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Evaluation of elevated liver values in primary care - a series of studies on the status quo of care in Germany with special reference to alcoholic liver disease

Evaluation of elevated liver values in primary care - a series of studies on the status quo of... Background: In primary care, elevated liver values often appear as incidental findings. As well considering the pre - senting symptoms, key factors in effective diagnosis are which liver values to include as indicators and when to refer patients for further diagnostics. It is also important that there is coordinated collaboration between GPs and special- ists. There has hitherto been a lack of reliable findings on the status quo regarding the evaluation of (abnormally) elevated liver values in primary care. Methods: Between 2017 and 2021, four written explorative surveys of GPs and gastroenterological specialists were conducted in various German states, aimed at taking stock of the current status of GP-based diagnostics of (abnor- mally) elevated liver values. In addition, interviews were conducted with 14 GPs and gastroenterological specialists. This review article discusses the overall findings of the series of studies in a condensed manner at a higher level. The article aims to derive starting points for optimising the diagnosis of liver cirrhosis in primary care. Results: There are various challenges and problems associated with the evaluation of elevated liver values. For exam- ple, GPs draw on very different laboratory parameters, which are combined in different clusters. When elevated liver values are found, a majority of GPs prefer a controlled wait-and-see period, but often make use of direct referrals to specialists due to diagnostic uncertainties. GPs report interface problems with gastroenterological specialists, which are associated, among other things, with the preliminary evaluation that has been made and the timing of referral. Both GPs and specialists consider the introduction of an evidence-based diagnostic algorithm to be an important starting point for improving early detection and better coordination between healthcare levels. Conclusions: Eor ff ts should be made to contribute to greater professionalisation and standardisation of primary care diagnostics and to better structure the interaction with gastroenterological specialists. These include a wider range of training formats, the development of a validated diagnostic pathway and the mandating of a liver function test as part of the check-up. The development of a GP-based guideline for managing elevated liver values also seems advisable. Keywords: Liver, Transaminases, GP, Algorithm, Early detection Background Elevated liver enzyme levels are a common incidental *Correspondence: julian.wangler@unimedizin-mainz.de Center for General Medicine and Geriatrics, University Medical Center finding in primary care [1]. At the same time, the prev - of the Johannes Gutenberg University Mainz, Am Pulverturm 13, alence of elevated liver enzyme levels among patients 55131 Mainz, Germany © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wangler and Jansky BMC Primary Care (2022) 23:104 Page 2 of 12 receiving primary care is largely unknown [1, 2]. For the the case of Germany, there is also the fact that GPs have clinical area, studies such as the Gutenberg Heart Study not yet been able to draw on explicitly GP-oriented, evi- showed that elevated liver values were found in around dence-based guidelines. 20% of patients [3]. With regard to the prevalence in To date, there are no systematic studies available in the general population, the SHIP study (cohort study of German-speaking countries that provide a reliable pic- 4310 adults aged 20 to 79 years at baseline in Pomerania) ture of the status quo of primary care in terms of elevated showed an elevated ALT level in a quarter of all included liver values and the associated challenges and problems. patients [4]. According to estimates and projections, As a result, there is a lack of knowledge about GP proce- the prevalence of abnormal liver function tests (LFTs) dures for dealing with (abnormally) elevated liver values, depends on the definition and population but is likely to about the requirement for technical apparatus or possible be between 15 and 20% in the general population [1]. interface problems between GPs and specialists. Various studies have now demonstrated that elevated liver enzyme levels are associated with a higher rate of Overall study and research interest mortality and comorbidity [2, 5–10]. Common causes This review summarises the results of a series of explor - include alcohol abuse, use of medication, non-alcoholic ative studies and compares the results with existing fatty liver disease and viral infections [11–14]. Since ele- research. The study, which consists of four sub-studies, vated liver values can indicate life-threatening diseases, it stands as an independent supplementary study in the is important that the healthcare system has the necessary broader context of the Innovation Fund model project prerequisites to detect and monitor elevated liver values SEAL (Structured Early Assessment for Asymptomatic at an early stage and, if necessary, to initiate further diag- Liver Cirrhosis) for the early detection of liver fibrosis or nostic steps. asymptomatic liver cirrhosis. In most cases, GPs are the first practitioners to dis - The main research questions for the overall study were cover (abnormally) elevated liver values in the course of as follows: a routine check-up [15–17]. In their role as primary care providers, they are responsible for assessing such find - • What are the prerequisites in the primary care set- ings and initiating further diagnostic steps. Given the ting for the detection and evaluation of elevated lev- time and resource constraints in the primary care setting, els of liver enzymes? differential diagnostic workup for the early detection of • How do GPs classify and assess (abnormally) elevated liver disease can be challenging [12, 18–21]. Apart from liver values? possible warning signs (like hämatemesis, caput medusae • How is the interdisciplinary collaboration between etc.) and the question of which values, in which refer- GPs and specialists in internal medicine or gastro- ence ranges and constellations, to include as meaningful enterology structured with regard to the diagnostic indicators [17, 19, 22], the key element of a GP’s approach work up and the treatment of patients with elevated to (abnormally) elevated liver values is to differentiate liver values? between cases where a wait-and-see approach (with rep- • How could the early detection and diagnosis of liver etition of the laboratory tests) is advisable and where an disease in the primary care setting be improved immediate diagnosis is indicated, e.g. by direct referral to (starting points for optimising the diagnosis of liver a specialist or to an outpatient liver clinic [17–19]. cirrhosis in primary care)? In Germany and other European countries, there are currently perceptible shortcomings in the consistent identification and evaluation of elevated liver values in Methods the primary care setting [3, 15, 21–23]. On the one hand, In line with the research questions, the aim was to take a low proportion of early diagnoses is criticised, and on stock of the current status of GP diagnosis of (abnor- the other, an inconsistent differential diagnostic proce - mally) elevated liver values. In particular, the aim should dure that is highly dependent on the individual GP. One be to identify current practices, challenges and problems. reason for this is thought to be the lack of structured, In order to gain the broadest possible knowledge relat- targeted screening programmes for chronic liver dis- ing to the formulated research interest, we sought the ease as part of the standard care regime [19, 20, 24]. In perspective not only of GPs but also registered doctors in addition, there is a lack of an evidence-based and widely gastroenterology practices. established diagnostic and clinical pathway to support Against the background of the findings, which are pre - GPs in the identification, classification and evaluation sented as a synopsis, the article aims to derive starting of elevated liver values, especially in the case of patients points for optimising the diagnosis of liver cirrhosis in at high risk of developing cirrhosis [11, 19, 25–30]. In primary care and making it more effective. The focus is W angler and Jansky BMC Primary Care (2022) 23:104 Page 3 of 12 Table 1 Overview of the quantitative sub-studies carried out including information on socio-demographics Group General practitioners Gastroenterological specialists Study A [31] B [32] C [33] D [34] Study period March–June 2017 October 2019–March 2020 January–March 2018 April–October 2020 N (response rate) 391 (16%) 2701 (26%) 54 (40%) 313 (59%) Gender 60% male, 40% female 61% male, 39% female 83% male, 17% female 84% male, 16% female (Specialist) Background 100% General Practice 75% General Practice, 25% Internal medi- 67% specialists in internal medicine and 65% specialists in internal medicine and cine (working as GP) gastroenterology, 29% specialists in gastroenterology, 28% specialists in inter- internal medicine, 4% other nal medicine, 7% other Mean age 51 (Median: 52) 52 (Median: 53) 54 (Median: 55) 58 (Median: 57) Office setting 47% in medium-sized and large towns or 49% in medium-sized and large towns or 80% in medium-sized and large towns or 67% in medium-sized and large towns or cities, 53% in small towns or rural areas cities, 51% in small towns or rural areas cities, 20% in small towns or rural areas cities, 33% in small towns or rural areas Type of office 49% individual doctor’s offices, 48% joint 51% individual doctor’s offices, 46% joint 33% individual doctor’s offices, 63% joint 40% individual doctor’s offices, 57% joint offices, 3% other offices, 3% other offices, 4% other offices, 3% other Patients per quarter 23% < 1.000, 37% 1.000–1.500, 19% 19% < 1.000, 38% 1.000–1.500, 19% 25% < 1000, 23% 1000–1500, 25% 30% < 1000, 19% 1000–1500, 22% 1.501–2.000, 21% > 2.000 1.501–2.000, 24% > 2.000 1500–2000, 27% > 2000 1500–2000, 29% > 2000 Wangler and Jansky BMC Primary Care (2022) 23:104 Page 4 of 12 therefore on weaknesses identified in the GP setting. All • Specialist survey: Several experts from the Cirrhosis sub-studies were deliberately designed to be exploratory. Centre of University Hospital Mainz were consulted during the development process, in order to check the completeness and appropriateness of the ques- Sub‑studies tionnaire [33] from a specialist’s point of view and Based on a preliminary study in which 391 GPs in Rhine- to align the questionnaire closely with the reality of land-Palatinate were interviewed about their approach to care. elevated liver values [31], the questionnaire was updated • Other preliminary studies by the authors on struc- for the purpose of more precise and in-depth investiga- tured, evidence-based primary care ([35] inter alia) tions (among other things, supplementing item batter- • General literature searches in the design of all sub- ies on symptoms and diagnostics, prioritizing indicators studies (papers focusing on the assessment of ele- for early detection of liver disease, questions on the fre- vated liver enzymes in primary care were used here) quency of liver disease in respective patients, use of ([36] inter alia) guidelines and other recommendations for action), and • Carrying out pre-tests in the run-up to data collec- the study was repeated on a significantly larger scale, in tion order to determine to what extent the first set of results are confirmed. This extended survey was conducted The aim was to keep the instruments used to interview between October 2019 and March 2020 and gathered the GPs and gastroenterologists mutually compatible. To this views and experiences of a total of 2701 GPs in Hesse and end, certain questions in both questionnaires (e.g. atti- Baden-Württemberg on their approach to elevated liver tude to the wait-and-see approach, starting points for values [32]. optimising early detection) were worded in a very similar An analogous procedure was followed for the survey of way. registered gastroenterology specialists. First, a prelimi- The survey instruments for the two more comprehen - nary survey was conducted in spring 2018, in which 54 sive surveys are included in the Additional file 1. gastroenterologists in Rhineland-Palatinate and Saarland were interviewed about their approach to elevated liver Data analysis values and their collaboration with GPs [33]. The ques - Data from the quantitative studies were evaluated using tionnaire, originally developed and conceptually tested SPSS 23.0. In order to highlight different approaches by the authors in 2017, was updated and resulted in an adopted by GPs, in addition to descriptive analysis, the extended study. Between April and October 2020, 313 method of factor analysis (Varimax rotation) was used, in doctors working in specialist gastroenterology practices which variables are combined into factors on the basis of in Baden-Württemberg, Hesse and Thuringia were inter - systematic relationships (correlations). After data collec- viewed in an online survey [34]. tion, the team evaluated the resulting transcripts using In addition, a smaller qualitative study was carried out qualitative content analysis according to Mayring [36]. after the aforementioned quantitative surveys. In the Our focus lay on forming logical categories from the vari- summer of 2021, seven GPs and seven established gas- ous opinions and experiences. Selected citations are pre- troenterological specialists in Rhineland-Palatinate (both sented to support the quantitative findings. randomly selected) were interviewed on the subject of clarification and interprofessional cooperation with Results regard to (unclear) elevated liver values. Figure 1 shows the starting points condensed from analy- Incentives were not used. Table  1 gives an overview of sis of the sub-studies with a view to more effective liver the studies described. diagnostics by GPs. In the following, each of the dimen- sions presented will be discussed with reference to the respective central findings and correlated with existing Development of survey instruments research. The surveys with the much larger samples serve Since the studies built on each other, there was a con- as the primary reference [32, 34]. tinuous learning process which informed the design of the subsequent sub-study. In addition, the survey instru- ments developed were supported by other elements: Liver values and liver value constellations The GP survey [32] has shown that, in everyday prac - • Preparations and exchanges within the SEAL project tice, there is a strong focus on a comparatively small • GP survey: The questionnaire [31], originally devel - number of selected liver parameters in the evaluation of oped in 2017, was enriched by a group discussion (abnormally) elevated liver values. For example, γ-GT with 10 GPs during the development process. is the main laboratory value considered (95%). About W angler and Jansky BMC Primary Care (2022) 23:104 Page 5 of 12 Fig. 1 Derived starting points for effective liver diagnostics by GPs (own figure) two-thirds (65%) include aspartate aminotransferase cific profession. Especially with moderate increases, (ASAT, AST, GOT) in their analysis, followed by ala- it is not always easy to draw the right conclusions. I nine aminotransferase (ALAT, ALT, GPT) (63%), alka- admit it’s hard for me.” (Interviewed GP 3m) line phosphatase (AP) (62%) and platelet count (57%). The survey of registered gastroenterologists [34] was able In a questionnaire, the respondents were asked to name to confirm that, from the specialist’s perspective, GPs rely which three indicators they considered to be most on highly divergent liver values to guide their everyday important and meaningful for the early detection of practice. For example, 57% of specialists experience it as liver cirrhosis. Analogously, γ-GT (92%), aspartate ami- a considerable inconvenience to have to constantly read- notransferase (83%) and alanine aminotransferase (79%) just to the diagnostic requirements due to the difference are mentioned here, while other values lag a considerable and lack of standardisation in the collection of liver val- distance behind. ues on the part of GPs. The spectrum for conclusions and At the same time, a factor analysis revealed a strongly further care decisions is correspondingly diverse. heterogeneous and divergent approach on the part of GPs in the diagnosis of potential chronic hepatic parenchymal “If you ask me: The behavior of general practitioners disease (see Table 2). u Th s, GPs not only pay attention to when considering and interpreting liver values is too very different symptoms, but also use different liver-asso - uncontrolled and not supported enough by evidence- ciated laboratory parameters or value constellations as based guidelines. As a result, we often have to adapt indicators for the identification of (incipient) liver disease our work to the preparatory work done by GPs from within the framework of laboratory diagnostics ordered scratch.” (Interviewed gastroenterologist 1m) by GPs. While one cluster focuses on functional param- eters such as bilirubin, PT according to Quick (INR), cholinesterase and albumin, another primarily looks at indicators of toxic cell damage or liver disease that has Diagnostic requirements already occurred. Among other parameters, alanine ami- The GP survey [32] showed that 29% of the GPs included notransferase receives particular attention. In addition, a in the study offer a special liver check-up in their own third cluster that focuses on γ-GT as a parameter for pos- practice in addition to the SHI screening. On the other sible liver disease stands out. hand, 66% do not offer such a service to supplement the SHI health check-up. In terms of the prerequisites “We general practitioners are all-rounders in our for diagnostic equipment, standard upper abdominal day-to-day practice. The classification of liver values sonography for the identification and further evaluation and the consideration of limit values is a very spe- Wangler and Jansky BMC Primary Care (2022) 23:104 Page 6 of 12 Table 2 Laboratory values observed. Question: Which laboratory findings potentially linked to liver disease do you usually examine in routine lab work for general screening check-ups? (N = 2.701, GPs) Rotated component matrix Overall agreement Comp. 1 (Expl. variation: Comp. 2 (Expl. variation: Comp. 3 (Expl. 26,1%) 18,2%) variation: 10,6%) Alanine aminotransferase (ALAT, ALT, GPT ) 63% −.055 .774 −.119 γ-glutamyltransferase (GGT ) 95% −.040 −.018 .884 Aspartate aminotransferase (ASAT, AST, GOT ) 65% .141 .576 .386 AP (alkaline phosphatase) 62% .542 .252 .305 Ferritin 26% .734 .035 −.102 Bilirubin 46% .686 .219 .213 PT according to Quick (INR) 27% .663 .207 −.165 Cholinesterase 19% .675 .139 −.023 Albumin 23% .740 −.027 .092 Platelet count 57% .256 .715 −.112 MCV 55% .192 .614 .165 Extraction method: Principal component analysis Rotation method: Varimax, Kaiser normalisation Rotation in 4 iterations for convergence Total explained variation: 54.9% Sampling adequacy, Kaiser-Meyer-Olkin: .787 Significance, Bartlett: p < 0.001 of liver disease is usually available in most GP practices expert opinions of medical societies or diagnostic path- (89%), and more rarely extended laboratory diagnostics ways offered by healthcare providers (e.g. German Liver (64%). 5% respectively offer an elastography or fibroscan Foundation). The interest articulated by a majority of investigation. respondents in an expansion of adequate further training As was found in a detailed interrogation via item set, offerings is also an indication of the need for the training the surveyed GPs focus on certain indicators of incipi- of GPs in this area. ent liver disease that prompt more in-depth diagnostics, “In my opinion, there should be more evidence-based while paying less attention to other indicators. From tools tailored to general practitioners – on this topic their previous experience, GPs pay particular atten- in particular.” (Interviewed GP 5w) tion to excessive alcohol consumption (94%) and also to signs such as upper abdominal complaints (76%), From the point of view of the specialists interviewed [34], symptoms of fatigue (75%), ascites (71%), itching (71%) it would also be useful if there were more training for- and skin changes (65%). In the experience of those sur- mats that gave GPs more confidence in evaluating liver veyed, symptoms such as loss of appetite, weight loss, values, as this would have a direct impact on the quality Dupuytren’s contracture, or gynaecomastia are less often and effectiveness of interdisciplinary collaboration. a sign of potential liver disease. “Fromt my point of view, primary care could do bet- Associated with this, there is evidence that GPs experi- ter at initial testing and diagnosis of (incipient) liver ence a lack of diagnostic certainty and a lack of guidance disease.” (Interviewed gastroenterologist 4m) options when clarifying (abnormally) elevated liver val- ues. For example, 38% consider themselves to be very or quite competent in the evaluation of elevated liver values, Referral behaviour while around 50% consider themselves to be less or not at In the light of the study results, the referral behaviour of all competent in this area. Only one third of the surveyed GPs reveals identifiable inconsistencies. On the one hand, GPs have consulted practice or action recommendations, almost two-thirds of the GPs surveyed [32] consider it sensible to initially practice a wait-and-see approach of several weeks (median: 5.0) after detecting moderately During the extended laboratory examination, liver and kidney values plus elevated liver values, and therefore only to consider refer- electrolytes are determined in addition to the blood count. This extended lab - ral to a higher specialist level after a repeat investigation oratory check is usually billed privately as a so-called private service. W angler and Jansky BMC Primary Care (2022) 23:104 Page 7 of 12 Table 3 Challenges experienced in the interdisciplinary relationship, GPs. Question: A variety of challenges may arise when general practitioners and district specialists for outpatients collaborate on diagnosing cirrhosis. How often have you experienced the following challenges? (N = 2.701, GPs) Statement Frequently Occasionally Rarely Never No response Resident gastroenterologists are fully booked long-term due to the many gastroduodenoscopy 69% 21% 6% 3% 1% and colonoscopy tests they are required to perform. District specialists do not have the time to discuss mostly complex patient problems with you. 41% 39% 10% 8% 2% There are too few nearby specialist internal medicine practices to diagnose liver counts the 37% 36% 11% 15% 1% way I would like. Specialists do not brief patients enough, who then go back to general practitioners out of 30% 42% 13% 13% 2% uncertainty. Gastroenterological district specialists are difficult for patients to reach. 35% 34% 16% 14% 1% Specialists do not issue direct referrals to a liver centre on suspicion of cirrhosis, so patients 23% 40% 20% 16% 1% come back to their general practitioners for the time being (going around in circles with time wasted). District specialists are booked out for too long, so I refer my patients straight to a specialist 21% 35% 19% 23% 2% clinic. I have to wait for a long time for district specialists to pass on their findings. 19% 33% 20% 27% 1% District specialists do not inform general practitioners enough about the tests they have 17% 35% 24% 23% 1% conducted or the results and/or diagnoses they have made. at a later point in time. However, the respondents give “In my experience, many general practitioners are divergent information about their actual referral behav- even too quick to refer patients with elevated liver iour, which they justify, in an open question, primarily on values of unknown aetiology. […] For example, many the basis of diagnostic uncertainties. Thus, around 40% simply look at γ-GT and refer patients to special- state that they usually refer patients directly to a special- ists for small increases. […] It would be good if they ist or even to a specialist outpatient clinic after noticing could do part of the diagnostic work themselves and abnormally elevated liver values. Only 32%, on the other thus better pre-select our patients.” (Interviewed gas- hand, have consistently waited. troenterologist 4m) “Of course, the manual says ‘controlled waiting’. But the reality is sometimes different. Elevated liver Interdisciplinary collaboration enzymes are complex and to be honest I sometimes Coordinated collaboration between GPs and special- feel overwhelmed on the subject. That’s why I tend to ists is essential for an effective, early diagnosis to explain transfer as quickly as possible.” (Interviewed GP 2w) elevated liver values and initiate appropriate treatment. Although both GPs and specialists experience collabo- 79% of the GPs reported that they had referred their ration with the other side as positive in the majority of patients to a gastroenterology practice; 44% had referred cases, considerable interface problems and hurdles in them directly to a liver outpatient clinic and 27% to a gas- interdisciplinary interaction are articulated. troenterology department or clinic. Apart from a lack of specialised internal medicine The results attest to the central pilot role of the GP practices in the vicinity (73%), frequent difficulties for within the healthcare system. 98% of the internal medi- GPs [32] are a lack of accessibility to discuss the usually cine specialists surveyed stated that patients with (abnor- complex patient problems (69%) (see Table  3). 90% state mally) elevated liver values are usually referred by their that there are often longer waiting times for an appoint- GP. 23% mention referral by another specialist and 20% ment for differential diagnostic assessment for suspected that patients visit their practice on the advice of the clinic liver disease. In rural areas, these challenges are exacer- (40% self-referrals by the patient). bated due to the significantly lower density of specialists. From the perspective of gastroenterological special- Another considerable problem experienced by GPs is that ists [34], it can be seen that they, for their part, criticise patients are not sufficiently informed about their condi - the referral behaviour of GPs, which, in their opinion, is tion by their specialist colleagues and so return to the GP often either significantly premature (64%) or too tardy due to uncertainty (72%). Likewise, the referral behav- (57%). In addition, patients with slightly or moderately iour of specialists following the diagnosis of liver disease elevated liver values often turned out to be not affected seems to be characterised by frequent referrals back to by (incipient) liver disease (69%). the GP (63%). In the absence of prompt presentation to Wangler and Jansky BMC Primary Care (2022) 23:104 Page 8 of 12 Table 4 Challenges experienced in the interdisciplinary relationship, gastroenterological specialists. Question: A variety of challenges may arise when gastroenterologists and general practitioners work together to diagnose and treat cirrhosis. How often have you experienced the following challenges? (N = 313, gastroenterological specialists) Statement Frequently Occasionally Rarely Never No response I have detected (incipient) liver disease that the general practitioner did not notice or remained 25% 59% 11% 4% 1% unaware of in a patient. Primary care could do better at initial testing and diagnosis of (incipient) liver disease. 29% 42% 17% 10% 2% General practitioners are not always sufficiently aware of elevated liver values with unknown 27% 43% 13% 13% 4% aetiology to notice the onset of liver disease at an early stage. Patients that general practitioners have referred to gastroenterologists for an elevated liver 18% 51% 15% 12% 4% count of unknown aetiology often turn out to be non-specific. General practitioners often fail to follow up on elevated liver values. 23% 42% 17% 15% 3% General practitioners are too quick to refer patients with elevated liver values of unknown aeti- 34% 30% 19% 14% 3% ology to gastroenterologists, leaving gastroenterologists booked out for long periods of time. General practitioners do not adequately inform gastroenterologists about the tests they 20% 43% 20% 16% 1% perform, the results and/or the diagnoses they have made. General practitioners are inconsistent in their approach to analysing liver values; this may 35% 22% 22% 20% 1% include varying liver values recorded depending on the general practitioner, so specialists need to keep adjusting to the preliminary work performed by general practitioners. General practitioners wait too long before referring patients with an elevated liver count of 30% 27% 25% 16% 2% unknown aetiology to a gastroenterologist. a specialist outpatient clinic, there is at least a risk of the occasionally (59%) encounter patients with liver disease patient entering an unnecessary loop as a result of being that has not been detected by the GP. referred back. “I don’t think the general practitioners or the special- “Working together with specialist colleagues is full ists are at fault. Communication and patient treat- of difficulties and stumbling blocks. Maybe it has ment simply need to be better interlinked between something to do with the fact that in Germany the the different levels of care. It would need a mecha - sectors are too separated from each other, but I can’t nism that creates a certain uniformity. I could well say that I’m usually well informed about what diag- imagine an established and well-tested algorithm nostic steps the gastroenterological colleague takes. here.” (Interviewed gastroenterologist 1m) Or what I have to do when the patient comes back to me.” (Interviewed GP 4m) Approaches for optimising primary care The views expressed by gastroenterological special - Respondents were given a list of various potential meas- ists [34] show that they are also critical of the interaction ures to increase the proportion of patients diagnosed with primary care (see Table  4). Apart from the timing early. There is a high level of agreement between the of patient presentation, the GP’s decision not to make a GPs and specialists included in the study. In view of genuine basic assessment and to refer based on suspi- the perceived inconsistency in the approach to evaluat- cion or doubt is experienced as a significant problem in ing elevated liver values in the outpatient sector, as well the interaction with GPs (71%). From the point of view as existing interface problems, 80% of GPs and 85% of of registered gastroenterologists, further impediments to specialists support the introduction of a structured, evi- the interaction with GPs arise from the fact that the lat- dence-based and broadly applicable diagnosis and treat- ter do not always follow up on elevated liver values (65%). ment algorithm as a (highly) effective measure. 65% of Some of the respondents see the fact that GPs often fol- GPs and 55% of specialists see an expansion of the labo- low a very different procedure for evaluating elevated ratory workup included in the health check-up from the liver values (e.g. collection of different liver values, 57%) age of 35 as an effective measure. 61% of GPs and 60% as an additional hurdle and this corresponds with the of specialists consider the development of an explicit, impression articulated by specialists that the investiga- evidence-based S3 guideline for the systematic evaluation tions, results and diagnoses are not always transparent of elevated liver values to be particularly effective. 50% of (63%). As a result of such interdisciplinary problems, GPs and 52% of specialists are in favour of introducing a 84% of the specialists report that they frequently (25%) or genuine liver check as part of the SHI regime. W angler and Jansky BMC Primary Care (2022) 23:104 Page 9 of 12 In addition, 70% of GPs and 76% of specialists believe and systemic autoimmune phenomena [32]. As well that a significant expansion of various kinds of training as the GPs’ self-assessment determined in the course events for GPs on how to evaluate liver enzyme levels and of the survey, the fact that practice recommendations practice a structured interaction within the healthcare and expert opinions of medical societies are used chain would be (very) effective. somewhat rarely also speaks in favour of greater sup- port for the diagnostic skills of GPs. Discussion • 3) There is evidence that GP referral behaviour is Principal findings and comparison with prior work not always appropriate when it comes to the need The wide-ranging survey of GPs and specialists in inter - for assessment of (abnormally) elevated liver val- nal medicine and gastroenterology in several large Ger- ues. This relates in particular to the extent to which man states [32, 34] confirms that elevated liver enzymes a controlled wait-and-see period is required after the levels are a common finding in primary care. This is asso - detection of elevated liver values and at what point ciated with the need for systematic and consistent evalu- a referral is indicated. Although, in principle, the ation as well as functioning collaboration with higher majority of respondents prefer a controlled waiting healthcare levels. The survey results confirm the findings period of up to 8 weeks, they make use of faster and of the previous studies [31, 33] in all areas and indicate more frequent referrals to specialists or liver outpa- that there are a number of weaknesses in the manage- tient clinics in everyday practice. Diagnostic uncer- ment of elevated liver values in primary care. tainties as well as system-related limitations (time required for in-depth analysis, laboratory budgeting, • 1) There is a strongly heterogeneous and divergent etc.) may also be partly responsible for this. Accord- approach on the part of GPs in the evaluation of ing to the specialists interviewed, it is more com- potential chronic hepatic parenchymal disease. For mon for GP referrals to be made too early or too late. example, GPs not only pay attention to very differ - Besides, GPs are not always sure what would be suit- ent symptoms, but also use different liver-associated able lab requests for their respective patient [35]. laboratory parameters or value constellations as indi- • 4) There are various challenges in the interdiscipli - cators for the identification of (incipient) liver dis - nary interaction and communication between GPs ease within the framework of laboratory diagnostics and registered internal medicine/gastroenterology ordered by GPs. Three clusters were identified in specialists. Especially problematic for GPs are the the analysis of laboratory values. These are probably lack of accessibility and the fact that there are quite related to the fact that the laboratories used do not often long waiting times for an appointment for dif- provide identical portfolios. At the same time, there ferential diagnosis in the case of suspected liver dis- seems to be a tendency among some GPs to focus ease. Moreover, the referral behaviour of specialists on as few easy-to-grasp parameters as possible in following the diagnosis of liver disease seems to be their everyday practice [19, 29]. Especially the level characterised by frequent referrals back to the GP of γ-GT seems to be an obvious and often exclusive [16, 17, 21]. However, the survey of gastroenterologi- indicator for many GPs, although an elevated γ-GT cal specialists shows that the GP’s failure to provide a level on its own, in the absence of alcohol consump- genuine basic assessment can be a significant prob - tion, does not necessarily indicate liver pathology [21, lem in the interaction with specialists. According 37, 38]. to some of the respondents, the fact that GPs often • 2) GP practices do not always have the necessary have a very divergent approach to the evaluation of diagnostic prerequisites for an adequate assess- elevated liver values is an additional hurdle. ment of elevated liver values. This applies to tech - nical equipment as well as the consistent availabil- The findings and problems that were identified can ity of diagnostic services (e.g. liver check-up). GPs be summarised as follows: the management of elevated themselves articulate a distinct need for training in liver values found in the course of a general blood test diagnostic skills and/or in the expansion of adequate is a diagnostic challenge, which has hitherto been highly advanced education offerings in this area and this dependent on the individual approach of each GP, so that is reflected, inter alia, in the fact that indicators of corresponding actions have been very heterogeneous. (incipient) liver disease are often selectively recorded. The results might correlate to the absence of a validated, Both in terms of medical history and test results, GPs widely accepted diagnostic algorithm for the identifica - seem to focus more on lifestyle-related liver diseases tion of patients with elevated liver enzymes at high risk such as alcoholic liver disease and less on the hepa- for liver cirrhosis in primary care [27–30]. Such a struc- tological problem of fatty liver, viral liver diseases tured diagnosis and clinical pathway applied right across Wangler and Jansky BMC Primary Care (2022) 23:104 Page 10 of 12 the healthcare system could be a valuable tool for evi- and management of elevated liver enzyme levels [15–17, dence-based professionalisation and standardisation of 29, 37]. GP practice [24, 26, 28]. For some time now, various research and support Strengths and limitations networks as well as professional societies have been The surveys that are presented here had already been pointing out the importance of a systematic diagnostic conceptually tested on the basis of several preliminary pathway. In connection with this, they have developed studies and were tailored to GP and specialist care provi- algorithms that can be adequately applied when elevated sion. In the course of the implementation, it was possible liver values are found [39]. Proposals have already been to obtain large, mixed samples, which provide a broad made for how a systematic and practicable diagnostic picture of GPs’ approaches to evaluating liver enzyme procedure could be structured for such a clinical path- levels, as well as the corresponding prerequisites. That way [12, 40, 41]. Holstege categorises procedures into said, none of the presented studies can claim to be repre- three different groups based on the pattern of pathologi - sentative (e.g. regional focus, limited response). Further- cally altered liver values [42]. If transaminases are ele- more, due to anonymisation - which was a prerequisite vated, it should first be clarified whether there is a viral for broad participation - it is not possible trace from genesis, a genetic metabolic disease or drug-related toxic which parts of the respective federal states GPs or spe- damage. Where cholestasis enzyme levels are elevated, cialists participated. Equally, it is possible that doctors sonography should be used to determine whether the with a greater interest in the subject have been more will- cause of cholestasis is intra- or extrahepatic. And last ing to participate. but not least, the generation and widespread establish- Notable limitations, especially relating to the GP sur- ment of a practical, situational algorithm for (further) vey, are that, both in terms of medical history and results, evaluation of elevated liver values would be valuable in greater emphasis is placed on alcoholic liver disease and overcoming interface problems [18, 37]. This would lead less on the problems of fatty liver, viral liver diseases and to better structuring of the differential diagnostic pro - systemic autoimmune phenomena [43]. Thus, the sur - cedure, avoid hasty or late referrals, optimise the infor- vey cannot comprehensively address the full spectrum mation flow and ensure a smoother division of labour of liver disease in primary care. Follow-up studies will be between GPs and specialists [34]. required to address this gap in the research. Four out of five GPs are in favour of the introduction It would be interesting for future studies to identify of a structured diagnostic algorithm and do not see this which measures GPs with hepatological expertise think as interfering with their therapeutic freedom [32]. The have given them greater confidence in the management same proportion of specialists advocate the introduction of elevated liver values and which measures these clini- of a structured diagnostic algorithm [34]. However, an cians think should be taken to improve the effectiveness important prerequisite for the successful introduction of of early detection in primary care. such an instrument will be that it is oriented as closely as possible to the reality of primary care [16, 37]. This Conclusions includes, among other things, the influence of costs and Elevated liver enzyme levels are a common incidental time expenditure, which must be taken into account by finding in primary care. It is therefore all the more impor - an evidence-based diagnostic path with regard to ques- tant to carry out effective assessment and exclusion diag - tions of clarification and referral behaviour [17]. nostics in order to avoid any existing liver disease being International studies suggests that a robust diagnos- overlooked. For this, it is not only relevant which liver tic algorithm applied right across the healthcare sys- values are used, in which constellations or when patients tem could generate key benefits, including cost-benefit are referred for further investigation but the quality of a effects, more consistent adherence to the chain of care, functioning interaction between GPs and specialists is quicker early detection, more effective follow-up, and also crucial. more individually tailored treatment that can prevent The study results indicate that currently early, consist - disease progression and even lead to cirrhosis regres- ent identification and evaluation of (abnormally) elevated sion [26–30]. These could be combined with additional liver values are not always possible in the primary care measures, structures and services that support clear care setting due to various barriers and challenges. In order to pathways, such as targeted training formats, firm anchor - successively increase the effectiveness of primary medi - ing of liver enzyme-associated blood tests within the cal care, it seems advisable to take measures that contrib- framework of the GP check-up, standardised parameters ute to greater professionalisation and standardisation of for routine laboratory tests and the development of an diagnostics and to structure the interaction with gastro- evidence-based, GP-oriented guideline for the detection enterological specialists more effectively. In this context, W angler and Jansky BMC Primary Care (2022) 23:104 Page 11 of 12 Consent for publication the establishment of a sufficiently validated diagnosis and Not applicable. clinical pathway oriented to the reality of outpatient care can be a valuable instrument. It would also make sense Competing interests The authors declare that they have no competing interests. to offer a broader range of topic-related training and further education formats and to include blood tests for Received: 30 October 2021 Accepted: 21 April 2022 liver enzyme levels as a mandatory component of medi- cal check-ups. The development of an evidence-based GP-oriented guideline for the detection and management of elevated liver values seems advisable in order to pro- References 1. Radcke S, Dillon JF, Murray AL. A systematic review of the prevalence of vide GPs in the outpatient sector with better and tailored mildly abnormal liver function tests and associated health outcomes. Eur guidance for the diagnostic assessment of liver enzyme J Gastroenterol Hepatol. 2015;27(1):1–7. PMID: 25380394. https:// doi. org/ levels. With the support of the above-mentioned meas- 10. 1097/ MEG. 00000 00000 000233. 2. Lobstein S, Kaiser T, Liebert U, et al. 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One and a half decades of disease management support for research data, including large and complex data types programs – status quo from the point of view of general practitioners. • gold Open Access which fosters wider collaboration and increased citations Dtsch Med Wochenschr. 2020;145(6):32–40. PMID: 31863449. https:// doi. org/ 10. 1055/a- 1008- 5848. maximum visibility for your research: over 100M website views per year 36. Mayring P. Qualitative content analysis. Theoretical foundation, basic procedures and software solution. Available from: URL: https:// nbn- resol At BMC, research is always in progress. ving. de/ urn: nbn: de: 0168- ssoar- 395173 [cited 22 Mar 2022]. Learn more biomedcentral.com/submissions 37. Lilford RJ, Bentham LM, Armstrong MJ, Neuberger J, Girling AJ. What is the best strategy for investigating abnormal liver function tests http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Primary Care Springer Journals

Evaluation of elevated liver values in primary care - a series of studies on the status quo of care in Germany with special reference to alcoholic liver disease

BMC Primary Care , Volume 23 (1) – May 3, 2022

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Abstract

Background: In primary care, elevated liver values often appear as incidental findings. As well considering the pre - senting symptoms, key factors in effective diagnosis are which liver values to include as indicators and when to refer patients for further diagnostics. It is also important that there is coordinated collaboration between GPs and special- ists. There has hitherto been a lack of reliable findings on the status quo regarding the evaluation of (abnormally) elevated liver values in primary care. Methods: Between 2017 and 2021, four written explorative surveys of GPs and gastroenterological specialists were conducted in various German states, aimed at taking stock of the current status of GP-based diagnostics of (abnor- mally) elevated liver values. In addition, interviews were conducted with 14 GPs and gastroenterological specialists. This review article discusses the overall findings of the series of studies in a condensed manner at a higher level. The article aims to derive starting points for optimising the diagnosis of liver cirrhosis in primary care. Results: There are various challenges and problems associated with the evaluation of elevated liver values. For exam- ple, GPs draw on very different laboratory parameters, which are combined in different clusters. When elevated liver values are found, a majority of GPs prefer a controlled wait-and-see period, but often make use of direct referrals to specialists due to diagnostic uncertainties. GPs report interface problems with gastroenterological specialists, which are associated, among other things, with the preliminary evaluation that has been made and the timing of referral. Both GPs and specialists consider the introduction of an evidence-based diagnostic algorithm to be an important starting point for improving early detection and better coordination between healthcare levels. Conclusions: Eor ff ts should be made to contribute to greater professionalisation and standardisation of primary care diagnostics and to better structure the interaction with gastroenterological specialists. These include a wider range of training formats, the development of a validated diagnostic pathway and the mandating of a liver function test as part of the check-up. The development of a GP-based guideline for managing elevated liver values also seems advisable. Keywords: Liver, Transaminases, GP, Algorithm, Early detection Background Elevated liver enzyme levels are a common incidental *Correspondence: julian.wangler@unimedizin-mainz.de Center for General Medicine and Geriatrics, University Medical Center finding in primary care [1]. At the same time, the prev - of the Johannes Gutenberg University Mainz, Am Pulverturm 13, alence of elevated liver enzyme levels among patients 55131 Mainz, Germany © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wangler and Jansky BMC Primary Care (2022) 23:104 Page 2 of 12 receiving primary care is largely unknown [1, 2]. For the the case of Germany, there is also the fact that GPs have clinical area, studies such as the Gutenberg Heart Study not yet been able to draw on explicitly GP-oriented, evi- showed that elevated liver values were found in around dence-based guidelines. 20% of patients [3]. With regard to the prevalence in To date, there are no systematic studies available in the general population, the SHIP study (cohort study of German-speaking countries that provide a reliable pic- 4310 adults aged 20 to 79 years at baseline in Pomerania) ture of the status quo of primary care in terms of elevated showed an elevated ALT level in a quarter of all included liver values and the associated challenges and problems. patients [4]. According to estimates and projections, As a result, there is a lack of knowledge about GP proce- the prevalence of abnormal liver function tests (LFTs) dures for dealing with (abnormally) elevated liver values, depends on the definition and population but is likely to about the requirement for technical apparatus or possible be between 15 and 20% in the general population [1]. interface problems between GPs and specialists. Various studies have now demonstrated that elevated liver enzyme levels are associated with a higher rate of Overall study and research interest mortality and comorbidity [2, 5–10]. Common causes This review summarises the results of a series of explor - include alcohol abuse, use of medication, non-alcoholic ative studies and compares the results with existing fatty liver disease and viral infections [11–14]. Since ele- research. The study, which consists of four sub-studies, vated liver values can indicate life-threatening diseases, it stands as an independent supplementary study in the is important that the healthcare system has the necessary broader context of the Innovation Fund model project prerequisites to detect and monitor elevated liver values SEAL (Structured Early Assessment for Asymptomatic at an early stage and, if necessary, to initiate further diag- Liver Cirrhosis) for the early detection of liver fibrosis or nostic steps. asymptomatic liver cirrhosis. In most cases, GPs are the first practitioners to dis - The main research questions for the overall study were cover (abnormally) elevated liver values in the course of as follows: a routine check-up [15–17]. In their role as primary care providers, they are responsible for assessing such find - • What are the prerequisites in the primary care set- ings and initiating further diagnostic steps. Given the ting for the detection and evaluation of elevated lev- time and resource constraints in the primary care setting, els of liver enzymes? differential diagnostic workup for the early detection of • How do GPs classify and assess (abnormally) elevated liver disease can be challenging [12, 18–21]. Apart from liver values? possible warning signs (like hämatemesis, caput medusae • How is the interdisciplinary collaboration between etc.) and the question of which values, in which refer- GPs and specialists in internal medicine or gastro- ence ranges and constellations, to include as meaningful enterology structured with regard to the diagnostic indicators [17, 19, 22], the key element of a GP’s approach work up and the treatment of patients with elevated to (abnormally) elevated liver values is to differentiate liver values? between cases where a wait-and-see approach (with rep- • How could the early detection and diagnosis of liver etition of the laboratory tests) is advisable and where an disease in the primary care setting be improved immediate diagnosis is indicated, e.g. by direct referral to (starting points for optimising the diagnosis of liver a specialist or to an outpatient liver clinic [17–19]. cirrhosis in primary care)? In Germany and other European countries, there are currently perceptible shortcomings in the consistent identification and evaluation of elevated liver values in Methods the primary care setting [3, 15, 21–23]. On the one hand, In line with the research questions, the aim was to take a low proportion of early diagnoses is criticised, and on stock of the current status of GP diagnosis of (abnor- the other, an inconsistent differential diagnostic proce - mally) elevated liver values. In particular, the aim should dure that is highly dependent on the individual GP. One be to identify current practices, challenges and problems. reason for this is thought to be the lack of structured, In order to gain the broadest possible knowledge relat- targeted screening programmes for chronic liver dis- ing to the formulated research interest, we sought the ease as part of the standard care regime [19, 20, 24]. In perspective not only of GPs but also registered doctors in addition, there is a lack of an evidence-based and widely gastroenterology practices. established diagnostic and clinical pathway to support Against the background of the findings, which are pre - GPs in the identification, classification and evaluation sented as a synopsis, the article aims to derive starting of elevated liver values, especially in the case of patients points for optimising the diagnosis of liver cirrhosis in at high risk of developing cirrhosis [11, 19, 25–30]. In primary care and making it more effective. The focus is W angler and Jansky BMC Primary Care (2022) 23:104 Page 3 of 12 Table 1 Overview of the quantitative sub-studies carried out including information on socio-demographics Group General practitioners Gastroenterological specialists Study A [31] B [32] C [33] D [34] Study period March–June 2017 October 2019–March 2020 January–March 2018 April–October 2020 N (response rate) 391 (16%) 2701 (26%) 54 (40%) 313 (59%) Gender 60% male, 40% female 61% male, 39% female 83% male, 17% female 84% male, 16% female (Specialist) Background 100% General Practice 75% General Practice, 25% Internal medi- 67% specialists in internal medicine and 65% specialists in internal medicine and cine (working as GP) gastroenterology, 29% specialists in gastroenterology, 28% specialists in inter- internal medicine, 4% other nal medicine, 7% other Mean age 51 (Median: 52) 52 (Median: 53) 54 (Median: 55) 58 (Median: 57) Office setting 47% in medium-sized and large towns or 49% in medium-sized and large towns or 80% in medium-sized and large towns or 67% in medium-sized and large towns or cities, 53% in small towns or rural areas cities, 51% in small towns or rural areas cities, 20% in small towns or rural areas cities, 33% in small towns or rural areas Type of office 49% individual doctor’s offices, 48% joint 51% individual doctor’s offices, 46% joint 33% individual doctor’s offices, 63% joint 40% individual doctor’s offices, 57% joint offices, 3% other offices, 3% other offices, 4% other offices, 3% other Patients per quarter 23% < 1.000, 37% 1.000–1.500, 19% 19% < 1.000, 38% 1.000–1.500, 19% 25% < 1000, 23% 1000–1500, 25% 30% < 1000, 19% 1000–1500, 22% 1.501–2.000, 21% > 2.000 1.501–2.000, 24% > 2.000 1500–2000, 27% > 2000 1500–2000, 29% > 2000 Wangler and Jansky BMC Primary Care (2022) 23:104 Page 4 of 12 therefore on weaknesses identified in the GP setting. All • Specialist survey: Several experts from the Cirrhosis sub-studies were deliberately designed to be exploratory. Centre of University Hospital Mainz were consulted during the development process, in order to check the completeness and appropriateness of the ques- Sub‑studies tionnaire [33] from a specialist’s point of view and Based on a preliminary study in which 391 GPs in Rhine- to align the questionnaire closely with the reality of land-Palatinate were interviewed about their approach to care. elevated liver values [31], the questionnaire was updated • Other preliminary studies by the authors on struc- for the purpose of more precise and in-depth investiga- tured, evidence-based primary care ([35] inter alia) tions (among other things, supplementing item batter- • General literature searches in the design of all sub- ies on symptoms and diagnostics, prioritizing indicators studies (papers focusing on the assessment of ele- for early detection of liver disease, questions on the fre- vated liver enzymes in primary care were used here) quency of liver disease in respective patients, use of ([36] inter alia) guidelines and other recommendations for action), and • Carrying out pre-tests in the run-up to data collec- the study was repeated on a significantly larger scale, in tion order to determine to what extent the first set of results are confirmed. This extended survey was conducted The aim was to keep the instruments used to interview between October 2019 and March 2020 and gathered the GPs and gastroenterologists mutually compatible. To this views and experiences of a total of 2701 GPs in Hesse and end, certain questions in both questionnaires (e.g. atti- Baden-Württemberg on their approach to elevated liver tude to the wait-and-see approach, starting points for values [32]. optimising early detection) were worded in a very similar An analogous procedure was followed for the survey of way. registered gastroenterology specialists. First, a prelimi- The survey instruments for the two more comprehen - nary survey was conducted in spring 2018, in which 54 sive surveys are included in the Additional file 1. gastroenterologists in Rhineland-Palatinate and Saarland were interviewed about their approach to elevated liver Data analysis values and their collaboration with GPs [33]. The ques - Data from the quantitative studies were evaluated using tionnaire, originally developed and conceptually tested SPSS 23.0. In order to highlight different approaches by the authors in 2017, was updated and resulted in an adopted by GPs, in addition to descriptive analysis, the extended study. Between April and October 2020, 313 method of factor analysis (Varimax rotation) was used, in doctors working in specialist gastroenterology practices which variables are combined into factors on the basis of in Baden-Württemberg, Hesse and Thuringia were inter - systematic relationships (correlations). After data collec- viewed in an online survey [34]. tion, the team evaluated the resulting transcripts using In addition, a smaller qualitative study was carried out qualitative content analysis according to Mayring [36]. after the aforementioned quantitative surveys. In the Our focus lay on forming logical categories from the vari- summer of 2021, seven GPs and seven established gas- ous opinions and experiences. Selected citations are pre- troenterological specialists in Rhineland-Palatinate (both sented to support the quantitative findings. randomly selected) were interviewed on the subject of clarification and interprofessional cooperation with Results regard to (unclear) elevated liver values. Figure 1 shows the starting points condensed from analy- Incentives were not used. Table  1 gives an overview of sis of the sub-studies with a view to more effective liver the studies described. diagnostics by GPs. In the following, each of the dimen- sions presented will be discussed with reference to the respective central findings and correlated with existing Development of survey instruments research. The surveys with the much larger samples serve Since the studies built on each other, there was a con- as the primary reference [32, 34]. tinuous learning process which informed the design of the subsequent sub-study. In addition, the survey instru- ments developed were supported by other elements: Liver values and liver value constellations The GP survey [32] has shown that, in everyday prac - • Preparations and exchanges within the SEAL project tice, there is a strong focus on a comparatively small • GP survey: The questionnaire [31], originally devel - number of selected liver parameters in the evaluation of oped in 2017, was enriched by a group discussion (abnormally) elevated liver values. For example, γ-GT with 10 GPs during the development process. is the main laboratory value considered (95%). About W angler and Jansky BMC Primary Care (2022) 23:104 Page 5 of 12 Fig. 1 Derived starting points for effective liver diagnostics by GPs (own figure) two-thirds (65%) include aspartate aminotransferase cific profession. Especially with moderate increases, (ASAT, AST, GOT) in their analysis, followed by ala- it is not always easy to draw the right conclusions. I nine aminotransferase (ALAT, ALT, GPT) (63%), alka- admit it’s hard for me.” (Interviewed GP 3m) line phosphatase (AP) (62%) and platelet count (57%). The survey of registered gastroenterologists [34] was able In a questionnaire, the respondents were asked to name to confirm that, from the specialist’s perspective, GPs rely which three indicators they considered to be most on highly divergent liver values to guide their everyday important and meaningful for the early detection of practice. For example, 57% of specialists experience it as liver cirrhosis. Analogously, γ-GT (92%), aspartate ami- a considerable inconvenience to have to constantly read- notransferase (83%) and alanine aminotransferase (79%) just to the diagnostic requirements due to the difference are mentioned here, while other values lag a considerable and lack of standardisation in the collection of liver val- distance behind. ues on the part of GPs. The spectrum for conclusions and At the same time, a factor analysis revealed a strongly further care decisions is correspondingly diverse. heterogeneous and divergent approach on the part of GPs in the diagnosis of potential chronic hepatic parenchymal “If you ask me: The behavior of general practitioners disease (see Table 2). u Th s, GPs not only pay attention to when considering and interpreting liver values is too very different symptoms, but also use different liver-asso - uncontrolled and not supported enough by evidence- ciated laboratory parameters or value constellations as based guidelines. As a result, we often have to adapt indicators for the identification of (incipient) liver disease our work to the preparatory work done by GPs from within the framework of laboratory diagnostics ordered scratch.” (Interviewed gastroenterologist 1m) by GPs. While one cluster focuses on functional param- eters such as bilirubin, PT according to Quick (INR), cholinesterase and albumin, another primarily looks at indicators of toxic cell damage or liver disease that has Diagnostic requirements already occurred. Among other parameters, alanine ami- The GP survey [32] showed that 29% of the GPs included notransferase receives particular attention. In addition, a in the study offer a special liver check-up in their own third cluster that focuses on γ-GT as a parameter for pos- practice in addition to the SHI screening. On the other sible liver disease stands out. hand, 66% do not offer such a service to supplement the SHI health check-up. In terms of the prerequisites “We general practitioners are all-rounders in our for diagnostic equipment, standard upper abdominal day-to-day practice. The classification of liver values sonography for the identification and further evaluation and the consideration of limit values is a very spe- Wangler and Jansky BMC Primary Care (2022) 23:104 Page 6 of 12 Table 2 Laboratory values observed. Question: Which laboratory findings potentially linked to liver disease do you usually examine in routine lab work for general screening check-ups? (N = 2.701, GPs) Rotated component matrix Overall agreement Comp. 1 (Expl. variation: Comp. 2 (Expl. variation: Comp. 3 (Expl. 26,1%) 18,2%) variation: 10,6%) Alanine aminotransferase (ALAT, ALT, GPT ) 63% −.055 .774 −.119 γ-glutamyltransferase (GGT ) 95% −.040 −.018 .884 Aspartate aminotransferase (ASAT, AST, GOT ) 65% .141 .576 .386 AP (alkaline phosphatase) 62% .542 .252 .305 Ferritin 26% .734 .035 −.102 Bilirubin 46% .686 .219 .213 PT according to Quick (INR) 27% .663 .207 −.165 Cholinesterase 19% .675 .139 −.023 Albumin 23% .740 −.027 .092 Platelet count 57% .256 .715 −.112 MCV 55% .192 .614 .165 Extraction method: Principal component analysis Rotation method: Varimax, Kaiser normalisation Rotation in 4 iterations for convergence Total explained variation: 54.9% Sampling adequacy, Kaiser-Meyer-Olkin: .787 Significance, Bartlett: p < 0.001 of liver disease is usually available in most GP practices expert opinions of medical societies or diagnostic path- (89%), and more rarely extended laboratory diagnostics ways offered by healthcare providers (e.g. German Liver (64%). 5% respectively offer an elastography or fibroscan Foundation). The interest articulated by a majority of investigation. respondents in an expansion of adequate further training As was found in a detailed interrogation via item set, offerings is also an indication of the need for the training the surveyed GPs focus on certain indicators of incipi- of GPs in this area. ent liver disease that prompt more in-depth diagnostics, “In my opinion, there should be more evidence-based while paying less attention to other indicators. From tools tailored to general practitioners – on this topic their previous experience, GPs pay particular atten- in particular.” (Interviewed GP 5w) tion to excessive alcohol consumption (94%) and also to signs such as upper abdominal complaints (76%), From the point of view of the specialists interviewed [34], symptoms of fatigue (75%), ascites (71%), itching (71%) it would also be useful if there were more training for- and skin changes (65%). In the experience of those sur- mats that gave GPs more confidence in evaluating liver veyed, symptoms such as loss of appetite, weight loss, values, as this would have a direct impact on the quality Dupuytren’s contracture, or gynaecomastia are less often and effectiveness of interdisciplinary collaboration. a sign of potential liver disease. “Fromt my point of view, primary care could do bet- Associated with this, there is evidence that GPs experi- ter at initial testing and diagnosis of (incipient) liver ence a lack of diagnostic certainty and a lack of guidance disease.” (Interviewed gastroenterologist 4m) options when clarifying (abnormally) elevated liver val- ues. For example, 38% consider themselves to be very or quite competent in the evaluation of elevated liver values, Referral behaviour while around 50% consider themselves to be less or not at In the light of the study results, the referral behaviour of all competent in this area. Only one third of the surveyed GPs reveals identifiable inconsistencies. On the one hand, GPs have consulted practice or action recommendations, almost two-thirds of the GPs surveyed [32] consider it sensible to initially practice a wait-and-see approach of several weeks (median: 5.0) after detecting moderately During the extended laboratory examination, liver and kidney values plus elevated liver values, and therefore only to consider refer- electrolytes are determined in addition to the blood count. This extended lab - ral to a higher specialist level after a repeat investigation oratory check is usually billed privately as a so-called private service. W angler and Jansky BMC Primary Care (2022) 23:104 Page 7 of 12 Table 3 Challenges experienced in the interdisciplinary relationship, GPs. Question: A variety of challenges may arise when general practitioners and district specialists for outpatients collaborate on diagnosing cirrhosis. How often have you experienced the following challenges? (N = 2.701, GPs) Statement Frequently Occasionally Rarely Never No response Resident gastroenterologists are fully booked long-term due to the many gastroduodenoscopy 69% 21% 6% 3% 1% and colonoscopy tests they are required to perform. District specialists do not have the time to discuss mostly complex patient problems with you. 41% 39% 10% 8% 2% There are too few nearby specialist internal medicine practices to diagnose liver counts the 37% 36% 11% 15% 1% way I would like. Specialists do not brief patients enough, who then go back to general practitioners out of 30% 42% 13% 13% 2% uncertainty. Gastroenterological district specialists are difficult for patients to reach. 35% 34% 16% 14% 1% Specialists do not issue direct referrals to a liver centre on suspicion of cirrhosis, so patients 23% 40% 20% 16% 1% come back to their general practitioners for the time being (going around in circles with time wasted). District specialists are booked out for too long, so I refer my patients straight to a specialist 21% 35% 19% 23% 2% clinic. I have to wait for a long time for district specialists to pass on their findings. 19% 33% 20% 27% 1% District specialists do not inform general practitioners enough about the tests they have 17% 35% 24% 23% 1% conducted or the results and/or diagnoses they have made. at a later point in time. However, the respondents give “In my experience, many general practitioners are divergent information about their actual referral behav- even too quick to refer patients with elevated liver iour, which they justify, in an open question, primarily on values of unknown aetiology. […] For example, many the basis of diagnostic uncertainties. Thus, around 40% simply look at γ-GT and refer patients to special- state that they usually refer patients directly to a special- ists for small increases. […] It would be good if they ist or even to a specialist outpatient clinic after noticing could do part of the diagnostic work themselves and abnormally elevated liver values. Only 32%, on the other thus better pre-select our patients.” (Interviewed gas- hand, have consistently waited. troenterologist 4m) “Of course, the manual says ‘controlled waiting’. But the reality is sometimes different. Elevated liver Interdisciplinary collaboration enzymes are complex and to be honest I sometimes Coordinated collaboration between GPs and special- feel overwhelmed on the subject. That’s why I tend to ists is essential for an effective, early diagnosis to explain transfer as quickly as possible.” (Interviewed GP 2w) elevated liver values and initiate appropriate treatment. Although both GPs and specialists experience collabo- 79% of the GPs reported that they had referred their ration with the other side as positive in the majority of patients to a gastroenterology practice; 44% had referred cases, considerable interface problems and hurdles in them directly to a liver outpatient clinic and 27% to a gas- interdisciplinary interaction are articulated. troenterology department or clinic. Apart from a lack of specialised internal medicine The results attest to the central pilot role of the GP practices in the vicinity (73%), frequent difficulties for within the healthcare system. 98% of the internal medi- GPs [32] are a lack of accessibility to discuss the usually cine specialists surveyed stated that patients with (abnor- complex patient problems (69%) (see Table  3). 90% state mally) elevated liver values are usually referred by their that there are often longer waiting times for an appoint- GP. 23% mention referral by another specialist and 20% ment for differential diagnostic assessment for suspected that patients visit their practice on the advice of the clinic liver disease. In rural areas, these challenges are exacer- (40% self-referrals by the patient). bated due to the significantly lower density of specialists. From the perspective of gastroenterological special- Another considerable problem experienced by GPs is that ists [34], it can be seen that they, for their part, criticise patients are not sufficiently informed about their condi - the referral behaviour of GPs, which, in their opinion, is tion by their specialist colleagues and so return to the GP often either significantly premature (64%) or too tardy due to uncertainty (72%). Likewise, the referral behav- (57%). In addition, patients with slightly or moderately iour of specialists following the diagnosis of liver disease elevated liver values often turned out to be not affected seems to be characterised by frequent referrals back to by (incipient) liver disease (69%). the GP (63%). In the absence of prompt presentation to Wangler and Jansky BMC Primary Care (2022) 23:104 Page 8 of 12 Table 4 Challenges experienced in the interdisciplinary relationship, gastroenterological specialists. Question: A variety of challenges may arise when gastroenterologists and general practitioners work together to diagnose and treat cirrhosis. How often have you experienced the following challenges? (N = 313, gastroenterological specialists) Statement Frequently Occasionally Rarely Never No response I have detected (incipient) liver disease that the general practitioner did not notice or remained 25% 59% 11% 4% 1% unaware of in a patient. Primary care could do better at initial testing and diagnosis of (incipient) liver disease. 29% 42% 17% 10% 2% General practitioners are not always sufficiently aware of elevated liver values with unknown 27% 43% 13% 13% 4% aetiology to notice the onset of liver disease at an early stage. Patients that general practitioners have referred to gastroenterologists for an elevated liver 18% 51% 15% 12% 4% count of unknown aetiology often turn out to be non-specific. General practitioners often fail to follow up on elevated liver values. 23% 42% 17% 15% 3% General practitioners are too quick to refer patients with elevated liver values of unknown aeti- 34% 30% 19% 14% 3% ology to gastroenterologists, leaving gastroenterologists booked out for long periods of time. General practitioners do not adequately inform gastroenterologists about the tests they 20% 43% 20% 16% 1% perform, the results and/or the diagnoses they have made. General practitioners are inconsistent in their approach to analysing liver values; this may 35% 22% 22% 20% 1% include varying liver values recorded depending on the general practitioner, so specialists need to keep adjusting to the preliminary work performed by general practitioners. General practitioners wait too long before referring patients with an elevated liver count of 30% 27% 25% 16% 2% unknown aetiology to a gastroenterologist. a specialist outpatient clinic, there is at least a risk of the occasionally (59%) encounter patients with liver disease patient entering an unnecessary loop as a result of being that has not been detected by the GP. referred back. “I don’t think the general practitioners or the special- “Working together with specialist colleagues is full ists are at fault. Communication and patient treat- of difficulties and stumbling blocks. Maybe it has ment simply need to be better interlinked between something to do with the fact that in Germany the the different levels of care. It would need a mecha - sectors are too separated from each other, but I can’t nism that creates a certain uniformity. I could well say that I’m usually well informed about what diag- imagine an established and well-tested algorithm nostic steps the gastroenterological colleague takes. here.” (Interviewed gastroenterologist 1m) Or what I have to do when the patient comes back to me.” (Interviewed GP 4m) Approaches for optimising primary care The views expressed by gastroenterological special - Respondents were given a list of various potential meas- ists [34] show that they are also critical of the interaction ures to increase the proportion of patients diagnosed with primary care (see Table  4). Apart from the timing early. There is a high level of agreement between the of patient presentation, the GP’s decision not to make a GPs and specialists included in the study. In view of genuine basic assessment and to refer based on suspi- the perceived inconsistency in the approach to evaluat- cion or doubt is experienced as a significant problem in ing elevated liver values in the outpatient sector, as well the interaction with GPs (71%). From the point of view as existing interface problems, 80% of GPs and 85% of of registered gastroenterologists, further impediments to specialists support the introduction of a structured, evi- the interaction with GPs arise from the fact that the lat- dence-based and broadly applicable diagnosis and treat- ter do not always follow up on elevated liver values (65%). ment algorithm as a (highly) effective measure. 65% of Some of the respondents see the fact that GPs often fol- GPs and 55% of specialists see an expansion of the labo- low a very different procedure for evaluating elevated ratory workup included in the health check-up from the liver values (e.g. collection of different liver values, 57%) age of 35 as an effective measure. 61% of GPs and 60% as an additional hurdle and this corresponds with the of specialists consider the development of an explicit, impression articulated by specialists that the investiga- evidence-based S3 guideline for the systematic evaluation tions, results and diagnoses are not always transparent of elevated liver values to be particularly effective. 50% of (63%). As a result of such interdisciplinary problems, GPs and 52% of specialists are in favour of introducing a 84% of the specialists report that they frequently (25%) or genuine liver check as part of the SHI regime. W angler and Jansky BMC Primary Care (2022) 23:104 Page 9 of 12 In addition, 70% of GPs and 76% of specialists believe and systemic autoimmune phenomena [32]. As well that a significant expansion of various kinds of training as the GPs’ self-assessment determined in the course events for GPs on how to evaluate liver enzyme levels and of the survey, the fact that practice recommendations practice a structured interaction within the healthcare and expert opinions of medical societies are used chain would be (very) effective. somewhat rarely also speaks in favour of greater sup- port for the diagnostic skills of GPs. Discussion • 3) There is evidence that GP referral behaviour is Principal findings and comparison with prior work not always appropriate when it comes to the need The wide-ranging survey of GPs and specialists in inter - for assessment of (abnormally) elevated liver val- nal medicine and gastroenterology in several large Ger- ues. This relates in particular to the extent to which man states [32, 34] confirms that elevated liver enzymes a controlled wait-and-see period is required after the levels are a common finding in primary care. This is asso - detection of elevated liver values and at what point ciated with the need for systematic and consistent evalu- a referral is indicated. Although, in principle, the ation as well as functioning collaboration with higher majority of respondents prefer a controlled waiting healthcare levels. The survey results confirm the findings period of up to 8 weeks, they make use of faster and of the previous studies [31, 33] in all areas and indicate more frequent referrals to specialists or liver outpa- that there are a number of weaknesses in the manage- tient clinics in everyday practice. Diagnostic uncer- ment of elevated liver values in primary care. tainties as well as system-related limitations (time required for in-depth analysis, laboratory budgeting, • 1) There is a strongly heterogeneous and divergent etc.) may also be partly responsible for this. Accord- approach on the part of GPs in the evaluation of ing to the specialists interviewed, it is more com- potential chronic hepatic parenchymal disease. For mon for GP referrals to be made too early or too late. example, GPs not only pay attention to very differ - Besides, GPs are not always sure what would be suit- ent symptoms, but also use different liver-associated able lab requests for their respective patient [35]. laboratory parameters or value constellations as indi- • 4) There are various challenges in the interdiscipli - cators for the identification of (incipient) liver dis - nary interaction and communication between GPs ease within the framework of laboratory diagnostics and registered internal medicine/gastroenterology ordered by GPs. Three clusters were identified in specialists. Especially problematic for GPs are the the analysis of laboratory values. These are probably lack of accessibility and the fact that there are quite related to the fact that the laboratories used do not often long waiting times for an appointment for dif- provide identical portfolios. At the same time, there ferential diagnosis in the case of suspected liver dis- seems to be a tendency among some GPs to focus ease. Moreover, the referral behaviour of specialists on as few easy-to-grasp parameters as possible in following the diagnosis of liver disease seems to be their everyday practice [19, 29]. Especially the level characterised by frequent referrals back to the GP of γ-GT seems to be an obvious and often exclusive [16, 17, 21]. However, the survey of gastroenterologi- indicator for many GPs, although an elevated γ-GT cal specialists shows that the GP’s failure to provide a level on its own, in the absence of alcohol consump- genuine basic assessment can be a significant prob - tion, does not necessarily indicate liver pathology [21, lem in the interaction with specialists. According 37, 38]. to some of the respondents, the fact that GPs often • 2) GP practices do not always have the necessary have a very divergent approach to the evaluation of diagnostic prerequisites for an adequate assess- elevated liver values is an additional hurdle. ment of elevated liver values. This applies to tech - nical equipment as well as the consistent availabil- The findings and problems that were identified can ity of diagnostic services (e.g. liver check-up). GPs be summarised as follows: the management of elevated themselves articulate a distinct need for training in liver values found in the course of a general blood test diagnostic skills and/or in the expansion of adequate is a diagnostic challenge, which has hitherto been highly advanced education offerings in this area and this dependent on the individual approach of each GP, so that is reflected, inter alia, in the fact that indicators of corresponding actions have been very heterogeneous. (incipient) liver disease are often selectively recorded. The results might correlate to the absence of a validated, Both in terms of medical history and test results, GPs widely accepted diagnostic algorithm for the identifica - seem to focus more on lifestyle-related liver diseases tion of patients with elevated liver enzymes at high risk such as alcoholic liver disease and less on the hepa- for liver cirrhosis in primary care [27–30]. Such a struc- tological problem of fatty liver, viral liver diseases tured diagnosis and clinical pathway applied right across Wangler and Jansky BMC Primary Care (2022) 23:104 Page 10 of 12 the healthcare system could be a valuable tool for evi- and management of elevated liver enzyme levels [15–17, dence-based professionalisation and standardisation of 29, 37]. GP practice [24, 26, 28]. For some time now, various research and support Strengths and limitations networks as well as professional societies have been The surveys that are presented here had already been pointing out the importance of a systematic diagnostic conceptually tested on the basis of several preliminary pathway. In connection with this, they have developed studies and were tailored to GP and specialist care provi- algorithms that can be adequately applied when elevated sion. In the course of the implementation, it was possible liver values are found [39]. Proposals have already been to obtain large, mixed samples, which provide a broad made for how a systematic and practicable diagnostic picture of GPs’ approaches to evaluating liver enzyme procedure could be structured for such a clinical path- levels, as well as the corresponding prerequisites. That way [12, 40, 41]. Holstege categorises procedures into said, none of the presented studies can claim to be repre- three different groups based on the pattern of pathologi - sentative (e.g. regional focus, limited response). Further- cally altered liver values [42]. If transaminases are ele- more, due to anonymisation - which was a prerequisite vated, it should first be clarified whether there is a viral for broad participation - it is not possible trace from genesis, a genetic metabolic disease or drug-related toxic which parts of the respective federal states GPs or spe- damage. Where cholestasis enzyme levels are elevated, cialists participated. Equally, it is possible that doctors sonography should be used to determine whether the with a greater interest in the subject have been more will- cause of cholestasis is intra- or extrahepatic. And last ing to participate. but not least, the generation and widespread establish- Notable limitations, especially relating to the GP sur- ment of a practical, situational algorithm for (further) vey, are that, both in terms of medical history and results, evaluation of elevated liver values would be valuable in greater emphasis is placed on alcoholic liver disease and overcoming interface problems [18, 37]. This would lead less on the problems of fatty liver, viral liver diseases and to better structuring of the differential diagnostic pro - systemic autoimmune phenomena [43]. Thus, the sur - cedure, avoid hasty or late referrals, optimise the infor- vey cannot comprehensively address the full spectrum mation flow and ensure a smoother division of labour of liver disease in primary care. Follow-up studies will be between GPs and specialists [34]. required to address this gap in the research. Four out of five GPs are in favour of the introduction It would be interesting for future studies to identify of a structured diagnostic algorithm and do not see this which measures GPs with hepatological expertise think as interfering with their therapeutic freedom [32]. The have given them greater confidence in the management same proportion of specialists advocate the introduction of elevated liver values and which measures these clini- of a structured diagnostic algorithm [34]. However, an cians think should be taken to improve the effectiveness important prerequisite for the successful introduction of of early detection in primary care. such an instrument will be that it is oriented as closely as possible to the reality of primary care [16, 37]. This Conclusions includes, among other things, the influence of costs and Elevated liver enzyme levels are a common incidental time expenditure, which must be taken into account by finding in primary care. It is therefore all the more impor - an evidence-based diagnostic path with regard to ques- tant to carry out effective assessment and exclusion diag - tions of clarification and referral behaviour [17]. nostics in order to avoid any existing liver disease being International studies suggests that a robust diagnos- overlooked. For this, it is not only relevant which liver tic algorithm applied right across the healthcare sys- values are used, in which constellations or when patients tem could generate key benefits, including cost-benefit are referred for further investigation but the quality of a effects, more consistent adherence to the chain of care, functioning interaction between GPs and specialists is quicker early detection, more effective follow-up, and also crucial. more individually tailored treatment that can prevent The study results indicate that currently early, consist - disease progression and even lead to cirrhosis regres- ent identification and evaluation of (abnormally) elevated sion [26–30]. These could be combined with additional liver values are not always possible in the primary care measures, structures and services that support clear care setting due to various barriers and challenges. In order to pathways, such as targeted training formats, firm anchor - successively increase the effectiveness of primary medi - ing of liver enzyme-associated blood tests within the cal care, it seems advisable to take measures that contrib- framework of the GP check-up, standardised parameters ute to greater professionalisation and standardisation of for routine laboratory tests and the development of an diagnostics and to structure the interaction with gastro- evidence-based, GP-oriented guideline for the detection enterological specialists more effectively. In this context, W angler and Jansky BMC Primary Care (2022) 23:104 Page 11 of 12 Consent for publication the establishment of a sufficiently validated diagnosis and Not applicable. clinical pathway oriented to the reality of outpatient care can be a valuable instrument. It would also make sense Competing interests The authors declare that they have no competing interests. to offer a broader range of topic-related training and further education formats and to include blood tests for Received: 30 October 2021 Accepted: 21 April 2022 liver enzyme levels as a mandatory component of medi- cal check-ups. The development of an evidence-based GP-oriented guideline for the detection and management of elevated liver values seems advisable in order to pro- References 1. Radcke S, Dillon JF, Murray AL. A systematic review of the prevalence of vide GPs in the outpatient sector with better and tailored mildly abnormal liver function tests and associated health outcomes. Eur guidance for the diagnostic assessment of liver enzyme J Gastroenterol Hepatol. 2015;27(1):1–7. PMID: 25380394. https:// doi. org/ levels. With the support of the above-mentioned meas- 10. 1097/ MEG. 00000 00000 000233. 2. Lobstein S, Kaiser T, Liebert U, et al. 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Journal

BMC Primary CareSpringer Journals

Published: May 3, 2022

Keywords: Liver; Transaminases; GP; Algorithm; Early detection

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