Hepatic Steatosis

Summary

Background:

At least one-quarter of the world’s population now suffers from hepatic steatosis (fatty liver disease), which, in current terminology, is called metabolic dysfunction-associated steatotic liver disease (MASLD). This disease and its more dangerous inflammatory variant, metabolic dysfunction-associated steatohepatitis (MASH), promote the development of serious secondary conditions including cardiovascular diseases (CVDs), type 2 diabetes mellitus, and hepatocellular carcinoma (HCC).

Methods:

This review is based on pertinent publications retrieved from the PubMed-MEDLINE and Google Scholar databases and on current guidelines.

Results:

Conditions that are known to be associated with MASLD and/or MASH include obesity (with or without insulin resistance), dyslipidemia, hypertension, type 2 diabetes mellitus, obstructive sleep apnea, CVDs, and chronic kidney disease (CKD). The frequency of serious secondary diseases (CVDs, CKD, HCC, and extrahepatic malignancies) increases with the degree of fibrosis progression. Cardiovascular events are the main cause of death. Intensive lifestyle changes, including a hypocaloric, low-sugar diet and physical activity and exercise in an adequate amount and intensity, are the first line of treatment and the basis for further treatment options (resmetirom, incretin analogues, bariatric surgery).

Conclusion:

In view of its high prevalence and its associated profile of elevated cardiovascular risk, MASLD should be recognized as clinical evidence of the danger of major secondary disease and integrated into a structured, interdisciplinary management program with strict risk stratification. Drugs are part of the therapeutic spectrum but are no substitute for lifestyle modification, which remains the basis of treatment.

Information on CME.

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The year 1980 marked a turning point in hepatology with the first description of nonalcoholic steatohepatitis (NASH). Ludwig et al. described the constellation of abnormal fatty changes in the liver, lobular hepatitis, focal necrosis with mixed inflammatory infiltrates and Mallory bodies (pathological hepatocellular intracytoplasmic protein aggregates), signs of fibrosis, and, in some cases, progression to cirrhosis (1). These changes were accompanied by mild liver dysfunction and hepatomegaly. The authors also noted an association with other metabolic disorders.

Since then, new designations have been introduced for nonalcoholic fatty liver disease (NAFLD) and NASH that omit the unfortunate term “nonalcoholic,” which is uninformative and misleading, implies that these diagnoses are reached by exclusion, and may stigmatize patients (despite the “non-”). The internationally accepted designations are now metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatotic hepatitis (MASH) (2, 3). The mainstay of MASLD/MASH treatment is nonpharmacological: it consists of intensive and sustained lifestyle modification to improve metabolic homeostasis and insulin resistance through weight loss (i.e., loss of fat mass) (4). Resmetirom was the first drug approved for patients with MASH. Other options include bariatric surgery or specialized endoscopic procedures to bring about weight loss.

Methods

This narrative review is based on publications retrieved by a search in the PubMed, MEDLINE, and Google Scholar databases. Original articles, clinical trials, systematic reviews, and guidelines published up to October 2025 were included, in particular the current American, European, and German guidelines on MASLD/MASH, as well as on dyslipidemia, arterial hypertension, and type 2 diabetes (5–8) (e1). Relevant publications by the authors of this review were included as well. This presentation focuses on the epidemiology, diagnosis, and treatment of MASLD/ MASH, as well as on the cardiometabolic comorbidities and treatment strategies of both. Only a few studies to date have assessed the effect of MASLD therapies on patient-relevant outcomes or the effect of treating comorbidities on the course of MASLD/MASH (e2).

Learning objectives

This article should enable readers to:

• know the key aspects of fatty liver disease and MASLD, a disease whose prevalence is already high and steadily rising around the world;

• enumerate the comorbidities of MASLD and MASH (both established and controversial);

• take note of the much higher incidence and prevalence of severe secondary diseases in people with these conditions, compared to people with a healthy liver;

• explain the importance of intensive lifestyle changes as the mainstay of treatment for MASLD and its metabolic comorbidities;

• list the drugs than can be used to treat MASH, including resmetirom and incretin analogues.

From NAFLD to MASLD—fatty liver is a pandemic condition under any name

The prevalence and mortality of liver diseases in general have risen markedly in recent decades, with MASLD showing the sharpest rise. The renaming of NAFLD as MASLD has not affected either its prevalence or the upward trend (eBox 1). Precise prevalence data are unavailable for Germany, but the current estimated MASLD prevalence of 23% in Germany is consistent with the estimate for Western Europe as a whole (25.10%, 95% confidence interval [20.55; 30.28]) (9). One-fifth of MASLD cases progress to MASH, which—if liver fibrosis progresses further to cirrhosis—may, in the end, necessitate liver transplantation. The estimated prevalence of MASH both in Germany and in Western Europe as a whole is 4%. 0.5% to 2.6 % of persons with MASH develop MASH-related hepatocellular carcinoma (HCC) (10). MASLD should not be understood solely as a liver disease, but rather as a manifestation of a systemic metabolic disorder with a marked atherogenic component that promotes the development of cardiovascular diseases and certain types of cancer. The most common causes of death among persons with MASLD are cardiovascular disease and extrahepatic cancer (7). The more extensive the hepatic fibrosis, the greater the risk of death: in an overall group of 570 patients, the liver-related standardized mortality ratio (SMR) compared to fibrosis grade 0 as a reference was 1.41 [0.17; 11.95] for grade 1 fibrosis, 9.57 [1.67; 54.93] for grade 2, 16.69 [2.92; 95.36] for grade 3, and 42.30 for grade 4 [3.51; 510.34]) (11). The most common causes of death among persons with MASH cirrhosis are liver failure and hepatocellular carcinoma (HCC) (F4 versus F0: HR 15.1 [5.27; 43.4]) (4, 11, 12, e3).

eBox 1. MASLD: The world’s most common chronic liver disease.

MASLD is now the world’s most common chronic liver disease, affecting approximately 30% of the global population (95% confidence interval: [27.9; 32.3]) (e53, e54) and up to 38% of adults worldwide (e55). Expert estimates and our own analyses of health insurance data suggest that MASLD and MASH are significantly underdiagnosed in Germany (e56, e57).

The clinical definition of MASLD includes all forms of fatty liver disease in which metabolic dysregulation can be identified as the primary cause. The definition requires an intrahepatic fat content of ≥ 5% as detected by histology or imaging, combined with at least one metabolic risk factor (obesity, T2DM, dyslipidemia, hypertension, or insulin resistance) (2). MASH can only be diagnosed histologically, its definition requiring not only hepatic steatosis, but also inflammation and ballooning (cell swelling) of the hepatocytes. Lifestyle interventions are the mainstay of primary prevention of MASLD: weight normalization, a Mediterranean diet, regular physical activity (≥ 150 min of endurance exercise and 2–3 strength training sessions per week), and a reduced intake of fructose, processed carbohydrates, and saturated fats (7). The early identification and treatment of metabolic comorbidities are crucial for secondary prevention and are discussed in greater detail below. Tertiary prevention focuses on slowing the progression of existing fibrosis or cirrhosis through strict risk factor control, including with drugs as indicated.

The current guidelines recommend a stepwise approach to the diagnosis of MASLD and risk stratification. For individuals with relevant cardiometabolic risk factors (e.g., obesity, T2DM, dyslipidemia) and evidence of fatty liver (laboratory values, imaging), fibrosis should first be rated with a simple, noninvasive score such as the FIB4 score (age, aspartate aminotransferase [AST], alanine aminotransferase [ALT], platelet count) (7). An FIB4 score below 1.3, rules out advanced liver fibrosis with 90% certainty, and the patient can continue to be treated in primary care, with monitoring of the FIB4 score every 1–3 years. A higher FIB4 score or any remaining uncertainty is an indication for vibration-controlled transient elastography (VCTE; e.g., Fibro-Scan), ultrasound-based methods (point shear-wave elastography [P-SWE], 2D shear-wave elastography [2D-SWE], or a specialized hepatological evaluation (7, 13). Any patient in whom advanced fibrosis or cirrhosis is detected must be referred to a specialized liver clinic (eBox 2). The follow-up management of patients with advanced liver fibrosis or cirrhosis includes HCC surveillance programs as well as monitoring for and prevention of portal hypertension. Hepatic and cardio-metabolic parameters must be rechecked at short intervals to enable the early detection of disease progression, decompensation, and systemic complications (Box 1).

eBox 2. The FIB-4 score versus vibration-controlled transient elastography.

The FIB-4 score is well suited for ruling out advanced liver fibrosis. In multiple clinical studies, however, FIB-4 was found to be only moderately accurate for the prediction of liver fibrosis, cirrhosis (PPV <70%), or cardiovascular endpoints (AUC = 0.654) (e58). In studies conducted at tertiary care centers, elastography techniques for the noninvasive assessment of fibrosis achieved higher AUC values (0.8–0.9) and were found to determine fat content more accurately via the CAP score (AUCs 0.7–0.96) (e59–e62). The high acquisition costs of the required ultrasound devices have been an impediment to wider use of this noninvasive method, which seems to be superior to the FIB-4 score.

Box 1. Stepwise diagnosis and treatment.

• Identification

  • –
    waist circumference >102 cm (m)/>88 cm (f) or BMI >30
  • –
    hypertension, hypercholesterolemia/dyslipidemia, cardiovascular history, prediabetes or T2DM
  • –
    persistently elevated transaminases
• Diagnosis

  • –
    HbA1c, fasting blood glucose, lipid profile
  • –
    liver function tests (ALT, AST, γ-GT, platelets)
  • –
    abdominal ultrasound (steatosis)
  • –
    to be excluded: significant alcohol consumption (>20 g/day for women, > 30 g/day for men), viral hepatitis (HCV/HBV), other liver diseases/drugs
• Treatment

  • –
    basic treatment: lifestyle intervention

    • –
      ≥ 150 min/week of moderate physical activity
    • –
      low-calorie, low-sugar diet; Mediterranean diet if appropriate
    • –
      goal: weight loss of ≥ 7–10 % within 12 months
  • –
    treatment of comorbidities:

    • –
      T2DM (e.g., GLP-1 receptor agonists, SGLT2 inhibitors)
    • –
      dyslipidemia (statins)
    • –
      hypertension

• further diagnostic testing as indicated (see Box 2)

Treatment of MASLD with lifestyle modification

The first-line treatment for MASLD is strict lifestyle modification for weight loss, consisting of caloric restriction, regular exercise including strength and endurance training, and the management of all comorbidities (hypertension, dyslipidemia, T2DM). Drug treatment is considered only for confirmed MASH with moderate to advanced fibrosis (e.g., F2–F3) (14). Bariatric surgery may be considered for severely obese persons, as it has been shown to yield improvement or remission of hepatic steatosis in more than half of all treated patients and reduction of fibrosis in one-quarter, as well as lowering the risk of primary cardiovascular events by 47% (e5–e7).

National and international guidelines, experts, and patient-education booklets recommend permanent lifestyle changes for weight loss and normal weight maintenance as the mainstay of treatment for overweight, obesity, MASLD, and all associated conditions (7, 15). It is essential for the patient to follow a diet that is low in calories and sugar and that can be sustained over the long term. The Mediterranean diet, i.e., one that is rich in unsaturated fatty acids, vegetables, fish, nuts, and whole grains, is suitable for this purpose (4). It has been shown to lower intrahepatic fat levels, improve lipid profiles, and reduce the risk of type 2 diabetes (T2DM) and cardiovascular diseases. Treatment success mainly depends on a sustained low-calorie diet, a reduction in free sugars, and the quality of macronutrients. The details of food intake within the framework of these requirements should be left up to the individual to promote long-term adherence, although feelings of hunger will be inevitable (e8, e9).

Regular physical activity is needed as well, ideally consisting of both endurance training (≥ 150 minutes/week of moderately intense to vigorous exercise) and strength training (2–3 times/week) (16) (eBox 3). Even without significant weight loss, this approach can yield a 15–30% reduction in relative liver fat (17, e10–e14). A major problem with it is low long-term adherence: for combined programs, adherence has been found to range from 25% to 40% at 24 months (e15, e16) (eBox 4). Structured programs combining nutrition, exercise, and psychological support are helpful in this regard.

eBox 3. Side note: Moderate activity.

Moderate aerobic exercise corresponds to a rating of 12–14 on the BORG scale (6–20) for self-assessed exertion: slightly strenuous to strenuous. This form of exercise increases breathing to a noticeable extent, but the individual should still be able to carry on a conversation. It is also associated with a heart rate of 55–74% of the individual’s maximum heart rate, roughly corresponding to 115 to 135 heartbeats/min.

Many people who are accustomed to low levels of activity in their daily lives and do not participate in sports overestimate the actual exertion involved in, for example, walks, leisurely hikes, or the famous 10 000 steps a day.

Exercise therapy alone for weight loss is generally ineffective. Conversely, weight loss achieved solely through diet changes can hardly ever be sustained without an accompanying increase in physical activity (17), as dieting alone causes a loss not only of fat, but also of lean body mass—that is, muscle—which, in turn, markedly lowers calorie expenditure in the long term. Especially in relation to MASLD, physical activity and exercise improve the mitochondrial activity of muscle cells, increase fat breakdown in the liver, and lower systemic inflammatory markers (16, e63). Studies have also identified strength training and muscle building, in particular, as key factors for increasing the basal metabolic rate and daily calorie expenditure, and thus for weight loss and reduced insulin resistance, making them ultimately particularly helpful for the treatment of MASLD (e8, e64).

eBox 4. Exercise and dietary therapy.

A low-calorie diet as an isolated measure is associated with adherence rates of 60–80% over a period of up to 6 months, but only 30–50% at 12 months and less than 20–30% in the long term (>24 months). 50–70% of patients regain the weight they have lost within 2–5 years (17) (e15, e16, e65–e67).

Short-term crash diets, in particular, rarely have a lasting benefit and can even transiently increase the burden on the liver when fat is lost rapidly. Exercise-only programs (typically lasting 8–12 weeks) are successfully completed by 70–85% of participants (e68, e69), but, 12 months later, only 30–45% of participants are still engaging in regular physical activity. In particular, only 20–35% of participants sustain the recommended intensity (≥ 150–300 minutes/week) over the long term. Structured programs with regular follow-up, multidisciplinary care, and clear target parameters achieve adherence rates of 40–60% at 12 months (e69). This is important because the effect size for weight loss—whether from lifestyle interventions or bariatric surgery—depends more on adherence than on the type of intervention (e68, e70).

Drug treatment for MASH

Drug treatment for MASH has only recently become available. Positive interim results from a randomized Phase 3 trial (18) led to the provisional approval of resmetirom in the USA in 2024 for the treatment of noncirrhotic MASH (eBox 5) (19). This drug was also approved for this purpose by the European Medicines Agency in August 2025. In the interim analysis of a randomized trial with 966 subjects, resmetirom reduced hepatic steatosis and inflammation at 52 weeks, with MASH resolution (reduction in the histological criteria for MASH) in 26–30% of the treated patients, compared with 10% in the placebo group (18). Hepatic fibrosis improved in 24–26% of patients, compared to 14% with placebo (p < 0.001 for both findings). Oral resmetirom is now indicated, in combination with dietary changes and physical activity, for the treatment of adults with non-cirrhotic MASH (fibrosis stages F2/F3) (e17). Common side effects include diarrhea, nausea, abdominal pain, constipation, headache, and dizziness. Itching and skin rashes may also occur. Long-term data on the treatment are not yet available.

eBox 5. Resmetirom for the treatment of non-cirrhotic MASH.

Resmetirom has been designated by the FDA as a breakthrough therapy; a re-evaluation will take place once final results are available at the end of the 54-month study period (e71). This selective agonist of the nuclear thyroid hormone receptor β promotes the breakdown of triglycerides—which is often impaired in patients with MASH—as well as mitochondrial fatty acid β-oxidation. Liver steatosis and inflammation were reduced after 52 weeks, leading to resolution of MASH, in 29.9% of participants (placebo: 9.7%), and an improvement in liver fibrosis was observed in 25.9%, versus 14.2% for placebo (18). Additionally, an improvement in dyslipidemia was observed without any effect on body weight, insulin, or glucose metabolism, underscoring the purely intrahepatic efficacy (7).

GLP-1 agonists and multiagonists have pleiotropic metabolic effects. They are already being used to treat obesity and/or T2DM and are expected to play a role in the treatment of MASH (e18, e19) (for study findings, see eBox 6).

eBox 6. The treatment of MASH with GLP-1 agonists and multiagonists that are already used to treat obesity and/or T2DM.

Oral nonpeptide GLP-1 agonists such as orforglipron yielded weight loss of up to 7.5–11% within 72 weeks in Phase 3 trials in obese patients (placebo, 2%) (e72). New unimolecular multiagonists that act simultaneously on GLP-1, GIP, and, in some cases, glucagon receptors have shown a high therapeutic potential for MASH in recent studies (7) (e73, e74). The dual GLP-1/GIP agonist tirzepatide, which has already been approved for the treatment of type 2 diabetes and obesity, led to MASH resolution in 44–62% of patients in a 52-week phase 2b trial (n = 190), compared with 10% in the placebo group (p >0.001). An improvement of fibrosis by at least one stage was observed in 51–55% of patients on tirzepatide and 30% of those taking placebo (difference 21% [1%; 42%]; –25% [5%; 46%]) (e75). Survodutid, another dual-action agonist, yielded comparable results in a randomized Phase 2 trial: after 48 weeks of treatment (n = 293), MASH resolution was seen in 43–62% of those treated with survodutid and in 14% of those on placebo (p < 0.001), and fibrosis improvement by at least 1 stage in 34–36% of those treated with survodutid and in 22% of those on placebo. Survodutid was associated with more gastrointestinal side effects than placebo: nausea (66% of patients versus 23%), diarrhea (49% versus 23%), and vomiting (41% versus 4%) (e76). Both substances are promising pharmacological candidates for the treatment of MASH.

The effects of treatment on comorbidities and patient-relevant endpoints

Treatments for MASLD also improve cardiometabolic comorbidities. Lifestyle interventions resulting in ≥7–10% weight loss not only reduce hepatic steatosis and resolve MASH but also improve insulin resistance, lipid profile, and blood pressure in up to 90% of patients (7). Bariatric procedures and incretin-based therapies also have significant effects on T2DM remission and the risk of cardiovascular events (e18).

Successful lifestyle interventions for obesity or metabolic syndrome improve patient-relevant outcomes (PROs) such as quality of life, physical function, and fatigue (e20–e23). The evidence from studies specifically about MASLD is still mixed, as PROs were often assessed only as secondary endpoints. Given the shared metabolic mechanisms, comparable improvements in PROs can also be expected in MASLD (Box 2).

Box 2. Further diagnostic tests and their clinical relevance.

• Further diagnostic tests

  • –
    Identification of high-risk patients: T2DM or obesity, or metabolic syndrome, or persistently elevated liver enzymes
  • –
    Determination of the FIB-4 score:

    • –
      A score <1.3, or <2.0 in persons over age 65, implies that advanced fibrosis is unlikely. The patient should be followed up every 1-3 years in primary care.
    • –
      A score ≥ 1.3 is an indication for secondary noninvasive diagnostic testing, with specialized consultation as needed.
  • –
    A transient elastography (VCTE) result of ≥ 8 kPa or an ELF test result of ≥ 9.8 indicates significant fibrosis (≥ F2) or cirrhosis. The patient should be referred to a specialized hepatology clinic or outpatient center for treatment and prognostic stratification.
• Clinical relevance

  • –
    Fibrotic MASH (≥ F2) is associated with markedly higher liver-related mortality (ca. 6.6 times higher for F3 and 11 times higher for F4). Noninvasive tests enable the risk-adapted selection of patients who need specialized hepatological evaluation.

MASLD/MASH and their comorbidities

The liver is the main metabolic organ for carbohydrates (particularly glucose), lipids, and amino acids, and performs a wide range of synthetic tasks (eBox 7). With all these functions, the liver is a key integrator of metabolic signals from the gastrointestinal tract and adipose tissue and plays an important role in obesity, insulin resistance, T2DM, and the metabolic syndrome. MASLD is therefore associated with metabolic and extrahepatic comorbidities whose close epidemiological links often do not allow clear distinctions between cause and effect. Comorbidities of MASLD include obesity, which in turn can exacerbate insulin resistance in the liver and muscles; type 2 diabetes mellitus (T2DM); hypertension and dyslipidemia, and thus also metabolic syndrome; obstructive sleep apnea; cardiovascular disease

eBox 7. Hepatic metabolism as the starting point of systemic dysregulation.

The liver regulates the homeostasis of all nutrient classes, synthesizes plasma proteins, clotting factors, and bile, stores vitamins and trace elements, and functions as the central detoxification organ. It plays a key role in lipid and cholesterol metabolism: hepatocytes produce endogenous cholesterol, package it into high-density, low-density, and very low-density lipoprotein (HDL, LDL, VLDL) particles, and play a major role in the reabsorption and conversion of cholesterol from the circulation. The liver thus determines both the plasma concentration of lipoproteins and the balance of lipoprotein synthesis, storage, and excretion in bile. It follows that even minor disturbances in hepatocellular insulin sensitivity or in lipid metabolism can upset the systemic energy balance. MASLD results from a complex dysregulation of fat intake, β-oxidation, lipogenesis, and VLDL secretion whose consequences extend beyond the liver to affect cardiometabolic and inflammatory processes throughout the body.

(CVD); chronic kidney disease (CKD); and hypothyroidism. There is ongoing debate about whether psoriasis, inflammatory bowel diseases, and pulmonary diseases should be considered extrahepatic comorbidities of MASLD/MASH in some cases (20–23). Patients with MASLD are also more susceptible to the harmful effects or side effects of alcohol, prescription drugs, illicit substances, polypharmacy, and other factors that impair liver function (eBox 8). The increase in MASLD and MASH has led to a rise in the global prevalence of MASH-related HCC (age-standardized prevalence rates of MASH-HCC per 100 000 people: in 1991, 0.4 [0.32; 0.49]; in 2021: 0.61 [0.49; 0.73]) (24, 25). This is also reflected in a higher age-standardized mortality rate from MASH-HCC (rates per 100 000 people; in 1991, 0.38 [0.3; 0.47]; in 2021: 0.48 [0.39; 0.58]). Early detection programs for HCC in MASLD (as is already standard practice for other chronic liver diseases) would probably improve the survival prospects of patients with advanced MASLD/MASH, whether or not they have reached the stage of cirrhosis (26).

eBox 8. More pronounced side effects of toxic substances in patients with MASLD.

The more pronounced side effects of toxic substances in patients with MASLD are likely due to multiple mechanisms. Oxidative stress, impaired mitochondrial function, and inflammation make hepatocytes more susceptible to additional stress from toxins; altered expression of cytochrome P450 enzymes and transport proteins impairs the elimination of many substances, including toxins; and impaired hepatocyte function in MASLD lowers hepatic reserve capacity on exposure to toxins (e77–e82).

Obesity

Obesity plays a key role in the development of MASLD and is generally defined in terms of the body mass index (BMI), which, however, has limited sensitivity (ca. 35 % in men and 50 % in women). Persons with a BMI of 30 or above are considered obese, although fat distribution is critical for the risk and prognosis of comorbidities. Abdominal obesity, which is associated with a markedly increased risk of cardiovascular disease, is defined as a waist circumference of 102 cm or more in men and 88 cm or more in women (27). An international panel of experts has recommended using BMI as a surrogate marker, primarily for epidemiological studies or screening for increased metabolic risk. For individual diagnosis and risk assessment, the body fat percentage, waist circumference, and waist-to-hip or waist-to-height ratios should always be measured directly (27) (eBox 9). A pooled analysis of 101 028 patients in a meta-analysis yielded a prevalence of 70% for MASLD among overweight individuals. In the general population, the prevalence of MASLD was 42.5%, and that of MASH was 33.5% (9, 28). Hepatic steatosis/MASLD is an expression of an independent, organ-specific metabolic disorder and not merely an extension of obesity or lipid storage outside adipose tissue.

eBox 9. MASLD and obesity rates.

The global obesity rate has risen dramatically in recent decades (e83). Those affected are getting younger, morbid obesity is on the rise, and the health consequences are only gradually becoming apparent (e83). It has long been known that the global burden of MASLD parallels the rise in obesity rates.

Treatment for obesity is indicated for a BMI ≥ 30, or a BMI above 25 and below 30 in the presence of abdominal obesity or obesity-related health conditions, such as hypertension or T2DM (e24). For a BMI between 25 and 35, the treatment goal should be weight loss of >5% over 6 to 12 months. For a BMI >35, weight loss of more than 10% should be targeted. Diet, exercise, and behavioral therapy (lifestyle modification) remain the foundation of prevention and long-term treatment for overweight or obesity and all associated diseases (including MASLD), despite limited long-term adherence. The drugs that have been approved in Germany for the treatment of obesity are orlistat, liraglutide, semaglutide, and naltrexone/bupropion. Orlistat and naltrexone/bupropion bring about only moderate weight loss (3–9%) without any consistent liverspecific effect (e15). Incretin-based therapies can achieve weight loss of 10–25%; in clinical trials, they markedly lessened hepatic steatosis and led to the resolution of MASH in 40–60% of patients (e25, e26). They also cause gastrointestinal side effects in up to 70–80% of treated patients, of whom 3–10% discontinue treatment. Moreover, there is evidence of an increased risk of biliary complications, and reliable long-term data are lacking; meticulous risk-benefit assessment is needed (29) (e26–e29). Drugs for obesity should always be combined with lifestyle interventions, as weight is usually regained when they are stopped. Severely obese patients (BMI ≥ 40) may benefit from bariatric surgery or endoscopic procedures, but these are associated with significant risks and do not guarantee long-term weight maintenance (e30, e31).

Dyslipidemia

Dyslipidemia is characterized by elevated plasma cholesterol and/or triglyceride levels, as well as low HDL cholesterol levels. This metabolic disorder can be either primary (genetic) or secondary (due to diet/lifestyle or medication use) and is associated with obesity, MASLD, T2DM, gallstones, and gout. Dyslipidemia is a major risk factor for CVD and stroke (30).

Treatment for dyslipidemia is mainly based on lifestyle interventions (see MASLD treatment), including smoking cessation (31). Lipid-lowering drugs are indicated in patients with moderate to high cardiovascular risk. Statins are the first line of treatment because of their efficacy and safety profile (7, 32) (eBox 10). As MASLD causes atherogenic dyslipidemia, statin therapy is often indicated in MASLD to prevent cardiovascular events. Observational data show lower overall mortality with statin use (hazard ratio 0.23; [0.13; 0.43]) as well as beneficial effects on liver inflammation, with no evidence of increased hepatotoxicity (33, 34). Combined statin-ezetimibe therapy lowers cholesterol levels even further and can preventively lessen the CVD risk (HR: 0.94) and the liver fat content (e32, e33).

eBox 10. The use of statins.

Statins (e.g., simvastatin, atorvastatin) lower cellular cholesterol levels by selectively inhibiting HMG-CoA reductase and thus lessening cholesterol biosynthesis. The lipid-lowering drug ezetimibe, which inhibits intestinal cholesterol reabsorption, can be used in addition. Epidemiological studies have confirmed that plasma cholesterol, and LDL cholesterol in particular, is a key risk factor for the development and progression of atherosclerotic cardiovascular diseases (28, 32, e77). Statins yield the greatest reduction in LDL cholesterol levels and are used for primary and secondary prevention as well as in coronary intervention strategies.

Table. Comorbidities of MASLD, with an overview of diagosis and treatment (modified from the EASL-EASD-EASO Clinical Practice Guidelines [7]).

Comorbidity	Prevalence in MASLD patients (e42)	Findings (summarized) and clinical relevance	DIagnostic evaluation (simplified)	Main forms of treatment and their clinical relevance
Dyslipidemia	60–70% (7, e43)	atherogenic profile: ↑TG, ↓HDL, ↑LDL; contributes to the burden of CVD	serum lipids (TG, LDL-C, HDL-C), non-HDL cholesterol if applicable	lifestyle + lipid-lowering treatment (statins/PCSK9 where indicated), monitoring of liver enzymes
Arterial hypertension	40–60% (7, e44)	exacerbates endothelial dysfunction and atherosclerotic risk; associated with progression of fibrosis and cardiovascular risk	repeated blood pressure measurements, 24-hour ambulatory blood pressure monitoring if applicable; evaluation of organ damage (kidneys, heart)	lifestyle intervention (weight loss, exercise, low-sodium diet); antihypertensive therapy according to guidelines, preferably ACE inhibitors or ARBs because of their favorable metabolic effects
Type 2 diabetes (T2DM)	30–50% (e45, e46)	strong bidirectional relationship: high prevalence of MASLD in T2DM; MASLD increases T2DM incidence (37)	screening with fasting glucose and/or HbA1c; increased vigilance in cases of fatty liver	weight loss, lifestyle changes; for drug therapy, consider GLP-1 agonists and their effects (beneficial for hepatic steatosis)
Cardiovascular diseases (coronary heart disease, stroke)	15–35% (e47, e48)	the most common cause of mortality in MASLD; MASLD i ncreases CVD risk independently of classic risk factors	lipids, HbA1c, blood pressure; if symptomatic, coronary CT/ stress test (scores: SCORE 2, SCORE-OP, ASCVD Risk Calculator)	strict control of cardiovascular risk factors (statin therapy, blood pressure, lifestyle); statins are generally not contraindicated in MASLD (e49)
Chronic kidney disease (CKD)	15–25% (incidence rises with degree of fibrosis [e50])	increased risk of CKD and progression; shared patho-mechanisms (e51)	serum creatinine, eGFR, albumin-to-creatinine ratio (UACR) at initial diagnosis and during follow-up	blood pressure and glucose control; RAAS blockade/renal protection as indicated; close collaboration with nephrologists
Obstructive sleep apnea syndrome (OSAS)	40–70% (e52)	especially in obesity, impaired metabolic control	screening questionnaires (STOP-BANG), polysomnography if indicated	weight loss, CPAP for diagnosed OSA—improves metabolic parameters
Specific cancers (extrahepatic) & HCC	5–10% (extrahepatic) 1–3% HCC	increased risk of HCC in MASH/fibrosis; increased risk of certain extrahepatic tumors. Surveillance for advanced fibrosis/cirrhosis	ultrasound ± AFP every 6 months in cases of cirrhosis/ high HCC risk; no routine surveillance without advanced fibrosis	HCC surveillance when indicated; tumor screening according to local algorithms; primary prevention through risk reduction
Endocrine/metabolic: PCOS, hypothyroidism, sarcopenia	15–25% female MASLD pts. with PCOS, 15–25% hypothyroidism, 20–35% sarcopenia	Sarcopenia worsens the prognosis	basic hormonal testing (TSH, androgens if symptoms are present); measure muscle mass/performance if sarcopenia is suspected	endocrinological evaluation and treatment; muscle building through strength training and protein optimization
Vulnerability to drugs and other toxins		Altered enzyme and transporter expression → increased susceptibility to hepatotoxic medications; increased alcohol sensitivity (37)	drug review (polypharmacy), alcohol history, monitor liver enzymes	avoidance of hepatotoxic medications, dose adjustment, close monitoring; patient education

ACE, angiotensin-converting enzyme; AFP, alpha-fetoprotein; ARB, angiotensin II receptor blocker; ASCVD, atherosclerotic cardiovascular disease;

CKD, chronic kidney disease; CPAP, continuous positive airway pressure; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; GLP, glucagon-like peptide; HCC, hepatocellular carcinoma; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MASLD, metabolic dysfunction-associated steatotic liver disease; OP, operation; OSA, obstructive sleep apnea; pt(s)., patient(s); PCOS, polycystic ovary syndrome; SCORE 2, Systematic Coronary Risk Estimation 2; RAAS, renin-angiotensin-aldosterone system; RF, risk factor; TG, triglycerides; TSH, thyroid-stimulating hormone; UACR, urinary albumin-to-creatinine ratio

Hypertension

Hypertension is uniformly defined internationally as a systolic blood pressure ≥ 140 mmHg and a diastolic blood pressure ≥ 90 mmHg (31, 35). It is one of the common cardiovascular comorbidities (40–70%) of MASLD and shares many pathophysiological mechanisms with it, including insulin resistance, chronic inflammation, and endothelial dysfunction (7). According to the guidelines, the diagnosis of hypertension requires repeated blood pressure measurements on different days (≥140/90 mmHg in a clinical setting or ≥135/85 mmHg for home or ambulatory measurements) (31, 35). 24-hour ambulatory blood pressure monitoring is also recommended to detect masked and white-coat hypertension. For risk stratification, the serum electrolytes and renal parameters should be measured, a urinalysis should be obtained to assess proteinuria, and an ECG should be performed. Echocardiography is indicated when there is clinical evidence of cardiac involvement or for further risk assessment. The goal of treatment is a sustained reduction of systolic blood pressure to below 130 mmHg. Here, too, lifestyle interventions such as weight loss, sodium restriction (<5 g/day), regular physical activity, and alcohol limitation are the mainstay of treatment (36). If blood pressure remains elevated, ACE inhibitors or angiotensin receptor blockers may be used, combined with calcium channel blockers or thiazide-like diuretics if necessary. In MASLD, the choice of antihypertensive drug should take cardiometabolic effects into account: ACE inhibitors and angiotensin receptor blockers improve insulin sensitivity and fibrosis markers (e34, e35).

Insulin resistance and type 2 diabetes mellitus (T2DM)

Insulin resistance is a key pathophysiological mechanism of MASLD and its link to T2DM. The two conditions worsen each other by way of chronic hyperinsulinemia, impaired lipid oxidation, and proinflammatory signaling pathways. Studies show that up to 80% of patients with T2DM have MASLD, while half of patients with MASLD have overt T2DM or prediabetes (7, 37). T2DM is diagnosed by the measurement of fasting glucose (≥ 126 mg/dL; 7.0 mmol/L) and HbAlc (≥ 6.5%), or by an oral glucose tolerance test (≥ 200 mg/dL after 2 hours) (38, e36). For patients with MASLD, the current guidelines recommend low-threshold screening for insulin resistance and impaired glucose tolerance (fasting glucose, HbA1c, HOMA-IR), because MASLD often begins before diabetes becomes clinically apparent. The aim of treatment for T2DM is lasting normalization of glucose homeostasis, leading to a lower cardiometabolic and hepatic risk. Here, too, lifestyle interventions—diet and regular physical activity—and weight loss (5–10 % of body weight) are the mainstay of treatment. The first-line drug against T2DM is metformin, because it simultaneously lowers blood sugar, improves lipid profiles, and can reduce hepatic insulin resistance (reduction in HbA1c of 1–1.5 %; triglycerides/cholesterol by ca. 10 mg/dL; HOMA-IR by 0.42 units) (7). If the blood sugar remains too high, GLP-1 receptor agonists or SGLT2 inhibitors should be considered early on. GLP-1 receptor agonists bring about weight loss (5–15 %) and a marked reduction in intra-hepatic fat content (30–60%, placebo 15%), while SGLT2 inhibitors have shown moderate but consistent effects on body weight (2–4% weight loss) and hepatic steatosis (20–30% reduction) (e25, e37, e38) (eBox 11). Overt MASH should be treated in an interdisciplinary collaboration with diabetologists and hepatologists. The presence of T2DM in MASLD is associated with an approximately doubled rate of advanced fibrosis as well as markedly increased risks of cardiovascular disease (HR: 1.8–2.3) and HCC (HR: 2.0–2.5) (e39). Effective glycemic control combined with weight loss of ≥ 7–10 % can resolve MASH in 60–90% of patients and improve fibrosis in one-third (e16, e40).

eBox 11. GLP-1 agonists in the treatment of MASH.

GLP-1 agonists reduce, among other things, gluconeogenesis, de novo lipogenesis, and hepatic steatosis in the liver, and increase insulin sensitivity in the liver and muscles. The incretin effect reduces pancreatic glucagon secretion and improves β-cell function by increasing insulin biosynthesis. In the upper gastrointestinal tract, GLP-1 agonists delay gastric emptying in a dose-dependent manner, thereby lowering postprandial hyperglycemia. GLP-1 agonists also have angioprotective, cardioprotective, and nephroprotective effects and improve natriuresis. Moreover, they have a key effect on the regulation of body weight, increasing the feeling of satiety and lowering food intake (e84–e87). In a Phase 3 trial, 72 weeks of treatment with semaglutide (interim analysis; n = 800) resulted in significant histological improvement in MASH (62.9% of patients, vs. 34.3% with placebo) and liver fibrosis (36.8% of patients, vs. 22.4% with placebo) (e26, e28). Body weight was lowered by 10.51%. Semaglutide is, therefore, already being used off-label for some patients with MASH but without T2DM.

Moreover, in patients who have MASH and T2DM as well, the lipid profile and blood pressure should be optimized, and sleep apnea and obesity should be strictly controlled.

Cardiovascular diseases

Cardiovascular diseases—coronary heart disease (CHD), heart failure, cerebrovascular events, and peripheral arterial disease (PAD)—account for 40–50% of deaths among MASLD patients, markedly outnumbering liver-related complications. MASLD is associated with a 40–70% increase in cardiovascular risk, independently of classic risk factors such as BMI and metabolic status (HR 1.45; [1,31; 1,61]); the cardiovascular risk is even higher in persons with MASH or advanced fibrosis (HR 2.50; [1.68; 3.72] (e41) (eBox 12). Any diagnosis of MASLD should be understood to imply an increased overall cardiovascular risk and should be integrated into an interdisciplinary prevention strategy. Interdisciplinary collaboration (cardiology, diabetology, hepatology) is essential to achieve therapeutic synergies, such as those involving lipid-lowering and antidiabetic drugs. The EASL-EASD-EASO guidelines recommend structured screening for cardiovascular risk factors in all patients with MASLD (7), incorporating established cardiovascular risk scores (SCORE2, SCORE2-OP) (39). Treatment focuses on the control of all cardio-metabolic risk factors, with MASLD being considered a cardiovascular risk multiplier. Lifestyle interventions (see MASLD treatment) are once again the foundation of treatment; they address both MASLD and cardiovascular risk (40). Drugs that can be used include lipidlowering agents (statins), antihypertensive drugs, and cardioprotective antidiabetic drugs (GLP-1 receptor agonists, SGLT2 inhibitors). In cases of established coronary heart disease or after a cardiovascular event, antiplatelet drugs (acetylsalicylic acid, clopidogrel, ticagrelor, prasugrel) are indicated for secondary prevention.

eBox 12. Multiple mechanisms contribute to the increased cardiovascular risk in MASLD.

Multiple mechanisms are thought to elevate cardiovascular risk in MASLD, including endothelial dysfunction, increased production of atherogenic lipoproteins (particularly VLDL and sdLDL), oxidative stress, inflammatory activation (TNF-α, IL-6, and CRP levels), and disruptions in bile acid signaling pathways (7) (e88, e89). Hepatic insulin resistance leads to increased VLDL secretion and, at the same time, reduces hepatic LDL receptor activity, lessening cholesterol clearance and promoting atherogenesis.

Extrahepatic cancers

MASLD/MASH is associated with HCC and with other serious secondary diseases, including a significantly elevated incidence of certain types of extrahepatic cancer. In particular, the risk or incidence of gastrointestinal and biliary tumors (colorectal, gastric, pancreatic), thyroid and breast cancer, and cancer of the urinary tract and female reproductive organs is increased by a factor of 1.2 to 2.5, depending on the tumor type (26) (eBox 13). Although some questions in this area remain unanswered, the indisputably higher risk of extrahepatic malignancies in MASLD should be considered in the treatment of these patients (eBox 14).

eBox 13. The risk of extrahepatic cancer.

Furthermore, the increased risk of developing an extrahepatic malignancy does not appear to depend on age, sex, smoking status, degree of obesity, T2DM, or the severity of MASLD/ MASH (e90). Accordingly, there may be not only a correlation but also a causal association between these malignancies and MASLD/MASH (e88, e90). Pharmacological management of MASLD with statins and metformin may have a protective effect against extrahepatic malignancies (e90). It remains unclear whether targeted screening for the aforementioned malignancies in patients with MASLD could improve the prognosis.

eBox 14. Effects of altered sleep habits.

In addition to (over)nutrition and physical inactivity, unhealthy sleep habits are often a part of the lifestyle in industrialized societies (e91). Disruptions of the intrinsic circadian rhythm may be associated with MASLD, sleep disorders, depression, and cognitive dysfunction (e92). Shiftwork is associated with a higher risk of metabolic syndrome (e93). A natural rhythm of light exposure, physical activity, food intake, and sleep could serve as a supportive factor for lifestyle interventions that are aimed at the prevention and treatment of MASLD (e92).

Conclusions

MASLD and MASH are very common in Germany and worldwide. In addition to their liver-specific morbidity and mortality (HCC, cirrhosis), these conditions are associated with markedly increased mortality from cardiovascular diseases and from extrahepatic cancers. Their comorbidities include obesity, dyslipidemia, hypertension, type 2 diabetes mellitus, cardiovascular disease, sleep apnea, and chronic kidney disease, all of which must be considered in the diagnostic evaluation, treatment, and monitoring of patients with MASLD. Intensive and sustained lifestyle modification for weight loss and subsequent weight stabilization is essential both before and during any drug treatment for these comorbidities. Lifestyle modification measures include a low-calorie, low-sugar diet and at least 150 minutes of moderate aerobic activity per week, ideally combined with strength training and additional high-intensity aerobic activity. MASLD is an important risk factor for metabolic complications and cardiovascular mortality, and its high prevalence in the general population is a major public health problem. Although new drugs have become available for the treatment of noncirrhotic MASLD, a sustainable reduction of the populationwide disease burden still crucially depends on the consistent implementation of prevention strategies and on an increased awareness of the metabolic and cardiovascular risks associated with MASLD.

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Questions on this article: Participation is possible at cme.aerzteblatt.de. The submission deadline is 17 September 2027.

Only one answer is possible per question. Please select the answer that is most appropriate.

• Question 1

  What findings are required for the diagnosis of MASLD?

  1. elevated transaminases and histologically confirmed inflammation
  2. liver cirrhosis in the presence of type 2 diabetes mellitus
  3. intrahepatic fat content ≥ 5% on biopsy, combined with at least one metabolic risk factor
  4. the definitive exclusion of alcohol consumption
  5. MASLD can only be diagnosed by a liver biopsy.

• Question 2

  What are the established metabolic and extrahepatic comorbidities of MASLD?

  1. psoriasis
  2. chronic kidney disease (CKD)
  3. ulcerative colitis
  4. Crohn’s disease
  5. chronic obstructive pulmonary disease (COPD)

• Question 3

  What is the leading cause of death among patients with MASLD/MASH without cirrhosis?

  1. cardiovascular diseases
  2. hepatocellular carcinoma
  3. hepatic encephalopathy
  4. autoimmune diseases
  5. the liver disease itself, e.g., MASH-associated cirrhosis and its complications

• Question 4

  What is known about the prevalence of MASLD in Germany?

  1. Exact, population-representative prevalence data are available for Germany.
  2. The prevalence of MASLD in the adult population of Germany is estimated at 23%.
  3. MASLD affects less than 5% of the adult population in Germany.
  4. The reclassification from NAFLD to MASLD has led to a marked drop in prevalence.
  5. The prevalence of MASH in Germany is estimated at 20%.

• Question 5

  According to current evidence, what drugs are particularly suitable for treating metabolic comorbidities such as CVD and CKD in MASH?

  1. THR-β receptor agonists for sarcopenia
  2. erythropoiesis-stimulating therapy to normalize hemoglobin levels in chronic kidney disease
  3. sedatives for sleep apnea
  4. reserpine as first-line therapy for arterial hypertension
  5. GLP-1 receptor agonists and SGLT-2 inhibitors for type 2 diabetes mellitus

• Question 6

  What should be recommended as primary prevention and basic therapy for MASLD/MASH?

  1. regular vitamin E supplementation; statins are contraindicated
  2. a glass of red wine with dinner
  3. If liver function tests are normal, no prevention or basic therapy is necessary.
  4. six-monthly liver detoxification regimens and a sugar-free diet
  5. weight normalization, a Mediterranean diet, and regular physical activity

• Question 7

  What recommendation about physical activity for MASLD is mentioned in the article?

  1. rest and avoidance of endurance exercise
  2. at least 150 minutes of endurance exercise per week, supplemented by strength training
  3. strength training only, once a month
  4. physical activity only after normalization of hepatic fat levels
  5. daily high-intensity training as the only effective option

• Question 8

  For which patients with MASH has drug treatment with resmetirom been described as an option?

  1. adults with noncirrhotic MASH and fibrosis stages F2/F3 or a VCTE liver stiffness measurement between 10–19.9 kPa, in addition to dietary changes and physical activity
  2. all patients with sonographically confirmed steatosis, regardless of the stage of fibrosis
  3. patients with decompensated liver cirrhosis as first-line therapy
  4. children and adolescents with MASLD without fibrosis
  5. only patients with alcohol-related liver disease

• Question 9

  Which statement about the FIB-4 score is true?

  1. A FIB-4 score below 1.3 strongly suggests the absence of advanced liver fibrosis.
  2. A FIB-4 score below 1.3 confirms MASH cirrhosis.
  3. The FIB-4 score can only be determined after a liver biopsy.
  4. The FIB-4 score takes only the body mass index and the HbA1c level into account.
  5. If the FIB-4 score is below 1.3, liver elastography is urgently indicated.

• Question 10

  What should be the first-line treatment and the goal of treatment for obese patients (BMI 30–35 kg/m²) with MASLD or suspected MASLD and a concomitant metabolic condition (dyslipidemia, T2DM, or hypertension)?

  1. intermittent fasting until 20 kg are lost
  2. a combination of statins, GLP-1 receptor agonists, ACE inhibitors, and remetirom; bariatric surgery should be pursued regardless of weight loss
  3. a low-calorie, low-sugar diet and at least 150 minutes of aerobic activity plus strength training sessions per week, with the goal of 5% weight loss within 12 months
  4. Approximately 10 000 steps daily and increased general activity suffice to achieve 10% weight loss in 6 months.