Prevalence, Incidence and Characteristics of NAFLD/NASH in Type 1 Diabetes Mellitus (NAFLDIA1)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Cardiovascular Diseases; Type 1 Diabetes; NAFLD
• Intervention / Treatment: Diagnostic test: ultrasound; Diagnostic test: elastography; Diagnostic test: controlled attenuation parameter (CAP); Diagnostic test: FLI; Diagnostic test: FIB-4; Diagnostic test: NFS

Detailed Description

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.

• Study Type: Observational
• Enrollment (Anticipated): 700

Contacts and Locations

• Study Contact: Name: Jonathan Mertens, M.D.; Phone Number: +328217304; Email: jonathan.mertens@uza.be
• Study Contact Backup: Name: Rie Braspenning, nurse; Email: rie.braspenning@uza.be

Study Locations

• Belgium
  • Antwerp
    • Edegem, Antwerp, Belgium, 2650
      • Recruiting
      • Antwerp University Hospital
      • Contact: Jonathan Mertens, M.D.; Phone Number: +328217304; Email: jonathan.mertens@uza.be

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Adult type 1 diabetes patients followed in the outpatient diabetes clinic of the Antwerp University Hospital

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Hospital, Antwerp
• Investigators: Principal Investigator: Christophe De Block, M.D., PhD, Universiteit Antwerpen; Principal Investigator: Sven Francque, M.D., PhD, Universiteit Antwerpen

Publications and helpful links

General Publications

• European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016 Jun;64(6):1388-402. doi: 10.1016/j.jhep.2015.11.004. Epub 2016 Apr 7. No abstract available.
• de Vries M, Westerink J, Kaasjager KHAH, de Valk HW. Prevalence of Nonalcoholic Fatty Liver Disease (NAFLD) in Patients With Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab. 2020 Dec 1;105(12):3842-53. doi: 10.1210/clinem/dgaa575.
• Tana C, Ballestri S, Ricci F, Di Vincenzo A, Ticinesi A, Gallina S, Giamberardino MA, Cipollone F, Sutton R, Vettor R, Fedorowski A, Meschi T. Cardiovascular Risk in Non-Alcoholic Fatty Liver Disease: Mechanisms and Therapeutic Implications. Int J Environ Res Public Health. 2019 Aug 26;16(17):3104. doi: 10.3390/ijerph16173104.
• Ismaiel A, Dumitrascu DL. Cardiovascular Risk in Fatty Liver Disease: The Liver-Heart Axis-Literature Review. Front Med (Lausanne). 2019 Sep 13;6:202. doi: 10.3389/fmed.2019.00202. eCollection 2019.
• De Block CEM, Shivalkar B, Goovaerts W, Brits T, Carpentier K, Verrijken A, Van Hoof V, Parizel PM, Vrints C, Van Gaal LF. Coronary artery calcifications and diastolic dysfunction versus visceral fat area in type 1 diabetes: VISCERA study. J Diabetes Complications. 2018 Mar;32(3):271-278. doi: 10.1016/j.jdiacomp.2017.11.008. Epub 2017 Nov 28.
• Hampson SJ. Nursing interventions for the first three postpartum months. J Obstet Gynecol Neonatal Nurs. 1989 Mar-Apr;18(2):116-22. doi: 10.1111/j.1552-6909.1989.tb00474.x.

Helpful Links

• only tool for quick determination of the NAFLD risk according to several scoring systems. The AntwerpNAFLDguide provides a follow-up interval recoomendation

Study record dates

Study Major Dates

• Study Start (Actual): September 17, 2018
• Primary Completion (Anticipated): July 30, 2023
• Study Completion (Anticipated): July 30, 2025

Study Registration Dates

• First Submitted: November 4, 2020
• First Submitted That Met QC Criteria: December 10, 2020
• First Posted (Actual): December 11, 2020

Study Record Updates

• Last Update Posted (Actual): March 4, 2022
• Last Update Submitted That Met QC Criteria: March 3, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: cardiovascular disease; NAFLD; insulin resistance; type 1 diabetes
• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Liver Diseases; Fatty Liver; Cardiovascular Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: 18/32/361

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: monocentric study

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No