NAFLD and NASH and ElastoUS

In the latter years in hepatology, due to new, very potent antiviral drugs that can eradicate or control viral replication in chronic hepatitis C and B patients, witnessed a change in focus has been witnessed: from chronic viral hepatitis  to  fatty  liver  disease. NAFLD  (non-alcoholic fatty  liver  disease)  affects  approximately  one  quarter of  the population  in developed  countries, while NASH (non-alcoholic  steato-hepatitis)  is  present  in  approximatively 2-4% [1,2]. Despite the fact that the course of NASH is quite long, the patients can develop liver cirrhosis and later hepatocellular carcinoma. In the last years, hepatologists  have  focused  on  how  to find  the  patients at risk for NAFLD and NASH, how to predict their evolution and maybe  to stratify  the  risk, considering  that a huge cohort of asymptomatic subjects (millions of people in an area) are dealt with at any one time.

The answer to the first question – how to find them? – is to evaluate the patients at risk for NAFLD and NASH: firstly the  overweight  and  obese  patients;  secondly  patients with type 2 diabetes: thirdly patients with metabolic syndrome and, of course, dyslipidemic subjects (many of them having all these risk factors) [3,4]. The second question is how to identify the subjects at risk to progress toward advanced liver disease. The general practitioner (GP) is the first gate of this strategy, being in direct contact with these patients, then the diabetologist who has most patients at risk under surveillance, usually for a long time (type 2 diabetes patients and dyslipidemic subjects), also the cardiologist  who  is  following-up  patients  with  metabolic syndrome.  Finally, the hepatologist/gastroenterologist  – whose duty  is  to establish  the disease severity,  the prognosis and the best treatment approach for these patients.

The first step in screening the population at risk is to find liver steatosis; the second – to find if this fatty infiltration has a significant  impact on  the  liver; and finally – for prognosis, to find if fibrosis is present. The first aim –  to discover steatosis and  to estimate its  severity  –  can  be  easily  and  inexpensively  reached by  using  liver  ultrasonography  (US). No  expensive  ultrasound machines  and  no  large  ultrasound  experience are required. The sensitivity of liver US for discovering and quantifying steatosis ranges between 60-80%, even higher  for severe steatosis  [5],  influenced by  the physician’s experience.  In centers where a FibroScan device is available, a more objective evaluation of steatosis can be performed using CAP (Controlled Attenuation Parameter). For CAP, cut-off values were calculated for different degrees of steatosis, with accuracy ranging from 80 to 85% [6,7]. In patients undergoing CT or MRI for other purposes, both techniques can give valuable information concerning  the  severity of  fatty  infiltration of  the  liver, but none of them are screening tools.

Considering  the  availability,  the  low  cost,  and  the relatively good sensitivity of US, it seems to be the best method to screen for steatosis in the general population. US can be performed by specialists or by a GP. The criticism for US can be that its accuracy is at its best only if fatty infiltration exceeds 20%. But considering carefully the increased echogenicity of the liver with posterior attenuation and the liver/right kidney gradient, the method is quite sensitive, at least for experienced people [8].

The next question  is how can  inflammation, and especially fibrosis, be assessed in patients with risk factors for NAFLD. A surrogate for inflammation can be the level of  aminotransferases  (ASAT/ALAT  ratio), useful  for general  practice  and  especially  for GP’s  screening. We must  advise  the GP,  the  diabetologist  and  cardiologist, that any small increase of aminotransferases in risk subjects must be evaluated by the hepatologist. Other more sophisticated  biological  tests  can  be  used,  such  as  the NAFLD test or FibroMax. Some of them are expensive (FibroMax) and not widely available. Cytokeratin 18 was proposed as a  surrogate  test  for  infammation detection and NASH [9].

 But let’s focus our discussion on liver fibrosis! This is the most important aspect, since it gives the prognosis. Liver fibrosis can be assessed by liver biopsy or non-invasively. But how can we speak about liver biopsy when NAFLD is an epidemic disease, with millions of cases?

This method  is  too  invasive  for  daily  practice  and  can lead to complications [10]. What about liver elastography? Lately it has became a  fashion! During  ILC Amsterdam  2017, many  papers and discussion were focused on this topic. More than 10 years  ago, Transient  Elastography  (TE)  arrived  on  the market,  performed  with  a  FibroScan  device.  It  evaluates  liver stiffness as a marker of fibrosis. Many papers demonstrated  its good value of  initially  in chronic viral hepatitis  and  later  also  in  NAFLD  [11].  The  new  XL probe (for obese subjects), that completed the M probe, improved the method’s feasibility to more than 90% [12]. Thus,  the vast majority of patients can be evaluated for fbrosis severity by TE. Cut-off values for various stages of fibrosis were calculated for different etiologies, so that TE became a “a must  to have”  in clinical hepatological practice.

During the last 5 years, other US based elastographic techniques were developed: point shear wave elastography (pSWE) or real time elastography (2D-SWE), all integrated into ultrasound machines, can provide liver steatosis  and  liver  stiffness  evaluation  in  the  same  session.

Very recently, an update on the EFSUMB Guidelines and recommendations on  liver elastography have been published [13]. We expect  that  in  the next few years, ultrasound systems with stiffness evaluation will be common in daily practice. The cost of such a system is still high (despite  the  fact  that  some  companies  have  introduced the  elastographic module  in  their mid-class  ultrasound machines),  but  many  hepatologists  (and  maybe  GPs) would  like  to have  such a  system  to evaluate a pathology that is increasing annually. The maintenance cost for such a system  is very  low and  thus  it can be used for a long time, without supplementary costs. One of the companies released very recently an ultrasound system able to perform both 2D-SWE and TE. Another company tried to combine pSWE and 2D-SWE in the same ultrasound machine.

Thus, very soon, the hepatologist (radiologist, diabetologist, maybe  the cardiologist, or GP) will be able  to start screening people at risk, in order to find significant liver  steatosis  and  significant  liver  fibrosis  using  ultrasound machines  and  liver  elastography.  In some  areas, such as the USA, where a lot of energy has been invested in Magnetic Resonance Elastography (MRE), this method can be a competitor. But it is still very expensive and probably not suitable  for screening purposes. The competition will be between the FibroScan with CAP (that quantifies steatosis and fibrosis severity) and ultrasound machines with elastography modules. Probably the analysis of the acquisition and maintenance costs will be the decisive factor. Of course, there  is a place also  for biological tests, but maybe decreasing the cost for complex tests (such as FibroMax) should be recommended.

In centers where systems are able to evaluate the severity of  liver steatosis and  liver fibrosis,  I believe  that it  is  the moment  to  start  screening  for  the  presence  of fatty liver and fibrosis in patients with risk factors (type 2  diabetes,  obese,  dyslipidemia,  metabolic  syndrome) [14]. Early diagnosis of significant disease is the best moment to start therapy (life style changes or drug therapy).

NAFLD is the more prevalent disease in hepatology now, in the developed world, and now is the time to start the fight against this disease!