Liver Disease

1. Liver Disease Lecture 6

2. Introduction • The liver has a central and critical biochemical role in the metabolism, digestion, detoxification, and elimination of substances from the body. • All blood from the intestinal tract initially passes through the liver, where products derived from digestion of food are processed, transformed, and (in some cases) stored. • These include amino acids, carbohydrates, fatty acids, cholesterol, lipids, vitamins, and minerals. • Most major plasma proteins (with the exception of immunoglobulins [Igs] and the von Willebrand factor) are mainly or exclusively synthesized in the liver.

3. Introduction • The liver responds to multiple hormonal and neural stimuli to regulate blood glucose concentrations. • it stores dietary glucose as glycogen for later use. • The major site for gluconeogenesis. • Central in lipid metabolism; • it extracts and processes dietary lipids, and it is the principal site of cholesterol, triglyceride, and lipoprotein synthesis. • The synthesis of bile acids from cholesterol, with secretion of these compounds into the bile, which facilitates the absorption of dietary fat and fat-soluble vitamins.

4. Introduction • The liver is also the primary site of metabolism of both endogenous substances and exogenous compounds (eg, drugs and toxins). • This process, known as biotransformation, converts lipophilic substances to hydrophilic ones for subsequent elimination. • The liver is a major site of catabolism of hormones, and thus participates in regulation of plasma hormone concentrations. • The liver is also involved in hormone synthesis, producing such hormones as insulin-like growth factor 1, angiotensinogen, hepcidin, prohormone 25-OH vitamin D. • Many of these hepatic functions can be assessed by laboratory procedures to gain insight into the integrity of the liver.

5. Introduction • As a large organ, the liver shares with many other organs the ability to perform its functions with extensive reserve capacity. • In many cases, individuals with liver disease maintain normal function despite extensive liver damage. • In such cases, liver disease may be recognized only by using tests that detect injury. • Most commonly, this is accomplished by measuring plasma activities of enzymes found within liver cells, which are released in somewhat specific patterns with different forms of injury.

6. Introduction • Chronic liver injury often involves fibrosis in the liver; markers of the fibrotic process might be indicators of the degree of injury. • Chronic damage is often due to chronic inflammation; cytokines alter the pattern of liver protein production, which allows detection of inflammation. • Some proteins are produced in increased amounts with liver regeneration and neoplasia; such markers may be useful in detecting liver cell proliferation.

7. CLINICAL MANIFESTATIONS OF LIVER DISEASE • Various characteristics indicate the presence of liver disease, including: • Fibrosis, • Jaundice, • Portal hypertension, • an increase in the blood pressure within a system of veins called the portal venous system • Veins coming from the stomach, intestine, spleen, and pancreas merge into the portal vein, which then branches into smaller vessels and travels through the liver. • If the vessels in the liver are blocked due to liver damage, blood cannot flow properly through the liver. As a result, high pressure in the portal system develops. • This may lead to the development of large, swollen veins (varices) within the esophagus, stomach, rectum, or umbilical area (belly button). • Varices can rupture and bleed, resulting in potentially life-threatening complications.

8. CLINICAL MANIFESTATIONS OF LIVER DISEASE The portal-venous system. • HV, Hepatic vein; • IMV, inferior mesenteric vein; • IVC, inferior vena cava; • LGV, left gastric vein; • LRV, left renal vein; • PV, portal vein; • RRV, right renal vein; • SMV, superior mesenteric vein; • SV, splenic vein.

9. CLINICAL MANIFESTATIONS OF LIVER DISEASE • Abnormal renal function, • Portal hypertension is a common factor in all cases of Hepatorenal Syndrome that develop in chronic liver disease, but HRS may also occur in acute liver failure. • Altered drug metabolism, • This is reflected in delayed metabolism. • Only patients with evidence of liver failure, such as encephalopathy, coagulopathy, or ascites, need alterations in dosing.

10. CLINICAL MANIFESTATIONS OF LIVER DISEASE

11. CLINICAL MANIFESTATIONS OF LIVER DISEASE • Nutritional and metabolic abnormalities, • alterations in glucose metabolism • hypokalemia caused by secondary hyperaldosteronism • hypoalbuminemia is frequently present because of decreased production and sinusoidal leakage of albumin in patients with portal hypertension • in patients with chronic cholestasis, impaired delivery of bile salts to the duodenum may result in malabsorption of lipids and fat-soluble vitamins, leading to deficiencies in vitamins A, D, E, and K

12. CLINICAL MANIFESTATIONS OF LIVER DISEASE • Disordered hemostasis, • The liver manufactures most of the soluble clotting factors (the major exceptions being factor VIII and von Willebrand factor) and a number of inhibitors of clotting (proteins C and S, antithrombin III). • The liver also clears activated clotting factors from the circulation. • Bile acids are necessary for vitamin K absorption and are needed to produce the active forms of several clotting factors, as well as proteins C and S

13. CLINICAL MANIFESTATIONS OF LIVER DISEASE • Release of enzymes into various body fluids • Enzymes are found at different locations within cells. • AST and ALT are cytosolic enzymes. As such, they can be released with cell injury and appear in plasma relatively rapidly. • In contrast, ALP and GGT are membrane-bound glycoprotein enzymes. • The most important location of both enzymes is on the canalicular membrane of hepatocytes. • Cell injury, the simplest mechanism, appears to allow leakage of cytoplasmic enzymes from cells • GGT and ALP into the circulation is less well understood. • GGT and ALP into the circulation is less well understood.

14. DISEASES OF THE LIVER • The liver has a limited number of ways of responding to injury. • Acute injury to the liver may be asymptomatic, but often presents as jaundice. • The major acute liver disorders are acute hepatitis and cholestasis. • Chronic liver injury generally takes the clinical form of chronic hepatitis; its long-term complications include cirrhosis and HCC.

15. DISEASES OF THE LIVERMechanisms and Patterns of Injury • Cell death occurs by necrosis (death of cell) or apoptosis (programmed cell death) or both. • The target cell determines the pattern of injury, with hepatocyte injury leading to hepatocellular disease and biliary cell injury leading to cholestasis. • All cellular injury induces fibrosis as an adaptive or healing response, with the duration of injury and genetic factors determining whether cirrhosis and ultimately carcinoma occur.

16. DISEASES OF THE LIVERMechanisms and Patterns of Injury

17. DISEASES OF THE LIVERMechanisms and Patterns of Injury • Cellular necrosis occurs as the result of an injurious environment has been referred to as “murder”. • It is characterized by cellular swelling with loss of membrane integrity. • Toxic injury from compounds such as carbon tetrachloride, aspirin, and acetaminophen occurs for the most part by necrosis. • Apoptosis occurs as the result of accelerated programmed death in which the cell participates in its own demise and thus commits “suicide”. • It is characterized by cell shrinkage, with nuclear chromatin condensation and fragmentation forming apoptotic bodies. • Most forms of hepatitis are associated with apoptosis. • Both typically leads to leakage of cytoplasmic enzymes.

18. DISEASES OF THE LIVERMechanisms and Patterns of Injury • Laboratory tests are helpful in distinguishing between: • The pattern of injury (hepatocellular vs cholestatic), • the aminotransferase enzymes and ALP are used • The chronicity of injury (acute vs chronic), • plasma albumin determines the chronicity • the severity of injury (mild vs severe) • the PT or factor V concentration determines the severity • Classically, liver fibrosis has been assessed using liver biopsy, but in recent years several noninvasive methods of assessment of liver fibrosis have been described and evaluated. • Although liver biopsy yields incomparable information about the nature, severity, and chronicity of liver disease, noninvasive tests may provide more accurate assessment of liver fibrosis, and in particular, disease severity and prognosis.

19. DISEASES OF THE LIVER Disorders of Bilirubin Metabolism

20. DISEASES OF THE LIVERAcute Hepatitis • Acute hepatitis refers to an acute injury directed against the hepatocytes. • The injury may be mediated: • Directly, which occurs with certain drugs, such as acetaminophen or with ischemia, • a typical rapid rise in cytosolic enzymes, such as AST, ALT, and lactate dehydrogenase (LDH), is followed by a rapid fall, with rates of decline similar to known half-lives of the enzymes. • Indirectly, which occurs with immunologically mediated injury from most of the hepatitis viruses and most drugs, including ethanol. • With immunologic injury, a gradual rise in cytosolic enzymes occurs, followed by a plateau phase and gradual resolution of enzyme elevation

21. DISEASES OF THE LIVERAcute Hepatitis • Although jaundice is a key clinical finding in acute hepatitis, it is often absent. • An increase in AST & ALT enzymes has sensitivity and specificity greater than 90% for acute hepatitis: • AST activity to greater than 200 U/L or • ALT activity to greater than 300 U/L • ALP usually is mildly elevated: • typically is < 3 times the upper reference limit in 90% of cases of acute hepatitis.

22. DISEASES OF THE LIVERAcute Hepatitis • Increased plasma concentration of bilirubin, when present, typically is predominantly due to direct reacting bilirubin; • indirect bilirubin is higher than direct bilirubin in approximately 15% of cases. • The distribution of direct bilirubin percentage is identical in acute hepatitis and bile duct obstruction, making the relative amount ofdirect bilirubin inconsequential in the differential between hepatitis and obstruction.

23. DISEASES OF THE LIVERAcute Hepatitis • Liver synthetic function usually is well preserved in most forms of acute hepatitis. • The outcome of acute hepatitis is variable. • In most cases, complete recovery occurs, and liver regeneration leads to normal structure and function. • With some viruses, failure to clear infection leads to development of chronic hepatitis. • In a small percentage of cases, massive destruction of the liver leads to acute (fulminant) hepatic failure, which is associated with high mortality unless liver transplantation is performed.

24. DISEASES OF THE LIVERAcute Hepatitis

25. DISEASES OF THE LIVERAcute Hepatitis: Toxic Hepatitis • Toxic hepatitis refers to direct damage of hepatocytes by a toxin or toxic metabolite. • Toxic reactions are usually predictable and are directly related to the dose of the agent ingested. • In North America and Europe, the most common cause of toxic hepatitis (and the most common cause of acute liver failure) is acetaminophen, a widely used nonprescription pain reliever. • The metabolism of acetaminophen is affected by: • Dose, • Induction of metabolic enzymes, and • Concentrations of glutathione.

26. DISEASES OF THE LIVERAcute Hepatitis: Toxic Hepatitis • When a large dose of acetaminophen is ingested (average lethal dose as a single ingestion is 15 g), • The metabolic pathways are overcome, glutathione is depleted, and toxic intermediates accumulate, causing liver damage. • When metabolic enzymes are induced (such as by ethanol) or glutathione is depleted (which occurs in alcoholism and with starvation), toxicity can occur with relatively small doses of acetaminophen (total doses of 2–4 g). • Toxicity can also occur with excessive cumulative doses of acetaminophen; such accidental overdoses appear to be responsible for approximately one-half of cases of toxicity.

27. DISEASES OF THE LIVERAcute Hepatitis: Toxic Hepatitis Non-toxic Non-toxic NAPBQI (N-acetyl-p-benzoquinone imine)

28. DISEASES OF THE LIVERAcute Hepatitis: Toxic Hepatitis • Diagnosis is often based on: • History and increased acetaminophen concentrations; • In patients who present later, and for whom a history cannot be obtained, • measurement of acetaminophen-protein adducts allows diagnosis. • The first laboratory abnormality to appear is: • An increase in PT, • 4 seconds above the control value in most cases • followed by increased activity of cytosolic enzymes, with AST tending to be higher than ALT. • Peak activities (typically >100 times the upper reference intervals) usually occur by 24 to 48 hours, • followed by rapid clearance at rates approximating the known half-lives of the enzymes.

29. DISEASES OF THE LIVERAcute Hepatitis: Toxic Hepatitis • Prognosis is related most closely to the prolonged increase in PT; • Persistent elevation of PT 4 days after ingestion is associated with a poor prognosis. • Other markers of risk include development of acute renal failure and the presence of lactic acidosis, particularly if the pH is less than 7.30.

30. DISEASES OF THE LIVERAcute Hepatitis: Ischemic Hepatitis (Shock Liver) • Hepatic hypoperfusion (ischemic hepatitis) is one of the most common causes of elevated cytosolic enzymes; in hospital patients, it is the cause of most cases of acute hepatitis. • Ischemic hepatitis may follow any cause of shock; • The most common causes are septic and cardiogenic shock • Not all patients with shock develop ischemic hepatitis; • in one recent study, only 13.8% of those with septic shock did, but mortality was significantly higher in such patients.

31. DISEASES OF THE LIVERAcute Hepatitis: Ischemic Hepatitis (Shock Liver) • Another study found that cardiac dysfunction, especially right heart failure, appeared necessary to cause the clinical picture of ischemic hepatitis. • Bilirubin elevations typically are minimal, and they usually peak several days after enzyme activity reaches its greatest point. • Laboratory findings are similar to those seen in toxic hepatitis, and acute renal failure is a common complicating factor. • Prognosis is primarily related to the underlying cause of hypotension; individuals with prolonged elevation of bilirubin appear to have a poor prognosis.

32. DISEASES OF THE LIVERAcute Hepatitis: Other Causes of Acute Hepatitis • Alcoholic hepatitis • Alcoholic hepatitis is often suspected by the combination of mild elevations in enzymes (peak AST typically <300 U/L), AST/ALT ratio >2, and leukocytosis.

33. DISEASES OF THE LIVERAcute Hepatitis: Other Causes of Acute Hepatitis • Drugs • Drugs can cause liver injury through a number of mechanisms, but the most common is immune-mediated injury to hepatocytes. • Criteria used to recognize drug-induced liver injury include: • A temporal relationship between drug exposure and onset of hepatitis, • Exclusion of other known causes of hepatitis, • The presence of extrahepatic hypersensitivity • especially skin rash, arthralgia, renal injury, and eosinophilia • The development of liver injury on rechallenge, • Previously published reports of similar reactions.

34. DISEASES OF THE LIVERAcute Hepatitis: Other Causes of Acute Hepatitis • Although usually associated with prescription drugs, complementary and alternative products are becoming increasingly recognized as causes of acute hepatitis and in a US study, these products were responsible for 9% of all cases. • Although drug reactions typically develop soon after that start of treatment, several months may elapse between the time of initial exposure and development of acute hepatitis. • Approximately 60% of cases cause severe acute hepatitis with jaundice. • Serious reactions are more common in individuals who are continued on the medication. • In 15% to 30% of cases, liver injury persists and becomes chronic after cessation of the drug.

35. DISEASES OF THE LIVERAcute Hepatitis: Other Causes of Acute Hepatitis • Some of the disorders that usually produce chronic may occasionally present in an acute fashion. • Auto-immune hepatitis (AIH) has an acute component in up to 40% of cases. • Clinically, it differs from other forms of acute hepatitis because it is characterized by: • decreased albumin, increased globulins, and a more prolonged increase in aminotransferases. • Acute AIH is diagnosed by the absence of other causes of acute hepatitis and the presence of autoimmune markers.

36. DISEASES OF THE LIVERApproach to the Patient With Acute Hepatitis • Once a diagnosis of acute hepatitis has been established, additional laboratory testing is usually required to determine the cause. • Although the incidence of acute viral hepatitis has decreased, serologic studies should be performed to rule out infectious causes. • A typical panel of tests should include: • IgM anti-HAV, HBsAg, IgM anti-HBc, anti-HCV, and HCV RNA (or HCV core antigen, if available). • Marked elevations (>100 times the upper reference intervals) in AST or ALT, particularly if AST is higher than ALT, should suggest the possibility of toxic or ischemic liver injury.

37. DISEASES OF THE LIVERApproach to the Patient With Acute Hepatitis • Minimal increases (<8 times the reference interval) in AST, with AST greater than ALT, in a patient with jaundice and leukocytosis indicate likely alcoholic hepatitis. • Imaging studies of the biliary tract are appropriate to rule out obstruction in those who present with sudden onset of symptoms, especially if accompanied by: • right upper quadrant pain and tenderness, laboratory evidence of pancreatitis, or a history of gallstones. • The presence of increased plasma globulin and decreased albumin concentrations suggest the possibility of AIH, while the presence of hemolytic anemia and acute renal failure, should suggest the possibility of Wilson disease.

38. DISEASES OF THE LIVERAcute Hepatitis

39. DISEASES OF THE LIVER Chronic Hepatitis • Chronic hepatitis is defined as chronic inflammation of the liver that persists for at least 6 months, or signs and symptoms of chronic liver disease in the presence of elevated cytosolic enzymes. • It is characterized by ongoing inflammatory damage to hepatocytes, which are often accompanied by hepatocyte regeneration and scarring. • Formerly, chronic hepatitis was subdivided into three forms (chronic persistent, chronic lobular, and chronic active) based on histologic characteristics.

40. DISEASES OF THE LIVER Chronic Hepatitis • Chronic persistent • inflammatory activity confined to portal areas. • Chronic lobular • inflammatory activity and necrosis scattered throughout the lobule -- good prognosis. • Chronic active • inflammation that spilled into the adjacent lobule associated with necrosis and fibrosis, which progress to cirrhosis and liver failure • It was recognized that individuals often had each of these diseases at different points in time, and often in different areas of the liver in the same biopsy. • Current classifications describe the cause and evaluate the severity of inflammatory injury (termed grade) and the extent of fibrosis (termed stage).

42. DISEASES OF THE LIVER Chronic Hepatitis

43. DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis • Nonalcoholic fatty liver disease is now a major cause of chronic liver disease and is increasing in prevalence. • Ludwig and colleagues first described patients who had histologic features identical to those of alcoholic hepatitis (including hepatocyte ballooning, presence of Mallory hyaline, and neutrophil infiltration), but who had no history of heavy alcohol intake (< 20 g/day) and did not have AST values higher than ALT values. • They introduced the term NASH to describe this entity, which was more common in women than in men, and was usually associated with diabetes and/or obesity.

44. DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis • Black arrowhead: Mallory's hyaline bodies (pink filamentous structures). • Black arrow: ballooned hepatocytes. • White arrow: hepatocytes containing fat globules. • White arrowhead: displaced nucleus

45. DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis

46. DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis • It is now recognized that NAFLD is associated strongly with the presence of the metabolic syndrome; • almost half of individuals who meet the criteria for metabolic syndrome have NAFLD, and • as many as 20% to 30% of the population in North America and Europe has NAFLD, making it far and away the most common form of liver disease and an extremely common condition in the population in the developed world. • Approximately 10% of those with NAFLD have the more severe form, NASH. • The frequency in obese or diabetic individuals is much higher, with NAFLD in 60% to 75% and NASH in 20% to 25%.

48. DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis • The frequency of cirrhosis in NASH is not well established, but it has been suggested that NASH may be a major cause of cryptogenic cirrhosis, that is, cirrhosis for which no underlying cause can be determined. • Because weight loss develops with chronic illness, fat may disappear from the liver, leaving only fibrosis.

49. DISEASES OF THE LIVER Chronic Hepatitis: Nonalcoholic Fatty Liver Disease & Nonalcoholic Steatohepatitis • Current evidence suggests that accumulation of fat in NAFLD is a consequence of insulin resistance. • A variety of mechanisms may lead to insulin resistance, including genetic predisposition, increased concentrations of free fatty acids, and the presence of cytokines such as TNF-α. • Because TNF-α is produced at a rate that correlates with body fat mass, and is critical to development of insulin resistance in obesity, it may be a key factor in the development of NAFLD. • However, the pathogenesis is more complicated because a variety of other factors lead to increased fat accumulation in the liver, but they have not been associated with the development of NASH, including: • increased carbohydrate intake, certain drugs, and mutations in lipid synthesis.

50. IRS1 is no longer phosphorylated on its tyrosine residues but on serine residues, resulting in nonfunctional, inhibitory proteins. • TNF-α also influences increased gene expressions of TNF-α but decreases GLUT4 expressions, resulting in lower levels of GLUT4 proteins. • Glucose uptake is reduced, leading to hyperglycemia and hyperinsulinemia. IR: insulin receptor; Y: tyrosine; S: serine; IRS1: insulin receptor substrate 1; PI3K: phosphoinositide kinase 3; PIP2: phosphatidylinositol 4,5-bisphosphate; TNF-α: tumour necrosis factor α; FFA: free fatty acid; IKK: a type of serine kinase; ROS: reactive oxygen species; PPARγ: peroxisome proliferator activator-receptor γ; GLUT4: glucose transporter 4.