Prevalence, Incidence and Characteristics of NAFLD/NASH in Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by intrahepatic fat accumulation. It is closely related to insulin resistance. To date, it remains unclear whether NAFLD is common in patients with type 1 diabetes or if NAFLD translates into an increased health burden in this population. Screening for NAFLD is challenging due to the limitations of non-invasive diagnostic tools. Liver biopsy remains the gold standard but is not suited for routine screening or clinical studies. Therefore, there is a great demand for accurate non-invasive screening tools that can not only diagnose but also stage NAFLD. This study aims to generate a large cohort of thoroughly characterized type 1 diabetes patients screened for NAFLD using multiple non-invasive tools including MRI, ultrasound, controlled attenuation parameter, and score panels. We aim to generate a biobank to promote a research collaboration network in the field of non-invasive diagnosis of NAFLD. A secondary endpoint is to investigate the potential correlation between the presence of NAFLD and the occurrence of micro-or macrovascular complications in patients with diabetes.

Detailed Description
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This study aims to characterize and follow a thoroughly characterized cohort of adult type 1 diabetes patients free from secondary liver disease due to excessive alcohol usage, viral hepatitis, alfa-1 antitrypsin deficiency, Wilson's disease or steatogenic or hepatotoxic drug use. The investigators will screen for NAFLD and fibrosis using multiple non-invasive techniques including ultrasound controlled attenuation parameter fatty liver index human steatosis index transient elastography FIB-4 NAFLD fibrosis score NASH algorithm based on multiple parameters Subjects will be screened for microvascular and microvascular complications with: ECG microfilament examination 24hour urine collection for microalbuminuria serum kidney test (creatinine, eGFR) fundoscopy peripheral arterial pulsation palpation The investigators will subsequently thoroughly characterize various metabolic and anthropometric parameters and document any microvascular or macrovascular complications. The patients will be annually rescreened for both NAFLD-related as cardiovascular variables. Therefore this study will assess the correlation between NAFLD, cardiovascular risk, and type 1 diabetes in a prospective manner.

Official Title
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Prevalence, Incidence and Characteristics of NAFLD/NASH in Type 1 Diabetes Mellitus Obtained Via a Non-invasive Screening Protocol

Conditions
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NAFLD, Type 1 Diabetes, Cardiovascular Diseases

Intervention / Treatment
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* Diagnostic Test: ultrasound
* Diagnostic Test: elastography
* Diagnostic Test: controlled attenuation parameter (CAP)
* Diagnostic Test: FLI
* Diagnostic Test: FIB-4
* Diagnostic Test: NFS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes Adult age Informed consent given Exclusion Criteria: Secondary liver disease Excess alcohol usage Pregnancy Use of steatogenic medication Active cancer or oncological treatment History of organ transplantation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| NAFLD + type 1 diabetes<br>type 1 diabetes patient with NAFLD on screening | Diagnostic Test: ultrasound<br>* ultrasound to check for NAFLD according to Saverymuttu criteria<br>Diagnostic Test: elastography<br>* elastography to compare liver stiffness indices<br>Diagnostic Test: controlled attenuation parameter (CAP)<br>* CAP is a non-invasive additive on Fibroscan (trademark) which can quantify hepatic steatosis<br>Diagnostic Test: FLI<br>* the FLI is a score panel designed to screen for NAFLD<br>Diagnostic Test: FIB-4<br>* the FIB-4 is a score panel designed to screen for significant fibrosis<br>Diagnostic Test: NFS<br>* the NFS is a score panel designed to screen for significant fibrosis<br>|
| noNAFLD + type 1 diabetes<br>type 1 diabetes patient without NAFLD on screening | Diagnostic Test: ultrasound<br>* ultrasound to check for NAFLD according to Saverymuttu criteria<br>Diagnostic Test: elastography<br>* elastography to compare liver stiffness indices<br>Diagnostic Test: controlled attenuation parameter (CAP)<br>* CAP is a non-invasive additive on Fibroscan (trademark) which can quantify hepatic steatosis<br>Diagnostic Test: FLI<br>* the FLI is a score panel designed to screen for NAFLD<br>Diagnostic Test: FIB-4<br>* the FIB-4 is a score panel designed to screen for significant fibrosis<br>Diagnostic Test: NFS<br>* the NFS is a score panel designed to screen for significant fibrosis<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of NAFLD in type 1 diabetes: percentage of patients with indices of liver steatosis and/or NASH and/or fibrosis. | Determination of the cross-sectional prevalence of NAFLD in a cohort of type 1 diabetes patient (population size approximately 1000 subjects) according to ultrasound criteria, FLI≥60, HSI≥36, controlled attenuation parameter >215dB/m (M-probe) or ≥250 dB/m (XL probe) and MRI-PDFF >5% hepatocyte steatosis (reference method). All measures will be performed in a combined and standardized protocol to explore their diagnostic accuracy (see outcome 4). | one year | 
| Incidence of NAFLD in type 1 diabetes. | Incidence of NAFLD in type 1 diabetes determined by new cases of NAFLD according to ultrasound criteria, FLI≥60, HSI≥36, controlled attenuation parameter >215dB/m (M-probe) or ≥250 dB/m (XL probe) or MRI-PDFF >5% hepatocyte fat infiltration (reference method) | five years | 
| correlation of NAFLD with microvascular and macrovascular complications in type 1 diabetes mellitus: odds ratio to have prevalent complications in NAFLD and diabetes compared to diabetes without NAFLD | The correlation between indices of microvascular (neuropathy assessed by microfilament test, nephropathy assessed by microalbuminuria rate and retinopathy assessed by fundoscopic criteria) or macrovascular (non-fatal ischemic coronary disease, non-fatal cerebrovascular disease, non-fatal peripheral artery disease, or mortality due to cardiovascular disease) complications will be compared between groups with and without NAFLD as determined by the abovementioned screening tools. | one year | 
| Association of NAFLD with microvascular and macrovascular complications in type 1 diabetes mellitus: odds ratio to develop in NAFLD and diabetes compared to diabetes without NAFLD in subjects with no prior complications | The association between indices of microvascular (neuropathy assessed by microfilament test, nephropathy assessed by microalbuminuria rate and retinopathy assessed by fundoscopic criteria) or macrovascular (non-fatal ischemic coronary disease, non-fatal cerebrovascular disease, non-fatal peripheral artery disease or mortality due to cardiovascular disease) complications will be assessed between groups with and without NAFLD, but all without prior micro- or macrovascular disease as determined by the abovementioned screening tools. | five years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Diagnostic accuracy of non-invasive tools for NAFLD in type 1 diabetes: comparison of AUROC and diagnostic accuracy | The investigators will compare the abovementioned non-invasive tools to diagnose and grade liver steatosis and fibrosis with the predefined gold standard (MRI-PDFF for steatosis and magnetic resonance elastography for fibrosis). Correlations and agreement statistics will be performed for each index. Using regression analysis, a new specific algorithm will be developed based on cohort-specific cutoffs. Using longitudinal data, a prediction score will be determined to predict NAFLD occurrence or NAFLD progression. | five years | 
| Natural history of NAFLD in type 1 diabetes | Timewise description of the progression of quantitative indices of liver steatosis and fibrosis on the abovementioned tools (ultrasound, score systems, elastography) to assess the natural evolution of NAFLD. Every year this assay will be performed. MRI-PDFF will be performed in 5 years as a reference method to mark the five-year follow-up window | five years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NAFLD, type 1 diabetes, cardiovascular disease, insulin resistance