Prognostic factors for chronic severe hepatitis and construction of a prognostic model

Author Affiliations: Intensive Care Unit, Tianjin Infectious Diseases Specialty Hospital, Tianjin 300193, China (Li Q, Yuan GY, Tang KC, Liu GW, Wang R and Cao WK)Corresponding Author: Qian Li, MD, Intensive Care Unit, Tianjin Infectious Diseases Specialty Hospital, Tianjin 300193, China (Tel: 86-22-27468210; Email: l191an@)© 2008, Hepatobiliary Pancreat Dis Int. All rights reserved.BACKGROUND: Chronic severe hepatitis is a serious illness with a high mortality rate. Discussion of prognostic judgment criteria for chronic severe hepatitis is of great value in clinical guidance. This study was designed to investigate the clinical and laboratory indices affecting the prognosis of chronic severe hepatitis and construct a prognostic model.METHODS: The clinical and laboratory indices of 213 patients with chronic severe hepatitis within 24 hours after diagnosis were analyzed retrospectively. Death or survival was limited to within 3 months after diagnosis. RESULTS: The mortality of all patients was 47.42%. Compared with the survival group, the age, basis of hepatocirrhosis, infection, degree of hepatic encephalopathy (HE) and the levels of total bilirubin (TBil), total cholesterol (CHO), cholinesterase (CHE), blood urea nitrogen (BUN), blood creatinine (Cr), blood sodium ion (Na), peripheral blood leukocytes (WBC), alpha-fetoprotein (AFP), international normalized ratio (INR) of blood coagulation and prothrombin time (PT) were significantly different in the group who died, but the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB) and hemoglobin (HGB) were not different between the two groups. At the same time, a regression model, Logit (P )=1.573×Age+1.338×HE-1.608×CHO+0.011×Cr-0.109×Na+1.298×INR+11.057, was constructed by logistic regression analysis and the prognostic value of the model was higher than that of the MELD score.CONCLUSIONS: Multivariate analysis excels univariate anlysis in the prognosis of chronic severe hepatitis, and the regression model is of significant value in the prognosis of this disease.(Hepatobiliary Pancreat Dis Int 2008; 7: 40-44)KEY WORDS: chronic severe hepatitis; mortality;prognostic model;logistic regression analysisIntroductionChronic severe hepatitis is hepatic failure due to massive necrosis of hepatic cells in cases of chronic hepatic disease. Changes in thestate of illness are complex and can be accompanied by different complications. It is a severe illness with a mortality of around 50%.[1] So far, treatment of chronic severe hepatitis mainly lies in combined medications, artificial liver-support and liver transplantation.[2-4] Moreover, liver cell transplantation and stem cell transplantation are under clinical investigation.[5-7] An accurate prognosis of the patient helps appropriate selection of a treatment program. In this study, we retrospectively analysed the factors affecting mortality in chronic severe hepatitis patients, processed the data, and established a prognostic model using logistic regression.MethodsSource of dataWe retrospectively summarized the data from 239 patients with chronic severe hepatitis at our hospital from 2003 to 2006, of whom 26 were excluded for incomplete data. In the remaining 213 patients, the diagnoses conformed to the Prevention and Treatment Program for Viral Hepatitis [8] formulated at the 10thPrognostic factors for chronic severe hepatitis and construction of a prognostic modelQian Li, Gui-Yu Yuan, Ke-Cheng Tang, Guo-Wang Liu, Rui Wang and Wu-Kui CaoTianjin, ChinaOriginal Article / L iverPrognostic factors for chronic severe hepatitis and construction of a prognostic modelNational Workshop on Viral Hepatitis held in 2000 in Xi'an. They comprised 167 men and 46 women, aged from 24 to 72 years (average, 45.29±9.71 years). Sixty-seven patients were in early stage, 98 in intermediate stage and 48 in late stage. Among the 213 patients, 210 were caused by hepatitis virus (179 with hepatitis B, 26 with hepatitis E and 5 with hepatitis D), 1 by primary autoimmune biliary cirrhosis, and 2 by autoimmune hepatitis. 101 patients (47.42%) died and 112 survived within 3 months after the diagnosis.MethodsThe clinical data were collected and processed. Liver function, kidney function, blood coagulation index, AFP and values of routine blood test were evaluated within 24 hours after diagnosis. Death or survival was recorded at 3 months.For the age factor, apart from making statistics of the actual ages, we divided the patients into two groups, ≥50 years and <50 years, based on the literature and clinical experience.[9, 10]As hepatic encephalopathy (HE) has complex clinical manifestations, subjective judgment has substantial impact on diagnosis, so we divided HE into 3 classes with reference to the criteria described in Prevention and Treatment Program for Viral Hepatitis: 0, without HE; 1, with grade Ⅰor grade ⅡHE; and 2, with grade Ⅲor grade ⅣHE. The diagnosis is based on the chapter on HE in Internal Medicine(People's Medical Publishing House, 5th Edition). Infections concurrent with severe hepatitis are complex and diversified, the commonest being primary peritonitis and lung infections. To facilitate the statistics, we only recorded whether infection existed. Liver cirrhosis was judged according to medical history, clinical data, color ultrasonography, gastroscopic examination and upper alimentary tract radiography.Calculation of MELD score: MELD score=3.8×Ln (TBil [mg/dl])+11.2×Ln (INR)+9.6×Ln (Cr [mg/ dl])+6.4×pathogenic factor (cholestatic: 0, others: 1). The final result was rounded up.Unit conversion: TBil: 1 mg/dl=17.1 μmol/L; Cr: 1 mg/dl=88.4 μmol/L.Statistical analysisA database was established with the collected data by means of Microsoft Excel and simple processing was carried out. The data were then imported to SPSS 13.0 for statistical analysis. Enumeration data were assessed by the Chi-square test and measurement data were assessed by Student's t test. Logarithmic values were taken for excessively discrete data and calculated. Logistic regression analysis was then used to establish a prognostic model and ROC curves were drawn based on the prognostic model and MELD scoring. The areas under the curves were compared by the z test. ResultsAge and sex (Table 1)Sex showed no statistical significance in the comparison between deaths and survivors (P>0.05), indicating that sex has no marked impact on mortality. Age showed marked statistical significance in the comparison between deaths and survivors (P>0.01); the older the patients, the higher the mortality. The mortality of patients aged over 50 years was 73.02%, significantly higher than that of patients under 50 years (P<0.01).Impact of infection, HE and liver cirrhosis on mortality (Table 2)The total incidence rate for infection was 23.00%. In deaths it was 34.65% and in survivors 12.50% (P<0.01). Infection had a significant impact on mortality.In 44 (20.66%) of the 213 patients who contracted HE, 34 (77.27%) died and 10 survived. The more severe the HE developed, the higher the mortality.The mortality was 73.13% in patients with chronic severe hepatitis resulted from liver cirrhosis. The prognosis for those patients with liver cirrhosis was poor.Impact of assay indices on mortality (Table 3) Alanine aminotransferase (ALT, U/L), aspartateTable 1. Impact of age and sex on mortalityGroup CasesDeaths10149.87±9.4046558021 Survivors11241.15±8.0117958725t or χ27.30623.5110.073P0.000 0.0000.787Table 2. Impact of infection, HE and liver cirrhosis on mortality Group CasesDeaths1013566 6723114952 Survivors1121498102 9 11894χ214.71521.19525.927P 0.000 0.000 0.000Hepatobiliary & Pancreatic Diseases International aminotransferase (AST, U/L), albumin (ALB, g/L)and hemoglobin (HGB, g/L) showed no statisticaldifferences between the deaths and survivors (P>0.05),indicating that these indices have no marked impact on mortality. Total bilirubin (TBil, μmol/L), total cholesterol (CHO, mmol/L), cholinesterase (CHE, U/L), blood urea nitrogen (BUN, mmol/L), blood creatinine (Cr, μmol/L), blood sodium ion (Na, mmol/ L), peripheral blood leukocytes (WBC, ×109/L), alpha-fetoprotein (AFP, ng/ml), international normalized ratio (INR) of blood coagulation and prothrombin time (PT) showed statistical differences between the two groups (P<0.05 or P<0.01). Among these indices, CHO, AFP and Na were lower in deaths than in the survivors and the remaining indices were higher in deaths than in survivors.Setup of prognostic modelThe data were imported to SPSS 13.0 for logistic multi-factorial regression analysis. While the Forward LR method was used. The final equation includes the following elements such as HE, age, CHO, INR, Cr and Na. The prognosis equation was as follows: Logit(P)=1.573×Age+1.338×HE-1.608×CHO+ 0.011×Cr-0.109×Na+1.298×INR+11.057.Logit (P)=ln [P/(1-P)]; P=1/(1+e-Logit(P)).Patients with P>0.5 were judged as deaths and those with P<0.5 as survivors; or if Logit(P) was >0 the patients was judged as death, while if Logit(P) <0 was judged as survivors. The accuracy was 83.6% when this equation was used in the judgment, with a sensitivity of 85.11% and a particularity of 82.35%. The model coefficient was statistically significant (χ2=143.709 and P=0.000); the model Hosmer-Lemeshow test of fit gives χ2=7.253, P=0.510. The regression coefficients in the model show statistical significance (Table 4). Prognostic judgment value of regression model and MELD scoringWe calculated the results of the regression models for all patients as well as the MELD scoring and drew the survival curves with SPSS 13.0. The areas under the curves were 0.836 and 0.916 (P=0.000). The difference was statistically significant and the above models all were of value of prognostic judgement. Upon further z testing, the areas under the regression model curve and the MELD curve (z=2.423, P<0.05) were significantly different, the area under the curve of the regression was greater, and the prognostic judgement value was greater than that of the MELD scoring (Fig.).DiscussionChronic severe hepatitis is a serious illness with a high mortality rate. Much research has been done world-wide about the factors affecting the prognosis of severe hepatitis. Different countries have,one Fig. ROC curves of CA19-9, CA242, CA50 and CEA.Table 3. Comparison of laboratory indices between deaths and survivorsItem Deaths Survivors t PLog (ALT)* 2.29±0.45 2.27±0.430.3150.753 Log (AST)* 2.37±0.37 2.30±0.38 1.2470.214 Log (TBil)* 2.62±0.10 2.57±0.11 3.5350.001 CHO 1.40±0.48 1.82±0.45 6.6240.000 Log (CHE)* 3.44±0.21 3.49±0.19 2.1380.034 ALB 28.82±3.48 29.41±3.43 1.2350.218 Log (BUN)* 0.80±0.36 0.68±0.28 2.6840.008 Log (Cr)* 2.11±0.34 1.87±0.19 6.2410.000 Na124.88±9.28132.49±6.297.0680.000 Log (WBC)* 0.87±0.23 0.72±0.21 4.7060.000 HB104.10±19.19105.36±19.540.4760.635 Log (AFP)* 1.31±0.43 1.76±0.467.4280.000 INR 3.11±0.99 2.50±0.59 5.5220.000 PT 35.79±11.40 28.76±6.80 5.5210.000Table 4. Regression coefficients and statistical tests of the indices in the final regression modelIndex βSE Wald df P Exp(β)HE 1.3380.470 8.09610.004 3.812 CHO-1.6080.46611.92510.0010.200Cr 0.0110.00315.54710.000 1.011Na-0.1090.02914.11410.0000.896 INR 1.2980.29818.98510.000 3.663 Constant11.057 3.795 8.48810.00463396.396*:Since the raw data were excessively discrete, showing abnormal distributions, we took their logarithmic values for comparison.Prognostic factors for chronic severe hepatitis and construction of a prognostic modelafter another, formulated scoring criteria, such as MELD scoring and KING scoring. Among them, the MELD scoring has been important in determining the order of liver transplantation.[11-18]Because of the causes of severe hepatitis are different in China, however, the diagnostic criteria are also different. For chronic severe hepatitis, investigators in China have formulated the diagnostic criteria according to their clinical experience. Discussion of China's prognostic judgment criteria for chronic severe hepatitis is of great value in clinical practice.In this study, the single-factor analysis showed significant differences between deaths and survivors in terms of their age, liver cirrhosis, infection, and levels of HE, TBil, CHO, CHE, BUN, Cr, Na, WBC, AFP, INR and PT. This finding indicates that the above-mentioned indices have great impact on judging the mortality rate of severe hepatitis. On the other hand, there were no significant differences in levels of ALT, AST, ALB and HGB. These results were consistent with those of other studies.[19-22] But single-factor analysis cannot fully reflect the complexity of liver function and the interrelations among various factors. Deviations may arise when it is used in analyzing disease conditions while making prognostic judgment. Along with the development of medical statistics, multi-factorial prognostic analysis, such as logistic regression analysis and Cox regression analysis, has been widely used. In our study the above-mentioned data were introduced into logistic regression analysis and a regression equation was established. The results showed that age, HE, CHO, Na, INR, and Cr are the indices of the greatest prognostic significance.Among the indices that make up this model, the value of the coagulation index in judging the mortality rate of chronic severe hepatitis is universally recognized. INR is the INR of PT, it balances the influences of different reagent manufacturers and different labs and increases the comparability of the test results from different hospitals. Many studies have verified that age, HE and Cr (or BUN) are independent indices that influence the mortality rate of severe hepatitis.[23, 24] In recent years, the influence of blood sodium on the prognosis of chronic severe hepatitis has attracted attention of researchers. Hyponatremia can result in loss of homeostasis or induce and aggravate hepatic coma and hepatorenal syndrome. Our study show that the lower level of blood sodium is related to the higher mortality rate. Blood sodium is also an independent factor influencing the prognosis of chronic severe hepatitis.[25] The level of cholesterol in dead patients is significantly lower than that in survivors,[26] but this has not received due attention. In this prognostic model, the level of cholesterol was an independent index affecting chronic severe hepatitis, and its value is in reverse proportion to the mortality rate. Our prognostic model reflects the synthesis functions of the liver and complications and shows that the identified factors are sensitive in the judgment of the mortality rate of patients with severe hepatitis. Indices reflecting the metabolic functions of the liver and indices reflecting the regeneration of liver cells, such as TBil and AFP, were eliminated in the regression analysis even although they differed significantly between deaths and survivors. Hence these factors are not very sensitive in prognostic judgment.The forecast accuracy of the prognostic judgment model established in this study was 83.6%. By comparing the areas below the ROC curves, we found that our model is of prognostic judgment value which is markedly higher than that of the MELD scoring. In the MELD scoring system, the cholestatic or alcoholic factor is set at 0 and other diseases are set at 1; but as chronic severe hepatitis is predominantly viral in China, this factor is not obviously significant. As compared with the MELD scoring, our model incorporates indices that have greater impact on the prognosis of chronic severe hepatitis (Na, CHO, age, and HE) but excludes bilirubin and its pathogenic factors. Except for HE, which is a subjective index, the indices used in this model are actually tested values. It is comparatively simple and manual calculation is possible, while the MELD scoring requires natural logarithmic values, making calculation complicated.As this research used cases exclusively from our hospital, this model was certainly subjected to the impact of geographical factors and the level of diagnosis and treatment. It is only intended to serve as a research method. To obtain a prognostic model that suits China's reality, we should use a forward-looking, polycentric and large-sample research approach, establish uniform standards for diagnosis and treatment and data collection, and use the Cox regression analysis to establish the best prognostic model for wide application.Funding: None.Ethical approval: Not needed.Contributors: LQ proposed the study and wrote the first draft. YGY analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. LQ is the guarantor.Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.Hepatobiliary & Pancreatic Diseases InternationalReferences1 Z hang DF. Hepatitis B: Pathogenesis and Clinic,Chongqing Publishing House;1998:264.2 H eidelbaugh JJ, Sherbondy M. Cirrhosis and chronic liverfailure: part II. Complications and treatment. 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