By Dr. Geoffrey Modest
And, the final blog on NAFLD (finally): Clinical practice guidelines from European Association for the Study of Liver Diseases, and others (see J Hepatol 2016; 64: 1388). Several of the studies referenced here were included in the prior 2 blogs.
- NAFLD is characterized by increased hepatic fat, insulin resistance (IR), and steatosis in >5% of hepatocytes. Diagnosis of NASH requires a liver biopsy. The NAS score (NAFLD activity score) cannot be used to diagnose NASH and has a low prognostic value
- Diagnosis is based on exclusion of secondary causes (hepatitis C, drug and other causes of liver injury) and daily alcohol consumption of >30g/d for men or >20 g/d for women (it’s arbitrarily considered alcoholic liver disease if above that).
Recommendations:
- Patients with IR (and/or metabolic syndrome or obesity) should get “diagnostic procedures for the diagnosis of NAFLD” (which from reading the text seems pretty clearly to be RUQ ultrasounds) to look for excessive liver fat. And vice versa: all with steatosis should be evaluated for metabolic syndrome.
- In those with risk factors for more advanced liver disease (age >50, type 2 diabetes, metabolic syndrome) “case finding for advanced disease (i.e. NASH with fibrosis) is advisable”.
- If steatosis present, assess for alcohol and other secondary causes, remembering that there can be other liver diseases coexisting with NAFLD.
- Unhealthy lifestyles can lead to the development and progression of NAFLD. So, important to do good assessment of diet (esp. high calorie/refined carbohydrate diets, sugar-sweetened drinks, high fructose intake, Western diet) and exercise
- Do NOT screen for the various genetic polymorphisms associated with higher liver fat content and increased risk for NASH
- Consider a combo of biomarkers and transient elastography to monitor fibrosis progression (they suggest one “may rely” on these markers “although this strategy requires validation”), especially if imaging not available or feasible. But the identification of advanced fibrosis/cirrhosis is less accurate with these noninvasive markers and needs to be confirmed by liver biopsy
- In those at high risk of liver disease progression, consider repeat liver biopsy after at least 5-year follow-up
- The HOMA-IR (a calculation of the product of fasting insulin and fasting glucose, divided by 22.5) in patients without diabetes is a reasonable surrogate marker for IR, but does not diagnose NAFLD (but does identify patients at higher risk of NASH or fibrosis progression, and provides further impetus to reinforcing weight loss, interventions to improve components of the metabolic syndrome)
- Follow-up is “mandatory” in those with obesity, but also consider in lean patients (even with BMI<25) with visceral fat adiposity or “dysfunctional adipose tissue” who can have NAFLD with either normal or abnormal LFTs (most lean patients will have features of IR)
- In people with NAFLD, always screen for diabetes. And, in those with diabetes, look for hepatic steatosis irrespective of liver enzyme levels (i.e. check ultrasound)
- NASH patients with fibrosis associated with hypertension should receive closer monitoring because of higher risk of disease progression
- All patients with NAFLD should have screening for cardiovascular disease, at least by detailed risk factor assessment [they do not specify further, but note that CRP and procoagulant/prothrombotic risk factors are elevated, as well as higher prevalence of abnormal echocardiograms and EKGs]
- In terms of HCC (hepatocellular carcinoma), NAFLD is a risk factor; HCC can develop in pre-cirrhotic patients (especially older ones, where 1/3 of cases are pre-cirrhotic), and if certain polymorphisms are present, but no recommendation regarding timing or cost-effectiveness of screening
Treatment recommendations:
- Stresses role of lifestyle changes: structured programs for healthy diet and physical activity, focus only on lifestyle changes in those without NASH or fibrosis (i.e., no drugs), 7-10% weight loss in those overweight/obese, avoid NAFLD-promoting foods (processed food, high fructose food and beverages), trying to implement the Mediterranean diet. Exercise should be both aerobic and resistance training, tailored to the patient’s preferences
- Drugs for NASH, esp with significant fibrosis (F2 or higher). No firm recommendations, but “pioglitazone (most efficacy data, but off-label if used outside of type 2 diabetes), or vitamin E (better safety and tolerability in the short-term) or their combination”
- Optimal treatment duration unknown. But in those with baseline increased ALT, stop if no reduction in transaminases after 6 months. No recommendation if normal ALT
- Statins “may be confidently used to reduce LDL and prevent cardiovascular risk, with no benefits or harm on liver disease”. Also n-3 polyunsats, but there are “no data to support their use specifically for NASH”
- Bariatric surgery should be considered (prospective data show improvement in all features of NASH including fibrosis), and liver transplantation, if it comes to that, for liver failure and/or HCC.
Commentary:
- One of the big issues above is screening: they do push ultrasounds for all with evidence of IR or diabetes, even suggesting that all obese get one. As per my prior NAFLD blogs, I think this might be quite reasonable, given the high prevalence of NAFLD, the potentially bad outcomes from NAFLD (including cardiovascular in those with NAFL in addition to hepatic in those with NASH), the potentially powerful benefit of lifestyle changes in improving NAFLD (which I think can be more effectively discussed through motivational interviewing in the context of documented NAFLD), potentially avoiding end-stage liver disease (given that probably most cases of “cryptogenic cirrhosis” are from NAFLD and not really so cryptogenic), and the potential for real impact: because of its striking prevalence, picking up NAFLD early dwarfs the potential benefit of many screening tests we do regularly. And it may well be reasonable to repeat ultrasounds at some unknown interval to pick up new cases or (though insensitive) changes suggesting increasing liver damage
- In terms of noninvasive markers of disease: NAFLD fibrosis score (NFS) and fibrosis 4 calculator (FIB-4) are externally validated in different NAFLD populations and predict overall mortality, cardiovascular mortality and liver-related mortality. NFS predicts subsequent diabetes. But these tests are better at distinguishing advanced vs non-advanced fibrosis though not significant vs no fibrosis. I.e., they can pretty well exclude severe disease. So, these biomarkers and scores of fibrosis (as well as transient elastography) are “acceptable” non-invasive procedures for identifying cases at low risk of advanced fibrosis/cirrhosis, and “might save a number of diagnostic liver biopsies”. Again, this is not a “recommendation” by the US authorities or by the extensive reviews in the first 2 blogs, but I suspect we will be moving more and more to these noninvasive tests (already being done much more frequently in several academic centers in Boston), though would be great to have more substantial data to support them.
- NAFLD is also present in 7% of normal-weight people, more often in females, at a younger age, and with normal liver enzymes, though the liver disease may still be progressive [so, should we do ultrasounds on everyone??? not sure how they expect this statement to be actualized in practice]
- In terms of drugs, in their text they mention:
- Scant evidence of benefit on hepatic fat. But I use pretty much all the time as first line drug in those with evidence of insulin resistance or dysglycemia/diabetes (see multitude of blogs in https://stg-blogs.bmj.com/bmjebmspotlight/category/diabetes/ , or you can go to the blog website as at http://ebm.bmj.com and search for “metformin”
- Thiazolidinediones: (see PIVENS study as described in the second blog). Pioglitazone improved all histological features except fibrosis. And more resolution of NASH than placebo. I am still somewhat hesitant given the associated weight gain and other adverse effects, but seems reasonable overall to use pioglitazone. I agree with them that I would use vitamin E before that, and would use the 400 IU strength to see how the transaminases respond, then increase to 800 IU if no/minimal response.
- GLP-1 agonists: small study of liraglutide showing NASH remission without worsening fibrosis. Again, as in my diabetes blogs, I have been using more of the GLP-1 agonists as my second line, behind the metformin. NAFLD is another reason.
- Vitamin E (PIVENS): improved steatosis, inflammation and ballooning and induced resolution of NASH in 36% (vs 21% on placebo). Reduction in ALT correlated with histologic improvement. Concerns about long-term safety.
- -PUFA data inconsistent. I do suggest increased fish consumption and/or fish oil supplementation, given the potential cardiovasc benefits as well, especially in those with IR and high triglycerides (also see: https://stg-blogs.bmj.com/bmjebmspotlight/2016/07/15/primary-care-corner-with-geoffrey-modest-md-w-3-fatty-acids-decrease-heart-disease/ )
- In 20% of patients, fibrosis rapidly progresses. Overall the rate of progression corresponds to 1 fibrosis stage in 14 years with NAFL and every 7 years with NASH. But this is twice as fast in those with hypertension. Hence the recommendation to monitor patients with NASH and fibrosis who are hypertensive should get closer monitoring. I’m not sure what they mean in this document by closer monitoring. But I would consider doing more regular FIB-4 and transient elastography, probably every 1-2 years.
- Cardiovascular disease (most common cause of death): higher with NAFLD and driven by the higher risk by the components of metabolic syndrome. The risk increases further with NASH and more so in those with advanced fibrosis. So, I would tend to be even more aggressive in cardiovasc risk reduction, including earlier use of statins (they underplay their potential benefit for NAFLD, though the prior blogs to highlight their likely benefit –e.g. see https://stg-blogs.bmj.com/bmjebmspotlight/2016/05/16/primary-care-corner-with-geoffrey-modest-md-use-of-statins-in-patients-with-hepatitis-looks-like-a-yes/ ).
- NAFLD also associated with colorectal cancer, metabolic bone disease (vitamin D deficiency, osteoporosis).
- The potential role of iron as an hepatoxin: it acts as an inducer of necroinflammatoin (?thru generation of free oxygen radicals), and of note insulin resistance is associated with increased hepatic iron stores and improving glycemic control is associated with decreased serum and hepatic iron levels. And prior blogs comment on ferritin levels as predictors of worse prognosis.
- But, alas, it is with a deep heart, no doubt to all of us, that they do not even mention the microbiome…..
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