Diagnostic Modalities for Nonalcoholic Fatty Liver Disease

Key Points

• NAFLD affects about 25% of adults globally, making it the most common chronic liver disease worldwide.
• Fibrosis stage, not NASH itself, is the strongest predictor of mortality in NAFLD, so identifying fibrosis is key.
• Noninvasive tests such as transient elastography and MRE can accurately measure liver stiffness and reduce the need for biopsy.
• MRE has a 0.97 negative predictive value for advanced fibrosis, so a negative result is highly reassuring.
• Most NAFLD patients die from cardiovascular disease, so managing heart health is essential for all patients.

Nonalcoholic fatty liver disease (NAFLD) affects approximately 25% of the global adult population, making it the most common cause of chronic liver disease worldwide. While liver biopsy remains the gold standard for diagnosing the more serious form called nonalcoholic steatohepatitis (NASH) and staging fibrosis, it has significant limitations including cost, invasiveness, and risk of complications. This article reviews the many noninvasive diagnostic tools being developed—from blood tests and predictive scores to advanced imaging techniques like transient elastography and magnetic resonance elastography—that are helping doctors identify which patients are at greatest risk for progressive liver disease without the need for a biopsy.

• Understanding NAFLD: What Is Fatty Liver Disease?
• The First Steps in Diagnosis
• The Role of Liver Biopsy: The Gold Standard
• Understanding the NAFLD Activity Score (NAS)
• Staging Fibrosis: The Key Predictor of Outcomes
• Imaging Tests: Looking at the Liver Without Surgery
• Noninvasive Blood Tests and Biomarkers for NASH
• Serum Fibrosis Markers: Measuring Scar Tissue
• What This Means for Patients
• Study Limitations
• Recommendations for Patients
• Source Information

Understanding NAFLD: What Is Fatty Liver Disease?

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. According to a recent meta-analysis, approximately 25% of the global adult population—that's one in four adults—may be affected by this condition. Although NAFLD was initially thought to be more common among Hispanic populations, it is now increasingly reported from all regions of the world.

NAFLD is actually a spectrum of liver conditions that ranges from simple fatty liver (isolated steatosis) to the more serious nonalcoholic steatohepatitis (NASH), which involves liver inflammation and damage, and can progress to advanced fibrosis (significant scarring) and cirrhosis (severe, irreversible scarring). The majority of people with NAFLD do not have NASH and do not carry a significant risk for liver-related adverse outcomes such as cirrhosis or death from liver disease.

Children are also affected. The prevalence of NAFLD in children is estimated at approximately 10%, which is concerning given the rising rates of childhood obesity.

The incidence (number of new cases) of NAFLD is estimated to be between 28 and 52 per 1,000 person-years. However, these numbers are probably underestimations, given the rising incidence of two of the primary risk factors for NAFLD: obesity and diabetes. Long-term observational studies show that most patients with NAFLD die primarily of cardiovascular complications (heart disease), not liver disease. However, there are subgroups of NAFLD patients—primarily those with NASH or significant hepatic fibrosis—who are at risk for developing advanced liver disease, hepatocellular carcinoma (the most common type of primary liver cancer), excess liver-related mortality, or becoming candidates for liver transplantation. Recent studies have suggested that the stage of fibrosis, independent of any other histological feature, predicts mortality in NAFLD. This is a critical finding because it means identifying fibrosis is the most important goal of diagnostic testing.

The economic burden of NAFLD and NASH is substantial. A recent Decision Analytic Markov Model estimated tremendous economic costs to both the United States and European economies. Beyond the financial impact, NASH also places a significant burden on patient-reported outcomes (standardized questionnaires that measure a patient's quality of life, physical function, and emotional well-being).

The First Steps in Diagnosis

Before jumping into exhaustive diagnostic tests for NAFLD, healthcare providers must first exclude other causes of fatty liver and coexisting common causes of chronic liver disease. This is an essential step to ensure the right diagnosis and treatment plan.

Specifically, the following must be ruled out:

• Excessive alcohol consumption—the "nonalcoholic" in NAFLD means the condition occurs in people who drink little or no alcohol
• Steatogenic medications—certain drugs that can cause fat to build up in the liver
• Iron overload—especially in patients with persistently high serum ferritin (an iron-storage protein) and increased iron saturation, particularly in the context of the C282Y HFE gene mutation (homozygote or heterozygote)—a condition called hereditary hemochromatosis
• Autoimmune liver disease—although low-titer autoimmune markers (low levels of antibodies that attack the body's own tissues) are frequently seen in patients with NAFLD, autoimmune liver disease should be ruled out in patients with high serum titers of autoantibodies in combination with other features such as high serum globulins

Once other causes of steatosis (fatty liver) have been ruled out, NAFLD should be considered. At this point, doctors should check for commonly associated conditions, including:

• Obesity
• Dyslipidemia (abnormal cholesterol or fat levels in the blood)
• Insulin resistance or diabetes
• Hypothyroidism (underactive thyroid)
• Polycystic ovary syndrome
• Sleep apnea

The Role of Liver Biopsy: The Gold Standard

Liver biopsy—a procedure in which a small sample of liver tissue is removed with a needle for examination under a microscope—has historically been the definitive technique for diagnosing and classifying NAFLD. The role of histopathology (the microscopic examination of tissue) is to establish a diagnosis, exclude other causes of liver disease, characterize the liver lesions, and correlate these lesions with potential clinical outcomes in the context of the natural history of the disease.

Interestingly, much of the terminology and concepts of the histopathological features of NAFLD were derived from studies of alcoholic liver disease. The conditions are analogous:

• Alcoholic fatty liver is analogous to simple steatosis (nonalcoholic fatty liver, or NAFL)
• Alcoholic hepatitis is analogous to NASH
• Alcoholic cirrhosis is analogous to the cirrhotic stage of NASH

Although there may be differences in degree, the features are sufficiently similar that a pathologist cannot make an etiological diagnosis (determining the cause) based on histology alone. The characteristic microscopic features that are investigated when diagnosing alcoholic or non-alcoholic fatty liver disease include:

1. Fat: accumulation of triglycerides (a type of fat) inside liver cells (hepatocellular triglyceride accumulation)
2. Hepatocellular injury: damage to liver cells in the centrilobular location (around the central vein of the liver lobule), which is most severe in the acinar zone (the functional unit of the liver)
3. Cyctoskeletal damage: shown as hepatocellular ballooning (swollen, damaged liver cells) with or without Mallory-Denk bodies (clumps of abnormal protein inside liver cells)
4. Parenchymal inflammation: inflammation of the liver tissue where lymphocytes and macrophages (types of white blood cells) predominate, though neutrophils (another type of white blood cell) may be present in severe cases
5. Perisinusoidal fibrosis: collagen deposition in the space of Disse (the space between liver cells and the blood vessels that supply them)

Despite being the gold standard, liver biopsy has significant limitations. It is invasive, costly, associated with potential complications (including pain, bleeding, and, rarely, death), and it suffers from interobserver variability—meaning two different pathologists may interpret the same biopsy differently. There is also the issue of sampling error: a biopsy takes a tiny sample of the liver, and the disease may not be evenly distributed throughout the organ.

Understanding the NAFLD Activity Score (NAS)

To help standardize the interpretation of liver biopsies and allow for statistical analysis in clinical trials, pathologists from the National Institutes of Health's NASH Clinical Research Network (NIH NASH CRN) developed a grading system called the NAFLD Activity Score (NAS).

The development of the NAS involved studying the interobserver and intraobserver variability (consistency between different pathologists and the same pathologist over time) of a variety of histological features. The features with the greatest reproducibility were chosen to formulate the score:

• Severity of steatosis (fat accumulation), graded from 0 to 3
• Hepatocellular ballooning (liver cell damage), graded from 0 to 2
• Lobular inflammation, graded from 0 to 3

The NAS score is the unweighted sum of these three numbers, with a total range from 0 to 8. When a patient's liver disease improves with treatment, the NAS score decreases, making it a useful tool for tracking treatment response in clinical trials.

More recently, a refinement of this scoring system called the SAF Score has been proposed. Although SAF appears to be a very similar system, it separates the degree of Steatosis (S) from the grade of necroinflammatory Activity (A) and Fibrosis (F), which may provide greater granularity in terms of disease activity and help better distinguish simple steatosis from the more serious NASH.

Staging Fibrosis: The Key Predictor of Outcomes

The histological feature with the greatest reproducibility is fibrosis (scarring)—a feature that is intentionally not part of the NAS score because fibrosis is considered a sign of the stage of disease rather than a grade of injury. Fibrosis staging is therefore scored separately.

In the NASH CRN system, fibrosis is staged as follows:

• Stage 0: No fibrosis
• Stage 1: Centrilobular pericellular fibrosis (scarring around the central vein area) or periportal fibrosis (scarring around the portal tracts) in children
• Stage 2: Centrilobular and periportal fibrosis (both areas affected)
• Stage 3: Bridging fibrosis (bands of scar tissue connecting different structures in the liver)
• Stage 4: Cirrhosis (severe, diffuse scarring that disrupts the liver's structure and function)

Research using this histological framework has led to important discoveries about the natural history of NAFLD:

Simple fatty liver is not always benign. Fatty liver, alone or with some lobular inflammation but without evidence of cytoskeletal damage (ballooning or Mallory-Denk bodies) or fibrosis, has long been considered nonprogressive liver disease. However, recent follow-up studies have found that a few patients do, in fact, eventually develop fibrosis and even cirrhosis.

Fibrosis, not NASH, predicts mortality. NASH with ballooning and Mallory-Denk bodies has long been thought to be the progressive form of NAFLD. However, recent long-term follow-up studies found that the single histological feature that predicted mortality was not NASH itself, but the presence of fibrosis in the liver biopsy. At the same time, studies of NAFLD patients with paired biopsies (two biopsies taken at different time points from the same patient) found that spontaneous regression of fibrosis may be an important feature in NASH, both in the long term and short term. This suggests the liver may have some capacity to heal itself.

Imaging Tests: Looking at the Liver Without Surgery

Because liver biopsy has so many limitations, there is an urgent need for accurate noninvasive diagnostic tools. When seeing a patient for the first time with suspected NAFLD, a clinician wants to answer four questions:

1. Does the patient have NAFLD?
2. Is the patient likely to have underlying NASH?
3. Does the patient have any fibrosis?
4. Does the patient have advanced fibrosis?

There are two main noninvasive approaches to answer these questions: imaging tests and blood-based tests (serum biomarkers).

Detecting Fat in the Liver

The first diagnostic challenge is to accurately show the presence of fat in the liver. Currently, 20%–33% fat content is considered a reliable threshold at which steatosis is detected by conventional imaging methods. However, the presence of fat greater than 5%–10% is considered abnormal.

Fat has its own chemical signature that can be detected directly by magnetic resonance spectroscopy (MRS). When performed properly, MRS quantifies the proton density fat fraction (PDFF)—a standardized measure of triglyceride (fat) in liver tissue. However, MRS has limitations: it is not widely available, requires expertise in protocol prescription, data collection, and spectral analysis, and is not available on routine scanners.

To overcome these barriers, magnetic resonance imaging (MRI)-based methods have been developed using MRI-PDFF to quantify liver fat without needing spectroscopy coils, using routinely available clinical MRI scanners. MRI-PDFF addresses confounding factors and is not affected by scanner field strength, patient factors (age, sex, body mass index, and the cause of liver disease), or concomitant liver abnormalities such as iron overload or necroinflammation. This makes it a robust and practical tool.

Measuring Liver Stiffness

In contrast to fat, fibrosis has no molecular signature that can be detected by current imaging techniques. All imaging tests for fibrosis therefore attempt to detect it indirectly using proposed biomarkers, which include stiffness, diffusion, perfusion, metabolites, and image texture. The leading biomarker is liver "stiffness" (or "elasticity"). The rationale is simple: collagen deposition associated with fibrosis makes the liver more rigid, and this rigidity can be measured. These techniques are collectively called "elastography."

Transient Elastography (TE)—also known as FibroScan—is an ultrasound-based method that measures liver stiffness through the skin. Its performance characteristics are well documented:

• Area under the receiver operating characteristic curve (AUROC) of 0.83 for advanced fibrosis when compared to blood tests
• 90% negative predictive value (NPV)—meaning if the test is negative, there's a 90% chance the patient truly doesn't have advanced fibrosis
• 88% sensitivity—it correctly identifies 88% of patients who do have advanced fibrosis
• Positive predictive value (PPV) of less than 65%—meaning a positive result doesn't always mean the patient has advanced fibrosis
• Places the fewest patients (43.6%) in what is considered "the gray zone" (an indeterminate range where results are not conclusive) compared to blood tests
• Has diagnostic accuracy of 80.8% and can categorize patients into subgroups found to have different prognoses

Magnetic Resonance Elastography (MRE) is a more advanced technique that combines MRI with low-frequency sound waves to measure liver stiffness. Its performance is even better:

• Using a stiffness cutoff of 3.63 kilopascals, MRE has a sensitivity of 0.86 (95% confidence interval [CI], 0.65–0.97)
• Specificity of 0.91 (95% CI, 0.83–0.96)—it correctly identifies 91% of patients who do not have advanced fibrosis
• Positive predictive value of 0.68 (95% CI, 0.48–0.84)
• Negative predictive value of 0.97 (95% CI, 0.91–0.99)—a negative result is highly reassuring
• AUROC of 0.924 for diagnosing advanced fibrosis—this is considered excellent accuracy

Even newer three-dimensional (3D) MRE has shown promise: at 40 Hz (a lower vibration frequency) with a stiffness cutoff of 2.43, it achieves an AUROC of 0.962—even better than standard MRE. In a recent study comparing acoustic radiation force impulse-based (another ultrasound method) versus MRE-based fibrosis assessment, MRE was significantly better. Furthermore, MRE was significantly better than TE when diagnosing cirrhosis (stage 4 fibrosis).

However, there are several caveats before using MRE:

• Cost of the procedure
• Patient size (some scanners have weight limits)
• Claustrophobia (fear of enclosed spaces)
• Presence of metal implants (which can be unsafe in MRI machines)

Although TE and other ultrasound-based tests are more accessible and easier to use, they are limited in patients with obesity, ascites (fluid buildup in the abdomen), or acute inflammation. MRE can overcome all of these issues except iron overload and acute inflammation, but it is limited by restricted accessibility at many centers—especially worldwide—and requires expertise to obtain adequate results, particularly with 3D MRE.

The key trade-off: as specificity goes up, accessibility and ease of use go down. It is reasonable to use ultrasound-based tests in nonobese individuals and consider using MRE in individuals with obesity, especially morbid obesity.

Noninvasive Blood Tests and Biomarkers for NASH

In addition to imaging, researchers are developing noninvasive biomarkers using predictive models and serum (blood) tests. These include markers based on liver enzyme levels, components of metabolic syndrome, circulating keratin-18 fragment levels, and tests based on soluble markers such as FibroMeter, microRNA (miRNA) panels, and lipidomic panels (measuring patterns of fats in the blood).

The Role of ALT (Alanine Aminotransferase)

ALT is a liver enzyme commonly measured in routine blood tests. It's often used as a marker of liver damage, but the picture is more nuanced in NAFLD:

• The frequency of NASH in individuals with normal ALT (less than 35 U/L) was 11%
• The frequency was 29% in those with elevated ALT (35 U/L or higher)
• If the ALT was 2 times the upper limit of normal (greater than 70 U/L), predicting NASH had only a 50% sensitivity and 61% specificity—meaning it's not a reliable stand-alone test
• Another study found that individuals with NAFLD can have normal ALT levels even as the disease progresses

This means a normal ALT does not rule out NASH or significant liver disease.

Cytokeratin-18 (CK-18) Fragments

In seminal work by Feldstein and colleagues, circulating levels of cytokeratin-18 (CK-18) fragments—pieces of a protein released when liver cells die—were found to predict NASH in patients with NAFLD. Since then, intense investigation has unequivocally found that increased circulating levels of CK-18 fragments are associated with NASH. However, several issues limit its current clinical usefulness:

• Lack of a commercially available clinical test
• Poor reproducibility with limited sensitivity/specificity at the individual patient level
• Lack of a clear cutoff point

Combined Panels and Scores

Because no single test is perfect, researchers have combined different measures to improve diagnostic accuracy:

Eicosanoid panel (lipidomics-based): Investigators examined a panel of eicosanoids (signaling molecules derived from fatty acids) for detecting NASH and demonstrated excellent diagnostic accuracy ranging between 0.9 and 1.0. However, these data need to be confirmed in larger, multicenter studies.

The NASH Test: This combines demographic characteristics (age, sex, body mass index), serum parameters (aminotransferases and lipids), and three proteins: alpha-2 macroglobulin, apolipoprotein A1, and haptoglobin. Its sensitivity is 33% with a specificity of 94%, giving it a good negative predictive value for NASH of 81%. In plain terms, it's good at confirming who does NOT have NASH, but not very good at identifying who does.

The NASH Diagnostics Panel: This uses the presence of CK-18 fragments, adiponectin (a hormone that regulates glucose and fat metabolism), and resistin (a hormone linked to insulin resistance). It performed well initially, but in a larger study it was not found to be as effective.

The NAFLD Diagnostic Panel: This used CK-18 fragments combined with the presence of type 2 diabetes mellitus, triglycerides (blood fats), and sex. Unfortunately, it did not perform any better than the NASH Diagnostics Panel.

The OXNASH Score: This uses aspartate aminotransferase (AST, another liver enzyme), age, BMI, and a ratio of 13-hydroxy-octadecadienoic acid to linoleic acid (both are fatty acid compounds). It correlates with histological features of NASH and provides the following AUROCs:

• Inflammation: 0.730 (95% CI, 0.637–0.823)
• Ballooning: 0.723 (95% CI, 0.630–0.816)
• Steatosis: 0.705 (95% CI, 0.570–0.840)
• Fibrosis: 0.673 (95% CI, 0.577–0.770)

The Hepascore: Derived from age, sex, bilirubin (a breakdown product of red blood cells), gamma glutamyltransferase (GGT, another liver enzyme), hyaluronic acid (a component of connective tissue), and alpha-2 macroglobulin. When compared to the simple BARD Index (BMI, AST, ALT, diabetes), it performed reasonably well in identifying fibrosis stages F2–F4, with AUROCs of 0.73 to 0.91, with more accuracy noted for patients with a fibrotic stage of 4 (cirrhosis).

The FibroMeter NAFLD: Uses age, weight, fasting glucose, AST, ALT, ferritin (an iron-storage protein), and platelet count. It performs reasonably well in identifying mild-to-moderate fibrosis:

• For identifying stage F=1 fibrosis: PPV of 84.9%, NPV of 66.7%, diagnostic accuracy of 80%
• For identifying stage F=3 fibrosis: PPV of 74.5%, NPV of 86.2%, diagnostic accuracy of 82.1%

Prognostic scores: Several other scores (Palekar score, Shimada index, Nice model, and Gholam's model) have also been developed, with all performing somewhat similarly with AUROC ranging from 0.76 to 0.90.

Metabolic Syndrome (MetS)

Metabolic syndrome (MetS) is a cluster of conditions—including abdominal obesity, high blood pressure, high blood sugar, and abnormal cholesterol levels—that increase the risk of heart disease and diabetes. Multiple studies have found a significant relationship between the increasing number of MetS components a patient has and the likelihood of NASH. However, what has not yet been explored is the combination of MetS, levels of ALT, and age to predict NASH—leaving another area for future research.

The article's authors make an important strategic point: with the continuing challenges in correctly diagnosing NASH, the scientific community needs to re-evaluate the need for predicting NASH in all patients. Instead, it may be best to focus on NASH with stage ≥2 fibrosis, because this is the subphenotype that is primarily targeted in phase 2B and 3 clinical trials of potential NASH treatments.

Serum Fibrosis Markers: Measuring Scar Tissue

Because the stage of fibrosis is the most important predictor of patient outcomes (more important than the presence of NASH itself), much effort has focused on determining the presence and severity of fibrosis noninvasively. In this context, NAFLD biomarkers can target three distinct domains:

1. Diagnostic markers: reflecting the current stage of fibrosis
2. Prognostic markers: stratifying individuals by fibrosis progression risk, discriminating fast versus slow progressors, and/or predicting long-term outcomes and hard endpoints (such as death or liver failure)
3. Monitoring markers: used to track disease progression or treatment response over time

Such biomarkers should be validated at one of four qualification levels (as defined by regulatory bodies like the FDA):

1. Exploration: early-phase experimental biomarkers
2. Demonstration: "probable valid" biomarkers
3. Characterization: "known valid" biomarkers
4. Surrogacy: biomarkers that can substitute for a clinical endpoint in regulatory decisions

Developing biomarkers that reach the highest qualification levels is essential for accelerating clinical trials and ultimately improving patient care.

What This Means for Patients

These research findings translate into several practical messages for patients living with or at risk for NAFLD:

Fibrosis is what matters most. Of all the tests and measurements discussed, the stage of liver fibrosis (scarring) is the single most important predictor of long-term outcomes—including mortality. Patients with simple fatty liver without fibrosis have a much better prognosis than those with advanced fibrosis.

Normal liver enzymes don't guarantee a healthy liver. Many patients with NAFLD and even advanced disease have normal ALT levels. You cannot rely on a standard liver function test alone to tell you whether your liver is healthy.

There are now excellent noninvasive options. The days of mandatory liver biopsy for diagnosis may be ending. Magnetic resonance elastography (MRE) has outstanding diagnostic accuracy, with an AUROC of 0.924 for advanced fibrosis, and a negative predictive value of 0.97—meaning if MRE says you don't have advanced fibrosis, you can be highly confident it's correct. Transient elastography (FibroScan) is more accessible and works well for many patients, though it's less reliable in those with obesity.

Not every patient needs a biopsy. The authors suggest that imaging-based tests can be used first to risk stratify patients. Ultrasound-based tests like TE are reasonable for nonobese individuals, while MRE is better suited for individuals with obesity—especially morbid obesity.

Cardiovascular risk is the bigger threat for most patients. Most people with NAFLD die of cardiovascular complications, not liver disease. Managing heart health through weight loss, exercise, and controlling blood pressure, cholesterol, and blood sugar is essential for all patients with NAFLD.

Study Limitations

While this article provides a comprehensive review of diagnostic modalities, several limitations are acknowledged:

• Liver biopsy remains the imperfect gold standard. All noninvasive tests are measured against biopsy, but the biopsy itself is subject to sampling error and interobserver variability. A "gold standard" that isn't perfect makes it harder to assess the true accuracy of newer tests.
• The "gray zone" problem. Many of the noninvasive tests leave a significant proportion of patients with indeterminate results. For example, TE places 43.6% of patients in the gray zone where results are not conclusive enough to make treatment decisions.
• Access and cost barriers. MRE, the most accurate imaging method, is expensive, not widely available, and requires specialized expertise. Many of the serum biomarker tests are not yet commercially available.
• Data on new markers is preliminary. The eicosanoid panel showed excellent diagnostic accuracy (0.9–1.0), but these results need confirmation in larger, multicenter studies.
• Underestimates in incidence. The reported incidence rates of 28–52 per 1,000 person-years are likely underestimations, given the rising rates of obesity and diabetes.

Recommendations for Patients

Based on this review, here are actionable steps for patients and their healthcare providers:

1. Know your risk factors. Obesity, type 2 diabetes, dyslipidemia (abnormal cholesterol), hypothyroidism, polycystic ovary syndrome, and sleep apnea are all associated with NAFLD. If you have any of these, ask your doctor about screening for liver disease.
2. Ask about noninvasive testing. If fatty liver is suspected, discuss noninvasive options—such as transient elastography (FibroScan) or MRE—with your gastroenterologist before agreeing to a liver biopsy.
3. Don't be falsely reassured by normal liver enzymes. A normal ALT does not exclude significant liver disease. If you have metabolic risk factors, you may still need imaging-based assessment.
4. If fibrosis is found, treat it seriously. Stage of fibrosis is the best predictor of liver-related outcomes. If you have stage 2 or higher fibrosis, you should be closely monitored by a liver specialist.
5. Focus on cardiovascular health. For most patients with NAFLD, heart disease is the greatest threat to longevity. Work with your doctor to manage blood pressure, cholesterol, blood sugar, and weight.
6. Consider clinical trials. Many new NASH medications are in development, with trials focusing on NASH with stage ≥2 fibrosis. If you have this condition, ask your doctor about whether you might be eligible for a clinical trial.
7. Lifestyle changes are the foundation of treatment. Although this article focuses on diagnostics, the data underscore that obesity and diabetes are the primary drivers of NAFLD. All patients with NAFLD should aim for weight loss, a healthy diet, and regular exercise.

Frequently Asked Questions

What is the difference between NAFLD and NASH?

NAFLD is a spectrum ranging from simple fatty liver to NASH, which adds liver inflammation and cell damage. Most people with NAFLD do not have NASH. NASH can progress to advanced fibrosis and cirrhosis, but fibrosis stage, not NASH itself, is the key predictor of long-term outcomes.

Why is liver biopsy no longer always needed for diagnosing fatty liver?

Liver biopsy is invasive, costly, and carries risks like pain and bleeding. It also has sampling error and variability between pathologists. Noninvasive tests, such as transient elastography and magnetic resonance elastography, can accurately measure fibrosis and help doctors risk-stratify patients, potentially avoiding biopsy in many cases.

What does a normal ALT blood test mean for someone with fatty liver?

A normal ALT does not rule out NASH or significant liver disease. In one study, 11% of people with normal ALT had NASH, and patients can have normal ALT even as disease progresses. Standard liver function tests alone are not reliable for assessing liver health in NAFLD.

What is transient elastography (FibroScan) and who is it suitable for?

Transient elastography is an ultrasound-based method that measures liver stiffness through the skin. It has a 90% negative predictive value for advanced fibrosis, but it is less reliable in patients with obesity, ascites, or acute inflammation. It is reasonable for nonobese individuals, while MRE is better for those with obesity.

Why is fibrosis stage more important than NASH in predicting outcomes?

Long-term follow-up studies found that the single histological feature predicting mortality was fibrosis, not NASH itself. While simple fatty liver can progress in a few patients, fibrosis stage independently predicts mortality. Therefore, identifying the presence and severity of fibrosis is the most important goal of diagnostic testing.

What lifestyle changes are recommended for patients with NAFLD?

Lifestyle changes are the foundation of treatment. Patients should aim for weight loss, a healthy diet, and regular exercise. Since most NAFLD patients die from cardiovascular complications, managing blood pressure, cholesterol, blood sugar, and weight is essential for all patients with NAFLD.

Source Information

Original Article Title: Diagnostic Modalities for Nonalcoholic Fatty Liver Disease

DOI: 10.1002/hep.29721

Authors: Zobair M. Younossi, Rohit Loomba, Quentin M. Anstee, Mary E. Rinella, Elisabetta Bugianesi, Giulio Marchesini, Brent A. Neuschwander-Tetri, Lawrence Serfaty, Francesco Negro, Stephen H. Caldwell, Vlad Ratziu, Kathleen E. Corey, Scott L. Friedman, Manal F. Abdelmalek, Stephen A. Harrison, Arun J. Sanyal, Joel E. Lavine, Philippe Mathurin, Michael R. Charlton, Zachary D. Goodman, Naga P. Chalasani, Kris V. Kowdley, Jacob George, and Keith Lindor

Publication: Hepatology, 2018 July; Volume 68(1): 349–360. doi:10.1002/hep.29721

Published in final edited form as an HHS Public Access author manuscript, available in PMC 2019 May 12.

This patient-friendly article is based on peer-reviewed research published by the American Association for the Study of Liver Diseases (AASLD) Emerging Trend Conference on NASH. It was written to help patients understand the findings and does not replace the advice of a qualified healthcare provider. Always discuss your specific condition and testing options with your doctor.