Think MASH:
Identifying and evaluating suspected cases

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ANSWER:

MASLD, formerly known as nonalcoholic fatty liver disease (NAFLD), is the most common cause of chronic liver disease affecting 25% of the global population.¹ The overall global prevalence rates for MASLD and MASH from 1990-2019 were estimated to be 30.1% and 5.3%, respectively.²*

The new overarching term of 'steatotic liver disease' encompasses the spectrum of causes of hepatic steatosis. Nonalcoholic fatty liver disease (NAFLD) has been renamed metabolic dysfunction‑associated steatotic liver disease (MASLD) to emphasize the metabolic basis behind the disease, which has long been considered "the hepatic manifestation of the metabolic syndrome". Similarly, nonalcoholic steatohepatitis (NASH) has been renamed metabolic dysfunction‑associated steatohepatitis (MASH). The updated nomenclature recognizes the overlapping biological processes that may contribute to fatty liver disease.³

MASLD, which can progress to MASH, is characterized by the accumulation of fat, or fatty infiltration (steatosis) in the liver, and is associated with one or more cardiometabolic risk factors such as obesity, diabetes, hypertension, and dyslipidemia.³

Individuals with chronic metabolic and organ dysfunction, such as those with metabolic syndrome, are more likely to develop MASLD compared with those without such dysfunction.^4-6

*Prevalence of MASLD and MASH according to global regions data collected 1990‑2019.²

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ANSWER:

Over time, poor diet and lifestyle lead to excessive accumulation of fat and circulating free fatty acid that impact a variety of organ systems, including the liver, heart, pancreas, and muscle, leading to a systemic state of insulin resistance. Together, fat distribution, adipose tissue functionality, and insulin resistance constitute the foundation of metabolic dysfunction, including diabetes and MASLD.^4,5

Chronic systemic inflammation and insulin resistance can be associated with a variety of potentially serious clinical outcomes, including obesity, hyperglycemia, T2D, cardiovascular disease (CVD), dyslipidemia, hypertension, and MASLD/MASH.^4,5

Despite a lack of MASH‑specific symptoms, patients with MASH can experience a high burden of systemic comorbidities in addition to principal cardiometabolic risk factors.^7,8 Of systemic comorbidities, the most common causes of death in patients with MASLD are CVD, extrahepatic malignancies, and liver disease.⁷

• Patients with MASLD may develop CVD such as atherosclerosis, valvular heart disease, left ventricular dysfunction and arrhythmias⁸
• After CVD, extrahepatic cancers (eg, colon) are the second most common cause of death in patients with MASLD⁸
• Patients with MASLD have an increased risk of liver-related complications, including progression to advanced fibrosis or cirrhosis, which can lead to the development of hepatocellular carcinoma (HCC)⁸

ALT: alanine aminotransferase; AST: aspartate aminotransferase; eGFR: estimated glomerular filtration rate; MASLD: metabolic dysfunction-associated steatotic liver disease

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ANSWER:

MASLD encompasses a spectrum of liver diseases associated with metabolic disorders and has an estimated global prevalence of ∼30%.^2,7 However, in many patients, MASLD is considered asymptomatic, which often leaves patients undiagnosed.^9,10 When symptoms are present, they are often vague or non‑specific and may include general fatigue, malaise, and right upper quadrant abdominal discomfort. Due to the generally asymptomatic nature of the disease, patients are often suspected of having MASLD on the basis of elevated liver enzymes or incidental findings of hepatic steatosis.^7,8

Screening at‑risk patients and a timely diagnosis may help prevent progression to potentially serious complications, such as severe liver damage (compensated and decompensated cirrhosis, liver transplant, HCC, fibrosis) and CVD, and increased mortality risk.^7,11-13

MASH, although often considered asymptomatic in early stages, may also have an impact on patients' HRQoL. NASH‑CHECK is an emerging, MASH‑specific patient‑reported outcome measure that was recently developed by an international task force and validated for use in a cohort of 253 adult patients with non‑cirrhotic MASH.¹⁴ NASH‑CHECK scores should not be used as an assessment of clinical severity.

CVD: cardiovascular disease; HCC: hepatocellular carcinoma; HRQoL: health‑related quality of life; MASLD: metabolic dysfunction‑associated steatotic liver disease

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Shared metabolic risk factors may contribute to the increased risk of CVD and liver fibrosis in patients with MASLD and MASH, including obesity, diabetes, dyslipidemia, and hypertension.^8,15-17

In patients diagnosed with obesity (BMI ≥30.0 kg/m², or BMI ≥27.5 kg/m² for Asian individuals), the prevalence of MASLD and MASH was 75% and 34%, respectively, as determined in a meta‑analysis of 151 studies up to 2022.¹⁸

A prevalence of MASLD and MASH in adult patients with T2D, of 56% and 37%, respectively, has been reported in a meta‑analysis across 80 studies from 1989 to 2018.¹⁹ This increased prevalence of MASLD and MASH in patients with T2D is supported by the central role of insulin resistance in the pathogenesis of MASLD. Furthermore, the presence of T2D is considered the most impactful risk factor for development of MASLD as well as fibrosis progression and development of HCC.⁷

Reversal of steatosis (liver fat) and liver fibrosis may be achieved through lifestyle modifications resulting in ≥10% weight loss.¹ In a prospective 12‑month study of 293 adult patients with histologically confirmed MASH, weight loss due to lifestyle changes alone was associated with improvements in the histologic features of MASH. In this study, 10% (29/293) of patients sustainably achieved ≥10% weight loss through lifestyle modifications. Among patients who lost ≥10% of their weight:²⁰

• 45% of patients had regression of fibrosis
• 100% had improvement in steatosis
• 90% had resolution of steatohepatitis

BMI: body-mass index; CVD: cardiovascular disease; HCC: hepatocellular carcinoma; MASLD: metabolic dysfunction‑associated steatotic liver disease; T2D: type 2 diabetes

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FIB‑4 is a simple and accessible non‑invasive blood test for primary fibrosis risk assessment based on four parameters: age, platelets, ALT, and AST.^1,7

Risk stratification by FIB-4 is graded as:^1,7

In the endocrinology setting, AACE guidelines recommend FIB‑4 for primary fibrosis risk stratification in patients considered high risk, which includes those with prediabetes, T2D, obesity, ≥2 cardiometabolic risk factors, hepatic steatosis, or elevated liver enzymes. Values determined by the FIB‑4 test will determine whether a patient is at low, indeterminate or high risk of fibrosis.¹

• Patients determined to be at low risk for fibrosis should remain in the endocrinology or primary care setting for continued care
• Patients with an indeterminate risk should undergo secondary risk assessment with an alternative testing method
• Patients at high risk should promptly be referred to a hepatologist or gastroenterologist

AACE: American Association of Clinical Endocrinology; ALT: alanine aminotransferase; AST: aspartate aminotransferase; FIB-4: fibrosis-4 index; PCP: primary care provider; T2D: type 2 diabetes

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Patients with a FIB‑4 score of 1.3‑2.67 are deemed at indeterminate risk and should undergo secondary assessment with either transient elastography (eg, FibroScan^®, VCTE) or ELF™.^1,7

Patients with a FIB‑4 score >2.67 are considered at high risk for advanced fibrosis and should be directly referred to a liver specialist.^1,7

Based on AASLD guidelines:⁷

• patients designated low risk should be periodically reassessed for potential worsening of fibrosis
• FIB‑4 should be repeated every 1‑2 years in patients with pre‑T2D or T2D or in those with ≥2 cardiometabolic risk factors
• FIB‑4 should be repeated every 2‑3 years in patients without T2D and those with <2 cardiometabolic risk factors

If the results of the initial non‑interventional tests (NITs) suggest the patient is at risk for advanced fibrosis, the patient should be referred to a hepatologist or gastroenterologist who will then determine if liver biopsy is necessary.^1,7 Liver biopsy is associated with limitations and is therefore reserved for selected patients and specific clinical scenarios; it is costly and invasive and carries risk of potential adverse effects.^1,7,21

AASLD: American Association for the Study of Liver Diseases; ELF: enhanced liver fibrosis; FIB‑4: fibrosis‑4 index; MASLD: metabolic dysfunction‑associated steatotic liver disease; T2D: type 2 diabetes; VCTE: vibration‑controlled transient elastography

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Indeterminate or inconclusive FIB‑4 scores indicate the need for further, secondary risk assessment. ELF™ and VCTE can be used to help determine the next step in the diagnosis and management pathway for patients with MASLD.

VCTE or FibroScan^® measures liver stiffness as a surrogate for fibrosis and cirrhosis.^1,7

• Patients with a VCTE/FibroScan^® score of <8 kPa can remain in the endocrinology or primary care setting
• Patients with a score of ≥8 kP are at indeterminate or high risk for fibrosis and should undergo additional assessments in either the hepatology or gastroenterology setting

ELF™ is a blood test that measures the levels of TIMP‑1, PIIINP, and hyaluronic acid to estimate the rate of liver extracellular metabolism, indicating the severity of liver fibrosis.^1,7

• Patients with a score of <7.7 can remain in the endocrinology or primary care setting
• Patients with a score ≥7.7 are at indeterminate or high risk for fibrosis and should undergo additional assessments in either the hepatology or gastroenterology setting

AACE Guidelines: secondary assessment for risk of fibrosis¹

Adapted from Cusi K, et al, 2022¹

*Cardiometabolic risk factors of the metabolic syndrome are: waist circumference >40 inches men, >35 inches women; triglycerides ≥150 mg/dL; HDL-C <40 mg/dL men, <50 mg/dL women; BP ≥130/≥85 mm Hg; fasting plasma glucose ≥100 mg/dL.

AACE: American Association of Clinical Endocrinology; ALT: alanine aminotransferase; AST: aspartate aminotransferase; BP: blood pressure; ELF: enhanced liver fibrosis; FIB‑4: fibrosis‑4 index; HDL‑C: high‑density lipoprotein cholesterol; MASLD: metabolic dysfunction‑associated steatotic liver disease; PCP: primary care provider; PIIINP: procollagen III amino‑terminal peptide; T2D: type 2 diabetes; TIMP‑1: tissue inhibitor of metalloproteinases 1; VCTE: vibration‑controlled transient elastography

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ANSWER:

Management of patients with MASLD or MASH is based on initial fibrosis risk stratification through NITs (eg, FIB‑4). Endocrinologists and PCPs should aim to manage all patients with MASLD or MASH, focusing on reducing cardiometabolic and cardiovascular risks through lifestyle modifications (eg, weight loss, diet, and physical activity).^1,7,11,22

In patients with more clinically significant fibrosis (≥F2), patients should also be co‑managed, in a multidisciplinary setting, by liver specialists who can focus on the associated fibrosis or cirrhosis.^1,7,11

Management of MASLD/MASH^1,7,11

Improved components of MASH with weight loss²⁰

In a prospective 12-month study of 293 adult patients with histologically confirmed MASH, weight loss due to lifestyle changes alone was associated with improvements in certain histologic features of MASH.²⁰

100% of patients who achieved ≥10% mean weight loss saw improvement in steatosis*

*Improvements in steatosis, ballooning, lobular inflammation, and portal inflammation scores were defined as a reduction of at least 1 point as compared with baseline values with no fibrosis impairment.²⁰
†Resolution of steatohepatitis was defined as the absence of the histologic features of definite steatohepatitis, which required lack of hepatocellular ballooning with no fibrosis impairment.²⁰
‡Defined as a decrease of at least 1 point in the fibrosis score.²⁰

ELF: enhanced liver fibrosis; F: fibrosis score; FIB‑4: fibrosis‑4 index; MASLD: metabolic dysfunction‑associated steatotic liver disease; NIT: non‑invasive test; PCP: primary care provider; T2D: type 2 diabetes

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ANSWER:

CVD is the leading cause of death in patients with MASLD and MASH; the increased risk for CVD in MASLD/MASH is likely due to shared metabolic risk factors, eg, obesity, hypertension, dyslipidemia, and insulin resistance,^7,15,17 and patients may develop atherosclerosis, valvular heart disease, left ventricular dysfunction, and arrhythmias.^7,8

A cohort study of 229 patients with biopsy proven MASLD conducted in Sweden has shown that patients with MASLD with advanced fibrosis (≥F3) had almost a four‑fold increase in the risk of cardiovascular mortality compared with a reference population.²³

CVD: cardiovascular disease; F: fibrosis stage; MASLD: metabolic dysfunction-associated steatotic liver disease

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ANSWER:

MASLD and MASH may improve through lifestyle modifications.²⁰ Currently, endocrinologists are encouraged to manage patients with MASLD and MASH through lifestyle intervention (ie, weight loss through diet and exercise), which has been reported to improve components of MASH, including steatosis and fibrosis.^1,7,20

Optimal management of MASH requires a multidisciplinary approach

Adapted from Rinella M E, et al, 2023.⁷

FIB‑4: fibrosis‑4 index; MASLD: metabolic dysfunction‑associated steatotic liver disease