Our study indicated that within a median follow-up period of 13.7 years, daytime napping was associated with an increased risk of liver cancer in Japanese older participants in their 60s and 70s of age by 66% and 72%, respectively. On the other hand, daytime napping was not related to liver cancer risk among younger age categories.
An early report using data from the JACC Study revealed that the age-adjusted association between daytime napping (yes versus no) and mortality from liver cancer was significant in women: HR (95% CI) 1.62 (1.17, 2.24) and tended to be significant in men 1.23 (0.97, 1.55) . Contrary to our study, the former JACC Study examined the risk of cancer mortality as a proxy for incidence, had a relatively short follow-up period, included nightshift and rotational shift workers who might show disturbed sleep and high risk of cancer [22, 23], did not adjust their results for most confounders including the history of liver diseases and alcohol intake, and did not examine the impact of age on the association.
Later, the Million Women Study showed that daytime napping was not associated with liver cancer risk, among women aged 50–64 years; relative risks (95% CIs) of liver cancer for daytime napping (sometimes/usually versus rarely/never) were 1.19 (0.84, 1.69) during the first four years and 1.09 (0.82, 1.46) in longer follow-up years . Though, the Women’s Health Initiative Study that included women aged 50–79 years, relatively older than the Million Women Study, showed that daytime nappers were at higher risk of liver cancer: HR (95 CI%) of liver cancer for daytime napping (≥ one to two times/day versus < one time/day) were 1.40 (1.02, 1.90). However, additional adjustments for sociodemographic and clinical characteristics attenuated the association 1.12 (0.80, 1.57) . Unfortunately, both studies did not stratify their results by age group.
The mechanisms underlying the association between daytime napping and liver cancer are unknown, but some explanations could be suggested. First, daytime napping may reflect a disturbed circadian clock . Peripheral clock genes that regulate the absorption of xenobiotics are predominantly expressed in the liver , and their mutation can lead to liver cancer . Second, the sudden rise in blood pressure and heart rate upon awakening from daytime napping activates the sympathetic nervous system , and this activation can induce hepatocarcinogenesis by activating the adrenergic receptors of cancer cells and promoting their survival in the liver . Third, daytime napping might be a consequence of obstructive sleep apnea , a common sleep disorder characterized by episodes of partial or complete upper airway collapse that result in fragmented sleep and daytime somnolence . Human and animal studies showed that intermittent hypoxia attributed to obstructive sleep apnea was independently associated with nonalcoholic fatty liver disease via inducing hepatic steatosis, inflammation, and cirrhosis [30, 31]. Patients with nonalcoholic fatty liver are at high risk of developing liver cancer [32, 33]. Interestingly, the Multi-Ethnic Study of Atherosclerosis showed that Asians had significantly more obstructive sleep apnea than Caucasians , which could partly explain the positive results in the JACC Study and the negative results in the Western studies. Unfortunately, we have no data about obstructive sleep apnea to test this assumption.
The positive association between daytime napping and liver cancer risk among older but not younger participants came in line with previous reports that showed a higher risk of all-cause, cardiovascular, and cancer mortality among older daytime nappers than younger ones [10, 35–37]. One explanation is that younger adults take short daytime naps because they have to go back to work while older adults, who are typically retired, have more free time to take longer daytime naps. Unlike long daytime napping, short daytime napping was shown to have no pathogenic impacts [37, 38]. People who take short daytime naps do not enter deep slow-wave sleep while those who take long daytime naps enter deep slow-wave sleep before disrupting the sleep cycle by awakening [39, 40]. Such disruption is strictly associated with a disturbed circadian clock . This explanation is supported by our sensitivity analysis that showed attenuation in the association between daytime napping and liver cancer risk after excluding participants who reported being unemployed or housemakers from the analysis.
This study included several strengths such as investigating a large cohort with no history of cancer, having a prospective cohort design with a long follow-up period, using standardized methods to diagnose liver cancer, measuring the impact of age on the association between daytime napping and risk of liver cancer, and adjusting for most potential confounders.
However, some limitations should be addressed. First, daytime napping was evaluated using a simple yes/no question making misclassification possible. Second, the daytime napping question did not assess the duration and frequency of daytime napping; thus, a dose-response relationship could not be attained. Two meta-analyses of prospective cohort studies showed that the risk of all-cause mortality was more evident among participants with daytime napping ≥ 60 min than participants with daytime napping < 60 min [11, 37]. Third, daytime napping was assessed at a one-time point; we do not know whether participants changed their daytime napping behavior during follow-up. Fourth, it could be speculated that the lifestyle and health conditions of daytime nappers were the reason behind the increased risk of liver cancer rather than daytime napping itself. This possibility cannot be entirely excluded, yet excluding participants with liver diseases including hepatitis, which is considered the chief risk factor for liver cancer among Japanese , did not affect the results. It could also be speculated that daytime napping could refer to a short or long sleep duration, which is considered a risk factor for liver diseases  and cancer . However, excluding participants with short or long sleep duration from the analysis did not affect the results. Also, the positive association between daytime napping and liver cancer risk remained significant after excluding participants with a follow-up period of ≤ three years suggesting that preclinical conditions cannot explain this association.