In a typical visit to the hepatologist or the liver transplant surgeon by a cirrhotic patient, our attention is mostly focused on what we have been well trained to do in medical schools and residency programs: reach the right diagnosis, estimate the prognosis, recommend the appropriate management, and explain these points to the patient and family.

But are these the same worries and concerns of the patient in front of us? Certainly, the patient is interested to learn about his or her diagnosis, wants to know what to expect from the disease and its associated prognosis, wishes to start treatment right away, and definitely wants to have a reasonable explanation from the doctor. However, the patient often has symptoms and complaints that are not always attended to by the doctor because they are either considered trivial or “have nothing to do with your liver disease.”

Although the majority of liver diseases seen in early stages are totally asymptomatic, like inactive hepatitis B virus (HBV) infection and nonalcoholic fatty liver disease (NAFLD), it is increasingly recognized that many patients have a significant impairment in their quality of life (QoL). This reduction in their QoL, which is more pronounced in those with advanced liver disease, often becomes the first and foremost concern when they meet their doctor. Conversely, and not infrequently, the patient may actually be unaware that these systemic symptoms are either directly or indirectly related to the liver disease.

In order to address this common problem effectively, physicians need to be mindful of the systemic symptoms that are commonly faced by their patients, especially in those with end-stage liver disease (ESLD), which significantly impact their QoL. Ignoring these symptoms or simply convincing oneself that they are unrelated to the overt liver disease, or focusing on treating the liver disease and hoping that these symptoms will abate or disappear is never a successful strategy.

The ever-improving medical management of liver disease portends that the majority of patients with chronic liver disease will live with the disease rather than dying from it. The commonplace notion that chronic liver disease connotes entirely to the consequences of ESLD is fundamentally flawed. Nonetheless, there is a growing awareness that a number of systemic symptoms may occur at any point in the natural history of chronic liver disease, causing functional impairment and reduced QoL.

Health-related QoL is a concept that reflects the physical, social, and emotional attitudes and behaviors of an individual as they relate to their prior and current health state [1]. The recognition that there is an additional disease burden in patients, linked with considerable functional deprivation, the management of which is vastly unrelated to that of the specific fallout of having ESLD, represents a paradigm shift in the approach to the disease.

In this chapter, we provide a general approach to this important problem and offer a structured framework for its management. Importantly, we focus on systemic symptoms that compromise the patients’ QoL rather than address specific clinical symptoms that are related to well-known sequelae of cirrhosis, like ascites and hepatic encephalopathy, because these are covered in other chapters.

As QoL is a term that is very difficult to define and measure, factors affecting it are also hard to capture. In general, there are many factors that affect QoL in patients with liver disease, primarily the physical effects stemming from the biology of the disease. This is clearly seen in patients with advanced liver disease. Symptoms like ascites, hepatic encephalopathy, and muscle wasting would significantly impair the patients’ functional ability. Fortunately, this part of the story is relatively easy to recognize and manage. In addition to the effects of symptoms and physical impairment, medical treatment also adds to the physical burden of disease: frequent physician visits, frequent testing and imaging, multiple admissions, medication side effects, and a plethora of other management-related issues, physical stress, and risk.

Second, there is the psychological component of the disease which is clearly seen across all aspects of liver disease and across all disease severity scales. These symptoms are much more difficult to recognize and manage. They include depression, anxiety, and personality disorders, among many others. In addition, the stress of obtaining, appreciating, and reacting to information related to the diagnosis and prognosis is paramount. The anxiety over the possibility of liver transplantation and the waiting list associated with it or having to identify a living related donor is also a major factor that has tremendous implications towards QoL.

Finally, there are other associated symptoms and systemic features that may be related to the biologic pathophysiology of liver disease or to its physiological consequences: fatigue, depression, sleep disturbances, cognitive impairment, and cardiac dysfunction [13]. These symptoms and systemic problems may interact with each another.

Assessing functional ability in an accurate and meaningful way is laden with difficulties in research settings, let alone the hectic schedule of an outpatient clinic. Crude measures of functional ability such as the ability to engage in hobbies or wash oneself, or employment status are indicators of function that are significantly impaired in chronic liver disease [14]. Complex processes such as being able to dress or wash oneself, let alone engage in complex social interactions are functions of daily living that are frequently taken for granted. Objective studies have confirmed that patients with chronic liver disease of many etiologies have reduced physical activity levels measured using continuous physical activity monitoring [1,15], although this approach may still underestimate the impact of disease on the complex functions required for effective daily living.

QoL and functional ability have been clearly shown to be compromised in many types of liver disease patients. In terms of functional ability, with the use of tools like PROMs, it has been established that patients with liver disease of various etiologies and at different stages of their disease have significant functional impairment [13] regardless of the etiology. For example, in a study by Elliott et al. [16], functional ability and symptom severity were compared in 103 consecutive liver transplant recipients and matched controls using the patient-reported functional outcome measure: Patient-Reported Outcomes Measurement Information System, Health Assessment Questionnaire (PROMIS HAQ). Symptoms frequently seen in chronic liver disease were quantified by: (i) Fatigue Impact Scale (FIS), (ii) Orthostatic Grading Scale (OGS: autonomic dysfunction), (iii) Cognitive Failures Questionnaire (CFQ), and (iv) Epworth Sleepiness Scale (ESS: Daytime Somnolence). There was a significant functional impairment in patients with cirrhosis which was present across all domains of functional ability and seen across different etiologies including alcoholic liver disease, NAFLD, primary biliary cirrhosis (PBC), and primary sclerosing cholangitis when compared with control subjects. This did not improve significantly after liver transplantation and liver transplant recipients exhibited a significant reduction in function across all domains of the PROMIS HAQ, suggesting that functional impairment is broad-based. Seventy-seven percent of all patients after liver transplant identified some difficulty with activities of daily living. Elevation in PROMIS HAQ score (and therefore functional impairment) was strongly associated with symptoms, particularly of fatigue, cognitive impairment, and daytime somnolence, and fatigue severity was independently associated with functional impairment.

Of all causes of liver disease, impairment in QoL has been best studied and documented in patients infected with the hepatitis C virus (HCV) [17]. Chronic HCV seems to directly alter health-related QoL. One of the largest studies, which included 642 HCV-infected patients, evaluated the impact of the virus on QoL before and after treatment with interferon-based antiviral therapy [18]. The authors clearly showed that the health-related QoL in patients with HCV was significantly reduced compared to a healthy control group, regardless of histologic severity. Ware et al. [19], as part of a study by the International Hepatitis Interventional Therapy Group, reported a significant reduction in five out of eight SF-36 concepts in patients with HCV compared with matched population norms. The reductions were seen in the physical functioning, role-physical, general health, vitality, and social functioning domains. In a British study, 72 unselected, sequential patients with chronic HCV and 30 sequential patients with chronic HBV infection were compared [20]. Patients who had any signs of cirrhosis were excluded. The SF-36 scores in all domains were greatly reduced in chronic HCV patients, implying that these patients felt that they were unwell and perceived themselves as having significantly reduced QoL. On the other hand, patients with chronic HBV infection did not report any significant reductions in their SF-36 scores except in the “mental health” and “general health perception” variables. Their SF-36 scores that assess a person’s ability to conduct physical activities were only marginally affected. When the HCV and HBV patients were compared, patients with HCV infection had poorer scores in the social functioning, physical limitations, and energy and fatigue domains compared with HBV-infected patients.

However, these results were not reproduced in other populations. Sixty Japanese patients with chronic HCV were subjected to the Todai Health Index (a checklist for a self-administered scoring system of a variety of physical and psychological symptoms) and showed no characteristic subjective symptoms when compared with a healthy control group apart from a lower aggression score [21]. Another Japanese study by Fukuhara et al. [22] utilized the SF-36 questionnaire to examine a group of HCV-infected patients and found no difference between patients and control subjects. Similar results were also obtained from two studies in North America. In the first study, Davis et al. [23] used the SIP to study health-related QoL, although this instrument is insensitive in identifying changes that are clinically relevant. The second study investigated a group of American blood donors who were incidentally found to have HCV. These donors, who had a high incidence of fatigue (61%) and headache (54%) in an earlier study [24], were compared with normal healthy blood donors without HCV infection. The non-HCV group reported a fatigue rate of up to 70%, indicating no difference between the two groups. The key item of interest of this study was that it evaluated a random sample from a random population wherein HCV symptoms and status were examined in a totally independent manner, distinctly different from the majority of studies which include patients from tertiary care centers [25].

Based on the above review, it is clear that patients with HCV infection do experience multiple symptoms and disease entities that adversely affect QoL. However, it is unclear how much of the effect is really due to the infection itself and its consequent liver disease or all the other associated features and factors that are directly or indirectly related such as ethnicity, route of infection, intravenous drug use status, and social and psychologic factors. Therefore, the question remains – is it the virus or the patient [26]?