Cirrhosis representsthe final common pathway of virtually all chronic liver diseases, and is characterized by an accumulation of extracellular matrix rich in fibrillar collagen.1
It 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.2
Liver 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
HBV is the most common cause of cirrhosis in Korea3
and Hong Kong (China).6
The 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.
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.8
Chronic HCV infection (CHC) was diagnosed in patients with positive anti-HCV antibody and detectable serum HCV RNA.9
Diagnosis 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.10
CHB 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.14
Other 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.
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 χ2
test. The method of the trend test15
was 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, samplestandarddeviation
serves as theestimated value of the population standard derivation. α=0.05,u0.05=1.96. A value ofP<0.05 was considered statistically significant.
The detailed age distribution was shown in Figure 1.
The majority of patients (1599 (75.46%)) were in the 40–65 years age group.
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%(χ2
C=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% (χ2
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).
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.
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).19
In 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,3
but not in Hong Kong (China).6
The 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.21
It is estimated that 50% of HBV infections are from carrier mothers to infants born in China.22
Patients 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,23
and 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,24
and closer to that in Japan7
In 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).6
The 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.24
In 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 condition25
that 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.26
In the USA, NASH has emerged as an important cause of cirrhosis, representing 2.9% of 546 liver transplantations performed at the Mayo Clinic in 1993–1998.27
In 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.
Lee JS, Semela D, Iredale J, Shah VH. Sinusoidal remodeling and anginogenesis: a new function for the liver-specific pericyte? Hepatology 2007; 45: 817-825.
National Center for Health Statistics Health, United States, 2006 with Chartbook on Trends in the Health of Americans. Report No: 2006-1232.
Jang JW. Current status of liver diseases in Korea: liver cirrhosis. Korean J Hepatol 2009; 15: S40-S49.
Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006; 45: 529-538.
Seeff LB, Hoofnagle JH. Epidemiology of hepatocellular carcinoma in areas of low hepatitis B and hepatitis C endemicity. Oncogene 2006; 25: 3771-3777.
Fung KT,Fung J,Lai CL,Yuen MF.Etiologies of chronic liver diseases in Hong Kong. Eur J Gastroenterol Hepatol 2007; 19: 659-664.
Michitaka K,Nishiguchi S,Aoyagi Y,Hiasa Y,Tokumoto Y,Onji M;JapanEtiology of Cirrhosis Study Group. Etiology of cirrhosis in Japan: a nationwide survey. J Gastroenterol 2010; 45: 86-94.
Lok AS,McMahon BJ. Chronic Hepatitis B: Update 2009, AASLD PRACTICE GUIDELINES. Hepatology 2009; 50: 1-36.
Shuhart MC,Davis GL,Bambha K,Cardenas A,Davern TJ,Franco J, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology 2009; 49: 1335-1374.
O’Shea RS,Dasarathy S, McCullough AJ. Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Alcoholic liver disease. Hepatology 2010; 51: 307-328.
Manns MP, Czaja AJ, Gorham JD, Krawitt EL, Mieli-Vergani G, Vergani D, et al; American Association for the Study of Liver Diseases. Diagnosis and management of autoimmune hepatitis. Hepatology 2010; 51: 2193-2213.
Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology 2009; 51: 291-308.
Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, et al; American Association for the Study of Liver Diseases. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010; 50: 660-678.
Roberts EA, Schilsky ML; American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of wilson disease: an update. Hepatology 2008; 47: 2089-2111.
Sun XW, Wu SL, Lin YJ, Wang B, Han HL, Dai XD. Trend Of morbidity and mortality of colorectal carcinoma in Nangang District of Harbin from 1992 to 2001. World Chin J Digestol (Chin) 2004; 12: 2302-2306.
Han YS, Kim BH, Baek IY, Lee DK, Kim KJ. The change of the etiology, complications and cause of death of the Cirrhosis in 1990s. Korean J Hepatol 2000; 6: 328-339.
Kim CY, Kim JW, Lee HS, Yoon YB, Song IS. Natural history and survival rate of chronic liver diseases in Korea –20 years prospective analysis. Korean J Med 1994; 46: 168-180.
Kim YS, Um SH, Ryu HS, Lee JB, Lee JW, Park DK, et al. The prognosis of Cirrhosis in recent years in Korea. J Korean Med Sci 2003; 18: 833-841.
McAvoy NC, Hayes PC. The cirrhosis epidemic in the UK: evaluating the causes in a European context. Expert Rev Gastroenterol Hepatol 2007; 1: 41-45.
Zhao SJ, Xu ZY, Lu Y. A mathematical model of hepatitis B virus transmission and its application for vaccination strategy in China. Inter J Epidemiol 2000; 29: 744-752.
Gust ID. Epidemiology of hepatitis B injection in the Western Pacific and South East Asia. Gut 1996; 38: S18-S23.
Liu FR, Du YD. The survey of hepatitis B virus about 7170 pregnant women. Henan J Preve Med (Chin) 2000; 11: 229-230.
Chen CJ, Wang LY, Yu MW. Epidemiology of hepatitis B virus infection in the Asia-pacific region. J Gastroenterol Hepatol 2000; 15: E3-E6.
Fleming KM, Aithal GP, Solaymani-Dodaran M, Card TR, West J. Incidence and prevalence of cirrhosis in the United Kingdom, 1992-2001: a general population-based study. J Hepatol 2008; 49: 732-738.
Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002; 346: 1221-1231.
Ekstedt M, Franzen LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006; 44: 865-873.
Charlton M, Kasparova P, Weston S, Lindor K, Maor-Kendler Y, Wiesner RH, et al. Frequency of nonalcoholic steatohepatitis as a cause of advanced liver disease. Liver Transplantation 2001; 7: 608-614.
(Received January 17, 2013)
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:email@example.com
Etiologies of presentation of the autoimmune diseases
||Number of patients (n)
PBC: Primary biliary cirrhosis; AIH: Autoimmune hepatitis; PSC: Primary sclerosing cholangitis; SS: Sjogren Syndrome.
Variation tendency of different etiology in recent 18 years (6 time segments)
*: 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.
Etiology spectrum in different genders
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.