Cirrhosis of the Liver.pptx..............

Liver cirrhosis

1. Cirrhosis of the Liver

2. Introduction Diffuse process of fibrosis that converts the liver architecture into structurally abnormal nodules. T he process follows or is accompanied by hepatocellular necrosis. Hepato -cellular necrosis can heal in one of two ways:- complete regeneration and restitution of normal architecture or replacement by collagen , leading to fibrosis, as in cirrhosis.

3. Focal conditions like focal nodular hyperplasia need to be differentiated from the diffuse nodular process in cirrhosis. Congenital hepatic fibrosis includes fibrosis and nodules, but the lobular architecture is maintained within the nodules.

4. CLASSIFICATION Morphologically, cirrhosis is classified as :- Micronodular :- Nodules are < 3 mm in diameter and are surrounded by thick fibrous septa. Liver is usually normal in size or enlarged .

5. 2. Macronodular :- Nodules are more variable in size, with many being >3 mm in diameter, some up to several centimetres . L iver size is usually reduced. 3. Mixed nodular :- - M icro- and macronodules are present in almost equal numbers.

6. AETIOLOGY Commonest causes of cirrhosis worldwide are alcohol abuse and viral hepatitis (B and C ). In India, alcohol abuse accounts for more than 50% of cases. Hepatitis B accounts for 30% of cases, with hepatitis C following in frequency . About 30% of alcoholics also have markers of hepatitis virus infection.

7. Adult Of patients exposed to hepatitis B, about 5% develop chronic hepatitis B, and about 20% of those patients will go on to develop cirrhosis . Hepatitis C virus (HCV), approximately 80% develop chronic hepatitis C, and of those, about 20–30% will develop cirrhosis over 20–30 years.

8. 40–80 g/d of ethanol produces fatty liver; 160 g/d for 10–20 years causes hepatitis or cirrhosis. Only 15% of alcoholics develop alcoholic liver disease. Women exhibit increased susceptibility to alcoholic liver disease at amounts >20 g/d. HCV infection concurrent with alcoholic liver disease is associated with younger age for severity, more advanced histology, decreased survival.

9. Causes of Cirrhosis Metabolic disorders Wilson’s disease* Haemochromatosis Alpha-1 antitrypsin deficiency Cystic fibrosis Glycogen storage diseases Galactosaemia

10. Autoimmune hepatitis Venous outflow obstruction Budd- Chiari syndrome Veno -occlusive disease Cardiac failure

11. Biliary obstruction Primary sclerosing cholangitis Primary biliary cirrhosis

12. Unknown causes Cryptogenic cirrhosis* (increasingly attributed to non-alcoholic steatohepatitis ) Indian childhood cirrhosis (infrequently reported now) Sarcoidosis, Sjögren’s syndrome, scleroderma, psoriasis, sickle cell disease. Drugs Methotrexate, oxyphenisatin

13. Malnutrition and mycotoxins (especially aflatoxin ) may initiate or aggravate cirrhosis

14. PATHOLOGY AND PATHOGENESIS The major pathways leading to cirrhosis are :- Hepatitis Fatty liver Portal and centrilobular fibrosis

15. Hepatitis Lobular hepato -cellular necrosis and central-portal bridging necrosis with fibrosis are important routes; piecemeal necrosis of hepatocytes may also be important. These changes of chronic hepatitis occur in viral hepatitis and in several other causes of cirrhosis .

16. Fatty liver Ballooned hepatocytes containing Mallory bodies and macrovesicular fat deposits, surrounded by neutrophils and lymphocytes and collagen deposits, is the predominant route in alcoholics . Severe steatohepatitis may lead to fibrous septa, which contract and accentuate the architectural distortion caused by necrosis . A similar picture is seen in non-alcoholic steatohepatitis .

17. Portal and centrilobular fibrosis Bile duct disease causes cirrhosis by initiating fibrosis in the portal tracts, with linking of these tracts ultimately. A similar process of fibrosis sets in the centrilobular area in patients with venous outflow obstruction . The end-result of all these pathways is fibrosis and scarring with distortion of the architecture.

18. Intrahepatic portal-systemic shunting of blood is a consequence of the necrotic bridges . Portal hypertension follows collagen deposition in the space of Disse and compression of the vasculature by regenerative nodules, fibrosis and hepatocyte enlargement.

19. Pathogenesis of Alcoholic Cirrhosis Ethanol is mainly absorbed by the small intestine. Majority of ethanol oxidation occurs via ADH to form acetaldehyde , which is a highly reactive molecule that may have multiple effects. Ultimately, acetaldehyde is metabolized to acetate by aldehyde dehydrogenase (ALDH).

20. Intake of ethanol increases intracellular accumulation of triglycerides by increasing fatty acid uptake and by reducing fatty acid oxidation and lipoprotein secretion . Oxidative damage to hepatocyte membranes occurs due to the formation of reactive oxygen species; acetaldehyde is a highly reactive molecule that combines with proteins to form protein-acetaldehyde adducts.

21. With acetaldehyde-mediated hepatocyte damage, certain reactive oxygen species can result in Kupffer cell activation . As a result, profibrogenic cytokines are produced that initiate and perpetuate stellate cell activation , with the resultant production of excess collagen and extracellular matrix .

22. Connective tissue appears in both periportal and pericentral zones and eventually connects portal triads with central veins forming regenerative nodules. Hepatocyte loss occurs, and with increased collagen production and deposition, the liver contracts and shrinks in size.

23. CLINICAL FEATURES 1/3 rd of patients with cirrhosis are asymptomatic because just 10% of the liver cell mass is adequate to maintain metabolic functions. Weakness and fatigability. W eight loss may be masked by fluid retention.

24. Clinical Features of Hepatocellular Failure Jaundice Foetor hepaticus Parotid enlargement Spider naevi , bruises and purpura Loss of axillary and pubic hairs Breast atrophy, gynaecomastia /testicular atrophy Dupuytren’s contracture, flaps, white nails with clubbing Pedal oedema

25. Spider angiomas ( naevi ) and palmar erythema are seen in alcoholics . The naevi consist of a central arteriole with radiating capillaries ; pressure on the arteriole with a pinhead obliterates the naevus . Such naevi vary in size from a few millimetres to a centimetre , are found commonly on the face, chest and upper Limbs.

26. They can also be found uncommonly in normal subjects, especially in pregnancy, in rheumatoid arthritis and in patients on oestrogen therapy. Palmar erythema appears as reddening of the thenar and hypothenar eminences and finger pulp, with sparing of the rest of the palm.

27. Gynaecomastia in men is believed to be due to increased conversion of androgens into oestrogens in the peripheral tissues; spironolactone therapy can also induce gynaecomastia . Hypogonadism manifests in men by testicular atrophy and loss of libido, especially in alcoholics, and in women by oligomenorrhoea or amenorrhoea . Infertility is common in both sexes.

28. Anaemia in cirrhosis is due to several factors: nutritional iron or folate deficiency, blood loss, bone marrow hypofunction , hypersplenism , and haemolysis . Impaired coagulation due to decrease in the synthesis of coagulation factors in the liver, disseminated intravascular coagulopathy, and thrombocytopaenia secondary to hypersplenism may manifest with ecchymosis , purpura or gingival haemorrhage .

29. Low-grade fever, white opaque nails, clubbing of nails, Dupuytren’s contracture (in alcoholics), cyanosis (central and peripheral), and foetor hepaticus ( ammonical smell of breath in hepatic encephalopathy ) are infrequent manifestations. The Kayser - Fleischer corneal ring should be looked for in all young cirrhotics , in whom Wilson’s disease should be suspected.

30. The other major manifestations in decompensated cirrhosis are features of hepatocellular failure and portal hypertension, viz. jaundice , ascites and hepatic hydrothorax, gastrointestinal ( GI) bleeding , and encephalopathy. Jaundice is usually due to failure of hepatocytes to excrete bilirubin, with resulting conjugated hyperbilirubinaemia .

31. Ascites is frequently associated with oedema of the feet. Distension of abdomen, anorexia and fullness after small meals U mbilical or inguinal hernia may be the present. Ascites is a sequel of portal hypertension (high hydrostatic pressure), along with decreased serum albumin levels (low osmotic pressure) due to low functional hepatocyte mass. Both hepatic and splanchnic lymph spillover may contribute to its formation.

32. On examination, the abdomen is distended with bulging of the flanks. The abdominal wall is thin due to loss of subcutaneous fat and muscle mass . Veins in the wall may therefore appear prominent and should be distinguished from the dilated veins of intrahepatic portal hypertension and inferior vena cava block. Dilated veins radiating from the umbilicus (caput medusa).

33. The puddle sign around the umbilicus can detect small amounts of fluid. Flank dullness (indicating at least 1500 mL of fluid) and shifting dullness are other signs in ascites. A fluid thrill can be elicited when the abdomen is tense. Tense ascites is diagnosed when organomegaly cannot be detected despite deep palpation. About 5% to 10% of patients with ascites have pleural effusion (‘ hepatic hydrothorax ’), on the right side in about 70% of them. The fluid is drawn up through defects in the diaphragm by the negative intrathoracic pressure.

34. The most common source of upper GI haemorrhage in cirrhosis is oesophageal varices , which are collateral vessels decompressing the portal hypertension . Portal hypertensive (‘congestive ’) gastropathy , gastric antral vascular ectasias , gastric erosions and peptic ulcers are other potential sites of bleed in cirrhosis .

35. Hepatic encephalopathy may occur spontaneously due to poor hepatocyte function and portal- systemic shunting, or may be precipitated by various factors.

36. Precipitating Factors for Hepatic Encephalopathy High-protein diet Constipation GI bleeding Infection, including spontaneous bacterial peritonitis Excessive diuretics causing hyponatraemia , hypokalaemia , renal failure Sedatives and hypnotics Interventional procedures

37. Ammonia is the best- characterised neurotoxin in the spontaneous cases; mercaptans and phenolic compounds are others . Gamma aminobutyric acid (GABA), the most important inhibitory neurotransmitter , is activated.

38. D epletion of glutamate, the most important excitatory neurotransmitter. Decrease in concentrations of the branched chain amino acids ( valine , leucine and isoleucine) as a consequence of increased levels of aromatic amino acids has also been implicated as a mechanism.

39. INVESTIGATIONS Among biochemical investigations , decreased serum albumin level and increased serum globulin may be the only abnormalities . An AST:ALT ratio >1 in patients with chronic viral hepatitis and non-alcoholic fatty liver disease may suggest the presence of cirrhosis, particularly if associated with low platelet count . In alcoholic liver disease, the ratio is >2 even in the absence of cirrhosis.

40. Elevated gammaglutamyl transferase is suggestive of alcohol abuse. Serum alkaline phosphatase is elevated markedly in patients with biliary cirrhosis or sclerosing cholangitis.

41. Tests for hepatitis B and C viruses; autoantibodies; serum copper and ceruloplasmin and urinary copper; serum iron and transferrin ; and alpha-1 antitrypsin levels should be undertaken based on the clinical suspicion of aetiology of the disease . Tests for serum ammonia.

42. Imaging techniques useful in the diagnosis and evaluation of cirrhosis include ultrasonography, CT scan, radionuclide scan and MRI. Radionuclide scan can reliably differentiate cirrhosis from non-cirrhotic portal hypertension.

43. Endoscopy is performed to detect oesophageal varices ( a reliable sign of portal hypertension) and other potential sites of bleeding. When indicated, endoscopic therapeutic measures can be instituted.

44. Ascitic fluid paracentesis is done to determine the characteristics of the fluid . In most of the uncomplicated cases, the fluid has low protein concentration (<2.5 g/ dL ) and few cells. A high protein level may be seen in patients on diuretics . Serum ascites albumin gradient ( SAAG) of >1.1 g/ dL is highly specific for ascites due to portal hypertension , even in the presence of complicating factors .

45. A high ascitic fluid polymorphonuclear cell count (> 250/mm3) suggests spontaneous bacterial peritonitis . Fluid adenosine deaminase levels (in tuberculous peritonitis ), amylase levels (in pancreatic ascites), and cytology ( in malignant ascites) should be tested when clinical suspicion exists.

46. Liver biopsy is the most reliable test for the diagnosis of cirrhosis but is not required if other evidence is available. If an additional focal lesion, like hepato -cellular carcinoma, is suspected, imaging-guided biopsy is indicated.

47. MANAGEMENT There is as yet no specific treatment for cirrhosis. Increasing evidence suggests though that the fibrosis in cirrhosis may be reversible , especially when specific therapy is available for the aetiology . Liver transplantation is the only definitive treatment for advanced disease.

48. A balanced diet with 1 gram protein and 30 kcal per kg bodyweight per day must be ensured; malnourished patients may need more protein. No item of diet (except salt in the salt-retaining state) needs to be restricted. Alcohol should be avoided even in non-alcoholic cirrhosis.

49. Hepatoprotective agents like ursodeoxycholic acid (UDCA ), silymarin , and phosphatidyl choline have given variable results. Colchicine has been used with some benefit in primary biliary cirrhosis and as an anti-fibrotic agent.

50. Some causes of cirrhosis have specific therapy available; for example:- antiviral agents in cirrhosis with activity due to hepatitis B and C , D- penicillamine or zinc therapy in Wilson’s disease , iron chelation and phlebotomy in haemochromatosis , corticosteroids and immunosuppressants in autoimmune disease .

51. Ascites Bed rest and sodium restriction. Restriction of sodium intake in diet to 2-3 grams (40-60 mEq ) per day. Fluid intake is restricted only in those with hyponatraemia .

52. The aldosterone antagonist spironolactone has a weaker natriuretic effect than loop diuretics but counters the secondary hyperaldosteronism in these patients. Low doses (100 to 150 mg per day) are effective in most cases but higher doses may be required in those with marked hyperaldosteronism . Simultaneous administration of the loop diuretics frusemide or torsamide increases the natriuretic effect of both drugs and reduces the risk of potassium imbalance. The goal of diuretic therapy should generally be to achieve a weight loss of 0.5 kg a day in patients without peripheral oedema and up to 1 kg a day in those with oedema .

53. Hyponatraemia is a common complication of diuretic therapy. Approximately 20% of patients develop azotaemia due to intravascular volume depletion. These , along with the hypokalaemia complicating frusemide therapy, contribute to the precipitation of hepatic encephalopathy.

54. Ascites refractory to diuretics can be managed by one of the following modalities:- Therapeutic paracentesis ( large-volume or total paracentesis with intravenous infusion of plasma expanders like human albumin or colloids); P lacement of transjugular intrahepatic porto -systemic shunt (TIPSS); Insertion of a peritoneovenous shunt ( LeVeen shunt or equivalent); or portacaval shunt.

55. Portal Hypertension Portal hypertension is the most common and lethal complication of cirrhosis. It is defined as clinically significant by an increase in the portal pressure gradient above 10 mm Hg (for formation of varices ) or 12 mm Hg (for variceal bleeding, ascites). Varices develop in most patients during long-term follow-up.

56. Endoscopic band ligation is the preferred mode of treatment for bleeding oesophageal varices ; I njection sclerotherapy is done if band ligation is technically difficult.

57. Drugs used to treat portal hypertension are usually vasoconstrictors, and include vasopressin, terlipressin , somatostatin , propranolol. Failure of medical and endoscopic treatment can be managed by placement of a transjugular intrahepatic portosystemic shunt (TIPS) .

58. Hepatic Encephalopathy Most precipitating events for encephalopathy are correctable with appropriate therapy. Thus , fluid, electrolyte and glucose levels must be monitored and corrected where indicated; diuretic therapy may have to be discontinued, if it contributes to the imbalance . A search should be made for a focus of infection , which in most cases is either spontaneous bacterial peritonitis or urinary or lower respiratory infection .

59. If GI haemorrhage is present, appropriate therapy should be instituted, as this will also reduce the intestinal protein load. All medication with sedative effect should be discontinued.

60. Dietary protein should be restricted initially to 0.5 g per kg body weight . Vegetable proteins are safer than animal proteins. Protein overload should be avoided.

61. To reduce intestinal ammonia load, the colon should be cleansed with acidifying solutions like lactulose; enema is ineffective . Ammoniagenic bacteria should be eliminated with antibiotics; rifaximin is the current choice.

62. COMPLICATIONS Portal hypertension - Gastroesophageal varices -   Portal hypertensive gastropathy Splenomegaly , hypersplenism    Ascites   Spontaneous bacterial peritonitis Hepatorenal syndrome

63. Hepatic encephalopathy Hepatopulmonary syndrome Portopulmonary hypertension Malnutrition Coagulopathy     Factor deficiency     Fibrinolysis     Thrombocytopenia

64. Bone disease     Osteopenia     Osteoporosis      Osteomalacia Hematologic abnormalities     Anemia     Hemolysis     Thrombocytopenia     Neutropenia

65. The risk of developing this complication in patients with ascites is estimated at 30% and 40% at 2 and 5 years , respectively. The renal failure is secondary to alterations in systemic haemodynamics and renal perfusion; the kidneys themselves are otherwise normal. The most serious clinical type (‘ hepatorenal syndrome’) is characterised by a rapid rise in blood urea and serum creatinine , progressive oliguria, dilutional hyponatraemia and hyperkalaemia . Most patients have tense ascites . Early institution of terlipressin and albumin infusion may help arrest this otherwise fatal development.

66. Spontaneous bacterial peritonitis is an infection of low-protein ascitic fluid by organisms translocated from the alimentary tract. The infection is usually monomicrobial , unlike in secondary bacterial peritonitis.

67. Portal vein thrombosis can complicate cirrhosis. Hepatocellular carcinoma develops in 10% to 25% of patients with liver cirrhosis depending on the cause and survival duration. The risk is much higher in patients with hepatitis B or C infection. The hepatopulmonary syndrome and portopulmonary hypertension are two dreaded complications of cirrhosis for which therapy (short of liver transplantation) is presently unsatisfactory

68. PROGNOSIS C ompensated cirrhosis become decompensated at the rate of approximately 10% per year. Five year survival in compensated and decompensated cirrhosis is about 50% and 20%, respectively . Ascites is usually the first sign of decompensation . Among those with ascites, presence of tense ascites or functional renal failure carries a grave prognosis.

69. Child- Turcotte -Pugh Grading of Severity of Liver Disease useful in determining prognosis. M ore accurate Model for endstage liver disease (MELD) score has been used to predict survival as well as to determine priority for liver transplantation . The MELD score is calculated using the equation: 3.8 x log (e ) ( bilirubin mg/dL) + 11.2 x log (e) (INR) + 9.6 log (e) ( creatinine mg/ dL ). Scores range from 6 (least ill patient) to 40 (sickest patient).