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:
- 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.
- 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.
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.
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)
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. |
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(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.
Paragraph. Klik hier om te bewerken.
Link to website with article, click here.
Introduction
Norursodeoxycholic acid is a homologue of ursodeoxycholic acid that may have hepatoprotective and antifibrotic properties. In this study the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease (NAFLD) was evaluated.
Patients and Methods
A multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial for patients with non-alcoholic fatty liver disease was performed. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and an elevated serum alanine aminotransferase (ALT) concentration were randomly assigned over either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment.
Results
198 individuals were included in the analysis. 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT level between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change −27·8%, 95% repeated CI −34·7 to −14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).
Conclusion
Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT in NAFLD patients within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated. Further studies are awaited.
Paragraph. Klik hier om te bewerken.
Link to website with article, click here.
New treatment option for nonalcoholic fatty liver disease
Article on: medicalxpress.com. 29 July 2019 by Medical University of Vienna.
Abstract below written by Prof. Joost Hoekstra.
Stefan Traussnigg et al.
Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial, The Lancet Gastroenterology & Hepatology (2019).
Introduction
Norursodeoxycholic acid is a homologue of ursodeoxycholic acid that may have hepatoprotective and antifibrotic properties. In this study the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease (NAFLD) was evaluated.
Patients and Methods
A multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial for patients with non-alcoholic fatty liver disease was performed. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and an elevated serum alanine aminotransferase (ALT) concentration were randomly assigned over either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment.
Results
198 individuals were included in the analysis. 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT level between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change −27·8%, 95% repeated CI −34·7 to −14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).
Conclusion
Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT in NAFLD patients within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated. Further studies are awaited.
Link to website with article: click here.
Abstract below written by Prof. Joost Hoekstra.
Stefan Traussnigg et al.
Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial, The Lancet Gastroenterology & Hepatology (2019).
Introduction
Norursodeoxycholic acid is a homologue of ursodeoxycholic acid that may have hepatoprotective and antifibrotic properties. In this study the efficacy of two doses of norursodeoxycholic acid versus placebo for the treatment of non-alcoholic fatty liver disease (NAFLD) was evaluated.
Patients and Methods
A multicentre, double-blind, placebo-controlled, randomised, phase 2 dose-finding clinical trial for patients with non-alcoholic fatty liver disease was performed. Patients with a clinical diagnosis of non-alcoholic fatty liver disease and an elevated serum alanine aminotransferase (ALT) concentration were randomly assigned over either norursodeoxycholic acid capsules at 500 mg per day or 1500 mg per day, or placebo, for 12 weeks. The primary efficacy endpoint was the mean relative percentage change in ALT concentrations between baseline and end of treatment.
Results
198 individuals were included in the analysis. 67 patients were randomly assigned to receive 500 mg norursodeoxycholic acid, 67 to 1500 mg norursodeoxycholic acid, and 64 to placebo. A dose-dependent reduction in serum ALT level between baseline and end of treatment was observed with norursodeoxycholic acid versus placebo, with a significant effect in the 1500 mg group (mean change −27·8%, 95% repeated CI −34·7 to −14·4; p<0·0001). Serious adverse events (n=6) and treatment-emergent adverse events (n=314) were reported in a similar proportion of patients across groups. The most frequent adverse events were headache, gastrointestinal disorders, and infections (eg, diarrhoea, abdominal pain, or nasopharyngitis).
Conclusion
Norursodeoxycholic acid at 1500 mg resulted in a significant reduction of serum ALT in NAFLD patients within 12 weeks of treatment when compared with placebo. Norursodeoxycholic acid was safe and well tolerated. Further studies are awaited.
Link to website with article: click here.
Obesity and Liver Disease: The New Era of Liver Transplantation
Article in: Hepatology. Journal of the American College of Cardiology. 13 July 2019 B. Jorge A. Marrero.
Abstract below written by Prof. Joost Hoekstra.
In this editorial Marrero emphasizes that NAFLD is now the most common chronic liver disease in many developed countries. And further on that according to the relevant scientific registry of transplant recipients (SRTR), hepatitis C (HCV) is no longer the most common indication for a liver transplant. Nowadays the leading indication has become “other/unknown etiology”, which probably means NAFLD.
But what is the best management of the 2019 NAFLD-and-obesity candidate of liver transplantation? That remains undefined. Probably not weight loss, for which it seems too late. Bariatric surgery has been performed prior to transplantation, but the number of reported patients is too small for a conclusion. And what effect has the degree of obesity on the success rate of liver transplantation? It appears that in obese patients a Body Mass Index (BMI) of <40 kg/m2 does not influence the overall or graft survival after liver transplantation compared to lean individuals. However, a BMI of > 40 kg/m2 is associated with a reduced overall or graft survival. Therefore, the American Association for Study of Liver Diseases has determined a BMI of > 40 kg/m2 as a relative contraindication for liver transplantation.
Marrero further emphasizes the new role of the hepatologist of today: his role shifts from infectious disease to metabolic disease. He will become a member of the team of endocrinologists, psychologists, dieticians, health- and lifestyle advisers, endoscopists and surgeons to work on both the preventive and therapeutic interventions in NAFLD and NASH
Link to website: click here.
Abstract below written by Prof. Joost Hoekstra.
In this editorial Marrero emphasizes that NAFLD is now the most common chronic liver disease in many developed countries. And further on that according to the relevant scientific registry of transplant recipients (SRTR), hepatitis C (HCV) is no longer the most common indication for a liver transplant. Nowadays the leading indication has become “other/unknown etiology”, which probably means NAFLD.
But what is the best management of the 2019 NAFLD-and-obesity candidate of liver transplantation? That remains undefined. Probably not weight loss, for which it seems too late. Bariatric surgery has been performed prior to transplantation, but the number of reported patients is too small for a conclusion. And what effect has the degree of obesity on the success rate of liver transplantation? It appears that in obese patients a Body Mass Index (BMI) of <40 kg/m2 does not influence the overall or graft survival after liver transplantation compared to lean individuals. However, a BMI of > 40 kg/m2 is associated with a reduced overall or graft survival. Therefore, the American Association for Study of Liver Diseases has determined a BMI of > 40 kg/m2 as a relative contraindication for liver transplantation.
Marrero further emphasizes the new role of the hepatologist of today: his role shifts from infectious disease to metabolic disease. He will become a member of the team of endocrinologists, psychologists, dieticians, health- and lifestyle advisers, endoscopists and surgeons to work on both the preventive and therapeutic interventions in NAFLD and NASH
Link to website: click here.
nonalcoholic fatty liver disease and the heart
jacc state-of-the-art review
Article in: Hepatology. Journal of the American College of Cardiology. 2019 By the American College of Cardiolofy Foundation - Published by Elsavier.
Accreditation and Designation Statement
The American College of Cardiology Foundation (ACCF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ACCF designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1 Medical Knowledge MOC point in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
Accreditation and Designation Statement
The American College of Cardiology Foundation (ACCF) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ACCF designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1 Medical Knowledge MOC point in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.
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International NASH Day -
June 12
NASH Clinical team is proud to join this initiative in raising awareness of this important health issue.
NASH Clinical movie
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June 2019
Every now and then an article on NASH is published that is really relevant for both clinicians and scientists. To our opinion that is the case with the April 2019 article in Hepatology: Defining Improvement in Nonalcoholic Steatohepatitis for Treatment Trial Endpoints: Recommendations from the Liver Forum, by Cheung et al*. So, when can we speak of a real improvement due to treatment in NASH patients? If you happen to have some 5 minutes left, have a look at this NASH Clinical video! We think it is worthwhile. * Journal of the American College of Cardiology. 2019 By the American College of Cardiolofy Foundation - Published by Elsavier. |
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First Drug for Fatty Liver Disease May Hit Shelves by Year’s End
May 2019 - Source: Medicalpress.com
High rates of liver disease progression and mortality observed in patients with NAFLD/NASH
Two independent national studies have reported high rates of liver disease progression and mortality among patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). The studies reported today at The International Liver Congress 2019 in Vienna, Austria, found that within 10 years of diagnosis, up to 11% of patients with NAFLD/NASH had progressed to advanced liver diseases (defined as NAFLD/NASH patients with compensated cirrhosis [CC], decompensated cirrhosis [DCC], liver transplant [LT] or hepatocellular carcinoma [HCC]), and up to 27% of patients with NAFLD/NASH and CC had developed liver decompensation.
Read the full article here.
High rates of liver disease progression and mortality observed in patients with NAFLD/NASH
Two independent national studies have reported high rates of liver disease progression and mortality among patients with non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH). The studies reported today at The International Liver Congress 2019 in Vienna, Austria, found that within 10 years of diagnosis, up to 11% of patients with NAFLD/NASH had progressed to advanced liver diseases (defined as NAFLD/NASH patients with compensated cirrhosis [CC], decompensated cirrhosis [DCC], liver transplant [LT] or hepatocellular carcinoma [HCC]), and up to 27% of patients with NAFLD/NASH and CC had developed liver decompensation.
Read the full article here.
First Drug for Fatty Liver Disease May Hit Shelves by Year’s End
March 2019 - Source: Healthline.com
Intercept Pharmaceuticals officials say their new drug performed well in a phase III clinical trial, so they’ll ask for FDA approval.
Nonalcoholic steatohepatitis (NASH), a type of nonalcoholic fatty liver disease, is a tough condition to live with — namely because there are no drugs on the market designed to treat it.
That could soon change, however, if a pharmaceutical company is able to push a new drug onto pharmacy shelves.
Intercept Pharmaceuticals, a company known for developing treatments for chronic liver diseases, announced earlier this month that they’ve successfully completed a phase III trial of the REGENERATE study.
The goal? Creating a drug designed to treat NASH as well as liver fibrosis.
Intercept Pharmaceuticals officials say their new drug performed well in a phase III clinical trial, so they’ll ask for FDA approval.
Nonalcoholic steatohepatitis (NASH), a type of nonalcoholic fatty liver disease, is a tough condition to live with — namely because there are no drugs on the market designed to treat it.
That could soon change, however, if a pharmaceutical company is able to push a new drug onto pharmacy shelves.
Intercept Pharmaceuticals, a company known for developing treatments for chronic liver diseases, announced earlier this month that they’ve successfully completed a phase III trial of the REGENERATE study.
The goal? Creating a drug designed to treat NASH as well as liver fibrosis.
Some impressions of the 2nd Global NASH Congress 2019 in London UK, 25-26 February
19 March 2019 - Prof. dr. Joost Hoekstra
The large inter-individual difference in progression of NAFLD to NASH was stressed by Cynthia Moylan, Duke University, Texas, USA. How to explain this difference? A help in predicting disease progression appeared to be the determining of DNA methylation, as was performed in a child cohort. More research, however, is necessary before a firm prediction model can be established.
Several speakers discussed the potential benefit of weight loss in NAFLD patients. Does losing weight really help? Unfortunately, no new data were available. So, we have to stick to reviews such as the one by Romero-Gomez (J.Hepatol. 2017) concluding that a 10 % weight reduction can induce a resolution of NASH and probably diminish fibrosis with one stage. The Mediterranean diet including reduced carbohydrate intake (especially sugars) and increased intake of monounsaturated fat and omega-3 fatty acids might reduce liver fat even without weight loss. All speakers stressed to enormous burden for the patients to considerably lose weight.
Is there a causal relation between NASH and cardiovascular disease (CVD) or is there only an association? Quite a relevant question. This topic was discussed in depth in a round table. It was concluded that we cannot establish causality unless there are results of well designed, prospective long lasting trials with effective drugs.
The large inter-individual difference in progression of NAFLD to NASH was stressed by Cynthia Moylan, Duke University, Texas, USA. How to explain this difference? A help in predicting disease progression appeared to be the determining of DNA methylation, as was performed in a child cohort. More research, however, is necessary before a firm prediction model can be established.
Several speakers discussed the potential benefit of weight loss in NAFLD patients. Does losing weight really help? Unfortunately, no new data were available. So, we have to stick to reviews such as the one by Romero-Gomez (J.Hepatol. 2017) concluding that a 10 % weight reduction can induce a resolution of NASH and probably diminish fibrosis with one stage. The Mediterranean diet including reduced carbohydrate intake (especially sugars) and increased intake of monounsaturated fat and omega-3 fatty acids might reduce liver fat even without weight loss. All speakers stressed to enormous burden for the patients to considerably lose weight.
Is there a causal relation between NASH and cardiovascular disease (CVD) or is there only an association? Quite a relevant question. This topic was discussed in depth in a round table. It was concluded that we cannot establish causality unless there are results of well designed, prospective long lasting trials with effective drugs.
