Scoring in liver disease

Scoring in liver disease

1. Assessment of disease severity in CLD- Scoring system Presenter: Dr Sushil Tamang Moderator: Dr Sangeeta Deka

2. topics Child-Pugh Score MELD score MELD score derivatives PELD score Prognosis according to specific causes of cirrhosis Prognosis in different setting of non-transplant surgery, ICU and liver transplantation Perspectives beyond MELD scores

3. Main objectives of prognostic scores in cirrhotic patients: To estimate probability of death within given time interval To estimate reserve in terms of liver function To estimate capacity to stand up to surgery or other aggressive therapeutic interventions Address important issues: Help determine most appropriate therapeutic option with respect to patient’s condition Whether a patient has acceptable chance of survival after a given treatment (liver resection or arterial chemoembolization) Whether a resource spending therapy (such as transplantation) is justified

4. Child-Pugh Score Child or Child- Turcotte score: 1964 Score 5-8: Group A Score 9-11: Group B Score 12-15: Group C

5. Child-Pugh Score Child-Pugh score: 10 years later Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60:646-9

6. Child-Pugh Score Total range of points not distributed equally across grades A, B and C: attempt to mirror more efficiently clinical impact of each grade in terms of prognosis

7. Child-Pugh Score Variables Variables represent prognostic markers coming from broader source than pure assessment of liver functions Albumin: hepatic synthetic function, transvascular escape or clearance (sepsis and ascites) Bilirubin: increased in renal insufficiency, hemolysis and sepsis Decreased prothrombin index related to activations of coagulation by sepsis Metabolic encephalopathy precipitated by sepsis or renal insufficiency C-P score: multiorgan assessment

8. Child-Pugh Score D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol. 2006;44:217-31. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124:91-6.

9. Child-Pugh Score Validation Initially for evaluation of surgery for portal hypertension ( portocaval shunting and transection of esophagus) Multivariate analyses using C-P score: independent prognostic value Ascites, ruptured esophageal varices, subclinical encephalopathy, HCC, liver surgery, alcoholic cirrhosis, decompensated HCV related cirrhosis, PSC, PBC, and Budd-Chiari syndrome

10. Child-Pugh Score Applications To stratify or to select patients for prognostic analyses, retrospective assessment of non-randomly administered therapy , RCTs Widely used, at the bedside, as simple descriptive or prognostic indicator

11. Child-Pugh Score Limitations Five basic components selected empirically: not all variables have independent influence (albumin and coagulation factors in same scoring system) Arbitrary use of cut-off values: No evidence that these cut-off values are optimal for defining significant changes in mortality risk No evidence that mortality risk increases linearly across grade A, B and C: ceiling effect

12. Child-Pugh Score Each variable given same weight: weight of bilirubin and INR differs by factor 1-3 in MELD score Cut-off values for quantitative variable (ascites and encephalopathy) subjective Important prognostic factors not taken into account Renal function: weight of creatinine more than twice as high as that of bilirubin in MELD score Markers of portal hypertension (esophageal varices, portal blood velocity and hepatic venous pressure gradient)

13. Child-Pugh Score Does not take into account cause of cirrhosis, possible coexistence of several causal factors and persistence of damaging process such as persistent alcohol abuse, ongoing HBV or HCV replication or inflammatory activity of autoimmune hepatitis

14. MELD Score To address complex issues of optimal indications for transplantation and prioritization for the allocation of liver grafts Originally created with aim of predicting survival after TIPS Multivariate analysis using Cox model: Among a list of predetermined variables, four objective variables had a significant and independent impact on survival: bilirubin, creatinine, INR and cause of cirrhosis (alcoholic and cholestatic versus others)

15. MELD Score

16. MELD Score Logarithmic transformation of quantitative values: lessen influence of extreme values in statistical analysis Regression coefficient attributed to each prognostic variables as a reflect of their proper weight on mortality Adequately predicts mortality in hospitalized as well as ambulatory cirrhotic patients Generalizable to patients of various causes and severity of cirrhosis Useful scale for assessing very short term (1 week) survival

17. MELD Score Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124:91-6.

18. MELD Score Validation In contrast to C-P score, the variables of MELD score have been selected in a given population and the score has been thereafter validated in independent sample MELD is a robust risk score in patients undergoing TIPS MELD score tested in setting of ALF and emergency retransplantation for early graft failure: highly questionable since neurological status, a crucial prognostic index in this context is not taken into account

19. MELD Score Applications Ranking candidates for transplantation In contrast to its ability to evaluate pre-transplant mortality risk in candidates for transplantation, pre-transplant MELD score seems to be a poor predictor of post-transplantation survival, except for extreme values (>35)

20. MELD Score Limitations Some important variable might not have been taken into account: multivariate analysis performed on the basis of variables which initially were also selected empirically Variables like creatinine and bilirubin, though objective can be altered by therapeutic interventions (diuretics), sepsis or hemolysis The choice of INR rather than other markers of coagulation including PT and prothrombin index: not all centers use INR as marker of coagulation in cirrhotic patients

21. MELD Score Does not take into account the cause of cirrhosis and aggravating factors Need for computation: limitation to its usefulness at bedside

22. MELD Score derivatives: MELD-NA With implementation of MELD score, refractory ascites was removed from the list of variables used for assessing prognosis Persistent ascites and low serum sodium identified a subset of patients with relatively low MELD scores (below 21) and a high risk of early death

23. MELD Score derivatives: MELD-NA Serum sodium: simple, readiy available, objective marker of disease severity Systemic arterial vasodilation  ADH  dilution hyponatremia Correlates with degree of portal HTN Several studies have shown that hyponatremia is a strong predictor of early mortality, independent of MELD score

24. MELD Score derivatives: MELD-NA Changes in survival pronounced for Na : 120-135 mEq/L Within this range, a decrease in serum sodium of 1 mEq/L corresponds to a 12% decrease in 3 month probability of survival

25. MELD Score derivatives: MELD-NA Accuracy of MELD-Na superior to that of MELD in candidates in transplantation Effect of hyponatremia higher in patients with low MELD socre compared with high MELD score

26. MELD Score derivatives: MELD-NA Limitations Serum sodium concentration changes due to several factors in cirrhosis: diuretics, intravenous hypotonic fluids

27. MELD Score derivatives: MELD-xi INR: highest weight in MELD score INR hardly interpretable in patients receiving anticoagulation therapy: portal vein thrombosis, Budd-Chiari syndrome INR artificially increased: MELD score may overestimate disease severity MELD-XI excludes INR Relies only on bilirubin and creatinine Coefficients ascribed to bilirubin and creatinine changed to obtain optimal linear correlation between MELD and MELD-XI: mortality comparable to MELD score

28. MELD Score derivatives: MELD-xi Validation of MELD-XI score shows that its accuracy for assessing 3-month mortality risk is comparable to that of MELD Validation based in population not under anticoagulation Patients under anticoagulation: multiple comorbidities  further validation required

29. MELD Score derivatives: Delta MELD Difference between current MELD and the lowest MELD measured within 30 days prior to current MELD Was shown to be predictive of mortality in patients with cirrhosis on urivariate analysis No longer predictive of mortality when entered in multivariated model with current MELD score Current MELD score: the only predictor of mortality

30. MODIFICATIONS OF MELD

31. Peld score For childrens <12 years of age. PELD = 4.80[Ln serum bilirubin (mg/dL)] + 18.57[Ln INR] - 6.87[Ln albumin (g/dL)] + 4.36(<1 year old) + 6.67(growth failure <2 SD) Sum predicts risk of death and allows comparision between patients. High scores = worse outcomes.( Bourdeaux et al 2005, Barshes et al 2006)

32. Peld score Use Accurate predictor of waitlist mortality. Predicts post OLT survival.

33. Peld score Limitations Appears less successful than MELD at predicting outcome: diverse etiologies and wide variation in progression of pediatric liver disease (Olthoff et al, 2004) Underestimates severity of illness in pediatric patients (Schneider et al) Lack of scoring for extrahepatic manifestations of liver disease such as HPS Doesnot identify patients who are either too sick or too well to undergo liver transplantation Potential liver transplant recipients with ALF and certain other indications such as hepatoblastoma are excluded and need to be prioritized according to local or national criteria

34. PROGNOSIS ACC. TO SPECIFIC CAUSES OF CIRRHOSIS: Alcoholic cirrhosis and alcoholic hepatitis Alcoholic hepatitis superimposed in alcoholic cirrhosis: Potentially reversible condition: likely to improve within the first month following discontinuation of alcohol, may return to compensated cirrhosis Severe alcoholic hepatitis: Maddrey discriminant function >32

35. PROGNOSIS ACC. TO SPECIFIC CAUSES OF CIRRHOSIS: Alcoholic cirrhosis and alcoholic hepatitis MELD score : as efficacious as or even superior to Maddrey discriminant function

36. PROGNOSIS ACC. TO SPECIFIC CAUSES OF CIRRHOSIS: Alcoholic cirrhosis and alcoholic hepatitis Lille model Created on the basis of larger series of patients with alcoholic hepatitis treated with steroids Includes a dynamic variable corresponding to early response to steroids (change in bilirubin between day 0 and day 7)

37. PROGNOSIS ACC. TO SPECIFIC CAUSES OF CIRRHOSIS: Alcoholic cirrhosis and alcoholic hepatitis More accurate than MELD and CP score and Maddrey score for predicting six month survival Patients with score >0.45: 6 month mortality of 75% while those <0.45 had mortality of only 15%

38. PROGNOSIS ACC. TO SPECIFIC CAUSES OF CIRRHOSIS: hbv and hcv Patients with decompensated HBV related cirrhosis receiving antiviral therapy: biphasic survival pattern Better survival rates compared to those not receiving therapy Mortality rate in first 6 month of antiviral therapy: 15% Mortality rate after 6 months: 10 times lower Subgroup of patients who survive more than 6 months, 3 year survival >85%

39. PROGNOSIS ACC. TO SPECIFIC CAUSES OF CIRRHOSIS: hbv and hcv Specific score: patients receiving lamivudine HCV related cirrhosis : no specific model for predicting the outcome according to viral load, genotype and response to therapy Sustained virological response to interferon shown to improve outcome by reducing the incidence of liver-related complications

40. PROGNOSIS ACC. TO SPECIFIC CAUSES OF CIRRHOSIS: pbc Aim: to determine the optimal timing for transplantation Mayo risk score Probability of survival without transplantation for a risk score of 7.8 is 63% and 39% at 1 and 2 years respectively Risk of post-transplant mortaliy increases significantly when risk score exceeds 7.8: patients be referred to transplantation centers before reaching this value

41. PROGNOSIS ACC. TO SPECIFIC CAUSES OF CIRRHOSIS: pbc Birmingham risk score Survival benefit from transplantation increases when probability of survival without transplantation falls below 0.85 In non-transplanted patients, this occurs on average of 8 months before death which in most cases gives sufficient time to bridge patients to transplantation

42. PROGNOSIS ACC. TO SPECIFIC CAUSES OF CIRRHOSIS: pbc MELD: No evidence that MELD score misclassify PBC patients No evidence that above score are superior to MELD However, no discriminant value of MELD established to specifically identify PBC patients who may benefit from transplantation

43. PROGNOSIS ACC. TO SPECIFIC CAUSES OF CIRRHOSIS: psc Mayo risk score for PSC More accurate that CP score for predicting survival, especially in the patients with less-advanced disease Score <0: low risk Score 0-2: moderate risk Score >2: high risk Five year survival above 90% in low risk group and <40% in high risk patients

44. PROGNOSIS ACC. TO SPECIFIC CAUSES OF CIRRHOSIS: psc MELD: Not been specifically assessed for PSC Unlikely that disease severity is underestimated by MELD However some patients with low markers of severity have repeated episodes of cholangitis which has deleterious effect on outcome Also bilirubin levels are fluctuating

45. PROGNOSIS IN SETTING OF NONTRANSPLANT SURGERY Patients with cirrhosis: high risk of surgical morbidity and mortality In-hospital mortality as high as 10-20% High rate of post-operative decompensation Increased risk of bacterial infection When non surgical alternatives exist, prognostic markers should help determine whether the risk of surgery is justified

46. PROGNOSIS IN SETTING OF NONTRANSPLANT SURGERY MELD score 1% increase in mortality risk per MELD point below a score of 20 2% increase in mortality risk per MELD point above a score of 20 Mortality higher for intra-abdominal surgery (up to 25%) compared with other types of surgery

47. PROGNOSIS IN SETTING OF NONTRANSPLANT SURGERY Rescue transplantation in cirrhotic patients who have severe decompensation and profound liver insufficiency after liver resection Persistence of decrease in prothrombin index below 50% of normal (INR of 1.7) and an increase in serum bilirubin above 50 micromol/L on POD 5 associated with 60% risk of early mortality: early identification of patients needing emergency transplantation

48. PROGNOSIS IN SETTING OF ICU Mortality rates in patients with failure of two or three organ systems estimated to be 75% and 95% respectively Mortality much higher than that of noncirrhotic patients with multi-organ failure APACHE II and SOFA score: extensively validated in ICU settings Superior to liver-oriented prognostic scores

49. PROGNOSIS IN SETTING OF LIVER TRANSPLANTATION Sickest first policy adoped widely for organ allocation with aim of reducing wait list mortality MELD MELD score adopted in USA in 2002 as the reference scoring system to rank patients for liver transplantation 12% decrease in total number of new candidates listed for transplantation 3.5% reduction in mortality on the waiting list 10% increase in total number of deceased donor transplantation Threefold increase in number of patients listed with diagnosis of HCC

50. PROGNOSIS IN SETTING OF LIVER TRANSPLANTATION Transplant survival benefit steadily increased in increasing MELD score Only patients with MELD score exceeding 15-17 derive a significant benefit from transplantation Patients with lower MELD score would have higher risk of dying from transplantation than they have of dying from complications of cirrhosis

51. PROGNOSIS IN SETTING OF LIVER TRANSPLANTATION Candidates with HCC: compensated cirrhosis and low MELD score and unlikely to be transplanted unless receiving extra points Listed with a MELD score equivalent to a 10% (20 points) and 15% (24 points) risk of death within 3 months according to which the tumor is classified as stage I or II Stage I: single nodule less than 2 cm Stage II: single nodule between 2 and 5 cm, or 2 or 3 nodules each less than 3 cm If not transplanted within 3 months, receive additional MELD points equivalent to a 10% increase in pre-transplant mortality every 3 months until transplanted or determined unsuitable for transplantation due to excessive tumor progression

52. PROGNOSIS IN SETTING OF LIVER TRANSPLANTATION MELD Exceptions February 27, 2002 allocation of livers to waitlisted transplant candidtes based on urgency-based disease severity model: MELD Imperfect correlation between MELD score and waitlist outcome Some patients may be sicker than their MELD score and have mortality equivalent to those of higher MELD score, due to multiple complications of portal HTN, inaccurate measurement of renal function due to a low creatinine from low muscle mass, or have complications of liver disease requiring timely transplant that are not captured by the MELD score Exception points: to award increased waitlist priority

53. PROGNOSIS IN SETTING OF LIVER TRANSPLANTATION Standardized exceptions : sufficient data to warrant allocating automatic exception points to patients meeting formalized exception criteria i.e. HCC, HPS, cholagiocarcinoma , familial amyloid polyneuropathy, cystic fibrosis, POPH Non-standardized exceptions : conditions deemed important by transplant team but risk of mortality not clear cut requiring review on a case-by-case basis; regional review board within each UNOS region: hyponatremia, refractory ascites or variceal bleeding, failure to thrive, recurrent cholangitis

54. PERSPECTIVES BEYOND MELD SCORES PORTAL HYPERTENSION Variables related to portal hypertension: size of esophageal varices and history of GI bleed: additional information HVPG: Independent predictive value in majority of available multivariate analyses including CP sscore or its components Still not clear when the most predictive HVPG value should be collected: presentation or few months of follow-up More informative on patients with compensated than with decompensated cirrhosis

55. PERSPECTIVES BEYOND MELD SCORES HVPG <10 mm Hg associated with 90% probability of not developing clinical decompensation in a media follow up of 4 years

56. PERSPECTIVES BEYOND MELD SCORES NUTRITIONAL STATUS Poor nutritional status: strongly associated with worsening CP class What remains to be clarified is the optimal index for nutrition in terms of reproducibility, clinical availability and prognostic performance

57. PERSPECTIVES BEYOND MELD SCORES GLUCOSE TOLERANCE Multivariate analyses have shown independent negative effect of glucose intolerance or frank diabetes

58. PERSPECTIVES BEYOND MELD SCORES Karnofsky Performance Status Scale Assessment tool for functional impairment Used to compare effectiveness of different therapies Assess prognosis in individual patients In liver transplant Pts with cirrhosis listed for transplant poor performance scale based on KPS was associted with increased mortality( Orman et al) Unable to objectively assess fraility and elucidate underlying mechanism

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