Chinese Medical Journal 2013;126(13):2430-2434
Etiological features of cirrhosis inpatients in Beijing, China

SONG Guang-jun, FENG Bo, RAO Hui-ying and WEI Lai

Keywords
etiology; cirrhosis; hepatitis B; hepatitis C; autoimmune liver disease; alcoholic liver disease
Abstract
Background The etiological spectrum of cirrhosis has changed over the years, but our knowledge of it is limited. The present study aimed to investigate the etiological features of cirrhosis inpatients and their variation in the past 18 years in Beijing.
Methods A retrospective analysis was performed on all patients with cirrhosis diagnosed for the first time in Peking University People’s Hospital from January 1, 1993, to October 25, 2010. Data were analyzed using SPSS 20.0.
Results A total of 2119 cirrhosis inpatients were included in this study: 1412 (66.6%) male and 707 (33.4%) female. Chronic hepatitis B accounted for 58.7%; chronic hepatitis C for 7.6%; chronic hepatitis B and hepatitis C virus co-infection for 0.8% (16 cases); alcoholic liver disease for 9.4% (200 cases); and autoimmune diseases for 9.4% (199 cases). In the past 18 years, the percentage of chronic hepatitis B has decreased from 75.2% to 48.7%; alcoholic liver disease has increased from 5.1% to 10.6%; and autoimmune disease has increased from 2.2% to 12.9%. The percentages of chronic hepatitis B and alcoholic liver disease were higher among men, whereas the percentages of chronic hepatitis C, autoimmune diseases and cryptogenic cirrhosis were higher among women.
Conclusions Chronic hepatitis B was still the most common etiology of cirrhosis in China, but the percentage has been decreasing. The percentages of alcoholic liver disease and autoimmune diseases have been increasing. The etiological spectrum of cirrhosis inpatients differed significantly according to sex.
Cirrhosis representsthe final common pathway of virtually all chronic liver diseases, and is characterized by an accumulation of extracellular matrix rich in fibrillar collagen.1It ultimately results in liver failure and portal hypertension, and is associated with an increased risk of liver cancer. Many patients remain asymptomatic until the occurrence of decompensation, characterized by ascites, variceal bleeding, spontaneous bacterial peritonitis, hepatic encephalopathy, or hepatorenal syndrome.
Cirrhosis is a major cause of death, accounting for an estimated 800 000 deaths each year worldwide (WHO Mortality Database, 2006). Cirrhosis is reported to be the sixth or seventh most common cause of death in the 25–44 and 45–64 years age groups in the United States.2Liver diseases including cirrhosis are one of the 10 leading causes of morbidity and mortality in China and Korea.3
Chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV), and alcohol consumption are the major global causes of cirrhosis, but the epidemiology and etiology are not well described. Alcohol and HCV are common causes of cirrhosis in European, North American and other developed countries, whereas HBV is the major cause in many Asian and African countries.4,5HBV is the most common cause of cirrhosis in Korea3and Hong Kong (China).6The major etiology of cirrhosis in Japan remains HCV.7
Undoubtedly chronic hepatitis B (CHB) is the major etiology of cirrhosis in China, but with economic progress, especially vaccination programs, potent antiviral therapies for chronic hepatitis, and increasing alcohol consumption, the etiological spectrum of cirrhosis inpatients has probably changed. Data regarding these changes are limited.
This study was a retrospective study of 2119 cirrhosis inpatients diagnosed for the first time in Peking University People’s Hospital from January 1, 1993, to October 25, 2010, to explore the etiological features of cirrhosis inpatients and the variation in its etiology over the past 18 years in China.
METHODS
Patients
We included 2119 cirrhosis inpatients diagnosed for the first time in Peking University People’s Hospital from January 1, 1993, to October 25, 2010.There were 1412 (66.6%) male and 707 (33.4%) female patients. The mean age of the male patients was (52.77±12.60) years, and that of the female patients was (57.71±12.80) years. The male patients were significantly younger (t= –8.465,P<0.01). The following information was obtained from medical records: sex; age at diagnosis; alcohol consumption; etiology of cirrhosis; presence of ascites and esophageal varices; laboratory data including hepatitis virus, autoimmune markers, serum copper, and ceruloplasmin; and abdominal ultrasonography or computed tomography (CT) outcome.
Criteria for diagnosis of cirrhosis7
Diagnosis of cirrhosis was established by a combination of clinical, biochemical, serological, radiological and histological features, where appropriate. Liver biopsy was not available in all patients. The diagnosis was based on confirmation of the presence of cirrhosis by liver histology, or unequivocal evidence on abdominal ultrasonography or CT (left lobe hypertrophy with splenomegaly, irregular margins of the liver, nodular changes in liver surface, nodularity of the liver with or without presence of portal hypertension: dilated portal vein, splenomegaly and esophageal varices). Laboratory findings (low platelet count, albumin, and/or prolonged prothrombin time) compatible with cirrhosis were also considered, and diagnosed in patients with clinical findings of esophageal varices, ascites, or hepatic encephalopathy.
Criteria for etiology of cirrhosis
The diagnosis of CHB was based on positivity for hepatitis B surface antigen (HBsAg) for at least 6 months.8Chronic HCV infection (CHC) was diagnosed in patients with positive anti-HCV antibody and detectable serum HCV RNA.9Diagnosis of alcoholic liver disease (ALD) was made in cases with elevated liver enzymes and a history of alcohol abuse, without any other known cause of liver injury. Alcohol abuse was defined as mean daily alcohol consumption >40 g for men or >20 g for women at least during the past 5 years.10CHB or CHC in combination with alcoholic liver injury indicates that the patients have a history of alcohol consumption, but some of them may not reach the standard for ALD diagnosis. Autoimmune markers including antinuclear antibody, anti-smooth muscle antibody, soluble liver antigen, liver kidney/microsome, anti-mitochondrial antibody, and perinuclear anti-neutrophil cytoplasmic antibody were routinely screened. Diagnosis of autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) was made according to the guidelines.11-13Serum copper, ceruloplasmin, serum iron, serum transferrin andα-1 antitrypsin levels were measured in cases in which the etiology was not obvious, and diagnosis was made according to the American Association for the Study of Liver Diseases (AASLD) guidelines.14Other causes such as drug-induced cirrhosis, idiopathic portal hypertension, and cardiac cirrhosis were decided upon by a group of specialists. The cause was accepted to be cryptogenic when all the above causes were excluded. Unknown of the causes means the cirrhosis inpatients were enrolled in hospital because of other diseases, not further identifying the etiology of the cirrhosis, or because the patient’s condition was serious, having no time to make the etiology clear.
Statistical analysis
Data were analyzed using SPSS version 20.0 (SPSS Inc., USA). Quantitative variables were expressed as mean ± standard deviation (SD). Statistical analysis was performed using thettest. Comparison between proportions was carried out using the χ2test. The method of the trend test15was to calculate the ordinal of each observed value; the ordinal was the number of observed values that were greater than and less than the observed value. The statistical hypothesiswas tested by the formula:
u=|r–R|÷σr=|4∑P÷n(n–1) –1–R|÷[2 (2n+5)÷9n(n–1)]–2
∑P: sum of the ordinals;n: number of observed values; r: trend coefficient, r= +1, escalating trend steady, r= –1, downtrend steady; R: overall trend coefficient, based on the test of statistical hypothesis, R=0; σr: population standard derivation, samplestandarddeviationserves as theestimated value of the population standard derivation. α=0.05,u0.05=1.96. A value ofP<0.05 was considered statistically significant.
RESULTS
Age distribution
The detailed age distribution was shown in Figure 1. The majority of patients (1599 (75.46%)) were in the 40–65 years age group.
Etiology spectrum
Chronic HBV infection was the most important cause of cirrhosis among inpatients in China, accounting for 58.7% (1245 cases). CHC accounted for 7.6% (161 cases), chronic HBV and HCV co-infection 0.8% (16 cases), ALD 9.4% (200 cases), and autoimmune diseases including AIH, PBC, PSC, Sjogren’s syndrome, and systemic sclerosisaccounted for 9.4% (199 cases). Other infrequent causes such as Wilson’s disease, drug-induced cirrhosis, idiopathic portal hypertension, and cardiac cirrhosis accounted for 3.7% (79 cases); cryptogenic cirrhosis 5.3% (113 cases); and unknown cause 5.0% (106 cases). The above percentages are shown in Figure 2, and the autoimmune diseases are outlined in Table 1, including one case of Sjogren’s syndrome in combination with progressive systemic sclerosis, and one case of systemic sclerosis in combination with secondary Sjogren’s syndrome. Among these, 172 (86.4%) cases were female and 27 (13.6%) were male.
Change in etiological spectrum in the past 18 years
Eighteen years were divided into six equivalent time segments of 3 years. The trendutest revealed that cirrhosis morbidity of inpatients was stable (u=1.32,P >0.05). The percentage of cirrhosis due to CHB was decreasing (u=2.82,P<0.05): in the first 3 years it accounted for 75.2%, and in the sixth 3-year period, it accounted for 48.7%; a decrease of 35.2% (χ2=32.73,P<0.01). ALD had increased from 5.1% to 10.6% (χ2=3.94,P=0.047), but the ascending trend was not significant (u=1.69,P >0.05). Autoimmune diseases had increased from 2.2% to 12.9%(χ2C=12.27,P<0.01), and the ascending trend was significant (u=2.82,P<0.05) (Table 2 and Figure 3). The etiology of CHC in the first 3 years accounted for 4.4%, and in the sixth 3-year period, for 7.9% (χ2C=2.08,P=0.15).
Comparison among different etiology groups
The average age of the CHB group was (52.38±11.77) years, and that of the CHC group was (60.04±11.58) years. The difference between them was significant (t= –7.783,P<0.01).
The CHB group was divided into two subgroups; one had no history of alcohol consumption, and the other did have a history, but some of them may not have reached the level for ALD diagnosis. The average age of the first group was (53.06±12.18) years and the second was (49.71±9.54) years, and the difference between them was also significant (t=4.679,P<0.01).
Sex differences
Table 3 showed differences in the etiology of liver cirrhosis between male and female patients. The percentages of CHB and ALD were higher among male than female patients, whereas the percentages of CHC, autoimmune diseases andcryptogenic cirrhosis were higher among female patients.
DISCUSSION
HBV infection is prevalent in China. Undoubtedly, CHB is the most frequent etiology of cirrhosis in Chinese inpatients, as in Korea,16-18which differs from developed countries. In the western world the escalation in the incidence of cirrhosis has been attributable to three main causes: alcohol abuse, HCV and nonalcoholic fatty liver disease (NAFLD).19In our study, the percentage of cases of cirrhosis caused by CHB decreased from 75.2% to 48.7%; a decrease of 35.2% in the past 18 years. A similar decreasing tendency was also seen in Korea,3but not in Hong Kong (China).6The change was probably due to the introduction of antiviral therapy for hepatitis B. In China, some effective measurements have been taken to control HBV infection, including vaccination programs, strengthening the management of blood sources and blood products, prevention of nosocomial HBV infection, and improving health education on HBV infection and safe injection techniques. According to the 2006 survey of the national screening program for HBV, the incidence of HBsAg positivity had decreased by 26.36% compared with 1992, and the number of children who had ever been infected by HBV had decreased by 80 million since 1992. In children aged <10 years, the proportion carrying HBV has decreased to 0.53% in Shanghai. In some rural areas, HBV carriers have decreased to 1%–2%, as long as all newborns are vaccinated according to schedule.20
Despite its decreasing incidence, in the near future CHB will remain the major cause of cirrhosis in China. Although vertical transmission of HBV differs among countries and races, it is the main mode of transmission in Asia.21It is estimated that 50% of HBV infections are from carrier mothers to infants born in China.22Patients with CHB were mostly born before China officially introduced hepatitis B vaccination into their national immunization programs, and some of these patients will inevitably develop cirrhosis in the future. There is a higher percentage of male patients with CHB; probably owing to women having resistance than men to HBV,23and the sex difference in the persistence of HBV infection needs further investigation. The CHB subgroup with alcohol consumption was younger than that without alcohol consumption, probably because alcohol can be a significant cofactor in addition to other causes of chronic liver disease, which indicates that CHB patients should not consume a lot of alcohol.
In this study, ALD and autoimmune diseases were both secondary causes of cirrhosis, representing 9.4%, respectively. The percentage of cirrhosis caused by ALD was lower than that in the western world,24and closer to that in Japan7and Korea.3In this study, the percentage increased from 5.1% to 10.6% in the past 18 years; probably related to the increasing average per capita alcohol consumption.
The percentage of inpatients with cirrhosis due to autoimmune diseases increased from 2.2% to 12.9% in this study. New techniques and detection methods have made it easier to detect a variety of autoantibodies, which may help us to diagnose corresponding autoimmune diseases. The rapid increase was also probably related to the rise in the morbidity of the autoimmune diseases themselves, due to environmental and climatic changes. In clinical practice, adequate importance should be attached to ALD and autoimmune diseases.
In our study, 7.6% of the cases of cirrhosis were attributed to CHC, which was similar to Hong Kong (China).6The mean age of patients with HCV-associated cirrhosis was found to be higher than that of the CHB group. In leading to cirrhosis, CHC progresses more slowly than CHB, and in CHC patients, time from infection to cirrhosis is prolonged, with a rate of 20% after 20 years and 70% after 60 years.24In the past 18 years, the percentage of patients with CHC-associated cirrhosis had not changed significantly,but it is anticipated that HCV-related cirrhosis will increase in the future. The percentage of HCV-related cirrhosis was higher among female patients; probably because they are more likely to undergosurgery or blood transfusion during childbirth.
NAFLD is a common condition25that usually does not result in advanced liver disease. However, in the subgroup of patients with nonalcoholic steatohepatitis (NASH), some may progress to end-stage liver disease.26In the USA, NASH has emerged as an important cause of cirrhosis, representing 2.9% of 546 liver transplantations performed at the Mayo Clinic in 1993–1998.27In the present study, NASH-related cirrhosis was classified as cryptogenic cirrhosis because no etiological factor was found.
There were some possible limitations to our study. The data came from a single hospital, and a small number of patients were enrolled. Nevertheless, the patients admitted to our hospital come from all over the country, especially Northern China; therefore, our results could give us information for all over the country, especially the northern area. More hospitals and more patients are needed to study the alterations in the etiology of liver cirrhosis in China.
In conclusion, CHB is the most common etiology of cirrhosis in Chinese inpatients, although the percentage has been decreasing. ALD and autoimmune diseases are the second and third causes, respectively, and have been on the increase. The etiological spectrum of cirrhosis differs significantly between male and female patients.
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(Received January 17, 2013)
Edited by JI Yuan-yuan
DOI: 10.3760/cma.j.issn.0366-6999.20130184
Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University, Beijing 100044, China (Song GJ, Feng B, Rao HY and Wei L)
Correspondence to: WEI Lai, Peking University People’s Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Peking University, Beijing 100044, China (Email:weilai@pkuph.edu.cn)

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Figure 1.Numbers and percentages of cases of cirrhosis in different age groups.
Figure 2.Percentages of patients with different etiology of cirrhosis.
Figure 3.Variation in percentages of cirrhosis caused by CHB, ALD and autoimmune diseases. CHB accounted for 75.2% of cases of cirrhosis in the first 3 years, and 48.7% in the sixth 3-year period; a decrease of 35.2% (χ2=32.73,P<0.01). ALD increased from 5.1% to 10.6% (χ2=3.94,P=0.047), and autoimmune diseases from 2.2% to 12.9% (χ2=12.27,P<0.01).
Table 1.Etiologies of presentation of the autoimmune diseases
Etiologies Number of patients (n) Percentage (%,n/199)
PBC 131 65.8
AIH 19 9.6
PSC 3 1.5
SS 14 7.0
PBC+SS 22 11.1
AIH+SS 6 3.0
AIH+PBC 2 1.0
PBC: Primary biliary cirrhosis; AIH: Autoimmune hepatitis; PSC: Primary sclerosing cholangitis; SS: Sjogren Syndrome.
Table 2.Variation tendency of different etiology in recent 18 years (6 time segments)
Items 1993–1995 1996–1998 1999–2001 2002–2004 2005–2007 2008–2010 uvalues Pvalues
Total inpatients*(n) 37464 49430 70068 79192 102073 131352
Cirrhosis†(n(%)) 137 (0.366) 182 (0.368) 294 (0.420) 383 (0.484) 347 (0.340) 776 (0.591) 1.32 >0.05
CHB‡ 103 (75.2) 125 (68.7) 199 (67.7) 237 (61.9) 203 (58.5) 378 (48.7) 2.82 <0.05
ALD‡ 7 (5.1) 7 (3.8) 26 (8.8) 43 (11.2) 35 (10.1) 82 (10.6) 1.69 >0.05
Autoimmune diseases‡ 3 (2.2) 6 (3.3) 15 (5.1) 36 (9.4) 39 (11.2) 100 (12.9) 2.82 <0.05
*: The number of total inpatients during corresponding time segment. †: Cirrhosis inpatients diagnosed for the first time during corresponding time segment absolute number as well as the percentage in total inpatients. ‡: Cirrhosis inpatients due to CHB, ALD or autoimmune diseases absolute number as well as the percentage in total cirrhosis inpatients.
Table 3.Etiology spectrum in different genders
Gender CHB CHC ALD Autoimmune diseases Cryptogenic cirrhosis
Male (%) 67.4 6.0 14.1 1.9 2.8
Female (%) 41.6 10.7 0.14 24.3 10.3
χ2values 1.29 15.01 105.66 2.13 67.73
Pvalues <0.01 <0.01 <0.01 <0.01 <0.01
CHB: chronic hepatitis B; CHC: chronic hepatitis C; ALD: alcoholic liver disease.
The percentages of CHB and ALD were higher among males, whereas the percentages of CHC, autoimmune diseases and cryptogenic cirrhosis were higher among females.