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A diagnosis of NAFLD is relatively straightforward and requires the presence of steatosis in ≥ 5% of hepatocytes in the absence of any other contributory factors, such as excessive alcohol consumption.[1,34] Diagnosing NASH requires a liver biopsy, and the diagnosis depends on the presence of hepatic steatosis with both ballooning and lobular inflammation. Hepatic steatosis can be identified by imaging techniques such as ultrasonography, where the echo brightness of the liver is compared with the kidney. If the liver is brighter than the kidney, it is termed “echobright”—thus indicating a fatty liver. Ultrasonography is limited, however, in that it cannot be used to evaluate the extent of steatosis and becomes unreliable at detecting steatosis < 20% or in those with a high BMI. Modalities such as controlled attenuation parameter may enhance sensitivity and allow for quantification of the degree of steatosis.
Suspicion of NAFLD should be prompted by the presence of associated risk factors discussed earlier in this module, such as obesity and type 2 diabetes mellitus, although these are not always present. As part of making a diagnosis, a thorough history of alcohol consumption should be taken. For the purposes of diagnosing NAFLD and NASH, the European Association for the Study of the Liver defines excessive alcohol consumption as a daily intake of alcohol ≥ 20 g for women and ≥ 30 g for men. Although NAFLD and excessive alcohol consumption can coexist, it remains problematic to make the diagnosis of NAFLD or NASH with confidence in the setting of increased alcohol intake.
Patients with NAFLD will often—but not always—have elevations in serum liver enzymes. As such, they should have a liver etiology screen to investigate for other treatable causes of liver damage such as hepatitis C virus infection and autoimmune diseases. Weakly positive liver autoantibodies and elevations of serum ferritin are often observed in the setting of NAFLD, but these findings rarely indicate additional pathology.
A challenging element of the diagnostic workup of patients with NAFLD is the determination of disease severity. The goal here is to identify patients with more advanced disease at increased risk for morbidity and mortality. Percutaneous liver biopsy remains the gold standard for making a precise diagnosis of NAFLD with specification categorization and is necessary to assess the histopathologic criteria essential to making a diagnosis of NASH.[1,34] Biopsy allows for confirmation of steatosis as well as determining the degree of lobular inflammation, ballooning, and fibrosis. Commonly used scoring systems for evaluating the severity of NAFLD include the NAFLD Activity Score, which evaluates and assigns scores to 4 domains: steatosis (0-3), lobular inflammation (0-3), hepatocyte ballooning (0-2), and liver fibrosis (0-4) (Table 1). The first 3 elements can be summed to generate an aggregate value whereas fibrosis staging is kept separate.
There is variation in opinion as to what constitutes significant or advanced liver fibrosis:
NASH is diagnosed based on an overall assessment by a pathologist using scoring systems such as the Steatosis, Activity, and Fibrosis (SAF) score, which evaluates of the presence and extent of each individual component of steatosis, inflammation, and ballooning (Table 1). NASH can be diagnosed using a validated algorithm based on the SAF scoring system (Table 2).
Table 1. Grading and Staging Systems for NAFLD and NASH[41-43]
Table 2. Diagnostic Algorithm for NASH Based on SAF System
Given the morbidity and mortality associated with percutaneous liver biopsy, there have been extensive efforts to develop noninvasive diagnostic strategies. Noninvasive tests draw on assessments of demographic factors, blood parameters, and/or imaging modalities. Commonly used algorithms include the NAFLD fibrosis score (NFS) and FIB-4, which evaluate parameters such as BMI, presence of T2DM/impaired fasting glycemia, liver enzymes, and platelet count to determine the likelihood of liver fibrosis. These tests classify patients into fibrosis risk categories defined as low risk, high risk, and indeterminate for having advanced (stage 3) fibrosis (Table 3).
Table 3. Score Cutoffs for NFS and FIB-4 Algorithms
In general, patients with a low-risk score can be considered to not have fibrosis and remain under care of their primary care physician, with management strategies focused on achieving a gradual, long-term weight loss. Those with indeterminate or high-risk scores will require further evaluation. It is important to note that there are many false positives in the setting of an indeterminate or high score, especially if the patient is older than 65 years of age when specificity decreases dramatically; patients should be counseled on this limitation when they are being evaluated.
For patients with indeterminate scores, the next stage of evaluation can include liver biopsy, although additional noninvasive testing may reduce the need for biopsy. Noninvasive options include second-line tests such as the serum Enhanced Liver Fibrosis Score (ELF), FibroScan transient elastography (TE), or Acoustic Radiation Force Impulse (ARFI) elastography. The choice of second-line tests should be based on local expertise and availability of equipment. TE is a widely used modality that can be performed in the clinic and provides a reading of liver stiffness. TE relies on the principle that the speed of wave conduction is linked to tissue stiffness, which reflects the degree of liver fibrosis. The serum ELF test consists of a panel of candidate biomarkers that are linked to fibrosis. Both tests can be used to further stratify patients with indeterminate scores to decide which require further investigation by liver biopsy. Although published cutoffs vary depending on the clinical context, in general, the cutoff for advanced fibrosis (≥ F3) is ≥ 9.8 for serum ELF measurements and > 10 kPa for FibroScan.[46,50-52] Cutoffs for ARFI vary according to the device manufacturer.