Liver Disease

1. Liver Disease Lindsay Higgins

2. Anatomy • The Falciform Ligament separates the right and left anatomic lobes. • Blood supply distinguishes the surgical lobes by the bifurcation of the right and left Hepatic Artery and Portal Vein. There are a total of 8 surgical segments.

3. Anatomy (cont.) • 50-100,000 lobules. • Hepatocytes are arranged cylindrically around a central vein. • 4-6 portal tracts (hepatic arterioles, portal venules, bile canaliculi, lymphatics, and nerves) surround each lobule.

4. Anatomy (cont.) • The functional unit of the liver is the acinus, with the portal tract in the middle and the central veins in the periphery. • Zone 1 is closest to the portal tract and receives the most O2. • Zone 3 is closest to the central vein, receives the least O2 and is the most susceptible to ischemia.

5. Vascular Supply • Blood Flow (30% of cardiac output) • 75% Portal Vein • 25% Hepatic Artery • Oxygen Supply • 55% PORTAL VEIN(O2 saturation is 85%) • 45% Hepatic Artery • Hepatic Artery flow is dependent on autoregulationpostprandially (not during fasting). • Portal Vein blood flow is dependent on spleen and GI tract flow. • Some compensation between Portal Vein and Hepatic Artery (decrease in flow from one increases flow from the other)

6. Sympathetic Input • Hepatic Artery • Vasoconstriction • α1 • Vasodilation • β2 • D1 • Cholinergic • Portal Vein • Vasoconstriction • α1 • Vasodilation • β2 • Note: β2 input also stimulates Glycogenolysis and Gluconeogenesis.

7. Functions of the Liver: Blood Reservoir • Portal Vein pressure is normally 7-10 mm Hg, but the low resistance of the hepatic sinusoids allows large blood flows/volumes in the portal veins  small changes in hepatic venous tone causes large changes in hepatic blood volume • Decrease in CVP (hemorrhage)  Decrease in hepatic venous pressure  shifts blood from liver into circulation (300 mL) • Increase in CVP (CHF patients)  Increase in hepatic venous pressure  blood accumulates in the liver (1L)

8. Functions of the Liver:Blood Cleansing/Immune Function • Kupffer cells lining the sinusoids are part of the monocyte-macrophage (reticuloendothelial) system. • Phagocytosis (colonic bacteria, endotoxin, cellular debris, viruses proteins, etc.) • Processing of antigens • Release of proteins, enzymes, cytokines

9. Liver Functions:Carbohydrate Metabolism • Only the liver (and to some extent the muscle) are able to store glycogen • Insulin enhances glycogenesis. • Epinephrine and Glucagon enhance glycogenolysis. • Glycogen stores are depleted after 24 hours of fasting (after that the body is dependent on gluconeogenesis (de novo synthesis of glucose). • Only the liver and kidney can form glucose from lactate, pyruvate, amino acids and glycerol. Gluconeogenesis is vital for the maintenance of a normal blood glucose. • Glucocorticoids, Catecholamines, Glucagon, and thyroid hormone enhance gluconeogenesis. • Insulin inhibits gluconeogenesis.

10. Liver Function:Carbohydrate Metabolism (cont.) • Final products of carbohydrate metabolism are galactose, glucose, and fructose. • All cells turn glucose  ATP • Citric Acid Cycle (aerobic) • Glycolysis (anaerobic) • Phosphogluconate (only in the liver and adipose tissue) • Liver and kidney can turn lactate, pyruvate, amino acids, and glycerol into glucose.

11. Liver Function:Fat Metabolism • When carbohydrate stores are saturated, the liver converts the excess carbohydrates (and proteins) into fat (fatty acids), which can be used directly as fuel or stored in the liver or adipose tissue. • Only RBCs and the renal medulla can utilize only glucose (even neurons can switch to fatty acid breakdown products – ketone bodies – after several days of starvation).

12. Liver Function:Protein Metabolism • The liver performs CRITICAL steps in protein metabolism. Without this function, death occurs in a matter of days. • Deamination of amino acids (converts them to carbs and fats – “transamination”) • Formation of Urea (formed from ammonia) • Interconversions between nonessential amino acids • Formation of plasma proteins • Nearly all plasma proteins (except for immunoglobulins) • Albumin • ALL COAGULATION FACTORS (except for Factor VIII and vWF) • Vit K: Factors II, VII, IX, X • Plasma Cholinesterase (pseudocholinesterase)

13. Liver Function:Drug Metabolism • Most drugs undergo hepatic biotransformation. • End products are inactivated or more soluble (more easily excreted in kidney or by bile) • Phase I: via oxidases and P-450 • Oxidation • Reduction • Deamination • Sulfoxidation • Dealkylation • Methylation Phase II: conjugation

14. P-450 Inducers • Queen Barb Steals Phen-Phen and Refuses Greasy Carbs, Chronic Alcohol, and Glucose • Quinidine • Barbituates/Benzodiazepines • St. John’s Wart • Phenytoin • Rifampin • Griseofulvin • Carbamazepine • Chronic Alcohol • Glucocorticoids

15. P-450 Inhibitors • Inhibit yourself from drinking alcohol from a KEG. It will make you a SICCO and give you crazy AIDS. • Acute Alcohol • Ketoconazole • Erythromycin (& other Macrolides) • Grapefruit Juice • Sulfonamides • Izoniazid • Cimetidine • Chloramphenicol • Omeprazole • SSRI/SNRI • Antipsychotics • Ritonavir

16. Liver Function:Other Metabolic Functions • Converts T4  T3 • Degradation of Thyroid Hormone, Insulin, Estrogen, Aldosterone, Cortisol, Glucagon, ADH • Storage of Vitamins A, B12, E, D, and K • Production of transferrin, haptoglobin, and ceruloplasmin

17. Liver Function:Bile Formation and Excretion • Bile is important for absorption of fat and excretion of bilirubin, cholesterol, and drugs. • Hepatocytes secrete bile salts, cholesterol, phospholipids, conjugated bilirubin into bile canaliculi. • Bile salts allow the absorption of fat soluble vitamins (A, D, E, and K). Vitamin K deficiency manifests as a coagulopathy due to impaired formation of Factors VII, IX, and X.

18. Hepatic Synthetic Function Tests • Serum Albumin • Prothrombin Time • Cholesterol • Pseudocholinesterase • AST/ALT measure hepatocellular integrity rather than function. • Due to the liver’s large functional reserve, cirrhosis may be present without lab abnormalities.

19. Liver Dysfunction • 2 types based on lab tests: • Parenchymal Disorders • Obstructive Disorders

20. Albumin • Half life is 2-3 weeks, so may initially be normal with acute liver disease • Normally is 3.5-5.5 g/dL • If less than 2.5 g/dL is indicative of: • Chronic Liver Disease • Acute Stress • Severe Malnutrition • Nephrotic Syndrome • Protein-Losing Enteropathy

21. Prothrombin Time • Evaluates synthetic function • Normally 11-14 seconds • Half life is 4-6 hours • Measures the activity of • Fibringogen • Prothrombin • Factors V, VII, and X • Prolonged PT (greater than 3-4 seconds or INR 1.5) usually reflects severe liver disease unless Vitamin K deficiency is present

22. Effect of Anesthesia on the Liver:Hepatic Blood Flow • Hepatic blood flow is decreased • All volatiles decrease portal blood flow in proportion to MAP and CO • Most with Halothane • Least with Isoflurane • Neuraxial anesthesia decreases blood flow by lowering arterial BP • Controlled positive pressure ventilation and high peak airway pressures decrease hepatic blood flow by decreasing venous return • Decrease liver blood flow: • Hypoxemia (via sympathetic stimulation) • Surgical procedures near the liver can decrease blood flow 60% • Beta blockers, α1 agonists, H2 receptor blockers and vasopressin • Low dose Dopamine may increase liver blood flow

23. Effect of Anesthesia on the Liver:Metabolic Functions • Stress response from surgery  increased catecholamines, glucagon, and cortisol • Mobilization of glucose stores  hyperglycemia • Mobilization of protein stores  negative nitrogen balance • This can be reduced by regional anesthesia, deep general, or blockade of the sympathetic system.

24. Effect of Anesthesia on the Liver:Drug Metabolism • Halothane has been reported to inhibit hepatic metabolism of drugs (phenytoin, warfarin, and ketamine), but this is likely due to the resulting decrease in hepatic blood flow

25. Effect of Anesthesia on the Liver:Biliary Function • Opioids spasm of the sphincter of Oddi • Incidence (highest to lowest) • Fentanyl • Morphine • Meperidine • Butorphanol • Nalbuphine

26. Effect of Anesthesia on the Liver:Liver Tests • Mild postoperative liver dysfunction in healthy people is not uncommon and it is likely due to decreased hepatic blood flow. • When the results of LFTs are elevated postoperatively, it’s usually due to underlying liver disease or the surgical procedure itself. • Postoperative jaundice is most commonly from overproduction of bilirubin due to resorption of a large hematoma or red cell breakdown following a transfusion

27. Halogenated Anesthetics • “Halothane Hepatitis” • Due to hepatotoxic intermediates? Immune hypersensitivity? • Consider Viral hepatitis, CMV, EBV, and Herpes • Incidence of fatal hepatic necrosis is 1:35,000 • Risk factors: obesity, middle age, female, repeat exposure to halothane (esp within 28 days) • Also with Methoxyflurane, Enflurane, and Isoflurane

28. Acute Hepatitis • Viral • Hepatitis A, B, C, D, or E, EBV, herpes, CMV, or Coxsackieviruses • Chronic hepatitis: 3-10% with Hep B and 50% with Hep C • Drug Induced • Alcoholic is the most common • Acetaminophen (25 grams is usually fatal dose) • Halothane

29. Acute Hepatitis:Preoperative Evaluation • Patients with acute hepatitis should have any elective procedure postponed until the acute phase has resolved (normalized LFTs). • Risk of deterioration of hepatic function, encephalopathy, coagulopathy, or hepatorenal syndrome • Acute viral hepatitis: Morbidity 12% and Mortality 10% • Alcohol withdrawal: Mortality 50% • BUN, CMP, PT, platelet count, HBsAg • Transaminases don’t correlate with disease severity • Persistent elevation of PT after Vitamin K is indicative of severe liver disease • Determine the cause and extent of liver disease • Drug exposures • Recent Transfusions • Prior Anesthetics • May need Vitamin K or FFP to correct coagulopathy

30. Acute Hepatitis:Intraoperative Considerations • Avoid factors that are detrimental to the liver • Avoid factors that are known to decrease blood flow to the liver (hypotension, excessive sympathetic activation, high mean airway pressures) • Inhalational agents are preferred to IV because they don’t require metabolism by the liver • Isoflurane • Standard doses of induction agents can be used because termination of their effect is due to redistribution not metabolism

31. Chronic Hepatitis • Elevated transaminases for 6 months (note that transaminases correlate poorly with severity of disease) • 3 Types • Chronic Persistent Hepatitis – resolves • Chronic Lobular Hepatitis – resolves but has recurrent exacerbations • Chronic Active Hepatitis – destruction of normal cellular architecture on biopsy • 20-50% have Cirrhosis • Most commonly due to Hepatitis B and C

32. Chronic Hepatitis:Intraoperative Considerations • Chronic Persistent Hepatitis and Chronic Lobular Hepatitis is treated like acute hepatitis • Chronic Active Hepatitis is treated like Cirrhosis

33. Cirrhosis • Most common cause in the US is alcohol • Hepatocyte necrosis is followed by fibrosis and nodular regeneration • Distortion of the liver’s normal cellular and vascular structure leads to portal hypertension • Impairment of synthetic functions lead to multisystem disease • Clinical signs and symptoms often do not correlate well with severity of disease

34. Cirrhosis:Possible Complications • Variceal hemorrhage from portal hypertension • Intractable fluid retention (ascites and hepatorenal syndrome) • Hepatic encephalopathy or coma • 10% also develop at least one episode of spontaneous bacterial peritonitis • A few diseases can cause hepatic fibrosis without necrosis: • Schistosomiasis • Idiopathic Portal Fibrosis • Congenital Hepatic Fibrosis • Budd Chiari Syndrome (obstruction of the portal vein)

35. Cirrhosis:GI Considerations • Portal hypertension (greater than 10 mm Hg) leads to extensive portal-systemic venous collateral channels • Gastroesophageal major source of morbidity and mortality • Hemorrhoidal • Periumbilical • Retroperitoneal • Treatment of variceal bleed: • Reduce the rate of blood loss • Vasopressin • Somatostatin • Propranolol • Fluids/Blood Products • Balloon Tamponade • Endoscopic Sclerosis • TIPS may decrease portal hypertension but increases risk of encephalopathy

36. Cirrhosis:Hematological Considerations • Anemia – due to blood loss increased destruction, bone marrow suppression, nutritional deficiencies • Splenomegally • Thrombocytopenia • Leukopenia • Decreased synthesis of coagulation factors coagulopathy • Excessive blood transfusions can increase nitrogen load and worsen encephalopathy • Consider platelet transfusions if less than 100,000

37. Cirrhosis:Circulatory Considerations • Hyperdynamic state • Generalized peripheral vasodilation • AV shunting + decreased viscosity 2/2 anemia = increased CO • Cirrhotic Cardiomyopathy: CO is dependent on higher than normal filling pressures and below normal SVR • Intravascularly depleted

38. Cirrhosis:Respiratory Considerations • Hyperventilation  respiratory alkalosis • Hypoxemia due to left-right shunting (up to 40% of CO) • Pulmonary AV shunts • V/Q mismatching • Elevation of the diaphragm from ascites decreases lung volumes, especially FRC and predisposes to atelectasis • Ascites causes a restrictive effect • Consider paracentesis if severe ascites

39. Cirrhosis:Renal Considerations • Ascites • Portal hypertension  increases hydrostatic pressure • Hypoalbuminemia decreases oncotic pressure • Renal sodium and water retention due to relative hypovolemia and secondary hyperaldosteronism • Edema • Electrolyte Disturbances: hyponatremia and hypokalemia • Hepatorenal Syndrome: Usually follows GI bleeding, aggressive duresis, sepsis or surgery. • Progressive Oliguria • Sodium retention • Azotemia • Ascites • Very high mortality • Treatment is supportive; usually unsuccessful unless liver transplantation

40. Cirrhosis:CNS Considerations • Hepatic Encephalopathy • AMS • Fluctuating CNS signs: asterixis, hyperreflexia, inverted plantar reflex • EEG changes: symmetric high voltage, slow wave activity • Increased ICP (some) • Related to the amount of hepatic damage and the amount of blood shunted away from the liver directly into systemic circulation • Toxins: Ammonia, Mercaptans, short chain fatty acids, phenols • Increased permeability of BBB • Precipitate encephalopathy: GI bleeding, increased dietary protein, hypokalemic alkalosis (vomiting or diuresis), infections • Treat aggressively • Lactulose – osmotic laxative and inhibits GI bacterial ammonia production • Neomycin – inhibits GI bacterial ammonia production

41. Cirrhosis:Intraoperative Considerations • Drug Responses • Increased Vd (expanded ECF): Need higher loading doses • Changes in CNS sensitivity • Decreased protein binding • Decreased drug metabolism • Decreased drug elimination • Anesthetic Technique • Barbituate or Propofol followed by Isoflurane (avoid Halothane) • Opioid supplementation (caution b/c decreased metabolism) • Cisatricurium • RSI: Ketamine or Etomidate with SCh

42. Cirrhosis:Intraoperative Considerations • Monitoring • Aline • May require PEEP (if intrapulmonary shunts) • CVP or Pulmonary Artery Catheter (monitor volume status) • Follow UOP closely (mannitol) • Preop, usually are sodium restricted, but intraop preservation of intravascular volume is the priority • Following the removal of large amounts of ascites often requires subsequent colloid replacement to prevent hypotension and renal failure • Blood transfusions  citrate toxicity (normally metabolized by the liver) hypocalcemia