1. Hepatic Physiology Tariq Alzahrani Demonstrator College of Medicine King Saud University

2. Objectives It is an important topic? Hepatic Anatomy Hepatic Physiology Effect of anaesthesia Effect of surgery

3. The largest organ in the body is the liver Involved with almost all of the biochemical pathways that allow growth, fight disease, supply nutrients, provide energy, and aid reproduction Dual blood supply: portal-venous (75%) and hepatic-arterial (25%). Surgery and anesthesia impact hepatic function primarily due to their impact on hepatic blood flow and not primarily as a result of the medications or anesthetic technique utilized

4. (Conn, 1991Approximately 1 of every 700 patients admitted for elective surgery has abnormal liver chemistry test results (Conn, 1991). (Jackson, 1968).Up to 10% of patients with end-stage liver disease may have surgery during the last 2 years of their lives (Jackson, 1968).

5. Liver location Inferior to diaphragm Mainly right side Protected by rib cage Large – 1.4 kg Superior to stomach Right upper quadrant

6. Liver gross anatomy Falciform ligament –Attached to diaphragm and anterior abdominal wall –Round ligament remnant of umbilical vein

7. Liver gross anatomy Hepatic portal vein Hepatic artery hepatic veins Common hepatic duct Gall bladder

8. Liver microscopic anatomy Liver lobule –Structural & functional unit –Hexagonal solid –Cords of hepatocytes around central vein –Components

9. Liver microscopic anatomy Portal triads at periphery –Branch of hepatic artery –Branch of hepatic portal vein –Bile duct

10. Liver microscopic anatomy Hepatic sinusoids between liver cords

11. Liver microscopic anatomy Kupffer cells – liver macrophages along sinusoids Hepatocytes Bile canaliculi – between hepatocytes, leads to bile duct

12. Hepatocytes synthesize and secretes several plasma proteins –Albumin –Globulins –Fibrinogen produces bile salts, detoxifies poisons Peroxisomes detoxify alcohol Storage of glycogen

13. Blood flow in liver Hepatic artery branch –Oxygenated blood to lobule Portal vein branch –Deoxygenated blood with substances from intestine Blood flows through sinusoids –Kupffer cells phagocytize bacteria, foreign material, old rbc’s Plasma seeps out and bathes hepatocytes

14. According to the its blood supply, liver is divided into 8 segments. Sympathetic : T6-11 (Celiac plexus), Parasympathetic: RT &LT vagi,RT phrenic. Gall bladder : right vagus.

15. Hepatic Physiology Only major organ in the body that receives a dual afferent blood supply 2 vessels supplying (hepatic artery and portal vein) –Portal vein = 75% of HBF (55% of 0 2 ) –Hepatic artery = 25% of HBF (45% of 0 2 ) –Total hepatic blood flow = 25% of CO Portal venous pressure is normally 7-10mmHg

16. Liver Functions Protein synthesis Glucose homeostasis Lipid and lipoprotein synthesis Vitamin storage Clotting factor synthesis Bile acid synthesis Drug metabolism

17. Physiology ~ carbohydrate metabolism Main role ~ storage of glycogen. Normally, about 75 grams of glycogen is found in the liver Depleted by 24-48 hours of starvation Poor nutrition or pre-existing liver disease may lower glycogen stores ~ prone to hypoglycemia

18. hepatic glucose production and storage of glycogen Regulation of lipolysis Adipose tissue Carbohydrate Blood Glucose Digestive enzymes Gut Pancreas Muscle Liver Insulin Insulin-stimulated glucose uptake

19. The Liver is the only organ which contain glucose-6- phosphatase,so: - It is the only organ,which can liberate glucose from glycogen into the circulation. - Other organs, e.g. muscle, can also store glycogen but are only able to utilize it locally.

21. Physiology ~ fat & protein metabolism Beta oxidation of fatty acids and the formation of lipoproteins. Synthesis of plasma proteins ~ All proteins, except immunoglobulins, antihemophiliac factor (8) & v W f. Normally, 10-15 grams of albumin are produced daily (3.5-5.5 g/dl)

22. Clotting factors V, VII, IX, X, prothrombin and fibrinogen are all dependent on the liver for synthesis ~ many of the factors require only 20-30% of normal levels to stop bleeding, significant impairment of liver function must occur before problems begin. Important facts:  Plasma half-lives of clotting factors are measured in hours. Therefore, acute liver dysfunction can lead to coagulopathies.  Both severe parenchymal disease and biliary disease may lead to coagulopathy - the former due to impaired synthesis and the second by decreased vitamin K absorption due to the absence of bile salts secondary to biliary obstruction.

23. Physiology ~ drug metablism Divided into 2 phase: 1.Phase I metabolism  Oxidation  Reduction 2.Phase II metabolism  Conjugation

24. Factor affecting drug metabolism:  microsomal enzyme system  route of administration  liver blood flow  competitive inhibition

25. Hepatic Excretion Some drug molecules are not metabolized before excretion –May see decreased metabolites or accumulation of metabolites if excretion impaired To be eliminated, the drug must cross sinusoidal membrane and return to blood as it flows toward central vein, or be transported into bile

26. Factors affecting HE: –Blood flow –Protein binding –Hepatic intrinsic clearance (ability of hepatocytes to remove drug from liver when blood flow, protein binding, and translocation to the site of metabolism or elimination are not rate-limiting)

27. Hepatic Clearance Volume of blood from which drug is removed completely per unit time Hepatic clearance is not equal to systemic clearance

28. Bioavailability Fraction of the absorbed dose that reaches the systemic circulatio

29. Volume of Distribution V d = D % C May or may not be affected by liver disease, depending on extravascular distribution and tissue binding

30. Effect of anaesthesia Most inhalation agents decrease hepatic blood flow Fatal hepatic necrosis resulting from halothane is rare (1 case in 35,000), but severe liver dysfunction may occur in 1 case in 6000 Isoflurane is a safer choice because the effect on hepatic blood flow and oxygenation is much less than that of halothane. In fact, isoflurane increases hepatic arterial blood flow.

31. Nitrous oxide is not hepatotoxic Hypotension resulting in "shock liver injury" is possible Delayed clearance of drugs such as midazolam, fentanyl, and morphine Hypercarbia causes decreased portal blood flow and must be avoided

32. Effect of surgery Splanchnic traction and exploratory laparotomy can reduce blood flow to the intestines and the liver Upper abdominal surgery is associated with the greatest reduction in hepatic blood flow Elevation of liver chemistry tests is more likely to occur after biliary tract procedures than after nonabdominal procedures