1. Prospective derivation and validation of early dynamic model for predicting outcome in patients with acute liver failure
R1 김형오 / Prof. 심재준

2. Introduction Acute liver failure
Rapid development of hepatocellular dysfunction
Coagulopathy
Mental status changes (encephalopathy)
High mortality without liver transplantation
The prognostic models to select liver transplantation candidate
To select appropriate candidate for liver transplantation
Liver transplantation is an expensive treatment
Requires lifelong immunosuppression
To prevent avoidable liver transplantation

3. Introduction Prognostic models King’s College Hospital Criteria
Model for End stage Liver Disease (MELD)
Clichy criteria
Serum group-specific component protein levels
Liver volume on CT scanning
Blood lactate levels
Hyperphosphatemia
Acute physiology and chronic health evaluation II score
Unfortunately, none of these models has consistently demonstrated a reliable accuracy in predicting outcome
In general, these prognostic markers have high specificity but unacceptably low sensitivity

4. Aim
To develop a prognostic model based on early changes in levels of variables which predicted outcome independently at admission in a cohort of patients with acute liver failure
Unfortunately, none of these models has consistently demonstrated a reliable accuracy in predicting outcome
In general, these prognostic markers have high specificity but unacceptably low sensitivity

5. Patients And Methods January 2004~ June 2011, prospective evaluation
405 consecutive patients with acute liver failure
All institute of Medical Sciences
Patients died on or before day 2 after admission excluded (n=25)
380 patients
244 patients of derivation cohort
136 patients of validation cohort
The study was approved by the ethics committee of our institute and consent was obtained from the nearest relative of the patient at the time of enrolment.

6. Definitions of variables
Acute liver failure
The occurrence of encephalopathy within 4 weeks of symptoms of absence of pre-existing liver disease
Cerebral edema
Presence of spontaneous or inducible decerebrate posturing
Or any two of the followings
Hypertension BP >150/90mmHg
Bradycardia <60/min
Pupillary change
Neurogenic hyperventilation
Hepatic encephalopathy grading
Grade 1 : Loss of sleep rhythm, drowsiness, confusion, flapping tremor
Grade 2 : Grade 1 + loss of sphincter control
Grade 3 : Unconsciousness with no response to oral commands
Grade 4 : Deep unconscious state with no response to pain
The study was approved by the ethics committee of our institute and consent was obtained from the nearest relative of the patient at the time of enrolment.

7. Management protocol Managed in the intensive care unit
Stress ulcer prophylaxis
Monitoring and correction of blood sugar levels
Mean arterial pressure >60 mmHg maintenance
Elective ventilation for patients
Grade 4 encephalopathy
Grade 3 encephalopathy with cerebral edema
Intravenous mannitol was used to control cerebral edema
Daily microbiological surveillance to detect infection
Prophylactic antibiotics given in all cases
The study was approved by the ethics committee of our institute and consent was obtained from the nearest relative of the patient at the time of enrolment.
Ammonia : No lactulose, probiotics, prebiotics, non-absorbable antibiotics

8. Patient characteristic
Derivation cohort값이 의미있게 감소…

9. Prognostic model development
4-variable model
AUROC 0.67
Hosmer-Lemeshow test discriminative ability modest
ALFED model : early changes of significant variable
AUROC 0.91 (0.92 in validative cohort)
Hosmer-Lemeshow test
Excellent discrimination, good calibration
Hosmer Lemeshow goodness of fit test
4-variable model : modest
ROC : false positive change, true positive rate로 model의 변별력을 측정
AUROC : model의 설명력을 평가

10. Risk stratification by ALFED score
88.5% of patients in the high risk category died (77/87)
2.6% of patients in the low risk category died (2/78)
Hosmer Lemeshow goodness of fit test
4-variable model : modest
ROC : false positive change, true positive rate로 model의 변별력을 측정
AUROC : model의 설명력을 평가

11. Comparison with other predictive models
ALFED AUROC derivation cohort 0.91, validation cohort 0.92
MELD Score = (0.957 * ln(Serum Cr) * ln(Serum Bilirubin) * ln(INR) ) * 10
AAP
Arterial pH < 7.3 (taken by sampling of blood from an artery)
All three of an international normalized ratio (INR) of greater than 6.5, 
serum creatinine of greater than 300 micromoles per litre and the presence of encephalopathy (of grade III or IV).
These three are markers ofcoagulopathy, kidney function and mental status.[2]
Non AAP
INR greater than 6.5; or,
Three of the following five criteria:
Patient age of less than 11 or greater than 40;
Serum bilirubin of greater than 300 micromoles per litre;
Time from onset of jaundice to the development of coma of greater than seven days;
INR greater than 3.5; or,
Drug toxicity, regardless of whether it was the cause of the acute liver failure.
MELD at 3 days
Best cut-off score 35
AUROC 0.72 in the derivation, 0.76 in the validation cohort
KCH criteria at 3 days
AUROC 0.70 in the derivation, 0.62 in the validation cohort

12. Discordance between predictive models
KCH(-), 140 patients
ALFED high risk : 31 patients(22%)
25 patients died
MELD < 35, 130 patients
ALFED high risk : 26 patients(20%)
21 patients died
ALFED low-risk, 78 patients
KCH(+), 18 patients (17 survived)
MELD >35, 20 patients (18 survived)
In derivative cohort

13. In summary
ALFED
Prospectively derived, validated
Simple, reliable, accurate
This model might be very useful in risk stratification and clinical decision making