Targeted Literature Review

Our search strategy (end date March 2021) yielded 1070 articles that were further screened based on their titles, followed by their abstracts, to identify the top 100 most relevant articles. Subsequent screening, based on articles pertaining to patients’ experiences and PBC symptoms and impacts, led to the shortlisting of 22 articles. Of these, 11 (two independent surveys, two clinical trial publications with a patient survey component, six literature reviews, and a qualitative study) were selected for a full-text review to extract relevant signs, symptoms, and impacts of PBC (Table S2). Almost all articles mentioned fatigue and pruritus as the main PBC symptoms; one article primarily focused on fatigue, and four focused on pruritus, although they also mentioned other signs, symptoms, and impacts of PBC.

The TLR identified 20 signs and symptoms of PBC, which were organized in the PCM based on their relation to the disease (n = 8), its treatment (n = 10), or both (n = 2). The most prevalent (≥ 50%) symptoms in the literature were fatigue, pruritus, pain/discomfort, and gastrointestinal symptoms. While pain or discomfort is attributed to the disease, gastrointestinal symptoms only result from treatment. Fatigue and pruritus, on the other hand, can be attributed to both the disease and its treatment. These signs and symptoms were organized in the PCM with these considerations in mind.

The TLR also identified 17 impacts (immediate, 6; distal, 9; broader, 2) of PBC. The most prevalent (≥ 50%) immediate impacts were on physical activity, scratching due to itching, sleep deprivation/abnormal sleep patterns, and diet changes. Emotional dysfunction, social isolation/social disturbance, and the inability to work were the most frequently reported distal impacts. The broader impacts (decreased HRQoL and limitations in lifestyle) were also highly prevalent in the literature.

Clinician InterviewsBackground and Experience

The clinicians included in this study had 20–30 years of experience, and all of them specialized in hepatology; one clinician also specialized in gastroenterology (Table S3). Clinicians reported that their patients were mostly White, female, and in their 50s.

Signs and Symptoms of PBC Based on Clinicians’ Experience of Managing the Condition

During the interviews, clinicians reported that most patients were asymptomatic at diagnosis, and those who reported symptoms were often diagnosed at an advanced stage (Table S4). The presence of biochemical abnormalities (abnormally high levels of gamma-glutamyl transpeptidase, alkaline phosphatase, and bilirubin) and a positive anti-mitochondrial antibodies test were typically used by clinicians to confirm diagnosis. They reported that UDCA was generally well tolerated by patients. According to one clinician, younger patients tended to have aggressive disease and experienced disease progression faster than older patients, who were less likely to experience symptoms and develop complications (liver stiffness, liver fibrosis, ductopenia, cirrhosis, decompensated liver disease, liver cancer, and end-stage liver disease/liver failure). Any changes in therapy in the younger cohort were aimed at prolonging the time to clinical events.

Clinicians stated that patients with PBC commonly experienced fatigue, which tended to worsen as the day progressed. According to the clinicians, severe fatigue is generalized and could be described as an extreme exhaustion that patients associated with mental fatigue or “brain fog.” It can also be related to sleep disturbances due to nighttime pruritus.

“The patients are embarrassed, and other people are telling them, ‘Stop itching. Stop scratching,’ as if they could control it. So that leads to social isolation … they’re exhausted because they didn’t sleep, so that adds to their fatigue. That leads to depression.” – CLIN04

“Frequently, with the fatigue, they will report they have to take naps in the middle of the day, and they will get progressively more tired, such that they’re able to work or maybe do the minimal household activities, but not have energy for doing any kind of extra activities.” – CLIN02

“Of course, fatigue can be overwhelming, and people can’t do anything, right? They barely can get out of bed, and they have real trouble doing their activities of daily living, and so it can be really overwhelming. I mean that’s severe disease, but it’s not life-threatening.” – CLIN06

Clinicians reported that patients who were symptomatic at diagnosis commonly experienced pruritus, although it did not correlate with the histological stage of PBC. Further, there was no consensus on whether pruritus is related to disease progression, as it can subside when patients become more cholestatic and require liver transplants. A higher alkaline phosphatase level was associated with a greater likelihood of experiencing pruritus. According to the clinicians, patients commonly developed pruritus in the extremities (soles of the feet, palms of the hands); it was associated with skin drying and tended to be worse during winters and at night. Clinicians reported that patients were bothered by the pruritus, and discussions with them on the impact of pruritus on their daily lives were critical to make decisions regarding treatment. Patients could develop serious mental health issues if the pruritus was refractory to medical therapy, and liver transplantation may be indicated when the patient is suicidal as a result of pruritus.

“Pruritus can bring patients to become suicidal, and that is an indication for liver transplantation when pruritus is refractory to everything, and patients are that distressed.” – CLIN04

Apart from fatigue and pruritus, other common PBC symptoms reported by clinicians included dry eyes, dry mouth, portal hypertension, abdominal discomfort in the right upper quadrant, and muscle weakness (or muscle dysfunction/muscle wasting).

Impacts of PBC Based on Clinicians’ Experience of Managing the Condition

During the interviews, clinicians reported that pruritus resulted in excessive scratching, which led to scarring and skin discoloration (Table S4). Consequently, patients tended to change their clothing style to hide their damaged skin and to even wear gloves to avoid scratching themselves while sleeping. Pruritus also interfered with the patients’ ability to sleep at night, due to which they felt tired during the day. Further, the clinicians reported potential emotional impacts, such as anxiety and depression resulting from social isolation and embarrassment, frustration, stress, and the feeling of not being understood by others.

Clinicians reported that dry mouth caused dental problems, such as tooth decay in patients with PBC, and the dry eyes could lead to corneal ulcerations. They reported that patients experienced a decline in physical and cognitive function over time and found it difficult to perform daily chores; patients also often found it difficult to keep up with others due to a need to rest during the day. Clinicians noted that, consequently, patients often reported to them that they experienced reduced working hours, employment loss, and financial stress. Clinicians also stated that patients with PBC experienced social isolation, as they were unable to perform recreational activities and avoided going out.

“Because of the depression and anxiety that is very tightly interconnected with fatigue, many patients are unable to work. I have prescribed disability for many patients, total disability.” – CLIN02

Clinicians’ perspectives regarding changes in pruritus are described in the supplementary results.

Conceptual Model

Clinicians’ review of the PCM resulted in the addition of 13 signs and symptoms and the elimination of four signs and symptoms—obstructive sleep apnea, piloerection, urine frequency change, and neuropsychiatric symptoms (e.g., visual hallucinations). In total, there were 28 signs and symptoms included. Further, eight immediate impacts (scarring/excoriation of the skin due to scratching, clothing changes, needing rest during the day, eating challenges, difficulty with dental hygiene/dental loss, urge to drink/sucking, corneal ulcerations, and inability to wear contact lenses) and three distal impacts (inability to engage in recreational activities, impacts on activities of daily living, and difficulty taking care of family) were added to the conceptual model.

Patient InterviewsDemographic and Clinical Characteristics

Concept-elicitation interviews were conducted with 19 women and one man (average age, 50 years; range, 29–68 years; Tables S5 and S6); of the 20 patients, 16 were from the USA, and four were from Canada. Due to difficulty in recruiting patients, one patient was recruited despite being 3 years older than the upper age limit of 65 years. Physicians confirmed the PBC diagnosis and specified the disease stage. During the interviews, all patients reported that they had received UDCA (n = 20) for PBC; six patients had received OCA, and four patients had received cholestyramine. Two patients reported receiving ondansetron, and one patient reported receiving dextroamphetamine and levoamphetamine for symptomatic treatment. Overall, patients received their PBC diagnosis at a median of 5 years preceding the interview. During the study, almost half of the patients had stage 1 disease and reported experiencing moderate pruritus in the past month (n = 9 for both). Consistent with the literature [26, 27], no association was observed between disease stage and severity of pruritus.

Signs and Symptoms of PBC Experienced by Patients

Patients reported 41 unique signs and symptoms during the interviews; 11 symptoms were mentioned by more than half the patients. Fatigue (n = 19) and pruritus (n = 20) were the most frequently reported symptoms; dry eyes and sensitivity to cold (n = 14 for both) were other common symptoms. The most salient symptoms identified by patients were fatigue, pruritus, dry eyes, dry mouth, skin surface change, and pain (Fig. 1).

Fig. 1

Saliency map of patient-reported signs and symptoms

Patients’ Experience of Fatigue

Nineteen patients reported experiencing fatigue (Table S7). Patients stated that fatigue was “the worst thing,” that they were “extremely tired” all the time, or that it varied from day to day and worsened with increased activity. One patient rarely experienced fatigue. Patients also reported having mental fatigue and/or physical fatigue and that both types of fatigue impacted their daily lives.

“The worst thing is the fatigue. The fatigue is the worst thing because I still work full time. There’s days I can barely function I’m so tired.” – P04

“It’s just the overall feeling of basically being very tired all the time. It doesn’t really seem to matter how much sleep I get. I don’t sleep a lot, but during the times that I do manage to get sleep, I’m still extremely tired … I haven’t found anything yet that helps.” – P02

When patients were asked to describe what made their fatigue worse, they usually responded by attributing it to PBC or to a comorbidity (e.g., Hashimoto’s disease). Others stated that the fatigue was due to the medicine they took for PBC or other symptoms, such as nausea.

“I think it’s the disease. I think it is the PBC. They tell me it is. I have expressed to my doctors about the fatigue, but because where I had the bleed, my blood is extremely low and, for some reason they can’t get it back up. She said that with low blood and the disease, it’s something basically I gotta live with. There’s not much they can do for it.” – P04

Patients’ Experience of Pruritus

Patients described pruritus as “unbearable” or “torturous,” like a “burning sensation,” “bugs underneath the skin,” or “falling into a beehive” (Table S7). They reported that it occurred at different locations, such as the head or scalp, in the upper or lower body (including the extremities), or around the torso (including the waist and groin). Pruritus varied from one patient to another, from being constant to occurring occasionally. Each patient experienced day-to-day variation in the occurrence and severity of pruritus, which interfered with their sleep and caused stress. The most bothersome aspect of pruritus was that it was not relieved by scratching. In fact, scratching caused bleeding and prevented patients from engaging in different activities. Patients described pruritus as an annoyance, and reported being anxious (n = 19) and embarrassed (n = 11) by the itching. For almost all patients (n = 19), pruritus was the worst at night and interfered with their sleep. Patients reported that changes in environmental temperatures tended to worsen pruritus. Two patients mentioned that OCA made their pruritus worse, and one patient reported that UDCA made it worse. Two patients reported that hydroxyzine provided relief from pruritus; six patients said antihistamines helped them feel sleepy at night. Although patients tried different over-the-counter solutions, most reported that creams and lotions did not provide any relief.

Impacts of PBC Experienced by Patients

Patients reported 31 unique impacts of PBC during their interviews, categorized as physical impacts, emotional impacts, cognitive impacts, role functioning impacts, social impacts, and other impacts (e.g., lifestyle changes). The most frequently reported physical impacts were scratching (n = 20), sleep problems (n = 19), and diet changes (n = 14). Of these, sleep problems (average disturbance rating 8.0/10) and scratching (7.9/10) were the most disturbing to patients. Anxiety/worry (n = 19), stress and sadness/depression (n = 15 for both), embarrassment (n = 11), and frustration (n = 10) were the most common emotional impacts, of which frustration was the most disturbing (7.8/10). The most common cognitive impacts were memory problems (n = 12) and attention problems (n = 10); and patients found the latter most disturbing (7.6/10). Twelve patients reported that PBC affected their work productivity (average disturbance rating 6.3/10); seven reported financial impacts (average disturbance rating 9.5/10). Thirteen patients also stated that PBC impacted their ability to spend time with others, especially because of their fatigue, and 10 patients explained that their relationship with their partner/family was affected. An inability to spend time with others was the most disturbing social impact (8.4/10), followed by the impact on their relationships (6.5/10). Finally, 17 patients stated that they had experienced a deterioration in HRQoL, and 15 patients said they had made lifestyle changes after being diagnosed with PBC. The impact on overall HRQoL was most disturbing to patients (6.6/10). Overall, the most salient impacts identified by patients were scratching, sleep problems, physical activities, activities of daily living, sadness/depression, frustration, attention problems, spending time with others, impacts on their relationships with their partner and family members, and HRQoL impacts (Fig. 2).

Fig. 2

Saliency map of patient-reported impacts. HRQoL health-related quality of life

Patients’ Experience of Scratching

Pruritus led to excessive scratching for all patients (n = 20); four patients referred to “scratching” as “itching” (Table S7). It was described as “maddening” by two patients, while two patients reported being less aware of their scratching. Five patients described scratching as causing skin bleeding and marks on the skin. Five patients stated that they were embarrassed by the scratching and its effects on their skin and were self-conscious about scratching in front of others.

Sleep Problems

Problems with sleep were reported by 19 patients. They often reported having problems falling asleep as a result of itching that would intensify at night (Table S7). Three patients stayed awake at night due to scratching, which interfered with their sleep. According to the patients, the lack of sleep and persistent fatigue made them feel helpless, emotional, and unable to function during the day.

“Literally, I sit at my desk, and I could fall asleep. When it hits, I just want to cry, I’m so tired. There’s days I just sit there with tears in my eyes saying, ‘I need to go to sleep.’ I take naps on my lunch. I go in the boardroom and just take a nap just to get me through the day, I’m so tired sometimes.” – P04

Concept Saturation

Of the 41 unique signs and symptoms reported by patients during the interviews, 33 symptoms (80%) emerged during the first wave of interviews. During wave 2, five new symptoms (12%) were elicited (hypertension, swelling, skin pain, taste issues, and odor sensitivity), and three new symptoms (7%) were elicited in wave 3 (appetite issues, breathing issues, and hair loss/thinning). No additional symptoms were elicited in wave 4. Thus, symptom saturation was reached after 15 interviews.

Of 31 unique impacts reported during the patient interviews, 28 impacts (90%) emerged in the first wave of interviews. In wave 2, two new impacts (6%) were elicited (emotional impact [guilt] and role functioning impact [change in employment status]), and one new impact (3%) was elicited in wave 3 (cognitive impacts [difficulty finding words]). No new impacts emerged in wave 4. Thus, impact saturation was reached after 15 interviews.

Revision and Finalization of the Conceptual Model

A comprehensive account of all symptoms and impacts reported by participants was summarized in the conceptual model. New symptoms that emerged from the patient interviews that were not reported in the literature or mentioned by clinicians were skin pain, nail problems, bleeding, nosebleeds, weight change, early satiety, swelling, odor sensitivity, breathing issues, difficulty tolerating cold or hot water (temperature sensitivity), dizziness, and vomiting. Similarly, new impacts included self-consciousness, not being understood by others, and change in alcohol consumption. In addition, patients mentioned having difficulty finding words and issues with work productivity as impacts of PBC. The conceptual model was revised based on feedback from patients, wherein patient-reported symptoms were added (e.g., weight change, skin pain, dizziness, and temperature sensitivity) and clinician-reported symptoms were removed (e.g., vaginal dryness, CK elevation, and discoloration of urine), except portal hypertension, which was retained. Amendments were made to the impacts as well (e.g., work productivity, difficulty finding words, and changes in alcohol consumption were added; corneal ulcerations, difficulty taking care of family, and liver transplant were removed). The final conceptual model is presented in Fig. 3.

Fig. 3

Final conceptual model. Black text represents concepts reported by patients and clinicians. Blue text represents patient-reported concepts. Green text represents clinician-reported important concepts. Bold text represents concepts reported as salient (≥ 50% mentions and ≥ 6.5 average disturbance rating). HRQoL health-related quality of life, TLR targeted literature review

Cognitive Debriefing Results

Table 1 shows the results of the cognitive debriefing section of the interviews with patients, along with illustrative quotes. Overall, patients found both tools to be relevant and comprehensive. Details of patients’ perspectives on meaningful improvements or worsening in fatigue and pruritus are provided in the supplementary results.

Table 1 Cognitive debriefing results (N = 20)