Nonalcoholic steatohepatitis-related hepatocellular carcinoma: is there a role for the androgen receptor pathway?

Figures & data

Table 1 Five parameters of the metabolic syndrome according to the WHO and AACE

Parameter	WHO (1998)	IDF (2005)	EGIR (1999)	NCEP-ATP III	ATP III (2001)	AHA/NHLBI (2005)
Required for diagnosis	Insulin resistance	Ethnicity-based increased waist circumference	Insulin resistance	–	Any three out of five	Any three out of five
+ Number of abnormalities	≥2	≥2	≥2	≥3	–	–
Glucose	DM	≥100 mg/dL	DM	≥100 mg/dL	≥110 mg/dL	≥100 mg/dL
HDL cholesterol	Males <35 mg/dL, females <39 mg/dL	Males <40 mg/dL, females <50 mg/dL	Males and females >39 mg/dL	Males <40 mg/dL, females <50 mg/dL	Males <40 mg/dL, females <50 mg/dL	Males <40 mg/dL, females <50 mg/dL
Triglycerides	≥150 mg/dL	≥150 mg/dL	≥150 mg/dL	≥150 mg/dL	≥150 mg/L	≥150 mg/L
Obesity	Waist/hip >0.9 (males) or >0.85 (females); BMI ≥30 kg/m^2	WC: males ≥102 cm, females ≥88 cm	WC: males ≥94 cm, females ≥80 cm	WC ≥94 cm	WC: males ≥102 cm, females ≥88 cm	WC: males ≥102 cm, females ≥88 cm
Hypertension	≥140/90 mmHg or use of antihypertensive drugs	≥130/85 mmHg or use of antihypertensive drugs	≥140/90 mmHg or use of antihypertensive drugs	≥130/85 mmHg or use of antihypertensive drugs	≥130/85 mmHg or use of antihypertensive drugs	>130/85 mmHg or use of antihypertensive drugs

Abbreviations: AACE, American Association of Clinical Endocrinologists; BMI, body mass index; DM, diabetes mellitus; HDL, high density lipoprotein; WC, waist circumference; WHO, World Health Organization; IDF, International Diabetes Federation; EGIR, European Group for the Study of Insulin Resistance; NCEP-ATPIII, National Cholesterol Education Program Adult Treatment Panel III; ATP III, Adult Treatment Panel III.

Figure 1 Pathways of androgen and AR in the pathogenesis of NASH, cirrhosis, and hepatocellular carcinoma.

Note: Visual Art: © 2015 The University of Texas MD Anderson Cancer Center.
Abbreviations: AR, androgen receptor; CCRK, cycle cycle-related kinase; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; IL, interleukin; MAPK, mitogen-activated protein kinase; NASH, nonalcoholic steatohepatitis; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; STAT 3, signal transducer and activator of transcription 3; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor; GSK3b, glycogen synthase kinase 3 beta; FFA, free fatty acid; HBVX, hepatitis B virus protein X; TGF1, tumor growth factor 1.

Table 2 Clinical studies that evaluated the role of androgen and its receptors in the recurrence of surgically treated HCC

Author	Year	Country	Sample size	HCC riskfactor	Sex (M/F)	AR expression	Recurrence rate	Survival rate
Nagasue et al^Citation87	1989	Japan	45	Alcoholic 15	31/12	31 AR+ (25 M/4 F)	AR+ 67.9%	AR+ 1 year: 84%; 5 years: 17.3%
				HBsAg 24		14 AR− (6 M/8 F)	AR− 33.3%	AR− 1 year: 100%; 5 years: 62.2%
				AntiHbc 32
				AntiHBs 15
Boix et al^Citation88	1995	Spain	43	Cirrhosis 40	30/13	30 AR+	AR+ 1 year: 34%; 2 years: 51%	Not reported
				Normal 3		13 AR−	AR− 1 year: 0%; 2 years: 20%

Abbreviations: AntiHbc, Anti Hepatitis B core antibodies; antiHBs, antihepatitis B surface antibodies; AR, androgen receptor; F, female; HBsAg, hepatitis B surface antigen; HCC, hepatocellular carcinoma; M, male.

Table 3 Clinical studies that evaluated the role of antiandrogen drugs in the treatment of HCC

Author	Year	Country	Sample size (N)	HCC risk factor	Sex (M/F)	Antiandrogen type	Stage of disease	Changes in testosterone level	Overall survival rate	Responses
Forbes et al^Citation93	1987	UK	25	Alcohol 10 HBV 8 Cryptogenic 3 PBC 3 Autoimmune 1	23/2	Cyproterone acetate	Unresectable (five metastatic)	↓	3 months	3 (12%)
Gupta et al^Citation94	1988	USA	8	Alcohol 7	7/1	Ketoconazole	Unresectable	↓	Not significant	NR
Nagasue et al^Citation87	1989	Japan	16	NR	16/0	Cyproterone acetate	Unresectable/recurrent	–	Not significant	3 (19%)
Chao et al^Citation95	1996	People’s Republic of China	32	Alcohol 1 Hepatitis 28 Cryptogenic 3	31/1	Flutamide	Unresectable		<3 months	NR
Grimaldi et al^Citation96	1998	France	238	Alcohol 89 HBV 46 Hemochromatosis 10	202/35	Nilutamide versus placebo Triptorelin versus placebo	Unresectable		Nilutamide 3.9 versus 5.5 months	NR
				Other 12 Missing 37					Triptorelin 3.4 versus 5.5 months
Manesis et al^Citation97	1995	Greece	85	Alcohol 21 HBV 53 HCV 11 HDV 10	66/19	Tamoxifen + triptorelin versus flutamide + triptorelin versus placebo	Unresectable	↓	4, 3, and 4 months, respectively	NR
GRETCH^Citation98	2004	France	375	Alcohol 242 HCV 54 HBV 23 Other 15	375/0	Leuprorelin + flutamide + tamoxifen versus tamoxifen	Unresectable	↓	135.5 and 176 days, respectively	Not significant

Note: ↓ represents decrease in testosterone level.

Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; HDV, hepatitis D virus; NR, not reported; PBC, primary biliary cirrhosis.

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