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LUCA MIELE, MD, PhD

Luca Miele, MD PhD

The main aim of the study is to set up an observational cohort with NAFLD (Non-alcoholic fatty liver disease) at different stage of disease (from simple steatosis to cirrhosis and/or HCC-Hepatocellular carcinoma) and for comparative purpose a cohort of subjects with diabetes and/or obesity and/or other risk factors (i.e. psoriasis, IBD (inflammatory bowel disease), dyslipidemia) without NAFLD in order to have a clinical phenotypical characterization and the collection of biological specimens.

We will collect clinical data, biological samples and imaging results in order to perform future cross-sectional studies and/or longitudinal studies for elucidating pathways of the disease and develop and validate biomarkers for diagnosis, prognosis and monitoring liver disease and comorbidities in order to contribute to precision medicine in this field.

Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive accumulation of triglycerides in the liver and is often associated, in the absence of significant alcohol consumption, to insulin resistance and to the metabolic syndrome of which it shares the most frequent clinical manifestations (hypertension, dyslipidemia, visceral adiposity, glucose intolerance). Because of the pandemic spread of obesity and diabetes and by virtue of the best control of viral hepatitis, in western countries NAFLD is the most common cause of liver injury with prevalence that is around 20-30% of the general population.

NAFLD encompasses a broad spectrum of liver conditions associated with fat accumulation that ranges from benign fatty liver (FL), non-progressive liver fat accumulation to severe liver injury, cirrhosis, and liver failure. The histological signature ballooning degeneration (with or without Mallory bodies) and/or inflammation and/or fibrosis is typical of nonalcoholic steatohepatitis (NASH), that may progress to: i) cirrhosis and contribute to one category of cryptogenic cirrhosis (CC), in which steatosis may be present or absent; ii) hepatocellular carcinoma (HCC). Furthermore, the correct indication of subjects with significant fibrosis in the highest risk populations could also contribute to reducing the increasing prevalence of cirrhosis secondary to NAFLD as an indication to liver transplantation. Moreover, the expected impact of NAFLD and its complication on public health is quite impressive worldwide.

Hepatic steatosis is emerging as an early and common determinant of many of these diseases and co-morbidities, as reported also by our research group. Fatty liver, in fact, may cause lipid accumulation, inflammation, and oxidative stress at the hepatic level leading to NAFLD, and facilitating the occurrence of additional clinical co-morbidities by the activation of common molecular and cellular mechanisms. In fact, NAFLD is correlated to several metabolic diseases, such as Metabolic Syndrome (MetS), Cardiovascular Diseases (CVD), Chronic Kidney Disease (CKD), Hepatocellular carcinoma (HCC), Obstructive sleep apnoea (OSA), Polycystic ovary syndrome (PCOS) and Chronic Plaque Psoriasis NAFLD is considered the liver manifestation of metabolic syndrome and beyond effects on the liver (risk of cirrhosis and HCC), can also increase the risk of morbidity due to CVD, CKD, psoriasis, PCOS, OSA, and mortality related to T2DM, coronary heart disease, even in absence of well-known risk factors (i.e. smoking, hypertension, T2DM, dyslipidaemia). In this regard, interventions such as lifestyle modification (proper nutrition and exercise), along with pharmacological agents are vital to reduce co-morbidities. Interestingly, the role of the liver seems to be central in the onset and progression of its co-morbidities. However, there are still insufficient information regarding the disease pathways and mechanisms common to these disorders co-occurring with NAFLD.

Within this scenario the appropriate management of NAFLD may have a beneficial effect also on the co-morbidities. At today, the investigation of the common pathogenic mechanisms of the abovementioned inter-related diseases has been approached rather ineffectively, leaving major holes and undermining the development of appropriate management programs for NAFLD/NASH and its related co-morbidities. In order to fill the gap and increase the quality of data for a multi-omic approach we decided to set up a certified local repository. Therefore, the understanding of the pathogenesis of NAFLD and its relevance in the development of related co-morbidities is crucial to guide the development of future treatments and to inform European Union health and economic policies. The clinical impact of NAFLD is considerable and represents a real driver of the major clinical outcomes that impact on the health of the individual, consequently creating a real burden of disease, especially in those populations considered at higher risk of fibrosis such as diabetics or obese. The global burden of NAFLD/NASH and CC require a multi-omic approach in order to prevent and to provide health plans for avoid implications for the population.

Despite the high epidemiology impact, there are still significant areas of unmet clinical need in NAFLD: i) the lack of knowledge on molecular mechanism leading to progression of liver disease; ii) a poor understanding of disease sub-phenotypes; iii) the lack of biomarkers of disease progression that allow risk stratification.

The current availability of the -omics technologies generating libraries of genome-wide data, metabolomes, proteomes and microbiome will allow a precision medicine approach in order to improve the knowledge of disease and to generate a personalized approach to improve the clinical practice and optimize the public health plans for prevention programs and NAFLD management.

Clinical data will be collected in the electronic form at baseline and thereafter on an annual basis.

In the prospective project, biological sample (DNA, RNA, sera or whole blood; urine, feces, bile and liver tissues) are collected, only on a voluntary basis, at the time of recruitment and follow-up and stored at the biobank facility XBIOGEM at Fondazione Policlinico Univ. A. Gemelli IRCCS in Rome

PROtocol of Metabolic and Cryptogenic livEr Disease regisTry for intEgration of Omic Studies

Set up an observational cohort with NAFLD at different stage of disease (from simple steatosis to cirrhosis and/or HCC)

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Diabetes Mellitus, Type 2

Endocrine System Diseases

Luca Miele

Non-alcoholic hepatic steatosis (NAFLD) is characterised by the excessive accumulation of triglycerides in the liver and is often associated, in the absence of significant alcohol consumption, with insulin resistance and metabolic syndrome with which it shares the most frequent clinical manifestations (hypertension, dyslipidaemia, visceral adiposity, glucose intolerance). Due to the pandemic spread of obesity and diabetes and by virtue of better control of viral hepatitis, NAFLD is the most common cause of liver damage in Western countries with a prevalence of around 20-30% of the general population.

The clinical impact of NAFLD in diabetes is considerable and represents a real driver of the major clinical outcomes that impact on the health of the individual, consequently creating a real 'burden of disease' especially in those populations considered to be at higher risk of disease severity.

Individuals with diabetes are, in fact, those at greatest risk of developing the clinical sequelae of NAFLD and often do not receive adequate hepatological support and a correct hepatic pathology. In fact, it has been documented in the literature that the presence of diabetes increases the severity of liver damage, bringing the risk of NASH up to 80% and increasing the risk of significant fibrosis to 30-40% of subjects with hepatic steatosis as well as representing an independent predictor for significant fibrosis. Lastly, the increased risk of hepatocarcinoma in subjects with diabetes and NAFLD should not be overlooked, as documented by our group and confirmed in a large Italian case series.

In subjects with diabetes, moreover, the presence of NAFLD is not only associated with worse glycaemic control, but also with micro- and macro-vascular complications as well as nephrological and neuropathic complications and increased mortality.

Therefore, the possibility of applying the non-invasive fibrosis scores currently available for NAFLD on a large scale, in a population at high risk of progressive liver disease, would make it possible to characterise (a) the true epidemiology of significant fibrosis (F3 or higher); (b) allow primary prevention actions to be carried out by optimising the use of resources or by identifying subjects at greater risk of damage progression; (c) understand, in cases with a long history of disease the true prevalence of clinical outcomes; (d) understand the epidemiology of comorbidities and polypharmacy as a function of significant fibrosis.

DIAbetes and NAFLD

Prevalence and Clinical Impact of Liver Fibrosis Associated With Non-alcoholic Hepatic Steatosis (NAFLD) in Individuals With Type 2 Diabetes and Relationship With Diabetes Therapies

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
PROtocol of Metabolic and Cryptogenic livEr Disease regisTry for intEgration of Omic Studies	NCT04371042	NAFLD - Nonalco... Diabetes Obesity Metabolic Syndr... Cirrhosis Liver Cancer NASH - Nonalcoh... HCC - Hepatocel... Fatty Liver		18 Years -	Fondazione Policlinico Universitario Agostino Gemelli IRCCS
DIAbetes and NAFLD	NCT06315361	NAFLD Diabetes NASH Fibrosis, Liver Cirrhosis, Live... Liver Cancer		18 Years - 80 Years	Fondazione Policlinico Universitario Agostino Gemelli IRCCS

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Every month we try and update this database with for nash cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for nash cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.