Viral Genotypes and Associated Risk Factors of Hepatocellular Carcinoma in India

Manash Pratim Sarma; Mohammad Asim; Subhash Medhi; Thayumanavan Bharathi; Richa Diwan; Premashis Kar

doi:10.7497/j.issn.2095-3941.2012.03.004

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Demographic characterization of HCC and control patients.

Characteristics	Healthy controls (n=120)	HCC (n=357)	Controls^† (n=357)
Gender
Male	71 (59.17)	305 (85.43)	249 (69.75)
Female	39 (40.87)	52 (14.57)	108 (31.25)
Age (years)
0-9	0 (0)	0 (0)	0 (0)
10-19	3 (2.50)	4 (1.12)	6 (0.16)
20-29	7 (5.83)	21 (5.88)	20 (5.60)
30-39	18 (15.0)	41 (11.48)	38 (10.64)
40-49	31 (25.83)	66 (18.49)	137 (38.37)
50-59	42 (35.0)	121 (33.89)	72 (20.17)
60-69	8 (6.67)	69 (19.32)	60 (16.80)
70-79	1 (0.83)	32 (8.96)	24 (6.72)
80-89	0 (0)	3 (0.84)	0 (0)

†: chronic hepatitis cases without HCC.

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Baseline characteristics of HCC patients in India.

Characteristics
Mean age (years)	54±13.23
Sex ratio (M:F)	5.87:1
Symptomatic HCC	323 (90.48)
Asymptomatic HCC	34 (9.52)
Portal Hypertension	269 (75.35)
Known cirrhotic at diagnosis	36 (10.08)
Underlying cirrhotic at diagnosis	217 (60.78)
Smoking status
Smokers (20/day for 10 years)	108 (30.25)
Non smokers	249 (69.75)
Alcohol intake
Alcoholics	211 (59.10)
Non alcoholics	146 (40.90)

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Clinical profile of HCC and control cases.

	HCC, n=357 (%)	Controls^†, n=357 (%)	P
Signs
Ascites	133 (37.25)	74 (20.73)	0.000000546
Hepatomegaly	187 (52.38)	177 (49.58)	0.2277
Pallor	162 (45.38)	115 (32.21)	0.0001559
Pedal Edema	101 (28.29)	67 (18.77)	0.001371
Icterus	114 (31.93)	92 (25.77)	0.03500
Spleenomegaly	142 (39.78)	97 (27.17)	0.0001820
Symptoms
Jaundice	101 (28.29)	85 (23.81)	0.08698
Weakness	212 (59.38)	71 (19.88)	<0.0000001
Weight loss	256 (71.70)	162 (45.38)	<0.0000001
Abdomen discomfort	294 (82.35)	191 (53.50)	<0.0000001
Anorexia	230 (64.4)	146 (40.90)	<0.0000001
Nausea	84 (23.53)	78 (21.85)	0.2967
Hepatic Encephalopathy	16 (4.48)	7 (1.96)	0.02994
Malena	40 (11.20)	28 (7.80)	0.06431

†, chronic hepatitis cases without HCC

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Prevalence of viral marker and heavy alcohol use among patients with hepatocellular carcinoma.

Causative factors
HBV markers
Overall		246 (68.91)
HBsAg+		201 (56.30)
Only Anti HBe+		17 (4.76)
Only IgG Anti HBc+		28 (7.84)
HCV markers
Overall		76 (21.29)
Anti HCV+ve & HCV RNA+ve		66 (18.49)
Anti HCV+ve & HCV RNA-ve		10 (2.80)
HBV & HCV	19 (5.32)
Heavy alcohol Use
Overall			67 (18.77)
Alcohol alone			20 (5.60)
Alcohol and virus			47 (13.17)
Alcohol & HBV			25 (7.0)
Alcohol & HCV			12 (3.36)
Alcohol, HBV & HCV			11 (3.08)
Negative for alcohol, smoking, HBV, HCV				65 (18.21)

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Distribution of HCV genotypes in HCC patients and controls positive for HCV RNA.

	HCV related HCC (%)	HCV related chronic hepatitis (%)	P
Anti HCV positive/HCV RNA positive	68	55
HCV Genotyping done	50 (73.53)	42 (73.36)	0.3637
Genotype 1	14 (28)	8 (19.05)	0.1994
Genotype 3	30 (60)	32 (76.19)	0.0633
Genotype 4	6 (12)	2 (4.76)	0.1379

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Distribution of HBV genotypes and viral loads in HCC patients.
HCC, n=246 (%)
HBV DNA
Negative 71 (38.9)
Positive 175 (71.1)
HBV genotype
A 27 (15.4)
D 119 (68.0)
A+D 29 (16.6)
Log₁₀ HBV DNA (copies/mL)
Low (<5) 58 (33.1)
High (≥5) 117 (66.9)

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Distribution of HCC patients and controls according to major risk factors.

Risk factors
HBV status
Any Marker	246 (68.91)	9 (7.5)	27.33 (12.87-60.0)
HBsAg+,antibody+	201 (56.30)	8 (6.67)	18.04 (8.22-41.19)
HBsAg-,antibody+	45 (12.60)	1 (0.83)	17.16 (2.51-338.85)
All markers-	111 (31.09)	111 (92.50)	Reference
HCV Status
Anti HCV + overall	76 (21.29)	3 (2.50)	10.55 (3.13-42.73)
Anti HCV+,RNA+	66 (18.49)	2 (1.66)	13.38 (3.15-80.27)
Anti HCV +,RNA-	10 (2.80)	1 (0.83)	3.43 (0.45-72.36)
All markers -	281 (78.71)	117 (97.50)	Reference
Heavy alcohol Use
+	67 (18.77)	13 (10.83)	1.90 (0.97-3.78)
-	290 (81.23)	107 (89.17)
Smoking status
Smokers (20/day for 10 years)	108 (30.25)	34 (28.33)	1.097 (0.6948- 1.732)
Non Smokers	249 (69.75)	86 (61.67)

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Profile of viral infection in HCC patients and controls with heavy alcohol use.

HBV and HCV status	HCC, n=67 (%)	Healthy controls, n=13 (%)	OR (95%CI)
HBV status
Any marker+	55 (82.08)	1 (7.6)	55.00 (6.24-1245)
HbsAg+, antibody+	44 (65.67)	1 (7.6)	22.96 (2.77-502.29)
HbsAg-, antibody+	11 (16.42)	0	-
HCV status
Overall	14 (20.90)	1 (7.6)	3.17 (0.37-70.71)
Anti HCV+, RNA +	12 (17.91)	1 (7.6)	2.62 (0.30-58.96)
Anti HCV+, RNA-	2 (2.98)	0	-

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Prevalence of viral infection and heavy alcohol use among HCC patients with and without cirrhosis.

Etiological association	HCC with cirrhosis, n=253 (%)	HCC without cirrhosis, n=104 (%)	P
HBV marker
Overall	176 (69.56)	61 (58.65)	0.02526
HbsAg+	154 (60.86)	54 (51.92)	0.06129
Only Anti HBe+	9 (3.56)	2 (1.92)	0.2266
Only IgG Anti HBc+	12 (4.74)	4 (3.85)	0.3716
HCV markers
Overall	55 (21.74)	3 (2.88)	0.000000638
Anti HCV+, HCV RNA+	43 (17.00)	3 (2.88)	0.00004147
Anti HCV+, HCV RNA-	12 (4.74)	0
HBV and HCV	24 (9.49)	0
Overall	65 (25.69)	14 (13.46)	0.004946
Alcohol alone	8 (3.16)	9 (8.65)	0.01940
Alcohol and virus	59 (23.32)	6 (5.77)	0.00001529
Alcohol and HBV	31 (12.25)	4 (3.85)	0.005667
Alcohol and HBVand HCV	9 (3.56)	0
Alcohol and HCV	16 (6.32)	1 (0.96)	0.01153
Negative for HBV, HCV and alcohol	37 (14.62)	30 (28.85)	0.001280

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Distribution of major risk factors in HCC patients with and without cirrhosis.

Risk factor	HCC with cirrhosis (n=253)			HCC without cirrhosis (n=104)
Risk factor	Cases positive	Healthy controls	OR (95%CI)	Cases positive	Healthy controls	OR(95%CI)
HBV status
Any marker+	176 (69.56)	9 (7.5)	28.19 (13.03-62.96)	61(58.65)	9 (7.5)	17.50 (7.58-41.59)
HBsAg+, antibody+	154 (60.86)	8 (6.67)	21.78 (9.77-50.50)	54 (51.92)	8 (6.67)	15.12 (6.35-37.30)
HbsAg-, antibody+	21 (8.30)	1 (0.83)	10.77 (1.51-217.67)	6 (5.77)	1 (0.83)	7.29 (0.85-163.31)
HCV status
Anti HCV+overall	55 (21.74)	3 (2.50)	10.83 (3.17-44.39)	3 (2.88)	3 (2.50)	1.16 (0.18-7.37)
Anti HCV+, HCV RNA+	43 (17.00)	2 (1.66)	12.08 (2.80-73.44)	3 (2.88)	2 (1.66)	1.75 (0.23-15.31)
Anti HCV+, HCV RNA-	12 (4.74)	1 (0.83)	5.93 (0.79-123.43)	0	1 (0.83)	-
Heavy alcohol Use		1 (0.83)			1 (0.83)
+	65 (25.69)	13 (10.83)	2.85 (1.44-5.70)	14 (13.46)	13 (10.83)	1.28 (0.53-3.08)

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Hematological and biochemical profile of HCC cases and controls.

Parameters	HCC (n=357)	Controls^† (n=357)	P
Hemoglobin (g/dL)	11.60± 2.10	11.30±2.80	0.1060
<10 mg/dL (%)	121 (33.89)	100 (28.0)	0.1050 [OR=1.32(0.95-1.83)]
WBC (×10³ /mm³)	6.60±0.40	6.50±0.20	0.0001*
DLC-P (%)	64.50±5.10	63.50±7.40	0.0359
DLC-L (%)	30.90±4.80	32.60±7.60	0.0004*
DLC-E (%)	3.05±1.40	2.90±5.10	0.5922
DLC-M (%)	1.50±0.80	1.90±1.80	0.0001*
Platelet (×10⁴/µL)	1.80±0.90	1.40±0.50	0.0001*
<1.5 lac/ µL (%)	115 (32.21)	105 (29.41)	0.4650 [OR=1.14 (0.82-1.59)]
INR	1.05±0.40	1.00±0.20	0.0350
Creatinine (mg/dL)	1.50±3.20	1.06±0.50	0.0105
>1.2 mg/dL (%)	101 (28.29)	69 (19.33)	0.0060* [OR=1.65 (1.14-2.37)]
AST (IU/L)	101.80±87.90	59.20±49.50	0.0001*
>2×ULN (%)	208 (58.26)	140 (39.21)	0.0000006*[OR=2.16 (1.59-2.95)]
ALT (IU/L)	67.10±46.30	57.30±47.40	0.0053
>2×ULN (%)	110 (30.81)	66 (18.48)	0.00018*[OR=1.96(1.36-2.83)]
ALP (IU/L)	4420.00±23.60	221.00±69.10	0.0001
>2×ULN (%)	172 (48.17)	135 (37.81)	0.0065*[OR=1.53(1.12-2.08)]
Bilirubin (mg/dL)	1.70±2.70	1.60±5.00	0.7396
>1.5 mg/dL (%)	192 (53.78)	103 (28.85)	0.00000*[OR=2.87(2.08-3.96)]
Albumin (g/dL)	3.60±0.70	3.70±0.90	0.0979
<3.5 g/dL (%)	265 (74.23)	174 (48.74)	0.00000*[OR=3.03(2.18-4.21)]
>3.5 g/dL (%)	92 (25.77)	183 (51.26)	0.00000*[OR=0.33(0.24-0.46)]
AFP (ng/mL)	6849.00±9652.00	5.90±1.20	0.0001*
<20 ng/mL (%)	68 (19.04)	311 (87.11)	0.00000*[OR=0.03(0.02-0.05)]
20-400 ng/mL (%)	96 (26.89)	46 (12.89)	0.0000043*[OR=2.49 (1.66-3.74)]
>400 ng/mL (%)	193 (54.06)	0 (0.0)	0.00000*[OR=UD]

†, chronic hepatitis cases without HCC;*,statistically significant

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Biochemical profile of HBV related HCC cases and controls.

Liver function indicators	HCC (n=246)	Controls^† (n=213)	P
ALT (U/liter)	70.20±49.80	51.80±33.20	<0.0001
AST (U/liter)	68.50±43.50	57.40±36.80	0.0036
ALP (U/liter)	407.00±522.00	237.00±60.50	<0.0001
ALB (g/liter)	3.10±0.60	3.70±1.08	<0.0001
T.BIL (mg/dL)	1.90±3.20	1.10±2.30	0.0026
Mean platelet count (10⁴/mm³)	1.32±0.40	1.89±0.50	<0.0001
INR (Sec)	1.03±0.50	1.02±0.17	0.7809
α-Fetoprotein (ng/mL)	4356.20±108.90	2.90±1.20	<0.0001

†, chronic hepatitis cases without HCC

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Overall radiological profile of HCC cases.

Characteristics	HCC Cases (%)
Distribution of HCC
Right lobe	199 (55.74)
Left lobe	110 (30.81)
Bilobar	48 (13.45)
Volume of HCC
<50%	228 (63.86)
>50%	129 (36.13)
No. of Lesions
1	102 (28.57)
2	117 (32.77)
≥3	138 (38.66)
Size of HCC, cm
≤2	52 (14.57)
>-5	98 (27.45)
≥5	207 (57.98)
US appearance
Heterogenous	99 (27.73)
Hypoechoic	137 (38.38)
Hyperechoic	90 (25.21)
Isoechoic	31 (8.68)
CT appearance^† (n=314)
Hypodense	138 (43.95)
Heterogenous	153 (48.73)
Hyperdense	23 (7.32)
MRI appearance (n=81)
T₂ WI
Hyperintense	62 (76.54)
Hypo/Isointense	19 (23.46)
T₁ WI
Hyperintense	28 (34.56)
Hypo/Isointense	53 (65.43)
Vascular Invasion
Portal vein	154 (43.13)
PV with IVC/HC	19 (5.32)
IVC and or HV	6 (1.68)

IVC, inferior vena cava; HV, hepatic vein; PV, portal vein. †, Biphasic CT abdomen was done in 314 cases. MRI of the abdomen was done in 81 cases.

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Patients with different staging systems of HCC.

Staging	n (%)
Okuda stage
I	132 (36.97)
II	184 (51.54)
III	42 (11.76)
CLIP score
0	52 (14.56)
1	97 (27.17)
2	60 (16.81)
3	93 (26.65)
4-6	55 (15.41)
BCLC stage
A₁	158 (44.26)
A₂	23 (6.44)
A₃	80 (22.41)
A₄	43 (12.04)
B	38 (10.64)
C	12 (3.36)
D	7 (1.97)

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	HCC, n=246 (%)
HBV DNA
Negative	71 (38.9)
Positive	175 (71.1)
HBV genotype
A	27 (15.4)
D	119 (68.0)
A+D	29 (16.6)
Log₁₀ HBV DNA (copies/mL)
Low (<5)	58 (33.1)
High (≥5)	117 (66.9)

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