Fibrosis[1]

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Fibrosis[1]

  1. 1. Liver Cirrhosis Diana Alcantara-Payawal, MD, MSc, FPCP, FPSG, FPSDE
  2. 2. CIRRHOSIS Anatomical: Presence of nodules of hepatocytes separated by fibrous septa. Micronodular Macronodular Incomplete Septal Cirrhosis with massive necrosis
  3. 4. Pathophysiology of Cirrhosis: Role of Endothelium-Derived Nitric Oxide <ul><li>Cirrhosis </li></ul><ul><li>Increased Hepatic Increased Splanchnic </li></ul><ul><li>Resistance Blood Flow </li></ul><ul><li> Decreased NO Increased NO </li></ul><ul><li> - increased caveolin - increased phosphorylation </li></ul><ul><li> - decreased phosphorylation -eNOS gene expression </li></ul><ul><li> (sustained flow) </li></ul>Iwakiri Y, Sessa WC. AASLD 2001
  4. 5. Pathophysiology of Cirrhosis <ul><li>Intrahepatic resistance Splanchnic BF </li></ul><ul><li>Portal HPN Systemic Hyperkinetic </li></ul><ul><li> Circulation and Hypotension </li></ul><ul><li>SBP PS-Shunts </li></ul><ul><li> Activ. Neurohumoral </li></ul><ul><li>factors </li></ul><ul><li>Variceal formation </li></ul><ul><li>Hepatic Enceph Sodium/Water retention </li></ul><ul><li>Pulmonary HPN </li></ul><ul><li>Hepatorenal Syn Ascites </li></ul>Didier Lubrec MD, AASLD, 2001 Fibrosis
  5. 7. Evolution of Cirrhosis <ul><li>INCOMPLETE SEPTAL CIRRHOSIS: </li></ul><ul><li>Presence of very slender septa radiating from enlarged fields toward the center of the lobule. There are distended efferent vessels around the septum. This type of cirrhosis produces only portal hypertension and no liver failure. The prognosis is very good if the portal hypertension is controlled. </li></ul><ul><li>EARLY CIRRHOSIS: </li></ul><ul><li>Thin fibrous septa with dissecting nodules. No regenerative nodules. Presence of multiple efferent vessels. </li></ul><ul><li>ADVANCED CIRRHOSIS: </li></ul><ul><li>Wide scars containing clusters of regenerative hepatocytes. Large scars may contain large portal fields. </li></ul>
  6. 8. Stages of Cirrhosis <ul><li>Compensated – absence of bleeding, ascites, encephalopathy, jaundice or carcinoma </li></ul><ul><ul><li>Median survival = 10 years </li></ul></ul><ul><ul><li>Prevalence of varices at 1 st endoscopy = 30% </li></ul></ul><ul><ul><li>and incidence increases at 5% per year. Rate of enlargement is unsettled. </li></ul></ul><ul><ul><li>Risk of death predicted by age, albumin and esophageal varices </li></ul></ul><ul><li>Decompensated- presence of bleeding, ascites, encephalopathy, jaundice, carcinoma </li></ul><ul><ul><li>Median survival from onset of bleeding = 2 years </li></ul></ul><ul><ul><li>Risk of death predicted by bleeding, albumin, grading of varices and CPT classification </li></ul></ul>Jensen Dennis. AASLD. 2001
  7. 9. Liver Disease Severity Scales in Decompensated HBV Cirrhosis <ul><li>Scale (Range) Mild Moderate Severe Reference </li></ul><ul><li>CTP score* (5 to 15) 5-6 7-9 10-15 28 </li></ul><ul><li>MELD score† (6-40) 6-10 10-24 25-40 27 </li></ul><ul><li>HBV risk profile‡ (1-50) 1-4 4-7 7-50 63 </li></ul><ul><li>*CTP score is the sum of serum albumin, bilirubin, INR, ascites, and encephalopathy components that are each assigned a value of 1, 2, or 3. </li></ul><ul><li>† MELD score = 9.57 2 loge(creatinine) + 3.78 2 loge(bilirubin) + 11.2 2 loge(INR) + 6.43. </li></ul><ul><li>‡ HBV risk profile for 6 month mortality = 0.5 2 bilirubin + 1.7 2 creatinine + HBV DNA (0 or 1). </li></ul>Robert J. Fontana, M.D. Semin Liver Dis. 2003
  8. 10. Decompensated Cirrhosis <ul><li>Treatment of Acute Variceal Bleed </li></ul><ul><li>Treatment of Spontaneous Bacterial Peritonitis (SBP) </li></ul><ul><li>Treatment of Ascites </li></ul><ul><li>Treatment of Hepatic Encephalopathy </li></ul><ul><li>Treatment of Hepatorenal syndrome </li></ul>
  9. 11. Agents Used for Hepatic Fibrosis <ul><li>Agents Studies done Results </li></ul><ul><li>Colchicine 3 RCTs no effect </li></ul><ul><li>Propylthiouracil (PTU) 4 RCTs no effect </li></ul><ul><li>D-penicillamine no effect </li></ul><ul><li>Vitamin E no effect </li></ul><ul><li>Cyanidol-3 no effect </li></ul><ul><li>Thioactic Acid no effect </li></ul><ul><li>Molotilate no effect </li></ul><ul><li>Amlodepine no effect </li></ul><ul><li>Silymarin 3 RCTs no effect </li></ul><ul><li>Insulin + Glucagon 5 RCTs no effect </li></ul><ul><li>Anabolic/Androgenic </li></ul><ul><li> Steroids 5 RCTs no effect </li></ul><ul><li>Corticosteroids 17 RCTs inconclusive </li></ul>Poynard T et al, Evid-based Gastro Hepato, 1999
  10. 12. Significance of Variceal bleeding <ul><li>50% of cirrhotic patients </li></ul><ul><li>40% in CTP A have varices </li></ul><ul><li>85% in CTP C have varices </li></ul><ul><li>Variceal bleed- 25-30 % in 2 years </li></ul><ul><li>Mortality following a bleed – 30% </li></ul>National Institutes of Health (NIH) consensus conference October 2003
  11. 13. Portal pressure Formation of varices Dilatation of varices Variceal Rupture Hepatic Resistance Portal Blood Flow Dilatation of pre existing vessels Repeated increase in portal pressure due to meals, ethanol, exercise, increase intrabdominal pressure Angiogenic factors Varices present in 40% at diagnosis 6% yearly incidence Small to large varices : 12% yearly Incidence of first bleeding: Large varices: 30% at 2 years Small varices: 10% at 2 years
  12. 14. Ascites <ul><li>Presentation is usually self evident </li></ul><ul><li>Physical exam reveals dullness in flanks </li></ul><ul><li>and shifting dullness (approx 1500cc). </li></ul><ul><li>Can be confirmed by U/S which can detect upto 100cc. </li></ul><ul><li>Diagnostic paracentesis myths related to coagulopathy and paracentesiis </li></ul>
  13. 15. <ul><li>All patients with new-onset ascites should have a DIAGNOSTIC PARACENTESIS </li></ul><ul><li>Studies needed on initial evaluation </li></ul><ul><li>albumin concentration cell count and diff </li></ul><ul><li>SAAG (serum-ascites albumin gradient) </li></ul><ul><li>> 1.1g/dl portal HTN related (97% accuracy) </li></ul><ul><li>< 1.1g/dl nonportal HTN causes(97% acc) </li></ul>
  14. 16. Ascites (SAAG) >1.1 g/dl Portal hypertension Cardiac causes CHF constrictive pericarditis Budd Chiarri Multifactorial Nephrotic syndrome < 1.1 g/dl Malignancy Tuberculosis Chylous ascites Pancreatic Multifactorial
  15. 17. Stepwise approach to the treatment of cirrhotic ascites Sodium restriction #1 + spirinolactone #1 + #2 + loop diuretic 10-20% >50% >90% Success rate LaBrecque Douglas MD, AASLD 2001
  16. 18. Treatment of uncomplicated ascites <ul><li>Not recommended , based on clinical trials demonstrating that other measures are either more effective or safe: </li></ul><ul><ul><li>Furosemide alone </li></ul></ul><ul><ul><li>Long-term antibiotic prophylaxis </li></ul></ul>Poynard T et al, Evid-based Gastro Hepato, 1999 NIH Consensus conference, October 2003 Practice Guidelines Runyon BA. Hepatology 2004 Mar
  17. 19. Treatment of hepatorenal syndrome <ul><li>Recommended (definitive): </li></ul><ul><ul><li>Liver transplant expedited (Grade II-3) </li></ul></ul><ul><ul><li>Systemic vasoconstrictors plus albumin (Grade II-1) </li></ul></ul>Poynard T et al, Evid-based Gastro Hepato, 1999 NIH Consensus conference, October 2003 Practice Guidelines Runyon BA. Hepatology 2004 Mar
  18. 20. Treatment of hepatorenal syndrome <ul><li>Under evaluation and cannot be recommended until additional information is available: </li></ul><ul><ul><li>TIPS </li></ul></ul><ul><ul><li>MARS </li></ul></ul>Poynard T et al, Evid-based Gastro Hepato, 1990 NIH Consensus conference, October 2003 Practice Guidelines Runyon BA. Hepatology 2004 Mar
  19. 21. Treatment of hepatorenal syndrome <ul><li>N ot recommended based on clinical trials demonstrating a lack of benefit compared to no therapy or placebo therapy: </li></ul><ul><ul><li>Octreotide alone </li></ul></ul><ul><ul><li>Prostaglandins </li></ul></ul><ul><ul><li>Dopamine </li></ul></ul><ul><ul><li>Dialysis </li></ul></ul>Poynard T et al, Evid-based Gastro Hepato, 1999 NIH Consensus conference, October 2003
  20. 22. Hepatic Encephalopathy Ammonia Synergistic Toxins GABA Endogenous Benzodiazepines Theories Blei AT. AASLD 2001
  21. 23. <ul><li>The main tenet of all theories of the pathogenesis of HE is firmly accepted: nitrogenous substances derived from the gut adversely affect brain function. </li></ul><ul><li>Abnormalities in glutamatergic, serotoninergic, g-aminobutyric acid–ergic (GABA-ergic), and catecholamine pathways, among others, have been described in experimental HE </li></ul>Pathophysiology of HE WCOG/AGA PRACTICE GUIDELINES. Hepatic Encephalopathy. 2001
  22. 24. Ammonia neurotoxicity hypothesis Described about a century ago Ammonia levels elevated in patients with cirrhosis but have no relation to severity of HE. Levels high due to shunting and decrease peripheral utilization of ammonia by muscle due to wasting. Ammonia affects brain function by altering the blood-brain barrier, reduced astrocyte uptake of glutamate altered cerebral metabolism
  23. 25. <ul><li>Acute Encephalopathy: acute confusional state that can evolve into </li></ul><ul><li>coma; most commonly associated with a precipitating factor </li></ul><ul><li>Recurrent Encephalopathy: recurrent episodes of an altered mental state may occur in the absence of precipitating factors; neurologic deficits may not completely reverse </li></ul><ul><li>Subclinical Encephalopathy: mild cognitive abnormalities only recognizable with psychometric or neurophysiologic tests. </li></ul>Clinical Subtypes (WCOG Consensus terminology) WCOG/AGA PRACTICE GUIDELINES. Hepatic Encephalopathy. 2001
  24. 26. Staging of HE <ul><li>West Craven Criteria </li></ul><ul><ul><li>Stage 0. Lack of detectable changes in personality or </li></ul></ul><ul><ul><li>behavior. Asterixis absent. </li></ul></ul><ul><ul><li>Stage 1. Trivial lack of awareness. Shortened attention </li></ul></ul><ul><ul><li>span. Impaired addition or subtraction. Hypersomnia, </li></ul></ul><ul><ul><li>insomnia, or inversion of sleep pattern. Euphoria or </li></ul></ul><ul><ul><li>depression. Asterixis can be detected. </li></ul></ul><ul><ul><li>Stage 2. Lethargy or apathy. Disorientation. Inappropriate </li></ul></ul><ul><ul><li>behavior. Slurred speech. Obvious asterixis. </li></ul></ul><ul><ul><li>Stage 3. Gross disorientation. Bizarre behavior. Semistupor to stupor. Asterixis generally absent. </li></ul></ul><ul><ul><li>Stage 4. Coma. </li></ul></ul><ul><li>Glasgow Coma Scale </li></ul>Andres T. Blei et al. The ACG Practice Guidelines, 2001
  25. 27. HE Grade 0 HE Grade 1 Weissenborn et al., J Hepatol 1998; 28: 646-653. NCT in Grade 0 to Grade I
  26. 28. Treatment of Hepatic Encephalopathy <ul><li>Recommended (based on clinical trials and expert opinion): </li></ul><ul><ul><li>Identification and treatment of precipitating event </li></ul></ul><ul><ul><li>Short-term protein restriction </li></ul></ul><ul><ul><li>Lactulose, adjusted to two to three bowel movements/day; enemas in patients who are unable to take it by mouth </li></ul></ul><ul><ul><li>In patients with chronic HE who cannot tolerate lactulose or do not respond to lactulose, treatment with laxatives plus neomycin can be considered </li></ul></ul>Poynard T et al, Evid-based Gastro Hepato, 1999 NIH Consensus conference, October 2003 Andres T. Blei et al. The ACG Practice Guidelines, 2001

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