1. The primary objective of the European NAFLD Registry observational study is to assemble a cohort of well-characterised patients with Non-Alcoholic Fatty Liver Disease (NAFLD) and to collect associated clinical information, biological samples and…
ID
Source
Brief title
Condition
- Hepatic and hepatobiliary disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Cross-sectional correlation of clinical phenotype data with blood-based
biomarkers (genetic, epigenetic, transcriptomic, metabolomics, proteomic and
metagenomic) and/or imaging biomarkers to develop and validate optimum
biomarker approaches for the diagnosis and risk stratification of NAFLD.
Secondary outcome
• Longitudinal correlation of clinical phenotype data with blood-based
biomarkers (genetic, epigenetic, transcriptomic, metabolomics, proteomic and
metagenomic) and/or imaging biomarkers to develop and validate optimum
biomarker approaches for the diagnosis, risk stratification and monitoring of
NAFLD.
• Study of dietary habits and lifestyle factors (sedentary behaviour/exercise
levels) in patients with NAFLD;
• Study of symptom burden in patients with NAFLD to develop and validate a new
disease-specific Patient Reported Outcome Measure (PROM) for NAFLD.
• Study the underlying pathogenic processes contributing to disease progression
in NAFLD:
o Conduct of candidate gene and genome-wide disease association studies (GWAS)
to identify genetic variants influencing disease severity in NAFLD;
o Analysis of circulating miRNA, mRNA and DNA methylation (mDNA) profiles in
the liver and/or blood of patients with NAFLD;
o Study of the blood lipid/metabolic/proteomic profiles of patients with NAFLD;
o Study of the intestinal bacterial flora of patients with NAFLD;
Background summary
Internationally, there is a dramatic increase in the number of patients
presenting with liver disease, with as many as 1 in 10 of the population having
some form of liver disorder. Recent estimates have suggested a doubling of
liver disease mortality over the next decade. Liver disease is also associated
with considerable morbidity, ranging from impaired quality of life through to
the classical complications of advanced liver disease including liver failure,
variceal bleeding, ascites, encephalopathy and hepatocellular carcinoma. These
conditions, all the result of progressive liver fibrosis, are the complications
that dominate the wards of Liver Units throughout the country. One of the major
reasons for the increase in mortality from liver disease is the well-publicised
"obesity epidemic" pre-disposing to non-alcoholic fatty liver disease (NAFLD)1.
Non-alcoholic fatty liver disease (NAFLD) represents a spectrum from isolated
hepatic fat accumulation (steatosis, NAFL); through hepatic fat accumulation
plus inflammation (non-alcoholic steatohepatitis, NASH); and ultimately
progressing to fibrosis/cirrhosis and potentially hepatocellular carcinoma in
the absence of excessive alcohol consumption2.
NAFLD is strongly associated with the Metabolic Syndrome (MetS) including
obesity, type 2 diabetes mellitus (T2DM) and dyslipidaemia2, 3. With the advent
of increasingly sedentary lifestyles and changing dietary patterns, NAFLD
prevalence has increased dramatically in concert with the rapidly progressing
epidemics of both adult and childhood obesity and T2DM. Although estimates
vary, one large European study found NAFLD in 94% of obese patients (BMI >30
kg/m2), 67% of overweight patients (BMI >25 kg/m2), and 25% of normal weight
patients3. The overall prevalence of NAFLD in T2DM ranges from 40-70%3. NAFLD
has therefore become one of the top concerns for practising
hepato-gastroenterologists and endocrinologists due to its potential to
progress to advanced liver disease and metabolic complications2, 4. NASH is
projected to be the principal aetiology for liver transplantation within the
decade. Importantly, there is a growing body of clinical and epidemiological
evidence suggesting that NAFLD leads to not only liver-related mortality but
also worsening insulin resistance and increased risk of ischaemic heart disease
and stroke2, 5. However, in planning health strategies related to obesity and
T2DM, MetS-related NAFLD and its clinical impact has often been forgotten.
NAFLD is characterized by substantial inter-patient variability in terms of
severity and rate of progression: although a large proportion of the population
is at risk, only a minority experience associated morbidity2, 6.
Epidemiological evidence indicates that patients with NASH are at significantly
greater risk than those with NAFL. However, what determines the progression to
NASH and beyond is not clear and these groups can only be differentiated by
liver biopsy, a procedure that is not well suited to widespread use given the
size of the population at risk of NAFLD4, 5. Key challenges are to understand
the biological and environmental factors that drive inter-patient variability
within the NAFLD spectrum and to use this understanding to develop robust
methods for diagnosis, risk stratification (e.g. NAFL vs. NASH) and therapy so
that effective medical care may be targeted to those at greatest risk7. Current
evidence suggests that pathogenesis is driven by a combination of
genetic/epigenetic factors8, 9 interacting with the intestinal microbiome and
nutritional factors2. However, many of the specific factors are unidentified or
uncharacterised and the nature of these interactions is not yet understood.
The transition from NAFL to NASH and the stage of fibrosis are important
discriminators between a relatively benign prognosis and an increased risk of
morbidity/mortality2, 10. Liver biopsy remains the established but imperfect
*gold standard* investigation being invasive, resource intensive, prone to
sampling error and carrying a small but significant risk of complications11.
Such invasive tests are not practical outside specialist practice, and are
particularly unsuitable with such a large *at risk* population. A lack of
tractable non-invasive biomarkers has impeded the diagnosis, risk
stratification and monitoring of patients6. It has also hampered drug
development and the conduct of clinical trials, which still depend on
histological effect as an endpoint. The overarching aim of LITMUS is to
develop, robustly validate and advance towards regulatory qualification
biomarkers that diagnose, risk stratify and/or monitor NAFLD/NASH progression
and fibrosis stage. Success will help target care to those at greatest risk,
facilitate drug development and ultimately give patients access to approved
medicines. To support drug development optimally, LITMUS will align its data
generation and processes to comply with the European Medicines Agency (EMA)/US
Food and Drug Administration (FDA) accord for Qualification of Biomarkers &
Clinical Outcome Assessments. Our ultimate goal is to establish a defined set
of biomarkers that, singly or in combination, enable detection and monitoring
of disease progression to/regression from NAFL through NASH to fibrosis and
cirrhosis; to provide a clear path for regulatory biomarker qualification as
surrogate endpoints for therapeutic trials or as diagnostics; to assist drug
development and to enable cost-effective diagnosis and management of NAFLD.
Study objective
1. The primary objective of the European NAFLD Registry observational study is
to assemble a cohort of well-characterised patients with Non-Alcoholic Fatty
Liver Disease (NAFLD) and to collect associated clinical information,
biological samples and imaging data for cross-sectional and longitudinal
analyses in order to robustly develop and validate biomarkers for the
diagnosis, risk assessment (prognosis) and monitoring of patients with liver
disease.
2. The secondary objectives are to explore the pathophysiology of NAFLD using a
range of start-of-the-art scientific techniques and an integrated data-analysis
approach:
a. This will characterise key intrinsic factors using a multiple *omics*
approach:
i. Genetic differences between patients of varying severity of NAFLD by
determining genome-wide single nucleotide polymorphism (SNP) profiles and
genetic variation.
ii. Epigenetic variation in liver tissue and circulating cell-free DNA from
patients with varying severity of NAFLD by measuring DNA methylation (mDNA)
and/or histone acetylation patterns in liver biopsy samples.
iii. Hepatic and circulating mRNA/miRNA expression profiles (transcriptomics)
in patients with varying severity of NAFLD.
iv. Circulating metabolomic/lipidomic and proteomic profiles that may reflect
underlying disease activity and progression.
v. Faecal bacterial diversity to determine how the above are influenced by the
microbiome.
b. Central reading and adjudication of liver biopsies by an international team
of expert hepatopathologists using standardised techniques as the *gold
standard* measure of disease severity. Digital imaging of liver biopsies to
generate a permanent record of histological variation in the LITMUS cohort.
c. These datasets will be computationally integrated and analysed to correlate
inter-individual variations with severity of liver injury, serum and hepatic
metabolomic/lipidomic/protemic/fibrotic profiles and behavioural
(exercise)/dietary factors. This study will thus deliver a substantial and
definitive atlas of pathophysiological variation across a spectrum of
progressive liver disease and support identification of novel biomarkers for
clinical use.
d. To determine whether factors identified in the cross-sectional study predict
long-term outcomes and future disease progression.
Study design
The European NAFLD Registry is a prospectively recruited, observational study
exploring the pathophysiology of progressive liver disease, disease outcomes
and predictive factors in a cohort of patients with NAFLD. The ultimate goal is
to establish a defined set of biomarkers that, singly or in combination, enable
detection and monitoring of disease progression to/regression from NAFL through
NASH to fibrosis and cirrhosis.
This Master Protocol focuses principally on the recruitment of patients into
the European NAFLD Registry, collection of available clinical, imaging and
laboratory data from care records generated during routine medical care as well
as the collection and use of biological samples for research use. It serves as
the basis for a broad international project to discover and validate biomarkers
for NAFLD and associated medical conditions (LITMUS). Out-with the current
study, following separate ethical approval and after separate consent, patients
who have agreed to join the European NAFLD Registry may also agree to
participate in a number of nested sub-studies with bi-directional sharing of
data as necessary (see Section 11.2).
Study burden and risks
Registry study, negligible risk
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
1. Age >=18 years
2. Clinically suspected NAFLD based on any of:
a. Patient with historical liver biopsy providing histological evidence of
NAFLD or,
b. Patient undergoing liver biopsy for suspected NAFLD with biochemical and/or
radiological findings consistent with NAFLD or,
c. Patient with radiological evidence of cirrhosis (in absence of an
alternative aetiology) plus presence of >=2 features indicative of the
*metabolic syndrome*:
i. Increased waist circumference by ethnically adjusted criteria (e.g. Europid
male/female >=94cm/80cm) or overweight/obese (BMI >=25);
ii. Raised fasting glucose >=100 mg/dL [5.6 mmol/L], HbA1c >=48mmol/mol (6.5%) or
previously diagnosed insulin resistance/type 2 diabetes mellitus (or on
treatment);
iii. Dyslipidaemia (fasting TG level >=150 mg/dL [1.7 mmol/L]; or fasting HDL
<40 mg/dL [1.03 mmol/L] in males and <50 mg/dL [1.29 mmol/L] in females; or on
treatment);
iv. Hypertension (systolic BP >=130 or diastolic BP >=85 mmHg, or on treatment).
3. Average alcohol consumption less than 21/14 units/week (males/females) in
preceding 6 months and no history of sustained excessive consumption of alcohol
in past 5 years.
Exclusion criteria
1. Refusal or inability (lack of capacity) to give informed consent.
2. Average alcohol ingestion greater than approximately 21/14 units/week
(males/females) in preceding 6 months or history of sustained excessive
consumption of alcohol in past 5 years.
3. History or presence of Type 1 diabetes mellitus.
4. Presence of any other form of chronic liver disease except NAFLD.
5. Recent (within 12 months) or concomitant use of agents known to cause
hepatic steatosis (long-term systemic corticosteroids [>10 days], amiodarone,
methotrexate, tamoxifen, tetracycline, high dose oestrogens, valproic acid).
6. Any contra-indication to liver biopsy.
7. Recent (within 3 months) change in dose/regimen or introduction of Vitamin E
(at a dose >=400 IU/day), betaine, s-adenosyl methionine, ursodeoxycholic acid,
silymarin or pentoxifylline.
8. Non-Dutch speaking/unable to access an interpreter. Due to the nature of the
study, Dutch language or access to a relevant interpreter is a necessary
criterion to ensure lifestyle (diet and exercise) and symptom data are collated.
9. Patients not meeting inclusion criteria or judged by the investigator to be
unsuitable for inclusion in the study.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL66777.018.18 |