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Steatotic Liver Disease in Type 2 Diabetes: Epidemiology, Biomarkers and Management in Primary Care
Linköping University, Department of Health, Medicine and Caring Sciences, Division of Prevention, Rehabilitation and Community Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Primary Care Center, Primary Health Care Center Ekholmen.ORCID iD: 0000-0001-8524-1900
2026 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Steatotic liver disease (SLD), which includes metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol-associated liver disease (MetALD), and alcohol-associated liver disease (ALD), affects up to 40% of the global population. Advanced fibrosis in SLD is more common in patients with type 2 diabetes (T2D) and is associated with a poorer prognosis. SLD is associated with other ectopic fat depositions and cardiac remodelling. Although MASLD is the most common chronic liver disease worldwide, evidence from Swedish primary care remains limited. 

The relationship between MASLD and microvascular complications of T2D remains uncertain. Activin A has been linked to fibrogenesis, but its value as a biomarker for advanced fibrosis is unclear. Although interest in SLD screening among patients with T2D is increasing, its optimal design and cost-effectiveness remain unresolved. 

This thesis examines the prevalence, clinical correlates, and management of MASLD, with or without advanced fibrosis, among patients with T2D in primary care. It also evaluates activin A as a biomarker for advanced fibrosis and assesses the cost-effectiveness of a screening and management algorithm for SLD. 

Paper I was a retrospective primary care cohort study of patients with T2D, using medical record review and non-invasive algorithms to assess steatosis and advanced fibrosis risk. Papers II and IV analysed baseline data from a prospective primary care cohort in which patients with T2D underwent magnetic resonance imaging/spectroscopy and transient elastography to assess MASLD, with or without advanced fibrosis; Paper II also included medical record review of microvascular complications. Paper III used follow-up data from a cohort of participants with biopsy-proven MASLD to assess activin A levels and PNPLA3 I148M genotype. Paper V used a lifetime microsimulation model to evaluate the costs and health outcomes of a SLD screening and management algorithm in primary care for patients with T2D. 

In Paper I, 350 participants were included. Most had increased steatosis risk, 29–65% had increased risk of advanced fibrosis, and few had known steatosis. In Paper II, which included 308 participants with T2D, MASLD was not associated with a higher overall prevalence of microvascular complications. In Paper III, 41 participants were included; higher activin A levels were associated with advanced fibrosis and the PNPLA3 I148M G/G genotype. In Paper IV, 59% of 308 participants had MASLD and 7% had suspected advanced fibrosis. MASLD was associated with obesity, ectopic fat deposition and distinct left ventricular characteristics. In Paper V, the ICER for screening and management compared with standard of care was EUR 128,072/QALY overall, ranging from EUR 5,168/QALY for ALD to EUR 157,489/QALY for MASLD. 

In conclusion, MASLD is common among patients with T2D in Swedish primary care, although advanced disease appears uncommon and awareness of MASLD has historically been low. MASLD was not associated with an overall increase in microvascular complications, whereas obesity was associated with both MASLD and advanced fibrosis. Activin A showed potential as a biomarker for advanced fibrosis. The SLD screening and management algorithm were unlikely to be cost-effective overall, despite substantial variation between SLD subtypes. 

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2026. , p. 102
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 2047
Keywords [en]
SLD, MASLD, MetALD, ALD, T2D, Primary care, Screening
National Category
General Medicine
Identifiers
URN: urn:nbn:se:liu:diva-227238DOI: 10.3384/9789181185553ISBN: 9789181185546 (print)ISBN: 9789181185553 (electronic)OAI: oai:DiVA.org:liu-227238DiVA, id: diva2:2097707
Public defence
2026-10-02, Berzeliussalen, Campus US, Linköping, 09:00
Opponent
Supervisors
Available from: 2026-09-02 Created: 2026-09-02 Last updated: 2026-09-02Bibliographically approved
List of papers
1. Low awareness of non-alcoholic fatty liver disease in patients with type 2 diabetes in Swedish Primary Health Care
Open this publication in new window or tab >>Low awareness of non-alcoholic fatty liver disease in patients with type 2 diabetes in Swedish Primary Health Care
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2022 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 57, no 1, p. 60-69Article in journal (Refereed) Published
Abstract [en]

Objectives Non-alcoholic fatty liver disease (NAFLD) is more common in patients with type 2 diabetes mellitus (T2DM) compared to individuals without. Recent guidelines recommend screening for NAFLD in patients with T2DM. Our aim was to investigate the prevalence of NAFLD in patients with T2DM in a Swedish primary health care setting, how they are cared for and assess the risk of biochemical signs of advanced fibrosis. Material and methods In this cohort study, patients with T2DM from five primary health care centers were included. Medical records were retrospectively reviewed and living habits, medical history, results of diagnostic imaging and anthropometric and biochemical features were noted in a standardized form. The risk of steatosis and advanced fibrosis was assessed using commonly used algorithms (FLI, HSI, NAFLD-LFS, NAFLD ridge score, FIB-4 and NFS). Results In total 350 patients were included. Diagnostic imaging had been performed in 132 patients and of these, 34 (26%) had steatosis, which was not noted in the medical records in 16 (47%) patients. One patient with steatosis had been referred to a hepatologist. Of assessable patients, 71-97% had a high to intermediate risk of steatosis and 29-65% had an intermediate to high risk of advanced fibrosis according to the algorithms used. Conclusion This study indicates a high prevalence of NAFLD among T2DM patients in Swedish primary care. Patients with known NAFLD were followed up to a very low extent. Using fibrosis algorithms in primary health care would result in many patients needing further assessment in secondary care.

Place, publisher, year, edition, pages
Taylor & Francis Ltd, 2022
Keywords
NAFLD; diabetes mellitus type 2; primary health care; epidemiology; population; risk
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-180676 (URN)10.1080/00365521.2021.1984572 (DOI)000705424200001 ()34618619 (PubMedID)
Note

Funding Agencies|ALF Grants (Region Ostergotland, Medical Research Council of Southeast Sweden)

Available from: 2021-10-29 Created: 2021-10-29 Last updated: 2026-09-02
2. Microvascular complications of type 2 diabetes with or without MASLD: the EPSOMIP study, a primary care cohort study
Open this publication in new window or tab >>Microvascular complications of type 2 diabetes with or without MASLD: the EPSOMIP study, a primary care cohort study
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2025 (English)In: BMC Primary Care, E-ISSN 2731-4553, Vol. 26, no 1, article id 354Article in journal (Refereed) Published
Abstract [en]

BackgroundPrevious studies have shown inconsistent results for the microvascular complication risk in patients with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). In addition, many of these studies have been done in specialist care setting. We therefore aimed to explore the association between MASLD and chronic kidney disease, retinopathy, neuropathy, and diabetic foot ulcers in a primary care setting.MethodsParticipants with type 2 diabetes were recruited in primary care. Hepatic triglyceride content was assessed using magnetic resonance imaging with liver proton density fat fraction (MASLD >= 5%) or vibration-controlled transient elastography with controlled attenuation parameter (MASLD >= 248 dB/m), and hepatic fibrosis was assessed using vibration-controlled transient elastography (advanced fibrosis >= 10 kPa). Data on chronic kidney disease, retinopathy, neuropathy, and diabetic foot ulcers were collected from medical records.ResultsA total of 308 participants were included. The median duration of diabetes was 7 years (IQR 3-13). MASLD was present in 181 participants (58.8%). Of these, 161 (52.3%) showed no evidence of advanced fibrosis, while 20 (6.5%) were assessed as having advanced fibrosis. Neuropathy was present in 64 participants (20.8%), retinopathy in 60 (19.5%), chronic kidney disease in 59 (19.2%), and diabetic foot ulcers in 13 (4.2%). No significant differences in these complications were observed between participants with and without MASLD. However, participants with MASLD and a higher histopathological fibrosis stage had an increased risk of microvascular complications in our study.ConclusionsParticipants with type 2 diabetes and concomitant MASLD recruited in primary care, did not have an increased risk of chronic kidney disease, neuropathy, or retinopathy, supporting previous findings of risk variation across different ethnicities and geographic locations.Trial registrationClinical trial number NCT03864510 (registration date 2019-02-12).

Place, publisher, year, edition, pages
BMC, 2025
Keywords
MASLD; Type 2 Diabetes; Diabetes Complications; Primary Care; Magnetic resonance imaging; Vibration Controlled Transient Elastography; Liver Biopsy
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:liu:diva-219787 (URN)10.1186/s12875-025-03096-2 (DOI)001611789900005 ()41219835 (PubMedID)2-s2.0-105021461123 (Scopus ID)
Note

Funding Agencies|Linkping University

Available from: 2025-12-08 Created: 2025-12-08 Last updated: 2026-09-02
3. Activin A levels in metabolic dysfunction-associated steatotic liver disease associates with fibrosis and the PNPLA3 I148M variant
Open this publication in new window or tab >>Activin A levels in metabolic dysfunction-associated steatotic liver disease associates with fibrosis and the PNPLA3 I148M variant
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2024 (English)In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 59, no 6, p. 737-741Article in journal (Refereed) Published
Abstract [en]

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver condition worldwide. There is an urgent need to develop new biomarkers to assess disease severity and to define patients with a progressive phenotype. Activin A is a new promising biomarker with conflicting results about liver fibrosis. In this study we investigate levels of Activin A in patients with biopsy proven MASLD. We assess levels of Activin A in regard to fibrosis stage and genetic variant I148M in the patatin-like phospholipase domain-containing protein 3 (PNPLA3). Methods: Activin A levels were assessed in plasma samples from patients with biopsy-proven MASLD in a cross-sectional study. All patients were clinically evaluated and the PNPLA3 I148M genotype of the cohort was assessed. Findings41 patients were included and 27% of these had advanced fibrosis. In MASLD patients with advanced fibrosis, Activin A levels was higher (p < 0.001) and could classify advanced fibrosis with an AUROC for activin A of 0.836 (p < 0.001). Patients homozygous for PNPLA3 I148M G/G had higher levels of activin A than non-homozygotes (p = 0.027). Conclusions: Circulating activin A levels were associated with advanced fibrosis and could be a potential blood biomarker for identifying advanced fibrosis in MASLD. Patients with the risk genotype PNPLA3 I148M G/G had higher levels of activin A proposing activin A as a contributor of the transition from simple steatosis to a fibrotic phenotype.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2024
Keywords
NAFLD; biomarkers; NIT; liver biopsy
National Category
Gastroenterology and Hepatology
Identifiers
urn:nbn:se:liu:diva-202487 (URN)10.1080/00365521.2024.2334804 (DOI)001195714400001 ()38563432 (PubMedID)2-s2.0-85189778753 (Scopus ID)
Note

Funding Agencies|ALF Grants; Region Ostergotland; Swedish Medical Society; Bengt Ihre Foundation; Ruth and Richard Julin Foundation; Wallenberg Centre for Molecular Medicine, Linkoping University

Available from: 2024-04-15 Created: 2024-04-15 Last updated: 2026-09-02Bibliographically approved
4. Evaluating the prevalence and severity of metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes mellitus in primary care
Open this publication in new window or tab >>Evaluating the prevalence and severity of metabolic dysfunction-associated steatotic liver disease in patients with type 2 diabetes mellitus in primary care
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2025 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 298, no 3, p. 173-187Article in journal (Refereed) Published
Abstract [en]

Background and aims The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has increased during the epidemic of obesity. Type 2 diabetes mellitus (T2DM) is associated with progressive MASLD. Therefore, many guidelines recommend screening for MASLD in patients with T2DM. Most studies in patients with MASLD have been conducted in specialist care. We investigated the prevalence and severity of MASLD in patients with T2DM from primary care. Methods Patients with T2DM were prospectively included from primary care facilities to undergo transient elastography with controlled attenuation parameter and whole-body magnetic resonance imaging (MRI) to assess liver fat, cardiac function, muscle composition, and distribution of body fat. Results Among 308 participants, 59% had MASLD, 7% had suspected advanced fibrosis (transient elastography >= 10 kPa), and 1.9% had cirrhosis. The mean age was 63.9 +/- 8.1 years; 37% were female, with no differences between the MASLD and the non-MASLD groups. Participants with MASLD had greater body mass index (31.1 +/- 4.4 vs. 27.4 +/- 4.1 kg/m(2), p < 0.001) and a higher prevalence of obesity (60% vs. 21%, p < 0.001). Obesity increased the risk of fibrotic MASLD eightfold, as confirmed by multivariable analysis. Participants with MASLD also had increased visceral and abdominal subcutaneous adipose tissue and muscle fat infiltration. On cardiac MRI, participants with MASLD had a lower left ventricular (LV) stroke volume index, a lower LV end-diastolic volume index, and an increased LV concentricity. Conclusions In this cohort of primary care patients with T2DM, 59% had MASLD, and 7% had suspected advanced fibrosis. Obesity was a strong predictor of fibrotic MASLD. MASLD was associated with alterations to the left ventricle and increased deposition of ectopic fat.

Place, publisher, year, edition, pages
WILEY, 2025
Keywords
fibrosis; MASLD; myosteatosis; obesity; primary care; sarcopenia; Type 2 diabetes mellitus
National Category
General Medicine
Identifiers
urn:nbn:se:liu:diva-215361 (URN)10.1111/joim.20103 (DOI)001509715700001 ()40518766 (PubMedID)2-s2.0-105008248888 (Scopus ID)
Note

Funding Agencies|Gilead Sciences

Available from: 2025-06-24 Created: 2025-06-24 Last updated: 2026-09-02

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