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.
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.
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.
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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.
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.
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.
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.
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.
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.
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.
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.
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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.
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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.
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
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.
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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).
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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.
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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.
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Kaplan-Meier curves for cardiovascular mortality for quartiles of FLI (A), 590 APRI (B), FIB-4 (C), NFS (D).
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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.
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FIGURE 1: MRS and MRI based PDFF values vs. histological steatosis grade as seen in hematoxylin and eosin stain. Median PDFF values for grade 1, 2, and 3 were 14.8%, 22.5%, and 26.1%, respectively, for PDFFMRS; 16.2%, 23.7%, and 28.2%, respectively, for PDFFMRI-M; and 13.6%, 20.7%, and 25.4%, respectively, for PDFFDixon. All three parameters showed a significant difference in medians between grades 1–2 and grades 1–3.
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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.
Fig. 1. Factors implicated in the pathogenesis of NASH and possible drug targets. The factors which lead to NAFLD are depicted in the outer circle, while the changes that occur inside the liver are shown within the red circle. The drug targets are shown in blue lightening arrows. Abbreviations: FXR, farnesoid X receptor; PNPLA, patatin-like phospholipase domain-containing protein A; PPAR, peroxisome proliferator-activated receptors; TM6SF4, transmembrane 6 superfamily 2 human gene; Vit E, vitamin E.
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.
Jeffrey V Lazarus 1, Adam Palayew 2, Patrizia Carrieri 3, Mattias Ekstedt 4, Giulio Marchesini 5, Katja Novak 6, Vlad Ratziu 7, Manuel Romero-Gómez 8, Frank Tacke 9, Shira Zelber-Sagi 10, Helena Cortez-Pinto 11, Quentin M Anstee 12 13
JHEP REP 2021; DOI: 10.1016/j.jhepr.2021.100234 |
Fig. 1. European NAFLD Preparedness Index and country rank (n = 29). The red line cut-off at 60 denotes countries that are unprepared. Above the green line (80) denotes prepared. NAFLD, non-alcoholic fatty liver disease. The index was calculated using a multiple correspondence analysis. |
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.
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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. |
Figure 2: Overview of the process of conventional and automated participant identification and data collection and the associated estimated time of
these processes. |
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.
Figure:
Relationship between percent non-alcoholic fatty liver diease activity score (NAS) variation with percent body mass index (BMI)
variation (A) and homeostatic model assessment of insulin resistance (HOMA-IR) variation (B). Straight lines are predictions from meta-regression analyses. Each circle represents the effect (NAS variation) of a treatment at a certain value of the independent variable (BMI variation or HOMAIR variation). For each treatment more points are considered if the treatment is evaluated in multiple studies. The size of the circles is proportional to the number of patients included in the treatment. BAs, bile acids; LAGB, laparoscopic adjustable gastric band; LM, lifestyle modifications; Met, metformin; UDCA, ursodeoxycholic acid.
Diabetes, Obesity and Metabolism, First published: 23 December 2020, DOI: (10.1111/dom.14304)
Relationship between percent non-alcoholic fatty liver diease activity score (NAS) variation with percent body mass index (BMI)
variation (A) and homeostatic model assessment of insulin resistance (HOMA-IR) variation (B). Straight lines are predictions from meta-regression analyses. Each circle represents the effect (NAS variation) of a treatment at a certain value of the independent variable (BMI variation or HOMAIR variation). For each treatment more points are considered if the treatment is evaluated in multiple studies. The size of the circles is proportional to the number of patients included in the treatment. BAs, bile acids; LAGB, laparoscopic adjustable gastric band; LM, lifestyle modifications; Met, metformin; UDCA, ursodeoxycholic acid.
Diabetes, Obesity and Metabolism, First published: 23 December 2020, DOI: (10.1111/dom.14304)
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).
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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. |
Figure 1
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Figure 1: Bar graph depicts proportion of bariatric surgeries by type (restrictive vs mixed), and line graph with smoothed trend line shows percent of bariatric surgeries performed in cirrhotics. Number within the bar represents the annual weighted number of procedures performed in cirrhotics by category. A minority of admissions had codes for both procedure categories (2%) and were excluded while categorizing bariatric procedures.
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.
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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. |
Figure 1
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Figure 1: Mechanism of action for nonalcoholic steatohepatitis treatment. OCA, obeticholic acid; HDL, high density lipoprotein; LDL, low density lipoprotein; SGLT2, sodium glucose cotransporter 2; FXR, farnesoid X receptor; THR-β, thyroid hormone receptor-β; LDL-R, low density lipoprotein receptor; SR-B1, scavenger receptor class B type 1; SREBP-2, sterol regulatory element-binding proteins-2; CYP7A1, cholesterol 7α-hydroxylase; SREBP-1c, sterol regulatory element binding protein-1c; ACC-1, acetyl-coenzyme A carboxylase-1; FAS, fatty acid synthase; SCD1, stearoyl-CoA desaturase 1; PPAR, peroxisome proliferator-activated receptor; LXRα, liver X receptor α; SHP, small heterodimer partner; ERK1/2, extracellular signal-regulated kinase 1/2; FGFR4, fibroblast growth factor receptor 4; FoxO1, forkhead box protein O1; CREB, cAMP response element-binding protein; FGF, fibroblast growth factor; FAO, fatty acid β-oxidation; CoA, coenzyme A; TCA, tricarboxylic acid; MPC, mitochondrial pyruvate carrier; TG, triglyceride; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6.
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.
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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. |
Figure 1: Comparison of clinical features within lean and overweight/obese NAFLD. AST, aspartate transaminase; ALT, alanine aminotransferase; NAFLD, non-alcoholic fatty liver disease |
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.
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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. |
Figure 1: Comparison of aspects of normal lipoprotein metabolism and atherogenic
dyslipidaemia. HDL, high‐density lipoprotein particles; HDL‐C, high‐density lipoprotein cholesterol; IDL, intermediate density lipoprotein particles; LDL, low‐density lipoprotein particles; LDL‐C, low‐density lipoprotein cholesterol; TG, triglycerides; VLDL, very low density lipoprotein |
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.
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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. |
Vertical Divider
(A) MRI-PDFF images with percentage fat fraction at baseline, week 12, and week 36. (B) Relative (median) fat reduction at week 12 and week 36 in placebo (n=38) and resmetirom (n=78). (C) Absolute (mean) fat reduction
at week 12 and week 36 in placebo (n=34) and resmetirom (n=74). Week 36 resmetirom 60 mg n=36 and resmetirom 80 mg n=33 (post-hoc analysis; appendix p 8). MRI-PDFF=MRI-proton density fat fraction. Source: Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. The lancet. |
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
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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. |
- 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.
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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.
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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.
| defining_improvement_in_nonalcoholic_steatohepatitis_for_treatment_trial_endpoints_recommendations_from_the_liver_forum.pdf |
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.
