Acute kidney injury and acute-on-chronic liver failure classifications in prognosis assessment of patients with acute decompensation of cirrhosis.

OBJECTIVE: Prognostic stratification of patients with cirrhosis is common clinical practice. This study compares the prognostic accuracy (28-day and 90-day transplant-free mortality) of the acute-on-chronic liver failure (ACLF) classification (no ACLF, ACLF grades 1, 2 and 3) with that of acute kidney injury (AKI) classification (no AKI, AKI stages 1, 2 and 3). DESIGN: The study was performed in 510 patients with an acute decompensation of cirrhosis previously included in the European Association for the Study of the Liver-Chronic Liver Failure consortium CANONIC study. ACLF was evaluated at enrollment and 48 h after enrollment, and AKI was evaluated at 48 h according to Acute Kidney Injury Network criteria. RESULTS: 240 patients (47.1%) met the criteria of ACLF at enrollment, while 98 patients (19.2%) developed AKI. The presence of ACLF and AKI was strongly associated with mortality. 28-day transplant-free mortality and 90-day transplant-free mortality of patients with ACLF (32% and 49.8%, respectively) were significantly higher with respect to those of patients without ACLF (6.2% and 16.4%, respectively; both p<0.001). Corresponding values in patients with and without AKI were 46% and 59%, and 12% and 25.6%, respectively (p<0.0001 for both). ACLF classification was more accurate than AKI classification in predicting 90-day mortality (area under the receiving operating characteristic curve=0.72 vs 0.62; p<0.0001) in the whole series of patients. Moreover, assessment of ACLF classification at 48 h had significantly better prognostic accuracy compared with that of both AKI classification and ACLF classification at enrollment. CONCLUSIONS: ACLF stratification is more accurate than AKI stratification in the prediction of short-term mortality in patients with acute decompensation of cirrhosis.

Random forest classification of etiologies for an orphan disease.

Classification of objects into pre-defined groups based on known information is a fundamental problem in the field of statistics. Although approaches for solving this problem exist, finding an accurate classification method can be challenging in an orphan disease setting, where data are minimal and often not normally distributed. The purpose of this paper is to illustrate the application of the random forest (RF) classification procedure in a real clinical setting and discuss typical questions that arise in the general classification framework as well as offer interpretations of RF results. This paper includes methods for assessing predictive performance, importance of predictor variables, and observation-specific information.

Pediatric acute liver failure: variations in referral timing are associated with disease subtypes.

UNLABELLED: In pediatric acute liver failure (PALF), rapid referral to a transplant center (TC) is advocated. Clinical variability of PALF may influence referral timing. We aimed to analyze early or late timing of referral in relation to clinical characteristics and outcome in PALF. We conducted a retrospective, single-center, comparative analysis of clinical and liver function parameters in two PALF cohorts (n = 23 per cohort): cohort 1 (early referral, duration of in-patient care before referral (DCR) <7 days) vs. cohort 2 (late referral, DCR ≥ 7 days). Compared to late referrals, patients referred early were more frequently non-icteric and encephalopathic at initial presentation (n = 14 vs. 5 and n = 13 vs. 4, each p < 0.05). Early referred PALF patients had lower hepatic encephalopathy (HE) grades and bilirubin (grade 1 vs. 2, p < 0.02; 215 vs. 439 µmol/l, p < 0.001, respectively) but higher alanine aminotransferase (ALAT) levels (4,340 vs. 963 U/l, p < 0.001). Cumulative poor prognostic indicators were lower in early referrals (2 vs. 4, p < 0.001). In multivariate analysis, subacute liver failure (SLF >7 days between disease onset and development of encephalopathy) was independently associated with late referral (relative risk 9.48; 95 % CI 1.37-64.85, p < 0.02). Differences in survival to discharge were not significant. CONCLUSION: In PALF, referral timing variability is associated with distinct clinical and liver function patterns. Early recognition of prognostic indicators and of SLF may help to improve referral timing and thus PALF management.

Two distinct subtypes of hepatitis B virus-related acute liver failure are separable by quantitative serum immunoglobulin M anti-hepatitis B core antibody and hepatitis B virus DNA levels.

UNLABELLED: Hepatitis B virus (HBV)-related acute liver failure (HBV-ALF) may occur after acute HBV infection (AHBV-ALF) or during an exacerbation of chronic HBV infection (CHBV-ALF). Clinical differentiation of the two is often difficult if a previous history of HBV is not available. Quantitative measurements of immunoglobulin M (IgM) anti-hepatitis B core antibody (anti-HBc) titers and of HBV viral loads (VLs) might allow the separation of AHBV-ALF from CHBV-ALF. Of 1,602 patients with ALF, 60 met clinical criteria for AHBV-ALF and 27 for CHBV-ALF. Sera were available on 47 and 23 patients, respectively. A quantitative immunoassay was used to determine IgM anti-HBc levels, and real-time polymerase chain reaction (rtPCR) was used to determine HBV VLs. AHBV-ALFs had much higher IgM anti-HBc titers than CHBV-ALFs (signal-to-noise [S/N] ratio median: 88.5; range, 0-1,120 versus 1.3, 0-750; P < 0.001); a cut point for a S/N ratio of 5.0 correctly identified 44 of 46 (96%) AHBV-ALFs and 16 of 23 (70%) CHBV-ALFs; the area under the receiver operator characteristic curve was 0.86 (P < 0.001). AHBV-ALF median admission VL was 3.9 (0-8.1) log10 IU/mL versus 5.2 (2.0-8.7) log10 IU/mL for CHBV-ALF (P < 0.025). Twenty percent (12 of 60) of the AHBV-ALF group had no hepatitis B surface antigen (HBsAg) detectable on admission to study, wheras no CHBV-ALF patients experienced HBsAg clearance. Rates of transplant-free survival were 33% (20 of 60) for AHBV-ALF versus 11% (3 of 27) for CHBV-ALF (P = 0.030). CONCLUSIONS: AHBV-ALF and CHBV-ALF differ markedly in IgM anti-HBc titers, in HBV VLs, and in prognosis, suggesting that the two forms are, indeed, different entities that might each have a unique pathogenesis.

A systematic review on prognostic indicators of acute on chronic liver failure and their predictive value for mortality.

BACKGROUND: An early and proper diagnosis of acute on chronic liver failure (ACLF), together with the identification of indicators associated with disease severity is critical for outcome prediction and therapy. OBJECTIVE: To systematically identify and summarize prognostic indicators for patients with ACLF and to evaluate the predictive value of these indicators. METHODS: Embase and Ovid-Medline were searched for English-language articles. The search criteria focused on identifying clinical trials and observational studies reporting on indicators used for prediction of mortality in patients with ACLF. RESULTS: Of 2382 studies identified, 19 were included for detailed analysis. Thirteen different definitions of ACLF were found. The main differences were related to acute deterioration in liver function, coagulopathy and hyperbilirubinaemia/jaundice. Seventy three prognostic indicators and their association with mortality were extracted and categorized into seven categories: general markers (n = 13), viral markers (n = 6), bio-markers (n = 22), hemodynamics (n = 1), morphology/histology (n = 17), scoring systems (n = 10) and treatments (n = 4). CONCLUSIONS: The ambiguity and variability in the definition of ACLF and in its predictive indicators hampers comparability among studies. There is a need for a single uniform definition of ACLF. Also absence of a gold standard is an obstacle to render one indicator superior to another. The age, hepatic encephalopathy, model for end-stage liver disease score, total bilirubin and International normalized ratio (prothrombin time) appeared to be promising candidates for evaluation in future studies. The result of this review may be useful as a starting point in developing a standard list of indicators for clinical outcome that concur with the clinicians' subjective views on prognosis in ACLF.

Acute liver failure.

Acute liver failure is a rare disorder with high mortality and resource cost. In the developing world, viral causes predominate, with hepatitis E infection recognised as a common cause in many countries. In the USA and much of western Europe, the incidence of virally induced disease has declined substantially in the past few years, with most cases now arising from drug-induced liver injury, often from paracetamol. However, a large proportion of cases are of unknown origin. Acute liver failure can be associated with rapidly progressive multiorgan failure and devastating complications; however, outcomes have been improved by use of emergency liver transplantation. An evidence base for practice is emerging for supportive care, and a better understanding of the pathophysiology of the disorder, especially in relation to hepatic encephalopathy, will probably soon lead to further improvements in survival rates.

A 20-year single-center experience with acute liver failure during pregnancy: is the prognosis really worse?

UNLABELLED: Pregnant patients with acute liver failure (ALF) are believed to have a worse outcome than nonpregnant women and men with ALF. However objective data supporting this supposition are scant. Therefore, the current study compared the outcome, complications, and causes of ALF among pregnant women and girls with age-matched nonpregnant women and girls and men and boys with ALF. One thousand fifteen consecutive ALF patients in the reproductive age group, admitted at the All India Institute of Medical Sciences, New Delhi, from January 1986 to December 2006, were included in the study. A total of 249 (38.5%) women were pregnant. They were compared with 341 nonpregnant women and girls and 425 men and boys, aged 15 to 45 years. The mortality rate of pregnant women and girls (53.8%) was similar to age-matched nonpregnant women and girls (57.2%), and men and boys (57.9%); P = 0.572. The clinical and biochemical features, disease severity, and complications were also similar in the three groups. A significantly higher proportion of ALF was attributable to hepatitis E virus (HEV) among women and girls who were pregnant (59.4%), as compared with both nonpregnant women and girls (30.4%), and men and boys (23.1%); P < 0.001. However, the outcome of HEV-related ALF was independent of the sex and pregnancy status of the patients (P = 0.103). Mortality in HEV-ALF and non-HEV-ALF patients in pregnant women and girls was 51% (74/145) and 54.7% (52/95)(P > 0.1), respectively. The outcome of pregnant ALF patients was also unrelated to the trimester of pregnancy. The mortality of non-HEV-related ALF among the pregnant women and girls (54.7%), age-matched nonpregnant women and girls (61.7%), and men and boys (62.8%) were also similar (P > 0.1). CONCLUSION: The mortality of pregnant patients with ALF is similar to that of nonpregnant women and girls and men and boys and is independent of the cause or trimester. Pregnancy per se should not be regarded as a poor prognostic factor for a patient with ALF.

Results of a protocol for the management of patients with fulminant liver failure.

OBJECTIVE: To assess the safety and efficacy of a protocol to support management of intracerebral pressure in patients with fulminant liver failure (FLF). DESIGN AND SETTING: A prospective series was conducted between May 2004 and September 2006 at Banner Good Samaritan Medical Center, a 650-bed teaching hospital in Phoenix, Arizona. PATIENTS: We recruited consecutive patients with FLF and stage 3 or 4 encephalopathy. INTERVENTIONS: We placed an intracranial pressure monitor in each patient and employed a protocol to support decisions regarding hemostatic management and prevention and treatment of intracranial hypertension (IHTN). Treatment modalities included hypothermia, hypocarbia, intravenous pentobarbital, intravenous mannitol and vasopressor titration for maintenance of cerebral perfusion pressure. The main outcome measure was survival in transplant candidates. MEASUREMENTS AND MAIN RESULTS: Twenty-two patients entered the study and 21 (95%) had at least one episode of IHTN. Eighty-two discrete episodes of IHTN occurred, and 78 of these (95%) resolved with treatment. Overall survival was 55%. Eleven of 18 (61%) of transplant candidates survived with good neurologic outcome. No patient died from isolated cerebral edema. Three patients had intracranial hemorrhages related to the intracranial pressure monitor. CONCLUSIONS: Protocol-driven management of intracranial pressure in FLF can result in good clinical outcomes in most transplant candidates, even if IHTN occurs.

Interlaboratory variability in assessment of the model of end-stage liver disease score.

BACKGROUND: The model of end-stage liver disease (MELD) score is nowadays widely used to prioritize patients for liver transplantation. AIMS: To assess the contribution of the individual components of the MELD score in interlaboratory variability. METHODS: We sent 15 samples from patients listed for liver transplantation to seven different European laboratories who were asked to measure all three variables. In addition, 10 samples from patients on oral anticoagulant treatment were sent to the same labs for the international normalised ratio (INR) measurement. RESULTS AND CONCLUSIONS: In all 15 samples, a substantial and clinically relevant variation in the calculated MELD score was observed between laboratories. The mean difference in the MELD score between the highest- and the lowest-scoring laboratory was 4.8. The variation in creatinine measurements resulted in differences of up to three MELD points in a single patient when comparing the highest and the lowest scoring lab. The variation in bilirubin measurements only accounted for a difference of one point between the highest- and the lowest-scoring laboratory, but the variation in INRs resulted in differences of 2 to 12 MELD points. MELD scores or INR values were not substantially different in laboratories that used the Owren instead of the more widely used Quick methodology for INR measurements. The variability in the INR in patients on oral anticoagulants was substantially less as compared with the variability in patients with liver disease. In conclusion, we observed a large interlaboratory variation in the MELD score. This variation in the MELD score is primarily caused by the INR.

Brain edema in acute liver failure.

Acute liver failure (ALF) is a syndrome of rapidly deteriorating liver function that manifests as coagulopathy and encephalopathy in a previously healthy individual. This article analyzes the repercussions of ALF on the brain through a discussion of special features of this syndrome, important for the interpretation of neurologic findings. Of particular interest within the context of ALF are hepatic encephalopathy and the pathogenesis of brain edema in acute liver failure as well as its clinical and therapeutic aspects.

The Pathology of Acute Liver Failure.

Varied injuries may manifest clinically as acute liver failure. The pathologic features include variable amounts of necrosis and regeneration. This article reviews pathologic classification of patterns of necrosis and associated inflammatory and regenerative responses in specimens from patients with acute liver failure. Detailed pathologic examination of these specimens with clinical pathologic correlation can give the multidisciplinary team vital information regarding etiology and timing as well as extent of injury, and regenerative response. Pathologists are a vital component of the health care team for patients with acute liver failure.

Classification and Epidemiologic Aspects of Acute Liver Failure.

Acute liver failure is a rare condition with high short-term morbidity and mortality. The most widely accepted definition is an abnormality in coagulation with any degree of encephalopathy in a patient without cirrhosis and an illness duration of less than 26 weeks. Multiple classifications systems are currently in use to help categorize the condition. This article reviews the most commonly used systems. The epidemiologic aspects of the disease are also reviewed, including incidence, prevalence, demographics, geographic distribution, and racial and cultural factors and are discussed for the various subtypes of acute liver failure.

Comparison scoring model of severe viral hepatitis and model of end stage liver disease for the prognosis of patients with liver failure in China.

AIM: To estimate the prognosis of patients with liver failure using a scoring model of severe viral hepatitis (SMSVH) and a model of end stage liver disease (MELD) to provide a scientific basis for clinical decision of treatment. METHODS: One hundred and twenty patients with liver failure due to severe viral hepatitis were investigated with SMSVH established. Patients with acute, subacute, and chronic liver failure were 40, 46 and 34, respectively. The follow-up time was 6 mo. The survival rates of patients with liver failure in 2 wk, 4 wk, 3 mo and 6 mo were estimated with Kaplan-Meier method. Comparison between SMSVH and MELD was made using ROC statistic analysis. RESULTS: The survival curves of group A (at low risk, SMSVH score or= 5) were significantly different (The 4-wk, 3-mo, 6-mo survival rates were 94.59%, 54.05%, 43.24% in group A, and 51.81%, 20.48%, 12.05% in group B, respectively, P < 0.001). The survival curves of group C (SMSVH scores unchanged or increased), group D (SMSVH scores decreased by 1) and group E (SMSVH scores decreased by 2 or more) were significantly different .The survival rates of groups C, D and E were 66.15%, 100%, 100% in 2-wk; 40.0%, 91.18%, 100% in 4-wk; 0%, 58.82%, 80.95% in 3-mo and 0%, 38.24%, 61.90% in 6-mo, respectively, P < 0.001). The area under the ROC curve (AUC) of SMSVH scores at baseline and after 2 wk of therapy was significantly higher than that under the ROC curve of MELD scores (0.804 and 0.934 vs 0.689, P < 0.001). CONCLUSION: SMSVH is superior to MELD in the estimation of the prognosis of patients with severe viral hepatitis within 6 mo. SMSVH may be regarded as a criterion for estimation of the efficacy of medical treatment and the decision of clinical treatment.

Liver transplantation for acute liver failure: trying to define when transplantation is futile.

BACKGROUND: Recently, the model of end-stage liver disease (MELD) index has been used to select patients with acute liver failure (ALF) or transplantation. By the time the indication for orthotopic liver transplantation (OLT) is defined, the patient's clinical status may worsen. OBJECTIVE: In this study, MELD was used to define patients beyond OLT. METHODS: Among adult patients ALF was responsible for 17 OLT. Their medical records were reviewed to calculate the MELD score just before the OLT. MELD of the deceased patients after OLT (group 1, n=8), was compared with the MELD score of living recipients (group 2, n=9). Creatinine level, need for dialysis, use of vasoactive amines, and mechanical ventilation before OLT were also analyzed in these groups. A significant difference was defined when P<.05. RESULTS: The mean MELD score+/-SD was 51.86+/-12.3 for group 1, and 38.47+/-7.1 for group 2 (P=.02). There was no difference between the creatinine values for patients in the 2 groups (P=.20). Also, the use of vasoactive amines or the need of dialysis before OLT were not different (P=.12 and P=.25, respectively). Group 1 was more frequently under mechanical ventilation, and showed a 4.29 relative risk for death after OLT. CONCLUSION: MELD score could be useful to define the prognosis of OLT among patients with ALF.

Utility of the MAYO End-Stage Liver Disease score, King's College Criteria, and a new in-hospital mortality score in the prognosis of in-hospital mortality in acute liver failure.

INTRODUCTION: Several prognostic scores attempt to aid in the selection of patients with acute liver failure (ALF) to be treated either medically or by liver transplantation; however, their lack of fulfillment does not predict spontaneous survival in ALF and refined prognostic criteria are needed to improve such selection. Our aim was to evaluate and compare a new ALF in-hospital mortality prediction score versus King's College Criteria (KCC) and model for End-Stage Disease (MELD) score. METHODS: First-time ALF-diagnosed individuals admitted to our institution (n = 58) were grouped according their final outcome as "alive" or "death," and those significantly different variables between groups entered into a logistic regression and lineal regression models. An ALF in-hospital mortality score (ALFIHMS) was produced and its sensitivity, specificity, and area under receiver operator characteristics were compared with those of KCC and MELD scores. RESULTS: Since no significant differences (P = .81) in mortality rates between fulminant and subfulminant hepatic failure were found, no further analysis according to ALF's classification was performed. After obtaining and comparing ALFIHMS with KCC and MELD, we found that ALFIHMS prediction accuracy is higher than that of KCC and MELD score and that an ALFIHMS cutoff point >15 points is associated with an in-hospital mortality probability >50%. CONCLUSIONS: ALFIHMS has higher prognostic accuracy than KCC and MELD scores in ALF.

MELD score as a prognostic model for listing acute liver failure patients for liver transplantation.

OBJECTIVES: The King's College Hospital (KCH) criteria are widely used for listing patients with acute liver failure (ALF) for liver transplantation (LT). Recent reports have suggested that the Model for End-Stage Liver Disease (MELD) score may be useful in assessing prognosis in ALF (nonparacetamol). This study compares prognostic accuracy of the two systems in patients with paracetamol (POD)-induced ALF treated in this unit. METHODS: Seventy-two patients (average age 38 years; F:M ratio 2:1) admitted from 1994 to 2005 with POD-related ALF were studied. Clinical and biochemical parameters were recorded. The effect of applying a MELD score of greater than 30 as listing criteria for LT was calculated and compared with the KCH criteria. Outcomes were defined as LT, death, or full recovery. RESULTS: Thirty-one patients (43%) recovered with medical therapy, 29 (40%) patients died, and 12 (17%) underwent LT. Sixty five percent of patients had a MELD > 30 and therefore could potentially be listed on admission; however, using KCH criteria only 24% patients were listed immediately. Sensitivity and negative predictive value of MELD was higher then KCH; however, we found KCH to have much higher specificity and positive predictive value. CONCLUSION: MELD has higher sensitivity and negative predictive value for POD-induced ALF than the KCH criteria. However, the high false-positive rate associated with MELD limits its clinical utility. The high negative predictive value of MELD score may allow it to be used in conjunction with KCH criteria to avoid unneeded LT in patients who will likely recover spontaneously.

From Child-Pugh to Model for End-Stage Liver Disease: Deciding Who Needs a Liver Transplant.

This article reviews the historical evolution of the liver transplant organ allocation policy and the indications/contraindications for liver transplant, and provides an overview of the liver transplant evaluation process. The article is intended to help internists determine whether and when referral to a liver transplant center is indicated, and to help internists to counsel patients whose initial evaluation at a transplant center is pending.