NASH Diagnosis Criteria: An Updated Guide for Clinicians

Nonalcoholic fatty liver disease (NAFLD) is characterized by the abnormal accumulation of fat in the liver, known as hepatic steatosis, in individuals who do not consume excessive alcohol. While a small amount of fat in the liver can be normal, a diagnosis of NAFLD is considered when fat deposition affects 5% or more of liver cells (hepatocytes). This condition encompasses a spectrum, ranging from nonalcoholic fatty liver (NAFL) to the more severe nonalcoholic steatohepatitis (NASH). NASH is distinguished by the presence of inflammation and liver cell injury in addition to steatosis. This article delves into the diagnostic criteria for NASH, building upon the foundation of NAFLD understanding.

Understanding NAFLD and NASH

NAFLD is broadly defined by fat accumulation in the liver without secondary causes. NASH, a subtype of NAFLD, is diagnosed when there is histological evidence of both steatosis and inflammation with hepatocyte injury. It’s crucial to differentiate NAFLD/NASH from alcoholic liver disease, with accepted thresholds for alcohol consumption being less than 20 g/day for men and 10 g/day for women. However, these limits are not absolute, especially in individuals with a history of heavy drinking or those genetically predisposed to NASH. NASH is not merely a diagnosis of exclusion; it can coexist with other liver conditions, such as chronic hepatitis C. Primary NASH is linked to metabolic disorders like obesity and diabetes, while secondary NASH can be induced by toxins or medications. This discussion will primarily focus on primary NASH and its diagnostic evaluation.

The Cornerstone of NASH Diagnosis: Liver Biopsy and Histopathology

The definitive diagnosis of NASH traditionally relies on liver biopsy, a procedure where a small sample of liver tissue is extracted and examined under a microscope. Histopathological assessment remains the gold standard for confirming NASH and determining the severity of liver damage.

Nash Diagnosis Criteria Based on Liver Biopsy

Liver biopsy allows for the evaluation of key histological features that define NASH:

Steatosis: The presence of fat droplets within hepatocytes. Pathological steatosis is defined as fat accumulation in more than 5% of hepatocytes. Steatosis can be macrovesicular (large droplets displacing the nucleus) or mixed macro- and microvesicular in NASH.
Hepatocyte Ballooning: This refers to the swelling and injury of liver cells, a hallmark of NASH. Ballooned hepatocytes are enlarged, rounded, and may have a rarefied cytoplasm.
Lobular Inflammation: Inflammatory cell infiltration within the liver lobules, typically composed of lymphocytes, macrophages, and occasional plasma cells.

Alt: Microscopic image of liver steatosis, demonstrating fat droplets within liver cells.

The NAFLD Activity Score (NAS)

To standardize the histological assessment of NASH, the NAFLD Activity Score (NAS) was developed. This scoring system grades the severity of NASH based on the aforementioned histological features:

Steatosis: Graded from 0 to 3 based on the percentage of hepatocytes affected (0: <5%, 1: 5-33%, 2: 34-66%, 3: >66%).
Lobular Inflammation: Graded from 0 to 3 based on the number of inflammatory foci per 200x field (0: none, 1: <2 foci, 2: 2-4 foci, 3: >4 foci).
Hepatocyte Ballooning: Graded from 0 to 2 (0: none, 1: few ballooned cells, 2: many ballooned cells).

The NAS is the sum of these three scores, ranging from 0 to 8. A NAS score of 5 or higher is generally considered indicative of NASH, while a score less than 3 is less likely to represent NASH. A score of 3 or 4 is considered borderline for NASH.

Fibrosis Staging

In addition to NAS, liver biopsies are also used to stage fibrosis, the scarring of the liver, which is a critical determinant of prognosis in NASH. Fibrosis is typically staged on a scale of 0 to 4:

Stage 0: No fibrosis.
Stage 1: Perisinusoidal or periportal fibrosis (mild).
Stage 2: Perisinusoidal and periportal fibrosis with rare bridging fibrosis (moderate).
Stage 3: Bridging fibrosis (advanced).
Stage 4: Cirrhosis (severe).

Limitations of Liver Biopsy

Despite being the gold standard, liver biopsy has limitations. It is an invasive procedure with potential risks, including pain, bleeding, and, rarely, more serious complications. Sampling error is another concern, as biopsy samples represent only a tiny fraction of the entire liver, and NASH features may not be uniformly distributed throughout the liver. Inter-observer variability in histological interpretation can also occur, although standardized scoring systems like NAS aim to minimize this. Due to these limitations, there is a growing need for non-invasive diagnostic methods.

Non-Invasive Diagnostic Approaches for NASH

Given the drawbacks of liver biopsy, non-invasive tests (NITs) are increasingly used in the evaluation of NAFLD and NASH. These tests can be broadly categorized into serologic tests and imaging techniques. While NITs may not directly diagnose NASH with the same certainty as liver biopsy in all cases, they play a crucial role in risk stratification, identifying patients at higher risk of NASH and advanced fibrosis who may benefit most from liver biopsy or treatment.

Serologic Tests

Several blood-based tests have been developed to assess fibrosis and, to a lesser extent, predict the likelihood of NASH. These tests are readily available and less invasive than biopsy.

AST to Platelet Ratio Index (APRI) and Fibrosis-4 (Fib-4) Calculator: These are simple, readily available scores calculated using routine blood tests (AST, platelets, ALT, age). They are primarily used to rule out advanced fibrosis. Low scores (APRI < 1, Fib-4 < 1.3) suggest a low probability of advanced fibrosis.
NAFLD Fibrosis Score (NFS): Similar to APRI and Fib-4, NFS uses readily available clinical and laboratory data to estimate fibrosis risk. A score less than -1.455 indicates a low risk of advanced fibrosis.
Enhanced Liver Fibrosis (ELF) Test and FibroTest: These are commercial panels that measure multiple serum biomarkers related to fibrosis. They can provide a more refined assessment of fibrosis severity than APRI, Fib-4, and NFS.

It is important to note that while these serologic tests are valuable for assessing fibrosis risk, they are not direct diagnostic tests for NASH itself. They can help identify patients with a lower likelihood of advanced fibrosis, potentially avoiding liver biopsy in this group. However, they are less accurate in diagnosing NASH or ruling it out, especially in individuals with milder disease.

Imaging Techniques

Imaging modalities can detect hepatic steatosis and assess liver stiffness, a surrogate marker for fibrosis.

Ultrasound: Widely available and inexpensive, ultrasound can detect moderate to severe steatosis but is less sensitive for mild steatosis. It has limited accuracy in assessing inflammation or fibrosis.
Computed Tomography (CT) and Magnetic Resonance Imaging (MRI): These imaging techniques are more sensitive than ultrasound for detecting steatosis. MRI-based techniques, such as MRI-proton density fat fraction (MRI-PDFF), can quantify liver fat content accurately.
Transient Elastography (FibroScan): This ultrasound-based technique measures liver stiffness, which correlates with fibrosis severity. A FibroScan score greater than 9.3 kPa (with XL probe) or 9.6 kPa (with M probe) suggests advanced fibrosis. Scores below 7.2 kPa and 7.9 kPa, respectively, can reliably exclude advanced fibrosis.
Acoustic Radiation Force Impulse (ARFI) Imaging and Magnetic Resonance Elastography (MRE): These are other elastography techniques that also assess liver stiffness and fibrosis. MRE is considered the most accurate non-invasive method for assessing fibrosis.

Alt: FibroScan device used for non-invasive liver assessment.

While imaging can detect steatosis and fibrosis, it generally cannot reliably diagnose NASH, which requires histological evidence of inflammation and hepatocyte injury. However, certain advanced MRI techniques are being investigated for their potential to detect NASH-related inflammation, but these are not yet widely used in routine clinical practice.

Integrating Nash Diagnosis Criteria in Clinical Practice

The diagnosis of NASH in clinical practice involves a combination of clinical assessment, laboratory tests, imaging, and potentially liver biopsy, guided by the “Nash Diagnosis Criteria.”

A Step-wise Approach to NASH Diagnosis:

Clinical Suspicion: NASH should be suspected in individuals with risk factors such as obesity, type 2 diabetes, metabolic syndrome, and unexplained elevated liver enzymes (especially ALT).
Exclusion of Other Liver Diseases: Rule out other causes of liver disease, including excessive alcohol consumption, viral hepatitis (B and C), autoimmune hepatitis, drug-induced liver injury, and hereditary liver diseases.
Assessment of Steatosis: Establish the presence of hepatic steatosis, typically using imaging (ultrasound, CT, or MRI).
Risk Stratification for Advanced Fibrosis: Utilize non-invasive fibrosis scores (APRI, Fib-4, NFS) and/or elastography (FibroScan, MRE) to assess the risk of advanced fibrosis.
Liver Biopsy (Selective): Liver biopsy is often recommended in patients at intermediate or high risk of advanced fibrosis based on NITs, or when NASH diagnosis is needed for clinical trial eligibility or to guide management decisions in uncertain cases. Liver biopsy remains crucial when non-invasive tests are inconclusive or discordant.
Histopathological Evaluation: If liver biopsy is performed, histological assessment using NAS and fibrosis staging is essential to confirm NASH and grade disease severity based on “Nash diagnosis criteria”.

When is Liver Biopsy Necessary?

Liver biopsy is generally considered when:

Non-invasive tests suggest intermediate or high risk of advanced fibrosis.
There is diagnostic uncertainty, and NASH confirmation is needed.
To stage the severity of NASH and fibrosis accurately for prognosis and treatment planning.
To rule out other liver diseases that may mimic NASH.
For enrollment in clinical trials.

In patients with a low likelihood of advanced fibrosis based on NITs, liver biopsy may be deferred, and management can focus on lifestyle modifications and monitoring.

Conclusion: Evolving Nash Diagnosis Criteria

The diagnosis of NASH relies on a combination of clinical, laboratory, imaging, and histological findings, centered around the “Nash diagnosis criteria”. Liver biopsy remains the gold standard for definitive diagnosis, providing essential information on steatosis, inflammation, hepatocyte injury, and fibrosis. However, non-invasive tests are increasingly important for risk stratification and reducing the need for liver biopsy. The field of NASH diagnostics is continuously evolving, with ongoing research aimed at developing more accurate and non-invasive methods for diagnosing NASH and assessing disease severity. Clinicians should utilize a step-wise approach, integrating both invasive and non-invasive tools to effectively diagnose and manage patients with NAFLD and NASH, ultimately improving patient outcomes.