Hepatitis C: Why Am I So Tired ? Fatigue In HCV
Fatigue is the most common symptom seen in chronic HCV, an area in hepatitis C research which has not been abundantly explored. I thought it may be interesting to compile some data relating to fatigue and HCV/ liver disease; the information collected will span from 2006 to 2011. Because HCV has been related to other disorders which may attribute to fatigue I thought we may begin here.
Other Health Problems That May Contribute To Fatigue In HCV
From Melissa Palmer, M.D.
Vitamin B 12 and folate are both crucial to the formation of red blood cells. Therefore, a deficiency of these vitamins often leads to anemia and associated fatigue. This explains why individuals with liver disease who suffer from excessive fatigue, often ask about vitamin B12 injections. However, their expectation that such an injection will provide an “extra boost ” of energy is misguided. Since vitamin B12 is commonly found in animal food products such as meat, fish, milk and eggs, a vitamin B12 deficiency is a very uncommon cause of fatigue in individuals with liver disease. A few exceptions must be made to this statement. One exception applies to individuals with alcoholic liver disease for whom the bulk of nutrients are obtained from alcohol. A vitamin B12 deficiency may develop among these individuals. Furthermore, since alcohol interferes with the absorption of vitamin B12, a vitamin B12 deficiency may develop if a person consumes an excessive amount of alcohol even if he or she maintains a well-balanced diet. A vitamin B 12 deficiency may also occur in individuals with chronic liver disease who maintain a strict vegetarian diet for a long period of time, such as is the case for those suffering with chronic encephalopathy. Finally, the older a person is, the more likely a B12 deficiency is to develop. This is because stomach acid is needed to absorb this vitamin from food, and, as a person ages, the amount of acid in the stomach diminishes. Therefore, individuals with liver disease who are over the age of sixty, or individuals with liver disease who are chronically on medications that block stomach acid - such as H2 blockers (for example Pepcid, Axid, Tagamet, and Zantac) or proton-pump inhibitors (for example, Prilosec, Nexium, Prevacid, Aciphex and Protonix) should be checked for a vitamin B 12 deficiency. As with vitamin B12, a folate deficiency can also produce anemia. In fact, vitamin B 12 must be present in order to activate folate, which accounts for the fact that a deficiency of one tends to simultaneously cause a deficiency of the other.
Nutritional deficiencies, such as a lack of protein, as well as disturbances in fluid and electrolyte balance, such as a low sodium level, also contribute to exhaustion.
Cirrhosis and Sleep Disturbances
People with liver disease often suffer from sleep disturbances which is a common cause of fatigue. In fact, approximately thirty-five to fifty percent of individuals with cirrhosis report having sleep-related difficulties. Some people have trouble falling asleep, whereas others have difficulty staying asleep. Many people complain of being tired all day, yet awake all night. Others complain of erratic sleeping habits characterized by days of excessive sleep (hypersomnia) alternating with days of lack of sleep (insomnia). Still others state that they experience delays of their usual bedtimes and wake-up times. For most people suffering from these sleep disorders, the sleep they do get is not refreshing. And, all of these forms of sleep disturbances may cause fatigue.
The cause of sleeping disorders in individuals with liver disease is unclear, but most likely relates to alterations in the body’s production of melatonin (a substance produced by the pineal gland and is involved in the sleep cycle). Sometimes, sleep disturbances stem from medications used in the treatment of liver disease. For example, interferon, ribavirin, prednisone and propanolol are all associated with insomnia. Also, caffeine, nicotine and alcohol consumption may contribute to disturbed sleep habits and, as such, abstinence from these substances will likely assist in the quest for a good night’s sleep. It should be noted that sleep disturbances may be a sign of impending encephalopathy.
Depression is associated with fatigue, either caused at the time of diagnosis, stigma, stress, or due to the ongoing prognosis.
Depression is one of the most common complications of chronic illness. It is estimated that up to one-third of individuals with a serious medical condition experience symptoms of depression. People diagnosed with chronic illnesses must adjust to the demands of the illness as well as to its treatment. The illness may affect a person’s mobility and independence, and change the way a person lives, sees him- or herself, and/or relates to others. These requirements can be stressful and cause a certain amount of despair or sadness that is normal.
Patients who have been diagnosed with hepatitis C may be more susceptible to developing type 2 diabetes, according to a study published in the journal Gastroenterology.
During the study, a team of investigators monitored a total of 29 patients with hepatitis C who showed signs of insulin resistance, a symptom of diabetes.
The results of the trial showed that 15 of the participants experienced insulin complications in their muscle tissue compared to the liver. The inability to properly absorb the sugar created high levels of the nutrient in the blood, which could lead to developing diabetes.
"At this stage, it is helpful for people with hepatitis C to understand insulin resistance and what it can mean for them," said Don Chisholm, co-author of the study. He added that "if they have relatives with type 2 diabetes, they will be genetically prone to developing it themselves and so would be advised to manage their diets very carefully and get plenty of exercise—to slow onset."
Dr Kerry Lee Milner and Professor Don Chisholm from Sydney's Garvan Institute of Medical Research, in collaboration with Professor Jacob George from the Storr Liver Unit, University of Sydney at Westmead
Related 2009; Risk Factors for the Development of Diabetes Mellitus in Chronic Hepatitis C Virus Genotype 4 Infection
Note: Carnitine (aka L-carnitine) is an amino acid produced in the liver and kidneys, stored in the muscles, heart, and brain, and used by the cells’ mitochondria to turn fatty acids into energy. Deficiencies occur when the body can’t make enough or can’t transport it to the tissues. Hepatitis C is a viral disease involving inflammation of the liver.]
Study findings suggest that plasma carnitine levels are inversely correlated with fatigue severity in patients with chronic hepatitis C (CHC).
Although the mechanisms involved in the occurrence of carnitine deficiency in CHC have not been investigated in the present study, it could be cautiously speculated that [hepatitis] virus C infection may alter the physiological process of carnitine biosynthesis in the liver," note the authors in the journal Alimentary Pharmacology and Therapeutics.
They explain that carnitine - an amino acid involved in energy production - is known to improve chronic fatigue states, such as those occurring in cancer and multiple sclerosis, and thus it is feasible that a carnitine deficiency may worsen fatigue in conditions like CHC.
Background: Fatigue is an important determinant of altered quality of life in patients affected by chronic hepatitis C or the irritable bowel syndrome (IBS).
Aim: In this study, we aimed at determining the contributory role of plasma levels of leptin and carnitine on fatigue in chronic hepatitis C and IBS. [Reportedly “the fatigue measured was not post exertional malaise.”]
Methods: We enrolled 70 patients with chronic hepatitis C, 42 with IBS and 44 healthy subjects.
Fatigue was evaluated using the Fatigue Impact Scale questionnaire. Body composition was assessed through impedance analysis. Plasma carnitine and leptin were measured.
• Fatigue scores were significantly more elevated in patients with chronic hepatitis C and IBS than in healthy subjects.
• Patients with chronic hepatitis C but not IBS, had significantly lower plasma levels of total and free carnitine adjusted for fat mass compared with healthy subjects.
• In patients with chronic hepatitis C and not with IBS, fatigue scores were negatively correlated with plasma levels of carnitine. [Those with more severe fatigue, had lower carnitine status & vice versa.]
Levels of free carnitine were significantly and independently associated with the severity of fatigue in patients with chronic hepatitis C [OR=2.019, P=0.02, CI 95% (1.01-1.23)].
Conclusions: In patients with chronic hepatitis C, the severity of fatigue is associated with a low level of carnitine, suggesting that an oral supplementation may be effective to relieve fatigue in chronic hepatitis C. The underlying mechanism of fatigue in IBS does not seem to involve carnitine.
Source: Alimentary Pharmacology and Therapeutics, Mar 2, 2011. PMID: 21366633, by Anty R, Marjoux S, Bekri S, Degalleani L, Dainese R, Gelsi E, Cherikh F, Tran A, Piche T. Institut National de la Santé et de la Recherche Médicale (INSERM); Centre Hospitalier Universitaire of Nice; Institut Hospitalo-Universitaire de Recherche Biomédicale (IHURB), Rouen, France. [E-mail: firstname.lastname@example.org]
October 8, 2010 By Raquel Maurier
A University of Alberta researcher specializing in neurological infections has discovered that the hepatitis C virus injures and inflames brain cells, resulting in neurological issues for some patients living with the disease. Until now, no one has been able to prove this.
A recent Canadian study suggests that 13 per cent of people with hepatitis C, a chronic condition that affects 300,000 Canadians, also have neurological problems. Other research has suggested the hepatitis C virus might penetrate the blood-brain barrier. Chris Power, the Canada Research Chair in Neurological Infection and Immunity with the Faculty of Medicine & Dentistry, and his team decided to tackle this theory conducting experiments on human cadavers.
“We saw the virus in the brain of a deceased patient who had hepatitis C,” said Powers, who noted that normally it is very difficult for any type of virus or infection to pass the blood-brain barrier. Based on this discovery, the researchers made three new and major findings. The hepatitis C virus damaged those neurons in the brain responsible for motor functions, memory and concentration. The virus also triggered inflammation of the brain, which contributed to more neurons being damaged. And, thirdly, the virus stopped a natural process in the brain cells called autophagy, in which the cells get rid of unwanted toxic proteins. So, instead, the brain cells were accumulating large amounts of these toxic proteins, causing further damage to the brain cells.
“For a long time, the medical community has recognized some people who have hepatitis C also have memory loss and poor concentration, which is very disabling for those patients,” says Power. “Now we have some understanding about the cause of these neurological symptoms that can lead to the development of future treatments for people with hepatitis C.
“This discovery is significant because this is the first time anyone has confirmed that the hepatitis C virus can infect and injure brain cells.”
Curr HepatitisRep (2010)
9:25–29 DOI 10.1007/s11901-010-0030-x
University of California Peer Reviewed
Author: Publication Date: 2010 ;
Chronic infection with the Hepatitis C virus= (CHC) is associated with physical and mental symptoms including fatigue and depression that adversely affect quality of life.
A related complaint, sleep disturbance, has received little attention in the literature, with the exception of sleep changes noted in cirrhosis and end-stage liver disease.
We present an overview of studies indicating sleep problems in patients with CHC, with about 60% to 65% of individuals reporting such complaints. Evidence suggests that impairments in sleep quality exist independent of antiviral therapy with interferon-α and prior to advanced stages of liver disease.
Further investigation of sleep disturbance in CHC patients with a mild stage of liver disease may provide important information on disease course as well as allow additional opportunities for patient support. .Introduction Chronic infection with the hepatitis c virus= (CHC) in the United States is reported to have peaked at 3.6 million Americans affected; however, the number of individuals with advanced fibrosis is projected to continue to rise until the year 2020 . Clinical investigations of CHC have identified decrements in physical and mental functioning that negatively impact quality of life= (QOL).
Among these complaints, physical tiredness or fatigue is the most prevalent symptom endorsed by a sample of patients living with CHC . In fact, studies of CHC have shown that up to 97% of individuals with CHC endorse fatigue .
A study of 94 CHC patients not receiving antiviral therapy identified predictors of fatigue to include poor social functioning, poor physical functioning, greater depression, and female gender ]. Although fatigue has been widely reported, one seemingly related factor, sleep disturbance, has received little attention in the literature. Clinical experience suggests that patients with CHC endorse sleeping problems, and large studies of CHC patients undergoing antiviral therapy with interferon (IFN)-α report insomnia as an adverse event endorsed by as many as 30%
However, the nature of sleep problems in CHC remains poorly understood. Exploration of sleep disturbance in patients with CHC may provide important information about the disease course and allow opportunities for additional supportive care of this patient group. Sleep may be particularly important to study in light of the recent finding that survival was strongly associated with sleep disturbance among 156 patients with cirrhosis . We hypothesized that patients with CHC report significant sleeping complaints. Such sleeping problems may occur prior to IFN treatment and in the absence of advanced stages of liver disease. '
Method PubMed and Medline searches using search terms “sleep and hepatitis C" were conducted to identify investigations of sleep disturbance in CHC published in English over the past 10 years (2000 to 2009).
Only articles that went beyond simply mentioning the presence or
occurrence of sleep disturbance and considered sleep problems independent of mood or other psychiatric disorders were reviewed. Because the search revealed a small number of articles on the specific topic of sleep and CHC and previous work has shown that about 50% of patients with cirrhosis reported unsatisfactory sleep the search was expanded to include search terms “sleep and cirrhosis” and “sleep and end-stage liver disease (ESLD)” but excluded articles that clearly focused on a specific cirrhotic patient sample that would not include patients with CHC (eg, primary biliary cirrhosis)
Results Six articles met criteria for inclusion using search terms
“sleep and hepatitis c.” Nine additional articles were identified using search terms “sleep and cirrhosis” and “sleep and end-stage liver disease”
The majority of literature on sleep problems focused on patients with cirrhosis.
Sleep and Hepatitis C Clifford et al.  examined sleep disturbance, along with depressive and anxious symptoms and cognitive functioning, in 264 patients with HIV, 30 of whom were coinfected with CHC. l Sleep problems were investigated using the Pittsburgh Sleep Quality Index (PSQI) , a 19-item self-report questionnaire used to study sleep quality over a 1-month interval. A global PSQI score and seven component scores are calculated providing information on subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medication, and daytime dysfunction. Patients with both CHC and HIV reported poorer sleep, overall, than patients with HIV only, with significant group differences in sleep quality and marginally significant differences in sleep disturbances. l Coinfected patients also reported significantly more depressive symptoms and demonstrated poorer performances on a task of psychomotor speed and working memory than HIV-only patients.
There were no differences in anxious symptoms. Lang et al.  surveyed 188 treatment-naive patients with CHC and found that sleep problems were reported by about 65% and were among the top 10 most prevalent symptoms endorsed. Sleep problems were endorsed equally as often by men as women, unlike depression, physical tiredness, mental tiredness, and forgetfulness, which were endorsed more frequently by women. CHC patients additionally rated symptom severity using a visual analogue scale (VAS) ranging from 0 to 10, with higher scores indicating worse severity over the previous 3 months. l The median severity score for individuals reporting sleep problems was 8 on the VAS (range 2 to 10), the highest ranked score among the 21 symptoms reported. Other investigations of sleep disturbances in early stages of disease were focused on the relationship between sleep disturbance and development of major depressive disorder (MDD) during the course of IFN treatment .
Researchers measured sleep problems with the PSQI and administered a semistructured clinical interview to diagnose MDD. Results suggested poor sleep quality is associated with subsequent depression during IFN therapy, but depression was not associated with changes in sleep quality . ; Moreover, sleep quality tended to be better in CHC patients with a particular genotype of the serotonin transporter length promoter region that was associated with a lower rate of MDD, suggesting a possible mediational role of sleep quality in resilience to MDD . Given the lack of research on sleep problems in untreated CHC patients, our group investigated sleep disturbance in 80 consecutive CHC patients seen in a tertiary hepatology clinic . All participants completed the PSQI and Fatigue Severity Scale (FSS), a nine-item self-report questionnaire measuring the impact of fatigue on daily functioning.
Information on psychiatric diagnoses and liver disease staging were also collected. Of the 80 CHC patients sampled, about 63% were identified as poor sleepers on the PSQI. Fifty-six (70%) of the participants met criteria for significant self-reported fatigue on the FSS. As expected, a significant relationship was found between the global PSQI and FSS scores (R=0.50, P> ;
Further analysis revealed no significant differences in sleep complaints endorsed by patients with or without psychiatric diagnoses. Finally, decrements in sleep quality did not differ according to stage of liver disease, suggesting that sleep disturbance is not only a function of advanced stages of liver disease. In their review article of sleep disturbance in CHC, also note the paucity of research in this area and describe in detail how to diagnose and treat the most common sleep disorders in CHC, including insomnia, hypersomnia, restless leg syndrome (RLS), and obstructive sleep apnea (OSA). ; They also review the literature on sleep disturbances in untreated CHC patients, as well as IFN-induced sleep disturbances, identifying 17 articles published on this topic between 1995 and 2008. Potential etiologies of sleep disturbance in CHC also are discussed. However, their review did not discuss 8 of the 14 articles included in the current review and the current review did not discuss diagnosis and treatment of sleep disorders. .
Sleep and Cirrhosis With regard to the articles addressing sleep in cirrhotic and ESLD patients, much of this work viewed sleep disturbance as part of hepatic encephalopathy (HE), particularly minimal HE.
Martino , for example, concluded that sleep electroencephalogram (EEG) revealed the existence of minimal HE and that changes of mean dominant frequency were early markers of cerebral dysfunction. Investigators then began to examine OSA as a complication of cirrhosis , finding that as the severity of cirrhosis increased, so did the presence of OSA, particularly in patients with Child-Pugh scores in class C . Additionally, patients with ascites were more likely to have OSA, which may be reversed with removal of ascitic fluid . Central sleep apnea, on the other hand, was not observed in a small sample of patients with cirrhosis.
Together, these findings suggest symptoms of sleep apnea in patients with cirrhosis may be related to an enlarged abdominal perimeter and changes in systemic hemodynamics and vasoactive systems associated with decompensated cirrhosis, particularly ascites .
More recent work has focused on understanding the qualitative aspects of sleep disturbance in patients with cirrhosis and investigating possible treatments. Mostacci et al.  reported that patients with cirrhosis complained of significantly more frequent daytime sleepiness and habitual napping, nighttime sleep problems, and nocturnal awakenings than controls, which were not related to clinical or laboratory parameters.
Nighttime sleep disturbance, daytime sleepiness, and preference
for evening activities also were noted in a study of the relationship between sleep and QOL in 87 patients with cirrhosis
In this study, almost 70% of patients were classified as “poor sleepers” using the PSQI, and nighttime sleep disturbance and evening preference were independent predictors of poorer QOL.
Montagnese et al. [23•] pointed out that nighttime sleep disturbance and daytime sleepiness were not correlated, but that daytime sleepiness was correlated with slowing on EEG, suggesting that daytime sleepiness might be a harbinger of minimal HE whereas nighttime sleep disturbance does not relate to or reflect the presence of HE. '
An initial study of the prevalence of RLS in a heterogeneous sample of 141 patients with chronic liver disease seen in an academic-based tertiary care hepatology clinic found that 62% of respondents indicated RLS . Prevalence of RLS did not differ by gender; the only significant difference between patients with and without reported RLS was the presence of neuropathy, which was more commonly reported in patients with RLS.
However, 16% of patients with RLS had no identifiable risk factor. In the only treatment study of sleep disturbance in cirrhotic patients, found that, compared with placebo, hydroxyzine, 25 mg, at bedtime significantly improved patients’ self-reported sleep disturbance assessed using a VAS, as well as their objective sleep efficiency as measured by wrist actigraphy. Importantly, performances on neuropsychologic tests were not affected by administration of hydroxyzine. ' However, one patient developed clinically overt HE, which was reversed with cessation of hydroxyzine, indicating this medication should be used with caution in cirrhotic patients.
' Although changes in sleep behavior appear to be common in patients with cirrhosis, the underlying mechanisms are not yet defined and are likely multifactorial. One hypothesis implicates abnormal liver metabolism of plasma melatonin, which is known to play a key role in sleep . Another hypothesis suggests sleep behavior alterations may result from dysregulation of histaminergic neurotransmission in the brain, because histamine is involved in regulation of sleepwake cycles and vigilance . Still another posits dysregulation of serotonin and corticospinal tracts, particularly in the etiology of RLS . ' A more detailed review of potential mechanisms for sleep disturbance in cirrhotic patients is beyond the scope of this article, however.
Discussion Literature on the nature of sleep disturbance in CHC appears quite limited. Initial data from the few available studies suggest a prevalence of sleep complaints of about 60% to 65% , with a moderate relationship between poorer sleep quality and greater fatigue.
Furthermore, preliminary findings suggest that sleep problems may exist independently of mood and other psychiatric disorders in CHC and may predict the onset of MDD in CHC patients undergoing IFN therapy.
It therefore seems prudent that clinicians monitor sleep complaints prior to treatment, because they may have the potential to aggravate symptoms of underlying mood or psychiatric problems, as well as other side effects of antiviral treatment. The literature also strongly points to the fact that sleep disturbance exists prior to the onset of cirrhosis and ESLD, suggesting that HE is not the only factor contributing to sleep problems in patients with chronic liver disease. Clearly, additional research is needed to characterize sleep problems in noncirrhotic patients with CHC.
Future studies on the effects of CHC infection on the brain may provide important information on the nature of sleep disturbance reported by patients with CHC. Growing research suggests that hepatitis C may be neurovirulent, affecting the central nervous system via a “Trojan horse” mechanism . Studies have shown evidence of cognitive deficits in CHC and a recent review summarized neuroimaging research on brain systems potentially affected It is unknown whether such effects on the brain may play a role in the sleep complaints reported by patients. Future research may benefit from further exploration of this potential relationship., Curr Hepatitis Rep (2010) 9:25–29 27
, In cirrhotic patients, sleep disturbance has long been recognized as part of HE, with OSA receiving the most attention by investigators. Recent research has begun to characterize qualitative aspects of sleep complaints in these patients , with one treatment study suggesting hydroxyzine may be of potential benefit. The etiologies of sleep problems in cirrhotic and ESLD patients are likely multifactorial, and may be related to liver metabolism of plasma melatonin, enlarged abdominal perimeter and associated effects, comorbid medical conditions, and/or dysregulation of neurotransmitter systems . ' Conclusions In summary, considerably more research studies focused on the role of CHC infection and sleep and its potential effects on the brain are needed. Future research should study patients with mild stages of disease and include objective measures of sleep quality, such as EEG, actigraphy, and/or polysomnography. It is important that future research also assess for sleep quality independent of mood and other psychiatric problems. With increased knowledge about the mechanisms that underlie sleep disturbance in patients with CHC, appropriate treatments can be developed that may improve patient care outcomes and QOL.
lDisclosure No potential conflict of interest relevant to this article was reported. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. l
Disclosure No potential conflict of interest relevant to this article was reported. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
ScienceDaily (Feb. 28, 2009) — New animal research in the February 18 issue of The Journal of Neuroscience may indicate how certain diseases make people feel so tired and listless. Although the brain is usually isolated from the immune system, the study suggests that certain behavioral changes suffered by those with chronic inflammatory diseases are caused by the infiltration of immune cells into the brain. The findings suggest possible new treatment avenues to improve patients' quality of life
Chronic inflammatory diseases like rheumatoid arthritis, inflammatory bowel disease, psoriasis, and liver disease cause "sickness behaviors," including fatigue, malaise, and loss of social interest. However, it has been unclear how inflammation in other organs in the body can impact the brain and behavior.
The researchers found that in mice with inflamed livers, white blood cells called monocytes infiltrated the brain. These findings support previous research demonstrating the presence of immune cells in the brain following organ inflammation, challenging the long-held belief that the blood-brain barrier prevents immune cells from accessing the brain.
"Using an experimental model of liver inflammation, our group has demonstrated for the first time the existence of a novel communication pathway between the inflamed liver and the brain," said the study's senior author Mark Swain, MD, Professor of Medicine at the University of Calgary.
Swain and his colleagues found that liver inflammation triggered brain cells called microglia to produce CCL2, a chemical that attracts monocytes. When the researchers blocked CCL2 signaling, monocytes did not enter the brain despite ongoing inflammation in the liver.
Liver inflammation also stimulated cells in the blood to make an immune chemical (TNFα). When the researchers blocked the signaling of this immune chemical, microglia produced less CCL2, and monocytes stayed out of the brain.
In the mice with inflamed livers, preventing the entry of monocytes into the brain reduced sickness behaviors; mice showed more mobility and social interaction. These findings suggest that people with chronic inflammatory diseases may benefit from treatments that limit monocyte access to the brain.
"Sickness behavior significantly impacts quality of life. Our findings further our understanding and may generate potential new avenues for treatment of these often crippling symptoms," said Swain.
"The brain is the master coordinator of many of our bodies' defense responses, so it must be able to sense injury and inflammation in distant body organs. This study starts to explain the peripheral communication signals that activate the brain," said Nancy Rothwell, PhD, DSc, at the University of Manchester, an expert on brain inflammation who is unaffiliated with the study.
The research was supported by the Canadian Institutes of Health Research, the Canadian Liver Foundation, and the Alberta Heritage Foundation for Medical Research.
Hepatitis C is a systemic disease that has many extrahepatic manifestations in addition to hepatic inflammation and fibrosis, some of which may result in a poor health-related quality of life (HRQOL). Fatigue is perhaps the most frequent and disabling extrahepatic symptom of hepatitis C virus (HCV), reported in almost one-half of all chronically infected individuals. Many other factors are associated with a poor quality of life in patients with HCV, including a number of physical and psychological factors. The objective of this article is to review the association between HCV and impaired HRQOL due to fatigue and psychological disturbances.
Hepatitis C virus (HCV) is the major cause of end-stage liver disease in many countries of the world with more than 170 million people found to be infected. 
Typically, HCV is a silent infection with symptoms and signs appearing only in those with severe and advanced disease. However, there is now a growing awareness that hepatitis C is a systemic disease that has many extrahepatic manifestations in addition to liver inflammation and fibrosis.  Some of these extrahepatic manifestations result in a poor health-related quality of life (HRQOL). These symptoms include fatigue, anorexia, myalgia, arthralgia, irritability, and headaches. Fatigue is perhaps the most frequent and disabling extrahepatic symptom of HCV, reported in almost one-half of all infected individuals.  Although vastly variable in intensity and expression, its presence often compromises the patient's quality of life. In addition to fatigue, many other factors are associated with a poor quality of life in patients with HCV, including a number of physical and psychological factors. The objective of this article is to review the association between HCV and impaired quality of life due to fatigue and psychological disturbances.
HCV and Poor Quality of Life
The effect of HCV on the quality of life in chronically infected patients has been the subject of many studies, some of which were summarized recently in a review.  Chronic HCV appears to directly compromise HRQOL. One of the largest studies conducted to date reported the results of interferon-based antiviral therapy in 642 HCV-infected patients, before and after treatment.  At presentation, there was a significant reduction in HRQOL in patients with HCV as compared to well-norms in the presence or absence of cirrhosis. In another study by the International Hepatitis Interventional therapy group, Ware et al . reported that five out of eight short-form 36 questionnaire (SF-36) (a special questionnaire designed to evaluate HRQOL) concepts: physical functioning, role-physical, general health, vitality, and social functioning, were significantly reduced in patients with HCV compared with matched population norms. 
In another study from Britain, 72 unselected, sequential patients with chronic HCV were compared with 30 sequential patients with chronic hepatitis B (HBV) infection and HBsAg positivity.  Patients with evidence of cirrhosis were excluded. All of the SF-36 scores were markedly reduced in patients with chronic HCV infection, indicating that these patients perceived themselves to be unwell and reported significant reduction in their quality of life. In contrast, chronic HBV patients exhibited no significant reductions in their SF-36 scores, except in the variables of "mental health" and "general health perception," and only minimal effects on the SF-36 scores that assess an individual's capacity for physical activities. When the two groups (HCV and HBV) were compared directly, HCV patients showed greater impairment in social functioning, physical limitations, energy, and fatigue parameters compared to HBV patients.
On the other hand, other studies in different populations of patients showed different results. A Japanese group applied the Todai Health Index (a checklist for a self-administered scoring system covering a variety of physical and psychological symptoms) to examine the potential symptoms in 60 patients with chronic HCV in comparison with normal controls.  They found no characteristic subjective symptoms in patients with HCV compared to healthy controls, except for a lower aggression score. In another Japanese study, Fukuhara et al. used the SF-36 questionnaire to test a group of Japanese patients with HCV. No significant differences between patients and controls were found.  In addition, two studies from North America also showed no difference in HRQOL. The first study by Davis et al. used the sickness impact profile.  This study was criticized because of the low sensitivity of this instrument to detect clinically relevant changes. In the second study, American blood donors who were found by chance to have HCV (who seemed to have a high incidence of fatigue [61%] and headache [54%] in a previous study),  were re-examined in comparison to normal healthy blood donors without HCV. The fatigue rate in the non-HCV group was as high as 70%, suggesting no difference between the two groups.  The importance of this study is paramount in that it studied a random sample from a random population in which symptoms and HCV status were assessed entirely independently, unlike most other studies which involved patients referred to tertiary care centers. 
Hepatitis C and Fatigue
Many uncontrolled studies suggest that a significant proportion of HCV patients suffer from fatigue. For example, Tong et al . found that 67% of patients with posttransfusion HCV reported fatigue  while Kenny-Walsh et al . reported fatigue in at least 81% of Irish women with HCV due to HCV-contaminated anti-D immune globulin.  Similarly, Barkhuizen et al. reported that in hepatology outpatients, fatigue was found in a significant (67%) proportion of HCV-positive patients compared to 44% of HCV-negative patients.  In one of the largest studies of its kind, Poynard et al . reported that among 1614 patients with HCV from France, 53% reported fatigue at their initial visit and the fatigue was severe in 17% of these patients.  This study also found that fatigue was associated independently with the female gender; age > 50 years, cirrhosis, depression, and purpura. Nevertheless, it is essential to note that there are hardly any studies investigating fatigue in HCV patients in comparison to a control group
Hepatitis C and Psychiatric Disorders
Many studies have reported a high incidence of depression in chronic HCV-infected patients. For example, Dwight et al . report that 28% of their HCV patients fulfil the criteria for major depression.  In an effort to determine the incidence of psychiatric co-morbidities among veterans in the US with HCV, Lehman et al . used well-established scoring criteria in various questionnaires to study 120 consecutive patients with chronic HCV.  Almost half of the patients had a history of nonsubstance abuse-related psychiatric disorders and about a third of the patients were receiving psychotropic medications at the time of the evaluation. Depression was found in 44%, anxiety in 38%, post-traumatic stress disorder in 20%, and alcohol-related problems in 26% of patients with HCV. However, this study may have overestimated the true prevalence of psychiatric disorders in the HCV population as it was performed in veterans who typically have a high level of alcohol consumption. Similar results of clinically significant emotional distress in 35% of HCV patients were reported by Fontana et al . in 220 unselected patients with compensated chronic HCV.  It is worth noting that in most of the above studies, there was no control group for comparison. On the other hand, in a large, controlled Italian study, a higher prevalence of lifetime major depression was observed among HCV patients than in HBV patients and controls. 
Is the Virus the Culprit ?
From the above discussion, it seems reasonable to conclude that patients with HCV have a decreased HRQOL that is associated with fatigue and many psychiatric co-morbidities. However, the question that remains unanswered is whether this poor quality of life is directly related to the virus and its interaction with the body or alternatively, related to the patient in terms of co-morbidities, reaction to the illness, reporting of symptoms, and other multiple factors? In the remainder of this review, the most important issues related to the interaction between viral, medical, social, and ethnic factors in relation to HRQOL in HCV-infected patients, will be summarized as follows:
Fatigue is common
Fatigue is a common phenomenon within the general population. For instance, in a study by Shakil et al ., fatigue was found in about 61% of American blood donors who were found to have HCV.  However, when the same investigators studied the healthy blood donors without HCV, they found that the incidence of fatigue was 70% in this group.  In another study dealing with a different infectious disease, Fukuda et al . found that >40% of people who had experienced an acute infection with Q fever fulfilled the criteria for chronic fatigue syndrome.  Of note, as mentioned before, many studies reporting decreased HRQOL in HCV patients did not include a control group. This makes it extremely difficult to isolate the effect of the virus on the development of fatigue in the background of these high rates of fatigue in the general population.
HCV is associated with other psychiatric disorders
As discussed above, HCV has been shown to be associated with many psychiatric disorders that may, by themselves, contribute to the reduced HRQL. These include depression, anxiety, post-traumatic stress disorder, and alcohol-related problems.  These psychiatric symptoms have been shown to be associated with fatigue, functional disability, and somatization in HCV patients.
The effect of knowledge of the diagnosis
The effect of knowledge of the diagnosis
The patient's awareness that he/she has a disease with potentially serious consequences can in itself lead to alterations in the quality of life. It is important to distinguish between psychological reactions to the knowledge that one has been infected with HCV and the direct effects of the virus itself. Previous studies have aimed to define the role that awareness of the diagnosis can play in altering the quality of life. In a study from Australia by Rogers, patients who were previously admitted to hospitals with acute hepatitis between 1971 and 1975 were traced and their stored serum was tested for hepatitis C markers.  Available patients (some aware and some unaware of their diagnosis) were interviewed and given the SF-36 questionnaire. Interestingly, individuals who were aware of their diagnosis ( n = 15) rated significantly worse on seven of the eight standard SF-36 scales compared to the normal Australian population. On the other hand, individuals who were unaware of their serostatus ( n = 19) scored significantly worse on only three scales. There were no other epidemiological, physical, or biochemical differences between the two groups. Similarly, 1286 rural Egyptian patients who were unaware of their hepatitis C status were prospectively interviewed by blinded investigators using the SF-12 QOL questionnaire. It was found that the 146 individuals who turned out to be infected, scored similar results compared to the 1140 individuals who where negative. 
Two interesting studies looked at patients presenting with chronic fatigue syndrome and assessed their HCV status retrospectively to avoid the psychological effects of knowing about the HCV infection. , Neither study reported any association between the quality of life and the HCV status. On the other hand, patients with HCV were found to have a more significant reduction in their quality of life than did patients with chronic hepatitis B in a study by Foster et al. This suggested that prior knowledge of the diagnosis of the viral infection was not important. 
This effect of knowledge of the diagnosis on the HRQOL has been reported with many other chronic diseases. For example, normotensive subjects who had been misdiagnosed with hypertension were substantially more likely (30 vs 8%) to have symptoms of depression compared to matched, unlabeled normotensive controls. 
The relation to the viral load
In the previously mentioned study on Irish women,  although fatigue was significantly increased in patients with HCV compared to controls, there was no difference between those who were HCV RNA-positive and those who were HCV RNA-negative , i.e., whether they were viremic or not. Moreover, in another study in hemophiliac patients, there was again no difference in the mean levels of fatigue in patients who were free of the virus (antibody-positive, but HCV RNA-negative) and those who were HCV RNA-positive.  If there was a true pathophysiological effect of the virus resulting in poor HRQOL, one would assume that this effect would only be present in viremic patients; but the evidence suggests otherwise.
The effect of liver disease
HCV is a major cause of chronic liver disease and most chronic liver diseases have been consistently reported to cause fatigue. In a study by Obhrai et al. , special questionnaires were used to assess fatigue and psychological disturbances in patients with various forms of chronic liver diseases, including HCV.  They found that total fatigue scores were significantly higher in all patient groups than in healthy subjects, although there were no significant differences in the total fatigue scores of patients with different liver diseases (chronic HCV, alcoholic liver disease, and dual HCV infection and alcohol). Interestingly, the impact of fatigue on the individual in the form of interference with physical activity or mental concentration was significantly greater in patients with HCV compared to other groups. This suggests that there was no increase in the actual fatigue scores in patients infected with HCV compared to other diseases, but that there may be a maladaptation with this symptom in HCV patients. In another study in which 239 patients with various causes of liver disease (including HCV) were examined in an outpatient setting, 70% had some form of musculoskeletal pain, and 54% had fatigue.  In this study, there was a significant association between HCV and pain, and between HCV and fatigue, but the overall prevalence of pain and fatigue in the study population was also high.
Effect of intravenous drug use
Intravenous drug use (IVDU) which is common in patients with HCV (especially in the west) is certainly an important factor that can contribute to poor HRQOL. Two studies have suggested that although IVDU is associated with a more marked reduction in the quality of life in HCV-infected patients, even patients without a prior history of IVDU have a reduced quality of life. Johnson et al . reported depression in drug users with or without HCV infection, and found a statistically insignificant trend toward increased depression in the HCV-positive patients.  These results were substantiated by Foster et al .  To investigate the effect of nonviral factors on the reduction in the quality of life, the investigators studied the effect of IVDU. When patients with no past history of IVDU were examined, they were found to have a small improvement in the overall quality-of-life scores compared to those with a prior history of IVDU. However, when compared with normal controls, patients with no history of IVDU had a significant reduction in the quality of life, suggesting that although the history of IVDU is associated with an inferior quality-of-life score, HCV patients without this background still had a compromised quality of life. In this study, there was no correlation between the quality-of-life scores and liver disease severity parameters such as liver enzymes or stage of disease as seen in liver histology.
Finally, if perception of the disease is indeed an important factor in reporting fatigue and other symptoms in patients with HCV, then many known and unknown factors will probably affect the response of the patients and their reporting of these symptoms. Such factors may include ethnic background, income, employment, education, etc. This may explain the differences seen between the rates of compromise in the quality of life seen in studies done in North America (reporting high incidence) and studies done in Japan (where two studies showed no significant reduction in the quality of life). , It may also partially explain the differences in the quality of life noticed between HCV- and HBV-infected patients. Although various factors may be responsible for such a disparity in study outcomes, the impact of ethnicity needs to be studied further before any further conclusions can be reached. 
Effect of Antiviral Treatment on Quality of Life
Many studies have reported a reduction in fatigue after eradication of HCV. ,, In a large study by Cacoub et al. conducted on 431 patients, fatigue decreased in 35% of responders to antiviral therapy vs 22% in patients who had detectable HCV at the end of treatment-a difference that was statistically significant.  In another study, all patients who had fatigue prior to therapy were reported to have complete disappearance of this symptom after eradication of the virus.  On the other hand, other studies showed no improvement in the quality of life after treatment.  Although a positive effect of treatment on fatigue does suggest that the virus itself may have a role in the pathogenesis of fatigue in these patients, this again does not rule out the effect of psychological factors in decreasing the fatigue. It is noteworthy that in only one study  were the patients blinded to the results of the HCV RNA status, a fact that can clearly introduce bias in the interpretation of such studies.
It is evident that patients with chronic HCV have a compromised quality of life, a higher prevalence of fatigue, and psychiatric disorders. These effects do not seem to be related to the severity of liver inflammation of fibrosis. What remains unclear is the exact role of the HCV virus in impairing the quality of life. It is likely that other related and seemingly unrelated factors such as psychological status and ethnic background, may also play a role in the subjective reporting of quality-of-life parameters.
In a paper written in 2006 by Calgary hepatologist Dr. Mark Swain which focus on fatigue in liver disease gives us some idea of why individuals infected with HCV suffer with this number one symptom.
Dr. Swain has classified fatigue as ; peripheral fatigue or central fatigue.
From HCV Advocate;
Peripheral fatigue is characterized as neuromuscular dysfunction.
This type of fatigue is related to muscle overuse, underuse and weakness. The author points out that this type of fatigue is generally not the type of fatigue that is associated with liver disease except for people with severe liver disease progression such as the type that people experience from decompensated cirrhosis.
Central fatigue is the result of altered neurotransmission within the brain and is the type of fatigue most commonly associated with a liver disease.
It was also noted that the degree of fatigue does not necessarily correlate with the degree or severity of liver disease, making the measurement of liver-related fatigue more difficult. The difficulty of zeroing in on the cause of the liver-related fatigue of liver disease is compounded by other factors, such as depression and anxiety over having a chronic illness, stigma associated with a disease, side effects of prescribed and over-the-counter medications, sleep problems, lack of exercise and many other factors.
As mentioned above, the exact cause of liver-related fatigue is unknown. It is theorized that the liver-related fatigue is caused by malfunction of the neurotransmitter systems of the central nervous system, which includes the brain. The chemicals that are believed to cause liver-related fatigue include corticotrophin-releasing hormone (CRH), serotonin, noradrenaline and other neurotransmitter chemicals.
• CRH’s have been identified as being widely distributed throughout the central nervous system and are involved in arousal (alertness or the state of being prepared to act) and behavioral activation (the way that someone behaves or reacts). It is theorized that defective CRH release may be a cause of liver-related fatigue.
Corticotropin-releasing hormone (CRH) acts in its traditional role to stimulate adrenocorticotropic hormone (ACTH) release from the anterior pituitary gland. However, CRH release from nerve fibres projecting to areas within the brain stimulates behavioural activation and arousal
• Abnormal levels of a brain chemical called serotonin are known to cause depression, anxiety and general fatigue. Selective serotonin reuptake inhibitors (SSRI) have been used to treat depression as well as chronic fatigue syndrome; however, the use of SSRI’s is not always successful in treating fatigue.
• Norepinephrine or noradrenaline is a stress hormone and neurotransmitter released by the brain and is most commonly associated with the ‘fight-or-flight response.’ Low functioning of norepinephrine has been associated with fatigue and depression although the role of norepinephrine on fatigue has not been well studied. Norepinephrine reuptake inhibitors (NRIs) are used to treat depression, smoking cessation (buproprion) and fatigue (off-label).
• Other neurotransmitters include the chemicals dopaminergic and cannabinoid in the brain, but no research has been conducted on the role of these neurotransmitters in relation to liver-related fatigue.
• Communication between the liver and the brain has also been theorized as the cause of liver-related fatigue due to cytokines (chemical messengers released by the immune system to fight disease) that find their way into the brain. Up until recently it was believed that cytokine molecules were too large to enter the brain, but it has been found that there are certain pathways or access points for larger molecules to enter the brain. This theory has been tested in rats and the results suggest that cytokines can enter and/or are synthesized within the brain and “in the setting of liver disease can induce fatigue when present at levels that are without effect in healthy patients.”
2006 Paper; Full Text