Papers by Stefano Ballestri
Digestive and Liver Disease, Oct 1, 2015
The diagnosis of non-alcoholic steatohepatitis (NASH) is based on the individual histological fea... more The diagnosis of non-alcoholic steatohepatitis (NASH) is based on the individual histological features: steatosis, lobular inflammation and ballooning. Non-alcoholic fatty liver disease (NAFLD) activity score (NAS ≥ 5) is used in clinical trials. Fibrosis dictates long-term NAFLD prognosis. Recently, morethan-mild portal inflammation has raised interest as a marker of NAFLD severity. We assessed the independent predictors of: (I) individual histological lesions of NASH; (II) diagnosis of NASH; (III) significant (stage ≥2) and advanced (stage ≥3) fibrosis; and (IV) more-than-mild portal inflammation. Methods: Data from 118 consecutive biopsy-proven NAFLD patients observed at our institution were retrospectively analyzed. Results: At stepwise multivariate logistic regression analyses, independent predictors were as follows. For the individual histological features of NASH: insulin resistance (IR), assessed with Homeostasis Model Assessment-IR (HOMA-IR), serum uric acid (SUA) and serum total cholesterol (TCH) for moderate-to-severe steatosis; waist circumference (waist), HOMA-IR and TCH for lobular inflammation; waist, HOMA-IR, metabolic syndrome (MS), serum alanine aminotransferase (ALT), SUA and TCH for ballooning. For NASH diagnosis: waist, HOMA-IR, MS, ALT, SUA and TCH (Brunt et al.'s classification); ALT, SUA and TCH for NAS ≥ 5. For significant and advanced fibrosis, respectively: waist, MS and ALT; age, platelets, HOMA-IR, diabetes and TCH. For more-than-mild portal inflammation: serum aspartate aminotransferase (AST), serum iron, NAS ≥ 5 and significant liver fibrosis. Conclusion: HOMA-IR, SUA, MS, ALT and TCH are independent predictors of NASH and its individual histological lesions, notably including fibrosis. Based on our findings, these factors should be considered major pathogenic drivers of NASH and, by inference, potential targets for treatment.
Rational government of patient fluxes from primary care to hepatology clinic is a priority of non... more Rational government of patient fluxes from primary care to hepatology clinic is a priority of nonalcoholic fatty liver disease (NAFLD) research. Estimating pre-test probability of disease, risk of fibrosis progression, and exclusion of competing causes of liver disease must be addressed. Here we propose a novel taxonomic classification of NAFLD based on hepatic, pathogenic and systemic features of disease in the individual patient. The variable course of disease in any given patient remains a clinical enigma. Therefore, future studies will have to better characterize the role of genetic polymorphisms, family and personal history, diet, alcohol, physical activity and drugs as modifiers of the course of disease and clues to the early diagnosis of hepatocellular carcinoma. A better understanding of these, together with a taxonomic diagnosis, may prompt a more accurate personalization of care. For example, understanding the putative role of psycho-depression in NAFLD promises to revolutionize disease management in a proportion of cases. Similarly, sex differences in outcome and response to treatment are insufficiently characterized. More studies are awaited regarding those forms of NAFLD which occur secondary to endocrine derangements. The intersections between NAFLD and the lung must better be defined. These include the bi-directional associations of NAFLD and chronic obstructive pulmonary disease and sleep apnoea syndrome, as well as the totally unexplored chapter of NAFLD and coronavirus disease 2019 (COVID-19). Finally, the therapeutic roles of intermittent fasting and anticoagulation must be assessed. In conclusion, over the last 20 years, NAFLD has taught us a lot regarding the pathogenic importance of insulin resistance, the limitations of correcting this in the treatment of NAFLD, the root causes of diabetes and the metabolic syndrome, sex differences in disease and the role of nuclear receptors. However, the overwhelming COVID-19 pandemic is now expected to reset the priorities of public health.
Future Medicinal Chemistry, Aug 1, 2019
This review article aims to synthesize the evidence regarding nonalcoholic fatty liver disease (N... more This review article aims to synthesize the evidence regarding nonalcoholic fatty liver disease (NAFLD) as a systemic disorder. We critically discuss the metabolic syndrome and its components; the cardiovascular and the endocrine system; chronic respiratory disorders; the musculoskeletal system; the skin; and extrahepatic tumors. We conclude that, while some of these extra-hepatic conditions clearly predispose to the development of secondary forms of NAFLD (typically hypothyroidism-induced NAFLD), others result from pre-existent NAFLD (e.g., certain extra-hepatic tumors) and others (such as Type 2 Diabetes) have, with NAFLD, mutual and bidirectional associations. Analyzed data imply that NAFLD is not merely a hepatic disease. It is also and possibly more importantly, a systemic disorder requiring a special awareness, a multidisciplinary approach and a multidimensional vision.
Hepatology Research, Aug 9, 2012
Digestive and Liver Disease, Mar 1, 2014
Inflammatory hepatocellular adenomatosis, metabolic syndrome, polycystic ovary syndrome and non-a... more Inflammatory hepatocellular adenomatosis, metabolic syndrome, polycystic ovary syndrome and non-alcoholic steatohepatitis: Chance tetrad or association by necessity? Dear Editor, Hepatocellular adenoma (HCA), and specifically HCA inflammatory variant, formerly associated with oestrogen-progestin use, has recently been recognized as a complication of obesity [1]. Obesity, metabolic syndrome (MS) and non-alcoholic steatohepatitis (NASH), in turn, are increasingly identified in association with polycystic ovary syndrome (PCOS) [2]. Although such a tetrad may be expected to occur more often than by chance alone, there are no published reports of concurrent MS, PCOS, NASH and inflammatory HCA. Supporting a non-chance association, we report on a patient presenting with full-blown MS, PCOS and liver adenomatosis, inflammatory subtype, arising in the background of biopsy-proven NASH. A 50-year-old woman was referred to our outpatient Liver Clinics for the assessment of focal liver lesions discovered incidentally on computed tomography (CT) scans performed, 18 months earlier, in another hospital, for alleged severe hypertriglyceridemiaassociated acute pancreatitis. Contrast-enhanced CT scanning had disclosed a steatotic liver with two focal lesions in the right lobe,
World Journal of Gastroenterology, 2017
AIM To characterize natural history of cryptogenic cirrhosis (CC) and compare its clinical featur... more AIM To characterize natural history of cryptogenic cirrhosis (CC) and compare its clinical features and outcomes to those of hepatitis C virus (HCV)-related cirrhosis. METHODS A prospective cohort of 102 consecutive patients at their first diagnosis of CC were enrolled in this study. The clinical data and outcomes were compared to an age
Liver International, May 14, 2015
Current Pharmaceutical Design, Sep 24, 2020
:Nonalcoholic fatty liver disease (NAFLD) embraces histopathological entities ranging from the re... more :Nonalcoholic fatty liver disease (NAFLD) embraces histopathological entities ranging from the relatively benign simple steatosis to the progressive form nonalcoholic steatohepatitis (NASH), which is associated with fibrosis and an increased risk of progression to cirrhosis and hepatocellular carcinoma. NAFLD is the most common liver disease and is associated with extrahepatic comorbidities including a major cardiovascular disease burden.:The non-invasive diagnosis of NAFLD and the identification of subjects at risk of progressive liver disease and cardio-metabolic complications are key in implementing personalized treatment schedules and follow-up strategies.:In this review, we highlight the potential role of ultrasound semiquantitative scores for detecting and assessing steatosis severity, progression of NAFLD, and cardio-metabolic risk.:Ultrasonographic scores of fatty liver severity act as sensors of cardio-metabolic health and may assist in selecting patients to submit to second-line non-invasive imaging techniques and/or liver biopsy.
Hepatology, Sep 23, 2019
In spite of tremendous research advancements in nonalcoholic fatty liver disease (NAFLD), our und... more In spite of tremendous research advancements in nonalcoholic fatty liver disease (NAFLD), our understanding of sex-differences in NAFLD remains insufficient. This review summarizes current knowledge on sex differences in NAFLD, identifies current gaps, and discusses important considerations for future research. The prevalence and severity of NAFLD are higher in men than in women during the reproductive age. However, after menopause, NAFLD occurs at a higher rate in women suggesting that estrogen is protective. Sex differences also exist for the major risk factors of NAFLD. In general, animal models of NAFLD recapitulate sex differences observed in patients with more severe steatosis and steatohepatitis, more pro-inflammatory/pro-fibrotic cytokines, and a higher incidence of hepatic tumors in males than females. Based on computer modeling, female and male livers are metabolically distinct with unique regulators modulating sex-specific metabolic outcomes. Analysis of the literature reveals that most published clinical and epidemiological studies fail to examine sex differences appropriately. Considering the paucity of data on sex differences and the knowledge that regulators of pathways relevant to current therapeutic targets for NAFLD differ by sex, clinical trials should be designed to test drug efficacy and safety according to sex, age, reproductive stage (i.e., menopause) and synthetic hormone use.Conclusion:Sex differences do exist in the prevalence, risk factors, fibrosis, and clinical outcomes of NAFLD suggesting that, while not yet incorporated, sex will probably be considered in future practice guidelines. Adequate consideration of sex differences, sex hormones/menopause status, age, and other reproductive information in clinical investigation and gene association studies of NAFLD are needed to fill current gaps and implement precision medicine for patients with NAFLD.
Digestive and Liver Disease, Oct 1, 2015
Alimentary Pharmacology & Therapeutics, Nov 1, 2005
Metabolic syndrome represents a common risk factor for premature cardiovascular disease and cance... more Metabolic syndrome represents a common risk factor for premature cardiovascular disease and cancer whose core cluster includes diabetes, hypertension, dyslipidaemia and obesity. The liver is a target organ in metabolic syndrome patients in which it manifests itself with nonalcoholic fatty liver disease spanning steatosis through hepatocellular carcinoma via steatohepatitis and cirrhosis. Given that metabolic syndrome and non-alcoholic fatty liver disease affect the same insulin-resistant patients, not unexpectedly, there are amazing similarities between metabolic syndrome and non-alcoholic fatty liver disease in terms of prevalence, pathogenesis, clinical features and outcome. The available drug weaponry for metabolic syndrome includes aspirin, metformin, peroxisome proliferator-activated receptor agonists, statins, ACE (angiotensin I-converting enzyme) inhibitors and sartans, which are potentially or clinically useful also to the non-alcoholic fatty liver disease patient. Studies are needed to highlight the grey areas in this topic. Issues to be addressed include: diagnostic criteria for metabolic syndrome; nomenclature of non-alcoholic fatty liver disease; enlargement of the clinical spectrum and characterization of the prognosis of insulin resistance-related diseases; evaluation of the most specific clinical predictors of metabolic syndrome/non-alcoholic fatty liver disease and assessment of their variability over the time; characterization of the importance of new risk factors for metabolic syndrome with regard to the development and progression of non-alcoholic fatty liver disease.
To evaluate multiecho MR techniques in the differentiation between steatohepatitis and steatosis,... more To evaluate multiecho MR techniques in the differentiation between steatohepatitis and steatosis, using liver biopsy as the reference standard, in patients with and without HIV infection
Journal of the International AIDS Society, 2008
We assessed endocrine system involvement in a multifactorial pathogenesis hypothesis of NAFLD in ... more We assessed endocrine system involvement in a multifactorial pathogenesis hypothesis of NAFLD in HIV-infected patients. Methods Cross-sectional observational study including all consecutive HIV-infected patients seen at a metabolic clinic who were screened for diabetes, thyroid dysfunction, male hypogonadism, female menopause, hypopituitarism. NAFLD was defined by liver-spleen attenuation values of ≤1.1 on computed tomography. Summary of results 225 patients were included. (Table 1.) We included endocrine variables (but not sex hormones) and known independent predicting variables (sex, waist circumference, ALT/AST, NRTI cumulative exposure) in a backward stepwise multivariate logistic regression analysis. Independent variables associated with NAFLD were NRTI cumulative exposure (OR = 1.11 per year; CI 1.01-1.20), ALT/AST (OR = 3.97; CI 1.78-8.87), waist circumference (OR = 1.06; CI 1.03-1.11). When including sex hormones in different gender groups insulin increased predictive value in female only (OR = 1.18; CI 1.03, 1.34). Conclusion Homeostasis of glucose appears the only endocrine system associated with NAFLD.
Hepatology, Apr 24, 2017
Of course, in our study, we considered the possibility of immediate stent migration. Accordingly,... more Of course, in our study, we considered the possibility of immediate stent migration. Accordingly, surveillance chest x-ray was routinely scheduled for its detection immediately after and at 12 hours following the procedure. This was also the very reason for which we allowed repositioning or replacement of the esophageal stent during the first 24 hours after its deployment. We chose this time lapse because of the recognized high risk of rebleeding during the first 24 hours, a risk that is known to progressively decrease thereafter. (4,5) As mentioned in the article, one of our patients randomized to receive the esophageal stent actually was treated by a Sengstaken tube because of a defect in the stent delivery system (rupture of the gastric balloon). In addition, 2 patients experienced stent migration, which was detected in the plain chest x-ray performed immediately after stent deployment. In both instances, stent migration was immediately corrected, by repositioning the stent in 1 case and by removing the migrated stent and placement of a second one in the other case. These were considered technical problems rather than complications, given that none were associated with failure in controlling bleeding or with the development of clinical complications. Admitedly, we do not know whether such an early detection of the stent migration in our 2 patients and its rapid resolution prevented the development of subsequent serious complications. Therefore, we agree with Gundling et al. that migration after the deployment of self-expanding esophageal metal stents represents a potential complication in the treatment of bleeding esophageal varices. Nevertheless, its consequences may be mitigated by scheduling a plain chest x-ray immediately after stent deployment and periodically thereafter, because this allows its early recognition and resolution.
Journal of Medical Ultrasonics, Oct 4, 2014
We report on a case of incidentally detected primary splenic lymphoma mimicking simple benign cys... more We report on a case of incidentally detected primary splenic lymphoma mimicking simple benign cysts on abdominal ultrasonography. On contrast-enhanced ultrasonography (CEUS), the lesions showed isoenhancement in the arterial phase with progressive washout and marked hypoenhancement in the parenchymal phase. This pattern enabled us to suspect the malignant nature of the disease, thus preventing a dangerous misdiagnosis. Accordingly, further characterization with other imaging studies (computed tomography, magnetic resonance imaging, and positron emission tomography) was pursued based on CEUS and taking into account the patient's clinical picture and medical history. Collectively, imaging data led us to a diagnosis of suspected primary splenic malignancy, most probably lymphoma, which was histologically confirmed on the surgical specimen after splenectomy.
Advances in Therapy, Oct 16, 2022
Atrial fibrillation (AF) and venous thromboembolism (VTE) are highly prevalent conditions with a ... more Atrial fibrillation (AF) and venous thromboembolism (VTE) are highly prevalent conditions with a significant healthcare burden, and represent the main indications for anticoagulation. Direct oral anticoagulants (DOACs) are the first choice treatment of AF/VTE, and have become the most prescribed class of anticoagulants globally, overtaking vitamin K antagonists (VKAs). Compared to VKAs, DOACs have a similar or better efficacy/safety profile, with reduced risk of intracerebral hemorrhage (ICH), while the risk of major bleeding and other bleeding harms may vary depending on the type of DOAC. We have critically reviewed available evidence from randomized controlled trials and observational studies regarding the risk of bleeding complications of DOACs compared to VKAs in patients with AF and VTE. Special patient populations (e.g., elderly, extreme body weights, chronic kidney disease) have specifically been addressed. Management of bleeding complications and possible resumption of anticoagulation, in particular after ICH and gastrointestinal bleeding, are also discussed. Finally, some suggestions are provided to choose the optimal DOAC to minimize adverse events according to individual patient characteristics and bleeding risk.
Antiviral Therapy, Aug 1, 2012
Atherosclerosis Supplements, 2006
age rahter than fatty liver is a predictor of atherosclerosis and is also teh only independent pr... more age rahter than fatty liver is a predictor of atherosclerosis and is also teh only independent predictor of CVD in patients with non alcoholic fatty liver
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Papers by Stefano Ballestri