Management of Fatigue in Primary Biliary Cholangitis

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease with a significant autoimmune component. It is characterised by progressive immune-mediated small and intermediate intrahepatic duct damage leading eventually to cirrhosis and associated complications. PBC has a female preponderance with a female/male ratio of 9:1. Diagnostic criterions set out in the EASL 2017 guidelines suggest that, in adult patients with cholestasis and no likelihood of systemic disease, a diagnosis of PBC can be made based on elevated ALP and the presence of anti-mitochondrial antibody (AMA) at a titre ≥ 1:40 [1].

Clinical presentation of PBC ranges from asymptomatic patients who have been found incidentally to have abnormal liver chemistry to patients presenting with complications of cirrhosis [2, 3]. It is now increasingly recognised that there is an additional clinical problem related to systemic symptoms of PBC, namely fatigue, pruritus, cognitive symptoms leading to social isolation and emotional dysfunction [4]. A patient-derived and fully validated assessment tool, the PBC-40, with domains covering localised symptoms, itch, fatigue, social, cognition and emotional dysfunction, is widely used in clinical practise and clinical trials as a patient-derived measure of quality of life [5]. Importantly, currently available first-line therapy Ursodeoxycholic acid (UDCA) and second-line therapies Obeticholic acid (OCA) are both ineffective in improving PBC-related symptoms [6, 7]. In this article, we focus on understanding the pathophysiology, impact on quality of life and available evidence on management of fatigue in PBC.

Fatigue is the most commonly reported symptom in PBC patients with 40–80% of patients encountering the symptom during the course of their illness. In addition to having debilitating physical effect on patients’ ability to perform usual day-to-day activities, fatigue also significantly impacts on mental health, social life, family life, sexual life and job performance [4, 8, 9]. This is exemplified by an early Canadian study by Cauch-Dudek and colleagues which reported fatigue in 81% of PBC patients, with 7% reporting fatigue interfering with their physical activity, 57% family life and 30% job performance [10]. Poor sleep quality and depression were frequently reported to be related to fatigue. Verbally reported fatigue of longer than 6-month duration was reported in 68% patients with equal rates in UDCA-treated and -untreated patients. Furthermore, no correlation was seen with patient age, duration of disease, level of daily physical activity, bilirubin levels or Mayo Risk Score. Fatigued patients had more difficulty with global sleep quality as measured by Pittsburgh Sleep Quality Index, reporting greater impairment in subjective sleep quality, habitual sleep efficiency, sleep disturbances and daytime dysfunction. Fatigued patients reported higher rates of depression symptoms (71%) compared to 18% in non-fatigued patients [10]. Similar findings have been reported in other studies [11, 12] including the nationwide UK-PBC study, which added the observation that the impact of fatigue on quality of life is greatest in younger patients [13•].

The pathophysiology of fatigue is poorly understood [14••]. PBC patients exhibit both peripheral and central components to their fatigue (Table 1); the latter is characterised by neurophysiological abnormalities and is shown to be related to cognitive symptoms, sleep disturbance and depression [10]. A complex interaction exists between depression, sleep disturbance and fatigue in these patients and correlates with the fatigue severity. In the UK-PBC studies of 2353 patients, the investigators used the PBC-40 measure, the Epworth Sleepiness Scale [ESS; a measure of daytime somnolence (score range of 0–24) and an ESS of 10 or more indicates clinically significant daytime somnolence], the Orthostatic Grading Scale [OGS; a measure of vasomotor autonomic dysfunction (score range 0–20 and a score of ≥ 4 indicates significant vasomotor autonomic dysfunction)] and the Hospital Anxiety & Depression Scale (HADS; a measure of depression and anxiety) [15, 16]. Significant numbers of PBC patients reported increased daytime somnolence contributing, in part, to their fatigue. A significant correlation was seen between fatigue severity and HADS-D score (p < 0.0001). In addition, autonomic dysfunction showed significant correlation with fatigue, cognitive impairment and sleep disturbance.

The role of autonomic dysfunction in fatigue development has been explored in detail. In one study, autonomic dysfunction was assessed using the Composite Autonomic Symptom Scale (COMPASS) and fatigue was assessed using the Fatigue Impact Scale (FIS) in two groups. Phase 1 (derivation phase), 40 chronic fatigue syndrome (CFS) patients and 40 age- and sex-matched controls; phase 2 (validation phase), 30 CFS patients, 37 normal controls and 60 patients with primary biliary cirrhosis. Symptoms of autonomic dysfunction were strongly and reproducibly associated with the presence of fatigue and correlated with severity of fatigue. Total COMPASS score > 32.5 was identified to have a positive predictive value of 0.96 (95%CI 0.86–0.99) and a negative predictive value of 0.84 (0.70–0.93) for the diagnosis of CFS and PBC patients and can be used to identify patients for targeted intervention studies [29]. The combination of depression with sleep disturbance and autonomic symptoms was seen more in patients with severe fatigue. In a related study, around 35% patient reported impaired perceived quality of life (QoL) (compared from 6% in healthy controls, p < 0.0001) [30].

There are also emerging data suggesting the presence of organic changes in the brains of PBC patients which may be associated with fatigue and linked cognitive symptoms [31, 32]. These fall into two groups, those demonstrating imaging changes typically with advanced MR methodologies and those demonstrating neurophysiological and function abnormality [33, 34, 35•]. These changes suggest a fluid organic process which may be amenable to therapeutic intervention. Importantly, however, imaging change can be seen in the first few months following disease presentation suggesting that injury may start early in the disease process [36•]. It may be that effective treatment of the processes linked to fatigue requires early intervention.

The peripheral component of fatigue is described by PBC patients as the inability to sustain physical activity, loss of energy or feeling of “batteries being run down”. Using a hand grip strength assessment protocol, it has been demonstrated that fatigued PBC patients show significantly accelerated decline in muscle function on repeated activity, with the rate of decline in grip strength being strongly correlated to severity of fatigue reported [37]. Intramuscular acidosis is a factor leading to muscle fatigue during prolonged and intense muscle activity; leading to reduction in contractile force and shortening velocity; and a prolongation of recovery time [38, 39].

Using cardio pulmonary exercise testing (CPET) in PBC patients undergoing transplant assessment, a baseline lowering in anaerobic threshold has been demonstrated compared with controls [40]. Over 95% of the PBC patients exhibit high titres of anti-PDH (pyruvate dehydrogenase) antibodies, directed against E2 and E3BP components of PDH, a key enzyme-regulating anaerobic metabolism. The level of bioenergetic mitochondrial abnormalities is directly related to anti-PDH levels [41, 42]. These findings suggest a possible excessive deviation from aerobic to anaerobic metabolism in fatigued PBC patients leading to excessive lactic acid accumulation.

Abnormal serum amino acid levels have also been implicated in the development of fatigue in PBC as observed in other chronic liver diseases. A study by Brog et al. demonstrated that PBC patients had significantly decreased levels of valine, isoleucine, and leucine. Tyrosine and phenylalanine were increased (p < 0.0002) and tryptophan decreased (p < 0.0001) in PBC. Furthermore, in fatigued PBC patients a significant inverse relation between tyrosine concentrations and fatigue and quality of life was found. Patients without fatigue and with good quality of life had increased tyrosine concentrations compared to fatigued patients [43].

In addition to directly disease mechanism-associated processes, it should be borne in mind that PBC is associated with other autoimmune conditions which are themselves associated with treatable fatigue [44]. There is high prevalence (up to 22%) of autoimmune hypothyroidism in PBC patients with a 20% prevalence of anti-thyroglobulin antibodies. Fatigue, lethargy and anorexia are among the array of symptoms that are common to hypothyroidism and PBC. Hence, in PBC patients who have concurrent hypothyroidism, the latter contributes at least partially to fatigue and is a very much treatable cause. It has been demonstrated that these symptoms improve with thyroxine supplementation [45].

Currently, there is no recommended, licenced therapy available to treat fatigue in PBC patients, though various agents have been trialled (Table 2). Our approach to management is therefore supportive, aimed at treating reversible contributors to fatigue and co-morbid diseases which may exacerbating it; the “so called treatable causes contributing to the fatigue”. These include, for example, hypothyroidism, itch (causing sleep disturbance and resultant day time fatigue and somnolence) and depression (Table 3). In addition, various non-pharmacological measures can help provide patients with coping and supportive strategies (Table 4). These include energy pacing and daytime planning (fatigue is typically worse later in the day meaning that it is helpful for patients to plan important activities for the morning. This structured approach, although lacking the headline impact of an effective drug can, nonetheless, lead to significant quality of life improvement [14••, 46].

There are currently no licenced drug therapies for the treatment of fatigue in PBC. Furthermore, there is no evidence to suggest that either of the currently licenced treatments (UDCA and OCA) for progression prevention is effective in reducing fatigue. A number of agents have been evaluated in clinical trials for the treatment of fatigue in PBC (Table 2).