hep phy

HEPATIC PHYSIOLOGY, LIVER FUNCTION TESTS AND ITS CLINICAL SIGNIFICANCE : 

HEPATIC PHYSIOLOGY, LIVER FUNCTION TESTS AND ITS CLINICAL SIGNIFICANCE Presenter: Dr. Lokesh M B Moderator: Dr. Md Yahya

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HEPATIC ANATOMY HEPATIC BLOOD FLOW EFFECT OF ANESTHETICS ON HEPATIC BLOOD FLOW BIOCHEMICAL AND PHYSIOLOGICAL FUNCTIONS LIVER FUNCTION TESTS

HEPATIC ANATOMY : 

HEPATIC ANATOMY

Macroscopic anatomy : 

Macroscopic anatomy Reddish brown boomerang shaped gland Highly vascular, friable, easily lacerated Spongy, conforms to the shape of adjacent structures

Supports of liver : 

Supports of liver 1. Diaphragm: via coronary, triangular ligaments and connective tissue 2. IVC, hepatic veins and connective tissue 3. Intra abdominal pressure pressing over the diaphragm

Ligaments of liver : 

Ligaments of liver

Physiologic anatomy : 

Physiologic anatomy Segments of liver: Singular independent segments of liver Each segment has its own blood supply and biliary drainage If any segment is affected by disease process, the goal is to remove entire segment Real physiologic anatomy is derived from superimposition of scan data (CECT, helical CT) with couinaud segments.

Segments of liver : 

1. couinaud’s classification Segments of liver

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2. bismuth classification

Microanatomy : 

Microanatomy Liver lobule,portal lobule, liver acinus An idealized classic liver lobule is a hexagonal prism with a central vein at its center and six vertically aligned portal canals. Each portal canal includes a connective tissue matrix, surrounding nerve fibers, lymphatic vessels, and a portal triad. The protal triad contains terminal branches of the portal vein, hepatic artery and a bile ductule.

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Liver acinus : 

Liver acinus

Microcirculation : 

Microcirculation Zone 1. periportal Rich in oxygen and nutrients Rich in mitochondria: Glycogen synthesis, oxidative metabolism Urea synthesis Zone 2. midzonal Zone 3. pericentral Rich in SER, CYP, NADPH Biotransformation and xenobiotics, anaerobic metabolism More prone for ischemia

SPLANCHNIC CIRCULATION AND HEPATIC BLOOD FLOW : 

SPLANCHNIC CIRCULATION AND HEPATIC BLOOD FLOW

Hepatic blood flow : 

Hepatic blood flow 25% of total cardiac output 1ml/g of liver tissue 2 afferents: Portal vein: From splanchnic circulation 75% of blood flow 50% of oxygen supply Hepatic artery: Branch of coeliac artery 25% of blood flow 50% of oxygen supply

Splanchnic reservior : 

Splanchnic reservior 15% of total blood vloume 400-500 ml of blood Largest reservior of blood in the body Regulated by sympathetic system Increase in post sinusoidal resistance can cause exudation-- edema (ascites).

Regulation of hepatic blood flow : 

Regulation of hepatic blood flow Intrinsic regulation Hepatic artery buffer response Changes in portal blood flow causes reciprocal changes in hepatic blood flow Mediated by adenosine Normally adenosine gets washed out due to portal blood flow. If flow is reduced adenosine accumulates-dilation of hepatic artery- washout of adenosine HABR can at the max double hepatic blood flow.

Intrinsic regulation : 

Intrinsic regulation Metabolic control: Decrease in oxy tension or pH in portal vein increase blood flow Pressure flow autoregulation: Tissue specific regulators- myogenic response A hypertensive episode increases vascular tone (VC) prevent increase in blood flow Portal vein doesn’t have this response Significant in hepatic artery only in the post prandial state Little significance in anesthesia

Extrinsic regulation : 

Extrinsic regulation Neural control: Mainly sympathetic Sym: increases splanchnic vascular tone Translocation of blood to systemic circulation Up to 80% of reserve volume 400-500ml can be translocated Vagal stimulation: alters tone of presinusiodal sphincters Redistribution of hepatic blood flow.

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Extrinsic regulation Humoral control

Extrinsic regulation : 

Extrinsic regulation Glucagon: dose dependent relaxation of arterial smooth muscle Block effect of physiologic vasoconstrictors Angiotensin II: vasoconstriction of hepatic and portal veins Vasopressin: elevates splanchnic arterial resistance reduces portal venous resistance Treatment of portal hypertension

EFFECTS OF ANESTHETIC AGENTS ON HEPATIC BLOOD FLOW : 

EFFECTS OF ANESTHETIC AGENTS ON HEPATIC BLOOD FLOW

VOLATILE ANESTHETICS : 

VOLATILE ANESTHETICS Halothane: Dose dependent reduction of hepatic blood flow Reduction in hepatic arterial flow Mortailty in 1 in 35000 anesthetics Non-fatal hepatitis- 1 in 3000 18% metabolised Trifluoroacetate- major metabolite

Halothane hepatitis : 

Halothane hepatitis Risk factors: Previous exposure Age (>50), children highly resistant Obesity Gender (women>men) Enzyme induction Genetics Unexplained fever and jaundice in a specific patient following the use of halothane should serve as a warning sign to avoid its subsequent use in that patient

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Clinical features: Fever, anorexia, nausea, chills, myalgia, rash followed by jaundice 3-6 days later. Characteristically seen after minor uneventful procedures of brief duration (<30min) Intrinsic or idiosyncratic mechanism

Clinical Features of Halothane Hepatitis : 

Clinical Features of Halothane Hepatitis Mild Form Incidence, 1 : 5 Repeat exposure not necessary Mild elevation of ALT, AST Focal necrosis Self-limited Fulminant Form Incidence, 1 : 10,000 Multiple exposures Marked elevation of ALT, AST, bilirubin, alkaline phosphatase Massive hepatic necrosis Mortality rate, 50% Antibodies to halothane-altered protein antigens

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Enflurane: Dose dependent decrease in portal venous blood flow Hepatic arterial flow is unchanged Desflurane: Decreases hepatic blood flow 1 MAC reduces blood flow by 30% Produce decrease in oxygen delivery to liver and intestine

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Isoflurane: 0.2% of drug in body metabolised Metabolism yields reactive intermediates Preserves hepatic blood flow Less likely to cause hepatic injury Sevoflurane: Metablosim is more than iso or des but less than halothane or enflurane Metabolites are conjugated and excreted. Neither produces reactive intermediates nor fluroacetylated proteins

Nitrous oxide : 

Nitrous oxide Mild increase in sympathetic nervous system tone (VC of portal and hepatic artery) Inhibit methionine synthase Induce functional vit B12 deficiency No convincing evidence that nitrous oxide per se causes hepatotoxicity in absence of reduced oxygen supply

Other agents : 

Other agents Ketamine: Moderate increase liver enzymes Mechanism not clear Opioids: Little effect on hepatic function Increase tone of CBD and sphincter of oddi Not contraindicated

BIOCHEMICAL AND PHYSIOLOGIC FUNCTIONS : 

BIOCHEMICAL AND PHYSIOLOGIC FUNCTIONS

Intermediary metabolism : 

Intermediary metabolism Carbohydrate: Homeostatic regulator of blood glucose Severity of hyop/hyperglycemia influence the rate of uptake or release of glucose Glycogen synthesis stimulated by increase in glucose in zone 1 hepatocytes Endocrine regulators of glycogen synthesis: Glucagon and catecholamines: stimulate Insulin inhibit

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Protein: Production and breakdown of proteins Most body proteins synthesised by liver Albumin: 15% of liver’s total protein production 12-15g produced per day Alpha fetoprotein: From yolk sac, hepatocytes, enterocytes Elevated levels in adults signify hepatocellular proliferation: injury, inflammation, neoplasia levels>400ng/ml suggest HCC

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Lipid: Fat from intestine are either stored as triglycerides or packed as lipoproteins and transported. Catabolism of lipoproteins: β oxidation Acetyl coA: ketone production Ketone: inportant source of energy to extrahepatic tissue

Bile metabolism : 

Bile metabolism 600-800ml produced daily Bile salts: 80%constituents of bile Activate lipases Promote micelle formation Enable intestinal uptake of fat soluble vitamins Facilitate excretion of lipophilic substances Regulate expression of lipoprotein receptors on hepatocytes- modulate plasma lipid levels

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Recycling 20-30 times Terminal ileum reabsorbs 95% of bile salts Opioid analgesics disrupt bile flow by inducing painful spasms of bile ducts and sphincter of oddi This effect reversed by: glucagon, opioid antagonists, SM relaxants, antimuscarinics, volatile anesthetics

Coagulation : 

Coagulation Hepatocytes secrete most of procoagulants except factors III(tissue thromboplastin), IV(calcium) , VIII(von-willebrand factor). Anticoagulant factors: Protein C&S-inactivate factorVIIIa-Va complex Protein Z- degrade factor X PAI inhibits activation of plasminogen

Vitamin K : 

Vitamin K Required for γcarboxylation of glutamate residues of coagulation factors Enables procoagulants to form complexes with calcium or other divalent cations Two stages: γcarboxylation of glutamate residues and oxidation of vit K to epoxide vit K regeneration of vit K Warfarin blocks 2nd stage and traps vit K in epoxide form. Warfarin inhibits γcarboxylation immediately after absorption but effect takes >1day

Erythropoiesis and erythrocytosis : 

Erythropoiesis and erythrocytosis Heme metabolism: 20% of total heme production is from liver. Rest is from bone marrow. Porphyrias: porphyrinogens exposed to oxygen are oxidised to corresponding porphyrins. Asymtomatic until some stressor induces porphyric crisis. Triggers: sex hormones, glucocorticoids, cigarette smoke, barbiturates and CYP inducers.

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Clinical features: recurrent, dramatic, fatal neurological reactions, abdominal pain, dark urine. Acute intermittent porphyria: most common. 1 in 10,000 in normal population 1 in 500 in psychiatric patients More in women

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Bilirubin metabolism 300 mg bilirubin produced per day Rate limiting- heme oxygenase End products: biliverdin, CO, free divalent iron. Functions of CO: Regulation of vascular tone Platelet aggregation Vascular myocyte proliferation Neurotransmitter release Cytoprotective, antiapoptotic, antioxidant effects.

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Immune and inflamatory response: Largest reticuloendothelial organ in the body. Kupffer cells: 10% of total liver mass Phagocytose foreign body Modulator of inflammation (attenuate or induce inflammation) Stellate cells: Perisinusoidal space Source of matrix deposition When activated by oxidative stress it gets transformed to collagen synthesizing myofibroblasts

Xenibiotics : 

Xenibiotics Lipophilic drugs not excreted by kidney Liver converts hydrophobic compounds into hydrophilic ones Chemical transformation to increase water solubility and inactivate or attenuate the biological activity of drugs

Pathways of metabolism : 

Pathways of metabolism Phase I: Includes oxidases, reductases, methylases, sulphatase, Convert drugs to more polar compounds by addition of polar group(OH, NH2, SH) or removal of non-polar group. Microsomal oxidase and cytochrome p450 More than 90% of metabolisms require CYP Zone 3 has highest content of CYP Promote formation of reactive oxygen species and free radicals- promote liver injury

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Phase II: Conjugation End products of phase I are substrates for phase II End result is a compound more water soluble, less active, less toxic and more readily excreted in bile or urine Conjugation with glucuronic acid, acetate, sulphate, amino acids, glutathione

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Phase III: Transport Facilitate excretion ATP binding cassette proteins CFTR MDR I (p-glycoproteins)

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Pharmacokinetics: Extraction ratio= intrinsic hepatic clearance Hepatic blood flow High extraction ratio: at clinically relevant concentrations most of the drug in afferent hepatic blood is eliminated on first pass metabolism-- flow dependent elimination Low extraction ratio: hepatic elimination is determined by their plasma concentration-- capacity dependent elimination

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Drugs that are Efficiently Versus Poorly Extracted from Blood Flowing through the Liver

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Poorly Extracted Drugs

LIVER FUNCTION TESTS : 

LIVER FUNCTION TESTS

Indices of hepatocellular damage: : 

Indices of hepatocellular damage: Aminotransferases: AST/SGOT Cytoplasmic and motichondria Seen in liver, heart, skeletal muscle, kidney, and brain ALT/SGPT Mitochondria More specific for liver

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Mild elevations (100-250IU/L) Hepatocyte injury-Steatosis, medications, alcohol, hemochromatosis, cholestasis, chronic viral hepatitis, neoplasms, cirrhosis Moderate elevations (250-1000IU/L) Acute viral hepatitis, drug induced, Large elevations (1000-2000IU/L) Acute on chronic hepatitis Extreme (>2000IU/L) Massive hepatic necrosis- fulminant viral hepatitis, severe drug induced liver injury, shock liver, hypoxic hepatitis

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Ratio of AST/ALT <1 non-alcohilic steatohepatitis 2-4 alcoholic liver injury >4 wilsons disease Aminotransferases don’t reveal the extent of liver damage Lactate dehydrogenase Increased levels signify massive liver damage. Increased LDH & ALP indicate malignancy No advantage over AST & ALT

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Glutathione-S-transferase Sensitive and specific for drug induced liver injury Plasma half life 90 min Localises zone 3 More sensitive marker of centrilobar necrosis (compared to AST/ALT)

Indices of obstructed bile flow : 

Indices of obstructed bile flow Alkaline phosphatase: Non-specific elevations can occur- after fatty meals, pregnancy Not confined to liver. Major sources include bone, intestine, kidney, leukocytes, placenta (third trimester of gestation), and neoplasms. Extreme elevations signify biliary obstruction or malignant liver disease Not a reliable marker for either disorders

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5` nucleatidase: Equally sensitive as ALP but more specific Release into circulation requires bile salts- so more specific marker of biliary obstruction. Disadvantage: may require many days to be detectable GGTP Equally sensitive as ALP but more specific Elevated along with ALP. Present in other tissues but less in bone (differenciate osseous or hepatic ALP elevation) Disadvantage: Can be induced by microsomal inducers

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Serum bilirubin: Centrl to evaluation of disorders Unconjugated, conjugated Pre-hepatic, hepatic, post hepatic Detected by van den berg reaction Direct, indirect

Indices of hepatic synthetic function : 

Indices of hepatic synthetic function Serum albumin: Indicator of hepatocyte function Not very sepcific: Hypoalbuminemia may have many causes May take more time to reflect function (t1/2= 3 weeks) Prothrombin time Early indicator Short half life- 4 hours of factor VII and 4 days for fibrinogen. Prognostic indicator Not a specific indicator- also elevated in cong disorders, vit K deficiency, drugs like warfarin

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Blood Tests and the Differential Diagnosis of hepatic dysfunction ▪BILIRUBIN ▪PARENCHYMAL ▪CHOLESTASIS OVERLOAD DYSFUNCTION (HEMOLYSIS) Aminotransferases Normal Increased Normal (may (may be be increased normal or in advanced decreased in stages) advanced stages) Alkaline phosphatase Normal Normal Increased Bilirubin Unconjugated Conjugated Conjugated Serum proteins Normal Decreased Normal (may be decreased In advanced stages) Prothrombin time Normal prolonged Normal (may (may be be prolonged normal in early in advanced stages) stages) Blood urea nitrogen Normal Normal (may Normal be decreased in advanced stages) BSP/ICG Normal Retention Normal or retention

Indices of hepatic blood flow : 

Indices of hepatic blood flow Clearance technique: Fick principle High intrinsic hepatic clearance and total body clearance ICG dye, gold 198, lidocaine, colloidal particle Severe liver disease renders clearance technique unreliable because of indeterminable effects on liver blood flow and capacity to eliminate substances

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Indicator dilution technique: Not related to hepatic blood flow Indicator must be uniformly mixed upon injection and resistant to hepatic clearance Direct measurements: Electromagnetic flow probes Themselves alter hepatic blood flow Probes left in place and blood flow measured later via telemetry ERCP MRCP

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