Metabolic Factors In Clinical Problems Associated With Cirrhotic Inpatients: A Retrospective Study

Background Liver cirrhosis is one of the most common chronic liver disease.Along with the Ministry of Health recommended routine immunization with the hepatitis B vaccine for routine immunization of infants since 1992, the positive ratio of Hepatitis B surface antigen declined from 9.8% to 7.2% in people aged 1-59 years old,and was only 1% in children aged under 5 years old. All these means that effective control of Hepatitis B virus infection and less importance of HBV in etiology of liver cirrhosis. Also, with the change of life style and improvement of life quality,the prevalence of obesity,diabetes,arterial hypertension and metabolic syndrome is growing. In 2002,the prevalence of obesity in China reached 7.1%, increasing obviously. Because of this, researchers payed more attention on the impact of metabolic factors on liver disease,especially on non-alcoholic fatty liver disease(NAFLD). In western countries,the prevalence of NAFLD was reported 30%,and the incidence of non-alcohlic steatohepatitis(NASH) and its related liver cirrhosis increased in recent years.In our country, the prevalence of NAFLD was about 15% in developed city such as Guangzhou and Shanghai.However, less is known about the data in general population of the whole country.And even less about the etilogical proportion of NASH related liver cirrhosis(NASH-LC) in total cirrhotic inpatients.Moreover,metabolic factors were reported to be associated with hepatocellular carcinoma(HCC).So the background of metabolic factors in cirrhotic patients is worth to be studied and whether the proportion of etiologies for cirrhosis is changing is also worth getting more attention. Obesity,diabetes and metabolic syndrome have been confirmed to be risk factors of arterial thrombosis,and they are also be considered as the important risk factors for venous thrombosis. Venous thrombosis was thought to be one manifestation of metabolic syndrome.Portal vein system thrombosis(PVST) is one common complication of liver cirrhosis, recent researches are mainly on the impact of hemodynamics on PVST. But less is known about the metabolic factors on the formation of PVST and there are also contravasaries about its impact on prognosis of cirrhosis.On one hand, cirrhotic patients are always with malnutrition status which is associated with increased mortality. On the other hand, obesity means excessive calorie in body. There are needs for more studies on the impact of metabolic factors on prognosis of non-neoplastic liver cirrhosis. Because of all the above, our study paid more attention on the metabolic factors in etiologies of cirrhosis and PVST in order to know its impact on the progression and prognosis of cirrhosis.Objective Several main aims are as follows.First, to know the ratio of obesity, diabetes,hypertension and metabolic syndrome in liver cirrhosis.Second, to know the proportion of NASH-LC in etiologies of cirrhosis and its changing trend.Third,to know the impact of metabolic fators on the risk of HCC.Forth,to know the effect of metabolic factors in the progression of PVST and prognosis of cirrhosis.Patients and Methods Part1.Clinical epidemiological research of metabolic factors in cirrhotic inpatients Patients:We reveiwed medical records of cirrhotic inpatients from June 2003 to July 2013 in our hospital,and 1582 patients were included.There were 1097 males and 485 females,the sex ratio was 2.26:1. And the average age was 52.8±12.8 years old. Methods: We reviewed the etiologies of all patients according to different standards for each kind of liver cirrhosis.For NASH-LC, the standard for diagnosing was made according to one Japan nationwide study.First, clinical supposed NASH-LC:○1 Alcohol consumption less than 20 g per day;○2No other etiology for liver cirrhosis;○3Body mass index over 25 Kg/m2 was necessary, combined with or without diabetes or metabolic syndrome which might induce NAFLD.If patients fulfilled the above criteria,then he could be diagnosed as NASH-LC clinically.Second, if clinical diagnosed NASH-LC met histological changes of NASH, such as micronodular cirrhosis,perisinudol fibrosis or fatty change, histological diagnosis of NASH-LC would be done.Besides the etiological information, we also collected information about metabolic factors, complications, labtorary tests and Child-Pugh scores according to the table we designed(available in supplement). Part2:Retrospective study of metabolic factors in non-neoplastic portal vein system thrombosis of cirrhosis Patients:On the basis of the information of 1582 cirrhotic patients in Part 1, we set criteria to include cirrhotic patients for this study. Inclusion criteria: :○1patients diagnosed as liver cirrhosis without HCC; ○2 patients got examination of enhanced comptuted tomograph(CT);Exclusion criteria:○1patients who did not get CT examination; ○2patients only get ordinary CT without enhanced CT; ○3patients with HCC;○4patients with other kinds of tumors;○5patients with liver transplantation;○6patients only with only endoscopy examination;○7the CT images could not be obtained.After all, 722 cirrhotic patients were included with 491 males and 231 females, and the average age was 53.8±12.9 years old. Methods: We collected CT images to know whether patients had PVST and to measure several main parameters according to our table(available in supplement), such as diameter of main portal vein,superior mesenteric vein and splenic vein.We followed up patients by phone call till the end of death or 31 st Dec 2015.Results Part1. Clinical epidemiological research of metabolic factors in cirrhotic inpatients 1.Etiology of liver cirrhosis The total number of cirrhotic patients was 1582, the most common etiology of liver cirrhosis was HBV infection.The positive ratio of Hepatitis B surface antigen is 68.5%(1083patients). HBV was found to be the only etiological factor in 938(59.3%) patients. In total, 298(18.7%) patients had a history of alcohol abuse(135 of them also had HBV infection, and 5 patients also had HCV infection; alcohol was the dominant factor in 158 patients). For NASH-related LC, 30 patients(1.9%)met our criteria. The proportion of NASH-LC was increasing in the whole cirrhotic patients and reached over 3% during 2011-2013. HBV was clearly the main etiology in both males and females(59.8% vs. 57.9%, respectively, p>0.05).The ratio of patients with alcohol abuse, HBV plus alcohol abuse, and HCV plus alcohol abuse were higher in males vs. females(11.2% vs. 1.0%, po0.01; 12.2% vs. 0.2%, p<0.01; and 0.5% vs. 0%, p<0.01, respectively). However,the ratios of AIH and PBC were much higher in females vs. males(4.9% vs. 0.7%, p<0.01; 12.6% vs.0.7%,p<0.01, respectively). No difference of the ratio of NASH-related LC between males and females existed(1.7% vs. 2.3%,respectively, p=0.47). 2.Clinical epidemics of metabolic factors in liver cirrhosis The average BMI of cirrhotic patients was 22.1±3.3 Kg/m2.The ratio of obesity was 14.5%, DM was 10.1% and hypertension 8.2%. No difference of the ratio of metabolic factors in cirrhotic inpatients was found between 2003-2008 to 2008-2013. 3.Comparision of hepatitis B virus related liver cirrhosis(HBV-LC) and NASH-LC Comparied with HBV-LC group, the patients of NASH-LC were elder(57.66±14.06 vs.50.15±11.69,p<0.01),and the sex ratio of NASH-LC group was smaller(1.73 vs. 2.34, p<0.01). Child-Pugh grades were mainly in A and B for NASH-LC group, the proportion of Child-Pugh C in NASH-LC was much smaller than that of HBV-LC(6.7% vs. 26.4%,p<0.01). No one in the NASH-LC group got HCC while the ratio of HCC in HBV-LC was 6.71%. 4.Risk factors of HCC The ratio of HCC during 2008-2013 was decreasing based on our data, compaired with that of 2003-2008(4.7% vs.7.3%,p=0.033). Only the sex ratio(male to female) and HBs Ag positivity ratio were significantly higher in HCC patients compared with non-HCC patients(p<0.05) by univariate analysis. Metabolic factors, which included obesity, DM, and hypertension, were not significantly different between HCC and without HCC. HBs Ag positivity was the sole risk factor for HCC in cirrhotic patients(p<0.001) in a multivariate analysis. Obesity and DM did not increase the HCC ratio in the whole cirrhotic group(5.7% vs. 5.5%, p=0.862; 5.0% vs.5.6%, p=0.849, respectively). However, among patients with cirrhosis induced only by HBV, a trend of higher ratio of HCC in obese and DM patients was found(8.4% vs. 6.5%,respectively, p=0.436; 7.1% vs. 6.7%, respectively, p=0.589) but without statistically significance. Part2: Retrospective study of metabolic factors in non-neoplastic portal vein system thrombosis of cirrhosis 1.Ratio of non-neoplastic PVST in cirrhosis 722 patients met our inclusion criteria, the ratio of obesity, DM, hypertension and Mets was 15.1%,12.0%,9.3% and 14.9% respectively. The ratio of PVST was 10.8%. There was no difference of the PVST ratio between each etiology in cirrhosis(p=0.598). The baseline of characteristics between PVST and non-PVST were similar, no significant difference exist in age,sex,BMI and Child-Pugh scores. 2.CT parameters The results of CT measurements found that diameter of main portal vein,superior mensentric vein and splenic vein of PVST were wider than that of non-PVST(p=0.00).And so were the anteraposterior,vertical, horiontal diameter of spleen(p=0.00). 3.Yerdel classification For the 78 PVST patients, only 59(75.6%,59/78) patients were suitable for Yerdel classification. 33(42.3%,33/78)of them were main portal vein thrombosis, and 26( 33.3%, 26/78) were both main portal vein and superior mesenteric vein thrombosis.According to Yerdel classificatio, 39 patients(66.1%,39/59) were Grade I and 19 patients(32.2%,19/59)were Grade II, only 1(1.7%,1/59)were Grade III. For the 19 PVST patients( 24.4%, 19/78) who were not suitable for Yerdel classification, 4 patients(5.1%,4/78) had thrombosis of all main portal vein, superior mesenteric vein and splenic vein. 5 patients(6.4%,5/78) were both thrombosis of main portal vein and splenic vein. 7 patients(9.0%,7/78) were only with superior mesenteric vein thrombosis,and 3 patients(3.9%,3/78) were only with splenic vein thrombosis. 4.Risk factors of PVST By logistic regression multivariate analysis, SMV( OR 11.247, 95%CI 3.844-32.904),anteraposterior diameter of spleen(OR 1.19,95%CI 1.077-1.316)and PLT(OR 1.007,95%CI 1.002-1.012)were the independent risk factors for PVST, while obesity was independent protective factor for PVST(OR 0.17,95%CI 0.04-0.75). DM,hypertension and Mets were not associated with PVST. Also Child-Pugh grades was not associated with PVST. 4.Prognosis of PVST Kaplan-Meier survival curve showed that survival rate of PVST was lower than that of non-PVST, but without significance(2c=3.278,P=0.070). Patients with obesity had a higher survival rate than that without obesity,but also without significance(2c =3.012,P=0.083).No difference of survival rate between patients with and without DM and hypertension(2c =0.013,P=0.909;2c =0.468,P=0.494).Cox regression showed that older age(HR 1.05,95%CI 1.017-1.084),MPV(HR 13.413,95%CI 3.29-54.61),vertical diameter of spleen(HR 1.335,95%CI 1.166-1.527),hyper brililiemia(HR1.009,95%CI 1.005-1.013)and HE(HR5.022,95%CI 1.569-16.076) were risk factors for prognosis of cirrhosis, but BMI was the only protective factor for prognosis(HR 0.79,95%CI 0.69-0.90).Conclusions 1.HBV infection was still prior to etiologies of liver cirrhosis, no obvious change was seen in the etiolgical proportion of whole cirrhosis for HBV.The proportion of NASH-LC was increasing in liver cirrhosis and was over 3% during 2011-2013.Compared with HBV-LC, NASH-LC was lower in age and better in liver function.In recent decades, the ratio of obesity,DM and arterial hypertension in liver cirrhosis did not change significantly. But the ratio of HCC in cirrhotic patients was decreasing based on our data. Obesity,DM and hypertension was not associated with HCC in whole cirrhotic patients according to our data.But HBV combined with obesity or DM might increase the ratio of HCC. 2. The ratio of non-neoplastic PVST in liver cirrhosis was 10.8%,similar with other studies in and out of China.Yerdel classification could not be applied for all kinds of PVST, so we classified PVST as follows:first, simple type(a,b,c),a means main portal vein thrombosis, b means simple superior mesenteric vein thrombosis and c means simple splenic vein thrombosis.Second, combined type(a,b,c),a means main portal vein thrombosis combined with superior mesenteric thrombosis, b means main portal vein combined with splenic vein thrombosis,and c means all PVST thrombosis,including main portal vein and superior mesenteric vein and splenic vein thrombosis.Diameter of superior messentric vein, anteroposterior diameter of spleen and platelet count is independent risk factors for PVST. BMI is not associated with PVST, but BMI≥25Kg/m2 is independent protective factor for PVST. DM,arterial hypertension and Mets are not associated with PVST. Older age,diameter of main portal vein, vertical diameter of spleen, hyperbilirubinemia and hepatic encephalopathy are risk factors for prognosis of liver cirrhosis. PVST and metabolic factors are not associated with prognosis of cirrhotic patients. BMI is a protective factor for prognosis of liver cirrhosis, which might mean that better nutrition status predicts better prognosis.