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Functions of the liver Assessment and interpretation of liver function tests

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Title: Functions of the liver Assessment and interpretation of liver function tests


1
Functions of the liver Assessment and
interpretation of liver function tests
Dr. Neha Kanojia
University College of Medical Science GTB
Hospital, Delhi
2
WHY ?
3
  • Liver is the largest internal organ largest
    gland in the human body.
  • Liver is at the epicenter of intermediary
    metabolism.
  • It performs versatile massive biochemical
    pathways.
  • It destroys bacteria, inactivate antigens,
    detoxify harmful chemicals.
  • Thus multiple diverse functions of liver have
    an impact on every tissue in the body.

4
Physiological functions of liver
  • Intermediary metabolism
  • Carbohydrate metabolism
  • Lipid metabolism
  • Bile metabolsim and entero- hepatic circulation
  • Protein metabolism
  • Coagulation
  • Heme metabolism
  • Bilirubin metabolism
  • Xenobiotics metabolism
  • Storage
  • Endocrine functions
  • Immune inflammatory response
  • Blood reservoir

5
Carbohydrate metabolism
  • Liver is an important homeostatic regulator of
    blood glucose.
  • It can either produce glucose or store glucose
  • In fed state- polymerize glucose to glycogen
  • In unfed state- depolymerize glycogen to glucose
  • Glucose ? hepatocytes ? glycogen
  • ?
    ?glucose

Lactate Glycerol aminoacids
6
Carbohydrate metabolism
  • Glycogen metabolism
  • Regulation 2 rate limiting enzymes
  • Glycogen synthase- synthesis of glycogen from
    monomers of UDP glucose.
  • Glycogen phosphorylase- clevage of glycogen to
    glucose-1-phosphate.

7
Carbohydrate metabolism
  • Gluconeogenesis
  • Liver glycogen stores depleted - hepatic
    gluconeogenesis to replenish blood glucose.
  • Substrates-
  • - lactate
  • - glycerol from hydrolysis
    of triglycerides
  • - gluconeogenic amino acid
    , alanine , glutamine

8
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9
Hormonal regulation of carbohydrate metabolism

10
  • Blood glucose regulation within a narrow limit
    (70-100 mg/dl) ? not affected in liver disease
    due to large reserve of hepatic function
  • Effects of anaesthesia on carbohydrate
    metabolism
  • Halothane
  • ? release of insulin
  • ? rate of glycogenolysis
  • Inhibition of gluconeogenic response
  • Isoflurane
  • Impaired insulin secretion

11
  • Lipid Metabolism
  • ? Oxidation of fatty acids
  • Fatty acids derived from plasma
  • ?
  • Enter into mitochondria
  • ?
  • ? oxidation fatty acids ? AcetylCoA ? citric
    acid cycle
  • Regulators
  • - Glucagon - activates
  • - Insulin - inhibits

12
  • Synthesis of lipoproteins
  • One of the major functions of the liver
  • Major classes
  • VLDL
  • LDL
  • HDL

13
  • VLDL
  • Acute or chronic liver disease ability to
    produce VLDL is markedly compromised
  • Liver VLDLs are associated with an important
    class of proteins, the apo B protein
  • Apo B100 - important for hepatic secretion of
    VLDL.
  • Decreased in ABETALIPOPROTEINEMIA
  • LDLs and HDLs
  • Liver produces them in a small amount

14
  • Production of ketone bodies
  • Most organs except the liver- use ketone bodies
    as fuel
  • Ketone bodies acetoacetic acid, acetone, ?
    hydroxybutyrate
  • Their formation by the liver is normal and
    physiologically important, e.g.
  • Fasting ? rapid depletion of glycogen stores in
    the liver ? shortage of substrates for citric
    acid cycle
  • AcetylCoA formed from ? oxidation ? ketone bodies
  • Ketosis - ? conc. of ketone bodies in blood
  • Starvation
  • DM
  • After high fat diet

15
  • Synthesis of cholesterol
  • Important role in cholesterol homeostasis
  • Liver cholesterol has both exogenous and
    endogenous source
  • Uses of hepatic cholesterol
  • Formation of bile acids- conjugated with other
    substances to form cholic acid.
  • Synthesis of VLDLs

16
Bile metabolism enterohepatic circulation
  • Bile salts are end products of cholesterol
    synthesis
  • Daily production 600- 800 ml/d
  • Functions-
  • - activate lipase
  • - promote micelle formation
  • - intestinal uptake of fat
    soluble vitamins, cholesterol
  • lipids
  • - facilitate excretion of
    xenobiotics, lipophillic
  • substances, bilirubin,
    amphipathic steroid hormone
  • derivative

17
  • Bile salts undergo enterohepatic circulation
    (20-30 times/day)
  • intrahepatic bile
    duct
  • ?
  • common hepatic
    duct
  • cystic duct
    CBD
  • ?
    ?
  • gall bladder
    small intestine ( terminal ileum)
  • Clinical implication
  • Opioids can induce spasm of bile duct spinter
    of oddi
  • Reversed by glucagon, opioid antagonists (
    naloxone),
  • smooth muscle relaxant
    (NTG), antimuscarinic
  • drugs( atropine),
    volatile anaesthetics.

18
Protein and amino acid metabolism
  • Deamination of amino acids
  • Required before they can be used for energy or
    before they can be converted into carbohydrates
    or fats
  • Formation of urea for removal of ammonia from the
    body fluids
  • Production of proteins and peptides.

19
Krebs- Hanseleit cycle
  • Major pathway for removing NH3 other
    nitrogenous wastes from body
  • Captures nitrogen in form of urea.
  • Failing liver- BUN remain low
  • - ammonia accumulates
  • in liver
  • ?
  • Hepatic encephalopathy

20
Proteins peptides
  • Albumin
  • Most abundant protein
  • Normal plasma conc- 3 - 5 g
  • Daily production -12-15 g/d
  • Plasma half life 15-20 days
  • Functions
  • maintains plasma oncotic pressure (80 by
    albumin)
  • binds ions, bilirubin, hormones drugs
  • Hypoalbuminemia ? Colloid oncotic pressure ?
    edema

21
  • ?- feto protein
  • Resembles albumin genetically functionally
  • Formation sites- yolksac, hepatocytes,
    enterocytes
  • Fetal neonatal life- major determinant of
    plasma oncotic pressure
  • 1 year of age- albumin largely replaces AFP
  • ? ? AFP- HCC

22
  • Fibrinogen
  • Synthesized exclusively by hepatocytes
  • Plasma fibrinogen 100-700 mg/dl
  • Functions polymerizes into long fibrin threads
    by the action of thrombin ? formation of clot

23
  • Haptoglobins
  • Forms stable complexes with free Hb ? prevents
    loss of iron through urinary excretion, protects
    kidney from damage
  • Ceruloplasmin binds with copper and helps in
    its transport and storage
  • Wilsons disease
  • Deficiency of ceruloplasmin ? free Cu2 ? in
    circulation ? deposited in brain and liver

24
Coagulation
  • Synthesize most of the procoagulants except-
  • factor III ( tissue thromboplastin)
  • Factor IV ( calcium)
  • Factor VIII ( von Willebrand factor )
  • Produce protein regulators of coagulation
    fibrinolytic pathways
  • Protein C, protein S ( protein C inactivate F
    VIIIa- Va complex)
  • protein Z ( degradation of Factor Xa )
  • plasminogen activator inhibitor (PAI) ( inhibits
    tissue plasminogen activators to convert
    plasminogen to plasmin )
  • antithrombin III

25
Liver as a Storage Organ
  • Vitamin A
  • Important role in the uptake, storage and
    maintenance of vitamin A levels by mobilizing its
    vitamin A store
  • Vitamin K
  • Vitamin K dependent factors II, VII, IX, X
  • Absorption of Vit K depends on normal fat
    absorption any mal-absorption of lipid ? vitamin
    K deficiency
  • Storage in liver- limited ? hypoprothrombinemia
    can develop within a few weeks.
  • Treatment
  • FFP
  • Antidote- parenteral vit K

26
Vitamin K cofactor ?- carboxylation
  • Factor II, VII., IX, X , protein C S- undergo
    Vit K dependent post translational modifications
  • Enables procoagulants to form complexes with
    calcium or other divalent cations for
    participation in the clotting cascade.
  • Clinical implication
  • Warfarin inhibits vit K epoxide reductase
  • ?
  • traps Vit K in epoxide form
  • ?
  • Inhibits y- carboxylation
  • T/T- Enteral / parenteral Vit K.


  • shuts

27
Storage Homeostasis of Iron
  • Major site of synthesis of proteins (Transferrin,
    Ferritin) involved in iron transport
    metabolism.
  • Heme metabolism
  • Clinical implication
  • Porphyrias
  • Acute Intermittent Porphyria commonest
  • Defects in the heme pathway- accumulation of
    porphyrinogens
  • Trigger substances- barbiturates, sex hormones,
    glucocorticoides, cigarette smoke, CYP inducers.

28
Bilirubin Metabolism
29
Bilirubin metabolism
  • Main source of bilirubin is heme metabolism
  • Daily production- 300mg
  • 80 derived from senescent erythrocytes by
    macrophages in RE system.
  • Heme
  • ? ( heme
    oxygenase o2 )
  • biliverdin IX CO free divalent
    iron
  • ? ( biliverdin
    reductase)
  • bilirubin

30
Plasma
Fragile RBCs
BILIRUBIN METABOLISM
RE System
unconjugated bilirubin (protein bound)
Liver
Urobilinogen
Kidneys
Liver
Conjugated bilirubin
Absorbed
Urobilinogen
Urobilin Urine
Bacterial action
Oxidation
Urobilinogen Stercobilinogen
Stercobilin Intestinal Contents
Oxidation
31
  • CO produced has many physiological roles
  • Vasodilation ( regulation of vascular tone)
  • Platelet aggregation
  • Vascular myocyte proliferation
  • Neurotransmitter release
  • Cytoprotective , antiapoptotic, antioxidant
    effects
  • Biliverdin confers protection from oxidative
    effects
  • rapidly converts to bilirubin

32
Metabolism of Drugs (Xenobiotics)
  • Phase-I reactions
  • Alter the parent drug by inserting or unmasking a
    polar group
  • Converts drugs to more polar compounds
  • Reactions oxidations, reduction, hydrolysis
  • Cytochrome P450 substrate binding site, located
    in the endoplasmic reticulum
  • Drugs barbiturates, benzodiazepines, halogenated
    volatile anaesthetics, pethidine etc.

33
  • Phase-II reactions
  • Creates conjugates of parent compound or its
    metabolite with endogenous hydrophilic substrate
  • Reactions
  • Glucoronidation
  • Sulphation
  • Methylation
  • Acetylation
  • Glucoronidation
  • Most common type
  • Hepatic microsomal enzyme, UDPglucuronyl
    transferase mediates the transfer of glucoronic
    acid from UDP glucuronic acid to the functional
    group on the xenobiotics

34
  • Drug handled by phase-II morphine, propofol,
    thiopentone (initially oxidized subsequently
    conjugated)
  • Phase-I reaction enzymes more susceptible to
    destruction in cirrhosis
  • Phase-II reactions enzymes more resistant,
    function even in advanced liver disease
  • Phase-III reactions
  • Involves ATP-binding cassette transport proteins
    (ABC)
  • These proteins use the energy of ATP hydrolysis
    to drive molecular transport
  • Dysfunction of ABC proteins hinders flow of bile
    ? predisposing to drug accumulation and
    cholestatic liver injury

35
Drug metabolism
Type of hepatic metabolism Extraction ratio Rate of hepatic drug meatabolism
Flow dependent elimination High ER. At clinically relevant conc, most of the drug in the afferent heaptic blood is eliminated on first pass through the liver Rapid . Drugs with high ER are metabolized rapidly, hepatic clearance roughly equals their rate of transport to the liver
Capacity limited Low ER. Hepatic elimination of these drugs is determined by their plasma conc. 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 the drug will continue to rise unless the dosing rate is decreased. Drug clearance has no real meaning in such settings
36
Microsomal enzyme induction
  • Anticonvulsants, rifampicin, isoniazid,
    glucocorticoids, chronic alcohol consumption
  • Consequences of enzyme induction
  • ? duration of action of drugs that are
    inactivated by metabolism
  • ? intensity of action of drugs that are activated
    by metabolism

37
Endocrine functions
  • Liver can modify or amplify hormone action
  • Metabolic conversion of Vitamin D to form
    25(OH)D
  • 25(OH)D ? 1,25(OH)2D in kidney
  • Peripheral conversion of T4 to T3
  • Pseudocholinesterase
  • Hydrolysis of succinylcholine
  • Plasma t½ - 14 days
  • Severe liver disease ? ? duration of action of
    succinylcholine

38
  • Insulin-like growth factors or somatomedins
    growth hormone like action
  • Important role in cartilage function by promoting
    uptake of sulphate and synthesis of collagen
  • Removes circulating hormones
  • Insulin, glucagon, growth hormone,
    gastrointestinal hormones, e.g. gastrin

39
  • Blood reservoir
  • Liver is an expandable organ
  • 10 -15 of total blood volume can be sequestered
    and quickly released after sympathetic
    stimulation .
  • Immune inflammatory responses
  • kuffer cells protect against foreign intrutions,
    degrade toxins, process antigens, and phagocytose
    bacteria.
  • Induce intensify inflammation by recruiting
    neutrophils
  • Release proinflammatory mediators

40
Liver Function Tests
  • Uses
  • To detect the presence of liver disease
  • To distinguish among different type of liver
    disorders
  • To guage the extent of known liver damage
  • To follow the response to treatment

41
  • Classification of LFTs
  • Tests based on detoxification and excretory
    functions
  • Serum bilirubin
  • Breakdown product of porphyrin ring of heme
    containing proteins
  • 2 fractions - conjugated (direct 30)
  • unconjugated (indirect 70)
  • Normal total serum bilirubin 1 mg/dl
  • ? in unconjugated fraction is rarely due to liver
    disease

42
Fractionate bilirubin
gt15 direct
lt15 direct
Dubin Johnson syndr Rotors syndr
Evaluation for hemolysis
-ve
ve
Crigler-Najjar syndr Gilberts syndr
Hemolysis
No further evaluation required
43
  • Urine bilirubin
  • Any bilirubin found in urine is conjugated,
    therefore bilrubinuria implies presence of liver
    disease
  • Blood ammonia
  • Detection of encephalopathy, monitoring hepatic
    synthetic function
  • Very poor predictor presence/ degree of acute
    encephalopathy
  • Serum enzymes
  • No known function in serum
  • ?ed level- ? rate of entrance into serum from
    damaged liver cells

44
  • Enzymes categories
  • Enzymes that reflect damage to hepatocytes
  • Enzymes that reflect cholestasis
  • Enzymes that reflect damage to hepatocytes
  • Aminotransferases
  • Aspartate aminotransferase (AST or SGOT) Liver,
    cardiac muscle, skeletal muscle, kidneys, brain,
    pancreas, etc.
  • Alanine aminotransferase (ALT or SGPT) 1 in
    liver
  • Sensitive indicators of liver cell injury
  • Normal levels lt35-45 IU/L

45
  • ? in aminotransferases
  • Mild - lt250 IU/l
  • Any pathologic process that causes hepatocellular
    injury, e.g. hepatic steatosis, alcohol or drug
    induced liver disease, chronic viral hepatitis,
    cirrhosis, hemachromatosis
  • Moderate 250-1000 IU/l
  • Disorder that produces hepatocellular necrosis
  • e.g. Acute viral hepatitis, drug induced
    hepatitis, exacerbation of chronic hepatitis
    (alcoholic)
  • Large - gt1000 IU/l
  • Viral or drug induced liver damage superimposed
    on ALD, autoimmune hepatitis

46
  • Extreme - gt2000 IU/l
  • Massive hepatic necrosis, usually from drugs
    (acetaminophan), halothane hepatitis, toxins,
    ischemic hepatitis (shock liver), acute viral
    hepatitis
  • AST/ALT ratio DERITIS QUOTIENT
  • Normal - 1 or slightly gt 1
  • lt1 non-alcoholic steatosis or hepatitis without
    cirrhosis
  • 2-4 ALD
  • gt4 Wilsonian hepatitis

AST/ ALT not ? in purely obstructive disorder
except Acute biliary obstruction caused by
passage of gallstones to CBD
47
  • LDH
  • Normal level -25-100 IU/L
  • Massive but transient - Ischemic hepatitis
  • Massive, sustained - Malignant infiltration of
    liver
  • Other causes of ? LDH
  • Hemolysis
  • Renal infarction
  • Acute stroke
  • Myocardial damage
  • Skeletal muscle injury

48
  • Glutathione S transferase
  • Relatively sensitive and specific test for
    detecting drug-induced hepatocellular injury
  • Plasma t½ 90 min, rapidly released into the
    circulation following hepatocellular injury
  • Plasma GST ( isoenzyme B ) reveal time course
    of hepatocellular injury from onset to resolution
  • GST located in the centrilobular region (zone
    3), where hepatocytes are most susceptible to
    injuries from hypoxia and reactive drug
    metabolism

49
  • Bromosulphathein excretion test
  • BSP dye- same mechanism as bilirubin
  • -binding
  • -conjugation
  • -excretion
  • BSP i/v 45 mins- levels in venous blood
  • Normally- lt5.
  • Slightly higher in old age
  • Sensitive test to detect mild impairement of liver

50
Enzymes reflecting cholestasis
  • Alkaline phosphatase- present in cells of the
    bile duct
  • Isoenzymes- bone , liver, intestine, placenta ,
    kidney , leukocytes.
  • Normal levels- 42-122 IU/L
  • - 3-13 KA units/dl

Non-pathological ? Pathological ?
Age gt60 yrs Bld group O B Growing children adolescents Late in normal pregnancy 1 biliary cirrhosis Choledocholithiasis Hepatic malignancy 1 2 Pagets disease
51
  • ? in serum ALP in an apparently healthy pt.
  • Fractionate the ALP to identify source of
    isoenzyme
  • ALP from different tissues differ in
    susceptibility inactivation by heat
  • Measure - 5' NT, GGT

52
  • 5' NT
  • Sensitive and specific for hepatobiliary
    disorders (HBD)
  • Normal pregnancy, bone growth and bone diseases
    do not affect 5' NT
  • In pts with HBD, changes in ALP are usually
    followed by similar changes in 5' NT
  • GGT
  • Inducible microsomal enzyme. N levels 5- 40
    IU/L.
  • Less specific than 5' NT as a marker for HBD
  • Unlike 5' NT, GGT may be released from many sites
    beside the hepatobiliary tree
  • Bone important source of ALP, has little GGT
    thus GGT useful for differentiating hepatic
    osseous sources of ALP

53
  • Tests for bio-synthetic function of the liver
  • Estimation of plasma proteins
  • Tests for reversal of AG ratio
  • Tests for coagulability of blood

Plasma protein Normal levels
Total 6.4 8.3 g
S. Albumin 3 5 g
Serum globulin 2 3 g
Serum fibrinogen 0.3 g
Serum prothrombin 40 mg
AG ratio 1.7 1
54
  • Serum albumin
  • S. albumin lt3 g/dl ? suspect chronic liver
    disease
  • Hypoalbuminemia not specific for liver disease
  • Protein malnutrition of any cause
  • Protein losing enteropathies
  • Nephrotic syndrome
  • Chronic infections
  • Burns
  • Reversal of A G ratio ? chronic liver
    dysfunction.

55
  • Serum globulin
  • ? in gamma globulin ? chronic liver disease
  • Ig M - ?? Primary billiary cirrhosis.
  • Ig A Alcoholic liver disease.
  • Ig G - ?? Auto immune hepatitis.
  • Thymol turbidity test
  • Test for reversal of AG ratio
  • Marked ? turbidity liver insufficiency

56
  • Coagulation factors
  • Factor I, II, V, VI, VII
  • Short t1/2 single best measure of acute hepatic
    synthetic function
  • Tests PT- N 11-16 sec
  • - PTTK N 30- 40 sec
  • Prognostic value-
  • PT gt 5 sec above control indicative of poor
    prognostic sign in acute viral hepatitis.
  • ? in hepatitis, cirrhosis, disorders leading to
    vit K deficiency such as obstructive jaundice or
    fat malabsorption

57
  • Immunological tests
  • Antibodies to specific etiologic agents-
  • HBV- HBsAg , HBcAg, HBeAg
  • Antibody to Entamoeba histolytica
  • Antibody to CMV, HCV, EBV
  • Non specific antibodies
  • Antimitochondrial antibody- PBC
  • Antismooth muscle antibody- Auto immune hepatitis
  • pANCA- Primary sclerosing cholangitis

58
  • Serum tumor markers
  • ? feto-protein - ? in HCC.
  • Hepatobiliary imaging
  • USG, CT scan - 1st line investigation
  • ERCP, PTC- visualization of biliary tract
  • Doppler USG MRI- hepatic vasculature
    heamodynamics
  • CT MRI- hepatic masses tumours

59
  • Others
  • FNAC
  • Biopsy percutaneous needle liver biopsy
  • a) VIM SILVERMAN ( cutting )
    needle
  • b) MENGHINIS ( aspiration )
    needle
  • Indications
  • Unexplained hepatomegaly
  • Cholestasis of unknown cause
  • Persistent abnormal LFTs
  • Infiltrative disorders- sarcoidosis, tuberculosis
  • Pyrexia of unknown origin
  • Primary/ metastatic liver diseases

60
Blood tests D/D of hepatic dysfunction
Bilirubin overload (hemolysis) Parenchymal dysfunction cholestasis
Aminotransferases Normal ? ( may be N or ? in advanced stages N ( may be ?in advanced stages)
ALP Normal Normal Increased
serum bilirubin ? unconjugated ? conjugated ? conjugated
Serum proteins Normal Decreased N (may be ? in advanced stages)
Prothrombin time Normal ? (may be N in early stages) N (may be prolonged in advanced stages)
Blood urea nitrogen Normal N (may be ? in advanced stages) Normal
Sulfobromophthalein / indocyanine green Normal Retention Normal or retention
61
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62
  • Shortcomings of LFTs
  • Can be normal in pts with serious liver disease
    and abnormal in pts with diseases that do not
    affect the liver
  • Rarely suggest a specific diagnosis
  • Only categorises into hepatocellular or
    cholestatic

63
Summary
  • Functions of liver

I. synthetic
Plasma protein (albumin) Hypoproteinimea ? oedema
Coagulants Haemorrhagic disorders
Enzymes Hepatocellular disorders
Urea / removal of NH3 ? bld urea, ?bld NH3

II. Metabolic
Carbohydrate ? glycogen more damage ? bld. Glucose muscle weakness, personality changes, tremors, slurred speech, convulsion, coma , death ? pre hepatic coma
Protein metabolism ? blood ammonia aminoaciduria
lipid metabolism Acc. Of FA in liver ? fatty liver ?pre hepatic hepatitis? fibrosis? cirrhosis? ? portal pressure? portal hypertension
64
III. Bile secretion
Bile salts acids steatorrhea
Conjugation of bilirubin Hepatocellular jaundice

IV. Miscellaneous
Vit A, K Deficiency- ?vit A , K
Antibacterial action Prevent infections
Destruction of RBCs Anemia , ? bilirubin
65
References
  • Hepatic physiology pathophysiology. Millers
    Anaesthesia , 6th ed.
  • Hepatic structure, function anaesthetic
    effects. International Practice of Anaesthesia.
    Prys- Roberts.
  • Evaluation of liver function tests. Harrisons
    Principles of Internal Medicine. 17th ed.
  • Hepatic anatomy, Function, Physiology. Clinical
    Anethesia
  • 6th ed.
  • Liver as an organ. Textbook of Medical
    Physiology, Guyton Hall. 10th ed.

66
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