PLOS ONE RESEARCH ARTICLE Stigmatization is common in patients with non-alcoholic fatty liver disease and correlates with quality of life Marta Carol1,2,3,4, Martina Pérez-Guasch1,2,3, Elsa Solà1,2,3,4, Marta Cervera1,2,3,4, Sara Martı́nez1,2,3, Adrià Juanola1,2,3, Ann T. Ma1,2,3, Emma Avitabile1,2,3, Laura Napoleone1,2,3, Elisa Pose1,2,3, Isabel Graupera1,2,3, Maria Honrubia4, Marko Korenjak ID5, Ferran Torres ID6,7, Pere Ginès ID1,2,3,4*, Núria Fabrellas1,2,3,4, for the LiverHope Consortium Investigators¶ a1111111111 1 Liver Unit, Hospital Clı́nic de Barcelona, University of Barcelona, Barcelona, Catalonia, Spain, 2 Institut a1111111111 d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain, 3 Centro de a1111111111 Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEReHD), Barcelona, a1111111111 Catalonia, Spain, 4 School of Medicine and Health Sciences, University of Barcelona, Barcelona, Catalonia, a1111111111 Spain, 5 European Liver Patients Association (ELPA), Brussels, Belgium, 6 Medical Statistics Core Facility, Institut d’Investigacions Biomèdiques August Pi-Sunyer (IDIBAPS), Hospital Clı́nic, Barcelona, Catalonia, Spain, 7 Biostatistics Unit, Faculty of Medicine, Universitat Autónoma de Barcelona, Barcelona, Catalonia, Spain ¶ Membership of the LiverHope Consortium Investigators is listed in the Acknowledgments. OPEN ACCESS * pgines@clinic.cat Citation: Carol M, Pérez-Guasch M, Solà E, Cervera M, Martı́nez S, Juanola A, et al. (2022) Stigmatization is common in patients with non- alcoholic fatty liver disease and correlates with Abstract quality of life. PLoS ONE 17(4): e0265153. https:// doi.org/10.1371/journal.pone.0265153 Background and aims Editor: Gopal Krishna Dhali, School of Digestive & Liver Diseases, Institute of Post Graduate Medical Stigmatization is a well-documented problem of some diseases. Perceived stigma is com- Education & Research, INDIA mon in alcohol-related liver disease and hepatitis C, but little information exists on stigma in Received: November 24, 2021 patients with non-alcoholic fatty liver disease (NAFLD). Aim of the study was to investigate frequency and characteristics of perceived stigma among patients with NAFLD. Accepted: February 24, 2022 Published: April 6, 2022 Methods Copyright: © 2022 Carol et al. This is an open One-hundred and ninety-seven patients seen at the liver clinic were included: a study group access article distributed under the terms of the Creative Commons Attribution License, which of 144 patients with NAFLD, 50 with cirrhosis (34 compensated, 16 decompensated), and a permits unrestricted use, distribution, and control group of 53 patients with alcohol-related cirrhosis. Demographic, clinical, and labora- reproduction in any medium, provided the original tory data were collected. Quality-of-life was assessed by chronic liver disease questionnaire author and source are credited. (CLDQ). Perceived stigma was assessed using a specific questionnaire for patients with Data Availability Statement: All relevant data are liver diseases categorized in 4 domains: stereotypes, discrimination, shame, and social within the paper and its Supporting Information files. isolation. Funding: Financial Support: Supported by the LiverHope grant (H20/20 SC1-2016-RTD, Grant/ Results Award number 73185). Also supported by a grand Perceived stigma was common in patients with NAFLD (99 patients, 69%) and affected all 4 to N.F. (PI18/01330) from the Fundación de domains assessed. The frequency was slightly higher, yet not significant, in patients with Investigación sanitaria and cofunded by Instituto Carlos III (ISCIII)-Subdirección General de NAFLD cirrhosis vs those without (72% vs 67%, respectively; p = 0.576). In patients without Evaluación and the European Regional cirrhosis perceived stigma was unrelated to stage of disease, since frequency was similar in PLOS ONE | https://doi.org/10.1371/journal.pone.0265153 April 6, 2022 1 / 14 PLOS ONE Perceived stigma in NAFLD Development Fund. Also supported by a grant from patients with no or mild fibrosis compared to those with moderate/severe fibrosis (66% vs Agencia de Gestió d’Ajuts Universitaris i de Recerca 68%, respectively). There were no differences in perceived stigma between patients with (AGAUR_SGR 01281). The funding sources had no role in the study design; the collection, analysis, compensated cirrhosis and these with decompensated cirrhosis. Among patients with cir- and interpretation of data; or in the writing of the rhosis, stigmatization was more common in alcohol-related vs NAFLD-cirrhosis, yet differ- report or decision to submit the paper. ences were only significant in two domains. In patients with NAFLD, perceived stigma Competing interests: Disclosures: PG reports correlated with poor quality-of-life, but not with demographic or clinical variables. Investigator Research grant and Advisory Board for Grı́fols, Investigator Research grant and Advisory Board for Gilead, Investigator Research grant from Conclusions Mallinckrodt, Advisory Board for Promethera, Perceived stigmatization is common among patients with NAFLD independently of disease Advisory Board for Martin-Pharmaceuticals, grants from Ferring-Pharmaceuticals, grants and Advisory stage, is associated with impaired quality-of-life, and may be responsible for stereotypes, Board work from Sequana, all outside the discrimination, shame, and social isolation, which may affect human and social rights of submitted work. The other authors have declared affected patients. no conflict of interests. Abbreviations: NAFLD, Non-alcoholic fatty liver disease; CLDQ, chronic liver disease questionnaire; QOL, quality of life; MELD, model for end-stage liver disease. Introduction and background Liver diseases are frequently stigmatized possibly because of their association with alcoholism and drug abuse. In fact, studies have shown that patients with hepatitis C and B infection are frequently stigmatized regardless of the method of transmission of the virus [1–4]. Likewise, patients with cirrhosis are frequently stigmatized irrespective of the etiology of the disease [5, 6]. Stigma was first defined as the situation of the individual who is disqualified from full social acceptance with an obvious consequence of social isolation [7]. A more recent definition char- acterizes stigma as a social process, experienced or anticipated, characterized by exclusion, rejection, blame or devaluation that results from experience, perception or reasonable antici- pation of an adverse social judgment about a person or a group [8]. Unfortunately, a large number of diseases suffer from stigmatization, including AIDS, neurological disorders such as multiple sclerosis and epilepsy, obesity, and a number of chronic diseases, including liver dis- eases [5, 6, 9–15]. Stigmatization has a large array of potential consequences on patients suffer- ing from these diseases that include depressive symptoms, feelings of helplessness and isolation, shame, poor psychological function, decreased physical and social activity, poor self- image, and reduced quality of life [1, 4, 10, 11, 16–20]. Stigmatization is currently considered a very relevant issue in some diseases because of its potential negative impact on patient health status and the fact that it reduces the possibility of patient access to care and recovery. In recent years, there has been a growing interest on fighting stigmatization of certain diseases with the objective of improving patients’ social acceptance and overall health status. Some of these ini- tiatives involve several stakeholders, including patients associations, scientific associations, healthcare professionals, and policymakers [21]. Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide that affects approximately 24% of the world population and is frequently associated with obe- sity and metabolic syndrome [22]. NAFLD is a progressive disease and a significant proportion of patients evolve from simple steatosis to cirrhosis or hepatocellular carcinoma during follow- up. It is possible that NAFLD is a stigmatized disease because it affects the liver and is fre- quently associated with obesity, two conditions that are frequent drivers of stigma. However, despite of this and the growing prevalence and increasing clinical interest in the disease, the information on stigmatization in patients with NAFLD is very scant. In fact, stigma of NAFLD PLOS ONE | https://doi.org/10.1371/journal.pone.0265153 April 6, 2022 2 / 14 PLOS ONE Perceived stigma in NAFLD is not mentioned in major guidelines of international societies [23, 24]. The most important mentions of stigma come from patients experiences posted in websites of organizations on liver diseases [25–29]. Along these lines, the European Liver Patients Association (ELPA) has brought attention to stigma as a significant problem in patients with NAFLD in some of its recent activities [30–36]. In this context, we designed a prospective study to evaluate the frequency and characteris- tics of perceived stigmatization in patients with NAFLD. Since NAFLD is frequently associated with impaired quality of life (QOL), we also explored the potential relationship between per- ceived stigma and QOL in these patients. Our findings indicate that perceived stigma is com- mon in patients with NAFLD and is associated with impaired QOL. Patients and methods Study objective The main objective of the study was to investigate the frequency and characteristics of per- ceived stigmatization in patients with NAFLD. Secondary objectives were to investigate differ- ences in perceived stigma between patients in different stages of NAFLD (without cirrhosis, with compensated cirrhosis and with decompensated cirrhosis), compare perceived stigma in patients with NAFLD-cirrhosis with that of patients with alcohol-related cirrhosis, and, finally, assess whether perceived stigma correlates with patients QOL, as assessed by chronic liver dis- ease questionnaire (CLDQ). Patient population Patients with the diagnosis of NAFLD seen at the clinics of chronic liver diseases and NAFLD of the Liver Unit of the Hospital Clı́nic of Barcelona were screened as potential candidates for inclusion in the study. The diagnosis of NAFLD required: 1/ abnormal liver tests and/or abnormal liver ultrasonography suggestive of steatosis; 2/ exclusion of alternate etiologies of chronic liver disease, including chronic viral hepatitis, autoimmune liver disease, primary bili- ary cholangitis, obstruction of biliary tree, drug liver toxicity, hemochromatosis, Wilson’s dis- ease, and alpha-1-antitrypsin deficiency; 3/ history of alcohol consumption of less than 21 units/week in males and 14 units/week in females; and 4/ histological diagnosis compatible with NAFLD in patients in whom liver biopsy was performed [23, 24]. Exclusion criteria were: 1/ age younger than 18 years; 2/ diagnosis of NAFLD made less than 12 months prior to the inclusion in the study; 3/ associated HIV infection; 4/ previous organ transplantation; 5/ important linguistic barrier; and 6/ lack of informed consent. Patients with a very recent diag- nosis of NAFLD were excluded from the study because it was considered that they probably did not have enough time with diagnosis of liver disease to perceive the effects of stigmatiza- tion. Patients meeting the inclusion criteria without exclusion criteria were invited to partici- pate in the study after explaining its characteristics and objectives. Patients with alcohol- related cirrhosis were also screened for inclusion in a comparative control group. All patients were identified from the electronic medical record system and were contacted by phone to explain them the characteristics and objectives of the study. Patients interested in participating were seen the day of the consultation to further explain the objectives of the study, sign the informed consent, and fill in all the information requested as well as the questionnaires. Patients were invited to fill in the questionnaires, alone, without family relatives, and with no time restriction. Patients with descompensated cirrhosis were invited to participate at least one month after an episode of acute descompensation with or without hospitalization. During the study period, 463 patients with chronic liver diseases were screened and 266 were excluded for different reasons (main reasons for exclusion were diagnosis made within less than 1 year in PLOS ONE | https://doi.org/10.1371/journal.pone.0265153 April 6, 2022 3 / 14 PLOS ONE Perceived stigma in NAFLD 159 cases, cognitive dysfunction in 27, and lack of informed consent in 35); therefore 197 patients constitute the study population, 144 with NAFLD and 53 with alcohol-related cirrho- sis. The study was approved by the Ethics Committee and all patients provided written informed consent (study reference number HCB 2018/1080). Data collection Demographic and clinical information was collected from the medical records of each patient. Liver tests had been performed within a period of less than 3 months before inclusion in the study in all subjects. Liver stiffness (LS) and control attenuation parameter (CAP) values were also collected if transient elastography had been performed within the previous 12 months before inclusion in the study. Chronic liver disease questionnaire (CLDQ) The CLDQ was administered to all patients included. The CLDQ is a liver disease-specific tool to assess areas of function important to patients with chronic liver diseases [37, 38], which has 29 items contained within 6 domains that include: abdominal symptoms, fatigue, systemic symptoms, activity, emotional function, and worry. The tool uses a Likert scale response for- mat for all items ranging from 1 (most important) to 7 (least important) and has been validated in Spanish version [38]. Scoring of each domain was performed by adding scores for each item and dividing by the total number of items of each domain. Overall CLDQ score was obtained by adding scores for each item and dividing by 29, which is the total number of items. Hepatic stigma questionnaire The questionnaire used for assessment of perceived hepatic stigma was designed by Vaughn- Sandler et al. [5]. This tool was developed in patients with cirrhosis of different etiologies and is based on 18 stigma-related questions that are categorized in 4 domains: stereotypes (ques- tions 1 to 4), discrimination (5 to 7), shame (8 to 11), and social isolation (12 to 18) (see S1 Table). Answers to questions are made on a 4-point Likert scale: “strongly disagree”, “dis- agree”, “agree” and “strongly agree”. The main analysis was performed using the 4 different domains. A given patient was considered positive for a particular domain if the answer to at least one question of the domain was one of the two highest in Likert scale, either “agree” or “strongly agree”. Statistical analysis Quantitative variables are expressed as mean plus/minus SD or median and IQR. Qualitative variables are expressed in numbers of percentages. Evaluation of significant differences between groups for continuous variables was performed using the Student t test and ANOVA or Kruskal-Wallis where appropriate. Comparisons between frequency data for significant dif- ferences were performed with chi-square or Fisher’s exact test, where appropriate. Correlations between quantitative assessment of perceived stigma (overall and its components) and CLDQ (total and its domains) were performed with Pearson coefficient. Cronbach’s alpha coefficient was used to assess the scores’ reliability. Significance was set at the p<0.05 level (two-sided). Statistical analysis was performed using SAS version 9.4 software (SAS Institute Inc., Cary, NC, USA). PLOS ONE | https://doi.org/10.1371/journal.pone.0265153 April 6, 2022 4 / 14 PLOS ONE Perceived stigma in NAFLD Sample size A sample size of 198 subjects randomly selected will suffice to estimate with an 84% confidence and a precision +/- 5 percent units, a population percentage considered to be around 50%. Population was divided into three subgroups according to disease stage. Patients with NAFLD without cirrhosis, patients with NAFLD with compensated cirrhosis and patients with NAFLD with decompensated cirrhosis. Additionally, a group of patients with alcohol-related cirrhosis was included as a control group. Results Characteristics of the patient population A total of 197 patients were included in the study, 144 with NAFLD and 53 with alcohol- related cirrhosis. Among patients with NAFLD, 94 had different stages of fibrosis but without cirrhosis and 50 had cirrhosis (34 compensated, 16 decompensated). The demographic and clinical characteristics of patients with NAFLD are shown in Table 1. Median age was 64 years and 52% were male. As expected, risk factors for NAFLD were very common, including obe- sity, type 2 diabetes mellitus, and arterial hypertension. Seventy-six percent of patients had Table 1. Baseline characteristics of patients with NAFLD included in the study categorized according the stage of the disease� . NAFLD without NAFLD compensated NAFLD decompensated All patients P value cirrhosis (n = 94) cirrhosis (n = 34) cirrhosis (n = 16) (n = 144) # Age (years) 62 (54–69) 69 (60–72) 54 (52–65) 64 (56–70) 0.033 Gender (male) 52 (55) 16 (47) 7 (44) 75 (52) 0.556 �� Marital Status Single/married/divorced/widowed 10/63/12/8 2/25/4/3 2/10/4/0 14/98/20/11 0.944 (%) Education status Primary school/high school/ 16/47/30�� 12/13/9 5/6/5 33/66/44 0.265 bachelor’s or master’s degree (%) Diabetes Mellitus (%) 47 (50) 23 (68) 10 (63) 80 (56) 0.176 Arterial hypertension (%) 57 (61) 21 (62) 8 (50) 86 (60) 0.099 Obesity (%) 60 (64) 17 (50) 9 (56) 86 (60) 0.357 BMI (kg/m2) 31 (29–35) 30 (28–33) 31 (28–33) 31 (28–34) 0.469 Time since diagnosis (years) 2.2 (1.3–5.4) 3.9 (1.7–6.9) 2.6 (1.1–6.2) 2.7 (1.3–5.5) 0.218 Hepatic Encephalopathy (%) 0 (0) 0 (0) 6 (38) 6 (4) <0.001 Gastrointestinal bleeding (%) 0 (0) 0 (0) 6 (38) 6 (4) <0.001 Ascites (%) 94/48/140 0 (0) 0 (0) 12 (75) 12 (8) <0.001 ��� Bacterial Infections (%) 94/47/139 0 (0) 1 (3) 1 (6) 2 (1) 0.009 AST (IU/L) 32 (23–48) 28 (25–47) 36 (24–44) 32 (24–47) 0.953 ALT (IU/L) 40 (27–61) 31 (26–52) 25 (21–33) 34 (25–56) 0.012 GGT (IU/L) 54 (32–89) 46 (31–73) 64 (39–80) 60 (33–89) 0.807 Bilirubin (mg/dL) 0.6 (0.5–0.9) 0.7 (0.5–1) 0.9 (0.8–1.6) 0.7 (0.5–0.9) 0.008 Albumin (g/L) 47 (44–48) 46 (43–47) 43 (37–46) 46 (43–48) <0.001 INR 0.98 (0.93–1.1) 1.05 (0.99–1.09) 1.18 (1.08–1.26) 1.0 (1.0–1.1) <0.001 Liver stiffness (kPa) ���� 6.5 (4.8–11.4) 16.3 (10.1–21.3) 31.9 (20.3–36.4) 9.3 (5.6–16.3) <0.001 ���� CAP (dB/m) 317 (289–353) 289 (240–320) 251 (228–304) 308 (270–341) 0.001 � Values are numbers or percentages (in brackets) or medians (IQR). # Comparison between the 3 groups of patients �� Data available in 93 patients. ��� Data available in 31 patients. ���� Available in 135 patients, 94 without cirrhosis and 41 with cirrhosis, within the previous 12 months before inclusion in the study. https://doi.org/10.1371/journal.pone.0265153.t001 PLOS ONE | https://doi.org/10.1371/journal.pone.0265153 April 6, 2022 5 / 14 PLOS ONE Perceived stigma in NAFLD education of high school or college level. In the cirrhosis group the diagnosis was confirmed by liver biopsy in 34 (68%) cases. In the remaining 16 patients evidence for the diagnosis of cir- rhosis derived from previous decompensations in 10 patients and biological signs of liver fail- ure together with evidence of portal hypertension in abdominal ultrasonography in 6 patients. In the non-cirrhosis group, the diagnosis was confirmed by liver biopsy in 45 (48%). In the remaining 49 patients liver function tests, including serum bilirubin, serum albumin and pro- thrombin time, were normal, abdominal ultrasonography did not show signs of portal hyper- tension, and median liver stiffness was 6.7 kPa (IQR 4.8–11.3). In the overall group, median time elapsed since diagnosis of NAFLD until inclusion in the study was 2.7 years (1.3–5.5). As mentioned before, a group of patients with alcohol-related cirrhosis (n = 53) was included in the study as positive control group. Comparison of characteristics of these patients and those of patients with NAFLD-cirrhosis are shown in S2 Table. More than half of patients with alcohol-related cirrhosis (28, 53%) had the diagnosis confirmed by liver biopsy. Most patients (44, 83%) had been abstinent from alcohol for at least 6 months before the study. There were no significant differences between groups with respect to the severity of cirrhosis, as estimated by liver function tests or severity scores (MELD and Child-Pugh). However, the median time elapsed since diagnosis of cirrhosis until inclusion in the study was significantly longer in patients with alcohol-related compared to NALFD-cirrhosis (6.6 vs 3.3 years, p<0.001) and a higher number of patients with alcohol-related cirrhosis had had previous epi- sodes of acute decompensation, particularly ascites and hepatic encephalopathy, which indi- cates a longer exposure to the disease together with a more severe course. As expected, obesity, type-2 diabetes and other components of metabolic syndrome were significantly more fre- quent in patients with NAFLD-cirrhosis than in those with alcohol-related cirrhosis. Internal reliability of perceived stigma scale For the perceived hepatic stigma scale, Cronbach’s α score in the whole series of patients was 0.750 indicating strong internal consistency reliability of the scale in this series. Similar α scores were found in patients with NAFLD, either overall or categorized according to presence or absence of cirrhosis, and in patients with alcohol-related cirrhosis (reliability coefficient val- ues of 0.717, 0.698, 0.728, and 0.732, respectively). Perceived stigma in patients with NAFLD A high proportion of patients with NAFLD indicated they felt stigmatized by providing an affirmative answer (either “agree” or “strongly agree”) for at least one of the stigma-related questions (99 out of the 144 patients, 69%). Frequency of perceived stigma was higher in patients with NAFLD-cirrhosis compared to that of patients without cirrhosis, yet the differ- ence did not reach statistical significance (72% vs 67%, respectively; p = 0.576). There were no significant differences in perceived stigma between patients in different disease stages (Fig 1). Questions that were answered affirmatively by more than 20% of patients belonged mainly to stereotypes, discrimination and shame (Table 2). Questions answered affirmatively by a very low proportion of patients (<5%) are shown in S3 Table. To investigate whether fibrosis sever- ity was related to perceived stigma in patients without cirrhosis, patients were classified into two subgroups using the severity of fibrosis in the liver biopsy or liver stiffness as cutoffs (