NAFLD: prospective outcome study

 A recent study assessed the outcomes of adults with Nonalcoholic Fatty Liver Disease (NAFLD) across the histologic spectrum (see nafld prospective outcome study nejm2021 in dropbox, or DOI: 10.1056/NEJMoa2029349) 

 

Details: 

-- 1773 adults with NAFLD in a perspective cohort study, from the NAFLD Database Study Phase 2 non-interventional registry of the NASH Clinical Research Network (NASH = Non-Alcoholic Steatohepatitis)

-- all had liver biopsies that found NAFLD and had at least one follow-up visit after 48 weeks 

-- to differentiate NAFLD from Alcoholic Fatty Liver Disease, a questionnaire was used to establish consumption of less than 20 g of alcohol daily for women and less than 30 g for men [biopsy analysis of NAFLD vs alcoholic fatty liver disease can be indistinguishable]

-- median age 52,  36% male, 85% white, 12% Latinx, BMI 33, mean time since NAFLD diagnosis 2.7 years

--75% of those with NAFLD had NASH

--mean ALT 51 , AST 38, Alk phosph 75 [overlapping interquartile ranges independent of the fibrosis stages, confirming the lack of utility of these tests in predicting stage]

-- follow-up: median of 4 years 

-- principal outcomes: death from any cause, hepatic decompensation (clinically apparent ascites, overt encephalopathy, variceal hemorrhage), MELD score (Model for End-stage Liver Disease) of 15 or higher, hepatocellular cancer, hepatic cancer, cardiovascular events (including MI, unstable angina, sudden death, revascularization, hospitalization for heart failure, cerebrovascular events, and chronic kidney disease 

   

 

Results: 

-- All-cause mortality: increased with increasing fibrosis stages  (the expected background  death rate is 0.4 deaths per 100 person-years): 

    -- stage F0 to F2 (no, mild, or moderate fibrosis): 18/1237 people, 0.32 deaths per 100 person-years

    -- stage F3 (bridging fibrosis): 16/369 people, 0.89 deaths per 100 persons-years 

    -- stage F4 (cirrhosis): 13/167 people, 1.76 deaths per 100 person-years 

 --liver-related complications, increased with fibrosis stage (F0 to F2 vs. F3 vs. F4): 

    -- variceal hemorrhage: 0/1232 vs 1/362 vs 5/163 people (0.00 vs. 0.06 vs. 0.70 per 100 person-yrs) 

    -- ascites:  2/1229 vs 9/363 vs 8/155 people (0.04 vs. 0.52 vs. 1.20 per 100 person-yrs) 

    -- encephalopathy: 1/1232 vs 13/364 vs 16/161 people (0.02 vs. 0.75 vs. 2.39 per 100 person-yrs) 

    -- hepatocellular cancer: 2/1232 vs 6/362 vs 1/165 people (0.04 vs. 0.34 vs. 0.14 per 100 person-yrs) 

--other complications (stage F4, as compared with patients with stage F0 to F2 fibrosis): 

    -- type 2 diabetes: 7.53 vs. 4.45 events per 100 person-years 

    -- decrease of more than 40% in the estimated glomerular filtration rate: 2.98 vs. 0.97 events per 100 person-years 

    -- cardiac events and nonhepatic cancers: similar across fibrosis stages 

-- any hepatic decompensation event (variceal hemorrhage, ascites, or encephalopathy), after adjustment for age, sex, race, diabetes status, and baseline histologic severity: 

    -- all-cause mortality increased, with adjusted hazard ratio, 6.8 (2.2 to 21.3)  

--also, the MELD score did not track well with fibrosis stage: a MELD score of 15 (used as cutpoint for entrance into the liver transplant registry) was found in 0.57/100 person-yrs in stage F0-2 vs 0.87 in those with stage F3, though did increase to 2.33 in those with F4

 

 

Commentary: 

-- NAFLD is incredibly common, affecting more than one quarter of all adults globally, and is now a major reason for liver transplantation

-- in the US, 9.8 million people have NASH and stage F0-2 fibrosis, 2 million have NASH and F3, and 1.3 million have NASH and F4.; annual deaths from NASH are estimated at 17,800 for F3 and 22,880 for F4

-- NAFLD fibrosis progresses: studies have found that 14% of those with F0-F2 progress to F3 and 2% to F4 over a median duration of 4.5 years, suggesting 15,000 additional deaths annually in those who progress

-- epidemiologically, NAFLD is associated with obesity, type II diabetes, and insulin resistance, and measures to deal with these (in particular diet and exercise) are associated with improvement (for review of NAFLD in a 3-part series in NEJM, see  http://gmodestmedblogs.blogspot.com/2016/08/there-have-been-several-articles.html , http://gmodestmedblogs.blogspot.com/2016/08/non-alcoholic-fatty-liver-disease-2.html  , http://gmodestmedblogs.blogspot.com/2016/08/non-alcoholic-fatty-liver-disease-3.html )

    --other blogs of note: Mediterranean diet helps (http://gmodestmedblogs.blogspot.com/2017/10/mediterranean-diet-helps-nafld.html ), and an article deciphering nature/nurture on developing NAFLD (http://gmodestmedblogs.blogspot.com/2017/06/nature-vs-nurture-studies-on-lipids-and.html )

-- but NAFLD also develops in non-overweight people (in this study 4% had BMI<25, 23% 25 to <30, 33% 30 to <35, and 40% >35)

-- besides the benefits noted with weight loss, diet and exercise, there can benefit from bariatric surgery in those unable to achieve weight loss over 6 months

 

-- this study, based on biopsy-documented fibrosis scores in those with NAFLD, did find a gradient of adverse liver-related complications and death tracking with the degree of fibrosis

-- most of the studies done so far on NAFLD are post hoc analyses, and population-based studies do not have the necessary biopsy information to assess disease status and outcomes, which is why this study is important

-- also, previous studies have not typically included other related causes of death such as the development of diabetes

 

-- in terms of treating NAFLD medically: liraglutide has helped in older studies and is noted in the 3-part NEJM review above, and a recent RCT found benefit by semaglutide (see  http://gmodestmedblogs.blogspot.com/2020/11/nash-semaglutide-helps.html ). There may also be benefit from vitamin E (studied in non-diabetic patients and those without decompensated cirrhosis), pioglitazone in diabetics, and some studies finding benefit from atorvastatin, omega-3 fatty acids, and aspirin

-- a very recent article also found benefit from a pan-PPAR (the peroxisome proliferator-activated receptor lanifibranor), see nafld lanifibranor helps nejm2021 in dropbox, or DOI: 10.1056/NEJMoa2036205) [PPARs have key regulatory roles in metabolism, inflammation and fibrogenesis. Pioglitazone, mentioned above, is a PPAR-gamma stimulator]

    --phase 2b study of 247 patients with noncirrhotic highly active NASH randomized to 2 different doses of lanifibranor vs placebo daily for 24 weeks

    --42% had diabetes and 76% had moderate or advanced fibrosis

    --those on the highest dose of lanifibranor had at least a 2-point reduction in SAF-A score (activity part of the Steatosis, Activity, Fibrosis score) without worsening of fibrosis (55% vs 33%), p=0.007

    --resolution of NASH occurred in 49% vs 22% on placebo [as a comparison, semaglutide 0.4mg daily vs placebo which had a 59% vs 17% biopsy-proven resolution of NASH in patients with F1-F3 fibrosis: pretty similar to lanifibranor and semaglutide has the advantage of lots of use and known adverse events].

    --resolution of NASH plus improvement in fibrosis stage of at least 1 in 35% vs 9%

    -- also improvement in liver enzymes, lipids, inflammatory markers, and fibrosis biomarkers (see their Table 2)

    -- some increase in diarrhea, nausea, peripheral edema, anemia, and weight gain on the med

    -- but bottom line:  decrease in Steatosis, Activity, Fibrosis score (SAF) associated with lanifibranor does not necessarily translate into improved clinical outcomes

Limitations:

--this was an observational study. fibrosis is associated with portal hypertension, which is associated with hepatic decompensation, but this was an observational study and cannot derive a causal link between fibrosis severity and all-cause mortality. For example, stage 3 fibrosis is associated with higher risk of hepatic decompensation and hepatocellular carcinoma, but it is untested whether regression from F3 to F2 fibrosis is associated with less hepatic decompensation

-- some of the evaluations in this study had very wide confidence intervals, reflecting the few numbers of actual events and short follow-up period, making it hard to draw firm conclusions

-- there is also considerable confounding in some of the results: 89% of the deaths in those with F2 fibrosis were not related to liver disease

-- these studies on NASH are from tertiary centers, and may not reflect the reality of those living with NAFLD/NASH in the community who may be less ill

-- there is not much racial/ethnic diversity in the studies, though this might reflect a predominance of white people having NAFLD (as found in NHANES), likely related to differing sociodemographic settings

-- a few issues with alcohol consumption: their information about alcohol quantity is self-reported and may be inaccurate. and many patients drinking pretty large amounts of alcohol do not have liver disease. so, the arbitrary cutoff of 20g/d for women and 30g/d for men is artificial. and some patients who drink a lot may actually have NAFLD, some drinking less may have alcoholic liver disease, and some may have a combo

-- distinguishing NAFLD from Nonalcoholic Steatohepatitis (NASH) requires a liver biopsy for diagnosis, showing steatosis, lobular inflammation and hepatocellular ballooning, with similar staging from F0 (no fibrosis) to F5 (cirrhosis), as with other hepatidites

    -- of note, biopsy is subject to sampling error and is not necessarily definitive, and has a significant mortality, on the order of 0.2%!!! (see https://pubmed.ncbi.nlm.nih.gov/20547160/ )

    -- non-invasive ways to assess NAFLD fibrosis scores, including biomarkers such as using the fibrosis 4 calculator (FIB-4) and measures of liver stiffness, are also not definitive

    -- still, biopsies are considered the most definitive of the evaluations, but there is a lot of variability of when to do biopsies, unless there is a significant concern that there is  a different etiology for the  liver disease

 

so, this study does provide useful data on NAFLD prognosis, as defined by the biopsy fibrosis scores, and might be useful in helping motivate patients to pursue more aggressively nonpharmacologic management (diet, exercise, weight loss), which is the mainstay of treatment. drugs may well have a role, since bad  outcomes of non-treated NASH are common and can be quite severe (more with NAFLD need liver transplants in the US now than with hepatitis C). but there really needs to be rigorous studies assessing clinical outcomes, and not just biopsy ones, with these interventions (especially the medication ones, since diet/exercise/weight loss are very important for many, many other outcomes...)

 

geoff

 

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