Understanding fatigue and pruritus in primary biliary cholangitis

INTRODUCTION AND EPIDEMIOLOGY

Primary biliary cholangitis (PBC) is a chronic progressive autoimmune disease of the hepatobiliary system. It is characterized by a cycle of immune-mediated epithelial injury of the small and intermediate intrahepatic bile ducts, resulting in periportal inflammation, cholestasis, fibrosis, and potentially end-stage biliary cirrhosis.^1,2 Predominantly affecting women, with a female-to-male ratio of 10:1,³ PBC is typically diagnosed in the fifth or sixth decade of life.⁴ Although pediatric onset has been reported, it is not classically encountered.⁵ Liver-associated chemistries demonstrate a cholestatic pattern with elevations in alkaline phosphatase, mild elevations in aminotransferase, and a potential rise in serum bilirubin as a marker of late progression of the disease.⁶

Without noteworthy correlation to the stage of liver disease, PBC is associated with a complex and significant symptom burden that results in a substantial deficit in perceived quality of life, much more so than in age-matched and sex-matched community control groups.^7,8 Major symptoms of PBC, most associated with impaired health status and social dysfunction, include significant fatigue and chronic cholestatic pruritus.^7,9 As the most prevalent symptom, fatigue is reported in up to 80% of patients, with approximately 40% experiencing severe fatigue.^10–12 This severity has the greatest impact on quality of life in patients with PBC and serves as a predictor of liver-related mortality and transplant outcomes.^10–12

Pruritus, the second most common symptom in PBC, is prevalent in 20%–70% of patients and is a major determinant of health-related quality of life. Intense nighttime itch can lead to sleep deprivation, worsening fatigue, depression, and even suicidal ideation.^13,14 An earlier onset is not only associated with a more aggressive disease and/or the ductopenic variant but also with poorer survival outcomes.^3,15

This review aims to provide a summary of the clinical presentation, current understanding of pathophysiology, evaluation, management, and a brief insight into potential future treatment perspectives of these debilitating symptoms.

FATIGUE IN PBC

Pathophysiology of fatigue in PBC

While the pathophysiology of fatigue in PBC remains uncertain, it is thought to be composed of central (lack of intention) and peripheral (lack of ability) components (Figure 1).^11,12 Central fatigue manifests as motivational fatigue and cognitive symptoms, such as concentration and memory deficits, and is strongly associated with sleep disturbance and depression. It is often described as “the failure to initiate and/or sustain attentional tasks and physical activities requiring self-motivation.”¹⁶ Cholestasis in PBC is theorized to lead to the accumulation of toxic bile acids, which, through toll-like receptor-mediated mechanisms, trigger inflammatory cytokines.^12,16 Moreover, chronic hepatic inflammation characteristic of PBC, stemming from its autoimmune nature, may also contribute to the increased cytokine pool.¹⁷ This cascade of events activates cerebral microglia, which subsequently recruit monocytes into the brain, triggering changes in central neural activity and ultimately causing central fatigue.^12,17 Animal models have illustrated such changes in brain function leading to diminished social interest and other behavioral irregularities analogous to the central fatigue observed in PBC.^12,17 These alterations notably had an inflammatory aspect as mice lacking essential inflammatory mediators, such as cytokines, TNF receptor 1, and adhesion molecules crucial for leukocyte recruitment into the brain, did not exhibit central nervous system symptoms in the setting of cholestasis.^12,16,17 Additionally, a study demonstrated an overall disturbance in the resting-state functional connectivity (rsFC) of deep gray matter brain structures in patients without cirrhosis and with PBC compared to matched controls.¹⁸ This altered connectivity was observed in association with both fatigue (exhibited by decreased rsFC of the putamen with the motor cortex)^18,19 and impaired cognitive performance, including deficits in concentration and verbal working memory (demonstrated by decreased rsFC of the putamen and amygdala with regions involved in cognitive processing such as the superior and inferior frontal and parietal gyri)^18,20,21 Moreover, patients with PBC showed a contrasting increase in rsFC in other regions, suggesting a potential compensatory homeostatic response to the chronic immune-mediated liver-to-brain signaling.^17,18 White matter brain lesions are also seen in patients with PBC with cognitive deficits and are associated with autonomic dysfunction and impaired cerebral autoregulation.^12,22 Such structural brain lesions have been identified in patients with early-stage PBC and are therefore likelier attributed to cholestasis than advanced liver disease or HE.^12,22 The theory suggesting that cholestasis early in disease progression leads to permanent alterations in the brain (subsequently resulting in central fatigue) is supported by an absence of fatigue improvement after liver transplantation.^12,23 This is further reinforced by neurophysiological testing in patients with fatigue and PBC, using paired-pulse transcranial magnetic stimulation, which demonstrated impaired central activation and distinct abnormalities correlating with sleep disturbance, that importantly showed no resolution post-transplant.^12,24

FIGURE 1.

Pathophysiology of fatigue in PBC. Abbreviation: PBC, Primary biliary cholangitis.

Altered central neurotransmission, specifically in the serotonergic and noradrenaline pathways, is also hypothesized to contribute to central fatigue in PBC.^11,25 However, treatments like ondansetron (serotonin receptor agonist) and selective serotonin reuptake inhibitors (SSRI), like fluoxetine, have not shown conclusive efficacy.^6,11

Peripheral fatigue includes neuromuscular dysfunction, such as reduced activity levels and an inability to sustain repetitive exercise.^12,26 It is often described by patients as “energy depletion” and “batteries running down.”¹² In patients with PBC, postexercise 31P magnetic resonance spectroscopy demonstrated increased muscle acidosis and a prolonged recovery time correlating with fatigue severity.²⁷ This muscle bioenergetic abnormality suggests an autonomic (where the autonomic nervous system plays a dual role in regulating proton transport and controlling vascular runoff from the muscle) and mitochondrial dysfunction. This leads to an excessive deviation from aerobic to anerobic metabolism, delayed recovery, and an ultimate decline in muscle function.¹¹ High titers of the characteristic antimitochondrial antibodies of PBC, targeting the pyruvate dehydrogenase complex, are linked to impaired mitochondrial function and are also suggested to be involved in the pathogenesis of peripheral fatigue.¹²

Contributing and exacerbating factors of fatigue in PBC

Many comorbid conditions and therapeutic agents may individually or collectively contribute to an increased fatigue burden in patients with PBC. These concurrent processes make it challenging to address fatigue adequately. Some of these conditions include cholestatic nocturnal pruritus, autoimmune conditions associated with PBC such as hypothyroidism, celiac disease, and anemia, certain age-related comorbidities like type II diabetes, renal failure, and heart failure, and medications including antibiotics and anti-hypertensives.^11,12

Anxiety and depressive symptoms are also more prevalent in patients with fatigue and PBC than in their nonfatigued counterparts and community controls.^12,28 It remains unclear whether depression precedes fatigue or emerges as a result of living with a chronic debilitating disease.^12,28 Where structured psychiatric evaluation, assessing depressive ideation, has been conducted in patients scoring highly on depression screening tools (such as the Beck Depression Inventory), only a low level of formal depressive disorders is seen.²⁸ Depressive symptoms are therefore likelier to be reactive consequences of the impact of fatigue. Sleep disorders are also often comorbid with fatigue in PBC. Patients with fatigue and PBC report various sleep-related issues, including poor sleep quality, delayed sleep timing, heightened sleep-wake disturbances, and notably, excessive daytime somnolence.^11,12 Like depressive symptoms, the causal connection between sleep disruption and fatigue is ambiguous, given that each can exacerbate the other.²⁹ Additionally, autonomic dysfunction, most typically in the form of vasomotor abnormalities such as low heart rate variability, paradoxical tachycardia with flushing, and postural hypotension (resulting in dizziness and a greater fall frequency), is strongly associated with fatigue in PBC.¹²

Although somnolence (attributed to HE) and autonomic abnormalities are common in late-stage cirrhosis, the fatigue associations of PBC can be distinguished, as they may manifest at all stages of liver disease.¹²

Evaluation of fatigue in PBC

Fatigue is widely considered a subjective patient-reported outcome. Thus, having reliable and valid tools to measure this health outcome from the patient’s perspective is essential for accurately evaluating the effects of interventions. Multiple scales may be used as assessment tools to clinically monitor fatigue in PBC.³⁰ One such standardized measure of fatigue is the National Institute of Health’s (NIH) Patient-Reported Outcomes Measurements Information System (PROMIS)–Fatigue Short Form.³¹ The PROMIS Fatigue Short Form comprises 7 items designed to assess both the experience of fatigue and its interference with daily activities over the past week.³² Responses to items such as “How often did you feel tired,” “How often were you too tired to take a bath/shower,” and “How often did you have enough energy to exercise strenuously” are measured on a 5-point Likert scale and a summative score is obtained, indicating fatigue severity.^12,32 Although it has not yet been validated in PBC, the PROMIS Fatigue Short Form is an efficient and precise unidimensional scale and can be useful as a screening tool or for assessing fatigue severity.¹¹ Conversely, multidimensional scales like the PBC-validated Fatigue Impact Scale provide more comprehensive information by assessing the impact of fatigue on psycho-social, cognitive, and physical activities.¹¹ However, the PBC-40 is an health-related quality of life measure specific to PBC. The 40-question survey encompasses 6 domains: fatigue, pruritus, emotional, social, cognitive function, and general symptoms.³³ With a validated fatigue domain, it is therefore ideal for quantifying PBC-related fatigue. Moreover, cognitive dysfunction may also be assessed using the PBC-40 cognitive symptom domain.^22,33 In addition to patient-reported outcomes, fatigue can also be evaluated through objective measures such as brain imaging, serological tests, and physical performance assessments.¹¹

Fatigue in PBC may also be difficult to address because of comorbid disease processes that may be contributing to and/or exacerbating fatigue symptoms. Hence, it’s crucial to conduct a complete assessment to screen for such conditions. A comprehensive approach involving detailed history-taking, thorough physical examination, biochemical and serological testing, and diagnostic imaging, if necessary, may be required to rule out or diagnose PBC-associated autoimmune disease and age-related conditions. Depressive symptoms may be screened and assessed using various tools, depending on clinician preference, such as the Beck Depression Inventory, the Patient Health Questionnaire-2 and Patient Health Questionnaire-9, and the Hamilton Depression Rating Scale, and may require appropriate specialist referrals.²⁸ Sleep disturbance may be assessed using the Epworth Sleepiness Scale or the PROMIS Sleep Disturbance and Impairment Short-Forms.^22,29,34 A formal assessment of autonomic dysfunction may include initial autonomic testing using deep breathing and Valsalva maneuver testing, 24-hour blood pressure monitoring, and heart rate variability monitoring using electrocardiograph measurements.^1,35 Tilt table testing may be considered if the initial evaluation does not yield a definitive or highly probable diagnosis despite the presence of signs and symptoms of autonomic instability, such as postural hypotension.^1,36

Management of fatigue in PBC

Currently, there is no recommended approved therapy for treating fatigue in PBC.⁶ While a first-line agent for treating PBC, ursodeoxycholic acid has not been proven to improve fatigue.¹¹ Fatigue is also unresponsive to obeticholic acid therapy and may be worsened by obeticholic acid’s dose-dependent increase in nocturnal pruritus.³⁷ Among the disease-modifying agents, off-label fibrates have reported a subjective improvement in fatigue in the BEZURSO trial; however, further studies are required to confirm these findings.³⁸ Liver transplantation is also not recommended for patients with severe fatigue due to post-transplant persistence.⁶

An effective structured management approach to fatigue in PBC involves evaluating and quantifying fatigue and its impacts (as discussed above), addressing contributing and exacerbating factors, and providing support to help patients cope with its impact (Figure 2).^1,11,12 Disease processes directly or indirectly contributing to fatigue, including other autoimmune conditions such as autoimmune anemias or hypothyroidism and demographic-associated conditions such as type II diabetes, can be effectively managed through therapeutic interventions and therefore must be adequately treated to improve the overall fatigue burden.

FIGURE 2.

A structured approach to managing fatigue in PBC. Abbreviations: AIH, autoimmune hepatitis; BP, blood pressure; PBC, primary biliary cholangitis; PPAR, peroxisome proliferator-activated receptor.

Once these contributing factors and comorbidities have been addressed, other fatigue-exacerbating processes—depression, sleep disturbance, and autonomic dysfunction must be formally addressed.¹ With the help of specialists, the right antidepressant regimen can improve overall function. Modafinil, while approved for the treatment of daytime somnolence, has not shown any significant improvements in PBC and must therefore be used with caution.³⁹ However, morning bright light therapy has shown some promise in improving sleep quality in patients with PBC and should be investigated further.⁴⁰ The underdiagnosed restless leg syndrome also represents a potential therapeutic option for patients with PBC with sleep disturbance and fatigue.⁴¹ Volume repletion and 24-hour blood pressure monitoring can help mitigate the effects of autonomic dysfunction.¹ Additionally, contrary to avoiding activity to conserve energy, patients may experience improvement in peripheral muscle function through structured exercise.^1,42

Finally, empathy, education, and counseling are of utmost importance in empowering patients to take ownership of disease and implement lifestyle adjustments for better fatigue management in PBC.⁶ Patients must be supported to develop coping mechanisms, such as timing (arranging key tasks earlier in the day as fatigue is typically worse later in the day) and pacing strategies (using available energy to its best advantage).¹ Psychological approaches such as cognitive behavioral therapy have also been found to be effective in supporting patients.⁵

Regarding future treatment options, seledelpar, a selective peroxisome proliferator-activated receptor delta agonist, and S-adenosyl-L-methionine, when combined with ursodeoxycholic acid, have demonstrated improved sleep quality and reduced fatigue in open-label trials among patients with PBC. Nevertheless, additional research is required to validate these findings.^43,44 Furthermore, in small-scale studies, plasmapheresis has intriguingly demonstrated a statistically significant reduction in the PBC-40 fatigue domain score, possibly by decreasing circulating anti-pyruvate dehydrogenase complex antibodies.⁴⁵ Conversely, rituximab has been proven to be less effective in this regard.⁴⁶

CHOLESTATIC PRURITUS IN PBC

Clinical presentation of pruritus in PBC

Pruritus in PBC is independent of cholestatic severity (assessed biochemically or histologically) and may present at any stage of the disease.¹⁴ It may arise as the first symptom of PBC or after an initial asymptomatic period and has even been reported to precede diagnosis for months to years.^47,48 The clinical course often fluctuates between periods of exacerbations and relative improvement, with itching sensations reportedly waning in advanced liver disease.⁶ A lack of primary pruritic skin lesions differentiates the cholestatic itch from other dermatological diagnoses. However, intense scratching may result in secondary lesions such as excoriations, lichenification, and prurigo nodularis.

Characteristically described as a relentless itch deep under the skin, pruritus in PBC is not completely alleviated by scratching and is often accompanied by a burning or stinging sensation.⁴⁹ Itch intensity demonstrates seasonal (exacerbated in heat) and diurnal variations with peaks in the late evening and at night, as evidenced by piezoelectric analyses in patients with PBC.⁵⁰ Typically localized at the extremities, more specifically the palmoplantar surfaces, generalized itching is also often reported. Itching is often exacerbated by stress, contact with fabrics such as wool, and during times of hormonal changes in women, such as menstruation, pregnancy, and hormone replacement.⁶

Pathophysiology of pruritus in PBC

The pathogenesis of pruritus in PBC is only partially understood. It is hypothesized that in cholestasis, pruritogenic compounds, which normally undergo hepatobiliary excretion, escape into the systemic circulation and diffuse from the plasma to the skin. They then stimulate primary sensorineural fibers that transmit the itch signal to the spinal cord and the thalamus, thereby eliciting a motor response of scratching.⁴⁹

Animal models, clinical observations, and positive responses to therapeutic interventions have identified several potential pruritogens, including bile acids, lysophosphatidic acid (LPA), and endogenous opioids (Figure 3).^6,13,49,50

1. Bile acids: Several bile components have long been suspected to contribute to pruritis. Elevated levels of bilirubin and bile acid subspecies are found in cholestasis.⁴⁹ Recently, itch-associated plasma membrane G-protein–coupled receptors TGR5 and mas-related Gq protein-coupled receptor X4, expressed in primary sensory neurons, have emerged as potential mediators of cholestatic itch.^49,51,52 These receptors are notably activated by bile salt subspecies and potentially bilirubin.^51,52 Significantly, the removal of biliary contents—either pharmacologically via anion-exchange resins and inhibitors of the ileal bile acid transporter or mechanically through interventions such as therapeutic drainage or extracorporeal albumin dialysis- results in a noteworthy reduction in pruritus.¹³

2. LPA: Increased concentrations of serum LPA, a lipid-signaling molecule and a potent itch neuron activator, have been reported in patients with PBC with pruritus compared to matched controls.^14,53,54 Patients with pruritic PBC also demonstrate increased activity of autotaxin (ATX), the enzyme responsible for hydrolyzing LPA.^6,55 Systemic ATX activity correlates with the intensity of itch perception and responds to therapeutic interventions.^6,55 Rifampicin, a potent pregnane X receptor agonist, causes a pregnane X receptor–dependent transcriptional inhibition of ATX expression.⁵⁵ Additionally, treatment of severe, refractory pruritus with molecular adsorbents recirculation system or therapeutic drainage also correlates with a reduction in ATX levels and results in a dramatic improvement in itch intensity.^13,55

3. Endogenous opioids: Systemically elevated opioid levels and upregulation of opioid markers in liver tissue have been observed in both rodent models and patients with cholestatic PBC.^13,56 While opioids such as morphine commonly induce pruritis as a side effect, opiate antagonists (eg, naltrexone) exhibit an antipruritic effect in patients with cholestasis.^6,14,50 Additionally, endogenous serotoninergic systems have also been identified as potential mediators of hepatic itch.¹⁴ SSRIs like sertraline have been shown to improve the intensity of itch perception.¹⁴

FIGURE 3.

Pathophysiology of cholestatic pruritus in PBC. Abbreviations: ATX, autotaxin; IBAT, ileal bile acid transporter; KOR, k-opioid receptor; LPAR, lysophosphatidic acid receptor; LPA, lysophosphatidic acid; MOR, m-opioid receptor; MRGPRX4, mas-related G protein-coupled receptor X4; NBD, nasobiliary drainage; OCA, obeticholic acid; TGR5, takeda G protein-coupled receptor 5.

EVALUATION OF PRURITUS IN PBC

The initial assessment of pruritus in PBC must include a systemic evaluation and exclusion or management of other cutaneous (eg, dermatitis, psoriasis), hematologic (eg, hemochromatosis, anemia), and systemic causes (eg, renal failure-related uremia, lymphoma, hypothyroidism, and autoimmune disorders). Because of its significant impact on health-related quality of life, pruritus must be explicitly enquired about and assessed at the time of diagnosis and through follow-up visits for adequate antipruritic treatment. Basic history and clinical examination must focus on the properties of pruritis, such as onset, time course, localization, severity, relieving, and exacerbating factors. Subject to considerable intraindividual and interindividual variation, itch sensations may be objectively quantified in clinical practice via evaluation tools, such as the visual analog scale, numeric rating scale, five-dimensional itch scale, and itch domain of the disease-specific PBC-40 questionnaire, for an algorithmic approach to treatment.⁴⁹ Visual analog scales and numeric rating scales, ranging from 0 to 10, are concise, clinically effective tools for tracking pruritus progression between consultations and gauging treatment efficacy.⁵⁷ Conversely, the PBC-40 itch domain and pruritus-specific five-dimensional itch scores offer a more comprehensive assessment of the symptom and its impact on quality of life.⁵⁷

MANAGEMENT OF PRURITUS IN PBC

According to current guidelines by the American Association for the Study of Liver Disease (AASLD) and the European Association for the Study of Liver (EASL) disease, pruritus in PBC is managed stepwise to achieve an adequate therapeutic response for improved health utility (Figure 4).^13,49,14, Lifestyle interventions are often initiated alongside disease-modifying therapy. Patients must be educated to avoid situations that exacerbate skin irritation or dryness, such as heat, stress, contact with irritants (eg, tea-tree oil), tight clothes made of wool, etc. General skin-protecting and antipruritic measures should be encouraged, including emollients, topical anesthetic and cooling agents with menthol, brief showers with tepid water, soft cotton-based fabrics, short fingernails, etc.¹³ Psychological interventions, such as relaxation techniques, may help cope with the itch-scratch-itch cycle.¹⁴

FIGURE 4.

A brief overview of management of cholestatic pruritus. Abbreviations: ATX, autotaxin; DIALIVE, liver dialysis device; IBAT, ileal bile acid transporter; LPA, lysophosphatidic acid; MARS, molecular adsorbents recirculation system; MRGPRX4, mas-related G protein-coupled receptor X4.

Although ursodeoxycholic acid is the first-line anti-cholestatic treatment for PBC, it has not been shown to improve pruritus. Anion-exchange resins and bile acid sequestrants, cholestyramine, colestipol, and colesevalam are first-line medications for pruritus in PBC but are usually not well tolerated because of their disagreeable taste and gastrointestinal side effects (Table 1).^13,49 In addition to bile acids, they also bind various other potential pruritogens in the intestine. To avoid impaired absorption of other medications, particularly the disease-modifying agents, patients should be educated about a 1–4 hour pause between the intake of cholestyramine and other agents.⁶ Insufficient improvement in pruritus after a 2-week trial warrants alternative treatment options.

TABLE 1.

Current guideline approved pharmacological therapy for pruritus in PBC

	First line	Second line	Third line	Fourth line
Medication	Cholestyramine Colesevalam	Rifampicin	Naltrexone	Sertraline
Dosage	4–16 g 3.75 g (2–3 divided doses)	150–600 g	12.5 (or low dose naloxone)- 150 mg	50–100 mg
Possible mechanism of action	Anion-exchange resins. Bind bile acids and other amphiphilic substances (that act as potential pruritogens) in the intestines and promote excretion	Pregnane X receptor (PXR) agonist Inducer of microsomal enzymes leading to increased metabolism and elimination of endogenous pruritogenic compounds PXR-mediated downregulation of ATX transcription Antibiotic effect on intestinal microbiota alters intestinal metabolism of pruritogens	Mu opioid antagonist	Serotonin reuptake inhibitor Unclear antipruritic mechanism
Adverse effects and interactions	Unpleasant taste Bloating, constipation, and diarrhea (less pronounced with colesevalam) Interference with intestinal absorption of other drugs, particularly disease-modifying agents like UDCA	DILIs- sometimes progressing to acute liver failure, hemolysis, renal impairment Orange/red colored body fluids Induction of hepatic enzymes causes altered metabolism of other drugs (eg, oral anticoagulants, oral contraceptives, antiepileptic drugs)	Opioid withdrawal-like reaction (abdominal pain, high blood pressure, tachycardia, goose bumps, nightmares, and depersonalization) Decreased pain threshold Confusion Hepatotoxicity (rare)	Hyponatremia QT prolongation Nausea, vomiting, Sleep disturbance Restlessness Change in appetite
Advice	1–4 hour interval between oral intake of other medications Change to other drugs if no response after a 2-wk trial	Monitor transaminases at 2, 6, and 12 wk, and afterward in 12-wk intervals or in case of dose changes. If symptom control is insufficient within 4 wk or adverse effects occur, patients can be started on naltrexone	Start at a low dose (12.5 mg/d or naloxone), increase by 12.5 mg/d every 2–3 d till amelioration of pruritus In-patient management of severe pruritus: i.v. naloxone (0.002–0.2 μg/kg/min; bolus 0.4 mg every 8 hours if necessary), and subsequently switch to naltrexone Monitor liver biochemistry	Starting at a low dose, incrementally titrate up to optimal therapeutic dosage (4-wk intervals) and continue for a minimum of 6–8 wk Regular monitoring of sodium ECG monitoring Paroxetine and other SSRIs may be used as alternates

Abbreviations: ATX, autotaxin; PXR, pregnane X receptor; UDCA, ursodeoxycholic acid.

Pruritus refractory to bile acid resins is treated with rifampicin, a safe second-line agent with the strongest evidence for improvement of cholestatic pruritus. It is reported to be effective in approximately 70% of patients.⁴⁹ As an inducer of hepatic enzymes, it potentially changes the metabolism and excretion of pruritogens. It can also decrease serum LPA, a pruritogen, by downregulating ATX expression through its pregnane X receptor agonism.¹³ Although uncommon, hepatotoxicity is a severe side effect that necessitates regular monitoring of liver biochemistries and avoidance in patients with bilirubin levels greater than 2.5 mg/dL.⁶ Rifampicin also interacts with several medications, such as SSRIs, necessitating caution when practicing polypharmacy. Similar to rifampicin, the barbiturate phenobarbital induces the enzyme CYP3A4, but has a reduced antipruritic effect and may worsen fatigue as a strong sedative.^6,13

µ-Opioid receptor antagonists, naloxone (i.v.) and naltrexone (oral), impede increased endogenous opioid levels in patients with cholestatic pruritus and are the recommended third-line agents for improving pruritus in patients with PBC.⁶ Dosages must be progressively titrated to avoid an opioid-like withdrawal syndrome. Prolonged usage may exacerbate underlying chronic pain. Additionally, hepatotoxicity, although rare, has been reported with naltrexone, which requires follow-up of liver biochemistries.⁴⁹

SSRIs, namely sertraline, are the fourth-line recommended agents with reported improvements in intensity of cholestatic pruritus independent of their antidepressive effect.¹³ Side effects, including agitation, sleep disturbances, and appetite suppression, may increase fatigue and should be monitored.

Medically refractory pruritus may be referred to expert tertiary centers for experimental medical or interventional therapy such as UV-B phototherapy, plasmapheresis, biliary drainage (external or nasobiliary), and extracorporeal albumin dialysis (eg, molecular adsorbent recirculating system).¹³ These therapies have proven to have an immediate, although temporary relief from cholestatic pruritus in case series but are not without their risks (eg, cholangitis after biliary drainage). Intractable pruritus refractory to all therapy is an indication for liver transplantation, even in the absence of synthetic liver dysfunction.⁶ Liver transplantation is highly effective in rapidly reducing pruritus severity, often within the initial 24 hours post-transplantation.⁶ However, in some cases, pruritus may persist.^6,58 Persistent pruritus in recipients of liver transplant is often attributed to cholestasis secondary to anastomotic or nonanastomotic biliary strictures or chronic ductopenic graft rejection, potentially necessitating retransplantation.⁵⁸

Ongoing research on the pathophysiology of cholestatic pruritus has provided additional possibilities for novel therapies. Ileal bile acid transporter inhibitors, such as linerixibat, are being investigated in a phase III GLISTEN trial after reporting efficacy in reducing itch severity in phase II studies, potentially via disruption of the enterohepatic circulation and increased elimination of potential pruritogens.^59,60 Peroxisome proliferator-activated receptor agonist fibrates, such as bezafibrate, have also been studied in the BEZURSO trial and FITCH trials, with marked success in reducing itch intensity.^27,61 Additionally, ATX inhibitors and LPA and mas-related Gq protein-coupled receptor X4 antagonists provide the basis for new therapeutics and further research.

CONCLUSIONS

Fatigue and cholestatic pruritus significantly impair the perceived quality of life of patients with PBC, yet they are often overlooked, resulting in inadequate treatment. Although much of the pathophysiology is still unknown, fatigue is believed to involve immune-mediated liver dysfunction, neurobiological changes, and cognitive and neuromuscular symptoms. Despite the absence of approved therapies specifically targeting fatigue in PBC, a structured approach to management involves assessing fatigue and its impacts through patient-reported outcomes, addressing contributing factors, and providing support to patients. Multiple pruritogens have been implicated in the development of cholestatic itch, including bile salts, LPA/ATX, and endogenous opioids. Because of its dramatic effect on quality of life, cholestatic pruritus necessitates regular evaluation during patient visits. Treatment typically involves lifestyle changes, medications, and interventional therapy. Despite advancements, challenges persist in managing these debilitating symptoms. Moving forward, continued research efforts aimed at better understanding pathophysiology and developing targeted interventions are imperative to alleviate the burden of fatigue and pruritus, ultimately enhancing holistic care and outcomes for individuals living with PBC.