lean NAFLD: higher mortality than non-lean?
Details:
-- 137,206 participants in the national community-based Constances cohort in France were assessed
-- people with excessive alcohol intake ( >30 g/d in men and >20 g/d in women), viral hepatitis, or other liver diseases were excluded
-- baseline characteristics, comparing those with lean-NAFLD versus NAFLD:
-- mean age: 45 versus 55yo
-- male sex: 43.7% versus 69.6%
-- mean BMI: 22.3 versus 30.9
-- waist circumference: 78.6 cm versus 103.2 cm
-- diabetes: 10.5% versus 17.9%
-- hypertriglyceridemia: 27% versus 36.1%
-- hypercholesterolemia: 25.1% versus 32.3%
-- high blood pressure: 30.6% versus 31.6%
-- ALT elevated: 34.3% versus 21%
-- GGT elevated: 31.1% versus 17.8%
-- alcohol consumption >10g/d: 43.8% versus 29%
-- Tobacco >10 pack-years: 28.4% versus 23.9%
-- no significant difference between groups in history of chronic kidney disease, extrahepatic malignancies, or cardiovascular diseases; also not much difference in physical activity, caffeine or soda consumption
-- lean patients were defined as a BMI<25, or <23 in Asian patients; obesity was defined as a BMI >30 , or >27.5 in Asian patients
-- the diagnosis of NAFLD and fibrosis were determined by the Fatty Liver Index and the Forns Index, respectively
-- Fatty Liver Index (FLI): a formula involving triglycerides, BMI, GGT, and waist circumference, found to be sensitive and specific in diagnosing NAFLD(see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1636651/ )
-- Forns Index (FI): a formula involving platelet count, GGT, age, and total cholesterol, found to be sensitive and specific in diagnosing liver cirrhosis (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1636651/ ). This index was chosen because the Constances database for this study did not include measurements of AST levels.
-- The interpretation of liver pathology based on these two tests was as follows:
-- non-NAFLD: FLI<60
-- NAFLD: FLI >60
-- NAFLD with mild fibrosis: FLI>60 and FI<4.2
-- NAFLD with intermediate fibrosis: FLI>60 and FI 4.2-6.9
-- NAFLD with advanced fibrosis: FLI>60 and FI>6.9
-- the history of alcohol consumption was assessed at baseline and annually throughout the study
-- median follow-up of 3.6 years
Results:
-- patients considered to have NAFLD (by having FLI score >60): 25,753 subjects (weighted prevalence 18.3%), including 3664 with lean NAFLD
-- prevalence of lean NAFLD in the overall study population: 2.9% (2.8-3.0%), similar % between men and women
-- comparing NAFLD by weight groups:
-- lean NAFLD prevalence 5.3% (5.2-5.4), with 16.3% (15.7-16.8) of NAFLD subjects being lean in this cohort
-- overweight people with NAFLD prevalence 28.5% (28-29%), with 41% (40.3-41.8) of NAFLD subjects being overweight in this cohort
-- obese people with NAFLD prevalence 79.2% (79.1-79.3%), with 42.7 % (42.0-43.4%) of NAFLD subjects being obese in this cohort
-- highest prevalence of lean NAFLD:
-- age: 29 to 38 years old, 5.6% (5.3-6.0%), and lowest prevalence in those >69yo
-- Asian individuals: 14.4% (13.0-15.7%), though this reached 30.1% (27.2-33.0%) in those 29-38yo
-- the prevalence of NAFLD in lean subjects was higher in those with diabetes (25.1%), with hypertension (7.8%), with hypercholesterolemia (16.4%), with hypertriglyceridemia (18.1%), and with elevated ALT (18.8%)
-- in lean NAFLD patients, for the combination of diabetes, hypertension, hypercholesterolemia, and hypertriglyceridemia, the prevalence of NAFLD range from 3.3% in those with no risk factors to 86.1% in one of those with all risk factors
-- Independent parameters associated with advanced fibrosis (FI score >6.9)
-- lean status: OR 1.26 (1.20-1.65),p=0.005
-- male sex: OR 2.67 (1.90-3.83), p<0.001
-- diabetes: OR 2.47 (1.85-3.30), p<0.001
-- hypertriglyceridemia: OR 2.72 (2.01-2.36), p<0.001
-- elevated ALT: OR 5.18 (3.89-6.90), p<0.0001
-- soda intake: OR 1.58 (1.14-2.15),p=0.004
-- coffee intake: OR 0.76 (0.57-0.98), p=0.006 [i.e., coffee was protective]
-- Asian origin: OR 5.45 (1.98-12.64 (, p=0.002
-- the five-year cumulative incidence of outcomes, comparing those with lean NAFLD versus non-lean https NAFLD versus no NAFLD, in events per 1000 person-years, all associations having p<0.0001:
-- liver related events: 7.89 versus 1.57 versus 0.99
-- cardiovascular disease: 2.03 versus 2.61 versus 2.16
-- extrahepatic malignancies: 4.43 versus 3.59 versus 2.13
-- CKD: 5.58 versus 3.02 versus 1.09
-- all cause death: 5.01 versus 2.15 versus 1.38
--Adjusting for demographics, metabolic risk factors, and lifestyle, lean status was associated with increased risk of:
-- advanced fibrosis (FI score>6.9): 3.7% in lean NAFLD versus 1.7% in non-lean, OR 1.26 (1.20-1.65), p=0.005
-- liver-related events: HR 5.84 (4.03-8.46)
-- chronic kidney disease: HR 2.49 (1.49-4.16)
-- all-cause mortality: HR 3.01 (2.21-4.11)
-- liver-related events and overall mortality were related to the severity of fibrosis, both in lean and non-lean NAFLD subjects
Commentary:
-- lean NAFLD was initially found in Asian populations, but has subsequently been found in European and US populations.
-- the global prevalence of NAFLD overall is 5.1% to 11.2% in the general populations, highest in Asia
-- the global prevalence of lean individuals within the group of NAFLD patients ranges from 19.2%-25.3%
-- in general, those with lean NAFLD versus healthy individuals have more metabolic risk factors, a genetic predisposition, and higher cardiovascular and liver mortality
-- but, compared to obese patients with NAFLD, lean NAFLD individuals have fewer metabolic disorders but a similar prevalence of genetic polymorphisms as their non-lean counterparts
-- in the current study, lean patients overall were significantly younger than non-lean ones, more often women, had fewer metabolic abnormalities, had significantly higher rates of moderate alcohol consumption and tobacco use, had a higher level of education and were more frequently of Asian origin
-- as per the last blog (https://gmodestmedblogs.blogspot.com/2023/10/nafld-utility-of-lower-cutpoint-of-alt.html ), NASH is associated with cirrhosis, end-stage liver disease, and hepatocellular cancer, as well as an array of non-hepatic outcomes including cardiovascular diseases, chronic kidney disease and extrahepatic cancers (colon, breast, prostate, lung thyroid, ovary, and uterus) and all-cause mortality
-- some (but not all) prior studies had found that those with lean biopsy-proven NAFLD had less severe histologic findings including stiletto hepatitis and fibrosis. Another population study (NHANES) using noninvasive biomarkers did find higher rates of advanced fibrosis in the lean cohort
-- This study, the largest population-based prospective study evaluating lean NAFLD, found that it was associated with a different profile than those with non-lean NAFLD: less diabetes, hypertension, and hyperlipidemia; more females; younger persons; but increased ALT/GGT; and more alcohol and tobacco use
-- unlike some other studies, this study found that lean NAFLD was associated with worse outcomes: more advanced liver fibrosis, more liver-related events (including hepatocellular carcinoma), more chronic kidney disease, and more than 3 times higher all-cause mortality than non-lean NAFLD (though the higher incidence of cardiovasc disease and extrahepatic malignancies were not statistically significant after adjusting for confounding factors, suggesting that the presence of obesity may be the real issue here)
-- and, the prevalence of NAFLD in this unselected French population was quite high: 5.3%
-- this prevalence increased dramatically to 86% in those who had a combination of diabetes, hypertension, hypercholesterolemia, and hypertriglyceridemia
-- A study from the NHANES database found some differences from the above one (more people with NAFLD were older and male) but NAFLD was still quite common (32.3% of the whole group, with 29.7% of these patients being non-obese). their lean NAFLD group also had more advanced fibrosis and higher mortality (more than 2-fold) than the non-lean NAFLD group. This study used FIB-4 index >2.67 as their marker of significant fibrosis (see J Intern Med. 2020;288:139–51, or Prevalence, characteristics and mortality outcomes of obese, nonobese and lean NAFLD in the United States, 1999–2016 (wiley.com) )
-- given the similarity of the NHANES study with the current one in their findings of both the prevalence of lean NAFLD and the outcomes, this does suggest that FIB-4 may be a reasonable screening test for lean NAFLD
-- I would like to extend further my argument in the last blog on the relationship between alcohol consumption and NAFLD:
-- NAFLD is currently defined as "lack of significant alcohol consumption” (ie, ongoing or recent alcohol consumption of >21 standard drinks/week for men or >14/week for women, where 1 standard drink is 14g of pure alcohol)
-- https://gmodestmedblogs.blogspot.com/2022/05/nafld-new-guidelines.html reviews the 2022 AASLD guidelines for NAFLD, with a great summary and recommendations for NAFLD/NASH, but still uses the alcohol definition which allows for "moderate" alcohol consumption in defining NAFLD
-- i could not find any compelling reason that this amount of an alcohol consumption threshold was in fact a clinically significant reflection of the role of alcohol in hepatic steatosis in patients with NAFLD
-- the Framingham Heart study did find that lower levels of alcohol consumption were still associated with hepatic steatosis (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569606/ ), with no clear lower limit, and there was a relationship with numbers of drinks/day but also with binge drinking since many people who drank did not drink daily (by the way, there can be problems in how we define a patient's alcohol consumption: assessing numbers of drinks/day may miss people with high consumption on weekends). In their multivariate adjustment model, the Framingham Study did find a big increase in hepatic steatosis in those drinking 21 drinks/week, with a smaller bump at 14 drinks/week: overall there was a 15% increase in hepatic steatosis for each standard deviation increase in number of alcoholic drinks/week. Of course, as with all observational studies such as this one, one cannot assume causality from these results: were there unanticipated important variables that determined causality that were not evaluated?? There certainly are lots of social variables that were not (stress, housing conditions, psych variables, etc etc).
-- this all raises some clear definitional issues:
-- some people without alcohol consumption do develop hepatic steatosis
-- it is clear that the higher levels of alcohol consumed are associated with worse liver effects (and, as per the last blog: even alcohol consumption within the recommended limits is associated with accelerated adverse liver disease outcomes (see NAFLD any ETOH is bad BMJ2022 in dropbox, or doi.org/10.1136/ bmjopen-2021-049767))
-- many people do consume smaller amounts of alcohol and have steatosis: is this from NAFLD or alcoholic fatty liver disease, or both concurrently?
-- are those with "lean" NAFLD and without the typical "high" risk factors actually having alcohol-related steatosis at sub-threshold limits per the current definition of NAFLD?
-- it was notable that the lean NAFLD cohort int his study did drink significantly more alcohol than the non-lean group: 43.8% of the lean group admitted to drinking >10g/d of alcohol vs 29% in the non-lean group (though there were no granular data on the actual breakdown of what percentage of people drank differing amounts of alcohol: ie how may drank 10 g/d vs 42g/d vs more (which would be average of 3 drinks/d for men).
-- should people drinking occasional alcohol at what is thought to be relatively safe levels be told that this is too much and they could be injuring their livers?
-- should we clinicians promote even lower alcohol thresholds, since there is a pretty strong tendency for people to understate their alcohol consumption. in fact, in the above lean NAFLD group in the lean NAFLD study above,
-- it seems that some people from different countries do have higher-than-expected risks of cardiovascular disease. For example I have been told that men from India do seem to have a higher risk of cardiovasc disease, even in lean men and often at a younger age. Some studies have suggested that immigrants from India to the United States have a higher prevalence of diabetes than would be expected by their age or BMI. Perhaps there is a higher incidence of NAFLD (and perhaps lean NAFLD in men without diabetes) in this population, maybe related to the identified genetic markers for NAFLD (eg see https://www.thelancet.com/journals/lansea/article/PIIS2772-3682(23)00016-1/fulltext )
-- there is an array of potential known genetic markers that seem to increase the prevalence of NAFLD: eg PNPLA3 and TM6SF2, which has been found to be more prevalent in Japanese people with NAFLD (and more so in those with lean NAFLD), which might help explain the poorer prognosis in Asian people in the current study, though:
-- other studies have not confirmed a difference in those polymorphisms between lean and non-lean people
-- there are other polymorphisms that have not been tested much, including HSD17B13, which been associated with the severity of NASH
-- there may well be important polymorphisms that are currently unknown and therefore not tested
-- there are likely very different polymorphisms/other risk factors in different subgroups of the many different Asian people from different countries and cultures.
-- and, there are often complex interactions between different polymorphisms and nongenetic factors (eg diet, exercise, etc), so it is important to have a more detailed analysis than just the polymorphisms themselves. and most genetic factors are not, by themselves, predictive of adverse outcomes, but may add to the risk when combined with environmental factors: for example:
-- http://gmodestmedblogs.blogspot.com/2016/11/lifestyle-changes-and-genetic-risk-for.html , a study combining genetic data from 3 prospective trials found that those at the highest genetic risk for coronary artery disease had the greatest benefit from lifestyle changes
-- http://gmodestmedblogs.blogspot.com/2018/01/dietary-effect-strong-when-high-genetic.html , a study finding that those with high genetic risk scores for developing obesity actually responded better to dietary interventions than those at lower genetic risk
-- ie, genetics are not necessarily determinant: for most chronic diseases associated with lifestyle (diabetes, hypertension, cardiovasc disease, etc), there is an interplay between environment and genetics
-- a mendelian randomization study assessing NAFLD did find that several NAFLD risk factors were associated with increased risk of having NAFLD: polymorphisms associated with lifetime smoking history, BMI, waist circumference, type 2 diabetes, systolic blood pressure, HDL, and triglycerides were also associated with increased NAFLD risk; though there was lower genetically predicted risk for alcohol, coffee and caffeine, and vigorous exercise were inversely associated with NAFLD: see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9329390/. a bit surprising about alcohol being protective. not sure what to do with this
-- and, importantly, no such studies for NASH, which is the real bad actor here
-- mechanistically, it does seem that insulin resistance may be a driver of hepatic fibrosis in NAFLD subjects, as well as fat mass/fat distribution and muscle mass in several studies. There are also some findings supporting a role of bile acids and the gut microbiome composition in the development of lean NAFLD. And there may be a genetic predisposition, as above
Limitations:
-- this was an observational study, so the conclusions should be interpreted as “associations” and not “causality”. Unfortunately, many observational/population studies are in this category, since it really is not possible to have large studies with randomization to different diets, exercise, alcohol use, stress levels, etc and with follow-up 10-20 years later. Yet, these observational studies are some of the most important studies we have for many of these important “lifestyle” issues and their related medical/psychological/social problems.
-- also, in this study some of these social variables (eg BMI, alcohol consumption, dietary components, etc) might have changed during the course of the study, potentially distorting the results
-- but, for example, we cannot conclude definitively that diabetes is a cause of NAFLD based on observational studies: there is a clear association between insulin resistance and NAFLD. And insulin resistance is associated with the development of diabetes. So, perhaps diabetes is only indirectly associated with developing NAFLD, mediated through insulin resistance??
-- there was no information about the spread of the ALT levels, only if they were >40 IU/L. this hinders our ability to evaluate the validity of ALT levels (or mathematical formulas using ALT levels, such as FIB-4) in both screening for NAFLD (and lean NAFLD) as well as the correlation with actual, biopsy-proven fibrosis or NASH. Perhaps lowering the normal range of ALT would really increase the test's sensitivity and help us in assessing for NAFLD, per the last blog
-- in general, this study and other large studies are dependent on non-invasive markers for NAFLD and NASH (ALT, FIB-4, Forns Index, Fatty Liver Index…). This is a necessity: one cannot really do definitive liver biopsies on a large community-based or other prospective study groups. But how accurate are these markers, since liver biopsy is the gold standard?
-- also, we cannot assume, for example, the generalizability of these markers in select groups of participants. for example, many studies are done in higher risk groups recruited in hepatology clinics. will their results be transferable to the general population??
-- this was a relatively short-term study (3.58 yrs) of a condition (NAFLD) that takes many years to develop the clinical outcomes assessed. Is this a long enough window to provide accurate results??
-- as a French population-based study with a relatively limited non-white population, is this generalizable to other populations in other countries?
so, lots of issues brought up by the study on lowering ALT "normal" levels, per blog https://gmodestmedblogs.blogspot.com/2023/10/nafld-utility-of-lower-cutpoint-of-alt.html , as well as the current blog on lean NAFLD individuals
-- it is clear that such a common problem as NAFLD, and its pretty frequent association with the bad actor NASH, is presenting us in the US and globally with an increasing prevalence of bad liver, cardiac, kidney, and cancer outcomes
-- one major reason i brought up the issues of lowering the ALT level and the lean NAFLD phenomenon now is that i think many of us in primary care are not aware of these concerns (i had been using high ALT levels as a marker to do further hepatic steatosis assessment, such as ultrasound, and elastography.)
-- the issues of "lean" NAFLD and lowering the ALT "normal" limits are not new. the 2022 AASLD guidelines on NAFLD mentioned both of these issues prominently, noting that the ALT range for normal is being considered by the American College of Gastroenterology to change to 19-25 U/L for women and 29-33 U/L for men. see https://gmodestmedblogs.blogspot.com/2022/05/nafld-new-guidelines.html.
-- and, as per above, the common "high risk" risk factors of metabolic syndrome, diabetes, and obesity, are notably absent or much less frequent in those with lean NAFLD
-- important noninvasive markers for NAFLD do use ALT as part of the calculation (eg FIB-4). should these calculators be modified/recalibrated to accommodate the higher pick-up of NAFLD found with lower ALT levels?
-- one difference found between lean vs non-lean subjects was the potential utility of ALT levels: 44% of lean subjects had elevated ALT levels >40 IU/L vs 29% of non-lean. Would the lower ALT cutpoint significantly improve the utility of ALT as a marker of NAFLD in lean subjects??? Would ALT itself then become a reasonable noninvasive marker for people with lean NAFLD, and a reliable discriminator that could initiate the next step of evaluation with an ultrasound???? Or, perhaps we should just use the FIB-4 index, since this seemed pretty good in both the above study and the NHANES study mentioned above
-- this all is an important clinical consideration, since we do not have a great non-invasive test to pick up NAFLD/NASH. perhaps, as was found in the blog on lowering ALT levels, there needs to be a better combination of factors to predict NAFLD. in that study they did find a combination that was more predictive of NAFLD. but these potential noninvasive instruments need to be tested further in other settings to determine what the best combination is (ie, many more studies need to be done)
-- one "helpful" thing now is that so many people get abdominal ultrasounds for a variety of reasons. many patients are found to have steatosis and then can be evaluated further based on that (though ultrasounds can miss mild hepatic fibrosis)
As with many such studies as above, we are left with more questions than answers. So, what is to be done???
-- this is really unclear, based on the array of studies noted above, many coming to different conclusions regarding the potential causes of NAFLD (and lean NAFLD) and potential noninvasive screening that should be performed.
-- we really do need studies assessing arrays/combinations of potential noninvasive markers to identify NAFLD, and these markers may well be different for lean vs non-lean patients.
-- and, of course, we then need studies in different populations to validate these markers, which may vary in different populations with different diets, other lifestyles (smoking, drinking, stresses, etc), other comorbidities, and other genetic markers. And the results of these studies may not find a uniform set of noninvasive markers from one part of the world to another
-- at this point, we should probably do what seems to be the consensus:
-- further work-up as below for those found to have elevated ALT and/or AST levels (though normal levels do not exclude NAFLD). This may be more useful in those who are lean
-- getting routine liver function tests, especially in high-risk groups, is reasonable. One needs AST, ALT and platelet counts to populate the FIB-4 index calculator
-- for those with hepatic steatosis (perhaps found incidentally on abdominal ultrasound): exclude non-NAFLD causes, such as viral hepatitis, other causes of steatosis, excessive alcohol consumption (though I would argue that the lower limit of acceptable alcohol consumption is unclear, and that especially patients with steatosis should be counseled to stop all alcohol)
-- the next step is an evaluation of the liver, and an ultrasound is reasonable and does not expose the patients to ionizing radiation (though may miss patients with mild fibrosis), and then followed by elastographic (VCTE) assessment for fibrosis, with the definitive liver biopsy reserved to those with unclear clinical diagnoses especially where the therapy would be different
-- high risk also includes abdominal obesity and/or metabolic syndrome at least 2 cardiometabolic risk factors (increased waist circumference, TG >150 mg/dL, HDL <40 mg/dL, men or <50 mg/dL women, BP >130/85. fasting blood glucose >100 mg/dL. Some consider age >54 also to be a risk factor
-- of note, the high risk group may well be different in those with lean NAFLD, which really complicates things: ALT may be a more useful marker. But what is the best ALT cutpoint for “normal”???
-- as a further confusion to this NAFLD issue, there is a relatively recent addition to the NAFLD family: MAFLD (metabolic dysfunction-associated fatty liver disease), which seems to confer higher levels of fibrosis risk (ie, adding at least 2 minor criteria of metabolic dysregulation(waist circumference, blood pressure, triglycerides, prediabetes, high CRP level, insulin resistance): https://gmodestmedblogs.blogspot.com/2022/06/mafld-heptaic-fibrosis-more-than-nafld.html . this is basically a codification of metabolic syndrome as a predictor of more severe NAFLD
-- but this may have some more limited utility with lean NAFLD, which is associated with several of the metabolic risk factors but not the obesity one).
-- there are other risk factors found, including OSA (see the 2023 AASLD practice guidelines for NAFLD: https://journals.lww.com/hep/Fulltext/2023/05000/AASLD_Practice_Guidance_on_the_clinical_assessment.31.aspx )
-- these updated AASLD guidelines do promote FIB-4 as the primary risk assessment for NAFLD in people at higher NAFLD risk, with those having a score of al teast 1.3 going on to a secondary assessemtent with VCTE
-- and, givent he progression to NAFLD and then to NASH in those with risk factos, the FIB-4 should be repeated evry 1-2 years (could be 2-3 years if no diabetes and <2 metabolic risk factors. also, all patients should have lifestyle management, ongoing alcohol intake assessment, and cardiometabolic risk reduction/preferential use of meds with potential NAFLD benefit: eg pioglitazone, esp if has diabetes, and vitamin E if no diabetes or cirrhosis.
-- but, the other big question: given the huge numbers of people with NAFLD (and a smaller but still huge number with NASH or who will morph into NASH in the near future), and given the dire consequences of NASH, and given that lean people are also subject to these consequences (perhaps at an even higher rate than non-lean people), it does seem to me that we should be doing more extensive screening than just the "targeted" high risk group (and many with lean NAFLD are not in that group). It also seems to me that screening all for NAFLD is likely more beneficial than a lot of the routine cancer screening tests we do: https://gmodestmedblogs.blogspot.com/2023/10/cancer-screening-test-are-they-effective.html .....
geoff
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