Hereditary hemochromatosis: Temporal trends, sociodemographic characteristics, and independent risk factor of hepatocellular cancer – nationwide population-based study

Table 1 Patient characteristics, comorbidities in hereditary hemochromatosis (excluding liver diseases) patients

Variables	Weighted, n	Weighted, % (95%Cl)
Total, n	18031
Sex
Female	6903	38.27 (36.59–39.9)
Male	11123	61.69 (59.9–63.4)
Age (y), mean (SD)	62.19 ± 34.36
Age groups (yr)
< 18	158	0.88 (0.54–1.20)
18-44	2046	11.37 (10.2–12.5)
45-64	7007	38.90 (37.15–40.6)
65-84	7933	43.93 (42.2–45.7)
85+	887	4.91 (4.15–5.69)
Race/Ethnicity
White	15850	87.87 (86.6–89.2)
Black	315	1.76 (1.30–2.19)
Hispanic	545	3.01 (2.42–3.62)
Asian or Pacific Islander	105	0.58 (0.33–0.83)
Native American	30	0.17 (0.03–0.30)
Other	1186	6.60 (5.52–7.63)
Comorbidities
Coronary artery disease	3357	18.61 (17.24–20.0)
Cardiomyopathy	900	4.99 (4.19–5.79)
Arrythmias	4250	23.57 (22.1–25.1)
Heart failure	2848	15.79 (14.5–17.1)
Liver cancer	209	1.16 (0.78–1.53)
HIV	35	0.19 (0.05–0.34)
Alpha1-antitrypsin deficiency	55	0.31 (0.11–0.49)
Disorders of porphyrin metabolism	105	0.58 (0.30–0.86)
Hepatomegaly	123	0.68 (0.38–0.98)
Splenomegaly	169	0.93 (0.56–1.32)
Hypertension	7892	43.76 (42.0–45.5)
Diabetes mellitus with chronic complications	2323	12.88 (11.7–14.1)
Diabetes mellitus without chronic complications	2485	13.78 (12.6–15.0)
Lipid metabolism disorders	6781	37.60 (35.9–39.3)
Thyroid disorders	3285	18.21 (16.9–15.6)
Pancreatitis	484	2.69 (2.13–3.23)
Pituitary disorders	259	1.43 (0.99–1.87)
Obesity	2971	16.48 (15.1–17.9)
Depression	2673	14.82 (13.5–16.1)
Symptoms
Musculoskeletal pain	1011	5.61 (4.79–6.42)
Malaise and fatigue	557	3.09 (2.49–3.68)
Arthropathy	384	2.13 (1.65–2.61)
Weight Loss	219	1.22 (0.81–1.61)
Loss of appetite	87	0.49 (0.26–0.70)
Hypogonadism	193	1.07 (0.66–1.49)
Erectile dysfunction	140	0.78 (0.45–1.10)
jaundice	184	1.02 (0.67–1.38)
Disorientation	374	2.07 (1.61–2.54)
Family history
Family history of diseases of the circulatory system	1109	6.15 (5.26–7.04)
Family history of diabetes mellitus	500	2.77 (2.17–3.37)
Family history of malignant neoplasms	814	4.51 (3.77–5.25)
Substance use
Smoking	7577	42.02 (40.2–43.8)
Alcohol	1536	8.52 (7.49–9.54)
Cannabis use	219	1.22 (0.83–1.60)
Opioids	315	1.74 (1.29–2.20)

HIV: Human immunodeficiency virus.

Table 2 Comparison of hepatocellular carcinoma risk factors in hepatocellular carcinoma vs age-, sex-, and race matched non-hepatocellular carcinoma patients, Weighted NIS 2011 to 2019

Variables	HCC = No, n, %Weighted, N = 542280, %	HCC = Yes, n, %Weighted, N = 548773, %	P value1
Hereditary hemochromatosis (without cirrhosis)	25 (0.005)	273 (0.05)	< 0.0001
Hereditary hemochromatosis (with cirrhosis)	55 (0.01)	651 (0.12)	< 0.0001
Alcoholic cirrhosis	8577 (1.58)	102871 (18.73)	< 0.0001
Non-alcoholic cirrhosis	9578 (1.75)	204717 (37.24)	< 0.0001
Biliary cirrhosis	193 (0.04)	2363 (0.43)	< 0.0001
Alcoholic liver disease	11551 (2.12)	105799 (19.27)	< 0.0001
NASH/NAFLD	6756 (1.24%)	46648 (8.52)	< 0.0001
Hepatitis B	2105 (0.39)	33358 (6.07)	< 0.0001
Hepatitis C	16857 (3.10)	210661 (38.40)	< 0.0001
Other viral hepatitis	4498 (0.83)	13317 (2.42)	< 0.0001
HIV	4679 (0.86)	7793 (1.42)	< 0.0001
HIV - Hepatitis B	246 (0.05)	1649 (0.30)	< 0.0001
HIV - Hepatitis C	1082 (0.20)	4834 (0.88)	< 0.0001
Obesity	76894 (14.12)	47330 (8.58)	< 0.0001
Diabetes mellitus with chronic complications	80055 (14.61)	69848 (12.64)	< 0.0001
Diabetes mellitus without chronic complications	110966 (20.51)	126860 (23.17)	< 0.0001
Hypertension	244715 (45.14)	216621 (39.45)	< 0.0001
Blood transfusion	14644 (2.65)	33381 (6.03)	< 0.0001
Alpha1-antitrypsin deficiency	163 (0.03)	641 (0.12)	< 0.0001
Disorders of porphyrin metabolism	68 (0.01)	353 (0.06)	< 0.0001
Glycogen storage diseases	50 (0.01)	105 (0.02)	0.0482
Wilson disease	33 (0.01)	143 (0.03)	0.0002
Smoking	193145 (35.40)	218897 (39.76)	< 0.0001
Alcohol	44983 (8.26)	119704 (21.79)	< 0.0001
Cannabis	8334 (1.52)	8775 (1.60)	0.1650
opioids	11534 (2.11)	16261 (2.95)	< 0.0001

¹Pearson Chi-Square 2-tailed test for association of two categorical variables. HIV: Human immunodeficiency virus; HCC: Hepatocellular carcinoma; NIS: National inpatient sample; NASH: Non-alcoholic steatohepatitis NAFLD: Non-alcoholic fatty liver disease.

Table 3 Univariate and multivariate analyses of clinical risk factors associated with liver cancer

Variables	Univariate analysis		Multivariate analysis
	Unadjusted odds ratio1 (95%CI)	P value	Adjusted odds ratio2 (95%CI)	P value
Hereditary hemochromatosis (without cirrhosis)	10.887 (4.376-27.087)	< 0.0001	28.838 (10.387-80.068)	< 0.0001
Alcoholic cirrhosis	14.398 (13.701-15.131)	< 0.0001	16.881 (15.949-17.868)	< 0.0001
Non-alcoholic cirrhosis	33.241 (31.732-34.822)	< 0.0001	17.446 (16.507-18.439)	< 0.0001
Biliary cirrhosis	12.278 (8.858-17.019)	< 0.0001	19.245 (13.439-27.557)	< 0.0001
NASH/NAFLD	7.393 (6.982-7.828)	< 0.0001	2.955 (2.732-3.196)	< 0.0001
Hepatitis B	16.711 (15.149-18.434)	< 0.0001	12.145 (10.848-13.597)	< 0.0001
Hepatitis C	19.488 (18.798-20.203)	< 0.0001	8.576 (8.195-8.975)	< 0.0001
Other viral hepatitis	2.978 (2.762-3.211)	< 0.0001	1.357 (1.216-1.514)	< 0.0001
HIV	1.666 (1.537-1.807)	< 0.0001	0.649 (0.571-0.737)	< 0.0001
Obesity	0.571 (0.556-0.587)	< 0.0001	0.614 (0.590-0.640)	< 0.0001
Diabetes mellitus with chronic complications	0.845 (0.825-0.866)	< 0.0001	0.855 (0.824-0.887)	< 0.0001
Diabetes mellitus without chronic complications	1.168 (1.145-1.192)	< 0.0001	1.168 (1.132-1.205)	< 0.0001
Hypertension	0.792 (0.779-0.806)	< 0.0001	0.850 (0.828-0.872)	< 0.0001
Blood transfusion	2.356 (2.255-2.463)	< 0.0001	1.801 (1.689-1.919)	< 0.0001
Alpha1-antitrypsin deficiency	3.912 (2.669-5.735)	< 0.0001	2.100 (1.210-3.643)	0.0087
Disorders of porphyrin metabolism	5.145 (2.902-9.120)	< 0.0001	2.428 (1.163-5.066)	0.0187
Wilson disease	4.099 (1.800-9.332)	0.0008	4.269 (1.182-15.414)	0.0279
Smoking	1.204 (1.184-1.225)	< 0.0001	0.874 (0.851-0.897)	< 0.0001
opioids	1.412 (1.338-1.490)	< 0.0001	0.687 (0.631-0.749)	< 0.0001

¹Univariate analysis is performed with logistic regression.

²Multivariate analysis is performed with multi-level mixed effect models. HIV: Human immunodeficiency virus; NASH: Non-alcoholic steatohepatitis NAFLD: Non-alcoholic fatty liver disease.