Primary Care Corner with Geoffrey Modest MD: Non-alcoholic Fatty Liver Disease 1

By Dr. Geoffrey Modest

There have been several articles recently on non-alcoholic fatty liver disease (NAFLD) in a recent special issue of the journal Digestive Diseases and Sciences, as well as a recent release of NAFLD clinical management guidelines by the European Assn for the study of NAFLD. Since NAFLD is so common throughout the world, since it is amenable to lifestyle interventions, and since there was so much interesting info on NAFLD but so many unresolved questions, I will devote 3 blogs to this:

  1. Natural history of NAFLD
  2. Review of therapies, with more detail on a couple of topics (e.g. the role of the microbiome and of specific dietary components, esp. fructose)
  3. A review of the EASL guidelines for NAFLD


NAFLD Natural history (see Goh G. Dig Dis Sci 2016; 61: 1226)

  • NAFLD (nonalcoholic fatty liver disease) was first defined only in 1980, which is rather surprising given that it is: incredibly common (in the US its prevalence has increased from 5.5 to 11% between 1988 and 2008), the most common liver disease in the world with estimated prevalence of 20-30%, the most rapidly rising indication for liver transplantation, and likely to be the number one indication for liver transplantation by 2020. The fact that the prevalence is increasing, however, is not so surprising, since NAFLD is so closely related to insulin resistance, obesity and metabolic syndrome. It is important to keep in mind that with all of these statistics, there are real issues of differing definitions and ascertainment bias overall. For example, in one study the prevalence of ultrasound-diagnosed hepatic steatosis with normal liver enzymes was 16.4%, but the prevalence of hepatic steatosis with abnormal LFTs was 3.1% (i.e., determining NAFLD by ultrasound vs abnormal LFTs as the NAFLD yields very different prevalences).
  • NAFLD is formally defined as the accumulation of >5% fat in the liver, not attributable to alcohol, drugs or other secondary causes, and represents the spectrum from NAFL (non-alcoholic fatty liver, or steatosis) to necroinflammatory changes of NASH (non-alcoholic steatohepatitis), advanced fibrosis, cirrhosis and HCC (hepatocellular carcinoma). The biopsy may be indistinguishable from alcoholic steatohepatitis.
  • Long-term prognosis: the most common causes of death are cardiovascular (the number one cause: see Mantovani A. Dig Dis Sci 2016; 61: 1246), malignancy and liver disease. And it seems likely that a large % of those diagnosed with “cryptogenic cirrhosis” actually have NAFLD. The extent of these outcomes varies in different studies, from not much of an increase to being equivalent to hepatitis C. However, it seems that most studies find the mortality increases significantly as one goes from NAFL (steatosis only) to NASH, and seems overall to be much worse with more severe stages of NASH (e.g. one study with 18.5 years of follow-up found that liver-related mortality increased from 3% in non-NASH to 18% in those with NASH). A meta-analysis found that mortality was not much higher in those with simple steatosis vs the general population, but in those with NASH there was still an 81% increase in overall mortality  and 471% increase in liver-related mortality.
  • Progression of NAFLD: in a meta-analysis of 133 patients with simple steatosis, 39% developed progressive fibrosis, 53% remained stable and 8% improved. This translates to an average annual progression rate of 1 fibrosis stage over 14 years. Also, NASH progresses: a study of 221 patients found that 37% had progressive fibrosis on repeat biopsy over 5 years. Overall, it seems that in patients with NASH and no fibrosis, there is a 1 stage progression of fibrosis over 7 years. BUT there are a small group who have much more rapid progression.
  • 10-25% of patients with NASH progress to advanced fibrosis/cirrhosis. In a small Australian study comparing patients with NASH cirrhosis to those with hepatitis C, about 40% of each group developed liver-related complications over 7 years, though other studies have found lower mortality rates than hep C (but with more cardiovascular mortality). There are some data suggesting that higher serum ferritin levels (> 1.5x upper limit of normal) is associated with a higher likelihood of NASH and more advanced fibrosis.
  • BUT, one counterintuitive point that makes it difficult to rely simply on noninvasive testing: there is no relationship with the height of serum transaminases and the degree of hepatic inflammation or fibrosis. And, there can be significant hepatic inflammation without increased transaminases.


  • These data make it very difficult to figure out what is best to do with patients who have increased ALT levels (really common). In general, we screen for other causes of increased LFTs, especially for viral hepatitides (esp hep B and C, but I also check to make sure either immune to hep A naturally or by immunization, and immunize against hep B if nonimmune), autoimmune hepatitis (e.g. ANA, anti-smooth muscle, anti-liver-kidney microsomal antibody-1), iron overload (iron, TIBC, ferritin). And get an ultrasound.
  • One concern with NAFLD as an entity is that it really is a diagnosis of exclusion. That makes it more likely that NAFLD is not a single condition: there could well be unknown causes of fatty liver that are lumped together in “NAFLD”; there seem to be a variety of predisposing conditions (though insulin resistance is the most common, there are many people with NAFLD without that); and there are such variable prognoses (some never progress, some regress, some advance, and some advance very quickly).
  • Should we be screening for NAFLD (not currently recommended)? From the NHANES data, its incidence has increased from 5.5% around 1990 to 11% in 2008, and the % of cases of chronic liver disease attributable to NAFLD has increased from 47% to 75% during this time. (i.e., much more common than for other causes, which we do screen for). And there are interventions that help (see later blog). I personally do screen with LFTs in obese kids and all adults, and (not surprisingly, given the frequency of NAFLD, have found many cases, much more than hepatitis C). And I have had some success in convincing patients to lose weight and do more exercise based on these results. But should we be doing more inclusive screening with an ultrasound, to pick up the many cases where the LFTs are normal (and we know that LFT changes can be transient, and may never be found, despite the possibility of significant hepatic inflammation)????? I am not doing that, but it certainly seems reasonable….
  • What is the best way to follow those with steatosis on ultrasound or raised ALT levels suggestive of NAFLD? Should we be following ultrasounds routinely to look for progression? And if we do serial ultrasounds, how often? Biopsy is currently considered the only method to really see if there is active inflammation or fibrosis. Hopefully in the not-so-distant-future we will have reliable non-invasive tests: e.g. transient elastography which might helpdifferentiate NAFL from NASH and also track its progression (some small studies found it was able to differentiate degrees of steatosis, and another finding a stepwise increase in liver stiffness that correlated with the degree of biopsy-proven hepatic fibrosis). And there are potential serum markers: e.g. FIB-4 (a calculation involving age, AST, ALT and platelet count), which correlates well with the degree of hepatic fibrosis; and other markers look promising (e.g., cytokeratin-18, which reflects hepatocyte apoptosis). More studies are needed on these, but there are glimmers of hope that we can avoid biopsies.
  • And if we decide to do a liver biopsy, how often should they be done, in light of the pretty high progression rate to NASH and fibrosis? What about trying to pick up those who are rapid progressors?
  • One other consideration: since NAFLD is so common and has an attendant increased risk of cardiovascular disease, I have a low threshold to prescribe a statin, especially in middle-aged and older patients. See blog which reviews several of the studies, in patients with NAFLD, hepatitis B and C, finding clinical benefit. In NAFLD, there are some data showing that statins both reduce cardiovascular mortality, but also have some benefit in improving NAFLD histology or its future complications (advanced fibrosis, etc.), as well (also see Mantovani A. Dig Dis Sci 2016; 61: 1246 for more info).