CE / CME
Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit
Nurses: 0.50 Nursing contact hour
Physicians: maximum of 0.50 AMA PRA Category 1 Credit™
Released: December 29, 2023
Expiration: December 28, 2024
Steatotic Liver Disease: Inclusive Rather Than Exclusive Criteria
In contrast to the now-replaced nomenclature for nonalcoholic fatty liver disease, steatotic liver disease is an inclusive term that encompasses many conditions associated with fat in the liver. These include MASLD, which itself includes MASH.
This umbrella term also includes MASLD combined with increased alcohol intake (metabolic and alcohol-associated/related liver disease [MetALD]), alcohol-associated/related liver disease (ALD), and other causes of hepatic steatosis.1
Classification of Steatotic Liver Disease
Steatotic liver disease can be classified based on the presence or absence of cardiometabolic criteria, including elevated BMI, fasting glucose, hypertension, or abnormal serum lipids, such as triglycerides.
The next step is to evaluate for other causes of hepatic steatosis, which then allows the healthcare professional to determine the particular steatotic liver disease harbored by the patient in question.1
Prevalence of MASLD and MASH
The worldwide prevalence of MASLD is considerable, with approximately 1 in 4 persons estimated to meet criteria. Some patients with liver steatosis experience associated inflammation, which can progress to liver scarring or fibrosis formation. It is estimated that 3% to 5% of people worldwide have MASH,2 with 1% to 2% being at risk of cirrhosis, the most advanced level of liver fibrosis attributed to this steatohepatitis.3
MASLD Presentation
Of interest, most patients with MASLD present as asymptomatic. Among the minority who do have related symptomatology, they may experience fatigue or right upper quadrant discomfort. Common scenarios leading to diagnosis include incidental findings of elevated liver enzymes, liver steatosis, and/or liver enlargement revealed by imaging studies. These tests may be obtained by primary care providers, endocrinologists managing diabetes, or even in insurance- or work-related physical examinations.4
Pragmatic First Steps in Suspected MASLD
When MASLD is suspected, it is important to evaluate for the presence of any metabolic syndrome. This can include type 2 diabetes, elevated BMI, hyperlipidemia, associated conditions such as polycystic ovary syndrome and obstructive sleep apnea, or pertinent family history. Heavy alcohol consumption and other liver diseases should be excluded from consideration.5
Basic testing includes a liver panel and testing for other underlying liver disease, including viral hepatitis and autoimmune liver disease serologies. A liver ultrasound also is indicated to identify the radiographic presence of liver fat.
PRELHIN Study: Liver Fibrosis Associated With Long-term Outcomes in Patients With MASLD
Among patients with MASLD, what determines their long-term outcome? As this study demonstrates, the presence of MASH, or pathologic steatohepatitis activity based on the MASLD activity score, was not an independent predictor of mortality or liver-related events. The sole important predictor is the presence and degree of liver fibrosis, with the risk of death and liver-related complications increasing dramatically at stage 3 and 4 fibrosis; stage 4 indicates the presence of cirrhosis.7
MASH Advanced Hepatic Fibrosis May Quickly Progress to Cirrhosis
In patients with MASH, advanced or stage 3 fibrosis can progress to cirrhosis rapidly, with more than 20% of individuals developing cirrhosis at a median of 29 months. Of these patients, nearly 20% developed a clinical event including decompensation of their cirrhosis, significant worsening of liver function, and/or death.8
Identifying Advanced Hepatic Fibrosis
It is therefore crucial for healthcare professionals to identify those patients at risk for progression to advanced fibrosis and cirrhosis prior to the onset of these end-stage liver disease complications.
Case Finding and High-Risk Populations
Among patients with MASLD, important predictors of MASH and fibrosis include age older than 50 years, the presence of type 2 diabetes, and having a first-degree relative with MASH-related cirrhosis. Other associated risks include lifestyle factors such as being overweight or obese, the presence of metabolic syndrome, particular ethnic backgrounds, and having certain associated conditions such as hyperlipidemia, polycystic ovary syndrome, or obstructive sleep apnea.5,9,10
Guideline Recommendations: Who Is at Risk for MASH and Advanced Fibrosis?
The American Association for the Study of Liver Diseases,5 European Association for the Study of the Liver,11 and American Diabetes Association specifically identified patients with type 2 diabetes as warranting further workup.12
Liver Biopsy: The Imperfect Gold Standard
When it comes to modalities to determine the presence and severity of steatohepatitis and fibrosis, liver biopsy is the gold standard. However, pertinent limitations include its invasive nature, cost, risk of complications, variability in sampling and pathologic interpretation, required expertise, and inability to be used on a large scale.13,14
Commonly Used Noninvasive Tests
Noninvasive testing is preferable to assess prognosis in patients with MASLD and MASH. These can include serum-based tests, as well as specialized imaging,15-17 both of which can provide similar information to liver biopsy without the related drawbacks.
Simple lab-based scores such as the FIB-4 score or the AST-to-platelet ratio index are readily obtained via basic blood work and online calculators, both of which are effective at excluding the presence of significant fibrosis.15,18
MASLD Fibrosis Score and FIB-4 Score: Online Calculators Easily Interpret Noninvasive Tests
Here you can see examples of the MASLD fibrosis score and the FIB-4 score calculators, which incorporate basic patient information such as age and laboratory results.19,20
ELF Test in MASH: Validation
The enhanced liver fibrosis (ELF) test was validated in a large cohort of patients with MASH and advanced fibrosis. Baseline ELF score and interval scores every 3 months were then compared with liver biopsy interpretations to identify advanced disease.18,21
This study demonstrated that the ELF test was more predictive of progression to cirrhosis than liver biopsy. A baseline ELF of 9.76 or greater and a greater change in ELF were both predictive of developing cirrhosis.22
ELF Test in MASH Predicts Progression to Cirrhosis More Accurately Than Biopsy
The ELF test also was more predictive of liver-related clinical events than liver biopsy. Using a threshold result of 11.27 was useful in distinguishing those at increased vs lower risk of experiencing an event. Both baseline ELF and change in ELF predicted these liver-related clinical events.22
Vibration-Controlled Transient Elastography
Vibration-controlled transient elastography, often known by the trade name FibroScan, is an increasingly available test that can be found in both office settings and radiology offices. It can be performed quickly and noninvasively to measure shear waves that correlate with liver stiffness and, ultimately, liver fibrosis.
Certain patients are not appropriate for transient ELF elastography assessment, including those with abdominal ascites and marked obesity, and this is a notable limitation of the technology.16
Vibration-Controlled Transient Elastography for MASH Fibrosis
The higher the result of liver stiffness, the more likely the patient is to have increasing amounts of liver fibrosis, placing them at risk for complications. It is most useful in ruling out advanced fibrosis.23,24 Overestimation of fibrosis can occur in the setting of liver inflammation, congestion, cholestasis, or obesity. High readings also can predict the presence of portal hypertension in patients with cirrhosis.25,26
2D Shear Wave Elastography
2D shear wave elastography uses an ultrasound system to map liver elasticity and thereby determine liver stiffness.16 This testing usually requires a trained sonographer but can be useful in cases of problematic obesity, as it is able to penetrate through more tissue.27
Magnetic Resonance Elastography: Detecting Advanced Hepatic Fibrosis in MASLD
Magnetic resonance elastography is a newer advanced imaging technique that can provide information similar to ultrasound-based techniques. Although not as readily available, magnetic resonance elastography displays high sensitivity and specificity in determining the presence or absence of advanced liver fibrosis.28
Common Imaging Tests for Hepatic Fibrosis: Summary
In summary, vibration-controlled transient elastography, or FibroScan, is the most reliable and widely available imaging test in ruling out advanced fibrosis. Magnetic resonance elastography, although less widely available, is more accurate and detailed.
2D shear wave elastography is relatively similar to FibroScan but may require a referral to a radiology center. Although radiographic assessments of hepatic fat content exist, these modalities primarily assess for the presence and severity of liver fibrosis.
Use of Sequential Noninvasive Tests Could Reduce the Number of Patients in Indeterminate Zone
The general concept here is that obtaining more than one of the previously discussed noninvasive tests can help decrease the likelihood of an indeterminate outcome and result in an accurate liver fibrosis assessment.29
Sequential Algorithms to Detect Advanced Hepatic Fibrosis due to MASH
In this large study, a single instance of noninvasive testing yielded approximately 50% indeterminate results regarding advanced fibrosis in patients with MASH, but sequential tests—such as starting with FIB-4, then following with ELF or elastography—decreased the number of indeterminate results by one half.30
Goal of MASLD Treatment
When it comes to MASLD and MASH, our goal of therapy is to achieve resolution of MASH and reversal of liver fibrosis. MASH clinical trials usually have 2 clinical outcomes, the first being resolution of MASH with no worsening of fibrosis and the second being improvement in fibrosis by at least 1 stage with no worsening of MASH.
Patients targeted for pharmacotherapy are those with true steatohepatitis and significant stage 2 or greater fibrosis.
Treatment of MASLD: Dietary Changes and Exercise
The mainstay of treatment for MASLD continues to be lifestyle modification, and adequate exercise is very effective at reducing liver fat. This includes at least 150-250 minutes of aerobic exercise per week and resistance training for 45 minutes 3 times per week. Eating a healthy diet is important, especially one lower in simple carbohydrates and high-fat foods that focuses on lean proteins, fruits, and vegetables.
Weight Loss Thresholds and Impact on MASLD
Weight loss has been repeatedly shown to affect outcomes in MASLD and MASH. The degree of goal weight loss by percentage of body weight varies based on the severity of MASLD. For example, losing just 3% of body weight can lead to liver fat loss in MASLD without steatohepatitis. However, greater than 10% sustained weight loss is needed to reverse fibrosis.31
Bariatric Surgery and MASLD
Unfortunately, it is often very challenging for patients to lose weight. Bariatric surgery is an important tool to assist in this goal, with sleeve gastrectomy or Roux-en-Y gastric bypass being the surgeries of choice.
Several studies have demonstrated improvement in MASLD and MASH histology after weight loss surgery. Unfortunately, patients who do not have reversal of MASH are less likely to see improvement in fibrosis, whereas resolution of MASH and decrease in fibrosis after 1 year continued at 5 years.32
A recent bariatric surgery series demonstrated that approximately 25% of patients with advanced fibrosis (F3) saw fibrosis regress to lesser stages, whereas some had complete regression to F0 or no fibrosis.33
Histologic Improvement in MASH
In terms of currently available pharmacologic therapies for MASH, excluding those in clinical trials, both vitamin E and pioglitazone, as well as thiazolidinediones, have been demonstrated to be effective. It should be noted that vitamin E was not studied in patients with diabetes, as it was not clear whether they would respond to treatment.34
Semaglutide Resolves MASH and May Improve Fibrosis
You may be wondering about the new popular weight loss drugs, such as the GLP-1 receptor agonist semaglutide. In terms of MASH, 37% of patients on this trial had both MASH resolution and improvement in fibrosis stage with the higher dose of semaglutide. However, it is not currently approved by the FDA for the management of MASLD.
More recent studies of GLP-1 receptor agonists have shown conflicting results with no significant improvement in fibrosis in patients with MASH cirrhosis and no statistically significantly increased MASH resolution compared with placebo.35
Summary
In summary, MASLD is highly prevalent with variable rates of progression to MASH and advanced hepatic fibrosis. It is crucial to identify those with MASH advanced hepatic fibrosis because it can quickly progress to cirrhosis, hepatocellular carcinoma, the need for liver transplant, and, ultimately, death.
Patients with type 2 diabetes warrant evaluation. Other risk factors include obesity, metabolic syndrome, and having a first-degree relative with MASH cirrhosis. Noninvasive prognostic biomarkers may facilitate risk stratification, and lifestyle modifications—especially weight loss—are the mainstays of management.
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