1. Hepatic Cirrhosis Bin Wu, MD & PhD Professor and Head Department of Gastroenterology The Third Affiliated Hospital Sun Yat-Sen University

2. Aim: Master: Clinical Manifestation and Diagnosis of Hepatic cirrhosis Acquaint: Distinguish Diagnosis and Complication as well as Rule of Treatment Know: Causes and Risk Factors , Mechanism. Times: 2 hours

3. Definition Hepatic c irrhosis is a chronic, degenerative disease in which normal liver cells are damaged and are then replaced by scar tissue.

4. Description Hepatic Cirrhosis changes the structure of the liver and the blood vessels that nourish it. The disease reduces the liver's ability to manufacture proteins and process hormones, nutrients, medications, and poisons.

6. Long-term alcoholism is the primary cause of cirrhosis in the United States. Men and women respond differently to alcohol. Although most men can safely consume two to five drinks a day, one to two drinks a day can cause liver damage in women. Individual tolerance to alcohol varies, but people who drink more and drink more often have a higher risk of developing cirrhosis. In some people, one drink a day can cause liver scarring.

7. Chronic liver infections, such as hepatitis B and particularly hepatitis C, are commonly linked to cirrhosis. People at high risk of contracting hepatitis B include those exposed to the virus through contact with blood and body fluids. This includes healthcare workers and intravenous (IV) drug users. In the past, people have contracted hepatitis C through blood transfusions. As of 2003, cirrhosis resulting from chronic hepatitis has emerged as a leading cause of death among HIV-positive patients; in Europe, about 30% of HIV-positive patients are coinfected with a hepatitis virus.

8. Liver injury, reactions to prescription medications, certain autoimmune disorders, exposure to toxic substances, and repeated episodes of heart failure with liver congestion can cause cirrhosis. A family history of diseases can genetically predispose a person to develop cirrhosis.

9. Cirrhosis is the seventh leading cause of disease related death in the United States . It is twice as common in men as in women. The disease occurs in more than half of all chronic alcoholics and kills about 25,000 peoples a year. It is the third most common cause of death in adults between the ages of 45 and 65.

10. Hepatitis is the first leading cause of disease related death in the China . So far, HBsAg + peoples are about 1200 million (1, 200, 000, 000), and peoples who are infected HCV are about 38 million (38, 000, 000).

11. Types of cirrhosis Portal or nutritional cirrhosis is the form of the disease most common in the United States. About 30–50% of all cases of cirrhosis are this type. Nine out of every 10 people who have nutritional cirrhosis have a history of alcoholism . Biliary cirrhosis is caused by intrahepatic bile-duct diseases that impede bile flow. Bile is formed in the liver and is carried by ducts to the intestines. Bile then helps digest fats in the intestines. Biliary cirrhosis can scar or block these ducts. It represents 15–20% of all cirrhosis. Various types of chronic hepatitis, especially hepatitis B and hepatitis C , can cause post-necrotic cirrhosis. This form of the disease affects up to 40% of all patients who have cirrhosis.

12. Chronic hepatitis B and C Alcoholic liver disease Drugs or toxins Cardiac cirrhosis (heart failure ) Certain parasitic infections (such as schistosomiasis) Primary biliary cirrhosis Autoimmune hepatitis Primary sclerosing cholangitis Other: such as Wilson's disease , Hereditary Hemochromatosis , Alpha 1-antitrypsin deficiency , Galactosemia , Cystic fibrosis In China, the chronic hepatitis is common cause, but not the alcoholic liver disease. Risk factors of Hepatic cirrhosis

13. Worldwide Prevalence of HBV and Incidence of HCC World prevalence of HBV carriers HBsAg carriers-prevalence <2% 2–7% >8% Poorly documented Annual incidence of primary HCC Cases/100,000 population 1–3 3–10 10–150 Poorly documented WHO 2003

14. Hepatitis B Related Death in China * >85% related to HBV infection He et al. NEJM 2006 Per 100,000 person/yr 10 1.3 16.0 113 Women 8 1.7 26.7 193 Men 8 1.5 21.3 306 Total Chronic liver diseases* Rank order Percentage of total death Mortality No. of Deaths Cause of death

17. Hepatocytes necrosis Hepatocytes regenerati on F ibrotic scar tissue R egenerative nodules form Virus Alcohol Other

19. Cirrhosis of Liver Spleen Cirrhosis of Liver N odular

21. This liver is slightly enlarged and has a pale yellow appearance, seen both on the capsule and cut surface. This uniform change is consistent with fatty metamorphosis (fatty change). Here are seen the lipid vacuoles within hepatocytes. The lipid accumulates when lipoprotein transport is disrupted and/or when fatty acids accumulate. Alcohol, the most common cause, is a hepatotoxin that interferes with mitochondrial and microsomal function in hepatocytes, leading to an accumulation of lipid. Fatty Liver H&E Fatty Liver lipid vacuoles Healthy

23. Normal liver Cirrhosis after hepatitis Cirrhosis after fatty liver R egenerative nodules F ibrotic scar tissue Hepatic lobule Centre vein Fatty granule H epatic cord

24. CBDL TAA CCl4 TAA

26. Ongoing liver damage with liver cell necrosis followed by fibrosis and hepatocyte regeneration results in cirrhosis. This produces a nodular, firm liver. The nodules seen here are larger than 3 mm and, hence, this is an example of macronodular cirrhosis. This is an example of a micronodular cirrhosis. The regenerative nodules are quite small, averaging less than 3 mm in size. The most common cause for this is chronic alcoholism. The process of cirrhosis develops over many years. M acronodular cirrhosis M icronodular cirrhosis >3.0mm <3.0mm Mix is including maro- and micronodular cirrhosis Pathology

27. Clinical Manifestation Compensation Stage: The signs and symptoms of cirrhosis are nonspecific and frequently related to the complications. anemia bleeding gums constipation decreased interest in sex diarrhea dull abdominal pain dry skin and itching fatigue fever fluid in the lungs hallucinations indigestion lethargy lightheadedness loss of appetite muscle weakness musty breath nausea neuritis vomiting weakness weight loss

30. Jaundice is a condition in which a person's skin and the whites of the eyes are discolored yellow due to an increased level of bile pigments in the blood resulting from liver disease. Jaundice is sometimes called icterus, from a Greek word for the condition.

31. Many of these outward-bound chemicals are excreted into the bile. One particular substance, bilirubin, is yellow. Bilirubin is a product of the breakdown of hemoglobin, which is the protein inside red blood cells. If bilirubin cannot leave the body, it accumulates and discolors other tissues. The normal total level of bilirubin in blood serum is between 0.2 mg/dL and 1.2 mg/dL. When it rises to 3 mg/dL or higher, the person's skin and the whites of the eyes become noticeably yellow.

32. J aundice , a yellow discoloration of all tissues and organs, including the eye and the skin.

33. After liver is damaged, the hepatocytes are not able to treat estrogen , resulting in Spider nevi and Palmar erythema.

34. Spider nevi

35. Palmar erythema

36. As the liver becomes fibrotic , there is obstruction of the blood flow through the liver. This results in portal hypertension , an increase in blood pressure within the portal vein and its tributaries. The obstructed hepatic blood flow also causes congestion of the spleen , leading to a markedly enlarged spleen ( splenomegaly ). Also, most people with cirrhosis eventually develop fluid in their abdomen (ascites) and are at an increased risk of developing a spontaneous intraabdominal infection.

37. A scites

38. A scites L egs edema

39. Cirrhosis of Liver Spleen enlarges Cirrhosis of Liver

40. Portal hypertension results from the abnormal blood flow pattern in liver created by cirrhosis. The increased pressure is transmitted to collateral venous channels. Sometimes these venous collaterals are dilated. Seen here is &quot;caput medusae&quot; which consists of dilated veins seen on the abdomen of a patient with cirrhosis of the liver. A bdomen varices Esophageal varices A much more serious problem produced by portal hypertension results when submucosal veins in the esophagus become dilated. These are known as esophageal varices. Varices are seen here in the lower esophagus as linear blue dilated veins. There is hemorrhage around one of them. Such varices are easily eroded, leading to massive gastrointestinal hemorrhage

41. Esophageal varices Red spot

42. Esophageal varices

43. Gastric varices

44. Image of portal hypertensive gastropathy seen on endoscopy of the stomach. The normally smooth mucosa of the stomach has developed a mosaic like appearance, that resembles snake -skin

45. gastric antral vascular ectasia

47. Esophageal varice al bleeding

48. Hepatocellular carcinoma

49. Hepatocellular carcinoma

50. P ortal vein stenosis

51. P ortal vein thrombus

52. Lab findings Aminotransferases - AST and ALT are moderately elevated, with AST > ALT. However, normal aminotransferases do not preclude cirrhosis. Alkaline phosphatase – ( AKP )usually slightly elevated. GGT -- correlates with AP levels. Typically much higher in chronic liver disease from alcohol. Bilirubin - may elevate as cirrhosis progresses. Albumin - levels fall as the synthetic function of the liver declines with worsening cirrhosis since albumin is exclusively synthesized in the liver Prothrombin time - increases since the liver synthesizes clotting factors. Globulins - increased due to shunting of bacterial antigens away from the liver to lymphoid tissue. Serum sodium - hyponatremia due to inability to excrete free water resulting from high levels of ADH and aldosterone . Thrombocytopenia - due to both congestive splenomegaly as well as decreased thrombopoietin from the liver. However this rarely results in platelet count < 50,000/mL. Leukopenia and neutropenia - due to splenomegaly with splenic margination. Coagulation defects - the liver produces most of the coagulation factors and thus coagulopathy correlates with worsening liver disease.

53. Other laboratory studies performed in newly diagnosed cirrhosis may include: Serology for hepatitis viruses, autoantibodies ( ANA , anti-smooth muscle, anti-mitochondria , anti-LKM) Ferritin and transferrin saturation (markers of iron overload), copper and ceruloplasmin (markers of copper overload) Immunoglobulin levels (IgG, IgM, IgA) - these are non-specific but may assist in distinguishing various causes Cholesterol and glucose Alpha 1-antitrypsin

54. Imaging Ultrasound , CT and MRI are routinely used in the evaluation of cirrhosis, where it may show a small and nodular liver in advanced cirrhosis along with increased echogenicity with irregular appearing areas. Ultrasound may also screen for hepatocellular carcinoma, portal hypertension and Budd-Chiari syndrome (by assessing flow in the hepatic vein).

56. MRI A scites Hepatic cirrhosis Enlarged spleen

57. DSA DSA Portal vein

58. Laparoscope can observe hepatic regenerative nodular , and get liver biopsy sample. Cirrhosis of Liver Spleen enlarges

59. Endoscopy Gastroscopy (endoscopic examination of the esophagus, stomach and duodenum) is performed in patients with established cirrhosis to exclude the possibility of esophageal varices. If these are found, prophylactic local therapy may be applied (sclerotherapy or banding) and beta blocker treatment may be commenced.

60. Esophageal varices

61. Portal hypertensive gastropathy

62. Liver biopsy: The gold standard for diagnosis of cirrhosis is a liver biops y , through a percutaneous, transjugular, laparoscopic, or fine-needle approach. However, a biopsy is not necessary if the clinical, laboratory, and radiologic data suggests cirrhosis. Furthermore, there is a small but significant risk to liver biopsy, and cirrhosis itself predisposes for complications due to liver biopsy .

63. A patient's medical history can reveal illnesses or lifestyles likely to lead to cirrhosis. Liver changes can be seen during a physical examination. A doctor who suspects cirrhosis may order blood and urine tests to measure liver function. Because only a small number of healthy cells are needed to carry out essential liver functions, test results may be normal even when cirrhosis is present. Diagnosis

64. In about 10 out of every 100 patients, the cause of cirrhosis cannot be determined. Many people who have cirrhosis do not have any symptoms (often called compensated cirrhosis). Their disease is detected during a routine physical or when tests for an unrelated medical problem are performed. This type of cirrhosis can also be detected when complications occur (decompensated cirrhosis).

65. Computed tomography scans (CT), ultrasound, and other imaging techniques can be used during diagnosis. They can help determine the size of the liver, indicate healthy and scarred areas of the organ, and detect gallstones. Cirrhosis is sometimes diagnosed during surgery or by examining the liver with a laparoscope. This viewing device is inserted into the patient's body through a tiny incision in the abdomen.

66. Liver biopsy is usually needed to confirm a diagnosis of cirrhosis. In this procedure, a tissue sample is removed from the liver and examined under a microscope in order to learn more about the organ's condition and to properly diagnose it.

67. A newer and less invasive test involves the measurement of hyaluronic acid (HA) in the patient's blood serum. As of 2003, however, the serum HA test is most useful in monitoring the progress of liver disease; it is unlikely to completely replace liver biopsy in the diagnosis of cirrhosis.

68. Prevention Eliminating alcohol abuse could prevent 75–80% of all cases of cirrhosis. Other preventive measures include: M aintaining a healthy diet that includes whole foods and grains, vegetable, and fruits O btaining counseling or other treatment for alcoholism T aking precautions ( practicing safe sex, avoiding dirty needles ) to prevent hepatitis G etting immunizations against hepatitis if a person is in a high-risk group receiving appropriate medical treatment quickly when diagnosed with hepatitis B or hepatitis C H aving blood drawn at regular intervals to rid the body of excess iron from hemochromatosis U sing medicines (chelating agents) to rid the body of excess copper from Wilson's disease W earing protective clothing and following product directions when using toxic chemicals at work, at home, or in the garden

71. The therapy of cirrhosis is aimed primarily at preventing or reducing the complications. Bleeding esophageal varices (collateral venous channels) are a frequent serious complication of cirrhosis. Various techniques are used to control the bleeding. In some individuals with severe portal hypertension , vascular shunts are made to reduce the pressure in the portal vein by bypassing the liver. Most frequently the portal vein is surgically connected to the inferior vena cava so that some of the blood in the portal vein does not pass through the liver. Treatment

74. Ref: De Franchis R. Digestive and liver disease 2004;36(S1):S93 Endoscopic sclerotherapy (EST) is an established method for controlling and preventing bleeding from oesophageal varices

75. Endoscopic sclerotherapy (EST)

76. AT Injection

77. P ortal hypertension Portal vein V ena cava

78. Distal Splenorenal Shunt

79. Harvard University

80. Harvard University

81. Harvard University

82. Harvard Medical School

83. The Third Affiliated Hospital Sun Yat-Sen University

84. Position Open Postdoctoral Fellow Ph.D. Program Master’s Program

85. Thank you