NAFLD: new guidelines

 

The American Association of Clinical Endocrinology as well as the AASLD just released their 2022 clinical practice guidelines for nonalcoholic fatty liver disease (NAFLD), which suggests some significant changes for us in primary care (see nafld clinical pract guidelines2022 in dropbox, or https://www.endocrinepractice.org/action/showPdf?pii=S1530-891X%2822%2900090-8 ). Will summarize the major recommendations below:

 

Review:

 

Background:

-- NAFLD is the most common cause of chronic liver disease, affecting 25% of the global population, although fewer than 5% of the people are aware of their liver disease

-- 12 to 14% of those with NAFLD have nonalcoholic steatohepatitis (NASH), a much more aggressive form that can progress to liver fibrosis/cirrhosis, liver failure and cancer (hepatocellular carcinoma, HCC); in the US, NASH is one of the most common causes of liver cancer and the second most common indication for liver transplantation (after hepatitis C)

-- NAFLD is especially common in those who are obese (25-30% of those with obesity have NASH, and 15% have clinically significant liver fibrosis, at least stage F2) or have type 2 diabetes (70% of diabetics have NAFLD and 30 to 40% have NASH), and is associated with cardiometabolic syndrome, including hypertension, dyslipidemia, and insulin resistance); women with polycystic ovary  syndrome are also at higher risk of having NAFLD (PCOS is also associated with increased severity of NASH)

    -- type 2 diabetes is a major driver of NAFLD progression; and age >50yo, insulin resistance, and features of the metabolic syndrome increase the probability of developing NASH

    -- given the increase globally of diabetes and obesity, as well as effective therapies for hepatitis B and C, NAFLD/NASH is soon likely to take over as a leading cause of HCC

-- there may be an increased risk of diabetic nephropathy and retinopathy in those who have NAFLD

-- in general, in people with cirrhosis associated with NAFLD, the most common causes of death are end-stage liver disease and HCC; those with less severe steatosis are more likely to have morbidity or mortality from cardiovascular disease and extrahepatic malignancies

-- NAFLD is diagnosed in the presence of hepatic steatosis, lack of “significant” alcohol consumption (ongoing recent consumption of <21 standard drinks per week for men and <14 for women), and exclusion of other liver diseases (e.g. hepatitis serology, AMA, ANA, anti-smooth muscle antibodies, serum ferritin, alpha-1 anti-trypsin, endocrine disorders of thyroid/Cushing's/hypogonadism) and imaging to evaluate for mass lesions/Budd-Chiari

 

Major recommendations (see article for complete set of 34):

 

-- diagnosis:

    -- high risk individuals: people with obesity and/or features of the metabolic syndrome, prediabetes or type II diabetes, or hepatic steatosis on any imaging study, and/or persistently elevated aminotransferase levels (grade B, intermediate/high strength of evidence SOE)

    -- blood tests to assess NAFLD: preferred noninvasive initial test is FIB-4 (grade B, intermediate SOE). [Of note, patients with NAFLD may not have increases in the serum transaminases]

        -- FIB-4 is a mathematical calculation based on age, AST and ALT levels, and platelet count

        -- the FIB-4 score "is used to assess the need for a biopsy", though biopsy may be considered in those with persistently elevated aminotransaminases and hepatic steatosis on imaging and intermediate or high risk

    -- consider elastography (eg, Fibroscan) for those at high risk, and to assess for clinically significant fibrosis (F2-F4)

    -- for all persons with diabetes: consider screening with FIB-4 even if liver enzymes are normal (grade B recommendation, SOE intermediate)

     -- here is their risk stratification by FIB4 results:

 

 

-- management:

    -- lifestyle: physical activity helps with NAFLD as well as cardiometabolic health; diet should include decreases in saturated fats, starch, and added sugar, such as with the Mediterranean diet. Weight loss is associated with liver histologic and cardiometabolic benefits

    -- medications: 

        -- type II diabetes and biopsy-proven NASH (biopsy is the gold-standard for NASH diagnosis and staging): pioglitazone and GLP-1 agonist, grade A, high SOE

        -- elevated probability of NASH based on aminotransferases and noninvasive tests: pioglitazone and GLP-1 agonists, grade A, high SOE 

            -- there is no evidence that SGLT-2 inhibitors benefit those with steatohepatitis, though these should be considered in patients at high cardiometabolic risk (there are a few open-label studies having potential bias finding decrease in transaminases, but no documentation of decreased steatohepatitis). the guidelines do suggest SGLT-2's, but only in those with low risk scores on FIB-4.

        -- metformin, acarbose, DPP4's, and insulin are not recommended for the treatment of steatohepatitis due to lack of evidence, but may be continued as needed for treatment of hyperglycemia, grade B, high SOE

        -- vitamin D can be considered for treatment of NASH without diabetes, but not enough evidence to recommend in those with diabetes or advanced fibrosis, grade B, high SOE

        -- vitamin E "cannot be recommended with the current evidence" given unevenness of the studies, lack of effect in improving fibrosis, benefit is at best moderate, and there is some concern about increased risk of cardiovascular disease and prostate cancer

        -- obesity and NAFLD/NASH: lifestyle modification is primary, goal of at least 5%, preferably >10% weight loss (more weight loss is associated with increasing liver histologic benefit); if BMI is >27, preferred meds are semaglutide 2.4 mg per week (preferred) or liraglutide 3 mg per day, grade B, high SOE

        -- consider referral for bariatric surgery if appropriate, though only if cirrhosis is not present

        -- for those with hypertension: ACE/ARB are suggested first-line therapy in those at lower or intermediate risk, but avoid these meds in those with decompensated cirrhosis. Calcium-channel blockers are okay, diuretics for those with low or intermediate risk but use cautiously in those with decompensated cirrhosis

-- pediatric NAFLD: focus on lifestyle changes including reducing sugar consumption and increasing physical activity for BMI optimization; consider GLP-1 agonists for treatment of pediatric obesity and type II diabetes, which may also benefit pediatric NAFLD though this is not an FDA-approved indication

 

Other comments:

-- though liver biopsy is the gold standard, in general it is probably sufficient to get an ultrasound finding fatty infiltration, other causes of been excluded, no signs or symptoms of cirrhosis, and patient at high risk for advanced fibrosis and cirrhosis as above

-- in terms of appropriate screening, this recommendation is stronger about screening than prior ones. There are no fixed recommendations in these new guidelines other than that screening is appropriate in high-risk individuals. Options include ultrasound, FIB-4, and Fibroscan/elastography. Probably the minimal screening is the FIB-4 calculation based on transaminases and platelet count.

--of note, the normal ranges for transaminases has changed a bit, 19 to 25 units per liter for women and 29 to 33 for men

-- hepatocellular carcinoma (HCC) screening should probably be done regularly in those with cirrhosis (see https://www.gastrojournal.org/article/S0016-5085(20)30127-X/fulltext#:~:text=In%20general%2C%20the%20incidence%20rate,based%20on%20cost%2Deffectiveness%20considerations. )

-- though there are not great large-scale studies, NAFLD is pretty common even in those of normal weight: eg an Indian study in a rural pupulation with overall low NAFLD incidence found that 54% with NAFLD had BMI <25 and 54% were neither overweight nor had abdominal obesity (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3959355/#:~:text=In%20conclusion%2C%20NAFLD%20should%20not,non%2Dalcoholic%20fatty%20liver%20disease. ). there was the comment in the press that of 3,386 US patients with NAFLD, 13% were lean or had normal BMI, 27% overweight and the rest obese. and of the lean patients, 49% were Asian American. see  https://labblog.uofmhealth.org/lab-report/lean-americans-nonalcoholic-fatty-liver-disease-have-lower-rates-of-cirrhosis 

-- there is an ongoing TARGET-NASH study, a 5-yr pragmatic longitudinal observational study of adults and kids to assess effectiveness of different clinical practice interventions on outcomes (see https://pubmed.ncbi.nlm.nih.gov/28735109/ ).

-- and, we definitely need to know more epidemiologic information regarding the prevalence of NAFLD and NASH done by random samplings of our population, with analysis by age, diet, BMI, exercise, alcohol intake, other sociodemographic info, and clinical comorbidities

-- these guidelines were not totally clear on the role of imaging to help with NAFLD diagnosis. One study mentioned in the first blog below noted the prevalence of ultrasound-diagnosed hepatic steatosis  with normal liver enzymes was found in 16.4%, but the prevalence of hepatic steatosis with abnormal transaminases was only 3.1%

 

A few years ago there was a three-part series on NAFLD:

-- part 1: http://gmodestmedblogs.blogspot.com/2016/08/there-have-been-several-articles.html

-- part 2: http://gmodestmedblogs.blogspot.com/2016/08/non-alcoholic-fatty-liver-disease-2.html

-- part 3: http://gmodestmedblogs.blogspot.com/2016/08/non-alcoholic-fatty-liver-disease-3.html

 

-- For a more recent review of a large prospective outcome study, see http://gmodestmedblogs.blogspot.com/2021/10/nafld-prospective-outcome-study.html

 

so, perhaps the most significant recommendation is to check for NAFLD in patients at moderate or higher risk, since NAFLD is diagnosed insufficiently  (<10% of those in primary care or endocrinology clinics). this guideline emphasized the importance of NAFLD assessment about 100 times, especially with much more testing: the FIB-4 analysis is easy and it seems appropriate (to me) to check liver enzymes and CBC in those at high risk (eg overweight and diabetes are shockingly present in our society...). Doing routine screening by ultrasound might also be quite reasonable, though we really need more epidemiologic data on the relative roles of FIB-4 and/or ultrasound screening. And, we need more clarification about screening in non-overweight people, since it seems that NAFLD is still a concern…

after all, we are currently checking for hepatitis C regularly (eg USPSTF recommends screening in all between 18-79yo: https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/hepatitis-c-screening ), which has effective but expensive treatments. Why not NAFLD which is similarly lethal, is picked up by a simple blood test and/or ultrasound, and has documented effective non-pharmacologic therapies…...

 

geoff

 

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