Etiology of liver cirrhosis

Transcription

1 Liver cirrhosis 1

2 Liver cirrhosis Liver cirrhosis is the progressive replacement of normal hepatic cells by fibrous scar tissue, This scarring is accompanied by the loss of viable hepatocytes, which are the functional cells of the liver. Progressive cirrhosis is irreversible and leads to portal hypertension with consequent complications of advanced liver disease. These consequences include (but are not limited to): 1- Ascites 2- Hepatic encephalopathy. 3- Variceal bleeding. 2

3 Etiology of liver cirrhosis 1. Chronic alcohol consumption. 2. Chronic viral hepatitis ( types B, C and D) 3. Metabolic and genetic disorders Hemochromatosis (Iron overload) Wilson's disease, Alpha-1 anti-trypsin deficiency. Gilbert's syndrome 4- Non alcoholic fatty liver disease 3

4 5- Immune disorders Autoimmune hepatitis (AIH) Primary biliary cirrhosis (PBC) Primary sclerosing cholangitis (PSC) 5- Vascular abnormalities - Budd Chiari syndrome (BCS) 6- Cryptogenic 10% 7- Sever congestive heart failure. 8- Drugs 4

5 Portal Hypertension Pathophysiology The portal vein is a blood vessel that carries blood from the small intestine, stomach, pancreas, and spleen into the liver. Portal hypertension is a consequence of increase resistance to blood flow through the portal vein due to Sinusoidal damage Pre-sinusoidal damage such as portal vein occlusion from trauma, malignancy, or thrombosis. Outflow obstruction of the hepatic vein. Sinusoidal damage from cirrhosis is the most common cause of portal hypertension. 5

6 Fibrosis and regenerative nodules of scar tissue modify the basic architecture of the liver, disrupting blood flow and liver function. Reduced hepatic blood flow alters normal metabolic breakdown processes and decreases protein synthesis within the liver. In cirrhosis, bilirubin (from the enzymatic breakdown of heme) can accumulate; this causes jaundice (yellowing of the skin), scleral icterus (yellowing of the sclera), and tea-colored urine (urinary bilirubin excretion). Changes in steroidal hormone production, conversion, and handling are also prominent features of cirrhosis. These changes can result in decreased libido, gynecomastia (development of breast tissue in men), testicular atrophy, and features of feminization in male patients. 6

7 Increased intra-hepatic resistance to portal flow increases pressure on the entire splanchnic An enlarged spleen (splenomegaly) is a common finding in cirrhotic patient and can result in thrombocytopenia due to splenic sequestration of the platelets. Portal hypertension mediates systemic and splanchnic arterial vasodilation through production of nitric oxide and other vasodilators in an attempt to counteract the increased pressure gradient. Nitric oxide causes a fall in systemic arterial pressure; unfortunately, this activates both the renninangiotensin-aldosterone and sympathetic nervous systems and increases anti-diuretic hormone (vasopressin) production. 7

8 The activation of these systems is an attempt to maintain arterial blood pressure through increases in renal sodium and water retention. Increased systemic and portal pressure put increased pressure on the vascular system. The aim of pharmacologic treatment in portal hypertension is to decrease portal pressure and reduce the effects of sympathetic activation. 8

9 Ascites Ascites is the accumulation of fluid within the abdominal cavity. The precise mechanism by which ascites develops in chronic liver disease is unclear, but the following are all thought to contribute: Activation of the renin angiotensin aldosterone axis A reduction in serum albumin and reduced oncotic pressure. Portal hypertension and splanchnic arterial vasodilation alters intestinal capillary pressure and permeability and so facilitates the accumulation of retained fluid in the abdominal cavity.

10 Oesophageal varices The increased pressure in the portal venous system leads to collateral vein formation and shunting of blood to the systemic circulation. Varices are weak superficial vessels, and any additional increase in pressure can cause these vessels to rupture and bleed. 10

11 Spontaneous Bacterial Peritonitis Spontaneous bacterial peritonitis (SBP) is an acute bacterial infection of peritoneal fluid in the absence of intraabdominal infection or intestinal perforation. Enteric gram-negative aerobes are the most common bacteria isolated from ascitic fluid; usually Escherichia coli or Klebsiella pneumoniae. Streptococcus pneumoniae is the most common grampositive pathogen associated with SBP. 11

12 Hepatic Encephalopathy In severe hepatic disease, systemic circulation bypasses the liver, so many of the substances normally metabolized by the liver remain in the systemic circulation and accumulate to toxic levels. In excess, these metabolic by-products, especially nitrogenous waste, cause alterations in central nervous system functioning. Ammonia (NH3) is just one of the toxins implicated in HE. It is a metabolic by-product of protein catabolism and is also generated by bacteria in the GI tract.in a normally functioning liver, hepatocytes take up ammonia and degrade it to form urea, which is then renally excreted. 12

13 In patients with cirrhosis, the conversion of ammonia to urea is retarded and ammonia accumulates, resulting in encephalopathy. This decrease in urea formation is manifest on laboratory assessment as decreased blood urea nitrogen (BUN).. 13

14 Coagulation defects The liver synthesis coagulation factors essential for blood clotting and maintenance of blood homeostasis. With advanced disease the liver is unable to synthesize these proteins, resulting in extended clotting times (e.g., prothrombin time) and bleeding abnormalities. An additional coagulation abnormality seen in advanced liver disease is thrombocytopenia. This is a result of decreased platelet production and splenic sequestration of platelets. 14

15 Clinical presentation of cirrhosis Patients with cirrhosis may exhibit nonspecific symptoms such as fatigue and weakness but may be asymptomatic until acute complications develop. Nonspecific symptoms include anorexia, fatigue, easy bruising and bleeding from minor injuries, decreased libido, and pruritus. Patients with ascites may complain of abdominal pain, nausea, increasing tightness and fullness in the abdomen, shortness of breath. Hemorrhage associated with variceal bleeding may be associated with nausea, vomiting, and hematemesis. Patients may also present with fatigue, and weakness from blood loss. if SBP occurs, symptoms of infection may include fever, chills, 15 and abdominal pain.

16 Nonspecific signs on physical exam include jaundice, tea colored urine, bruising, hepatomegaly, splenomegaly, palmar erythema, gynecomastia and testicular atrophy. Markers of hepatic encephalopathy include decreased cognition, confusion, changes in behavior, and asterixis. 16

17 Laboratory Abnormalities includes Hypoalbuminemia Elevated prothrombin time Thrombocytopenia Elevated alkaline phosphatase Elevated ALT, AST. 17

18 Ultrasound examination is used routinely to evaluate liver cirrhosis liver biopsy is the only way to diagnose cirrhosis definitively. 18

19 Treatment Non-pharmacologic treatment: Lifestyle modifications can limit disease complications and slow further liver damage. Immediate cessation of alcohol consumption. All patients with ascites require counseling on dietary sodium restriction. Medication use must be monitored carefully for potential hepatotoxicity. Hepatically metabolized medications have the potential to accumulate in patients with liver disease. In patients with variceal bleeding, nasogastric suction reduces the risk of aspirating stomach contents. Nasogastric suction is helpful in decreasing vomiting during acute episodes of variceal bleeding. Blood within the gastrointestinal tract is very nauseating; removal of the blood can decrease vomiting. 19

20 Treatment In acute hepatic encephalopathy, temporary-protein restriction to decrease the rate of ammonia production can be a useful adjuvant to pharmacologic therapy, but long-term protein restriction in cirrhotic patients is not recommended. These patients are already in a nutritionally deficient state, and prolonged protein restriction will exacerbate the problem. Vaccination against hepatitis A and B is recommended in patients with underlying cirrhosis to prevent additional liver damage from an acute viral infection. 20

21 Treatment Endoscopic band ligation and sclerotherapy are both means to stop acutely bleeding varices. Balloon tamponade involves the application of direct pressure to the area of bleeding with an inflatable balloon attached to a nasogastric tube. It is an option for patients in whom drug therapy and band ligation fail to stop variceal bleeding. Balloon tamponade is used only when other methods have failed. 21

22 Treatment Transjugular intrahepatic portosystemic shunting (TIPS) is an invasive procedure used to manage refractory ascites or control refractory variceal bleeding. TIPS placement is also associated with an increased incidence encephalopathy; this results from decreased detoxification of nitrogenous waste products because the shunt allows blood to escape metabolic processing. 22

23 Treatment Pharmacologic Treatment Drug therapy for portal hypertension and cirrhosis can alleviate symptoms and prevent complications but it cannot reverse cirrhosis. Drug therapy is available to treat the complications of ascites, varices, spontaneous bacterial peritonitis, hepatic encephalopathy, and coagulation abnormalities. Portal Hypertension (Non-selective B -blockers such as propranolol and nadolol are first-line treatments to reduce portal hypertension. This is effect reduces bleeding and decreases mortality in patients with known varices. 23

24 Treatment Blockade of B1 receptors reduces cardiac output, while B2- Adrenergic blockade prevents B2-receptor mediated splanchnic vasodilation leads to reduce portal blood flow. The combination of B1 and B2 effects makes the non-selective B blockers preferable to cardioselective agents in treating portal hypertension. Ascites The goals of treating ascites are to minimize acute discomfort, re-equilibrate ascitic fluid and prevent SBP. 24

25 Treatment In this case of tense ascites, relief of acute discomfort may be accomplished by therapeutic paracentesis. Often the removal of just 1 to 2 L of ascitic fluid provides relief of pain and fullness. When removing 5 L or more of fluid at once, volume resuscitation with 8 to 10 g of albumin given intravenously should be provided for each liter of fluid removed. If less than 5 L of fluid is removed in a hemodynamically stable patient, albumin is not warranted. 25

26 Diuretics Treatment Diuretics are often required in addition to the sodium restriction described previously. Spironolactone and furosemide form the basis of pharmacologic therapy for ascites. Spironolactone is an aldosterone antagonist and counteracts the effects of activation of the renin-angiotensin-aldosterone system. In hepatic disease not only is aldosterone production increased, but its half-life is prolonged because it is hepatically metabolized. Spironolactone acts to conserve the potassium that would be otherwise excreted because of elevated aldosterone levels. Spironolactone is usually used in combination with a loop diuretic (e.g., furosemide) for more potent diuresis. 26

27 Varices Treatment During acute variceal hemorrhage, crucial desired outcomes include controlling bleeding, preventing re-bleeding, and avoiding acute complications such SBP; mortality from first bleeding episode is up to 55%, and patients must by treated aggressively. Octreotide is a synthetic analogue of somatostatin; it selectively causes vasoconstriction of the splanchnic bed, decreasing portal venous pressure with few serious side effects. 27

28 Treatment Vasopressin ( terlipressin) has been used, but since it causes non-selective vasoconstriction, it carries the risk of systemic consequences, which limits its usefulness. 28

29 Spontaneous Bacterial Peritonitis Treatment Initiation of prophylactic antibiotics is recommended during acute variceal bleeding; this is typically done with an oral fluoroquinolone or an IV third-generation cephalosporin. Prophylactic antibiotic therapy reduces in hospital infections and mortality in patients hospitalized for variceal bleeding. Cefotaxime (2 g, 8 hourly) is effective in 85% of patients with SBP and is commonly used as first-line antimicrobial therapy. Other antibiotic regimens have been used including coamoxiclav, but third-generation cephalosporins are the treatment of choice. 29

30 Treatment Encephalopathy Lactulose Lactulose is the pharmacologic therapy to prevent and treat hepatic encephalopathy. It is a non-digestible synthetic disaccharide laxative that is hydrolyzed in the gut to an osmotically-active compound that draws water into the colon and stimulates defecation. Lactulose also lowers colonic ph, which favors the conversion of ammonia (NH3) to ammonium (NH4+). Ammonium is ionic and cannot cross back into systemic circulation; it is eliminated in the feces. Antibiotics such as metronidazole or neomycin may also be used to reduce ammonia production from gastro-intestinal bacteria. 30

31 Treatment Clotting Abnormalities Patients with liver disease should receive intravenous doses of phytomenadione (vitamin K), usually 10 mg daily for 3 days. Administration of vitamin K to patients with significant liver disease does not usually improve the prothrombin time because the liver is unable to utilise the vitamin to synthesis clotting factors. Aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and anticoagulants should be avoided in all patients with liver disease because of the risk of altering platelet function, causing gastric ulceration and bleeding. NSAIDs have also been implicated in precipitating renal dysfunction and variceal bleeding in patients with end-stage liver disease. Although COX-2 inhibitors may cause a lower incidence of bleeding complications, currently they are avoided in patients with liver disease as their use still poses a risk. 31