1. Hepatic Cirrhosis （肝硬化） Yu Baoping

2. Introduction CIRRHOSIS  Term was 1st coined by Laennec in 1826  Many definitions but common theme is injury, repair, regeneration and scarring  NOT a localized process; involves entire liver  Primary histologic features: 1.Marked fibrosis 2.Destruction of vascular & biliary elements 3.Regeneration 4.Nodule formation

3. Definition  Cirrhosis is a pathological diagnosis. It is characterized by widespread fibrosis with nodular regeneration. Its presence implies previous or continuing hepatic cell damage

6. Aetiology and Pathogenesis

7. Etiologic classification of cirrhosis  Alcohol (>70%)  Chronic infections hepatitis C, B, B+D hepatitis C, B, B+D brucellosis, syphilis brucellosis, syphilis  Chr. biliary obstruction PBC, PSC, stricture, PBC, PSC, stricture, stones, cystic fibrosis, cong.b. atresia, ~cysts stones, cystic fibrosis, cong.b. atresia, ~cysts  Autoimmune  Cardiovascular heart failure, pericarditis, heart failure, pericarditis, Budd-Chiary-sy Budd-Chiary-sy  Metabolic/genetic errors Fe, Cu, α 1 -AT, lipids, Fe, Cu, α 1 -AT, lipids,  Drugs and chemicals  NASH  Cryptogenic  Combined

8. Pathogenesis:  Diffuse liver injury leading to necrosis.  (Alcohol, virus, drugs, toxins, genetic etc.)  Chronic inflammation & healing (hepatitis).  Bridging fibrosis – loss of architecture.  Regeneration  nodules.  Obstruction to blood flow & shunts.  Portal hypertension  spleen, varices  Liver failure – Debilitation, Jaundice, Ascitis, edema, bleeding, jaundice.  Hormone imbalance – spider nevi, testes atrophy etc..

9. Pathology and Pathophysiology

10. Pathology （ liver ）

11. Classification of Cirrhosis  WHO divided cirrhosis into 3 categories based on morphological characteristics of the hepatic nodules 1.Micronodular 2.Macronodular 3.Mixed

12. Micronodular Cirrhosis  Nodules are <3 mm in diameter  Relatively uniform in size  Distributed throughout the liver  Rarely contain portal tracts or efferent veins  Liver is of uniform size or mildly enlarged  Reflect relatively early disease

13. Micronodular cirrhosis

14. Macronodular & Mixed Cirrhosis  Nodules are >3 mm in diameter and vary considerably in size  Usually contain portal tracts and efferent veins  Liver is usually normal or reduced in size  Mixed pattern if both type of nodules are present in equal proportions

15. Macronodular cirrhosis

16. Cirrhosis Fibrosis Regenerating Nodule

17. Pathology （ splenomegaly ）

18. Pathology （） Pathology （ others ）   gastrointestinal tract ， varicose veins ， hemorrhage ， congestion   Kidney glomerulonephritis   Endocrine muscular atrophy ， degeneration （ testis ， ovary ， thyroid ， adrenal cortex ）

19. Cirrhosis: Pathophysiology  Primary event is injury to hepatocellular elements  Triggering inflammatory response with cytokine release-toxic substances  Destruction of hepatocytes, bile duct cells, vascular endothelial cells  Repair thru cellular proliferation and regeneration  Formation of fibrous scar

20. Cirrhosis: Pathophysiology  Stellate cell is activated in response to injury and lead to expression of fibril-forming collagen  Above process is also influenced by Kupffer cells which activate stellate cells by eliciting production of cytokines  Sinusoidal fenestrations are obliterated because of collagen

21. Cirrhosis: Pathophysiology  Prevents normal flow of nutrients to hepatocytes and increases vascular resistance  Initially, fibrosis may be reversible if inciting events are removed  With sustained injury, process of fibrosis becomes irreversible and leads to cirrhosis

22. Pathophysiology Protal hypertension Ascitesendocrine respiratory systemhepatic hydrothorax respiratory system hepatic hydrothorax hepatopulmonary syndrome hepatopulmonary syndrome the urinary system : hepatorenal syndrom, HRS hematological system nervous system : HE

23. Portal Hypertension (PH)  Portal vein pressure above the normal range of 5 to 8 mm Hg  Portal vein - Hepatic vein pressure gradient greater than 5 mm Hg (>12 clinically significant)  Represents an increase of the hydrostatic pressure within the portal vein or its tributaries

24. Pathophysiology of PH  Cirrhosis results in scarring (perisinusoidal deposition of collagen)  Scarring narrows and compresses hepatic sinusoids (fibrosis)  Portal vein thrombosis, or hepatic venous obstruction also cause PH by increasing the resistance to portal blood flow  Progressive increase in resistance to portal venous blood flow results in PH

25. Pathophysiology of PH  As pressure increases, blood flow decreases and the pressure in the portal system is transmitted to its branches  Results in dilation of venous tributaries  Increased blood flow through collaterals and subsequently increased venous return cause an increase in cardiac output and total blood volume and a decrease in systemic vascular resistance  With progression of disease, blood pressure usually falls

26. Portal Vein Collaterals  Coronary vein and short gastric veins -> veins of the lesser curve of the stomach and the esophagus, leading to the formation of varices  Inferior mesenteric vein -> rectal branches which, when distended, form hemorrhoids  Umbilical vein ->epigastric venous system around the umbilicus (caput medusae)  Retroperitoneal collaterals ->gastrointestinal veins through the bare areas of the liver

28. Ascites  Sodium and water retention occur due to renin- angiotensin release secondary to arterial vasodilatation, caused by vasoactive substances such as nitric oxide  Portal hypertension per se causes fluid to accumulate in the peritoneal cavity due to increased hydrostatic pressure, hence further reduces intravascular volume and stimulates sodium and water retention via aldosterone.  Low albumin in plasma

29. Clinical presentation

30.  There may be no abnormal clinical or biochemical features of liver disease in initial times  Features of hepatocellular failure, portal hypertension, or both may appear in advanced times.

31. Cirrhosis Clinical Features

32. Symptoms of advanced cirrhosis  Fatique, weakness  Nausea, vomiting and loss of appetite  Weight loss, muscle wasting  Jaundice, dark urine  Spider naevi, caput Medusae  Bloody, black stools or unusually light- colored stools  Vomiting of blood  Abdominal swelling  Swollen feet or legs  Liver palms  Gynecomastia  Loss of sex drive  Menstrual changes in women  Generalized itching  Sleep disturbances, confusion,desorientat ion, tremor, asterixis

33. Clinical Features  Hepatocellular failure.  Malnutrition, low albumin & clotting factors, bleeding.  Hepatic encephalopathy.  Portal hypertension.  Ascites, Porta systemic shunts, varices, splenomegaly.

34. Gynecomastia Ascites Caput Medusae Umbilical hernia Visible signs of advanced liver cirrhosis

38. Complications

39. Complications  Upper gastrointestinal hemorrhage  Hepatic encephalopathy  Infection  Hepatorenal syndrome  Hepatopulmonary Syndrome  Primary carcinoma of the liver  Disturbance of electrolyte and acid-base balance

40. Laboratory tests and investigations

41. laboratory tests and investigations  Blood-RT anaemia ； hypersplenia:WBC ， Plt anaemia ； hypersplenia:WBC ， Plt  Urine-RT urine bilirubin ， urobilinogen ； sometimes albumen ， haematuria  Stool-RT melena

42. laboratory tests and investigations liver function tests   Compensation normal or abnormal slightly   Decompensation transaminase ： ALT AST cholesterol cholesterol albumin and globulin albumin and globulin prothrombin time prothrombin time bilirubin bilirubin P Ⅲ P, and so on P Ⅲ P, and so on Quantitation- liver function tests IGG

43. laboratory tests and investigations  Biochemistry can be surprisingly normal but some abnormality will often be present with slightly raised transaminases and alkaline phosphatases. In severe cases, all live enzymes will be abnormal. Low sodium and albumin are also seen.  Coagulopathy is a very sensitive indicator of liver dysfunction and is reflected in the prolonged prothrombin time.

44. laboratory tests and investigations   immunologic function test AFP virus hepatitis markers antinuclear antibody, ANA non-specificity antismooth muscle antibody autoantibody anti-mitochondrial antibody

45. laboratory tests and investigations  Imaging examination Barium meal Barium meal CT or MRI CT or MRI Ultrasound demonstrates fatty change, size, and Ultrasound demonstrates fatty change, size, and fibrosis as well as hepatocellular carcinoma fibrosis as well as hepatocellular carcinoma

46. laboratory tests and investigations

48. MRI Cirrhosis laboratory tests and investigations

49. Special test   Endoscope   Biopsy   Laparoscope   Hydroperitoneum test   Measure the Pressure of Portal Vein

51. Diagnosis and differential diagnosis

52. Diagnosis of liver cirrhosis  The gold standard: liver biopsy histology  Diffuse, chronic liver disease (hystory, physical, laboratory and US findings)  with evidences of portal hypertension (oesophageal varices on gastroscopy; dilated portal vein and its branches by US)

53. Child-Pugh’s classification Categories Classification Points 123 EncephalopathyNone Grade I & II Grade III & IV AscitesAbsentSlight-moderateTense Bilirubin (mg/dl) <2 (4) 2-3 (4-10) >3 (>10) Albumin (g/dl) >3.52.8-3.5<2.8 Prothrombin Time 1-44-6>6 Grade A: 5-6 Grade B: 7-9 Grade C: 10-15

54. Differential diagnosis  Liver diseases chronic hepatitis ； primary carcinoma of the liver ； schistosomiasis ； clonorchiasis sinensis ； hepatic hydatidosis ； hemopathy chronic hepatitis ； primary carcinoma of the liver ； schistosomiasis ； clonorchiasis sinensis ； hepatic hydatidosis ； hemopathy  Ascites and abdomen enlarged tuberculous peritonitis ； constrictive pericardium ； chronic glomerulonephritis ； ovarian cysts tuberculous peritonitis ； constrictive pericardium ； chronic glomerulonephritis ； ovarian cysts  Complications Upper gastrointestinal hemorrhage ； Infection ； Hepatic encephalopathy ； Hepatorenal syndrome ； Hepatopulmonary Syndrome ； Primary carcinoma of the liver Upper gastrointestinal hemorrhage ； Infection ； Hepatic encephalopathy ； Hepatorenal syndrome ； Hepatopulmonary Syndrome ； Primary carcinoma of the liver

55. Treatment

56. Treatment of liver cirrhosis  Removal of the etiological factors can stop or delay further progression may lead to regression may reduce complications  Prevention and treatment and of complications

57. Cirrhotic ascites  Rest   Diet  Treatment: bed rest, salt restriction,  Water immersion  diuretics: spironolactone, furosemide; under regular check-up (body wt, electrolyites, renal function) Refractory ascites:  large-volume paracentesis TIPS  peritoneovenous shunting

58. Complications  Spontaneos bacterial peritonitis (SBP): fever, sepsis, hypotension, fast deteoriation of liver function, azotaemia, encephalopathy, death Dg.: PMN count in the ascites > 250/μl; culture Th.: antibiotics; paracentesis  Hepatorenal syndrome: renal failure with severe liver disease without an intrinsic abnormality of the kidney Cause: reduction in RBF, GFR (vasoconstrictors!) Dg.: urine Na < 10 mM, oliguria without volume depletion Th.: prevention of hypovolemia, hypotension terlipressin; TIPS  Prognosis: lethal if the liver disease is untreatable

59. Bleeding oesophageal and gastric varices  Features: hematemesis, melena, shock  Dg. and treatment: stabilizing BP, replacing fluid and blood, somatostatin  endoscopic sclerotherapy or ligation or balloon tamponade; eradication of varices; TIPS, P-C shunting  Prevention: propranolol  Liver transplantation

60. Prognosis  Prognosis

62. "With ordinary talent and extraordinary perseverance, all things are attainable." - Thomas E. Buxton "Achievement is connected with action…..!” - Conrad Hilton