH, estrogens,
androgens and insulin.

19. +
Immune and Inflammatory
Responses
 Liver is the largest reticuloendothelial organ in the human body.
 Hepatic macrophages i.e Kupffer cells account for nearly 10%
of total liver mass.
 They degrade toxins, process antigens, and phagocytose
bacteria. They are important modulators of inflammation.
 The mediators released by the kupffer cells include cytokines,
chemokines, leukotrienes, proteases, nitro radicals and
reduced oxygen species.

20. +
Xenobiotic Metabolism and
Excretion
 The liver is the epicenter of biotransformation reactions.
 Liver chemically transforms drugs in ways that increase their
water solubility.
 Pathways of drug metabolism:
Phase 1 metabolism
Phase 2 metabolism
Phase 3 elimination

21. +
Phase 1 Metabolism
 Phase 1 utilizes CYP (cytochrome P450)and mixed function
oxidases to increase the polarity of drugs.
 The reactions include oxidation, reduction, deamination,
sulfoxidation, dealkylation, methylation.
 Oxidases promote the formation of highly active chemicals
including reactive oxygen species and free radical intermediates,
which can aggravate liver injury.
 P-450 can be induced by certain drugs like ethanol, barbiturates
and ketamine. This leads to increased tolerance to the drugs
effect. Conversely some agents like cimetidine and
chloramphenicol can prolong the effect of other drugs by inhibiting
these enzymes.

22. +
Phase 2 Metabolism
 These reactions conjugate xenobiotics with endogenous
hydrophilic molecules like :
Glucuronic acid
Acetate
Sulfates
Amino acids
Glutathione
Compared to their precursors, conjugated xenobiotics are usually
less efficacious, less toxic, more hydrophilic and more readily
excreted in bile.

23. +
Phase 3 Elimination
 Phase 3 reactions involve specific molecular transporters
known as ABC- ATP-binding-cassette transport proteins.
 They facilitate the excretion of xenobiotics and endogenous
compounds.
 These proteins usually use ATP hydrolysis to drive molecular
transport.
 Dysfunction of ABC transport proteins can disrupt the flow of
bile, impair excretion of xenobiotics and endogenous
compounds and induce cholestatic liver injury.

24. +
Determinants of Drug Metabolism
 Conditions leading to up regulation of CYP proteins- obesity,
fasting, diabetes.
 Conditions causing down regulation of CYP proteins- systemic
inflammatory disorders, fever, hepatic cirrhosis.
 PHARMOKINETICS:
Intrinsic hepatic clearance of drug/Hepatic blood flow =(ER)
ER- Extraction Ratio

25. + Efficiently Extracted Drugs Poorly Extracted Drugs
Amitriptyline Acetaminophen
Desipramine Amobarbital
Imipramine Antipyrine
Labetalol Aspirin
Lidocaine Clindamycin
Meperidine Diazepam
Metoprolol Digitoxin
Morphine Ethanol
Nortriptyline Hexobarbital
Pentazocine Phenobarbital
Propoxyphene Phenytoin
Propranolol Tolbutamide
Ranitidine Valproic Acid
Verapamil Warfarin
Zidovudine

26. +
Type of Hepatic
Elimination
Extraction Ratio (ER Rate of Hepatic Drug
Metabolism
Flow-dependent
elimination
High ER: At clinically
relevant
concentrations, most
of the drug in the
afferent hepatic blood
is eliminated on first
pass through the liver
Rapid: Because drugs
with a high ER are
metabolized so rapidly,
their hepatic
clearances roughly
equal their rates of
transport to the liver
(i.e., hepatic blood
Capacity-limited
elimination (also
referred to as dose-
dependent, nonlinear,
saturable, or zero-
order elimination)
Low ER: Hepatic
elimination of these
drugs is determined by
their plasma
concentration
Slow: When the capacity
of the liver to eliminate a
drug is less than the
dosing rate, a steady
state is unachievable;
plasma levels of drug will
continue to rise unless the
dosing rate is decreased.
Drug clearance has no
real meaning in such
settings

27. +
EVALUATION OF LIVER
FUNCTIONS
 Detection of hepatocellular injury: Aminotransferases, Lactate
Dehydrogenase, Glutathione-S-transferase.
 Assessment of hepatic protein synthesis: Serum Albumin,
Prothrombin time.
 Detection of cholestatic disorders: Alkaline Phosphatase,
5’neucleotidase, Glutamyl Transpeptidase, Serum Bilirubin
 Testing for specific diseases: Viral markers
 Quantitative liver tests
 Measurement of liver blood flow
 Radiologic and Endoscopic methods

28. +
Aminotransferases
 ALT- Alanine aminotransferase SGPT
 AST- Aspartate aminotransferase SGOT
 Both enzymes are involved in gluconeogenesis
 They are indicators of hepatocellular injury
 Ratios of aminotransferases hold clues to diagnose various
hepatic diseases:
AST/ALT ratio >4 :Wilsons disease
2-4:Alcoholic liver disease
<1:Non Alcoholic steatohepatitis

29. +
AST ALT LEVELS CAUSES
Mild 100-249 IU/L steatosis, medications, alcohol
consumption, hemochromatosis,
cholestasis, chronic viral hepatitis,
neoplasms, and cirrhosis
Moderate 250-999 IU/L acute viral hepatitis, drug-induced
liver injury, and flare-ups of
chronic liver disease (e.g., viral
hepatitis, steatohepatitis)
Large 1000-1999 IU/L acute hepatitis superimposed on
chronic active liver disease.
Extreme >2000 IU/L massive hepatic necrosis;
fulminant viral hepatitis, severe
drug-induced liver injury (e.g.,
from acetaminophen), shock liver
or hypoxic hepatitis, and in rare
instances, autoimmune hepatitis
or acute biliary obstruction

30. +
Lactate Dehydrogenase
 Elevated levels may refect hepatocellular injury, extrahepatic
disorders or both.
 Extreme increases signify massive liver damage
 Prolonged concurrent elevations in LDH and Alkaline
Phosphatase suggest malignant infiltration of the liver.
 An elevation in LDH that is solely due to hepatocellular injury is
accompanied by elevations in AST and ALT.

31. +
Glutathione-S-Transferase
 Sensitive and specific test for some drug induced liver injuries.
 The enzyme has a brief plasma half life
 GST localizes in acinar zone 3(centrilobular region). This zone
contains hepatocytes with highest susceptibility to injury from
hypoxia or reactive drug metabolites.

32. +
Serum Albumin
 Normal concentration 3.5-5.5g/dl
 Half life is about 2-3 weeks
 Albumin <2.5g/dl are generally indicative of:
Chronic Liver Disease
Acute Stress
Severe Malnutrition
Increased loss in urine- Nephrotic syndrome
Increased loss in gastrointestinal tract- Protein losing enteropathy

33. +
Prothrombin Time
 Liver-derived procoagulants have short half-lives, which range
from 4 hours for factor VII to 4 days for fibrinogen.
 Plasma levels of such procoagulants start to descend shortly
after the liver begins to fail.
 A prolonged PT secondary to liver failure generally reflects a
low blood level of factor VIIa, which has the shortest plasma
half-life of hepatic coagulant factors. (6h)
 PT > 3-4 secs from control are considered significant
 PT is of value for patients with drug-induced liver failure or
those with active liver disease and a surgical condition that
needs immediate attention.

34. +
Alkaline Phosphatase
 It lacks specificity for liver disease since it is produced by liver,
bone, kidneys and placenta.
 Extreme increases in AP suggest
(1) a major block in biliary flow as a result of disorders such as
primary biliary cirrhosis and choledocholithiasis
(2) a hepatic malignancy (primary or metastatic) that is
compressing small intrahepatic bile ducts.
5′-Nucleotidase and γ-Glutamyl Transpeptidase are used to
distinguish between the hepatic and extra-hepatic sources of AP.

35. +
Serum Bilirubin
 Total bilirubin is normally below 1gm/dl.
 At 3gm/dl scleral icterus is detectable with natural light.
 Conjugated Hyperbilirubinemia: (usually associated with
increased urinary urobilinogen)
(1) flow of bile is blocked within the hepatobiliary tree,
(2) hepatocytes produce more bilirubin conjugates than they can
efficiently transport into the canalicular space.
 Unconjugated Hyperbilirubinemia: Hemolysis,congenital or
acquired defects in bilirubin conjugation,

36. +Blood Test Bilirubin Overload
(Hemolysis)
Hepatocellular Injury Cholestasis
Aminotransferases Normal Increased—may be normal
or decreased in advanced
stages
Normal- may be increased in
advanced stages
S. Albumin Normal Decreased—may be normal
in acute fulminant hepatic
failure
Normal- may be decreased
in advanced stages
Prothrombin Time Normal Prolonged Normal- prolonged in
advanced stages
Bilirubin Unconjugated, (mild increase
in conjugated also)
Conjugated Conjuated
ALP Normal Normal/Increased Increased
GGTP & 5’NT Normal Normal Increased
BUN Normal Normal Normal
BSP/ICG Normal Retention type of dye Normal/ Retention type

37. +
Testing for specific disease
 (1) serologic testing to identify viral, microbial, and autoimmune
causes.
 (2) genetic testing to diagnose heritable metabolic disorders
 (3) tumor marker assays to detect hepatic malignancies

38. +
Quantitative Liver Tests
 Measuring the clearence of a substance that is avidly extracted
by the liver: Bromsulphalein, Indocyanine Green (ICG) or Rose
Bengal.
 Drug-metabolizing capacity of the liver can be measured by
several methods, such as caffeine clearance, galactose
elimination capacity, aminopyrine breath test, antipyrine
clearance, and monoethylglycinexylidide (MEGX).
 Quantitative tests are expensive and time consuming, with no
compelling evidence of being superior,

39. +
Measurement of Liver Blood Flow
 Clearance Techniques
 Indicator Dilution Techniques
 Direct Measurements

40. +
Radiologic and Endoscopic
Methods
 ERCP
 PTHC
 Esophagogastroscopy
 Splenoportography
 Portal Venography

41. +
 Millers Anesthesia 7th ed
 Morgans Clincal Anesthesiology 5th ed
 Harper’s Illustrated Biochemistry
 Robbins pathologic basis of disease