| 1. |
- Hegmar, Hannes, et al.
(författare)
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Performance of novel collagen turnover biomarkers to detect increased liver stiffness in MASLD
- 2024
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Ingår i: Journal of Internal Medicine. - : Wiley-Blackwell. - 0954-6820 .- 1365-2796. ; 296:2, s. 177-186
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cleavage products from collagen formation and degradation hold potential as first-line biomarkers for the risk of advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we evaluated the performance of PRO-C3, PRO-C6, C4M, PRO-C18L, and the clinical score ADAPT (age, diabetes, PRO-C3, and platelet count) to detect patients with an LSM >8 kPa or >12 kPa in comparison to the Fibrosis-4 Index (FIB-4).METHODS: Serum from patients with MASLD (n = 269) from six Swedish University Hospitals was analyzed using enzyme-linked immunosorbent assay-based methods. Liver stiffness measurement (LSM) by vibration-controlled transient elastography was performed. The area under the curve (AUC), calibration curves, and net benefit analysis were used.RESULTS: An LSM >8 kPa was found in 108 (40.1%) patients. PRO-C3, PRO-C6, C4M, and PRO-C18L had AUCs ranging from 0.48 to 0.62. ADAPT had the highest AUC (0.73, 95% confidence interval [CI] = 0.67-0.79) to detect patients >8 kPa, compared to FIB-4 (0.71, (95%CI = 0.64-0.77, p = 0.35), and had a higher net benefit compared to FIB-4 from a probability threshold of 15%. FIB-4 and ADAPT performed equally well to detect patients with an LSM >12 kPa, AUC 0.76 versus 0.76, p = 0.93.CONCLUSIONS: ADAPT seems to be marginally better than FIB-4 in identifying patients with an LSM >8 kPa. However, the clinical utility of ADAPT as a first line test is uncertain, especially in low-risk populations. The overall performance of FIB-4 was similar to that of ADAPT in detecting patients with an LSM of >12 kPa. Altogether, the results suggest that ADAPT might be useful to detect earlier stages of fibrosis in MASLD, but that FIB-4 remains a first-line test for advanced fibrosis.
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| 2. |
- Akbari, Camilla, et al.
(författare)
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Long-term major adverse liver outcomes in 1,260 patients with non-cirrhotic NAFLD
- 2024
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Ingår i: JHEP Reports. - : Elsevier. - 2589-5559. ; 6:2
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Tidskriftsartikel (refereegranskat)abstract
- Background & AimsLong-term studies of the prognosis of NAFLD are scarce. Here, we investigated the risk of major adverse liver outcomes (MALO) in a large cohort of patients with NAFLD.MethodsWe conducted a cohort study with data from Swedish university hospitals. Patients (n = 1,260) with NAFLD without cirrhosis were diagnosed through biopsy or radiology, and had fibrosis estimated through vibration-controlled transient elastography, biopsy, or FIB-4 score between 1974 and 2020 and followed up through 2020. Each patient was matched on age, sex, and municipality with up to 10 reference individuals from the general population (n = 12,529). MALO were ascertained from Swedish national registers. The rate of events was estimated by Cox regression.ResultsMALO occurred in 111 (8.8%, incidence rate = 5.9/1,000 person-years) patients with NAFLD and 197 (1.6%, incidence rate = 1.0/1,000 person-years) reference individuals during a median follow up of 13 years. The rate of MALO was higher in patients with NAFLD (hazard ratio = 6.6; 95% CI = 5.2–8.5). The risk of MALO was highly associated with the stage of fibrosis at diagnosis. In the biopsy subcohort (72% of total sample), there was no difference in risk between patients with and without non-alcoholic steatohepatitis. The 20-year cumulative incidences of MALO were 2% for the reference population, 3% for patients with F0, and 35% for F3. Prognostic information from biopsy was comparable to FIB-4 (C-indices around 0.73 vs. 0.72 at 10 years).ConclusionsThis study provides updated information on the natural history of NAFLD, showing a high rate of progression to cirrhosis in F3 and a similar prognostic capacity of non-invasive tests to liver biopsy.Impact and implicationsSeveral implications for clinical care and future research may be noted based on these results. First, the risk estimates for cirrhosis development are important when communicating risk to patients and deciding on clinical monitoring and treatment. Estimates can also be used in updated health-economic evaluations, and for regulatory agencies. Second, our results again highlight the low predictive information obtained from ascertaining NASHstatus by histology and call for more objective means by which to define NASH. Such methods may include artificial intelligence-supported digital pathology. We highlight that NASH is most likely the causal factor for fibrosis progression in NAFLD, but the subjective definition makes the prognostic value of a histological NASH diagnosis of limited value. Third, the finding that prognostic information from biopsy and the very simple Fibrosis-4 score were comparable is important as it may lead to fewer biopsies and further move the field towards non-invasive means by which to define fibrosis and, importantly, use non-invasive tests as outcomes in clinical trials. However, all modalities had modest discriminatory capacity and new risk stratification systems are needed in NAFLD. Repeated measures of non-invasive scores may be a potential solution.
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| 3. |
- Ekstedt, Mattias, et al.
(författare)
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Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up
- 2015
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Ingår i: Hepatology. - : John Wiley & Sons. - 0270-9139 .- 1527-3350. ; 61:5, s. 1547-1554
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Tidskriftsartikel (refereegranskat)abstract
- Background and rationale for the study: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, strongly associated with insulin resistance and the metabolic syndrome. Nonalcoholic steatohepatitis, i.e. fatty liver accompanied by necroinflammatory changes, is mostly defined by the NAFLD activity score (NAS). The aim of the current study was to determine disease-specific mortality in NAFLD, and evaluate the NAS and fibrosis stage as prognostic markers for overall and disease-specific mortality. Methods: In a cohort study, data from 229 well-characterized patients with biopsy-proven NAFLD were collected. Mean follow-up was 26.4 (± 5.6, range 6-33) years. A reference population was obtained from the National Registry of Population, and information on time and cause of death were obtained from the Registry of Causes of Death. Main results: NAFLD patients had an increased mortality compared with the reference population (HR 1.29, CI 1.04-1.59, p=0.020), with increased risk of cardiovascular disease (HR 1.55, CI 1.11-2.15, p=0.01), hepatocellular carcinoma (HR 6.55, CI 2.14-20.03, p=0.001), infectious disease (HR 2.71, CI 1.02-7.26, p=0.046), and cirrhosis (HR 3.2, CI 1.05-9.81, p=0.041). Overall mortality was not increased in patients with NAS 5-8 and fibrosis stage 0-2 (HR 1.41, CI 0.97-2.06, p=0.07), whereas patients with fibrosis stage 3-4, irrespective of NAS, had increased mortality (HR 3.3, CI 2.27-4.76, p<0.001). Conclusions: NAFLD patients have increased risk of death, with a high risk of death from cardiovascular disease and liver-related disease. The NAS was not able to predict overall mortality, whereas fibrosis stage predicted both overall and disease-specific mortality.
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| 4. |
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| 5. |
- Hagström, Hannes, et al.
(författare)
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Elevated serum ferritin is associated with increased mortality in non-alcoholic fatty liver disease after 16 years of follow-up
- 2016
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Ingår i: Liver international (Print). - : John Wiley & Sons. - 1478-3223 .- 1478-3231. ; 36:11, s. 1688-1695
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: High levels of ferritin in patients with non-alcoholic fatty liver disease (NAFLD) are associated with significant fibrosis and higher NAFLD activity score (NAS). It is unclear if this association has an impact on mortality. We investigated if high levels of ferritin, with or without iron overload, were associated with an increased mortality in NAFLD.METHODS: We included 222 patients between 1979 and 2009 with biopsy-proven NAFLD and available serum ferritin concentrations. The cohort was divided into "high" (n = 89) and "normal" (n = 133) ferritin values, using a cut-point of 350 μg/L in males, and 150 μg/L in females, and stratified upon iron overload status. Data on mortality was obtained from a national, population based register. Poisson regression was used to estimate hazard ratios for mortality. The estimates were adjusted for age at biopsy, sex, smoking, BMI, diabetes, hypertension, cardiovascular disease and fibrosis stage at the time of biopsy.RESULTS: The median follow-up time was 15.6 years (range: 0.5-34.2). Patients with high ferritin had more advanced fibrosis and higher NAS than patients with normal ferritin (p < 0.05). Fifteen years after diagnosis, and after adjusting for confounders, the high-ferritin group showed an increasingly higher mortality that was statistically significant (Hazard ratio = 1.10 per year, 95% Confidence interval 1.01-1.21, p < 0.05). There was no difference in mortality between patients with different iron overload patterns.CONCLUSIONS: High levels of ferritin are associated with a long-term increased risk of death. This article is protected by copyright. All rights reserved.
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| 6. |
- Hagström, Hannes, et al.
(författare)
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Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD
- 2017
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Ingår i: Journal of Hepatology. - : ELSEVIER SCIENCE BV. - 0168-8278 .- 1600-0641. ; 67:6, s. 1265-1273
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Tidskriftsartikel (refereegranskat)abstract
- Background amp; Aims: Non-alcoholic fatty liver disease (NAFLD) is very common in the general population, but identifying patients with increased risk of mortality and liver-specific morbidity remains a challenge. Non-alcoholic steatohepatitis (NASH) is thought to enhance this risk; therefore, resolution of NASH is a major endpoint in current pharmacologic studies. Herein, we aim to investigate the long-term prognosis of a large cohort of NAFLD patients, and to study the specific effect of NASH and fibrosis stage on prognosis. Methods: We conducted a retrospective cohort study of 646 biopsy-proven NAFLD patients. Each case was matched for age, sex and municipality to ten controls. Outcomes on mortality and severe liver disease, defined as cirrhosis, liver decompensation/failure or hepatocellular carcinoma, were evaluated using population-based registers. Cox regression models adjusted for age, sex and type 2 diabetes were used to examine the long-term risk according to fibrosis stage. Likelihood ratio tests were used to assess whether adding NASH to these models increased the predictive capacity. Laplace regression was used to estimate the time to severe liver disease according to stage of fibrosis. Results: During a follow-up of mean 20 years (range 0-40) equivalent to 139,163 person-years, 12% of NAFLD patients and 2.2% of controls developed severe liver disease (p amp;lt; 0.001). Compared to controls, the risk of severe liver disease increased per stage of fibrosis (hazard ratio ranging from 1.9 in F0 to 104.9 in F4). Accounting for the presence of NASH did not change these estimates significantly (likelihood ratio test amp;gt; 0.05 for all stages of fibrosis). Similar results were seen for overall mortality. The lower end of the 95% confidence interval for the 10th percentile of time to development of severe liver disease was 22-26 years in F0-1, 9.3 years in F2, 2.3 years in F3, and 0.9 years to liver decompensation in F4. Conclusions: In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions. (C) 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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| 7. |
- Hagström, Hannes, et al.
(författare)
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Health Care Costs of Patients With Biopsy-Confirmed Nonalcoholic Fatty Liver Disease Are Nearly Twice Those of Matched Controls
- 2020
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Ingår i: Clinical Gastroenterology and Hepatology. - : ELSEVIER SCIENCE INC. - 1542-3565 .- 1542-7714. ; 18:7, s. 1592-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Data on healthcare resource use and costs associated with nonalcoholic fatty liver disease (NAFLD) in clinical practice are lacking. We compared real-life healthcare costs of patients with NAFLD to matched controls. METHODS: We performed a retrospective study of 646 patients with biopsy-proven NAFLD in Sweden from 1971 through 2009. Each patient was matched for age, sex, and county of residence with 10 persons from the general population (controls). We retrieved all healthcare contacts through Dec 31, 2014 from national registers. Unit costs were assigned to arrive at a total healthcare cost (in USD [$]) per study subject. RESULTS: During a mean follow-up of 19.9 years, we recorded a mean of 0.27 hospitalizations per year for patients with NAFLD vs 0.16 for controls (P <.001). This corresponded to an incremental cost of $635 per year for patients with NAFLD. Patients with NAFLD had a higher mean use of outpatient care visits: 1.46 contacts per year compared with 0.86 per year in controls, corresponding to $255 in additional costs (P <.001). Total costs incurred by patients with stage 3-4 fibrosis were higher than by patients with fibrosis stage 0-2 (mean annual costs, $4397 vs $629). Cumulative costs were higher for all stages of fibrosis compared to controls. CONCLUSIONS: Healthcare costs are nearly twice as high in patients with NAFLD than in matched controls. This is mostly attributable to higher costs for hospitalizations, but also to more outpatient visits. Patients with advanced fibrosis had the highest costs.
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| 8. |
- Hagström, Hannes, et al.
(författare)
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Low to moderate lifetime alcohol consumption is associated with less advanced stages of fibrosis in non-alcoholic fatty liver disease
- 2017
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 52:2, s. 159-165
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Tidskriftsartikel (refereegranskat)abstract
- Background and aim: Moderate alcohol consumption has been associated with a lower risk of disease severity in non-alcoholic fatty liver disease (NAFLD). It is unclear if this reflects current or lifetime drinking, or can be attributed to confounders such as diet and exercise. We evaluated the impact of lifetime alcohol consumption on fibrosis severity in NAFLD. Methods: We prospectively enrolled 120 subjects with biopsy-proven NAFLD and through detailed questionnaires examined lifetime alcohol consumption, diet and physical activity. Main outcome measures were odds ratios (OR) for fibrosis stage, calculated through ordinal regression after adjustment for body mass index, diabetes mellitus type 2, smoking and age at biopsy. A biomarker for recent alcohol consumption, phosphatidyl ethanol (PEth) was sampled. Results: An increase in median weekly alcohol consumption to a maximum of 13 drinks per week was associated with lower fibrosis stage (adjusted OR for each incremental unit, 0.86; 95% CI, 0.76-0.97; p = .017). The lowest risk for fibrosis was found with the lowest odds seen in the top quartile of alcohol consumption (aOR 0.23; 95% CI 0.08-0.66; p = .006). Adding soft drink and coffee consumptions, and physical activity to the model did not change the estimates. Subjects with PEth >= 0.3 mu mol/L had higher ORs for a higher fibrosis stage (aOR 2.77; 95% CI 1.01-7.59; p = .047). Conclusion: Lifetime alcohol consumption with up to 13 units per week is associated with lower fibrosis stage in NAFLD. Elevated PEth is associated with higher stages of fibrosis.
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| 9. |
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| 10. |
- Hagström, Hannes, et al.
(författare)
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Risk for development of severe liver disease in lean patients with nonalcoholic fatty liver disease : A long-term follow-up study.
- 2018
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Ingår i: Hepatology communications. - : John Wiley & Sons. - 2471-254X. ; 2:1, s. 48-57
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Tidskriftsartikel (refereegranskat)abstract
- Most patients with nonalcoholic fatty liver disease (NAFLD) are overweight or obese. However, a significant proportion of patients have a normal body mass index (BMI), denoted as lean NAFLD. The long-term prognosis of lean NAFLD is unclear. We conducted a cohort study of 646 patients with biopsy-proven NAFLD. Patients were defined as lean (BMI < 25.0), overweight (BMI 25.0-29.9), or obese (BMI ≥ 30.0) at the time of biopsy. Each case was matched for age, sex, and municipality to 10 controls. Overall mortality and development of severe liver disease were evaluated using population-based registers. Cox regression models adjusted for age, sex, type 2 diabetes, and fibrosis stage were used to examine the long-term risk of mortality and liver-related events in lean and nonlean NAFLD. Lean NAFLD was seen in 19% of patients, while 52% were overweight and 29% were obese. Patients with lean NAFLD were older, had lower transaminases, lower stages of fibrosis, and lower prevalence of nonalcoholic steatohepatitis at baseline compared to patients with a higher BMI. During a mean follow-up of 19.9 years (range 0.4-40 years) representing 12,631 person years and compared to patients who were overweight, patients with lean NAFLD had no increased risk for overall mortality (hazard ratio 1.06; P = 0.73) while an increased risk for development of severe liver disease was found (hazard ratio 2.69; P = 0.007). Conclusion: Although patients with lean NAFLD have lower stages of fibrosis, they are at higher risk for development of severe liver disease compared to patients with NAFLD and a higher BMI, independent of available confounders. (Hepatology Communications 2018;2:48-57).
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