The impact of chronic hepatitis C infection on the circadian clock and sleep
Authors: Daniel Shouval
Journal: Journal of Hepatology (2014)

Active at night, sleepy all day – Sleep disturbances in patients with hepatitis C virus infectionJournal of HepatologyVol. 60Issue 4PreviewMore than 50% of patients with chronic hepatitis C with only mild liver disease complain about chronic fatigue, daytime sleepiness and poor sleep quality. The aim of the present study was to characterize and objectify the sleep disturbances in hepatitis C virus-infected patients. Full-Text PDF Sleep disturbance with reversal of the day and night cycle is a well known phenomenon in patients with hepatic encephalopathy irrespective of etiology as shown in animal models and in humans [1Jimenez-Anguiano A. Diaz-Medina V. Farfan-Labonne B.E. Giono-Chiang G. Kersenobich D. Garcia-Lorenzana M. et al.Modification of sleep architecture in an animal model of experimental cirrhosis.World J Gastroenterol. 2009; 15: 5176-5180Crossref PubMed Scopus (8) Google Scholar, 2Zee P.C. Mehta R. Turek F.W. Blei A.T. Portacaval anastomosis disrupts circadian locomotor activity and pineal melatonin rhythms in rats.Brain Res. 1991; 560: 17-22Crossref PubMed Scopus (60) Google Scholar, 3De Cruz S. Espiritu J.R. Zeidler M. Wang T.S. Sleep disorders in chronic liver disease.Semin Respir Crit Care Med. 2012; 33: 26-35Crossref PubMed Scopus (37) Google Scholar]. Furthermore, insomnia, fatigue, depression, and cognitive impairment are common symptoms in patients with chronic liver disease (CLD) with cirrhosis. During the past 15 years, several studies have been published on the impact of cirrhosis such as primary biliary cirrhosis, non-alcoholic fatty liver disease, and Wilson's disease on the quality of sleep [4Forton D.M. Patel N. Prince M. Oatridge A. Hamilton G. Goldblatt J. et al.Fatigue and primary biliary cirrhosis: association of globus pallidus magnetisation transfer ratio measurements with fatigue severity and blood manganese levels.Gut. 2004; 53: 587-592Crossref PubMed Scopus (93) Google Scholar, 5Cordoba J. Cabrera J. Lataif L. Penev P. Zee P. Blei A.T. High prevalence of sleep disturbance in cirrhosis.Hepatology. 1998; 27: 339-345Crossref PubMed Scopus (216) Google Scholar, 6Abbas G. Jorgensen R.A. Lindor K.D. Fatigue in primary biliary cirrhosis.Nat Rev Gastroenterol Hepatol. 2010; 7: 313-319PubMed Google Scholar]. However, it is less known that abnormal sleep patterns have also been documented in up to ∼50% of patients with cirrhosis in the absence of overt hepatic encephalopathy or even in patients with CLD without cirrhosis [[5]Cordoba J. Cabrera J. Lataif L. Penev P. Zee P. Blei A.T. High prevalence of sleep disturbance in cirrhosis.Hepatology. 1998; 27: 339-345Crossref PubMed Scopus (216) Google Scholar]. It is sometimes difficult to differentiate between an organic cause of fatigue and insomnia from psychiatric disorders of variable severity in CLD in general and in chronic hepatitis C patients in particular [[7]Modabbernia A. Poustchi H. Malekzadeh R. Neuropsychiatric and psychosocial issues of patients with hepatitis C infection: a selective literature review.Hepat Mon. 2013; 13: e8340Crossref PubMed Scopus (30) Google Scholar]. Sleep patterns are dictated by 24 h circadian clocks, subjected to light and darkness cycles, which control numerous metabolic activities such as body temperature, blood pressure, melatonin, cortisol and growth hormone levels, urine output as well as mood and cognitive abilities. Such endogenous circadian cycles exist not only in humans but also in animals, plants, algae, bacteria, and fungi [[8]Foster R.G. Kreitzman L. The rhythms of life – what your body clock means to you.Exp Physiol. 2013; ([Epub ahead of print])https://doi.org/10.1113/expphysiol.2012.071118Crossref Scopus (60) Google Scholar]. Disruption of clock genes, which control the circadian rhythms, have recently been linked to sleep disorders and have an impact on metabolic activities [9Marcheva B. Ramsey K.M. Peek C.B. Affinati A. Maury E. Bass J. Circadian clocks and metabolism.Handb Exp Pharmacol. 2013; : 127-155Crossref PubMed Scopus (151) Google Scholar, 10Ohdo S. Chronotherapeutic strategy: rhythm monitoring, manipulation and disruption.Adv Drug Deliv Rev. 2010; 62: 859-875Crossref PubMed Scopus (106) Google Scholar]. Sleep and circadian rhythm disruption may have serious consequences on emotional, cognitive, and somatic responses. For example, inadequate sleep may lead to exhaustion, increased irritability, mood fluctuation such as depression, anxiety or anger, reduced concentration, attention deficit disorder, decreased memory, decreased productivity and creativity, drowsiness, unintended sleep, weight gain, metabolic abnormalities such as hyperglycemia, and more [[11]Foster R.G. Peirson S.N. Wulff K. Winnebeck E. Vetter C. Roenneberg T. Sleep and circadian rhythm disruption in social jetlag and mental illness.Prog Mol Biol Transl Sci. 2013; 119: 325-346Crossref PubMed Scopus (133) Google Scholar]. (The interested reader is referred to a recent review entitled "Sleep Disorders in Chronic Liver Disease" [[3]De Cruz S. Espiritu J.R. Zeidler M. Wang T.S. Sleep disorders in chronic liver disease.Semin Respir Crit Care Med. 2012; 33: 26-35Crossref PubMed Scopus (37) Google Scholar].)In the past two decades, referral of patients with chronic hepatitis C (CHC) is dominating the practice of clinical hepatologist worldwide, yet sleep disturbances in CHC patients without cirrhosis have received relatively little attention [3De Cruz S. Espiritu J.R. Zeidler M. Wang T.S. Sleep disorders in chronic liver disease.Semin Respir Crit Care Med. 2012; 33: 26-35Crossref PubMed Scopus (37) Google Scholar, 12Carlson M.D. Hilsabeck R.C. Barakat F. Perry W. Role of sleep disturbance in chronic hepatitis C infection.Curr Hepat Rep. 2010; 9: 25-29Crossref PubMed Scopus (28) Google Scholar, 13Sockalingam S. Abbey S.E. Alosaimi F. Novak M. A review of sleep disturbance in hepatitis C.J Clin Gastroenterol. 2010; 44: 38-45Crossref PubMed Scopus (34) Google Scholar]. In the present issue of the journal, Dr. Heeren and co-workers from the Hannover Medical School in Germany report their observations on altered sleep quality in a cohort of CHC patients without overt cirrhosis or classical hepatic encephalopathy [[14]Heeren M. Sojref F. Schuppner R. Worthmann H. Pflugrad H. Tryc A.B. et al.Active at night, sleepy all day – sleep disturbances in patients with hepatitis C virus infection.J Hepatol. 2014; 60: 732-740Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar]. The study cohort (N = 20, mean age 56.8 yr) was recruited from a small subgroup (N = 143) of the original HCV infected 1833 women who received an HCV contaminated anti-D immunoglobulin over three decades ago [[15]Wiese M. Grungreiff K. Guthoff W. Lafrenz M. Oesen U. Porst H. Outcome in a hepatitis C (genotype 1b) single source outbreak in Germany – a 25-year multicenter study.J Hepatol. 2005; 43: 590-598Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar]. Thus twenty anti-HCV positive, genotype 1b patients of whom 12 were still HCV-RNA positive by PCR participated in the study. The control population consisted of 19 age matched healthy females (mean age 55.3 yr). The unique characteristic relevant to the goals of the discussed study is the relatively benign course of CHC without cirrhosis over a period of more than thirty years in this selected group of women who nevertheless complained among other symptoms of weakness, fatigue, and decreased exertional capacity.The methodology used to assess the various study variables is broad and quite complex. Participants were asked to fill a number of questionnaires including the Pittsburgh Sleep Quality Index measuring sleep quality; the Epworth Sleepiness Scale measuring daytime sleepiness; the Fatigue Impact Scale measuring the impact of fatigue on daily activity; the Back Depression Inventory measuring depression; the Hospital Anxiety and Depression Scale measuring emotional alteration and the SF-36 questionnaire measuring health related quality of life. Furthermore, patients had to fill a sleep diary and use an actigraph which is a wrist worn device for monitoring of motor activity over a period of 24 h/day for 5 days. Obtained scores from the various questionnaires filled by the study and control groups as well as actigraphy scores were compared and a Spearman correlation test was used to evaluate a relationship between fatigue, quality of life, sleep parameters, and actigraphy results.The major findings of this study indicate that in contrast to healthy controls, patients with a history of chronic hepatitis C virus infection without overt cirrhosis may develop a disrupted circadian rhythm. This so called circadian arrhythmia is associated with an altered sleep pattern, insomnia, fatigue, depression, and reduced quality of life, which correlate with one another. Although patients displayed an increased nocturnal activity, no correlation could be established between fatigue and sleep pattern abnormality and 24 h activity level.Comments: The reported results suggest and confirm previous observations that sleep disruption and its consequences should be regarded as an extra hepatic manifestation of chronic hepatitis C. Furthermore, these symptoms may already be present in patients with mild chronic hepatitis C without clinical evidence for cirrhosis. A previous report found a strong association between reduced survival and sleep disorders in patients with advanced liver disease [[16]Kanwal F. Gralnek I.M. Hays R.D. Zeringue A. Durazo F. Han S.B. et al.Health-related quality of life predicts mortality in patients with advanced chronic liver disease.Clin Gastroenterol Hepatol. 2009; 7: 793-799Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar]. The present cohort of patients with relatively mild CHC is already followed for more than 3 decades and so far there is apparently no indication to suspect a worse prognosis despite the reported abnormal sleep pattern. Interestingly, the abnormal sleep pattern was present in both the 12 viremic patients as well as in those 7 patients who were HCV-RNA negative by PCR. In this context it is worthwhile to mention a recent report suggesting that primary and precursor forms of liver specific microRNA (miR122) are regulated in a circadian rhythm in the liver of animals [[17]Cox E.M. Sagan S.M. Mortimer S.A. Doudna J.A. Sarnow P. Enhancement of hepatitis C viral RNA abundance by precursor miR-122 molecules.RNA. 2013; 19: 1825-1832Crossref PubMed Scopus (15) Google Scholar]. In the detailed and well referenced discussion of this paper, the authors express their belief that based on previous functional imaging studies, the described symptoms in both HCV-RNA positive and negative patients are the result of an encephalopathy, which is independent of the state of viremia. However, the relatively small sample size and the absence of functional imaging data for the specific study cohort does not enable yet a firm conclusion regarding the role of viremia in the above described symptoms.Heeren and co-workers' report is the result of an extensive effort which is a case control study and descriptive by nature. The investigators utilized a wide range of methods to reach their conclusions but their results do not provide a clue regarding the mechanism(s) involved in the sleep disturbance and its consequences in CHC and this will remain a goal of future research. Aberrant sleep patterns have previously been linked to central nervous system involvement in persistent HCV infection affecting up to 65% of CHC patients [12Carlson M.D. Hilsabeck R.C. Barakat F. Perry W. Role of sleep disturbance in chronic hepatitis C infection.Curr Hepat Rep. 2010; 9: 25-29Crossref PubMed Scopus (28) Google Scholar, 13Sockalingam S. Abbey S.E. Alosaimi F. Novak M. A review of sleep disturbance in hepatitis C.J Clin Gastroenterol. 2010; 44: 38-45Crossref PubMed Scopus (34) Google Scholar, 18Lee D.H. Jamal H. Regenstein F.G. Perrillo R.P. Morbidity of chronic hepatitis C as seen in a tertiary care medical center.Dig Dis Sci. 1997; 42: 186-191Crossref PubMed Scopus (99) Google Scholar]. It has been suggested that sleep and the circadian system regulate a number of immune functions or vice versa [19Besedovsky L. Lange T. Born J. Sleep and immune function.Pflugers Arch. 2012; 463: 121-137Crossref PubMed Scopus (462) Google Scholar, 20de Almeida C.M. de Lima T.A. Castro D.B. Torres K.L. da Silva Braga W. Peruhype-Magalhaes V. et al.Immunological/virological peripheral blood biomarkers and distinct patterns of sleeping quality in chronic hepatitis C patients.Scand J Immunol. 2011; 73: 486-495Crossref PubMed Scopus (11) Google Scholar]. For example, the number of undifferentiated naïve T cells and production of pro-inflammatory cytokines peak during early nocturnal sleep while cytotoxic NK cells and anti-inflammatory cytokines peak during day time [[19]Besedovsky L. Lange T. Born J. Sleep and immune function.Pflugers Arch. 2012; 463: 121-137Crossref PubMed Scopus (462) Google Scholar]. The impact of past or present HCV infection on these parameters in the context of sleep disturbances is still unknown. Sleep and the circadian timing systems are driven by a complex interaction between multiple brain regions, neurotransmitters and hormones. Moreover, up to 20 clock genes and their protein products have been linked to control of circadian rhythms through translational-transcriptional feedback loops [8Foster R.G. Kreitzman L. The rhythms of life – what your body clock means to you.Exp Physiol. 2013; ([Epub ahead of print])https://doi.org/10.1113/expphysiol.2012.071118Crossref Scopus (60) Google Scholar, 11Foster R.G. Peirson S.N. Wulff K. Winnebeck E. Vetter C. Roenneberg T. Sleep and circadian rhythm disruption in social jetlag and mental illness.Prog Mol Biol Transl Sci. 2013; 119: 325-346Crossref PubMed Scopus (133) Google Scholar]. However the interaction of the hepatitis C virus with these genes and its impact on the molecular clock is still unexplored except for a recent observation in vitro that a circadian protein called PER2 interferes in viral replication [[21]Benegiamo G. Mazzoccoli G. Cappello F. Rappa F. Scibetta N. Oben J. et al.Mutual antagonism between circadian protein period 2 and hepatitis C virus replication in hepatocytes.PLoS One. 2013; 8: e60527Crossref PubMed Scopus (32) Google Scholar].In summary, the discussed report provides descriptive evidence that a history of past or present mild chronic hepatitis C virus infection even without clinical evidence for cirrhosis or "traditional" hepatic encephalopathy is associated with an altered sleep pattern, which has a negative impact on quality of life and well being. Sleep disturbance with reversal of the day and night cycle is a well known phenomenon in patients with hepatic encephalopathy irrespective of etiology as shown in animal models and in humans [1Jimenez-Anguiano A. Diaz-Medina V. Farfan-Labonne B.E. Giono-Chiang G. Kersenobich D. Garcia-Lorenzana M. et al.Modification of sleep architecture in an animal model of experimental cirrhosis.World J Gastroenterol. 2009; 15: 5176-5180Crossref PubMed Scopus (8) Google Scholar, 2Zee P.C. Mehta R. Turek F.W. Blei A.T. Portacaval anastomosis disrupts circadian locomotor activity and pineal melatonin rhythms in rats.Brain Res. 1991; 560: 17-22Crossref PubMed Scopus (60) Google Scholar, 3De Cruz S. Espiritu J.R. Zeidler M. Wang T.S. Sleep disorders in chronic liver disease.Semin Respir Crit Care Med. 2012; 33: 26-35Crossref PubMed Scopus (37) Google Scholar]. Furthermore, insomnia, fatigue, depression, and cognitive impairment are common symptoms in patients with chronic liver disease (CLD) with cirrhosis. During the past 15 years, several studies have been published on the impact of cirrhosis such as primary biliary cirrhosis, non-alcoholic fatty liver disease, and Wilson's disease on the quality of sleep [4Forton D.M. Patel N. Prince M. Oatridge A. Hamilton G. Goldblatt J. et al.Fatigue and primary biliary cirrhosis: association of globus pallidus magnetisation transfer ratio measurements with fatigue severity and blood manganese levels.Gut. 2004; 53: 587-592Crossref PubMed Scopus (93) Google Scholar, 5Cordoba J. Cabrera J. Lataif L. Penev P. Zee P. Blei A.T. High prevalence of sleep disturbance in cirrhosis.Hepatology. 1998; 27: 339-345Crossref PubMed Scopus (216) Google Scholar, 6Abbas G. Jorgensen R.A. Lindor K.D. Fatigue in primary biliary cirrhosis.Nat Rev Gastroenterol Hepatol. 2010; 7: 313-319PubMed Google Scholar]. However, it is less known that abnormal sleep patterns have also been documented in up to ∼50% of patients with cirrhosis in the absence of overt hepatic encephalopathy or even in patients with CLD without cirrhosis [[5]Cordoba J. Cabrera J. Lataif L. Penev P. Zee P. Blei A.T. High prevalence of sleep disturbance in cirrhosis.Hepatology. 1998; 27: 339-345Crossref PubMed Scopus (216) Google Scholar]. It is sometimes difficult to differentiate between an organic cause of fatigue and insomnia from psychiatric disorders of variable severity in CLD in general and in chronic hepatitis C patients in particular [[7]Modabbernia A. Poustchi H. Malekzadeh R. Neuropsychiatric and psychosocial issues of patients with hepatitis C infection: a selective literature review.Hepat Mon. 2013; 13: e8340Crossref PubMed Scopus (30) Google Scholar]. Sleep patterns are dictated by 24 h circadian clocks, subjected to light and darkness cycles, which control numerous metabolic activities such as body temperature, blood pressure, melatonin, cortisol and growth hormone levels, urine output as well as mood and cognitive abilities. Such endogenous circadian cycles exist not only in humans but also in animals, plants, algae, bacteria, and fungi [[8]Foster R.G. Kreitzman L. The rhythms of life – what your body clock means to you.Exp Physiol. 2013; ([Epub ahead of print])https://doi.org/10.1113/expphysiol.2012.071118Crossref Scopus (60) Google Scholar]. Disruption of clock genes, which control the circadian rhythms, have recently been linked to sleep disorders and have an impact on metabolic activities [9Marcheva B. Ramsey K.M. Peek C.B. Affinati A. Maury E. Bass J. Circadian clocks and metabolism.Handb Exp Pharmacol. 2013; : 127-155Crossref PubMed Scopus (151) Google Scholar, 10Ohdo S. Chronotherapeutic strategy: rhythm monitoring, manipulation and disruption.Adv Drug Deliv Rev. 2010; 62: 859-875Crossref PubMed Scopus (106) Google Scholar]. Sleep and circadian rhythm disruption may have serious consequences on emotional, cognitive, and somatic responses. For example, inadequate sleep may lead to exhaustion, increased irritability, mood fluctuation such as depression, anxiety or anger, reduced concentration, attention deficit disorder, decreased memory, decreased productivity and creativity, drowsiness, unintended sleep, weight gain, metabolic abnormalities such as hyperglycemia, and more [[11]Foster R.G. Peirson S.N. Wulff K. Winnebeck E. Vetter C. Roenneberg T. Sleep and circadian rhythm disruption in social jetlag and mental illness.Prog Mol Biol Transl Sci. 2013; 119: 325-346Crossref PubMed Scopus (133) Google Scholar]. (The interested reader is referred to a recent review entitled "Sleep Disorders in Chronic Liver Disease" [[3]De Cruz S. Espiritu J.R. Zeidler M. Wang T.S. Sleep disorders in chronic liver disease.Semin Respir Crit Care Med. 2012; 33: 26-35Crossref PubMed Scopus (37) Google Scholar].) In the past two decades, referral of patients with chronic hepatitis C (CHC) is dominating the practice of clinical hepatologist worldwide, yet sleep disturbances in CHC patients without cirrhosis have received relatively little attention [3De Cruz S. Espiritu J.R. Zeidler M. Wang T.S. Sleep disorders in chronic liver disease.Semin Respir Crit Care Med. 2012; 33: 26-35Crossref PubMed Scopus (37) Google Scholar, 12Carlson M.D. Hilsabeck R.C. Barakat F. Perry W. Role of sleep disturbance in chronic hepatitis C infection.Curr Hepat Rep. 2010; 9: 25-29Crossref PubMed Scopus (28) Google Scholar, 13Sockalingam S. Abbey S.E. Alosaimi F. Novak M. A review of sleep disturbance in hepatitis C.J Clin Gastroenterol. 2010; 44: 38-45Crossref PubMed Scopus (34) Google Scholar]. In the present issue of the journal, Dr. Heeren and co-workers from the Hannover Medical School in Germany report their observations on altered sleep quality in a cohort of CHC patients without overt cirrhosis or classical hepatic encephalopathy [[14]Heeren M. Sojref F. Schuppner R. Worthmann H. Pflugrad H. Tryc A.B. et al.Active at night, sleepy all day – sleep disturbances in patients with hepatitis C virus infection.J Hepatol. 2014; 60: 732-740Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar]. The study cohort (N = 20, mean age 56.8 yr) was recruited from a small subgroup (N = 143) of the original HCV infected 1833 women who received an HCV contaminated anti-D immunoglobulin over three decades ago [[15]Wiese M. Grungreiff K. Guthoff W. Lafrenz M. Oesen U. Porst H. Outcome in a hepatitis C (genotype 1b) single source outbreak in Germany – a 25-year multicenter study.J Hepatol. 2005; 43: 590-598Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar]. Thus twenty anti-HCV positive, genotype 1b patients of whom 12 were still HCV-RNA positive by PCR participated in the study. The control population consisted of 19 age matched healthy females (mean age 55.3 yr). The unique characteristic relevant to the goals of the discussed study is the relatively benign course of CHC without cirrhosis over a period of more than thirty years in this selected group of women who nevertheless complained among other symptoms of weakness, fatigue, and decreased exertional capacity. The methodology used to assess the various study variables is broad and quite complex. Participants were asked to fill a number of questionnaires including the Pittsburgh Sleep Quality Index measuring sleep quality; the Epworth Sleepiness Scale measuring daytime sleepiness; the Fatigue Impact Scale measuring the impact of fatigue on daily activity; the Back Depression Inventory measuring depression; the Hospital Anxiety and Depression Scale measuring emotional alteration and the SF-36 questionnaire measuring health related quality of life. Furthermore, patients had to fill a sleep diary and use an actigraph which is a wrist worn device for monitoring of motor activity over a period of 24 h/day for 5 days. Obtained scores from the various questionnaires filled by the study and control groups as well as actigraphy scores were compared and a Spearman correlation test was used to evaluate a relationship between fatigue, quality of life, sleep parameters, and actigraphy results. The major findings of this study indicate that in contrast to healthy controls, patients with a history of chronic hepatitis C virus infection without overt cirrhosis may develop a disrupted circadian rhythm. This so called circadian arrhythmia is associated with an altered sleep pattern, insomnia, fatigue, depression, and reduced quality of life, which correlate with one another. Although patients displayed an increased nocturnal activity, no correlation could be established between fatigue and sleep pattern abnormality and 24 h activity level. Comments: The reported results suggest and confirm previous observations that sleep disruption and its consequences should be regarded as an extra hepatic manifestation of chronic hepatitis C. Furthermore, these symptoms may already be present in patients with mild chronic hepatitis C without clinical evidence for cirrhosis. A previous report found a strong association between reduced survival and sleep disorders in patients with advanced liver disease [[16]Kanwal F. Gralnek I.M. Hays R.D. Zeringue A. Durazo F. Han S.B. et al.Health-related quality of life predicts mortality in patients with advanced chronic liver disease.Clin Gastroenterol Hepatol. 2009; 7: 793-799Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar]. The present cohort of patients with relatively mild CHC is already followed for more than 3 decades and so far there is apparently no indication to suspect a worse prognosis despite the reported abnormal sleep pattern. Interestingly, the abnormal sleep pattern was present in both the 12 viremic patients as well as in those 7 patients who were HCV-RNA negative by PCR. In this context it is worthwhile to mention a recent report suggesting that primary and precursor forms of liver specific microRNA (miR122) are regulated in a circadian rhythm in the liver of animals [[17]Cox E.M. Sagan S.M. Mortimer S.A. Doudna J.A. Sarnow P. Enhancement of hepatitis C viral RNA abundance by precursor miR-122 molecules.RNA. 2013; 19: 1825-1832Crossref PubMed Scopus (15) Google Scholar]. In the detailed and well referenced discussion of this paper, the authors express their belief that based on previous functional imaging studies, the described symptoms in both HCV-RNA positive and negative patients are the result of an encephalopathy, which is independent of the state of viremia. However, the relatively small sample size and the absence of functional imaging data for the specific study cohort does not enable yet a firm conclusion regarding the role of viremia in the above described symptoms. Heeren and co-workers' report is the result of an extensive effort which is a case control study and descriptive by nature. The investigators utilized a wide range of methods to reach their conclusions but their results do not provide a clue regarding the mechanism(s) involved in the sleep disturbance and its consequences in CHC and this will remain a goal of future research. Aberrant sleep patterns have previously been linked to central nervous system involvement in persistent HCV infection affecting up to 65% of CHC patients [12Carlson M.D. Hilsabeck R.C. Barakat F. Perry W. Role of sleep disturbance in chronic hepatitis C infection.Curr Hepat Rep. 2010; 9: 25-29Crossref PubMed Scopus (28) Google Scholar, 13Sockalingam S. Abbey S.E. Alosaimi F. Novak M. A review of sleep disturbance in hepatitis C.J Clin Gastroenterol. 2010; 44: 38-45Crossref PubMed Scopus (34) Google Scholar, 18Lee D.H. Jamal H. Regenstein F.G. Perrillo R.P. Morbidity of chronic hepatitis C as seen in a tertiary care medical center.Dig Dis Sci. 1997; 42: 186-191Crossref PubMed Scopus (99) Google Scholar]. It has been suggested that sleep and the circadian system regulate a number of immune functions or vice versa [19Besedovsky L. Lange T. Born J. Sleep and immune function.Pflugers Arch. 2012; 463: 121-137Crossref PubMed Scopus (462) Google Scholar, 20de Almeida C.M. de Lima T.A. Castro D.B. Torres K.L. da Silva Braga W. Peruhype-Magalhaes V. et al.Immunological/virological peripheral blood biomarkers and distinct patterns of sleeping quality in chronic hepatitis C patients.Scand J Immunol. 2011; 73: 486-495Crossref PubMed Scopus (11) Google Scholar]. For example, the number of undifferentiated naïve T cells and production of pro-inflammatory cytokines peak during early nocturnal sleep while cytotoxic NK cells and anti-inflammatory cytokines peak during day time [[19]Besedovsky L. Lange T. Born J. Sleep and immune function.Pflugers Arch. 2012; 463: 121-137Crossref PubMed Scopus (462) Google Scholar]. The impact of past or present HCV infection on these parameters in the context of sleep disturbances is still unknown. Sleep and the circadian timing systems are driven by a complex interaction between multiple brain regions, neurotransmitters and hormones. Moreover, up to 20 clock genes and their protein products have been linked to control of circadian rhythms through translational-transcriptional feedback loops [8Foster R.G. Kreitzman L. The rhythms of life – what your body clock means to you.Exp Physiol. 2013; ([Epub ahead of print])https://doi.org/10.1113/expphysiol.2012.071118Crossref Scopus (60) Google Scholar, 11Foster R.G. Peirson S.N. Wulff K. Winnebeck E. Vetter C. Roenneberg T. Sleep and circadian rhythm disruption in social jetlag and mental illness.Prog Mol Biol Transl Sci. 2013; 119: 325-346Crossref PubMed Scopus (133) Google Scholar]. However the interaction of the hepatitis C virus with these genes and its impact on the molecular clock is still unexplored except for a recent observation in vitro that a circadian protein called PER2 interferes in viral replication [[21]Benegiamo G. Mazzoccoli G. Cappello F. Rappa F. Scibetta N. Oben J. et al.Mutual antagonism between circadian protein period 2 and hepatitis C virus replication in hepatocytes.PLoS One. 2013; 8: e60527Crossref PubMed Scopus (32) Google Scholar]. In summary, the discussed report provides descriptive evidence that a history of past or present mild chronic hepatitis C virus infection even without clinical evidence for cirrhosis or "traditional" hepatic encephalopathy is associated with an altered sleep pattern, which has a negative impact on quality of life and well being. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.