Highlighting Our Research at the 2024 EAS & EASL Congresses
We are proud to announce that Julius Clinical affiliated researchers presented two significant posters at recent international congresses. During the European Atherosclerosis Society (EAS) Congress in Lyon and the European Association for the Study of the Liver (EASL) Congress in Milan, our research made a noteworthy impact.
Alina Saidi showcased her research titled "Liver Fibrosis Identifies Obese Subjects at Highest Risk for Cardiovascular Disease: The Assisi Study". This study emphasizes the critical role of liver fibrosis as a marker for cardiovascular risk in obese individuals, providing valuable insights for early intervention and management.
Willy Theel presented his research on the "Effect of Pravastatin on Cardiovascular Diseases in an Elderly Population with Obesity and Liver Fibrosis". Willy's work not only garnered attention but was also selected as a top-rated poster presentation, highlighting the importance and quality of his findings. His research explores the potential benefits of pravastatin in reducing cardiovascular risks in elderly patients suffering from obesity and liver fibrosis.
Alina Saidi showcased her research titled "Liver Fibrosis Identifies Obese Subjects at Highest Risk for Cardiovascular Disease: The Assisi Study". This study emphasizes the critical role of liver fibrosis as a marker for cardiovascular risk in obese individuals, providing valuable insights for early intervention and management.
Willy Theel presented his research on the "Effect of Pravastatin on Cardiovascular Diseases in an Elderly Population with Obesity and Liver Fibrosis". Willy's work not only garnered attention but was also selected as a top-rated poster presentation, highlighting the importance and quality of his findings. His research explores the potential benefits of pravastatin in reducing cardiovascular risks in elderly patients suffering from obesity and liver fibrosis.
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Slide through the posters for reading
Resmetirom: a gamechanger in MASLD management
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
In 2019, Stephen Harrison and coworkers published the first phase 2 results of Resmetirom (MGL-3196) on NASH changes in 348 subjects in the Lancet. In a commentary from Julius Clinical I wrote: “This study is very promising and although the numbers are relatively small and the follow up short, the data support further development of compounds targeting the THR-β.”
Now, Stephen Harrison and coworkers published the results of the phase 3 MAESTRO-NASH trial in the February issue of the NEJM (NEJM 2024; 390: 497-509) showing NASH resolution and liver fibrosis improvement in 966 subjects included in the trial. This is the first drug convincingly showing positive results in a phase 3 NASH trial. This very positive results lead to approval by FDA of Rezdiffra® (resmetirom) to be used together with diet and exercise patients with NASH ( FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease | FDA ).
This is a great step forward in the management of our patients suffering from this disease. However, we need to realize that still much work needs to be done. For example, although twice as many participants in the Rezdiffra arms responded to therapy with reduction of fibrosis compared to placebo, the majority of the patients receiving the drug did not show these beneficial results. In addition, a considerable number of subjects taking the drug reported nausea (19—22%) and diarrhea (27-33%) compared to placebo 12,5 and 15,6, respectively). While Resmetirom is the first drug to treat this highly prevalent disease, we need more therapies for a personalized approach in the treatment of MASLD.
In 2019, Stephen Harrison and coworkers published the first phase 2 results of Resmetirom (MGL-3196) on NASH changes in 348 subjects in the Lancet. In a commentary from Julius Clinical I wrote: “This study is very promising and although the numbers are relatively small and the follow up short, the data support further development of compounds targeting the THR-β.”
Now, Stephen Harrison and coworkers published the results of the phase 3 MAESTRO-NASH trial in the February issue of the NEJM (NEJM 2024; 390: 497-509) showing NASH resolution and liver fibrosis improvement in 966 subjects included in the trial. This is the first drug convincingly showing positive results in a phase 3 NASH trial. This very positive results lead to approval by FDA of Rezdiffra® (resmetirom) to be used together with diet and exercise patients with NASH ( FDA Approves First Treatment for Patients with Liver Scarring Due to Fatty Liver Disease | FDA ).
This is a great step forward in the management of our patients suffering from this disease. However, we need to realize that still much work needs to be done. For example, although twice as many participants in the Rezdiffra arms responded to therapy with reduction of fibrosis compared to placebo, the majority of the patients receiving the drug did not show these beneficial results. In addition, a considerable number of subjects taking the drug reported nausea (19—22%) and diarrhea (27-33%) compared to placebo 12,5 and 15,6, respectively). While Resmetirom is the first drug to treat this highly prevalent disease, we need more therapies for a personalized approach in the treatment of MASLD.
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Metabolic dysfunction associated steatotic liver disease and the heart
Commentary by Dr. Marco Alings, MD PhD, Amphia Ziekenhuis, Breda; WCN, Utrecht; Scientific Officer at Julius Clinical
The estimated prevalence of Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) in the adult population is 31% and rising. In a extensive review, Driessen et al describe the link between MASLD and atherosclerotic cardiovascular disease (ASCVD), the desirability of therapy addressing both conditions, and the need for multidisciplinary management.
MASLD and ASCVD share common pathophysiological risk factors (obesity, insulin resistance and type 2 diabetes mellitus, hypertension) that increase concomitantly with increasing MASLD fibrosis stages. An effect of MASLD on ASCVD seems plausible given the fact that, (1) variation in certain genes that predispose to the development of MASLD also influence VLDL secretion and plasma lipids, and (2) MASLD increases the liver release of procoagulant and pro-inflammatory factors. Nevertheless, while MASLD is associated with increased cIMT and coronary calcification, evidence of an association between MASLD in general and cardiovascular mortality risk is still lacking. More advanced stages of MASLD, however, are associated with both fatal and non-fatal cardiovascular events. Thus, stratifying for the different disease stages of MASLD may further clarify the interrelations between MASLD and ASCVD. This underscores the need for a comprehensive cardiometabolic multidisciplinary risk management in these patients.
Lifestyle modification is the cornerstone in preventing both MASLD and CVD. In addition, development of new pharmacological drugs or repurposing of existing drugs targeting both MASLD and CVD would be highly valuable. Reducing hepatic steatosis will also affect various factors linked to heart disease. Understanding whether these changes happen because of fixing the fatty liver itself (as a direct cause) or alongside the improvement of the fatty liver (as a side effect) is crucial to understand a possible causal relation between MASLD and ASCVD. Statins, ACE-inhibitors/ARBs, SGLT2is, GLP-1 RAs, PPARS and TRH- β agonists are candidates for reducing hepatic steatosis and are likely to have pleiotropic cardiometabolic effects as well. The concomitant CVD effects of these drugs in patients with MASLD should be subject of ongoing clinical trials.
The increasing prevalence of MASLD and cardiometabolic comorbidities necessitates a multidisciplinary management. Healthcare professionals in cardiometabolic prevention need to be aware of MASLD, and hepatologists need to be mindful of an increased cardiovascular risk in metabolic liver patients. The AwareNASH research project aims to raise this awareness by educating clinicians managing patients with MAFLD.
Original article:
Driessen, S., Francque, S. M., Anker, S. D., Cabezas, M. C., Grobbee, D. E., Tushuizen, M. E., & Holleboom, A. G. (2023). Metabolic dysfunction associated steatotic liver disease and the heart. Hepatology, 10-1097.
This commentary was originally published on Julius Clinical.
The estimated prevalence of Metabolic Dysfunction Associated Steatotic Liver Disease (MASLD) in the adult population is 31% and rising. In a extensive review, Driessen et al describe the link between MASLD and atherosclerotic cardiovascular disease (ASCVD), the desirability of therapy addressing both conditions, and the need for multidisciplinary management.
MASLD and ASCVD share common pathophysiological risk factors (obesity, insulin resistance and type 2 diabetes mellitus, hypertension) that increase concomitantly with increasing MASLD fibrosis stages. An effect of MASLD on ASCVD seems plausible given the fact that, (1) variation in certain genes that predispose to the development of MASLD also influence VLDL secretion and plasma lipids, and (2) MASLD increases the liver release of procoagulant and pro-inflammatory factors. Nevertheless, while MASLD is associated with increased cIMT and coronary calcification, evidence of an association between MASLD in general and cardiovascular mortality risk is still lacking. More advanced stages of MASLD, however, are associated with both fatal and non-fatal cardiovascular events. Thus, stratifying for the different disease stages of MASLD may further clarify the interrelations between MASLD and ASCVD. This underscores the need for a comprehensive cardiometabolic multidisciplinary risk management in these patients.
Lifestyle modification is the cornerstone in preventing both MASLD and CVD. In addition, development of new pharmacological drugs or repurposing of existing drugs targeting both MASLD and CVD would be highly valuable. Reducing hepatic steatosis will also affect various factors linked to heart disease. Understanding whether these changes happen because of fixing the fatty liver itself (as a direct cause) or alongside the improvement of the fatty liver (as a side effect) is crucial to understand a possible causal relation between MASLD and ASCVD. Statins, ACE-inhibitors/ARBs, SGLT2is, GLP-1 RAs, PPARS and TRH- β agonists are candidates for reducing hepatic steatosis and are likely to have pleiotropic cardiometabolic effects as well. The concomitant CVD effects of these drugs in patients with MASLD should be subject of ongoing clinical trials.
The increasing prevalence of MASLD and cardiometabolic comorbidities necessitates a multidisciplinary management. Healthcare professionals in cardiometabolic prevention need to be aware of MASLD, and hepatologists need to be mindful of an increased cardiovascular risk in metabolic liver patients. The AwareNASH research project aims to raise this awareness by educating clinicians managing patients with MAFLD.
Original article:
Driessen, S., Francque, S. M., Anker, S. D., Cabezas, M. C., Grobbee, D. E., Tushuizen, M. E., & Holleboom, A. G. (2023). Metabolic dysfunction associated steatotic liver disease and the heart. Hepatology, 10-1097.
This commentary was originally published on Julius Clinical.
GRIPOnMASH received significant EU funding to improve prevention and care of Metabolic dysfunction-Associated SteatoHepatitis (MASH)
Utrecht, The Netherlands, 05-02-2024
GRIPonMASH, a newly founded consortium consisting of 27 European institutions and companies, has bundled resources to bring about a transformational change in the detection and treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Supported by the Innovative Health Initiative Joint Undertaking (IHI JU), the consortium will focus on developing the GRIPonMASH Diagnostic Platform which will allow early detection of patients with MASH, better patient stratification and personalized lifestyle advice.
Thirty percent of the world population suffers from Steatotic Liver Disease of which MASLD is one of the clinical presentations. Of these patients, about one in five will develop MASH, an advanced stage of MASLD in which liver inflammation occurs and the liver becomes severely damaged. Moreover, five percent will develop fibrotic MASH (liver scarring). Whilst MASLD is reversible, MASH and especially fibrotic MASH lead to irreversible complications and could even lead to liver decompensation or liver cancer. It is expected that by 2030, MASH will be the leading cause of liver transplants worldwide. Early detection of the disease is vital to ensure that the burden on care is lowered, and that patients can recover from MASH before it becomes chronic or even fatal.
The consortium
The consortium consists of 27 parties from all over Europe. They will be working closely together for the next four years to ensure the success of GRIPonMASH. The research was initiated by Julius Clinical, a spin-out of the University Medical Center Utrecht (UMCU) in the Netherlands. Together with UMCU and Echosens, they will be coordinating the project.
The GRIPonMASH platform
The 26-million-euro project will address the unmet public health need of reducing disease burden and comorbidities associated with MASLD by designing and optimizing a sustainable and scalable GRIPonMASH diagnostic platform.
The platform will provide:
“We believe that by creating early detection and diagnosis of MASH, we can improve many lives. Not just patients that go undiagnosed and only find out when it’s too late, but also healthcare professionals who can now focus on early treatment through proven lifestyle interventions”, said Prof. Dr. Manuel Castro Cabezas, scientific director and (together with Prof. Dr. D.E. (Rick) Grobbee) co-founder of GRIPonMASH.
“To be able to early detect and diagnose MASH, we need clear tools to diagnose and solid information for primary and secondary healthcare providers but also for patients. MASH is a disease caused by lifestyle and can luckily be reversed by changing habits. If we make sure this happens sooner, we can prevent a lot of unnecessary harm”, said Prof Oscar H. Franco, MD Principal Investigator of GRIPonMASH.
For questions, please contact:
Project Management Office – [email protected]
This project is supported by the Innovative Health Initiative Joint Undertaking (IHI JU) under grant agreement No 101132946. The JU receives support from the European Union’s Horizon Europe research and innovation programme and COCIR, Efpia, EuropaBio, MedTech Europe, Vaccines Europe and Mercodia Aktiebolag, Metadeq Limited and Julius Clinical Research BV. Funded by the European Union, the private members, and those contributing partners of the IHI JU.
Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the aforementioned parties. Neither of the aforementioned parties can be held responsible for them. www.ihi.europa.eu
GRIPonMASH, a newly founded consortium consisting of 27 European institutions and companies, has bundled resources to bring about a transformational change in the detection and treatment of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Supported by the Innovative Health Initiative Joint Undertaking (IHI JU), the consortium will focus on developing the GRIPonMASH Diagnostic Platform which will allow early detection of patients with MASH, better patient stratification and personalized lifestyle advice.
Thirty percent of the world population suffers from Steatotic Liver Disease of which MASLD is one of the clinical presentations. Of these patients, about one in five will develop MASH, an advanced stage of MASLD in which liver inflammation occurs and the liver becomes severely damaged. Moreover, five percent will develop fibrotic MASH (liver scarring). Whilst MASLD is reversible, MASH and especially fibrotic MASH lead to irreversible complications and could even lead to liver decompensation or liver cancer. It is expected that by 2030, MASH will be the leading cause of liver transplants worldwide. Early detection of the disease is vital to ensure that the burden on care is lowered, and that patients can recover from MASH before it becomes chronic or even fatal.
The consortium
The consortium consists of 27 parties from all over Europe. They will be working closely together for the next four years to ensure the success of GRIPonMASH. The research was initiated by Julius Clinical, a spin-out of the University Medical Center Utrecht (UMCU) in the Netherlands. Together with UMCU and Echosens, they will be coordinating the project.
The GRIPonMASH platform
The 26-million-euro project will address the unmet public health need of reducing disease burden and comorbidities associated with MASLD by designing and optimizing a sustainable and scalable GRIPonMASH diagnostic platform.
The platform will provide:
- Screening, diagnosis, management and long-term follow-up of MASH high-risk patients to ensure early detection
- Development of decision support tools and testing of existing and novel biomarkers for the detection of MASH patients through artificial intelligence-based decision support tools
- Development of non-invasive alternatives to diagnostic liver biopsies
- Assessment and personalization of lifestyle advice based on factors like physical activity, diet, sleep, smoking, alcohol consumption, and perception of stress
“We believe that by creating early detection and diagnosis of MASH, we can improve many lives. Not just patients that go undiagnosed and only find out when it’s too late, but also healthcare professionals who can now focus on early treatment through proven lifestyle interventions”, said Prof. Dr. Manuel Castro Cabezas, scientific director and (together with Prof. Dr. D.E. (Rick) Grobbee) co-founder of GRIPonMASH.
“To be able to early detect and diagnose MASH, we need clear tools to diagnose and solid information for primary and secondary healthcare providers but also for patients. MASH is a disease caused by lifestyle and can luckily be reversed by changing habits. If we make sure this happens sooner, we can prevent a lot of unnecessary harm”, said Prof Oscar H. Franco, MD Principal Investigator of GRIPonMASH.
For questions, please contact:
Project Management Office – [email protected]
This project is supported by the Innovative Health Initiative Joint Undertaking (IHI JU) under grant agreement No 101132946. The JU receives support from the European Union’s Horizon Europe research and innovation programme and COCIR, Efpia, EuropaBio, MedTech Europe, Vaccines Europe and Mercodia Aktiebolag, Metadeq Limited and Julius Clinical Research BV. Funded by the European Union, the private members, and those contributing partners of the IHI JU.
Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the aforementioned parties. Neither of the aforementioned parties can be held responsible for them. www.ihi.europa.eu
NAFLD becoming MASLD
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
Non-Alcoholic Fatty Liver Disease (NAFLD) is a highly prevalent condition closely associated to several metabolic disorders like diabetes mellitus, obesity and the metabolic syndrome. In all these conditions, insulin resistance is the common driver. Unsurprisingly, NAFLD is also very closely linked to hypertension, chronic kidney disease, cardiovascular disease and certain types of cancer. So, many health care workers deal with patients facing this condition. Not only hepatologists, but also general practitioners, endocrinologists, diabetologists and cardiologists see daily patients with this disorder. Interestingly, awareness of the condition and its clinical characteristics is still very low among health care workers as recently published by our group (1). Surprisingly, even gastroenterologists/hepatologists are not fully aware of the diagnostic criteria and other details of NAFLD. This knowledge gap needs to be addressed widely not only by the scientific and medical societies but also by policy makers and insurance companies.
While environmental factors like diet and exercise (and of course alcohol intake!) play a very important role in the development of fatty liver disease, insulin resistance leading to fatty liver may also depend on other factors. A very important determinant is of course the fatty acid flux from adipose tissue to the liver, which has been associated with several metabolic aspects of insulin resistance (2,3). Other sources of accumulating fat in the hepatocytes are “de novo lipogenesis” and fatty acids released during lipolysis of triglyceride rich lipoproteins. All these factors contribute to the generation of Steatotic Liver Disease (SLD) (Figure). In addition to these metabolic components, also genetic factors play an important role. For example, the patatin-like phospholipase domain-containing 3 (PNPLA3), the transmembrane 6 superfamily member 2 (TM6SF2) and the 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) genes have all been associated with the development of SLD (4).
The last years experts have questioned the use of the term “NAFLD” because of the negative associations connected to “alcoholic” and “fatty”. Health care providers and patients felt the need to change to a more neutral and pathophysiological adequate name. Recently, it was decided to rename NAFLD to “Metabolic dysfunction Associated Steatotic Liver Disease” (MASLD) (5) (Figure 1). The scientific community together with representatives from patient organizations, comprising 236 participants from 56 countries, decided to change the nomenclature for this specific liver condition finally ending the stigmatizing situation created with the previous name. At the same time, the term Non-Alcoholic Steatohepatitis (NASH) has been changed to Metabolic dysfunction Associated SteatoHepatitis (MASH). While these names will be widely adopted in the near future, it is to be expected that the “old” names will remain in clinical practice for those of us who have been using them so long. In addition, since new data have clearly shown that endogenous ethanol production may play a significant role in the pathogenesis of MASLD (6), it seems logical and fair to change to a more neutral and better description. Max Nieuwdorp’s group from Amsterdam UMC in collaboration with colleagues from several European institutions showed in an elegant study that in certain subjects with MASLD the liver may be chronically exposed to higher concentrations of ethanol produced by specific strains of gut micro-organisms, especially the Lactobacillaceae species (6). This finding and much more available evidence from the literature provides sufficient basis to finally change the name of the disorder. The current proposal by Rinella and colleagues (5) is a great improvement and will suit better the expectations from our patients facilitating the communication with their health care providers.
Non-Alcoholic Fatty Liver Disease (NAFLD) is a highly prevalent condition closely associated to several metabolic disorders like diabetes mellitus, obesity and the metabolic syndrome. In all these conditions, insulin resistance is the common driver. Unsurprisingly, NAFLD is also very closely linked to hypertension, chronic kidney disease, cardiovascular disease and certain types of cancer. So, many health care workers deal with patients facing this condition. Not only hepatologists, but also general practitioners, endocrinologists, diabetologists and cardiologists see daily patients with this disorder. Interestingly, awareness of the condition and its clinical characteristics is still very low among health care workers as recently published by our group (1). Surprisingly, even gastroenterologists/hepatologists are not fully aware of the diagnostic criteria and other details of NAFLD. This knowledge gap needs to be addressed widely not only by the scientific and medical societies but also by policy makers and insurance companies.
While environmental factors like diet and exercise (and of course alcohol intake!) play a very important role in the development of fatty liver disease, insulin resistance leading to fatty liver may also depend on other factors. A very important determinant is of course the fatty acid flux from adipose tissue to the liver, which has been associated with several metabolic aspects of insulin resistance (2,3). Other sources of accumulating fat in the hepatocytes are “de novo lipogenesis” and fatty acids released during lipolysis of triglyceride rich lipoproteins. All these factors contribute to the generation of Steatotic Liver Disease (SLD) (Figure). In addition to these metabolic components, also genetic factors play an important role. For example, the patatin-like phospholipase domain-containing 3 (PNPLA3), the transmembrane 6 superfamily member 2 (TM6SF2) and the 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13) genes have all been associated with the development of SLD (4).
The last years experts have questioned the use of the term “NAFLD” because of the negative associations connected to “alcoholic” and “fatty”. Health care providers and patients felt the need to change to a more neutral and pathophysiological adequate name. Recently, it was decided to rename NAFLD to “Metabolic dysfunction Associated Steatotic Liver Disease” (MASLD) (5) (Figure 1). The scientific community together with representatives from patient organizations, comprising 236 participants from 56 countries, decided to change the nomenclature for this specific liver condition finally ending the stigmatizing situation created with the previous name. At the same time, the term Non-Alcoholic Steatohepatitis (NASH) has been changed to Metabolic dysfunction Associated SteatoHepatitis (MASH). While these names will be widely adopted in the near future, it is to be expected that the “old” names will remain in clinical practice for those of us who have been using them so long. In addition, since new data have clearly shown that endogenous ethanol production may play a significant role in the pathogenesis of MASLD (6), it seems logical and fair to change to a more neutral and better description. Max Nieuwdorp’s group from Amsterdam UMC in collaboration with colleagues from several European institutions showed in an elegant study that in certain subjects with MASLD the liver may be chronically exposed to higher concentrations of ethanol produced by specific strains of gut micro-organisms, especially the Lactobacillaceae species (6). This finding and much more available evidence from the literature provides sufficient basis to finally change the name of the disorder. The current proposal by Rinella and colleagues (5) is a great improvement and will suit better the expectations from our patients facilitating the communication with their health care providers.
Journal of Hepatology DOI: (10.1016/j.jhep.2023.06.003) (Reference 5)
In my personal experience, patients have always been surprised when confronted with the name non-alcoholic steatohepatitis. Usually patients feel uncomfortable and think that they should convince me that they are not addicted to alcohol. It has always been unpleasant for them and for me to talk about this condition in which these stigmatizing terms were included. The new nomenclature puts the condition in a more pathophysiological context making it easier for everybody to discuss details. Of course, the clear relationship with overweight and obesity remains and the importance of a healthy lifestyle should always be underscored, but now we can avoid the “alcoholic” term. This does not mean that care workers should not discuss the important contribution of alcohol to the development of SLD. A healthy recommendation to all people with SLD, but also to the general population, should be to minimize alcohol intake, preferably avoiding its use completely. For people like me, coming from a Mediterranean country (in my specific situation Spain), this may be a little bit paradoxical. The Mediterranean dietary recommendation includes the use of small amounts of alcoholic beverages, especially red wine (2-3 for males and 1-2 for female, daily; Figure 2) in contrast to North European countries like the Netherlands, where the recommendation is to refrain completely from alcohol use. Notwithstanding this discussion, the fact that now nomenclature is available that will help us in our communication with patients is a great clinical step forward.
We should welcome MASH and forget about NASH just as we should embrace MASLD and forget NAFLD. Our colleagues who have put so much effort in the change of nomenclature deserve our gratitude. I am sure that also our patients welcome this change.
We should welcome MASH and forget about NASH just as we should embrace MASLD and forget NAFLD. Our colleagues who have put so much effort in the change of nomenclature deserve our gratitude. I am sure that also our patients welcome this change.
References:
- Driessen S, et al. A global survey of health care workers’ awareness of non-alcoholic fatty liver disease: the AwareNASH survey. United Eur Gastroenterol J 2023: doi 10.1002/ueg2.12445.
- Castro Cabezas M et al. Impaired fatty acid metabolism in familial combined hyperlipidemia. J Clin Invest 1993; 92: 160-168
- Meijssen S et al. In vivo evidence of defective postprandial and postabsorptive free fatty acid metabolism in familial combined hyperlipidemia. J Lipid Res 2000; 41: 1096-1102.
- Trépo E & Valenti L. Update on NAFLD genetics: from new variants to clinic. J Hepatol 2020; 72: 1196-1209.
- Rinella ME et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol 2023; doi.org: 10.1016/j.jhep.2023.06.003.
- Meijnikman AS et al. Microbiome-derived ethanol in nonalcoholic fatty liver disease. Nature Medicine 2022; doi.org/10.1038/s41591-022-02026-6.
Showcasing Posters at the 2023 EASL SLD Summit
Written by Vivian de Jong, scientific officer at Julius Clinical who also presented two of the posters.
Last week, at the EASL SLD Summit in Prague several abstracts from Julius Clinical affiliated researchers were presented. Three of the abstracts delve into the associations between statin use, genetics and (cardiovascular) endpoints in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. We demonstrated that a high FIB-4 classification is associated with an increased risk of all-cause mortality in elderly. Interestingly, pravastatin treatment appears to abolish this increased risk. Additionally, the preliminary results of the first 137 subjects of the Franciscus Obesity Nash Study (FONS) were shown.
Slide through the posters for reading
Last week, at the EASL SLD Summit in Prague several abstracts from Julius Clinical affiliated researchers were presented. Three of the abstracts delve into the associations between statin use, genetics and (cardiovascular) endpoints in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. We demonstrated that a high FIB-4 classification is associated with an increased risk of all-cause mortality in elderly. Interestingly, pravastatin treatment appears to abolish this increased risk. Additionally, the preliminary results of the first 137 subjects of the Franciscus Obesity Nash Study (FONS) were shown.
Slide through the posters for reading
Introducing MASH and MASLD NomenclaturE
New NASH and NAFLD nomenclature were introduced at the EASL Conference in Vienna. NAFLD is now Metabolic dysfunction-associated Steatotic Liver Disease (MASLD), and NASH is now Metabolic dysfunction-associated Steatohepatitis (MASH). This change provides a non-stigmatizing diagnosis, gaining widespread approval through a transparent Delphi process. Importantly, this change won't affect the disease's natural history, clinical trials, or biomarkers. The staging and severity criteria remain unchanged. Our ongoing work aims to increase disease awareness, reduce stigma, and expedite drug and biomarker development for patients with MASH/MASLD. Stay tuned for our implementation plan.
THE AWARENASH SURVEY: REVEALING HEALTHCARE PROFESSIONALS' AWARENESS OF NAFLD (MASLD)
We are excited to share the results of our recent research project, titled "A global survey of health care workers' awareness of non-alcoholic fatty liver disease: The AwareNASH survey." This report summarizes the project's results, a collaboration led by Julius Clinical and Leiden University Medical Center.
The study covered a wide survey across 88 countries, with 613 healthcare professionals involved, including 488 physicians. The outcomes highlighted a noteworthy finding: a significant 64% of the surveyed doctors exhibited limited familiarity with the recent developments in NAFLD, now termed as MASLD. This underscores the ongoing necessity for continuous medical education within the hepatology field.
Read Full Article here
The study covered a wide survey across 88 countries, with 613 healthcare professionals involved, including 488 physicians. The outcomes highlighted a noteworthy finding: a significant 64% of the surveyed doctors exhibited limited familiarity with the recent developments in NAFLD, now termed as MASLD. This underscores the ongoing necessity for continuous medical education within the hepatology field.
Read Full Article here
NAFLD/NASH: The necessity of knowledge transfer into the cardiovascular domain
Commentary by Dr. Marco Alings, MD PhD, Amphia Ziekenhuis, Breda; WCN, Utrecht; Scientific Officer at Julius Clinical.
NAFLD has become a significant global public health challenge, affecting millions of people with a prevalence of approximately 25%. A number of studies have shown that NAFLD is a risk factor for cardiovascular disease (CVD), independent of traditional risk factors.
With obesity, insulin resistance, type 2 diabetes and dyslipidemia NAFLD/NASH and cardiovascular disease share the same risk factors and have common pathophysiolocial pathways. Simply put, metabolic syndrome leads to insulin resistance which increases lipolysis causing increased levels of free fatty acids. The consequences of elevated free fatty acid levels are twofold. On one hand, it triggers mitochondrial dysfunction, leading to oxidative stress and cellular damage. On the other hand, it also gives rise to increased levels of triglycerides-rich VLDL.
Other than dyslipidemia, systemic inflammation and endothelial dysfunction contribute to both progression of NAFLD as well as of accelerated atherogenesis.
Thus, it may come to no surprise that NAFLD has been associated with an increased risk of myocardial infarction and stroke. Interventions that reduce the common riskfactors likely will benefit both disorders.
By lowering cholesterol levels in the blood, statins reduce plaque buildup in arteries and decrease the risk of atherosclerotic cardiovascular disease. On average, statins reduce the relative risk of major cardiovascular events by approximately 25% to 35%.
In addition to cholesterol lowering, statins reduce the expression of pro-inflammatory mediators (a.o. TNFα, interleukin-6 and interferon-γ), and have antioxidant effects.
In high-risk patients with NAFLD, cholesterol-lowering reduces cardiovascular risk more than in non-NAFLD patients. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. (World J Hepatol 2022; 14(1): 119-139)
Fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Preliminary data for the eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies. (World J Hepatol 2022; 14(1): 119-139)
In the “2021 ESC Guidelines on cardiovascular disease prevention” it is recommended that patients with NAFLD should be evaluated for other cardiometabolic risk factors. (Eur Heart J (2021) 42; 3227-3337).
Given the shared risk factors, I suspect that screening for the presence of cardiovascular disease in patients with NAFLD is common practice. However, screening for the presence of NAFLD in high-risk cardiovascular patients is not. Despite its increasing prevalence, cardiologists lack awareness of NAFLD.
To identify potential NAFLD patients in the cardiovascular clinic, in high-risk patients the FIB-4 score could be used as a first line triage, enabling early referral and intervention. (J of Hepatology 2015(63):237-64) should be,
Addressing the lack of awareness requires educational initiatives and collaboration between hepatologists and cardiologists. Training programs should incorporate comprehensive teachings about NAFLD and NASH, emphasizing their relevance to cardiovascular health.
NAFLD has become a significant global public health challenge, affecting millions of people with a prevalence of approximately 25%. A number of studies have shown that NAFLD is a risk factor for cardiovascular disease (CVD), independent of traditional risk factors.
With obesity, insulin resistance, type 2 diabetes and dyslipidemia NAFLD/NASH and cardiovascular disease share the same risk factors and have common pathophysiolocial pathways. Simply put, metabolic syndrome leads to insulin resistance which increases lipolysis causing increased levels of free fatty acids. The consequences of elevated free fatty acid levels are twofold. On one hand, it triggers mitochondrial dysfunction, leading to oxidative stress and cellular damage. On the other hand, it also gives rise to increased levels of triglycerides-rich VLDL.
Other than dyslipidemia, systemic inflammation and endothelial dysfunction contribute to both progression of NAFLD as well as of accelerated atherogenesis.
Thus, it may come to no surprise that NAFLD has been associated with an increased risk of myocardial infarction and stroke. Interventions that reduce the common riskfactors likely will benefit both disorders.
By lowering cholesterol levels in the blood, statins reduce plaque buildup in arteries and decrease the risk of atherosclerotic cardiovascular disease. On average, statins reduce the relative risk of major cardiovascular events by approximately 25% to 35%.
In addition to cholesterol lowering, statins reduce the expression of pro-inflammatory mediators (a.o. TNFα, interleukin-6 and interferon-γ), and have antioxidant effects.
In high-risk patients with NAFLD, cholesterol-lowering reduces cardiovascular risk more than in non-NAFLD patients. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. (World J Hepatol 2022; 14(1): 119-139)
Fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Preliminary data for the eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies. (World J Hepatol 2022; 14(1): 119-139)
In the “2021 ESC Guidelines on cardiovascular disease prevention” it is recommended that patients with NAFLD should be evaluated for other cardiometabolic risk factors. (Eur Heart J (2021) 42; 3227-3337).
Given the shared risk factors, I suspect that screening for the presence of cardiovascular disease in patients with NAFLD is common practice. However, screening for the presence of NAFLD in high-risk cardiovascular patients is not. Despite its increasing prevalence, cardiologists lack awareness of NAFLD.
To identify potential NAFLD patients in the cardiovascular clinic, in high-risk patients the FIB-4 score could be used as a first line triage, enabling early referral and intervention. (J of Hepatology 2015(63):237-64) should be,
Addressing the lack of awareness requires educational initiatives and collaboration between hepatologists and cardiologists. Training programs should incorporate comprehensive teachings about NAFLD and NASH, emphasizing their relevance to cardiovascular health.
The FONS study protocol is now published!
NAFLD affects a significant portion of the population, with prevalence ranging from 25% in the general population to 90% in obese patients undergoing bariatric surgery. The FONS study aims to address knowledge gaps regarding the effectiveness of bariatric surgery on NAFLD/NASH. This comprehensive research encompasses metabolic and cardiovascular analyses, as well as genomic, lipidomic, and metabolomic studies. Valuable insights will be gained from microbiome analyses and transient elastography measurements.
The study began in September 2022 at the obesity center in Franciscus Gasthuis & Vlietland. We are eagerly looking forward to following the participants for five years after their bariatric surgery, carefully evaluating the effects of weight loss on NAFLD/NASH. The results from this study have the potential to transform our understanding of these conditions and inform future treatment strategies.
Read Full Article here
The study began in September 2022 at the obesity center in Franciscus Gasthuis & Vlietland. We are eagerly looking forward to following the participants for five years after their bariatric surgery, carefully evaluating the effects of weight loss on NAFLD/NASH. The results from this study have the potential to transform our understanding of these conditions and inform future treatment strategies.
Read Full Article here
NASH/NAFLD & THE HEART
Commentary by Dr. Marco Alings, MD PhD, Amphia Ziekenhuis, Breda; WCN, Utrecht; Scientific Officer at Julius Clinical.
In proportion to rising rates of obesity, the metabolic syndrome and type 2 diabetes, NAFLD is an increasingly common condition with an expected global prevalence of NAFLD >35% within the next decade.
NAFLD occurs in association with insulin resistance, with or without hyperglycemia, obesity (especially visceral adiposity), metabolic syndrome, and atherogenic dyslipidemia. Many risk factors for NAFLD are also risk factors for atherosclerotic cardiovascular disease (ASCVD), which is the principal cause of death in patients with NAFLD. A component of the increased risk of ASCVD in NAFLD is attributable to individual risk factors, but NAFLD is also associated with endothelial dysfunction, heightened systemic inflammatory tone, and ectopic fat deposition with increased epicardial fat pad volume. As a result, the presence of NAFLD is associated with increased ASCVD risk compared with individuals who have the same ASCVD risk factors without NAFLD. [1]
The main comorbidities associated with NAFLD/NASH are common in patients with heart failure with preserved ejection fraction (HFpEF) as well. In a review in Circulation, Capone et al. propose that shared pathogenetic events are key to the development and progression of both NAFLD/NASH and cardiometabolic HFpEF.[2]
Although epidemiologic data on the prevalence of NAFLD/NASH in HFpEF is limited, NAFLD and HFpEF often coexist. A single-center case series of 181 patients with HFpEF suggested that NAFLD was present in 27% of the full cohort (50% of those with imaging), approximately half of whom had advanced liver fibrosis.
In the metabolic syndrome, adipose tissue dysfunction causes lipid “spillover” into the circulation and increased lipid uptake by peripheral organs. In NAFLD/NASH liver injury is often induced by metabolically active lipid species. Similar pathogenetic mechanisms have been proposed in cardiometabolic HFpEF. In both syndromes, lipotoxicity contributes to mitochondrial dysfunction.
Inflammation also contributes to the development of both hepatocyte and cardiomyocyte dysfunction in these 2 syndromes: activation of inflammatory pathways and increase in proinflammatory cytokines are common findings in both NASH and cardiometabolic HFpEF. Although differences between the liver and the heart may limit the transferability of knowledge on the underlying pathophysiological mechanisms of NAFLD/NASH and HFpEF, the similarities between NAFLD/NASH and cardiometabolic HFpEF indicate that common lines of research may be worth pursuing.
Such an approach could lead to the discovery of shared pathogenetic mechanisms and joint drug discovery in NAFLD/NASH and HFpEF. Indeed, a beneficial effect of SGLT2i has been reported not only in patients with HFpEF, but observed in meta-analytic data of NAFLD/NASH as well.
References
In proportion to rising rates of obesity, the metabolic syndrome and type 2 diabetes, NAFLD is an increasingly common condition with an expected global prevalence of NAFLD >35% within the next decade.
NAFLD occurs in association with insulin resistance, with or without hyperglycemia, obesity (especially visceral adiposity), metabolic syndrome, and atherogenic dyslipidemia. Many risk factors for NAFLD are also risk factors for atherosclerotic cardiovascular disease (ASCVD), which is the principal cause of death in patients with NAFLD. A component of the increased risk of ASCVD in NAFLD is attributable to individual risk factors, but NAFLD is also associated with endothelial dysfunction, heightened systemic inflammatory tone, and ectopic fat deposition with increased epicardial fat pad volume. As a result, the presence of NAFLD is associated with increased ASCVD risk compared with individuals who have the same ASCVD risk factors without NAFLD. [1]
The main comorbidities associated with NAFLD/NASH are common in patients with heart failure with preserved ejection fraction (HFpEF) as well. In a review in Circulation, Capone et al. propose that shared pathogenetic events are key to the development and progression of both NAFLD/NASH and cardiometabolic HFpEF.[2]
Although epidemiologic data on the prevalence of NAFLD/NASH in HFpEF is limited, NAFLD and HFpEF often coexist. A single-center case series of 181 patients with HFpEF suggested that NAFLD was present in 27% of the full cohort (50% of those with imaging), approximately half of whom had advanced liver fibrosis.
In the metabolic syndrome, adipose tissue dysfunction causes lipid “spillover” into the circulation and increased lipid uptake by peripheral organs. In NAFLD/NASH liver injury is often induced by metabolically active lipid species. Similar pathogenetic mechanisms have been proposed in cardiometabolic HFpEF. In both syndromes, lipotoxicity contributes to mitochondrial dysfunction.
Inflammation also contributes to the development of both hepatocyte and cardiomyocyte dysfunction in these 2 syndromes: activation of inflammatory pathways and increase in proinflammatory cytokines are common findings in both NASH and cardiometabolic HFpEF. Although differences between the liver and the heart may limit the transferability of knowledge on the underlying pathophysiological mechanisms of NAFLD/NASH and HFpEF, the similarities between NAFLD/NASH and cardiometabolic HFpEF indicate that common lines of research may be worth pursuing.
Such an approach could lead to the discovery of shared pathogenetic mechanisms and joint drug discovery in NAFLD/NASH and HFpEF. Indeed, a beneficial effect of SGLT2i has been reported not only in patients with HFpEF, but observed in meta-analytic data of NAFLD/NASH as well.
References
- Nonalcoholic Fatty Liver Disease and Cardiovascular Risk: A Scientific Statement From the American Heart Association. Arterioscler Thromb Vasc Biol. 2022;42:e168–e185.
- Cardiometabolic HFpEF: NASH of the Heart. Capone F; Vettor R; Schiattarella GG; Circulation. 2023;147:451–453.
NAFLD: It’s all about calories
Paper: Effects of Time-Restricted Eating on Nonalcoholic Fatty Liver Disease: The TREATY-FLD Randomized Clinical Trial.
By: Wei, X., Lin, B., Huang, Y., Yang, S., Huang, C., Shi, L., ... & Zhang, H. (2023).
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
JAMA Network Open, 6(3), e233513-e233513.
While new drugs will become available soon for the treatment of NAFLD, diet as part of a lifestyle intervention remains the most efficient and clinically the only accepted approach for his condition. Most diets are similarly effective on the long run with respect to body weight reduction. However, the effects on NAFLD have been less well studied. The most efficient and widely recommended diet in this respect is a Mediterranean-style diet. A newly promoted intervention to lose weight is “time-restricted eating”. Some authors, like myself, believe that the only reason why this “diet” works is the fact that the total daily amount of calories ingested in this way decreases significantly, thereby resulting in weight reduction. In the accompanying paper Wei et al compared time-restricted eating to daily calorie restriction in a RCT. The total calorie intake was identical in both groups after 12 months. Body composition and body weight improved similarly in both groups. There was no difference in intrahepatic TG content or liver elasticity when measured by MRI.
Once again, it’s calories that count.
However, the quality of food is also relevant. The relationship between NAFLD and fructose intake, for example, has been convincingly established.
By: Wei, X., Lin, B., Huang, Y., Yang, S., Huang, C., Shi, L., ... & Zhang, H. (2023).
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
JAMA Network Open, 6(3), e233513-e233513.
While new drugs will become available soon for the treatment of NAFLD, diet as part of a lifestyle intervention remains the most efficient and clinically the only accepted approach for his condition. Most diets are similarly effective on the long run with respect to body weight reduction. However, the effects on NAFLD have been less well studied. The most efficient and widely recommended diet in this respect is a Mediterranean-style diet. A newly promoted intervention to lose weight is “time-restricted eating”. Some authors, like myself, believe that the only reason why this “diet” works is the fact that the total daily amount of calories ingested in this way decreases significantly, thereby resulting in weight reduction. In the accompanying paper Wei et al compared time-restricted eating to daily calorie restriction in a RCT. The total calorie intake was identical in both groups after 12 months. Body composition and body weight improved similarly in both groups. There was no difference in intrahepatic TG content or liver elasticity when measured by MRI.
Once again, it’s calories that count.
However, the quality of food is also relevant. The relationship between NAFLD and fructose intake, for example, has been convincingly established.
Read Full Article here
The Franciscus Obesity NASH Study (FONS): An Observational Prospective Cohort Study on the Impact of Bariatric Surgery on NAFLD/NASH
Written by Dr. Willy Theel, physician assistant and PhD candidate in Internal Medicine at Franciscus Gasthuis & Vlietland. Dr. Theel collaborates closely with Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
The prevalence of nonalcoholic fatty liver disease (NAFLD) ranges from 25% in the general population to 90% in patients with obesity scheduled for bariatric surgery. NAFLD can progress towards nonalcoholic steatohepatitis (NASH) associated with complications like cirrhosis, hepatocellular carcinoma and cardiovascular disease. To date, losing weight and lifestyle modifications are the best known treatments for NASH. Bariatric surgery significantly improves NAFLD/NASH in the short term. However, the extent of this improvement is not yet clear and long term data on the natural course of NAFLD/NASH after bariatric surgery are lacking. The factors involved in NAFLD/NASH regression after bariatric surgery have not been elucidated.
The Franciscus Obesity NASH Study (FONS) is an observational prospective cohort study including patients scheduled for bariatric surgery in the Franciscus Gasthuis in Rotterdam. Extensive metabolic and cardiovascular analyses will be carried out including measurements of carotid intima media thickness and pulse wave velocity. Genomic, lipidomic and metabolomic studies will be done. Microbioma analyses before and 1 year after surgery will be done. Transient elastography measurements will be performed before and at 1, 3 and 5 years after surgery. For those with an elevated preoperative transient elastography measurement by Fibroscan, a laparoscopic liver biopsy will be performed during surgery. Primary outcome measures are the change of steatosis and liver fibrosis 5 years after surgery. Secondary outcome measure is the comparison of the transient elastography measurements with the NAFLD Activity Score from the biopsies.
The prevalence of nonalcoholic fatty liver disease (NAFLD) ranges from 25% in the general population to 90% in patients with obesity scheduled for bariatric surgery. NAFLD can progress towards nonalcoholic steatohepatitis (NASH) associated with complications like cirrhosis, hepatocellular carcinoma and cardiovascular disease. To date, losing weight and lifestyle modifications are the best known treatments for NASH. Bariatric surgery significantly improves NAFLD/NASH in the short term. However, the extent of this improvement is not yet clear and long term data on the natural course of NAFLD/NASH after bariatric surgery are lacking. The factors involved in NAFLD/NASH regression after bariatric surgery have not been elucidated.
The Franciscus Obesity NASH Study (FONS) is an observational prospective cohort study including patients scheduled for bariatric surgery in the Franciscus Gasthuis in Rotterdam. Extensive metabolic and cardiovascular analyses will be carried out including measurements of carotid intima media thickness and pulse wave velocity. Genomic, lipidomic and metabolomic studies will be done. Microbioma analyses before and 1 year after surgery will be done. Transient elastography measurements will be performed before and at 1, 3 and 5 years after surgery. For those with an elevated preoperative transient elastography measurement by Fibroscan, a laparoscopic liver biopsy will be performed during surgery. Primary outcome measures are the change of steatosis and liver fibrosis 5 years after surgery. Secondary outcome measure is the comparison of the transient elastography measurements with the NAFLD Activity Score from the biopsies.
INNOVATIONS IN NAFLD CARE WORKSHOP 2023: ABSTRACT SUBMISSION
We are proud to endorse the Innovations in NAFLD Care Workshop 2023, organized by Academic Medical Education in collaboration with Drs. Jeffrey Lazarus and Jörn Schattenberg.
The aim of the workshop is to provide a platform to bring together the relevant stakeholders and patients to optimize NAFLD care. The 2-day program will explore the different perspectives that healthcare professionals and patients with NAFLD face daily. It will highlight where healthcare providers and policymakers can implement the most comprehensive models of NAFLD care.
Are you working on innovations in NAFLD care? Then make sure to submit your findings and share your research with your peers on 26-27 May 2023. Registration fees are waived for healthcare professionals from resource-limited settings and young professionals with an accepted abstract.
Abstract Deadline: Tuesday, 28 February 2023
The aim of the workshop is to provide a platform to bring together the relevant stakeholders and patients to optimize NAFLD care. The 2-day program will explore the different perspectives that healthcare professionals and patients with NAFLD face daily. It will highlight where healthcare providers and policymakers can implement the most comprehensive models of NAFLD care.
Are you working on innovations in NAFLD care? Then make sure to submit your findings and share your research with your peers on 26-27 May 2023. Registration fees are waived for healthcare professionals from resource-limited settings and young professionals with an accepted abstract.
Abstract Deadline: Tuesday, 28 February 2023
Review article: the epidemiologic burden of non-alcoholic fatty liver disease across the world
Linda Henry | James Paik | Zobair M. Younossi
Aliment Pharmacol Ther. 2022 Sep;56(6):942-956. doi: 10.1111/apt.17158. Epub 2022 Jul 26.
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
The estimated prevalence of NAFLD was until recent around 25%. Novel data from Zobair Younossi’s group now show that the prevalence is rising rapidly, even over 30%! These are alarming figures and a call to action for policy makers, caregivers and patient organizations. Of course we need to keep in mind that these are data extrapolated from different databases and need confirmation in real life. Active screening in high risk populations like T2DM, obesity and in patients with hypertension and a cardiovascular history is needed. For this purpose more precise and widely available non-invasive tests are needed. This can only be done if awareness for this great public problem increases.
Aliment Pharmacol Ther. 2022 Sep;56(6):942-956. doi: 10.1111/apt.17158. Epub 2022 Jul 26.
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
The estimated prevalence of NAFLD was until recent around 25%. Novel data from Zobair Younossi’s group now show that the prevalence is rising rapidly, even over 30%! These are alarming figures and a call to action for policy makers, caregivers and patient organizations. Of course we need to keep in mind that these are data extrapolated from different databases and need confirmation in real life. Active screening in high risk populations like T2DM, obesity and in patients with hypertension and a cardiovascular history is needed. For this purpose more precise and widely available non-invasive tests are needed. This can only be done if awareness for this great public problem increases.
Read Full Article here
The fibrosis-4 score is associated with long-term mortality in different phenotypes of acute heart failure
Chih-Hsueh Tseng, Wei-Min Huang, Wen-Chung Yu1, Hao-Min Cheng, Hao-Chih Chang, Pai-Feng Hsu1, Chern-En Chiang, Chen-Huan Chen, Shih-Hsien Sung.
Eur J Clin Invest. 2022;52:e13856
Commentary by Marco Aligns, scientific officer at Julius Clinical.
Acute heart failure is often accompanied by increased central venous pressure and hepatic congestion. In a retrospective observational study, the authors investigated the prognostic value of FIB4 in acute heart failure (AHF). Baseline characteristics, echocardiographic parameters and admission biochemistry were collected from 1854 patients admitted for AHF between 2003 and 2012. Mortality data up to 5 years after discharge were obtained from Taiwan’s national death registry.
Mean age was 75 yr. A third of the patients had new onset HF. HF with preserved ejection fraction (HFpEF) was present in 59% of the patients, and HF with reduced ejection fraction (HFrEF) in 26%. Hypertension, diabetes and chronic kidney disease ≥stage 3 was present in 58%, 35% and 71% respectively.
Baseline medication comprised betablockers, RAS inhibition and mineralocorticoid inhibitors in 34%, 54% and 32% respectively.
During a mean follow-up of 28.3 ± 21.8 months, 51% of the patients died.
Patients with a FIB4 score >3.25 were older (mean 79 yr) than patients with a FIB4 score <1.45 (mean 66 yr). Compared to patients with a FIB4 score <1.45, both all cause and cardiovascular death was significantly higher in patients with a FIB4 score >3.25. After adjusting for various baseline variables (among which age, comorbidities, left ventricular ejection fraction and medication), FIB4 score remained predictive of 5 year mortality.
Review: The results of the study should be interpreted in light of limitations inherent to a retrospective study. In addition, the reported heart failure treatment is not representative for contemporary treatment. It seems plausible that scarring of the liver is related to the duration of hepatic congestion, and is more present with longstanding heart failure. However, no stratification was made for the duration of heart failure, and a third of the patients even had new onset HF. Indeed, highest FIB4 scores were seen in older patients, and more often in patients with worsening heart failure.
The FIB4 index was originally developed to predict liver fibrosis in patients with HIV/HCV coinfection using routine laboratory tests. Fib4 is calculated from age, ALT, AST and the platelet count: FIB4 = (age [yr] x AST [U/L]) / ((PLT [10(9)/L]) x (ÖALT [U/L])).
FIB4 <1.45 had a negative predictive value of 90% and a sensitivity of 70% to exclude advanced fibrosis. Fib4 >3.25 had a positive predictive value of 65% and a specificity of 97%. [1]
Top tertile and quartile of Fib4 scores have been shown to be associated with cardiovascular events and all-cause mortality in AF patients,[2] in patients with HFpEF,[3] in patients with acute HF [4] and in patients with ischemic stroke.[5] In critically ill patients FIB4 score was associated with clinical outcomes as well.[6] In the general population, FIB4 was associated with an increased incidence of renal failure,[7] with liver cancer,[8] and depression,[9] but not with cardiovascular events.[10]
Whether in the current studie FIB4 was a marker of true hepatic fibrosis or a marker of advanced (co)morbidities remains to be seen. Prospective observational studies are needed to establish the predictive value of FIB4 in heart failure patients.
Lifestyle-related diseases, such as obesity, type 2 diabetes, dyslipidemia, and hypertension, are closely associated with both cardiovascular disease and with NAFLD. As the FIB4 score is a cheap and readily available screening tool, standard FIB4 determination in heart failure patients with prospective follow up could provide insight in the impact of (the duration of) heart failure on liver fibrosis, and on the consequences of liver fibrosis in the setting of heart failure.
Eur J Clin Invest. 2022;52:e13856
Commentary by Marco Aligns, scientific officer at Julius Clinical.
Acute heart failure is often accompanied by increased central venous pressure and hepatic congestion. In a retrospective observational study, the authors investigated the prognostic value of FIB4 in acute heart failure (AHF). Baseline characteristics, echocardiographic parameters and admission biochemistry were collected from 1854 patients admitted for AHF between 2003 and 2012. Mortality data up to 5 years after discharge were obtained from Taiwan’s national death registry.
Mean age was 75 yr. A third of the patients had new onset HF. HF with preserved ejection fraction (HFpEF) was present in 59% of the patients, and HF with reduced ejection fraction (HFrEF) in 26%. Hypertension, diabetes and chronic kidney disease ≥stage 3 was present in 58%, 35% and 71% respectively.
Baseline medication comprised betablockers, RAS inhibition and mineralocorticoid inhibitors in 34%, 54% and 32% respectively.
During a mean follow-up of 28.3 ± 21.8 months, 51% of the patients died.
Patients with a FIB4 score >3.25 were older (mean 79 yr) than patients with a FIB4 score <1.45 (mean 66 yr). Compared to patients with a FIB4 score <1.45, both all cause and cardiovascular death was significantly higher in patients with a FIB4 score >3.25. After adjusting for various baseline variables (among which age, comorbidities, left ventricular ejection fraction and medication), FIB4 score remained predictive of 5 year mortality.
Review: The results of the study should be interpreted in light of limitations inherent to a retrospective study. In addition, the reported heart failure treatment is not representative for contemporary treatment. It seems plausible that scarring of the liver is related to the duration of hepatic congestion, and is more present with longstanding heart failure. However, no stratification was made for the duration of heart failure, and a third of the patients even had new onset HF. Indeed, highest FIB4 scores were seen in older patients, and more often in patients with worsening heart failure.
The FIB4 index was originally developed to predict liver fibrosis in patients with HIV/HCV coinfection using routine laboratory tests. Fib4 is calculated from age, ALT, AST and the platelet count: FIB4 = (age [yr] x AST [U/L]) / ((PLT [10(9)/L]) x (ÖALT [U/L])).
FIB4 <1.45 had a negative predictive value of 90% and a sensitivity of 70% to exclude advanced fibrosis. Fib4 >3.25 had a positive predictive value of 65% and a specificity of 97%. [1]
Top tertile and quartile of Fib4 scores have been shown to be associated with cardiovascular events and all-cause mortality in AF patients,[2] in patients with HFpEF,[3] in patients with acute HF [4] and in patients with ischemic stroke.[5] In critically ill patients FIB4 score was associated with clinical outcomes as well.[6] In the general population, FIB4 was associated with an increased incidence of renal failure,[7] with liver cancer,[8] and depression,[9] but not with cardiovascular events.[10]
Whether in the current studie FIB4 was a marker of true hepatic fibrosis or a marker of advanced (co)morbidities remains to be seen. Prospective observational studies are needed to establish the predictive value of FIB4 in heart failure patients.
Lifestyle-related diseases, such as obesity, type 2 diabetes, dyslipidemia, and hypertension, are closely associated with both cardiovascular disease and with NAFLD. As the FIB4 score is a cheap and readily available screening tool, standard FIB4 determination in heart failure patients with prospective follow up could provide insight in the impact of (the duration of) heart failure on liver fibrosis, and on the consequences of liver fibrosis in the setting of heart failure.
Read Full Article here
References
- Sterling R.K., Lissen E., Clumeck N., Sola R., Correa M.C., Montaner J., Sulkowski M.S., Torriani F.J., Dieterich D.T., Thomas D.L., et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43:1317–1325
- Yuki Saito et al. Impact of the Fibrosis-4 Index on Risk Stratification of Cardiovascular Events and Mortality in Patients with Atrial Fibrillation: Findings from a Japanese Multicenter Registry. J Clin Med. 2020 Feb; 9(2): 584
- Naoki Shibata et al., Impact of predictive value of Fibrosis-4 index in patients hospitalized for acute heart failure. Int J Cardiol. 2021;324:90-95
- Masafumi Takae et al., Prognostic significance of liver stiffness assessed by fibrosis-4 index in patients with heart failure. ESC Heart Fail 2021;8(5):3809-3821
- Baik M et al., Advanced Liver Fibrosis Predicts Unfavorable Long-Term Prognosis in First-Ever Ischemic Stroke or Transient Ischemic Attack. Cerebrovasc Dis. 2020;49(5):474-480
- Yi-Yi Shi et al., Association of FIB-4 index and clinical outcomes in critically ill patients with acute kidney injury: a cohort study. BMC Gastroenterol 2021;21(1):483.
- Schleicher EM. A higher FIB-4 index is associated with an increased incidence of renal failure in the general population. Hepatol Commun. 2022, doi: 10.1002/hep4.2104. Online ahead of print
- Loosen SH et al., An elevated FIB-4 score is associated with an increased incidence of liver cancer: A longitudinal analysis among 248,224 outpatients in Germany. Eur J Cancer. 2022;168:41-50
- Schöler D et al., An Elevated FIB-4 Score Is Associated with an Increased Incidence of Depression among Outpatients in Germany. J Clin Med. 2022 Apr 15;11(8):2214
- Loosen S et al., An elevated FIB-4 score is not associated with cardiovascular events: a longitudinal analysis from 137 842 patients with and without chronic liver disease. Eur J Gastroenterol Hepatol 2022;34(6):717-723
Liver fibrosis and steatosis markers: long term improvement by PPAR α/γ agonist aleglitazar
Paper: Improvement of non-invasive tests of liver steatosis and fibrosis as indicators for nonalcoholic fatty liver disease in type 2 diabetes mellitus patients with elevated cardiovascular risk profile using the PPAR-α/γ agonist aleglitazar.
Esmée J Grobbee, Vivian D de Jong, Ilse C Schrieks, Maarten E Tushuizen, Adriaan G Holleboom, Jean-Claude Tardif, A Michael Lincoff, Gregory G Schwartz, Manuel Castro Cabezas, Diederick E Grobbee.
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
PLOS ONE 2022-17(11): e0277706
Long term data of liver fibrosis and steatosis markers from ramdomized clinical trials in T2DM are very scarce. The Julius Clinical NASH Team in collaboration with a group of international collaborators recently published a subanalysis from the Alecardio intervention trial dealing with this specific subject. The data clearly show beneficial effects over 2 years in T2DM subjects taking aleglitazar (n=3616), a PPAR α/γ agonist. LFS, LAP, FIB-4 and NFS showed persistent lower results compared to placebo (n=3610). Interestingly, these results were independent from BMI changes, since a small increase was observed in the Aleglitazar group. These data underscore the importance of the PPAR pathway in the management of NAFLD in subjects with T2DM. New analyses describing other interesting aspects from the Alecardio trial will appear soon.
Esmée J Grobbee, Vivian D de Jong, Ilse C Schrieks, Maarten E Tushuizen, Adriaan G Holleboom, Jean-Claude Tardif, A Michael Lincoff, Gregory G Schwartz, Manuel Castro Cabezas, Diederick E Grobbee.
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
PLOS ONE 2022-17(11): e0277706
Long term data of liver fibrosis and steatosis markers from ramdomized clinical trials in T2DM are very scarce. The Julius Clinical NASH Team in collaboration with a group of international collaborators recently published a subanalysis from the Alecardio intervention trial dealing with this specific subject. The data clearly show beneficial effects over 2 years in T2DM subjects taking aleglitazar (n=3616), a PPAR α/γ agonist. LFS, LAP, FIB-4 and NFS showed persistent lower results compared to placebo (n=3610). Interestingly, these results were independent from BMI changes, since a small increase was observed in the Aleglitazar group. These data underscore the importance of the PPAR pathway in the management of NAFLD in subjects with T2DM. New analyses describing other interesting aspects from the Alecardio trial will appear soon.
Read Full Article here
NAFLD, PPARS and TRIGLYCERIDES: PROMINENT shift from CIRCULATION to the LIVER
Paper: Triglyceride lowering with pemafibrate to reduce cardiovascular risk, N Engl J Med 2022: doi: 10.1056/NEJMoa2210645
By: A. Das Pradhan et al.
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
Date: November 15, 2022
Triglyceride metabolism is a key factor in the development of NAFLD. The interplay between adipose tissue, circulatory and liver triglycerides is currently being investigated in great detail. Liver steatosis can result in NASH and other liver and cardiovascular complications. Fibrates (PPAR alfa agonists) have been used to decrease circulatory triglycerides in the hope that cardiovascular disease risk could be managed. The publication of the PROMINENT trial in which pemafibrate was used in a population of patients with mild hypertriglyceridemia seems to mark the end of the fibrate story to reduce cardiovascular risk. PROMINENT was stopped prematurely due to futility with respect to the primary cardiovascular endpoint. However, the paper reports a 22% risk reduction for investigator-reported NAFLD. Unfortunately, data on diagnostic procedures to establish NAFLD were not provided in the paper. Publication of more details are needed to evaluate this effect objectively. This report aligns with other publications suggesting that PPAR alfa agonists may have beneficial effects with respect to NAFLD. In addition, pan-PPAR agonists like lanifibranor are being studied and promising results have been published in relation to NAFLD/NASH. The results of the NATIVE phase 3 study will help to establish the PPAR position in the treatment of this condition.
By: A. Das Pradhan et al.
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
Date: November 15, 2022
Triglyceride metabolism is a key factor in the development of NAFLD. The interplay between adipose tissue, circulatory and liver triglycerides is currently being investigated in great detail. Liver steatosis can result in NASH and other liver and cardiovascular complications. Fibrates (PPAR alfa agonists) have been used to decrease circulatory triglycerides in the hope that cardiovascular disease risk could be managed. The publication of the PROMINENT trial in which pemafibrate was used in a population of patients with mild hypertriglyceridemia seems to mark the end of the fibrate story to reduce cardiovascular risk. PROMINENT was stopped prematurely due to futility with respect to the primary cardiovascular endpoint. However, the paper reports a 22% risk reduction for investigator-reported NAFLD. Unfortunately, data on diagnostic procedures to establish NAFLD were not provided in the paper. Publication of more details are needed to evaluate this effect objectively. This report aligns with other publications suggesting that PPAR alfa agonists may have beneficial effects with respect to NAFLD. In addition, pan-PPAR agonists like lanifibranor are being studied and promising results have been published in relation to NAFLD/NASH. The results of the NATIVE phase 3 study will help to establish the PPAR position in the treatment of this condition.
Alcohol -produced by the gut microbiota- does play a role in non-alcoholic fatty liver disease
Paper: Microbiome-derived ethanol in nonalcoholic fatty liver disease, Nature Medicine, 2022
By: AS Meijnikman et al.
Commentary by Vivian de Jong, scientific officer at Julius Clinical.
Date: 13 October 2022
NAFLD and alcoholic fatty liver disease (ALD) are categorized as two different diseases, although there is overlap in the histology of affected livers. The gut microbiota produces different metabolites, and under certain circumstances also ethanol (alcohol). The question is, whether the gut microbiota can produce enough ethanol to negatively impact the liver. The authors of the current paper carried out a set of elegant experiments to answer this question.
Endogenous produced ethanol moves to the liver through the portal vein, where it will be metabolized. Measurements in portal vein blood are technically difficult. The research team overcame this hurdle by taking portal vein blood samples during bariatric surgery in their cohort and in a validation cohort. They found that portal vein microbial ethanol concentrations were higher in the NAFL and NASH groups compared to patients without steatosis. In accordance, a mixed-meal test raised peripheral ethanol concentrations, and again the raise was more profound in the NAFL and NASH groups. Additional intervention studies were carried out. When ethanol metabolization was blocked with a selective alcohol dehydrogenase (ADH) inhibitor, the ethanol levels in peripheral blood were raised. Furthermore, when antibiotics were given to deplete the microbiome, almost no ethanol was detected anymore.
This led the authors to conclude that the gut microbiota of severe obese individuals produces large amounts of ethanol that can be clinically relevant for the pathogenesis of NAFLD, and the ethanol could be a driving force in disease development and progression. And thus, NAFLD and AFL might be more similar than thought previously.
By: AS Meijnikman et al.
Commentary by Vivian de Jong, scientific officer at Julius Clinical.
Date: 13 October 2022
NAFLD and alcoholic fatty liver disease (ALD) are categorized as two different diseases, although there is overlap in the histology of affected livers. The gut microbiota produces different metabolites, and under certain circumstances also ethanol (alcohol). The question is, whether the gut microbiota can produce enough ethanol to negatively impact the liver. The authors of the current paper carried out a set of elegant experiments to answer this question.
Endogenous produced ethanol moves to the liver through the portal vein, where it will be metabolized. Measurements in portal vein blood are technically difficult. The research team overcame this hurdle by taking portal vein blood samples during bariatric surgery in their cohort and in a validation cohort. They found that portal vein microbial ethanol concentrations were higher in the NAFL and NASH groups compared to patients without steatosis. In accordance, a mixed-meal test raised peripheral ethanol concentrations, and again the raise was more profound in the NAFL and NASH groups. Additional intervention studies were carried out. When ethanol metabolization was blocked with a selective alcohol dehydrogenase (ADH) inhibitor, the ethanol levels in peripheral blood were raised. Furthermore, when antibiotics were given to deplete the microbiome, almost no ethanol was detected anymore.
This led the authors to conclude that the gut microbiota of severe obese individuals produces large amounts of ethanol that can be clinically relevant for the pathogenesis of NAFLD, and the ethanol could be a driving force in disease development and progression. And thus, NAFLD and AFL might be more similar than thought previously.
Read Full Article here
DNL genes and CAD
Paper: Association between de novo lipogenesis susceptibility genes and coronary artery disease
Pomme I.H.G. Simons, Olivier Valkenburg, Coen D.A. Stehouwer and Martijn C.G.J. Brouwers
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
Nutr Metab Cardiovasc Disease 2022, in press.
The controversy about the increased risk of cardiovascular disease in patients with NAFLD, seems to be settled now most international cardiology and atherosclerosis societies have published statements confirming this association. NAFLD is now being accepted as an important cardiovascular risk factor. The pathophysiological mechanisms, are not that clear yet. While the typical dyslipidemia of the metabolic syndrome (low HDL-C/high triglycerides), the systemic inflammation and the clustering of risk factors in NAFLD may all play a role, the clinical consequences are less well clear. The Maastricht group led by Professors Martijn Brouwers and Coen Stehouwer used a genetic epidemiology approach including 2 different databases (the CARDIoGRAM and UK Biobank datasets), showing that the genes associated to de novo lipogenesis, which is one of the major pathophysiological drivers in NAFLD, are more closely connected to the risk of coronary artery disease (CAD) than genes directly involved in fatty acid metabolism. This elegant study contributes to our understanding of the pathogenesis of CAD in NAFLD.
Pomme I.H.G. Simons, Olivier Valkenburg, Coen D.A. Stehouwer and Martijn C.G.J. Brouwers
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
Nutr Metab Cardiovasc Disease 2022, in press.
The controversy about the increased risk of cardiovascular disease in patients with NAFLD, seems to be settled now most international cardiology and atherosclerosis societies have published statements confirming this association. NAFLD is now being accepted as an important cardiovascular risk factor. The pathophysiological mechanisms, are not that clear yet. While the typical dyslipidemia of the metabolic syndrome (low HDL-C/high triglycerides), the systemic inflammation and the clustering of risk factors in NAFLD may all play a role, the clinical consequences are less well clear. The Maastricht group led by Professors Martijn Brouwers and Coen Stehouwer used a genetic epidemiology approach including 2 different databases (the CARDIoGRAM and UK Biobank datasets), showing that the genes associated to de novo lipogenesis, which is one of the major pathophysiological drivers in NAFLD, are more closely connected to the risk of coronary artery disease (CAD) than genes directly involved in fatty acid metabolism. This elegant study contributes to our understanding of the pathogenesis of CAD in NAFLD.
Read Full Article here
Prognostic non-invasive biomarkers for all-cause mortality in non-alcoholic fatty liver disease: A systematic review and meta-analysis
Cianci N, Subhani M, Hill T, Khanna A, Zheng D, Sheth A, Crooks C, Aithal GP. World J Hepatol 2022 May 27; 14(5): 866-1052
Commentary by J.B.L.Hoekstra, internist, Professor of Internal Medicine, University of Amsterdam and scientific officer at Julius Clinical.
Introduction
Every clinician involved in patients with diseases of the liver recognizes the clinical problem: ‘yes, this patient has without doubt nonalcoholic fatty liver disease (NAFLD), but no, I can’t tell him/her what his/her prognosis as for mortality is, unless a liver biopsy is being performed’. And a liver biopsy is of course quite an invasive procedure. This clinical problem is urgent as NAFLD is a growing and yet a major public health concern. Population based studies using imaging showed that at least 25% of American adults have a fatty liver. Morbidity and mortality in them are elevated. So, a relevant question is, what non-invasive tools could clinicians use to predict the prognosis of their patient? That is the subject of the recent systematic review and meta-analysis.
Methods
The authors performed electronic searches of Medline and EMBASE until 2021 of studies in NAFLD populations. Prognostic markers included serum biomarkers, non-invasive scoring systems such as NAFLD fibrosis score (NFS), fibrosis-4 index (FIB-4), and Enhanced Liver Fibrosis score (ELF), BARD score, AST to platelet ratio index and non-invasive imaging. The population included all spectrums of disease severity, including NAFLD and non-alcoholic steatohepatitis (NASH). Outcomes included all-cause and cardiovascular mortality. All non-invasive tests were synthesised in a narrative systematic review. Finally, a meta-analysis of non-invasive scoring systems for predicting all-cause and cardiovascular mortality was conducted, calculating pooled hazard ratios and 95% confidence.
Results
2850 studies were identified of which 24 were included. 16 studies reported non-invasive scoring systems, 10 studies reported individual biomarkers, and 1 study reported imaging modalities. 4 studies on non-invasive scoring systems (6324 participants) had data available for inclusion in the meta-analysis. The non-invasive scoring system that performed best at predicting all-cause mortality was NFS [HR 3.07 (1.62-5.83)], followed by FIB-4 [HR 3.06 (1.54-6.07)], BARD [HR 2.87 (1.27-6.46)], and AST to platelet ratio index [HR 1.90 (1.32-2.73)]. NFS was also prognostic of cardiovascular-related mortality [HR 3.09 (1.78-5.34)].
Conclusion and relevance for clinical practice
This study proves once more that non-invasive scoring systems are reliable prognostic markers of all-cause mortality. Best performing are NFS and FIB-4; NFS also predicts cardiovascular mortality in NAFLD patients. Does this mean that the problem of the clinician has been fully solved? No, but it is reassuring that non-invasive markers such as NFS and FIB-4 can help the clinician in stratifying patients, so in choosing to perform a liver biopsy of not in NAFLD patients.
Commentary by J.B.L.Hoekstra, internist, Professor of Internal Medicine, University of Amsterdam and scientific officer at Julius Clinical.
Introduction
Every clinician involved in patients with diseases of the liver recognizes the clinical problem: ‘yes, this patient has without doubt nonalcoholic fatty liver disease (NAFLD), but no, I can’t tell him/her what his/her prognosis as for mortality is, unless a liver biopsy is being performed’. And a liver biopsy is of course quite an invasive procedure. This clinical problem is urgent as NAFLD is a growing and yet a major public health concern. Population based studies using imaging showed that at least 25% of American adults have a fatty liver. Morbidity and mortality in them are elevated. So, a relevant question is, what non-invasive tools could clinicians use to predict the prognosis of their patient? That is the subject of the recent systematic review and meta-analysis.
Methods
The authors performed electronic searches of Medline and EMBASE until 2021 of studies in NAFLD populations. Prognostic markers included serum biomarkers, non-invasive scoring systems such as NAFLD fibrosis score (NFS), fibrosis-4 index (FIB-4), and Enhanced Liver Fibrosis score (ELF), BARD score, AST to platelet ratio index and non-invasive imaging. The population included all spectrums of disease severity, including NAFLD and non-alcoholic steatohepatitis (NASH). Outcomes included all-cause and cardiovascular mortality. All non-invasive tests were synthesised in a narrative systematic review. Finally, a meta-analysis of non-invasive scoring systems for predicting all-cause and cardiovascular mortality was conducted, calculating pooled hazard ratios and 95% confidence.
Results
2850 studies were identified of which 24 were included. 16 studies reported non-invasive scoring systems, 10 studies reported individual biomarkers, and 1 study reported imaging modalities. 4 studies on non-invasive scoring systems (6324 participants) had data available for inclusion in the meta-analysis. The non-invasive scoring system that performed best at predicting all-cause mortality was NFS [HR 3.07 (1.62-5.83)], followed by FIB-4 [HR 3.06 (1.54-6.07)], BARD [HR 2.87 (1.27-6.46)], and AST to platelet ratio index [HR 1.90 (1.32-2.73)]. NFS was also prognostic of cardiovascular-related mortality [HR 3.09 (1.78-5.34)].
Conclusion and relevance for clinical practice
This study proves once more that non-invasive scoring systems are reliable prognostic markers of all-cause mortality. Best performing are NFS and FIB-4; NFS also predicts cardiovascular mortality in NAFLD patients. Does this mean that the problem of the clinician has been fully solved? No, but it is reassuring that non-invasive markers such as NFS and FIB-4 can help the clinician in stratifying patients, so in choosing to perform a liver biopsy of not in NAFLD patients.
Monitoring NAFLD by repeated NITs
Paper: Repeated measurements of non-invasive fibrosis tests to monitor the progression of non-alcoholic fatty liver disease: A long-term follow-up study
Wile Balkhed, Fredrik O Åberg, Patrik Nasr, Mattias Ekstedt, & Stergios Kechagias
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
Liver International 2022; 42: 1545-1556.
Current guidelines advocate the use of non-invasive tests (NITs) to monitor NAFLD progression in individual patients. Data supporting this approach in clinical practice are scarce. Balkhed and colleagues collected data retrospectively in 135 patients in whom different blood-based tests were available during a period of around 12 years. In 74 subjects paired liver biopsies were available both at baseline and follow up. The NITs included were FIB-4, NFS, APRI and dAAR. NFS changes were not associated to disease progression at all. The diagnostic precision was suboptimal for the other 3 NITs with AUROCs of 0.56-0.64, making these tests less useful in the follow up of these patients. In their discussion, the authors make comparisons with previous studies by Siddiqui et al and Hagström et al, reaching different conclusions. Of course, more prospective data are needed to solve this issue. However, nobody will argue that other NITs like for example transient elastography, will be more suitable for the follow up of patients at risk. Unfortunately, the availability of these devices is limited and therefore, clinicians will have to rely on less accurate methods like the ones evaluated in the current paper.
Wile Balkhed, Fredrik O Åberg, Patrik Nasr, Mattias Ekstedt, & Stergios Kechagias
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
Liver International 2022; 42: 1545-1556.
Current guidelines advocate the use of non-invasive tests (NITs) to monitor NAFLD progression in individual patients. Data supporting this approach in clinical practice are scarce. Balkhed and colleagues collected data retrospectively in 135 patients in whom different blood-based tests were available during a period of around 12 years. In 74 subjects paired liver biopsies were available both at baseline and follow up. The NITs included were FIB-4, NFS, APRI and dAAR. NFS changes were not associated to disease progression at all. The diagnostic precision was suboptimal for the other 3 NITs with AUROCs of 0.56-0.64, making these tests less useful in the follow up of these patients. In their discussion, the authors make comparisons with previous studies by Siddiqui et al and Hagström et al, reaching different conclusions. Of course, more prospective data are needed to solve this issue. However, nobody will argue that other NITs like for example transient elastography, will be more suitable for the follow up of patients at risk. Unfortunately, the availability of these devices is limited and therefore, clinicians will have to rely on less accurate methods like the ones evaluated in the current paper.
Combined therapy for NASH: tackling inflammation and metabolism
Paper: Combined Therapy with a CCR2/CCR5 Antagonist and FGF21 Analogue Synergizes in Ameliorating Steatohepatitis and Fibrosis
Tobias Puengel, Sander Lefere, Jana Hundertmark, Marlene Kohlhepp, Christian Penners, Frederique Van de Velde, Bruno Lapauw, Anne Hoorens, Lindsey Devisscher, Anja Geerts, Stephanie Boehm, Qihong Zhao, John Krupinski, Edgar D. Charles, Bradley Zinker, and Frank Tacke.
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
Int J Mol Sciences 2022: 23,6696
It is generally accepted that the future of NASH treatment lies in combination therapy. While several promising phase 3 trials are being conducted with single drug interventions, these same compounds are already being tested in pre-clinical and clinical studies as combination therapy. The current paper by Puengel and colleagues is an excellent example of this approach. Ex vivo data in humans also indicated a close correlation between CCL2 serum levels and several inflammtory markers and FGF21 was best correlated to biomarkers of steatohepatitis. The authors studied CCR2/5 inhibition and FGF21 agonism in a rodent NASH model and found amelioration of steatohepatitis and fibrosis. This paper is one of the many showing that NASH regression will ultimately depend on interventions modulating multiple pathways.
Tobias Puengel, Sander Lefere, Jana Hundertmark, Marlene Kohlhepp, Christian Penners, Frederique Van de Velde, Bruno Lapauw, Anne Hoorens, Lindsey Devisscher, Anja Geerts, Stephanie Boehm, Qihong Zhao, John Krupinski, Edgar D. Charles, Bradley Zinker, and Frank Tacke.
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
Int J Mol Sciences 2022: 23,6696
It is generally accepted that the future of NASH treatment lies in combination therapy. While several promising phase 3 trials are being conducted with single drug interventions, these same compounds are already being tested in pre-clinical and clinical studies as combination therapy. The current paper by Puengel and colleagues is an excellent example of this approach. Ex vivo data in humans also indicated a close correlation between CCL2 serum levels and several inflammtory markers and FGF21 was best correlated to biomarkers of steatohepatitis. The authors studied CCR2/5 inhibition and FGF21 agonism in a rodent NASH model and found amelioration of steatohepatitis and fibrosis. This paper is one of the many showing that NASH regression will ultimately depend on interventions modulating multiple pathways.
Read Full Article here
5th Global NASH Congress Wrap-Up: NAFLD Screening in Primary Care Practices With The GRIP Program
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Our Chief Scientific Officer Rick Grobbee was recently interviewed by Louise Campbell for the Surfing the NASH Tsunami podcast.
Most of their conversation centered around our innovative GRIP on NASH Program. Furthermore, Louise and Rick discussed the value of a FibroScan or other scanning device in motivating patients as compared to blood tests and the need to create guidelines that make medical and economic sense in primary care practices. |
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Available at the Surfing the NASH Tsunami website:
Available on Spotify:
Noninvasive liver tests in severe obesity
Paper: Evaluation of nonalcoholic fatty liver disease (NAFLD) in severe obesity using noninvasive tests and imaging techniques
Willy Theel | Bianca M. Boxma-de Klerk | Femme Dirksmeier-Harinck | Elisabeth F. C. van Rossum | Danny A. Kanhai | Jan Apers | Bas M. van Dalen | Robert J. de Knegt | Anthony G. Holleboom | Maarten E. Tushuizen | Diederick E. Grobbee | Janneke Wiebolt | Manuel Castro Cabezas.
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
Obesity Reviews. 2022;1–18.
Obesity is one of the conditions closely associated to NAFLD. Patients with severe obesity scheduled for bariatric surgery should be screened for the presence of NAFLD and high risk subejcts with severe stages of fibrosis or even cirrhosis, should be identified preoperatively. The Julius Clinical NASH team in close collaboration with Academic partners in Rotterdam, Amsterdam and Leiden recently published a comprehensive review dealing with this important subject. Willy Theel and colleagues describe the clinical use of noninvaisve tests and different imaging techniques for identification of patients at risk. In addition, the pathogenesis and key elements in the development of NASH in severe obesity are being described. The authors also included very clear recommendations for cut-off values for different stages of steatosis and fibrosis when using the Fibroscan for screening purposes.
Willy Theel | Bianca M. Boxma-de Klerk | Femme Dirksmeier-Harinck | Elisabeth F. C. van Rossum | Danny A. Kanhai | Jan Apers | Bas M. van Dalen | Robert J. de Knegt | Anthony G. Holleboom | Maarten E. Tushuizen | Diederick E. Grobbee | Janneke Wiebolt | Manuel Castro Cabezas.
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
Obesity Reviews. 2022;1–18.
Obesity is one of the conditions closely associated to NAFLD. Patients with severe obesity scheduled for bariatric surgery should be screened for the presence of NAFLD and high risk subejcts with severe stages of fibrosis or even cirrhosis, should be identified preoperatively. The Julius Clinical NASH team in close collaboration with Academic partners in Rotterdam, Amsterdam and Leiden recently published a comprehensive review dealing with this important subject. Willy Theel and colleagues describe the clinical use of noninvaisve tests and different imaging techniques for identification of patients at risk. In addition, the pathogenesis and key elements in the development of NASH in severe obesity are being described. The authors also included very clear recommendations for cut-off values for different stages of steatosis and fibrosis when using the Fibroscan for screening purposes.
therapeutics in NASH
Paper: Breakthroughs in therapies for NASH and remaining challenges
Vlad Ratziu, Sven Francque & Arun Sanyal.
Commentary by M. Castro Cabezas, M, PhD, associate professor Internal Medicine at Erasmus MC and Franciscus Gasthuis & Vlietland and scientific officer at Julius Clinical.
J Hepatol 2022; 76: 1263-1278
While we still wait for the biggest step in NASH treatment, namely a pharmacological intervention which is safe, efficient and affordable Drs Ratziu, Francque and Sanyal published a timely and comprehensive review describing the most important breakthroughs in NASH treatment over the last decade or so. The authors describe very elegantly the major developments for five different classes of compounds (FXR agonists, Thyromimetics, Incretins, PPAR agonists and lipogenesis inhibitors). These interventions would never have led to the clinical trial stages if identification of pathways involved in the development of NASH would not have taken place. It is thanks to the efforts and perseverance of many investigators, not in the last place the authors of this paper, that great progress has been achieved in understanding the pathogenesis of NASH. Very interestingly, these authors also propose new regulatory requirements for approval of NASH medications in which results based on NITs outcomes may be considered instead of the now only accepted endpoints based on histology. This would facilitate drug development and it would increase our treatment modalities and improve clinical care for this group of patients for whom we have to rely on lifestyle intervention so far.
Vlad Ratziu, Sven Francque & Arun Sanyal.
Commentary by M. Castro Cabezas, M, PhD, associate professor Internal Medicine at Erasmus MC and Franciscus Gasthuis & Vlietland and scientific officer at Julius Clinical.
J Hepatol 2022; 76: 1263-1278
While we still wait for the biggest step in NASH treatment, namely a pharmacological intervention which is safe, efficient and affordable Drs Ratziu, Francque and Sanyal published a timely and comprehensive review describing the most important breakthroughs in NASH treatment over the last decade or so. The authors describe very elegantly the major developments for five different classes of compounds (FXR agonists, Thyromimetics, Incretins, PPAR agonists and lipogenesis inhibitors). These interventions would never have led to the clinical trial stages if identification of pathways involved in the development of NASH would not have taken place. It is thanks to the efforts and perseverance of many investigators, not in the last place the authors of this paper, that great progress has been achieved in understanding the pathogenesis of NASH. Very interestingly, these authors also propose new regulatory requirements for approval of NASH medications in which results based on NITs outcomes may be considered instead of the now only accepted endpoints based on histology. This would facilitate drug development and it would increase our treatment modalities and improve clinical care for this group of patients for whom we have to rely on lifestyle intervention so far.
Read Full Article here
NAFLD and Cardiovascular Disease: (un)settled?
Paper: Nonalcoholic Fatty Liver Disease and Cardiovascular Risk. A Scientific Statement From the American Heart Association
P. Barton Duell, MD, Chair; Francine K. Welty, MD, Vice Chair; Michael Miller, MD; Alan Chait, MD; Gmerice Hammond, MD, MPH; Zahid Ahmad, MD; David E. Cohen, MD, PhD; Jay D. Horton, MD; Gregg S. Pressman, MD; Peter P. Toth, MD, PhD; on behalf of the American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Hypertension; Council on the Kidney in Cardiovascular Disease; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
While many experts are convinced that NAFLD is an independent risk factor for CVD, just as many believe exactly the opposite. This debate has been going on for many years. The cause for this discrepancy is the fact that it is almost impossible to differentiate between NAFLD as a causal factor for CVD and the accompanying features usually present and related to insulin resistance. Many patients with NAFLD also have T2DM, metabolic syndrome, obesity, hypertension or dyslipidemia, which are all very closely related tot cardiovascular complications. The American Heart Associaton released a scientific statement drawing attention tot his growing clinical problem to create awareness among professionals dealing with these patients. In this comprehensive review, the authors urge professionals to consider NAFLD in high risk patients like those with metabolic syndrome and T2DM. The authors suggest that in these patients the threshold to consider a liver biopsy in order to establish the diagnosis, should be lower. Moreover, the authors advice to consider the presence of NAFLD as a risk enhancer when estimating cardiovascular risk. However, so far NAFLD has not been included in current cardiovascular risk guidelines. Given the current debates on this issue, probably more data will be needed before this is the case.
P. Barton Duell, MD, Chair; Francine K. Welty, MD, Vice Chair; Michael Miller, MD; Alan Chait, MD; Gmerice Hammond, MD, MPH; Zahid Ahmad, MD; David E. Cohen, MD, PhD; Jay D. Horton, MD; Gregg S. Pressman, MD; Peter P. Toth, MD, PhD; on behalf of the American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Hypertension; Council on the Kidney in Cardiovascular Disease; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
While many experts are convinced that NAFLD is an independent risk factor for CVD, just as many believe exactly the opposite. This debate has been going on for many years. The cause for this discrepancy is the fact that it is almost impossible to differentiate between NAFLD as a causal factor for CVD and the accompanying features usually present and related to insulin resistance. Many patients with NAFLD also have T2DM, metabolic syndrome, obesity, hypertension or dyslipidemia, which are all very closely related tot cardiovascular complications. The American Heart Associaton released a scientific statement drawing attention tot his growing clinical problem to create awareness among professionals dealing with these patients. In this comprehensive review, the authors urge professionals to consider NAFLD in high risk patients like those with metabolic syndrome and T2DM. The authors suggest that in these patients the threshold to consider a liver biopsy in order to establish the diagnosis, should be lower. Moreover, the authors advice to consider the presence of NAFLD as a risk enhancer when estimating cardiovascular risk. However, so far NAFLD has not been included in current cardiovascular risk guidelines. Given the current debates on this issue, probably more data will be needed before this is the case.
NAFLD in patients receiving dialysis
Paper: Prevalence and outcomes of chronic liver disease in patients receiving dialysis: systematic review and meta-analysis
Oscar Swift, Shivani Sharma, Sivaramakrishnan Ramanarayanan, Hamza Umar, Keith R. Laws, Enric Vilar and Ken Farrington
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
Clin Kidney J 2022: 15: 747-757
Chronic Kidney Disease (CKD) has been suggested to be closely associated to NAFLD. The relationship may be bidirectionally. This assumption is based on indirect observations or studies including very limited number of subjects. In the current paper, Swift and co-workers provide an elegant overview of the available evidence in patients undergoing haemodialysis. These patients have a very high cardiovascular and mortality risk. Swift et al describe that the evidence available points at a twice increased mortality risk in patients with NAFLD. The number of studies is very limited suggesting a NAFLD prevalence of over 50%, as shown in the accompanying figure from the paper. The authors conclude that more studies are necessary to evaluate the real contribution of NAFLD to the complications seen in these high-risk patients. So far, no studies have been performed with the newly developed drugs in this population of patients. First, more data should be collected on the prevalence of NAFLD/NASH, not only in patients on haemodialysis, but also in those with CKD. This represents an important unmet clinical need.
Oscar Swift, Shivani Sharma, Sivaramakrishnan Ramanarayanan, Hamza Umar, Keith R. Laws, Enric Vilar and Ken Farrington
Commentary by Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist and scientific officer at Julius Clinical.
Clin Kidney J 2022: 15: 747-757
Chronic Kidney Disease (CKD) has been suggested to be closely associated to NAFLD. The relationship may be bidirectionally. This assumption is based on indirect observations or studies including very limited number of subjects. In the current paper, Swift and co-workers provide an elegant overview of the available evidence in patients undergoing haemodialysis. These patients have a very high cardiovascular and mortality risk. Swift et al describe that the evidence available points at a twice increased mortality risk in patients with NAFLD. The number of studies is very limited suggesting a NAFLD prevalence of over 50%, as shown in the accompanying figure from the paper. The authors conclude that more studies are necessary to evaluate the real contribution of NAFLD to the complications seen in these high-risk patients. So far, no studies have been performed with the newly developed drugs in this population of patients. First, more data should be collected on the prevalence of NAFLD/NASH, not only in patients on haemodialysis, but also in those with CKD. This represents an important unmet clinical need.
Read Full Article here
AWARENASH PROJECT | CONTRIBUTE TO AWARENESS FOR NASH/NAFLD
Are you a healthcare professional, and do you want to contribute to improving the awareness for NAFLD and NASH? The AwareNASH project wants to increase awareness of NAFLD/NASH by developing educational activities.
SGLT2 inhibition and hepatic fatty acid oxidation: lessons from the postprandial state
Paper: Effects of dapagliflozin on postprandial lipid metabolism in type 2 diabetes mellitus
Benjamin Burggraaf, Nadine M C Pouw, Salvador Fernández Arroyo, Leonie C van Vark-van der Zee, Gert-Jan M van de Geijn, Erwin Birnie, Jeannine Huisbrink, Ellen M van der Zwan, Wouter W de Herder, Monique T Mulder, Patrick C N Rensen and Manuel Castro Cabezas
Commentary by: Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist
Scientific officer at Julius Clinical.
Eur J Endocrinol 2022: 186: 597-605
Treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) is becoming an important pillar in the treatment of T2DM. These compounds not only improve glucose metabolism, but they also confer unexpected cardiovascular protection. Not surprisingly, most guidelines for treatment of T2DM patients have prioritized the use of these drugs in high risk patients. SGLT2 inhibitors may also have beneficial effects for other conditions like NAFLD. SGLT2i increase hepatic fatty acid oxidation resulting in stimulated ketogenesis. The mechanism behind this process is still not well understood. Potentially, increased fatty acid oxidation may lead to lower hepatic fat contents. The accompanying study by Burggraaf et al from our group presents novel data on postprandial fatty acid oxidation and ketogenesis by dapagliflozin in T2DM. Interestingly, this study also found a significant reduction of postabsorptive apoB48-containing remnants, which may play a role in the cardioprotective studies reported in large clinical trials so far. It would not be surprising if in the near future these compounds will also be used in the treatment of NAFLD.
Benjamin Burggraaf, Nadine M C Pouw, Salvador Fernández Arroyo, Leonie C van Vark-van der Zee, Gert-Jan M van de Geijn, Erwin Birnie, Jeannine Huisbrink, Ellen M van der Zwan, Wouter W de Herder, Monique T Mulder, Patrick C N Rensen and Manuel Castro Cabezas
Commentary by: Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist
Scientific officer at Julius Clinical.
Eur J Endocrinol 2022: 186: 597-605
Treatment with sodium-glucose cotransporter 2 inhibitors (SGLT2i) is becoming an important pillar in the treatment of T2DM. These compounds not only improve glucose metabolism, but they also confer unexpected cardiovascular protection. Not surprisingly, most guidelines for treatment of T2DM patients have prioritized the use of these drugs in high risk patients. SGLT2 inhibitors may also have beneficial effects for other conditions like NAFLD. SGLT2i increase hepatic fatty acid oxidation resulting in stimulated ketogenesis. The mechanism behind this process is still not well understood. Potentially, increased fatty acid oxidation may lead to lower hepatic fat contents. The accompanying study by Burggraaf et al from our group presents novel data on postprandial fatty acid oxidation and ketogenesis by dapagliflozin in T2DM. Interestingly, this study also found a significant reduction of postabsorptive apoB48-containing remnants, which may play a role in the cardioprotective studies reported in large clinical trials so far. It would not be surprising if in the near future these compounds will also be used in the treatment of NAFLD.
Read Full Article here
Innovations in NAFLD Care Workshop 2022: abstract submission
We are happy to announce that the deadline for abstract submission for the 2022 Innovations in NAFLD Care Workshop has been extended! You now have until Wednesday, 9 March at 23:59 CET to submit your findings on NAFLD. Share your research and join the cross-disciplinary discussion – either in-person or online.
The NAFLD Care Workshop accepts original research as well as encored abstracts. Healthcare professionals from resource-limited settings and young professionals with an accepted abstract receive a 100% discount on their registration fee.
The NAFLD Care Workshop accepts original research as well as encored abstracts. Healthcare professionals from resource-limited settings and young professionals with an accepted abstract receive a 100% discount on their registration fee.
SPLENDOR shows reduction of MACE and liver related endpoints in liver biopsy proven NASH
Paper: Association of Bariatric Surgery With Major Adverse Liver and Cardiovascular Outcomes in Patients With Biopsy-Proven Nonalcoholic Steatohepatitis
Ali Aminian, MD; Abbas Al-Kurd, MD; Rickesha Wilson, MD; James Bena, MS; Hana Fayazzadeh, MD; Tavankit Singh, MD; Vance L. Albaugh, MD, PhD; Faiz U. Shariff, MD; Noe A. Rodriguez, MD; Jian Jin, MS; Stacy A. Brethauer, MD, MBA; Srinivasan Dasarathy, MD; Naim Alkhouri, MD; Philip R. Schauer, MD; Arthur J. McCullough, MD; Steven E. Nissen, MD
Commentary by: Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist
Scientific officer at Julius Clinical
The only treatment for NASH at this moment is lifestyle intervention and body weight reduction.
In the Surgical Procedures and Long-term Effectiveness in NASH Disease and Obesity Risk (SPLENDOR) study, Steven Nissen and his group evaluated retrospectively the effect of bariatric surgery on MACE and liver related endpoints. In this study, 1158 subjects were identified who had undergone a liver biopsy and in whom NASH had been established. In the final analysis 462 subjects underwent bariatric surgery (most of them Roux-en-Y gastric bypass surgery) and 462 subjects served as non-surgical controls. The median follow up was 7 years for each group. The NAFLD activity score varied from 3 (30,7%), 4 (29,2%), 5 (16,5%) 6 (4,8%) to 7 (0,4%).The cumulative incidence of liver related events was 2,3% in the surgical group and 9,6% in the control group, which was statistical significant. MACE occurred in 39 patients in the surgery group and 60 in the control group (adjusted HR 0,30 [95% CI, 0,12-0,72],P=0,007). This study clearly shows that bariatric surgery in patients with NASH has clinical benefits and the authors suggest that NASH may be an indication for bariatric surgery in the future. Guidelines for bariatric surgery should include NASH as a condition requiring intervention.
Ali Aminian, MD; Abbas Al-Kurd, MD; Rickesha Wilson, MD; James Bena, MS; Hana Fayazzadeh, MD; Tavankit Singh, MD; Vance L. Albaugh, MD, PhD; Faiz U. Shariff, MD; Noe A. Rodriguez, MD; Jian Jin, MS; Stacy A. Brethauer, MD, MBA; Srinivasan Dasarathy, MD; Naim Alkhouri, MD; Philip R. Schauer, MD; Arthur J. McCullough, MD; Steven E. Nissen, MD
Commentary by: Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist
Scientific officer at Julius Clinical
The only treatment for NASH at this moment is lifestyle intervention and body weight reduction.
In the Surgical Procedures and Long-term Effectiveness in NASH Disease and Obesity Risk (SPLENDOR) study, Steven Nissen and his group evaluated retrospectively the effect of bariatric surgery on MACE and liver related endpoints. In this study, 1158 subjects were identified who had undergone a liver biopsy and in whom NASH had been established. In the final analysis 462 subjects underwent bariatric surgery (most of them Roux-en-Y gastric bypass surgery) and 462 subjects served as non-surgical controls. The median follow up was 7 years for each group. The NAFLD activity score varied from 3 (30,7%), 4 (29,2%), 5 (16,5%) 6 (4,8%) to 7 (0,4%).The cumulative incidence of liver related events was 2,3% in the surgical group and 9,6% in the control group, which was statistical significant. MACE occurred in 39 patients in the surgery group and 60 in the control group (adjusted HR 0,30 [95% CI, 0,12-0,72],P=0,007). This study clearly shows that bariatric surgery in patients with NASH has clinical benefits and the authors suggest that NASH may be an indication for bariatric surgery in the future. Guidelines for bariatric surgery should include NASH as a condition requiring intervention.
Read Full Article here
Considerable Placebo Effect in NASH Trials:
A dynamic process, not to be underestimated
Paper: Placebo Effect on Progression and Regression in Non-Alcoholic Steatohepatitis. Evidence from a Meta-Analysis
Authors: Cheng Han Ng, Jieling Xiao, Wen Hui Lim, et al
Comment by: Manuel Castro Cabezas, MD, PhD
Journal: Hepatology 2022, doi: 10.1002/HEP.32315
Commentary:
In the accompanying paper by Ng and co-workers, the effect of participation in a NASH trial in the placebo arm have been analyzed in detail. The authors conducted a meta-analysis of 43 RCTs, including 2,649 placebo-treated patients. The majority of the studies (n=30) lasted for 6-12 months. The primary endpoints were resolution of NASH and 2 point reduction in NAS without worsening of fibrosis. According to the FDA criteria, resolution of NASH is defined as absence of fatty liver disease or isolated steatosis without steatohepatitis and a NAS score of 0–1 for inflammation, 0 for ballooning, and any value for steatosis.
Authors: Cheng Han Ng, Jieling Xiao, Wen Hui Lim, et al
Comment by: Manuel Castro Cabezas, MD, PhD
Journal: Hepatology 2022, doi: 10.1002/HEP.32315
Commentary:
In the accompanying paper by Ng and co-workers, the effect of participation in a NASH trial in the placebo arm have been analyzed in detail. The authors conducted a meta-analysis of 43 RCTs, including 2,649 placebo-treated patients. The majority of the studies (n=30) lasted for 6-12 months. The primary endpoints were resolution of NASH and 2 point reduction in NAS without worsening of fibrosis. According to the FDA criteria, resolution of NASH is defined as absence of fatty liver disease or isolated steatosis without steatohepatitis and a NAS score of 0–1 for inflammation, 0 for ballooning, and any value for steatosis.
Approximately one tenth of participants (11.65%) had NASH resolution without worsening of fibrosis while one fifth had a 2-point reduction in NAS without worsening of fibrosis or 1-point reduction in fibrosis that were independent of reduction in BMI. Conversely, 22.74% (CI: 19.63 to 26.17) of NASH patients had an advancement in fibrosis and 9.85% (CI: 5.45% to 17.13%) had progression in steatosis. According to the authors, these effects could not be explained by BMI changes. The authors suggest in their paper that “NASH is a dynamic disease that progresses and regresses with time and the confluence of changes in the metabolic milieu can affect the state of the disease”. These findings are extremely relevant for current and future trials in the NASH field. This large placebo effect needs to be taken into account and has a major impact in the power calculations of these trials.
Read Full Article here
Liver Disease Prioritized in Europe: Time for ActioN
Paper: The EASL–Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality
Authors: Tom H Karlsen, Nick Sheron, Shira Zelber-Sagi, et al
Comment by: Manuel Castro Cabezas, MD, PhD
Journal: Lancet 2021 https://doi.org/10.1016/ S0140-6736(21)01701-3
Commentary:
In the accompanying paper, the Lancet Liver commission draws attention to the huge impact of liver disease in the population. The fact that liver disease is now the second major cause of years of working life lost in Europe, after ischemic heart disease, is shocking and unexpected. This underlines the need for increased awareness among professionals and policy makers. While the combat against hepatitis B and C has been very successful, now we are facing the challenge of major changes concerning alcohol consumption (Europe has the highest alcohol consumption in the world!) but also in the development of NAFLD and NASH. Especially, these latter conditions can only be addressed by a multidisciplinary approach in which hepatologists, diabetologists, dietitians, cardiologists, and general practitioners (GPs) work together. In addition, the authors, very clearly state that a public health action on prevention is badly needed also including interventions for body weight control, stimulation of physical exercise and ban smoking. Altogether the authors plead for a broad implementation of a healthy lifestyle which remains the basis of successful liver disease interventions.
Authors: Tom H Karlsen, Nick Sheron, Shira Zelber-Sagi, et al
Comment by: Manuel Castro Cabezas, MD, PhD
Journal: Lancet 2021 https://doi.org/10.1016/ S0140-6736(21)01701-3
Commentary:
In the accompanying paper, the Lancet Liver commission draws attention to the huge impact of liver disease in the population. The fact that liver disease is now the second major cause of years of working life lost in Europe, after ischemic heart disease, is shocking and unexpected. This underlines the need for increased awareness among professionals and policy makers. While the combat against hepatitis B and C has been very successful, now we are facing the challenge of major changes concerning alcohol consumption (Europe has the highest alcohol consumption in the world!) but also in the development of NAFLD and NASH. Especially, these latter conditions can only be addressed by a multidisciplinary approach in which hepatologists, diabetologists, dietitians, cardiologists, and general practitioners (GPs) work together. In addition, the authors, very clearly state that a public health action on prevention is badly needed also including interventions for body weight control, stimulation of physical exercise and ban smoking. Altogether the authors plead for a broad implementation of a healthy lifestyle which remains the basis of successful liver disease interventions.
INnovations in NAFLD Care Webinar 2022
NASH Clinical is very proud to announce to be an endorser of the all-new NAFLD Care virtual webinar on 19 January 2022.
Organized by Academic Medical Education and chaired by Dr. Jeffrey Lazarus and Prof. Jörn Schattenberg, this series aim to bring together relevant stakeholders, leading healthcare professionals, and patient advocates to implement a multidisciplinary approach using comprehensive models of care for NAFLD. The growing burden of Non-Alcoholic Fatty Liver Disease (NAFLD) requires a concise effort involving multiple stakeholders to provide the best care for patients. The management of patients across different disease stages and the cascade of care, from prevention and diagnosis to treatment, should be outlined.
The first meeting in the series will be the Innovations in NAFLD Care Webinar 2022 taking place virtually on 19 January. The second meeting will be the Innovations in NAFLD Care Workshop 2022 taking place as a hybrid workshop in Barcelona, Spain, on 6-7 May
Organized by Academic Medical Education and chaired by Dr. Jeffrey Lazarus and Prof. Jörn Schattenberg, this series aim to bring together relevant stakeholders, leading healthcare professionals, and patient advocates to implement a multidisciplinary approach using comprehensive models of care for NAFLD. The growing burden of Non-Alcoholic Fatty Liver Disease (NAFLD) requires a concise effort involving multiple stakeholders to provide the best care for patients. The management of patients across different disease stages and the cascade of care, from prevention and diagnosis to treatment, should be outlined.
The first meeting in the series will be the Innovations in NAFLD Care Webinar 2022 taking place virtually on 19 January. The second meeting will be the Innovations in NAFLD Care Workshop 2022 taking place as a hybrid workshop in Barcelona, Spain, on 6-7 May
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Register now and join Dr. Jeffrey V. Lazarus and Prof. Dr. Jörn M. Schattenberg and hear a multidisciplinary discussion designed to optimize NAFLD care.
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Consensus Statement on NAFLD Strategy: moving towards compensated advanced chronic liver disease (cACLD)
Paper:
Lazarus JE, Mark HE, Anstee QM, et al. Advancing the global public health agenda for NAFLD: a consensus statement. Nature Rev Gastroenterol & Hepatol 2021.
By: Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist
Scientific officer at Julius Clinical
Date: December 10, 2021
NAFLD has become one of the most challenging conditions in medicine. While the magnitude of this medical problem is unprecedented, the gap with awareness and knowledge is enormous. Many scientific societies are trying to create awareness and have developed different programs to educate professionals and provide them with the tools to face this medical challenge. A very recent publication in Nature Reviews from Jeffrey Lazarus and colleagues, all well-known experts and frontrunners in the field, aims to help professionals and policy makers, to recognize and manage NAFLD and its complications. The authors used the Delphi method design to collect data and reflexions on NAFLD. Interestingly, the authors propose a new name to be used: compensated advanced chronic liver disease (cACLD), taking the “alcohol” quote out of the equation. This consensus statement from world leaders in the field, is an important document that should be widely spread among all stakeholders in all countries. It may also help national scientific societies in the implementation of guidelines.
Lazarus JE, Mark HE, Anstee QM, et al. Advancing the global public health agenda for NAFLD: a consensus statement. Nature Rev Gastroenterol & Hepatol 2021.
By: Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist
Scientific officer at Julius Clinical
Date: December 10, 2021
NAFLD has become one of the most challenging conditions in medicine. While the magnitude of this medical problem is unprecedented, the gap with awareness and knowledge is enormous. Many scientific societies are trying to create awareness and have developed different programs to educate professionals and provide them with the tools to face this medical challenge. A very recent publication in Nature Reviews from Jeffrey Lazarus and colleagues, all well-known experts and frontrunners in the field, aims to help professionals and policy makers, to recognize and manage NAFLD and its complications. The authors used the Delphi method design to collect data and reflexions on NAFLD. Interestingly, the authors propose a new name to be used: compensated advanced chronic liver disease (cACLD), taking the “alcohol” quote out of the equation. This consensus statement from world leaders in the field, is an important document that should be widely spread among all stakeholders in all countries. It may also help national scientific societies in the implementation of guidelines.
De novo lipogenesis and NASH: Dyrk1b, a new kid on the block
Paper:
Bhat N, Narayanan A, Fathzadeh M, Kahn M, et al. Dyrkb1 promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice. . J Clin Invest 2021
By: Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist
Scientific officer at Julius Clinical
Date: December 7, 2021
Liver fat accumulation has been proposed to depend on the capacity of the liver to oxidize lipids by beta oxidation, the inflow of fatty acids derived from intravascular lipolysis of triglyceride-rich lipoproteins and from adipose tissue stores, and from de novo lipogenesis (DNL). For instance, already in 2005 Kerry Donnelly and colleagues published in the JCI that while most of the hepatic triglycerides were derived from circulating NEFAs (59%), 26% originated from DNL and 14,9% from the diet. This observation was of great importance to understand how hepatic lipids accumulate and to identify the targets available to modulate this process. Several pharmaceutical companies have identified DNL as an important target to decrease hepatic lipids. For example, Liver X receptor (LXT) alpha-inhibitors have been tested but have not yet entered later phases in clinical trials. One of the possible causes may be the fact that (liver) insulin sensitivity does not improve by this intervention.
Now, a major breakthrough comes from a collaboration between investigators of Yale, Stanford and Columbia Universities. The authors discovered a new potentially interesting target for modulation of DNL and opening new options for drug discovery programs in the NASH. Dyrk1b (Dual-Specificity Tyrosine phosphorylation-regulated kinase 1b) plays a central role in hepatic lipogenesis and in liver insulin sensitivity modulating the influx of fatty acids by a direct effect on FABP1 and CD36 expression (see the accompanying figure of the recent publication included in this commentary). Inhibiting the expression of Dyrk1b may reduce liver fat and help to reduce NAFLD and prevent NASH. Dyrk1b seems to be a promising new kid on the block in the combat against fatty liver disease.
Bhat N, Narayanan A, Fathzadeh M, Kahn M, et al. Dyrkb1 promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice. . J Clin Invest 2021
By: Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist
Scientific officer at Julius Clinical
Date: December 7, 2021
Liver fat accumulation has been proposed to depend on the capacity of the liver to oxidize lipids by beta oxidation, the inflow of fatty acids derived from intravascular lipolysis of triglyceride-rich lipoproteins and from adipose tissue stores, and from de novo lipogenesis (DNL). For instance, already in 2005 Kerry Donnelly and colleagues published in the JCI that while most of the hepatic triglycerides were derived from circulating NEFAs (59%), 26% originated from DNL and 14,9% from the diet. This observation was of great importance to understand how hepatic lipids accumulate and to identify the targets available to modulate this process. Several pharmaceutical companies have identified DNL as an important target to decrease hepatic lipids. For example, Liver X receptor (LXT) alpha-inhibitors have been tested but have not yet entered later phases in clinical trials. One of the possible causes may be the fact that (liver) insulin sensitivity does not improve by this intervention.
Now, a major breakthrough comes from a collaboration between investigators of Yale, Stanford and Columbia Universities. The authors discovered a new potentially interesting target for modulation of DNL and opening new options for drug discovery programs in the NASH. Dyrk1b (Dual-Specificity Tyrosine phosphorylation-regulated kinase 1b) plays a central role in hepatic lipogenesis and in liver insulin sensitivity modulating the influx of fatty acids by a direct effect on FABP1 and CD36 expression (see the accompanying figure of the recent publication included in this commentary). Inhibiting the expression of Dyrk1b may reduce liver fat and help to reduce NAFLD and prevent NASH. Dyrk1b seems to be a promising new kid on the block in the combat against fatty liver disease.
References:
- Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in the liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 2005; 115: 1343-1351.
- Bhat N, Narayanan A, Fathzadeh M, Kahn M, et al. Dyrkb1 promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice. J Clin Invest 2021; https: //doi.org/10.1172/JCI153724
Good news for patients with nash!
Papers:
A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH
Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial
A Randomized, Controlled Trial of the Pan-PPAR Agonist Lanifibranor in NASH
Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial
S.M. Francque et al. A randomized, controlled trial of the Pan-PPAR agonist lanifibranor in NASH. N Engl J Med 2021; 385: 1547-1558.
V. Ratziu et al. Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2B trial. Nature Medicine 2021; doi.org/10.1038/s41591-021-01495-3
By: Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist
Scientific officer at Julius Clinical
Date: November 14, 2021
Pharmacological intervention in NASH has been rather disappointing so far. Several promising trials have not delivered the long awaited answer for this overwhelmingly prevalent condition, either by insufficient effects on NASH regression or by considerable side effects.
There is now time for optimism. Two recent phase 2B trials, one appearing in the NEJM by Sven Francque and colleagues describing the effects of lanifibranor (a Pan-PPAR agonist) and the other by Vlad Ratziu and colleagues with Aramchol (a partial inhibitor of hepatic stearoyl-CoA desaturase [SCD1])) in Nature Medicine, showed significant improvement in predefined NASH end points. NASH resolution without worsening of fibrosis one of the two most important endpoints in NASH trials, was established in both trials. In addition, side effects in both studies were very mild. The lanifibranor paper identified the 1200 mg dose as the most potent one, as is shown in the figure below from the publication.
V. Ratziu et al. Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2B trial. Nature Medicine 2021; doi.org/10.1038/s41591-021-01495-3
By: Dr. Manuel Castro Cabezas, internist-endocrinologist-vascular specialist
Scientific officer at Julius Clinical
Date: November 14, 2021
Pharmacological intervention in NASH has been rather disappointing so far. Several promising trials have not delivered the long awaited answer for this overwhelmingly prevalent condition, either by insufficient effects on NASH regression or by considerable side effects.
There is now time for optimism. Two recent phase 2B trials, one appearing in the NEJM by Sven Francque and colleagues describing the effects of lanifibranor (a Pan-PPAR agonist) and the other by Vlad Ratziu and colleagues with Aramchol (a partial inhibitor of hepatic stearoyl-CoA desaturase [SCD1])) in Nature Medicine, showed significant improvement in predefined NASH end points. NASH resolution without worsening of fibrosis one of the two most important endpoints in NASH trials, was established in both trials. In addition, side effects in both studies were very mild. The lanifibranor paper identified the 1200 mg dose as the most potent one, as is shown in the figure below from the publication.
If you want to receive the second paper, Aramchol in patients with nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled phase 2b trial, get in contact via [email protected]
Defective lipid droplet – lysosome interaction causes fatty liver disease as evidenced by human mutations in TMEM199 and CCDC115.
Larsen LE, van den Boogert MAW, Rios-Ocampo WA, Jansen JC, Conlon D, Chong PLE, Levels JHM, Eilers RE, Sachdev VV, Zelcer N, Raabe T, He M, Hand NJ, Drenth JPH, Rader DJ, Stroes ESG, Lefeber DJ, Jonker JW, Holleboom AG, Defective lipid droplet – lysosome interaction causes fatty liver disease as evidenced by human mutations in TMEM199 and CCDC115., Cellular and Molecular Gastroenterology and Hepatology (2021), doi: https://doi.org/10.1016/ j.jcmgh.2021.09.013.
Recently, novel inborn errors of metabolism were identified due to mutations in V-ATPase assembly factors TMEM199 and CCDC115. Patients are characterized by generalized protein glycosylation defects, hypercholesterolemia and fatty liver disease. Here, we set out to characterize the lipid and fatty liver phenotype in human plasma, cell models and a mouse model.
Recently, novel inborn errors of metabolism were identified due to mutations in V-ATPase assembly factors TMEM199 and CCDC115. Patients are characterized by generalized protein glycosylation defects, hypercholesterolemia and fatty liver disease. Here, we set out to characterize the lipid and fatty liver phenotype in human plasma, cell models and a mouse model.
AGEM Symposium: "Treating NASH: Translating new molecular insights into targeted therapy"
Thursday November 25, 2021
Meet the expert Lunch 13.00 - 14.00 CET | Symposium 15.00 - 21.00 CET
On November 25th 2021, AGEM organizes in collaboration with the Dutch NAFLD-NL consortium:the AGEM Symposium "Treating NASH: Translating new molecular insights into targeted therapy" in collaboration with the Dutch NAFLD-NL consortium in lecture hall 4 of the AMC and online via Zoom.
Great speakers including Paul M Yen, MD, FACP, Stefano Romeo, Stan Van De Graaf, Patrick Rensen and Vlad Ratziu will discuss the latest developments in NASH treatment.
Meet the expert Lunch 13.00 - 14.00 CET | Symposium 15.00 - 21.00 CET
On November 25th 2021, AGEM organizes in collaboration with the Dutch NAFLD-NL consortium:the AGEM Symposium "Treating NASH: Translating new molecular insights into targeted therapy" in collaboration with the Dutch NAFLD-NL consortium in lecture hall 4 of the AMC and online via Zoom.
Great speakers including Paul M Yen, MD, FACP, Stefano Romeo, Stan Van De Graaf, Patrick Rensen and Vlad Ratziu will discuss the latest developments in NASH treatment.
NASH WEBINAR:
Nonalcoholic Steatohepatitis: Update and Future Perspectives
In collaboration with Echosens™, we presented the webinar ”Nonalcoholic Steatohepatitis: Update and Future Perspectives”.
Topics addressed during this webinar:
This webinar was presented by:
Curious about the latest insights about NASH? Watch the webinar "Nonalcoholic Steatohepatitis: Update and Future Perspectives”.
Topics addressed during this webinar:
- NASH early identification, patients at risk, diagnostic algorithm and FibroScan
- Implementation of a patient care path and guidelines
- Ongoing trials, drug development and expectations for introduction in clinical practice
This webinar was presented by:
- Dr. Onno Holleboom – Internist and endocrinologist(speaker)
- Dr. Manuel Castro Cabezas – Internist (speaker)
- Prof. Rick Grobbee – Professor of Clinical Epidemiology (host)
Curious about the latest insights about NASH? Watch the webinar "Nonalcoholic Steatohepatitis: Update and Future Perspectives”.
Non-alcoholic fatty liver disease: A patient guideline
Article: Francque SM et al. Non-alcoholic fatty liver disease: A patient guideline. JHEP Reports 2021 (in press)
Commentary: Patient Empowerment in NAFLD
By: Manuel Castro Cabezas, scientific officer Julius Clinical
Commentary: Patient Empowerment in NAFLD
By: Manuel Castro Cabezas, scientific officer Julius Clinical
Most guidelines are prepared by professionals for professionals with some suport from patient organisations. Sven Francque and colleagues together with representatives from the European Liver Patients Association and Liver Patients International, published a timely paper for patients with NAFLD. In this easy to read and very comprehensive article, a thourough update on NAFLD is given aiming at creating awareness and providing information to our patients with this highly prevalent condition. The authors should be complimented with this contribution to promote better understanding among patients. The paper is complete and attractive, thanks to the colourful and well designed graphs. Clinicians should recommend this article to their patients seeking more information on their condition. Personally, I enjoyed very much the paragraphs on lifestyle modifications and especially the fact that the Mediterranean Diet is being promoted as one of the best interventions for NAFLD. Of course, the authors also point at the available and upcoming pharmacological interventions. This paper is a must-read for patients (and professionals) dealing with NAFLD.
Download the paper here.
Download the paper here.
Preparing for the NASH Epidemic: A Call to Action
A call to action for the NASH Epidemic
Kanwal et al. Preparing for the NASH Epidemic: A Call to Action. Diab Care 2021; 44: 1-11
Comments by Manuel Castro Cabezas:
Kanwal et al. Preparing for the NASH Epidemic: A Call to Action. Diab Care 2021; 44: 1-11
Comments by Manuel Castro Cabezas:
The urgency for more awareness and a call to action for improved detection and management of NASH is very clearly underlined by the recent paper from Kanwal and colleagues. This is a report from a meeting organized by the AGA in collaboration with the ADA and the Obesity Society (1). In this paper the authors summarize the results from a recent survey including 751 participants from 46 different states in the USA (gastroenterologists, hepatologists, endocrinologists, and primary care providers). The lack of knowledge about NAFLD/NASH in these professionals was striking with, for example only 32% recognizing that severely obese patients are likely to have NAFLD. Surprisingly, only 49% of the endocrinologists were aware of the fact that NAFLD is highly prevalent in T2DM and 78% of the participants thought that ultrasound can identify NAFLD patients with NASH. These worrying data are very much in line with the recent European publication pointing at the lack of preparedness to face the growing NAFLD/NASH problem (2).
As Kanwal and colleagues clearly describe, by the year 2030, NASH-related advanced fibrosis will double causing 800.000 liver-related deaths. Since most patients with NASH die from cardiovascular disease, the numbers of NASH-related casualties will be overwhelming. Kanwal and colleagues urge to implement a patient care pathway together with primary care providers, where most of the patients at risk are to be found.
A multidisciplinary approach in which GP’s and hospital doctors (hepatologists, endocrinologists, diabetologists) collaborate closely and provide the adequate care to these patients is of utmost importance. It is time that all parties involved in patient care programs realize that action is needed. The first step should be implementation of current guidelines an case-finding by screening of high risk groups like patients with diabetes, pre-diabetes, obesity and hypertension. Of course, we also need more efficient treatment strategies to help these patients. Establishing the diagnosis, will not solve the problem. While vitamin E, pioglitazone and bariatric surgery may be used in certain patients, these therapies are not being implemented at this moment. The reasons are multiple; lack of sufficient clinical evidence and possible side effects in the case of vitamin E and pioglitazone and the invasiveness of bariatric surgery. Close collaboration between professionals, policy makers, insurance companies and pharmaceutical companies is urgently needed to tackle this epidemic.
Download the paper here.
Download the paper here.
References:
- Kanwal et al. Preparing for the NASH Epidemic: A Call to Action. Diab Care 2021; 44: 1-11
- Lazarus et al. European “NAFLD preparedness index”- Is Europe ready to meet the challenge of fatty liver disease? JHEP Reports 2021; doi.org/10.1016/j.jhepr.2021.100234
Cardiovascular risk and NAFLD/NASH in LURIC: surrogate markers are not useful
Surrogate markers of advanced fibrosis in NAFLD/NASH do not predict mortality in patients with medium-to-high
cardiovascular risk
From: Graciela E Delgado et al.
Am J Physiol Gastrointest Liver Pathophysiol 2021. Doi: 10.1152/ajpgi.00058.2021
Comments by Manuel Castro Cabezas:
cardiovascular risk
From: Graciela E Delgado et al.
Am J Physiol Gastrointest Liver Pathophysiol 2021. Doi: 10.1152/ajpgi.00058.2021
Comments by Manuel Castro Cabezas:
NAFLD has unequivocally been associated with cardiovascular complications and therefore, aggressive risk factor modification has been advocated (1-4). Most studies including significant numbers of patients, evaluating this association have used ultrasound to establish the diagnosis of NAFLD or used retrospective analyses (2). Only a very limited number of studies including histological evaluation have been published. Overall, although it is widely accepted that NAFLD is associated with an increased cardiovascular (CV) risk some controversy exists on whether the different stages of NASH are related to CV risk (2). There is general agreement that more studies with sufficient follow up and with histological diagnosis are necessary to gain more insight in this field. In the accompanying paper, Graciela Delgado and colleagues used data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study from 3316 Caucasians undergoing coronary angiography between 1997 and 2000 with a median follow up of 9.8 years (range 0.1-11.3 years). Complete data were available in 2882 subjects. The authors calculated FLI, FIB-4, APRI and NFS and investigated their predictive value for cardiovascular mortality. There was a large number of events (n=849 patients had died). Although FIB-4 and NFS showed significant associations with all-cause and cardiovascular mortality when only adjustment was done for CV risk factors not included in the calculation of the scores, after adjustment for all cardiovascular risk factors there was no association with any of the surrogate markers. The authors conclude that these surrogate markers for NAFLD/NASH do not add information in assessing cardiovascular risk in this medium-to-high risk population. While this study provides useful clinical information it underlines the unmet clinical need for adequate, long-term, prospective studies including histological diagnosis.
Download the paper here.
Download the paper here.
References:
- Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J Hepatol 2016; 65: 589-600.
- Targher G, Byrne CD, Tilg H. NSAFLD and increased risk of cardiovascular disease: clinical associations, pathophysiological mechanisms and pharmacological implications. Gut 2020: doi: 10.1136/gutjnl-2020-320622
- Stols-Goncalves D, Hovingh GK, Nieuwdorp M, Holleboom AG. NAFLD and atherosclerosis: Two sides of the same dysmetabolic coin? Trends Endocrinol Metab 2019; 30: 891- 902
- Janssen A, Grobbee DE, Dendale P. Non-alcoholic fatty liver disease, a new growing risk indicator for cardiovascular disease. Eur J Prev Cardiol 2020; 27: 1059-1063
- Delgado GE, Kleber ME, Moissl A, Yazdani B, et al. Surrogate markers of advanced fibrosis in NAFLD/NASH do not predict mortality in patients with medium-to-high cardiovascular risk. Am J Physiol Gastrointest Liver Pathophysiol 2021. Doi: 10.1152/ajpgi.00058.2021
ASSESSMENT OF IMAGING MODALITIES AGAINST LIVER BIOPSY IN NONALCOHOLIC FATTY LIVER DISEASE:
THE AMSTERDAM NAFLD-NASH COHORT
By: Marian A. Troelstra et al
Journal: J. Magn Reson Imaging 2021; doi: 1002/jmri.27703
Abstract by Manuel Castro Cabezas.
Journal: J. Magn Reson Imaging 2021; doi: 1002/jmri.27703
Abstract by Manuel Castro Cabezas.
NITs from ANCHOR
For the diagnosis and evaluation of interventions in NAFLD, non-invasive test (NITs) are badly needed. While several biomarkers and imaging tools are being used in clinical practice (1), the liver biopsy remains the god standard. For this purpose, the NAFLD activity score has been developed which provides information on the severity of NASH based on three components: steatosis score (0-3), lobular inflammation (0-3) and hepatocyte ballooning (0-2). A total NAS score ≥5 suggesting severe NASH. In addition, fibrosis is scored separately into 5 stages from no fibrosis (0) to cirrhosis (stage 4). A different widely used scoring system is the Steatosis Activity and Fibrosis score (SAF). While these scoring systems are widely accepted and are considered to be the only valid technique recognized by regulatory agencies to diagnose NASH, they also have some disadvantages. Liver biopsy besides being invasive and costly, can also be misleading by sampling error. Moreover, inter-observer variability also needs to be considered and has been shown to be poor. Therefore, centralized evaluation of liver biopsies is needed when performing multicenter trials. For these reasons, NASH workers are searching for other options to quantify NASH. Onno Holleboom and his team at Amsterdam UMC in collaboration with colleagues from France and the UK evaluated the diagnostic performance of multiparametric magnetic resonance imaging (MRI) to assess disease severity compared to histological scores and Fibroscan scores in 37 subjects participating in the Amsterdam NAFLD-NASH cohort study (ANCHOR). This is a 5 years observational, prospective study aiming to identify and validate NITs for assessment of the whole NAFLD spectrum.
The participants were 49 years old, mostly male (62%) and obese (mean BMI 33,2 Kg/m2). T2DM was present in 43% of the participants. All subjects underwent MRI and Fibroscan measurements and liver biopsies were graded according to SAF scores. The authors found that MR elastography and intravoxel incoherent motion (IVIM) diffusion had the highest ROC for distinction between simple steatosis and NASH (0.79 and 0.73, respectively). This study provides important data supporting the use of MRI for assessment of liver steatosis and fibrosis. Whether this technique will ever replace histology as a primary outcome in registration trials, remains to bee seen.
For the diagnosis and evaluation of interventions in NAFLD, non-invasive test (NITs) are badly needed. While several biomarkers and imaging tools are being used in clinical practice (1), the liver biopsy remains the god standard. For this purpose, the NAFLD activity score has been developed which provides information on the severity of NASH based on three components: steatosis score (0-3), lobular inflammation (0-3) and hepatocyte ballooning (0-2). A total NAS score ≥5 suggesting severe NASH. In addition, fibrosis is scored separately into 5 stages from no fibrosis (0) to cirrhosis (stage 4). A different widely used scoring system is the Steatosis Activity and Fibrosis score (SAF). While these scoring systems are widely accepted and are considered to be the only valid technique recognized by regulatory agencies to diagnose NASH, they also have some disadvantages. Liver biopsy besides being invasive and costly, can also be misleading by sampling error. Moreover, inter-observer variability also needs to be considered and has been shown to be poor. Therefore, centralized evaluation of liver biopsies is needed when performing multicenter trials. For these reasons, NASH workers are searching for other options to quantify NASH. Onno Holleboom and his team at Amsterdam UMC in collaboration with colleagues from France and the UK evaluated the diagnostic performance of multiparametric magnetic resonance imaging (MRI) to assess disease severity compared to histological scores and Fibroscan scores in 37 subjects participating in the Amsterdam NAFLD-NASH cohort study (ANCHOR). This is a 5 years observational, prospective study aiming to identify and validate NITs for assessment of the whole NAFLD spectrum.
The participants were 49 years old, mostly male (62%) and obese (mean BMI 33,2 Kg/m2). T2DM was present in 43% of the participants. All subjects underwent MRI and Fibroscan measurements and liver biopsies were graded according to SAF scores. The authors found that MR elastography and intravoxel incoherent motion (IVIM) diffusion had the highest ROC for distinction between simple steatosis and NASH (0.79 and 0.73, respectively). This study provides important data supporting the use of MRI for assessment of liver steatosis and fibrosis. Whether this technique will ever replace histology as a primary outcome in registration trials, remains to bee seen.
References:
1. Alhinai A, Patel K, Fonseca VA, Sebastiani G. Non-invasive diagnosis of nonalcoholic fatty liver disease in patiets with type 2 diabetes. J Diab Compl 2021; doi.org/10.1016/j.diacomp.2021.107978.
2. Troelstra MA, Witjes JJ, van dijk A-M, Mal Al et al. Assessment of imaging modalities against liver biopsy in nonalcoholic fatty liver disease: The Amsterdam NAFLD-NASH Cohort. J. Magn Reson Imaging 2021; doi: 1002/jmri.27703
1. Alhinai A, Patel K, Fonseca VA, Sebastiani G. Non-invasive diagnosis of nonalcoholic fatty liver disease in patiets with type 2 diabetes. J Diab Compl 2021; doi.org/10.1016/j.diacomp.2021.107978.
2. Troelstra MA, Witjes JJ, van dijk A-M, Mal Al et al. Assessment of imaging modalities against liver biopsy in nonalcoholic fatty liver disease: The Amsterdam NAFLD-NASH Cohort. J. Magn Reson Imaging 2021; doi: 1002/jmri.27703
“Lifestyle modifications for nonalcohol-related fatty liver disease: a network meta-analysis” (Cochrane Review)
E Buzetti et al, Cochrane Database of Systematic Reviews 2021, Issue 6. Art. No.: CD013156. DOI: 10.1002/14651858.CD013156.pub2.
Abstract by Manuel Castro Cabezas.
Abstract by Manuel Castro Cabezas.
The recommended treatment for nonalcohol-related fatty liver disease (NAFLD) in all guidelines is lifestyle modification and body weight reduction. Usually, the Mediterranean diet is mentioned as the best studied and most efficient in the treatment of NAFLD. In the accompanying paper, Elena Buzetti and co-workers performed a network meta-analysis of trials using lifestyle interventions for the treatment of NAFLD. The authors identified 59 RCT’s including 3631 subjects with a relatively short follow up varying from 2 to 24 months, which in the case of NAFLD is very short to obtain important information on relevant clinical outcomes like mortality, cardiovascular complications, development of liver cirrhosis or liver transplantation.
The authors found several risks of bias, as shown in the accompanying figure from the publication. Buzetti et al. underscore the importance of adequate clinical trials in this field. So far, the lack of relevant data do not support the current recommendations and there is urgent need for that information, awaiting the very much needed pharmacological interventions which are underway. Buzetti et al provide options which may be implemented using available information of different registries of ongoing trials with multiple interventions. Of course, for such an approach it is of utmost importance to identify biomarkers or other non-invasive tests that need to be included in these trials. To the best of our knowledge, such markers are not routinely included in trials with a different focus than NAFLD. Establishing an international collaboration of experts with a broad network who are aware of long-term interventions including high risk patients with cardiometabolic disorders will help to direct attention to this very relevant objective
The authors found several risks of bias, as shown in the accompanying figure from the publication. Buzetti et al. underscore the importance of adequate clinical trials in this field. So far, the lack of relevant data do not support the current recommendations and there is urgent need for that information, awaiting the very much needed pharmacological interventions which are underway. Buzetti et al provide options which may be implemented using available information of different registries of ongoing trials with multiple interventions. Of course, for such an approach it is of utmost importance to identify biomarkers or other non-invasive tests that need to be included in these trials. To the best of our knowledge, such markers are not routinely included in trials with a different focus than NAFLD. Establishing an international collaboration of experts with a broad network who are aware of long-term interventions including high risk patients with cardiometabolic disorders will help to direct attention to this very relevant objective
Paper: A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis.
P.N. Newsome et al. N Engl J Med 2021;384:1113-24. DOI: 10.1056/NEJMoa2028395.
Abstract by professor Joost Hoekstra, internist
Abstract by professor Joost Hoekstra, internist
BACKGROUND
Nonalcoholic steatohepatitis (NASH) is associated with increased morbidity and mortality. However, treatment options are limited. Considerable weight reduction is effective but extremely difficult to achieve. There is no effective pharmacological intervention sofar. What about the glucagon-like peptide-1 receptor agonist semaglutide?
METHODS
In a 72-week, double-blind phase 2 trial patients with biopsy confirmed NASH and liver fibrosis of stage F1, F2, or F3 were studied. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or placebo. The primary endpoint was resolution of NASH with no worsening of fibrosis. The secondary endpoint was an improvement of at least one fibrosis stage without worsening of NASH. These analyses were performed only in patients with stage F2 or F3 fibrosis.
RESULTS
320 patients (of whom 230 with stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group.
Nonalcoholic steatohepatitis (NASH) is associated with increased morbidity and mortality. However, treatment options are limited. Considerable weight reduction is effective but extremely difficult to achieve. There is no effective pharmacological intervention sofar. What about the glucagon-like peptide-1 receptor agonist semaglutide?
METHODS
In a 72-week, double-blind phase 2 trial patients with biopsy confirmed NASH and liver fibrosis of stage F1, F2, or F3 were studied. Patients were randomly assigned, in a 3:3:3:1:1:1 ratio, to receive once-daily subcutaneous semaglutide at a dose of 0.1, 0.2, or 0.4 mg or placebo. The primary endpoint was resolution of NASH with no worsening of fibrosis. The secondary endpoint was an improvement of at least one fibrosis stage without worsening of NASH. These analyses were performed only in patients with stage F2 or F3 fibrosis.
RESULTS
320 patients (of whom 230 with stage F2 or F3 fibrosis) were randomly assigned to receive semaglutide at a dose of 0.1 mg (80 patients), 0.2 mg (78 patients), or 0.4 mg (82 patients) or to receive placebo (80 patients). The percentage of patients in whom NASH resolution was achieved with no worsening of fibrosis was 40% in the 0.1-mg group, 36% in the 0.2-mg group, 59% in the 0.4-mg group, and 17% in the placebo group (P<0.001 for semaglutide 0.4 mg vs. placebo). An improvement in fibrosis stage occurred in 43% of the patients in the 0.4-mg group and in 33% of the patients in the placebo group (P = 0.48). The mean percent weight loss was 13% in the 0.4-mg group and 1% in the placebo group.
CONCLUSIONS
In this phase 2 trial a significantly higher percentage of patients showed resolution of NASH after treatment with semaglutide compared to placebo. However, no significant between-group difference in the percentage of patients with an improvement in fibrosis stage was found.
In this phase 2 trial a significantly higher percentage of patients showed resolution of NASH after treatment with semaglutide compared to placebo. However, no significant between-group difference in the percentage of patients with an improvement in fibrosis stage was found.
DISCUSSION
It is disappointing that treatment with semaglutide, despite a considerable weight reduction, did not result in decreasing of liver fibrosis. A self-evident question that remains is: would a prolonged treatment with semaglutide, so longer than 1.5 year, diminish fibrose? A phase 3 trial may answer this question. As for now we know that semaglutide does indeed diminish NASH, however not the relevant complication of fibrosis.
Download the paper here.
It is disappointing that treatment with semaglutide, despite a considerable weight reduction, did not result in decreasing of liver fibrosis. A self-evident question that remains is: would a prolonged treatment with semaglutide, so longer than 1.5 year, diminish fibrose? A phase 3 trial may answer this question. As for now we know that semaglutide does indeed diminish NASH, however not the relevant complication of fibrosis.
Download the paper here.
Paper: Drugs for non-alcoholic steatohepatitis (NASH): Quest for the Holy Grail.
By Mithun Sharma et al
J Clin Transl Hepatol 20121: : 40-50
Commentary by: Manuel Castro Cabezas, MD, PhD
The growing prevalence of NASH and the great impact on society, has resulted in a contest for many pharmaceutical companies to be the first to get FDA approval for a drug to combat this very relevant clinical problem. While many overviews on recent developments have been published recently, the accompanying paper by Sharma and colleagues stands out due to its clarity and the very adequate background information. This paper provides an update on the available interventions, including the key issues of lifestyle intervention and the ongoing trials with the most promising compounds, besides a very brief but rather complete description of the usual endpoints. This paper is highly recommended for readers in search for the most recent information in NASH trials.
Download the paper here.
J Clin Transl Hepatol 20121: : 40-50
Commentary by: Manuel Castro Cabezas, MD, PhD
The growing prevalence of NASH and the great impact on society, has resulted in a contest for many pharmaceutical companies to be the first to get FDA approval for a drug to combat this very relevant clinical problem. While many overviews on recent developments have been published recently, the accompanying paper by Sharma and colleagues stands out due to its clarity and the very adequate background information. This paper provides an update on the available interventions, including the key issues of lifestyle intervention and the ongoing trials with the most promising compounds, besides a very brief but rather complete description of the usual endpoints. This paper is highly recommended for readers in search for the most recent information in NASH trials.
Download the paper here.
Paper: European ‘NAFLD Preparedness Index’ — Is Europe ready to meet the challenge of fatty liver disease?
Commentary by: Manuel Castro Cabezas, MD, PhD
Which European countries are prepared to meet the NAFLD challenge or where to go with your NASH trials?
In the accompanying paper, Lazarus and co-workers describe which countries in Europe have organized patient care around NAFLD in such a way that it will meet the high quality requirements needed to give these patients the care they deserve. In the opinion of the authors, in addition to increased awareness, also a multidisciplinary patient-centred approach needs to be in place for NAFLD care.
Which European countries are prepared to meet the NAFLD challenge or where to go with your NASH trials?
In the accompanying paper, Lazarus and co-workers describe which countries in Europe have organized patient care around NAFLD in such a way that it will meet the high quality requirements needed to give these patients the care they deserve. In the opinion of the authors, in addition to increased awareness, also a multidisciplinary patient-centred approach needs to be in place for NAFLD care.
The authors collected data from 29 European countries based on 41-item questionnaire concerning NAFLD. Data were transformed so that a standardised preparedness index could be calculated. The best score was obtained for the UK, Spain and Denmark, although the level of preparedness was still insufficient according to the authors, even in these countries. As the authors clearly state, this report reflects engagement by professionals and policy makers, adherence to guidelines, data on epidemiology and care management. In all these domains, much is still to be gained. This paper is of great interest for organizations dealing with NAFLD/NASH and for companies planning to initiate trials in this field.
Download the paper here.
Download the paper here.
Paper: THE IMPORTANCE OF ADEQUATE LDL MANAGEMENT IN PATIENTS WITH TYPE 2 DIABETES
Managing diabetic dyslipidemia is sometimes a challenge. In high-risk patients with diabetes, treatment targets have been intensified in recent international guidelines. At this stage, only 3 major lipid lowering strategies to reduce LDL-C are available: statins, ezetimibe and PCK9 inhibitors. Bempedoic acid is a welcome addition to consider. The accompanying paper in Dutch describes how bempedoic acid could be used in patients with diabetes especially in the situation in the Netherlands. The paper reflects the personal view of Dr. Manuel Castro Cabezas, internist at Franciscus Gasthuis& Vlietland and scientific officer at Julius Clinical”.
Download the paper here (paper in Dutch)
Download the paper here (paper in Dutch)
Paper: Text-mining in electronic healthcare records can be used as efficient tool for screening and data collection in cardiovascular trials: a multicenter validation study
Commentary to the paper by van Dijk et al EJP 2021
How to improve patient inclusion in NASH trials: Lessons from cardiovascular outcome trials
“Automated text-mining facilitates identification of eligible patients for specific treatments and improves inclusion rates in clinical trials”
One of the great challenges in clinical trials is to identify the right patients and to minimize inclusion failures. In the recent paper by van Dijk and co-workers in close collaboration with Professor Rick Grobbee from UMC Utrecht and Julius Clinical, a novel strategy was evaluated. The authors used text-mining in 3 different centers with 3 different electronic health records. The data mining tool with text-mining features CTcue was used. The population included in the analysis was the LoDoCo2 trial population. Using this tool, the number of patients needed to be screened for the trial was reduced by 80% (instead of over 92.000 patients attending the cardiology clinics, the number to be screened was reduced to 18.603 patients of whom 82,4% had indeed been included in the trial). This approach may lead to a more efficient selection of patients, likely reflecting more precisely a real-world sample of participants. It will make it easier to enrol patients reaching the desired number of patients much faster.
How to improve patient inclusion in NASH trials: Lessons from cardiovascular outcome trials
“Automated text-mining facilitates identification of eligible patients for specific treatments and improves inclusion rates in clinical trials”
One of the great challenges in clinical trials is to identify the right patients and to minimize inclusion failures. In the recent paper by van Dijk and co-workers in close collaboration with Professor Rick Grobbee from UMC Utrecht and Julius Clinical, a novel strategy was evaluated. The authors used text-mining in 3 different centers with 3 different electronic health records. The data mining tool with text-mining features CTcue was used. The population included in the analysis was the LoDoCo2 trial population. Using this tool, the number of patients needed to be screened for the trial was reduced by 80% (instead of over 92.000 patients attending the cardiology clinics, the number to be screened was reduced to 18.603 patients of whom 82,4% had indeed been included in the trial). This approach may lead to a more efficient selection of patients, likely reflecting more precisely a real-world sample of participants. It will make it easier to enrol patients reaching the desired number of patients much faster.
This strategy may also be applied for other purposes. For example, when information is needed on correct implementation of interventional or diagnostics strategies, data mining can provide more detailed data on numbers of patients eligible for these strategies and these data can then be compared to the actual numbers being diagnosed or treated for these specific conditions. But also in NASH trials, this approach can facilitate the identification of potential candidates attending outpatient clinics.
Commentary by: Manuel Castro Cabezas, MD, PhD
Download the paper in PDF here.
Commentary by: Manuel Castro Cabezas, MD, PhD
Download the paper in PDF here.
Journal of Clinical Epidemiology 132 (2021) 97e105
REVIEW PAPER:
Pioglitazone and bariatric surgery are the most effective treatments for non-alcoholic steato-hepatitis: a hierarchical network meta-analysis
BY SIMONA PANUNZI ET AL. , IN DIABETES OBESITY & METABOLISM 2020; DOI:10.1111/DOM.14304.
Abstract below by: Manuel Castro Cabezas, MD, PhD
While non-alcoholic fatty liver disease (NAFLD) is becoming a worldwide clinical problem with serious complications ranging from non-alcoholic steato-hepatitis (NASH), to cirrhosis, liver failure, hepatocellular carcinoma and premature death, many efforts are being directed to the identification of effective therapies. It is expected that in the next few years, several drugs acting on different targets will enter the market providing the long-awaited therapy to prevent the earlier mentioned complications. In the recent paper from Professor Geltrude Mingrone’s group, an attempt has been made to evaluate available data on the resolution of NASH and fibrosis. The authors identified 48 trials including 2356 adults in whom liver biopsies had been carried out before and after intervention. The authors used a smart and sophisticated approach comprising a hierarchical network meta-analysis. According to the authors, available data show that pioglitazone (a PPAR gamma agonist with some PPAR alfa activity), Roux-en-Y Gastric-Bypass and a to lesser extent, rosiglitazone (PPAR-gamma only), have the strongest evidence showing improvement of NASH. The authors identified 2 factors responsible for these effects. The main effect was attributed to body weight decrease, showing that 1% decline in BMI was associated to 1.3% reduction of NAFLD activity score (NAS). On the other hand, 1% reduction of HOMA-IR, reflecting insulin resistance, reduced NAS by 0.3%. Antioxidants appeared to have the strongest effects on the reduction of fibrosis.
Abstract below by: Manuel Castro Cabezas, MD, PhD
While non-alcoholic fatty liver disease (NAFLD) is becoming a worldwide clinical problem with serious complications ranging from non-alcoholic steato-hepatitis (NASH), to cirrhosis, liver failure, hepatocellular carcinoma and premature death, many efforts are being directed to the identification of effective therapies. It is expected that in the next few years, several drugs acting on different targets will enter the market providing the long-awaited therapy to prevent the earlier mentioned complications. In the recent paper from Professor Geltrude Mingrone’s group, an attempt has been made to evaluate available data on the resolution of NASH and fibrosis. The authors identified 48 trials including 2356 adults in whom liver biopsies had been carried out before and after intervention. The authors used a smart and sophisticated approach comprising a hierarchical network meta-analysis. According to the authors, available data show that pioglitazone (a PPAR gamma agonist with some PPAR alfa activity), Roux-en-Y Gastric-Bypass and a to lesser extent, rosiglitazone (PPAR-gamma only), have the strongest evidence showing improvement of NASH. The authors identified 2 factors responsible for these effects. The main effect was attributed to body weight decrease, showing that 1% decline in BMI was associated to 1.3% reduction of NAFLD activity score (NAS). On the other hand, 1% reduction of HOMA-IR, reflecting insulin resistance, reduced NAS by 0.3%. Antioxidants appeared to have the strongest effects on the reduction of fibrosis.
This paper represents a huge amount of work. The authors must be complimented for their effort and accuracy. Their report contributes significantly to our understanding of the mechanisms which have been successful in the treatment of NASH. Furthermore, the paper draws attention to the PPAR-dependent mechanisms. While these drugs may not be very popular in the control of diabetes, they seem to be promising in terms of fatty liver disease and its complications. Unfortunately, long term studies with these drugs in the field of NASH are lacking. While we all wait for those drugs at the end of the pipeline that seem so promising, this paper may give some guidance to physicians treating patients with complicated fatty liver disease.
Download the article in PDF here.
Download the article in PDF here.
REVIEW PAPER:
IMPROVING OUTCOMES OF BARIATRIC SURGERY IN PATIENTS WITH CIRRHOSIS IN THE UNITED STATES: A NATIONWIDE ASSESMENT
Article by VS Are et al, Am J Gastroenterol 2020; 115: 1849-1856
Abstract below by: Manuel Castro Cabezas, MD, PhD
“Obesity, bariatric surgery and cirrhosis: high-volume centers show the best results
Obesity is becoming one of the greatest challenges in the Western world. The growing incidence parallels the rising frequencies of T2DM and fatty liver disease. In the accompanying paper Vilay Are and coworkers extracted data from the Healthcare Cost and Utilization – National Inpatient Sample database between 2004 and 2016. This database covers 97% of the US population representing over 35 million annual hospitalizations. The authors selected all codes for bariatric surgery and used the diagnosis codes indicating cirrhosis. In total over 1,5 million admissions for bariatric surgery were recorded of which almost 10 thousand (0,585) included a code for cirrhosis. The mean cost for admissions with cirrhosis was 2-3 times higher than in those without cirrhosis. Interestingly, in the centers were more than 50 procedures per year were performed (high-volume centers), the number of complications was significantly lower. The type of procedure was also an important determinant of outcome. Restrictive surgery, which was applied increasingly frequent over the years, showed less complications than mixed surgery (malabsorptive and restrictive).
Abstract below by: Manuel Castro Cabezas, MD, PhD
“Obesity, bariatric surgery and cirrhosis: high-volume centers show the best results
Obesity is becoming one of the greatest challenges in the Western world. The growing incidence parallels the rising frequencies of T2DM and fatty liver disease. In the accompanying paper Vilay Are and coworkers extracted data from the Healthcare Cost and Utilization – National Inpatient Sample database between 2004 and 2016. This database covers 97% of the US population representing over 35 million annual hospitalizations. The authors selected all codes for bariatric surgery and used the diagnosis codes indicating cirrhosis. In total over 1,5 million admissions for bariatric surgery were recorded of which almost 10 thousand (0,585) included a code for cirrhosis. The mean cost for admissions with cirrhosis was 2-3 times higher than in those without cirrhosis. Interestingly, in the centers were more than 50 procedures per year were performed (high-volume centers), the number of complications was significantly lower. The type of procedure was also an important determinant of outcome. Restrictive surgery, which was applied increasingly frequent over the years, showed less complications than mixed surgery (malabsorptive and restrictive).
This is an interesting paper describing current trends in bariatric surgery and outcome in patients suffering from cirrhosis, of whom many will have NASH. With the increasing trends in obesity, fatty liver disease will grow. Since NAFLD and NASH are not accepted indications for bariatric surgery, the need for therapies to combat this growing problem become more and more urgent. This paper once again points at the importance of concentrating certain types of procedures in specialized high-volume centers to decrease complications.''
Download the article in PDF here.
Download the article in PDF here.
REVIEW PAPER:
NASH: the revolution from monotherapy to multi targeted interventions
By: Soung Won Jeong
In: e-dmj.org
Diabetes Metab J. 2020;44(5):640-657.
Published online: October 21, 2020
DOI: https://doi.org/10.4093/dmj.2020.0115
Abstract below by: Manuel Castro Cabezas, MD, PhD
The recent paper by Soung Won Jeong from Soonchunhyang University Seoul Hospital provides a comprehensive update on drug development programs for NAFLD and describes promising compounds in clinical trials reaching phase 2 and phase 3. The author clearly points at the unmet need for treatment options to tackle this worldwide problem. While lifestyle modification still remains the cornerstone of intervention, additional pharmacological therapies are badly needed, especially in high risk patients facing the complications of NASH. This elegant paper points at the different pathways involved in the development of NASH and currently being investigated in clinical trials: bile acid pathways, insulin resistance, inflammation, hepatic specific thyroid hormone receptor β analogues, intracellular hepatic fat metabolism and fibrosis.
In: e-dmj.org
Diabetes Metab J. 2020;44(5):640-657.
Published online: October 21, 2020
DOI: https://doi.org/10.4093/dmj.2020.0115
Abstract below by: Manuel Castro Cabezas, MD, PhD
The recent paper by Soung Won Jeong from Soonchunhyang University Seoul Hospital provides a comprehensive update on drug development programs for NAFLD and describes promising compounds in clinical trials reaching phase 2 and phase 3. The author clearly points at the unmet need for treatment options to tackle this worldwide problem. While lifestyle modification still remains the cornerstone of intervention, additional pharmacological therapies are badly needed, especially in high risk patients facing the complications of NASH. This elegant paper points at the different pathways involved in the development of NASH and currently being investigated in clinical trials: bile acid pathways, insulin resistance, inflammation, hepatic specific thyroid hormone receptor β analogues, intracellular hepatic fat metabolism and fibrosis.
In total, 200 different compounds are being investigated in NASH trials.The current paper provides interesting information on the molecular mechanisms of the different drugs, the number of subjects included in the trials and the estimated duration. The author points at the current concept aiming at multiple targets to treat NASH more efficiently, thereby combining different drugs in the most recent clinical trials which are expected to appear soon. This paper is of interest to workers in the field who want to have an updated overview of current drug development programs.
Download the article in PDF here.
Download the article in PDF here.
REVIEW PAPER:
Non-alcoholic fatty liver disease (NAFLD) in non-obese individuals
By: Meaghan Phipps, Julia Wattacheril
In: Frontline Gastroenterology 2020;11:478–483. doi:10.1136/flgastro-20 18-101119
Abstract below by: Joost Hoekstra, Internist
Do individuals with NAFLD who lack the classical risk factor of obesity have the ability to develop non-alcoholic steatohepatitis (NASH) and progression to more advanced liver disease? The answer of the authors of this review obviously is yes. The pathophysiology for the development of NAFLD in non-obese persons is not fully understood but seems to be closely related to insulin resistance, atherogenic dyslipidaemia and alterations in body composition. The prevalence of NAFLD in subjects with a BMI below 25 kg/m2 is estimated 7% in the USA and even 19% in Asia.
What are the clinical features and risk factors associated with so called lean NAFLD? It appears that overweight and obese patients with NAFLD (BMI >25 kg/m2) had higher fasting plasma glucose levels and a higher blood pressure, but lower levels aspartate transaminase (AST), alanine aminotransferase (ALT) and triglycerides than lean patients with NAFLD (BMI ≤25 kg/m2).
Histological studies of lean NAFLD reveal increased lobular inflammation and hepatocellular ballooning when compared with overweight and obese groups. Fibrosis seems to be similar across groups.
In: Frontline Gastroenterology 2020;11:478–483. doi:10.1136/flgastro-20 18-101119
Abstract below by: Joost Hoekstra, Internist
Do individuals with NAFLD who lack the classical risk factor of obesity have the ability to develop non-alcoholic steatohepatitis (NASH) and progression to more advanced liver disease? The answer of the authors of this review obviously is yes. The pathophysiology for the development of NAFLD in non-obese persons is not fully understood but seems to be closely related to insulin resistance, atherogenic dyslipidaemia and alterations in body composition. The prevalence of NAFLD in subjects with a BMI below 25 kg/m2 is estimated 7% in the USA and even 19% in Asia.
What are the clinical features and risk factors associated with so called lean NAFLD? It appears that overweight and obese patients with NAFLD (BMI >25 kg/m2) had higher fasting plasma glucose levels and a higher blood pressure, but lower levels aspartate transaminase (AST), alanine aminotransferase (ALT) and triglycerides than lean patients with NAFLD (BMI ≤25 kg/m2).
Histological studies of lean NAFLD reveal increased lobular inflammation and hepatocellular ballooning when compared with overweight and obese groups. Fibrosis seems to be similar across groups.
The clinical approach to lean NAFLD is challenging and rather unique in that the major clinical risk, overweight or obesity, is not present, thereby limiting conventional interventions such as caloric restriction and exercise. Lean patients with NAFLD are often referred to as metabolically obese normal weight (MONW), as they have insulin resistance, atherogenic dyslipidaemia and increased mortality from the cardiovascular disease despite their normal BMI. The body composition of MONW individuals is one that favours visceral as opposed to peripheral adiposity. There are currently only limited options in terms of pharmacologic agents. Of course, an important clinical consideration in lean NAFLD patients, as in in all patients with liver disease, is HCC surveillance.
Download the article in PDF here.
Download the article in PDF here.
REVIEW PAPER: THE IMPACT OF LIVER-DIRECTED THERAPIES ON THE ATHEROGENIC RISK PROFILE IN NON-ALCOHOLIC STEATOHEPATITIS
By: Margery A. Connelly, Jonathan Velez Rivera, John R. Guyton, Mohammad Shadab Siddiqui, Arun J. Sanyal
In: © 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd
Abstract below by: Manuel Castro Cabezas, MD, PhD
The presence of non-alcoholic steatohepatitis has been associated with an increased cardiovascular risk. Atherothrombotic complications and heart failure have been linked to NASH. While this is a widely accepted relationship, large studies confirming these complications in NASH are lacking. There is some observational evidence for this association in non-alcoholic fatty liver disease (NAFLD) (1-3), but for NASH the data are less clear. One of the proposed mechanisms is the fact that both NAFLD and NASH may be associated with an atherogenic lipoprotein profile, characterized by decreased HDL-C, increased small dense LDL and elevated triglycerides.
In: © 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd
Abstract below by: Manuel Castro Cabezas, MD, PhD
The presence of non-alcoholic steatohepatitis has been associated with an increased cardiovascular risk. Atherothrombotic complications and heart failure have been linked to NASH. While this is a widely accepted relationship, large studies confirming these complications in NASH are lacking. There is some observational evidence for this association in non-alcoholic fatty liver disease (NAFLD) (1-3), but for NASH the data are less clear. One of the proposed mechanisms is the fact that both NAFLD and NASH may be associated with an atherogenic lipoprotein profile, characterized by decreased HDL-C, increased small dense LDL and elevated triglycerides.
Many different targets are being evaluated for the treatment of NASH. It is of importance to evaluate the effect of these interventions on this atherogenic lipoprotein profile, as recently elegantly advocated by Martijn Brouwers and his colleagues from the Maastricht group (4).
The recent paper by Connelly and colleagues (5), provides a comprehensive review of the effects on lipoprotein changes by different drugs being evaluated for the treatment of NASH. The authors clearly show that while some drugs may have significant beneficial effects on NASH, the effects on lipids may vary and even require additional interventions with lipid lowering drugs. While this is an important observation, long term studies including the cardiovascular consequences of these drugs are needed. Drug development programs targeting NASH need to take this into account.
Find the article here online.
Download the article in PDF here.
The recent paper by Connelly and colleagues (5), provides a comprehensive review of the effects on lipoprotein changes by different drugs being evaluated for the treatment of NASH. The authors clearly show that while some drugs may have significant beneficial effects on NASH, the effects on lipids may vary and even require additional interventions with lipid lowering drugs. While this is an important observation, long term studies including the cardiovascular consequences of these drugs are needed. Drug development programs targeting NASH need to take this into account.
Find the article here online.
Download the article in PDF here.
References:
- Mahfood Haddad T, et al. Nonalcoholic fatty liver disease and the risk of clinical cardiovascular events: a systematic review and meta-analysis. Diab Metab Syndr Clin Res Rev 2017: 115: S209-S216.
- Janssen A, et al. Non-alcoholic fatty liver disease, a new and growing risk indicator for cardiovascular disease. Eur J Prev Cardiol 2019; doi:10.1177/2047487319891783.
- Stols-Goncalves D, eta l. NAFLD and atherosclerosis: two sides of the same metabolic coin? Trends Endocrinol Metab 2019: 30: 891-902.
- Brouwers MCG, et al. Non-alcoholic fatty liver disease and cardiovascular disease: assessing the evidence for causality. Diabetologia 2020; 63: 253-260.
- Connelly MA, et al. The impact of liver-directed therapies on the atherogenic risk profile in non-alcoholic steatohepatitis. Alim Pharmacol Ther 2020; doi: 10.1111/apt.15935
PAPER: accuracy of noninvasive fibrosis scores to detect advanced fibrosis in patients with type-2 diabetes with biopsy-proven non-alcoholic fatty liver disease
By: Singh A, Gosau F, Siddiqui MT, et al
In: J Clin Gastroenterol 2020, March 11: doi: 10.1097/MCG.0000000000001339
Abstract below by: Manuel Castro Cabezas, MD, PhD
One of the greatest challenges in NAFLD/NASH is how to identify subjects at high risk of developing (advanced) fibrosis. The gold standard is of course the liver biopsy. Due to its invasive character, professionals are searching for other ways to screen patients in the clinic. For these purposes, several equations have been described with noninvasive scores. Singh et al investigated four widely used approaches (ASAT/ALAT ratio, APRI, FIB-4 index, NFS) and included a large number of subjects with type 2 DM (n= 1157 subjects). The strength of this study is not only the large number of participants, but also the fact that a liver biopsy was also included to serve as comparator. While the specificity of these algorithms was acceptable (FIB-4: 70%) to rather good (NFS: 93%), the sensitivity was very poor (7% by APRI to 44% using NFS), making these methods not suitable for routine clinical screening purposes. This study once again underscores the difficulties of NASH diagnosis and the problems clinicians encounter to identify those subjects that are at highest risk. We are in urgent need of more specific and sensitive tools to help us in the clinic and in this way facilitate the identification of subjects who should be monitored more closely in order to decrease the well-known complications associated to advanced liver fibrosis.
In: J Clin Gastroenterol 2020, March 11: doi: 10.1097/MCG.0000000000001339
Abstract below by: Manuel Castro Cabezas, MD, PhD
One of the greatest challenges in NAFLD/NASH is how to identify subjects at high risk of developing (advanced) fibrosis. The gold standard is of course the liver biopsy. Due to its invasive character, professionals are searching for other ways to screen patients in the clinic. For these purposes, several equations have been described with noninvasive scores. Singh et al investigated four widely used approaches (ASAT/ALAT ratio, APRI, FIB-4 index, NFS) and included a large number of subjects with type 2 DM (n= 1157 subjects). The strength of this study is not only the large number of participants, but also the fact that a liver biopsy was also included to serve as comparator. While the specificity of these algorithms was acceptable (FIB-4: 70%) to rather good (NFS: 93%), the sensitivity was very poor (7% by APRI to 44% using NFS), making these methods not suitable for routine clinical screening purposes. This study once again underscores the difficulties of NASH diagnosis and the problems clinicians encounter to identify those subjects that are at highest risk. We are in urgent need of more specific and sensitive tools to help us in the clinic and in this way facilitate the identification of subjects who should be monitored more closely in order to decrease the well-known complications associated to advanced liver fibrosis.
Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial
Stephen A Harrison, Mustafa R Bashir, Cynthia D Guy, Rong Zhou, Cynthia A Moylan, Juan P Frias, Naim Alkhouri, Meena B Bansal, Seth Baum, Brent A Neuschwander-Tetri, Rebecca Taub, Sam E Moussa
Lancet 2019; 394: 2012–24
Thyroid hormone receptor β (THR-β) has been recognized as an important target for the regulation of fat metabolism in the liver. Since it is highly expressed in the liver, compounds binding to this receptor are tissue specific. Harrison and colleagues carried out a randomised, double-blind, placebo-controlled clinical trial using Resmetirom (MGL-3196) which has been developed by Madrigal Pharmaceuticals for the treatment of NASH. In this elegant study, 125 patients were followed for 36 weeks. The Resmetirom group consisted of 84 subjects of whom 74 completed the 36 weeks follow up and underwent a liver biopsy. The placebo group consisted of 41 subjects; all completed the 36 weeks follow up and a liver biopsy was performed in 34.
Lancet 2019; 394: 2012–24
Thyroid hormone receptor β (THR-β) has been recognized as an important target for the regulation of fat metabolism in the liver. Since it is highly expressed in the liver, compounds binding to this receptor are tissue specific. Harrison and colleagues carried out a randomised, double-blind, placebo-controlled clinical trial using Resmetirom (MGL-3196) which has been developed by Madrigal Pharmaceuticals for the treatment of NASH. In this elegant study, 125 patients were followed for 36 weeks. The Resmetirom group consisted of 84 subjects of whom 74 completed the 36 weeks follow up and underwent a liver biopsy. The placebo group consisted of 41 subjects; all completed the 36 weeks follow up and a liver biopsy was performed in 34.
To be eligible to participate, patients had to have biopsy confirmed NASH. It is of interest to realize that 25 centres in the USA participated and that 348 subjects were screened, so 1 out of 3 screened subjects was included. For a NASH trial, this seems an excellent outcome. Change in MRI-proton density fat fraction (MRI-PDFF) was the primary endpoint. The Resmetirom treated subjects showed a 3-fold higher reduction in hepatic fat content than the placebo group at week 12. These differences persisted at week 36.
This study is very promising and although the numbers are relatively small and the follow up short, the data support further development of compounds targeting the THR-β. Moreover, very convincing and positive results on plasma lipids were found. So, not only liver fat content was reduced but the pro-atherogenic lipid profile was also modulated by this intervention. This paper opens new ways to treat patients with NASH, but also patients in whom overproduction of atherogenic hepatic lipoproteins plays a role. One could think of subjects with familial combined hyperlipidemia in whom VLDL overproduction is one of the basic metabolic disturbances.
Find the full article here.
This study is very promising and although the numbers are relatively small and the follow up short, the data support further development of compounds targeting the THR-β. Moreover, very convincing and positive results on plasma lipids were found. So, not only liver fat content was reduced but the pro-atherogenic lipid profile was also modulated by this intervention. This paper opens new ways to treat patients with NASH, but also patients in whom overproduction of atherogenic hepatic lipoproteins plays a role. One could think of subjects with familial combined hyperlipidemia in whom VLDL overproduction is one of the basic metabolic disturbances.
Find the full article here.
NON-alcoholic fatty liver disease, a new and growing risk indicator for cardiovascular disease
It is well established that NAFLD and NASH are closely associated to an increased of cardiovascular disease. The accompanying paper in the European Journal of Preventive Cardiology by Janssen and colleagues provides an excellent review of current knowledge in the field. The paper underscores the importance of early identification of these conditions and more intensive evaluation and treatment of risk factors for the prevention of cardiovascular complications. While a specific drug treatment for NAFLD and NASH is not yet available, cardiovascular risk management is indicated and should be implemented. For this purpose, close collaboration between cardiologists, hepatologists and internists-diabetologists is necessary.
Find the full article here.
Find the full article here.
Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease
Traditionally NAFLD and NASH have been associated with an increased risk for cardiovascular disease, based on several propective studies elegantly presented in the publication by Targher et al in the New England Journal of Medicine in 2010 (1).
The mechanism proposed was chronic inflammation originating in the expanded visceral adipose tissue.
Recently, Alexander and Sattar and co-workers have published data concerning a matched cohort study of 18 million European adults of whom 120.795 had the diagnosis of NAFLD or NASH (2).
In this real world primary care record study the authors did not find evidence for an increased risk of acute myocardial infarction or stroke, after correction for classical risk factors. The authors did not have access to all risk factors like BMI and HDLC, for instance, which may have influenced the outcome. While the data seem robust, confounding factors could not be fully excluded. This study underscores the need for improving adequate cardiovascular risk management for traditional risk factors in patients with NAFLD and NASH to decrease the cardiovascular risk in these patients. The authors conclude that this should be carried out in a similar way as in the general population.
The mechanism proposed was chronic inflammation originating in the expanded visceral adipose tissue.
Recently, Alexander and Sattar and co-workers have published data concerning a matched cohort study of 18 million European adults of whom 120.795 had the diagnosis of NAFLD or NASH (2).
In this real world primary care record study the authors did not find evidence for an increased risk of acute myocardial infarction or stroke, after correction for classical risk factors. The authors did not have access to all risk factors like BMI and HDLC, for instance, which may have influenced the outcome. While the data seem robust, confounding factors could not be fully excluded. This study underscores the need for improving adequate cardiovascular risk management for traditional risk factors in patients with NAFLD and NASH to decrease the cardiovascular risk in these patients. The authors conclude that this should be carried out in a similar way as in the general population.
- Targher G, Day ChP, Bonora E. Risk of Cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 2010; 363: 1341-50
- Alexander M, Loomis AK, van der Lei A, et al. Non-alcohoic fatty liver disease and risk of incident acute myocardial infarction and stroke: findings from matched cohort study of 18 million Euiropean adults. BMJ 2019; 367: 15367
PHASE 3 Drug pipelines in the treatment of NASH
NASH is becoming the leading cause of liver transplantation. There is an urgent need for treatment modalities that will lead to regression of the inflammation and fibrosis so characteristic of NASH. While lifestyle interventions and weight less are effective, patients have great troubles adhering in the long term to these recommendations and usually weight increases during time, leading to NASH progression and ultimately liver cirrhosis and cardiovascular disease. Therefore, pharmacotherapies are being investigated to treat NASH. In the accompanying paper Sumida and coworkers elegantly review the drugs that are being developed for this purpose and which are now in phase 3 trials. Five of these drugs (obeticholic acid, elafibranor, selonsertib, cenicriviroc and resmetirom) have a great potential to be admitted to clinical practice and the authors even foresee that the first drug may enter the market already in 2021.
This paper provides a comprehensive review of the actual development in drug therapy for NASH.
Read the full article here.
This paper provides a comprehensive review of the actual development in drug therapy for NASH.
Read the full article here.
Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial
Article in the Lancet Gastroenterology & Hepatology (2019) Stefan Traussnigg et al.
Introduction
Norursodeoxycholic acid is a homologue of ursodeoxycholic acid that may have hepatoprotective and antifibrotic properties. In this study the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease (NAFLD) was evaluated.
Patients and Methods
A multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial for patients with non-alcoholic fatty liver disease was performed. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and an elevated serum alanine aminotransferase (ALT) concentration were randomly assigned over either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment.
Results
198 individuals were included in the analysis. 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT level between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change −27·8%, 95% repeated CI −34·7 to −14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).
Conclusion
Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT in NAFLD patients within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated. Further studies are awaited.
Paragraph. Klik hier om te bewerken.
Link to website with article, click here.
Introduction
Norursodeoxycholic acid is a homologue of ursodeoxycholic acid that may have hepatoprotective and antifibrotic properties. In this study the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease (NAFLD) was evaluated.
Patients and Methods
A multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial for patients with non-alcoholic fatty liver disease was performed. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and an elevated serum alanine aminotransferase (ALT) concentration were randomly assigned over either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment.
Results
198 individuals were included in the analysis. 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT level between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change −27·8%, 95% repeated CI −34·7 to −14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).
Conclusion
Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT in NAFLD patients within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated. Further studies are awaited.
Paragraph. Klik hier om te bewerken.
Link to website with article, click here.
New treatment option for nonalcoholic fatty liver disease
Article on: medicalxpress.com. 29 July 2019 by Medical University of Vienna.
Abstract below written by Prof. Joost Hoekstra.
Stefan Traussnigg et al.
Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial, The Lancet Gastroenterology & Hepatology (2019).
Introduction
Norursodeoxycholic acid is a homologue of ursodeoxycholic acid that may have hepatoprotective and antifibrotic properties. In this study the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease (NAFLD) was evaluated.
Patients and Methods
A multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial for patients with non-alcoholic fatty liver disease was performed. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and an elevated serum alanine aminotransferase (ALT) concentration were randomly assigned over either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment.
Results
198 individuals were included in the analysis. 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT level between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change −27·8%, 95% repeated CI −34·7 to −14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).
Conclusion
Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT in NAFLD patients within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated. Further studies are awaited.
Link to website with article: click here.
Abstract below written by Prof. Joost Hoekstra.
Stefan Traussnigg et al.
Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial, The Lancet Gastroenterology & Hepatology (2019).
Introduction
Norursodeoxycholic acid is a homologue of ursodeoxycholic acid that may have hepatoprotective and antifibrotic properties. In this study the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease (NAFLD) was evaluated.
Patients and Methods
A multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial for patients with non-alcoholic fatty liver disease was performed. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and an elevated serum alanine aminotransferase (ALT) concentration were randomly assigned over either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment.
Results
198 individuals were included in the analysis. 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT level between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change −27·8%, 95% repeated CI −34·7 to −14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).
Conclusion
Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT in NAFLD patients within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated. Further studies are awaited.
Link to website with article: click here.
Obesity and Liver Disease: The New Era of Liver Transplantation
Article in: Hepatology. Journal of the American College of Cardiology. 13 July 2019 B. Jorge A. Marrero.
Abstract below written by Prof. Joost Hoekstra.
In this editorial Marrero emphasizes that NAFLD is now the most common chronic liver disease in many developed countries. And further on that according to the relevant scientific registry of transplant recipients (SRTR), hepatitis C (HCV) is no longer the most common indication for a liver transplant. Nowadays the leading indication has become “other/unknown etiology”, which probably means NAFLD.
But what is the best management of the 2019 NAFLD-and-obesity candidate of liver transplantation? That remains undefined. Probably not weight loss, for which it seems too late. Bariatric surgery has been performed prior to transplantation, but the number of reported patients is too small for a conclusion. And what effect has the degree of obesity on the success rate of liver transplantation? It appears that in obese patients a Body Mass Index (BMI) of <40 kg/m2 does not influence the overall or graft survival after liver transplantation compared to lean individuals. However, a BMI of > 40 kg/m2 is associated with a reduced overall or graft survival. Therefore, the American Association for Study of Liver Diseases has determined a BMI of > 40 kg/m2 as a relative contraindication for liver transplantation.
Marrero further emphasizes the new role of the hepatologist of today: his role shifts from infectious disease to metabolic disease. He will become a member of the team of endocrinologists, psychologists, dieticians, health- and lifestyle advisers, endoscopists and surgeons to work on both the preventive and therapeutic interventions in NAFLD and NASH
Link to website: click here.
Abstract below written by Prof. Joost Hoekstra.
In this editorial Marrero emphasizes that NAFLD is now the most common chronic liver disease in many developed countries. And further on that according to the relevant scientific registry of transplant recipients (SRTR), hepatitis C (HCV) is no longer the most common indication for a liver transplant. Nowadays the leading indication has become “other/unknown etiology”, which probably means NAFLD.
But what is the best management of the 2019 NAFLD-and-obesity candidate of liver transplantation? That remains undefined. Probably not weight loss, for which it seems too late. Bariatric surgery has been performed prior to transplantation, but the number of reported patients is too small for a conclusion. And what effect has the degree of obesity on the success rate of liver transplantation? It appears that in obese patients a Body Mass Index (BMI) of <40 kg/m2 does not influence the overall or graft survival after liver transplantation compared to lean individuals. However, a BMI of > 40 kg/m2 is associated with a reduced overall or graft survival. Therefore, the American Association for Study of Liver Diseases has determined a BMI of > 40 kg/m2 as a relative contraindication for liver transplantation.
Marrero further emphasizes the new role of the hepatologist of today: his role shifts from infectious disease to metabolic disease. He will become a member of the team of endocrinologists, psychologists, dieticians, health- and lifestyle advisers, endoscopists and surgeons to work on both the preventive and therapeutic interventions in NAFLD and NASH
Link to website: click here.
nonalcoholic fatty liver disease and the heart
jacc state-of-the-art review
Article in: Hepatology. Journal of the American College of Cardiology. 2019 By the American College of Cardiolofy Foundation - Published by Elsavier.
Accreditation and Designation Statement
The American College of Cardiology Foundation (ACCF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ACCF designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1 Medical Knowledge MOC point in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
Accreditation and Designation Statement
The American College of Cardiology Foundation (ACCF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ACCF designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1 Medical Knowledge MOC point in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
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International NASH Day -
June 12
NASH Clinical team is proud to join this initiative in raising awareness of this important health issue.
NASH Clinical movie
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June 2019
Every now and then an article on NASH is published that is really relevant for both clinicians and scientists. To our opinion that is the case with the April 2019 article in Hepatology: Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations from the Liver Forum, by Cheung et al*. So, when can we speak of a real improvement due to treatment in NASH patients? If you happen to have some 5 minutes left, have a look at this NASH Clinical video! We think it is worthwhile. * Journal of the American College of Cardiology. 2019 By the American College of Cardiolofy Foundation - Published by Elsavier. |
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First Drug for Fatty Liver Disease May Hit Shelves by Year’s End
May 2019 - Source: Medicalpress.com
High rates of liver disease progression and mortality observed in patients with NAFLD/NASH
Two independent national studies have reported high rates of liver disease progression and mortality among patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). The studies reported today at The International Liver Congress 2019 in Vienna, Austria, found that within 10 years of diagnosis, up to 11% of patients with NAFLD/NASH had progressed to advanced liver diseases (defined as NAFLD/NASH patients with compensated cirrhosis [CC], decompensated cirrhosis [DCC], liver transplant [LT] or hepatocellular carcinoma [HCC]), and up to 27% of patients with NAFLD/NASH and CC had developed liver decompensation.
Read the full article here.
High rates of liver disease progression and mortality observed in patients with NAFLD/NASH
Two independent national studies have reported high rates of liver disease progression and mortality among patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). The studies reported today at The International Liver Congress 2019 in Vienna, Austria, found that within 10 years of diagnosis, up to 11% of patients with NAFLD/NASH had progressed to advanced liver diseases (defined as NAFLD/NASH patients with compensated cirrhosis [CC], decompensated cirrhosis [DCC], liver transplant [LT] or hepatocellular carcinoma [HCC]), and up to 27% of patients with NAFLD/NASH and CC had developed liver decompensation.
Read the full article here.
First Drug for Fatty Liver Disease May Hit Shelves by Year’s End
March 2019 - Source: Healthline.com
Intercept Pharmaceuticals officials say their new drug performed well in a phase III clinical trial, so they’ll ask for FDA approval.
Nonalcoholic steatohepatitis (NASH), a type of nonalcoholic fatty liver disease, is a tough condition to live with — namely because there are no drugs on the market designed to treat it.
That could soon change, however, if a pharmaceutical company is able to push a new drug onto pharmacy shelves.
Intercept Pharmaceuticals, a company known for developing treatments for chronic liver diseases, announced earlier this month that they’ve successfully completed a phase III trial of the REGENERATE study.
The goal? Creating a drug designed to treat NASH as well as liver fibrosis.
Intercept Pharmaceuticals officials say their new drug performed well in a phase III clinical trial, so they’ll ask for FDA approval.
Nonalcoholic steatohepatitis (NASH), a type of nonalcoholic fatty liver disease, is a tough condition to live with — namely because there are no drugs on the market designed to treat it.
That could soon change, however, if a pharmaceutical company is able to push a new drug onto pharmacy shelves.
Intercept Pharmaceuticals, a company known for developing treatments for chronic liver diseases, announced earlier this month that they’ve successfully completed a phase III trial of the REGENERATE study.
The goal? Creating a drug designed to treat NASH as well as liver fibrosis.
Some impressions of the 2nd Global NASH Congress 2019 in London UK, 25-26 February
19 March 2019 - Prof. dr. Joost Hoekstra
The large inter-individual difference in progression of NAFLD to NASH was stressed by Cynthia Moylan, Duke University, Texas, USA. How to explain this difference? A help in predicting disease progression appeared to be the determining of DNA methylation, as was performed in a child cohort. More research, however, is necessary before a firm prediction model can be established.
Several speakers discussed the potential benefit of weight loss in NAFLD patients. Does losing weight really help? Unfortunately, no new data were available. So, we have to stick to reviews such as the one by Romero-Gomez (J.Hepatol. 2017) concluding that a 10 % weight reduction can induce a resolution of NASH and probably diminish fibrosis with one stage. The Mediterranean diet including reduced carbohydrate intake (especially sugars) and increased intake of monounsaturated fat and omega-3 fatty acids might reduce liver fat even without weight loss. All speakers stressed to enormous burden for the patients to considerably lose weight.
Is there a causal relation between NASH and cardiovascular disease (CVD) or is there only an association? Quite a relevant question. This topic was discussed in depth in a round table. It was concluded that we cannot establish causality unless there are results of well designed, prospective long lasting trials with effective drugs.
The large inter-individual difference in progression of NAFLD to NASH was stressed by Cynthia Moylan, Duke University, Texas, USA. How to explain this difference? A help in predicting disease progression appeared to be the determining of DNA methylation, as was performed in a child cohort. More research, however, is necessary before a firm prediction model can be established.
Several speakers discussed the potential benefit of weight loss in NAFLD patients. Does losing weight really help? Unfortunately, no new data were available. So, we have to stick to reviews such as the one by Romero-Gomez (J.Hepatol. 2017) concluding that a 10 % weight reduction can induce a resolution of NASH and probably diminish fibrosis with one stage. The Mediterranean diet including reduced carbohydrate intake (especially sugars) and increased intake of monounsaturated fat and omega-3 fatty acids might reduce liver fat even without weight loss. All speakers stressed to enormous burden for the patients to considerably lose weight.
Is there a causal relation between NASH and cardiovascular disease (CVD) or is there only an association? Quite a relevant question. This topic was discussed in depth in a round table. It was concluded that we cannot establish causality unless there are results of well designed, prospective long lasting trials with effective drugs.