Study of liver cirrhosis over ten consecutive years in Southern China

Table 1 Criteria for the etiological diagnosis of liver cirrhosis

Viral hepatitis

Hepatitis B virus (HBV): positive for HBsAg for at least 6 mo

Hepatitis C virus (HCV): positive for anti-HCV or HCV-RNA

HBV + HCV: HBV overlap with HCV

HBV + Hepatitis D virus (HDV): positive for HBsAg and anti-HDV

Alcoholic cirrhosis

The diagnosis was made by a history of alcohol use ( ≥ 40 g/d for males and ≥ 20 g/d for females or > 80 g/d within past 2 wk), physical examinations for signs of chronic liver disease, laboratory abnormalities [including elevation of aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transferase (GGT) and prothrombin time] or typical imaging features of fatty liver and cirrhosis and the exclusion of other causes of LC[10]

Autoimmune diseases

Autoimmune hepatitis (AIH)[11]

Primary biliary cirrhosis (PBC)[12]

AIH + PBC: AIH and PBC overlap syndrome

Primary sclerosing cholangitis[13]

Secondary biliary cirrhosis

Established when compatible with the diagnosis of liver cirrhosis, excluding some common causes of LC and indicated by cholestatic biomarkers (such as elevated alkaline phosphatase and GGT)

Metabolic diseases

Wilson’s disease[14]

Hereditary hemochromatosis[15]

Non-alcoholic fatty liver disease[16]

Others (amyloidosis, glycogen storage disease, etc.)

Drugs

Established when the liver function test abnormalities related to drug intake and other causes of LC were excluded[17]

Vascular diseases

Budd-Chiari syndrome[18]

Cardiac[19]

Parasite cirrhosis

The diagnosis was based on clinical manifestations, epidemiologic features, and lab tests, excluding other types of LC; the diagnosis needed to be verified by a positive pathogenic finding

Infantile hepatitis syndrome

The diagnosis was based on criteria of Roberts[20]

Mixed etiology

HBV + Alcohol

HBV + HCV + Alcohol

Other known etiology

Cases with a definite known etiology but not listed above

Cryptogenic cirrhosis

Diagnosed only after an extensive evaluation excluded recognizable etiologies[21]

Table 2 Liver function characteristics of the study population n (%)

Male	6719 (83.2)
Mean age (yr)	50.5 ± 13.0
Child-Pugh score
A	2521 (31.2)
B	3369 (41.7)
C	2190 (27.1)
Mean ± SD	8.0 ± 2.3
MELD score (mean ± SD)	15.3 ± 7.2
MELD: median (extreme)	13.6 (6-65)

The MELD score was calculated from 7145 cases in the study population because the creatinine value was not available from the others. MELD: Model for end-stage liver disease.

Table 3 Etiology of the 8080 enrolled liver cirrhosis patients n (%)

Etiology	Total	Male	Female	P value
	(n = 8080)	(n = 6719)	(n = 1361)
Viral hepatitis	6514 (80.62)	5489 (81.69)	1025 (75.31)	< 0.001
HBV	6239 (77.22)	5316 (79.12)	923 (67.82)
HCV	226 (2.80)	135 (2.01)	91 (6.69)
HBV + HDV	2 (0.02)	2 (0.03)	0 (0.00)
HBV + HCV	47 (0.58)	36 (0.54)	11 (0.81)
Alcohol	459 (5.68)	451 (6.71)	8 (0.59)	< 0.001
Autoimmune	163 (2.03)	30 (0.43)	133 (9.77)	< 0.001
AIH	54 (0.67)	13 (0.19)	41 (3.01)
PBC	87 (1.08)	15 (0.22)	72 (5.29)
AIH + PBC	19 (0.24)	1 (0.01)	18 (1.32)
PSC	3 (0.04)	1 (0.01)	2 (0.15)
Secondary biliary	38 (0.47)	22 (0.33)	16 (1.18)	< 0.001
Metabolic diseases	114 (1.40)	73 (1.09)	41 (3.02)	< 0.001
WD	106 (1.31)	67 (1.00)	39 (2.87)
HH	2 (0.02)	2 (0.03)	0 (0.00)
NAFLD	4 (0.05)	2 (0.03)	2 (0.15)
Others	2 (0.02)	2 (0.03)	0 (0.00)
Drugs	9 (0.11)	6 (0.09)	3 (0.22)	0.186
Vascular diseases	46 (0.57)	30 (0.44)	16 (1.17)	0.001
BCS	31 (0.38)	21 (0.31)	10 (0.73)
Cardiac	15 (0.19)	9 (0.13)	6 (0.44)
Parasites	33 (0.41)	26 (0.39)	7 (0.51)	0.502
IHS	8 (0.10)	7 (0.10)	1 (0.07)	1.000
Mixed etiology	400 (4.95)	399 (5.93)	1 (0.07)	< 0.001
HBV + Alcohol	389 (4.81)	388 (5.77)	1 (0.07)
HBV + HCV + Alcohol	11 (0.14)	11 (0.16)	0 (0.00)
Other known etiology	59 (0.73)	51 (0.76)	8 (0.58)	0.499
Cryptogenic cirrhosis	237 (2.93)	135 (2.01)	102 (7.49)	< 0.001

The differences in gender proportion were determined using the χ² test. HBV: Hepatitis B virus; HCV: Hepatitis C virus; HDV: Hepatitis D virus; AIH: Autoimmune hepatitis; PBC: Primary biliary cirrhosis; PSC: Primary sclerosing cholangitis; WD: Wilson’s disease; HH: Hereditary hemochromatosis; NAFLD: Non-alcoholic fatty liver disease; BCS: Budd-Chiari syndrome; IHS: Infantile hepatitis syndrome.

Table 4 Etiology of the 8080 liver cirrhosis patients by age

Etiology	Age, yr
LC classification	mean ± SD	t value	P value
Viral hepatitis	50.7 ± 12.4
Alcohol	52.2 ± 11.0	-1.48	0.308
Autoimmune	54.3 ± 12.9	-3.66	0.029
Secondary biliary	46.3 ± 25.1	4.33	1.000
Metabolic diseases	27.2 ± 14.1	23.49	< 0.001
Drugs	56.0 ± 18.2	-5.33	1.000
Vascular diseases	42.8 ± 17.6	7.87	0.212
Parasites	58.1 ± 14.9	-7.42	0.319
IHS	2.5 ± 3.9	48.18	< 0.001
Mixed etiology	51.2 ± 9.7	-0.52	1.000
Other known etiology	44.7 ± 13.6	5.98	0.079
Cryptogenic cirrhosis	55.0 ± 17.5	-4.29	0.015

The P values were determined using the independent samples t-test. The viral hepatitis patients were used as the reference group when comparing differences in age for different etiologies. LC: Liver cirrhosis; IHS: Infantile hepatitis syndrome.

Table 5 Etiologic analysis for the years 2001-2005 and the years 2006-2010 n (%)

Etiology	2001-2005 (n = 2907)	2006-2010 (n = 5173)	χ2-value	P value	P-trend
Viral hepatitis	2462 (84.7)	4052 (78.3)	48.22	< 0.001	< 0.001
HBV	2381 (81.9)	3858 (74.6)	56.78	< 0.001	< 0.001
HCV	67 (2.3)	159 (3.1)	4.05	0.044	0.263
HBV + HCV	12 (0.4)	35 (0.7)	2.24	0.135	0.267
HBV + HDV	2 (0.1)	0 (0.0)	-	0.129	-
Alcohol	155 (5.3)	304 (5.9)	1.031	0.31	0.919
Autoimmune	34 (1.2)	129 (2.5)	16.509	< 0.001	< 0.001
Secondary biliary	12 (0.4)	26 (0.5)	0.321	0.571	0.369
Metabolic diseases	32 (1.1)	82 (1.6)	3.139	0.076	0.07
Drugs	1 (0.0)	8 (0.2)	1.459	0.227	0.161
Vascular diseases	17 (0.6)	29 (0.6)	0.019	0.89	0.551
Parasites	14 (0.5)	19 (0.4)	0.598	0.439	0.154
IHS	2 (0.1)	6 (0.1)	0.078	0.78	0.696
Mixed etiology	87 (3.0)	313 (6.1)	36.984	< 0.001	< 0.001
Other known etiology	16 (0.5)	43 (0.8)	2.95	0.086	0.285
Cryptogenic cirrhosis	75 (2.6)	162 (3.1)	1.989	0.158	0.011

The P values were determined using the χ² test by comparing the proportion of 2001-2005 with that of 2006-2010. The P-trend values were determined using ANOVA by comparing proportions of separated years and reflected the general trend of the etiology proportion in the 10 consecutive years.

Table 6 Complications in the 8080 liver cirrhosis patients by gender n (%)

Complication	Total(n = 8080)	Male(n = 6719)	Female(n = 1361)	χ2value	P value
UGIB	1006 (12.5)	875 (13.0)	131 (9.6)	12.00	0.001
Infection	2177 (26.9)	1806 (26.9)	371 (27.3)	0.08	0.773
Ascites	4493 (55.6)	3739 (55.6)	754 (55.4)	0.03	0.867
HCC	2399 (29.7)	2157 (32.1)	242 (17.8)	111.21	< 0.001
HE	544 (6.7)	464 (6.9)	80 (5.9)	1.90	0.168
PVT	405 (5.0)	342 (5.1)	63 (4.6)	0.51	0.477
PVTT	783 (9.7)	733 (10.9)	50 (3.7)	67.7	< 0.001
CTPV	250 (3.1)	229 (3.4)	21 (1.5)	13.13	< 0.001
HRS	293 (3.6)	252 (3.8)	41 (3.0)	1.76	0.184
HPS	6 (0.1)	4 (0.1)	2 (0.1)	1.17	0.280
HHT	398 (4.9)	337 (5.0)	61 (4.5)	0.69	0.407

Because some patients have more than one complication, number is greater than 8080; The P values were determined using the χ² test. UGIB: Upper gastrointestinal bleeding; HCC: Hepatocellular carcinoma; HE: Hepatic encephalopathy; PVT: Portal vein thrombosis; PVTT: Portal vein tumor thrombosis; CTPV: Cavernous transformation of the portal vein; HRS: Hepatorenal syndrome; HPS: Hepatopulmonary syndrome; HHT: Hepatic hydrothorax.

Table 7 Odds ratios of the different etiologies with respect to the complications of upper gastrointestinal bleeding

Complication	HBV cirrhosis	HCV cirrhosis	Alcoholic cirrhosis	Autoimmune cirrhosis	Mixed etiology	Cryptogenic cirrhosis	Others
	(n = 6239)	(n = 226)	(n = 459)	(n = 163)	(n = 400)	(n = 237)	(n = 356)
UGIB (Y/N)	739/5500	24/202	98/361	16/147	47/353	41/196	41/315
OR	1.00	1.07	1.89	0.90	0.83	1.76	1.01
95%CI		0.68-1.69	1.48-2.41	0.50-1.60	0.60-1.16	1.21-2.52	0.72-1.44
P value		0.759	< 0.001	0.713	0.282	0.002	0.938

Others: cases excluding the six previous etiologies; OR (95%CI) was calculated with a multivariate logistic model adjusted for age, gender, year, birthplace (Cantonese, Other Chinese, Foreigner), and Child-Pugh value using the stepwise forward method, and the P values were determined by unconditioned logistic regression. HBV: Hepatitis B virus; HCV: Hepatitis C virus; UGIB: Upper gastrointestinal bleeding.

Table 8 Odds ratios of different etiologies with respect to the complications of hepatocellular carcinoma

Complication	HBV cirrhosis	HCV cirrhosis	Alcoholic cirrhosis	Autoimmune cirrhosis	Mixed etiology	Cryptogenic cirrhosis	Others
	(n = 6239)	(n = 226)	(n = 459)	(n = 163)	(n = 400)	(n = 237)	(n = 356)
HCC (Y/N)	2118/4121	51/175	41/418	4/159	97/303	57/180	325/31
OR	1.00	0.54	0.16	0.05	0.58	0.60	0.20
95%CI		0.38-0.75	0.11-0.22	0.02-0.17	0.45-0.74	0.44-0.83	0.13-0.31
P value		< 0.001	< 0.001	< 0.001	< 0.001	0.002	< 0.001

Others: cases excluding the six previous etiologies. The OR (95%CI) was calculated with a multivariate logistic model adjusted for age, gender, year, birthplace (Cantonese, Other Chinese, Foreigner), and Child-Pugh value using the stepwise forward method, and the P values were determined by unconditioned logistic regression. HBV: Hepatitis B virus; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma.