Diagnosis of metabolic dysfunction-associated steatohepatitis (MASH)

Review, Part 2

The economic consequences of MASLD and MASH are considerable, with direct annual costs to the healthcare system running into billions. This also underlines the need to effectively address the burden of disease. Improved coordination and awareness-raising among physicians, as well as an adjustment of the healthcare policy framework, are necessary to enable more effective early detection and treatment of MASH. This includes the implementation of screening measures in disease management programs (DMPs), the integration of transient elastography into the benefits catalog of statutory health insurance, and the standardization of diagnostic procedures.

>> The current S2k guideline presents a screening algorithm for the early detection of MASH, which can also be performed by general practitioners in routine clinical practice. A screening procedure is of great importance for the diagnosis of MASLD, as the symptoms of early and often moderate MASH are often very nonspecific (e.g., reduced performance, fatigue, upper abdominal discomfort) and therefore do not directly indicate the presence of this specific disease.
Therefore, a screening procedure should be used in known risk populations that can identify potential patients with incipient or even advanced MASH at an early stage. Key risk groups for the development of MASLD, identified by epidemiological studies, are patients with type 2 diabetes mellitus, obesity, or metabolic syndrome (1), which, according to the criteria of the International Diabetes Federation (IDF), includes type 2 diabetes mellitus or a fasting blood glucose ≥100 mg/dL (≥ 5.6 mmol/L) and trunk-predominant obesity as key factors, in addition to elevated triglycerides, low HDL cholesterol, and elevated blood pressure (2). The current S2k guideline therefore explicitly recommends comprehensive metabolic diagnostics in patients with liver steatosis, which includes these parameters.
Patients with these risk factors should initially undergo one of the following tests, depending on availability: laboratory diagnostics with liver function tests (ALT) and AST, an ultrasound examination, or a calculation of the Fatty Liver Index. The Fatty Liver Index (FLI) is comprised of easily measurable parameters such as height, weight, and waist circumference, as well as laboratory values of triglycerides and gamma-GT. It can detect fatty liver disease (steatosis hepatis) at a cutoff value ≥ 60, with a specificity of 86% and a positive likelihood ratio of 4.3 (3).
In case of repeatedly or continuously elevated GPT (ALT) values, a direct referral to a gastroenterologist/hepatologist should be made for differential diagnosis of hepatopathy. In case of a primarily conspicuous ultrasound finding or a fatty liver index above 60, the FIB-4 test should be performed to clarify liver steatosis.
or NFS score can be calculated (see section on fibrosis scores). The sequence of FLI and FIB-4 has been specifically studied for screening in a high-risk group of type 2 diabetics (4). If the FIB-4 or NFS result is high, referral to a gastroenterologist or hepatologist should be made. If the risk is intermediate, referral can be considered, or regular follow-up using GPT (ALT) can be performed, which is also recommended for low-risk patients (3).
The intervals of clinical follow-up in MASLD patients depend on the risk constellation and are specified by the European Liver Society (EASL) as follows: Patients with bland steatosis without increased risk in fibrosis markers can be monitored every 2 years; if liver enzymes are normal over time and steatosis is absent on ultrasound, the interval can even be 3–5 years (5).
The gastroenterologists and hepatologists then carry out clinical risk stratification, taking into account potential differential diagnoses and comorbidities, as well as another core element of non-invasive diagnostics in MASLD, elastography, which uses a standardized,
independent liver stiffness measurement is performed to reliably assess the risk of higher-grade fibrosis.
A significantly elevated liver stiffness value of over 12 kPa using vibration-controlled transient elastography (VCTE) can already serve as a basis for multimodal therapy. The indication for liver biopsy in cases of clinically unclear fibrosis status is further explained in Chapter 2.2 Invasive Diagnostics (3).
Supply situation in the
Diagnosis of MASH
The current MASH diagnostic care situation in Germany and worldwide remains severely limited due to multiple factors and can be significantly optimized in several aspects of patient care and organization (6). The screening algorithm presented in the guideline is not yet widely established in large parts of Germany and, due to various structural and financial constraints, is currently only partially implementable in many clinical and outpatient settings of gastroenterological and general medical care (3).
A key bottleneck is the definitive diagnosis, which requires a liver biopsy. However, many patients refuse this procedure due to the high effort involved – a biopsy often requires an inpatient stay – and the associated risk of complications. This results in a low diagnosis rate of MASH, which is only detectable histologically, compared to the presumed prevalence within the overall group of patients with MASLD. Whether this histological confirmation of MASH will also be a prerequisite for the indication of future new MASH medications is currently unclear.
Based on statutory health insurance data from 2018, 4.66% of insured persons were diagnosed with MASLD, while only 0.09% were diagnosed with MASH. This difference is not in line with the expected proportion of the total number of MASLD diagnoses (7). According to study results, MASH is present in 5–20% of MASLD patients, and in individuals with MASLD and comorbid diabetes mellitus, the probability of MASH is even approximately 40% (8–11). Thus, the number of patients with an actual MASH diagnosis is very likely significantly lower than realistically assumed, which is why many patients remain undiagnosed and thus possibly inadequately treated.

Frequency of diagnosed fatty liver disease
The prevalence of steatotic fatty liver disease (MASLD), associated with metabolic dysfunction, is high; worldwide, more than 25% of the adult population suffers from MASLD (11). In 2016, Germany ranked third in terms of estimated nationwide prevalence, behind Greece and Italy with 22.9% (9). The burden on the healthcare system from MASH and MASLD is expected to increase significantly in the coming years. A study by Estes et al. In 2018, the American Society of Hematology (ASH) predicted an increase in the number of MASH diagnoses by 63% by 2030 in the USA and an increase of 21% by 2030 for MASLD (12). Similar developments are forecast for Germany: The number of patients with MASLD is expected to rise from the current 18.4 million to approximately 21 million patients in 2030, and the number of patients with MASH fibrosis, estimated at 600,000, is expected to double during this period (12).
The economic consequences of MASLD are significant. In a 2018 study, Younossi et al. calculated the annual direct costs of MASLD in the four European countries of France, Germany, England, and Italy at a total of €35 billion. This amount would represent a 10-year burden of €302 billion, assuming a constant incidence and standard interest rate assumptions. If the incidence trend is based on the increase in obesity incidence in the USA in recent years, the burden would even reach €334 billion (10).
Adding the societal costs of lost QALYs due to MASLD to the direct costs results in annual costs of €227.84 billion. This calculation does not include indirect costs such as lost labor capacity or specific treatment costs due to the lack of targeted therapies for MASLD and MASH (10). Comparably detailed data on the economic burden of MASH specifically are not currently available; however, one study calculated the annual direct care costs of MASH in Germany at €1,900 per patient (7, 13).
Approval of specific treatment options for MASLD
and MASH is expected to increase in the medium and long term due to the significant disease burden and the need for targeted therapy. Due to this change and the increasing prevalence, the economic burden of MASLD and MASH may increase significantly and become a significant factor in healthcare budgets. In this context, the successful treatment of obesity and concomitant type 2 diabetes mellitus is also highly relevant for the development of MASH diagnosis rates.
In the current resolution of the Disease Management Program Requirements Guideline for Obesity of the Federal Joint Committee (G-BA), “obesity-specific measures, especially for weight reduction, are considered (as) the most important component of the therapy of non-alcoholic fatty liver disease” (14).

Reimbursement options for diagnostic procedures
The first step in the diagnostic algorithm recommended by the S2k guideline involves risk assessment using one of the two recommended fibrosis scores, NFS or FIB-4. Both scores are relatively easy to calculate from standard laboratory values such as ALT, AST, platelets, albumin, etc. (see Chapter 2.1.1. Fibrosis Scores).
The collection of GPT (ALT) and GOT (AST) is billable to statutory health insurance (GKV) under EBM codes 32069 and 3270 at €0.25 each. Supplemented by the collection of platelets (EBM 32120 at €0.50 each) or the determination of albumin (EBM 32435 at €3.40 each), both tests would generally be billable to statutory health insurance.
However, liver stiffness measurement using transient elastography or shear wave elastography, recommended by the guidelines for patients with increased risk, is not covered by statutory health insurance. These procedures are currently offered as self-pay services for approximately €60–100.
For inpatient care, there is an OPS code for "Complex differential diagnostic sonography using Tissue Doppler Imaging (TDI) and tissue deformation analysis" (OPS 3-034). While an OPS code is a crucial element for documenting medical services as a basis for reimbursement under the DRG system, it is not directly linked to a reimbursement amount.
A liver biopsy, however, is covered by statutory health insurance. It can generally be performed on an outpatient or inpatient basis. An OPS code exists for inpatient treatment (1-442.0 – Percutaneous biopsy of the hepatobiliary system and pancreas guided by imaging techniques: liver). Alternatively, the service can also be performed as an outpatient procedure according to Section 115b of the German Social Code (SGB V).
On an outpatient basis, a liver puncture is reimbursed at €16.35 under EBM 02341. Additional billing codes may apply for postoperative monitoring and additional costs for pathological findings (EBM 13910 at €9.91).
In conclusion, the diagnosis of MASLD and MASH is indeed included in the statutory health insurance (GKV) benefits catalog. However, the possibility of using noninvasive elastography to identify larger risk groups is not reflected in the benefits package.
Impact of new diagnostic approaches on the care situation
Patients with MASLD exhibit high healthcare utilization (15). An important factor, which is central in Germany but also in other high-income countries such as the USA, France, the UK, and Canada, is the continued significant role of liver biopsy in the definitive diagnosis of MASH, which is viewed as highly critical by many patients and often rejected due to potentially life-threatening complications (15, 16).
In a 2017 survey of 121 physicians specializing in relevant fields in the aforementioned countries, concerns about diagnostic methods were cited by the surveyed physicians as the most important suspected reason for the low rate of diagnostically confirmed MASH cases (16). 57% of all physicians surveyed and 53% of all physicians surveyed in Germany cited this reason in the study.
The next most common reasons given were the current symptoms or the current health status of the patients, a lack of expertise and awareness regarding MASH among general practitioners and a lack of availability of diagnostic methods, both in Germany and in the total sample (16).
A new diagnostic approach that does not require invasive diagnostics and is widely applicable could potentially significantly increase the number of MASH diagnoses and thus significantly improve the therapeutic care of patients with MASH. From a socioeconomic perspective, a higher rate of diagnosed MASH cases would increase the direct disease-associated care costs, but could also significantly reduce overall care costs by preventing very costly consequences of advanced stages of the disease, such as liver transplantation.
In the USA, fatty liver disease is currently the second most common reason for liver transplantation after alcohol-related liver disease (7). A liver transplant costs an average of approximately €105,000 in the year of transplantation and €20,000 in the following year (7, 17). However, liver transplant patients often require very close medical support and immunosuppressive therapy in all subsequent years.
10–20% of MASH patients develop advanced fibrosis, and approximately 5% develop liver cirrhosis. Severe disease progression, often involving frequent hospital visits and intensive medical and nursing care, is not uncommon and results in significant costs (7). In the presence of liver cirrhosis, the risk of hepatocellular carcinoma is approximately 2% per year, meaning that even avoidable oncological therapies, which account for a large proportion of treatment costs in Germany, may become necessary during the course of the disease (18).

Analysis of current care gaps and challenges
In addition to the challenges in MASH care posed by invasive diagnosis, there are other factors that systematically complicate the medical treatment of MASH patients. Disease awareness among the population and treating physicians is particularly important here. A survey of 224 physicians specializing in relevant fields in Germany, Italy, England, and the USA showed that many specialists perceive a lack of expertise and disease awareness among general practitioners in the four countries, including regarding the necessary screening indicators (19).
At the same time, 89% of respondents agreed with the statement that general practitioners should be more involved in the screening of patients with MASH. 77% of respondents stated that patients with suspected MASH often reached specialized specialists with a significant delay. Regarding current screening algorithms, a lack of consensus was noted at the time of the survey, and some screening protocols were considered clinically impractical (19). Thus, raising awareness of MASH among physicians, better coordination of the screening process, and better integration of general practitioners into this process are of great importance for improving the care situation as well as increasing standardization and more pragmatic design of screening algorithms (6).
In the study by Cook et al. (2020) mentioned in the previous section, the physicians surveyed were also asked about the
They were asked about the methods they used, with several methods available for selection. 94% of the respondents indicated blood tests as their method, 93% indicated ultrasound, and 79% indicated transient elastography (16). A confirmatory liver biopsy was indicated by 81% of the physicians as their method of choice.
Transient elastography was reported significantly more frequently by physicians in England and Canada (90%) than by physicians in Germany (60%). MRI and CT were used relatively frequently (48%) and 46%), respectively, although the German guideline does not recommend these procedures primarily as diagnostic procedures for MASH, but only as additional parameters if an MRI or CT is performed anyway for other reasons (3). Thus, increased standardization and systematization of the selected diagnostic methods in general practice and specialist settings are also of great importance for the care of MASH.
Recommendations for action to improve the supply situation
The increasing prevalence of MASLD and MASH, as well as associated metabolic diseases such as obesity and type 2 diabetes, highlights the importance of targeted screening and diagnostics for liver disease in these patient populations.
Several fields of action open up as starting points for the implementation of the recommendations of the evidence-based S2k guideline, in particular with regard to the inclusion of screening measures in the relevant DMP, the implementation of early detection measures in the health examination guideline and the inclusion of transient elastography in the standard service catalogue of the statutory health insurance.

Reflect screening recommendations in DMPs
A DMP exists for the at-risk population of patients with type 2 diabetes, but it currently does not include recommendations for screening for MASLD. While the DMP for type 2 diabetes makes no reference to liver disease (14), the recently developed guideline for the DMP for obesity by the Federal Joint Committee (G-BA) states that obesity-specific measures are the most important component of MASLD treatment, but does not mention guideline-compliant screening (14).
Within the framework of the DMP guidelines, it is also fundamentally standard to stipulate regular screening for concomitant and secondary diseases and subsequently measure their implementation as a quality assurance measure in accordance with Section 137f of the German Social Code (SGB V). For obesity, the goal is to prevent arterial hypertension and diabetes mellitus; for existing diabetes mellitus, the goal is to prevent kidney and cardiovascular diseases, as well as retinopathy and blindness. It therefore seems questionable that fatty liver disease is not considered in these high-risk groups.
The importance of MASLD and MASH, as well as the screening recommendations, were already highlighted in the commentary process on the guideline synopsis on obesity prepared by the German Institute for Quality and Efficiency in Health Care (IQWiG). However, the IQWiG refused to consider the S2k guideline as it is "not specific for obese patients with NAFLD" (20).
Implementing the screening recommendations in both DMPs would be extremely simple. The collection of GOT (AST) and GPT (ALT)1 (EBM 32069, 3270, €0.25 each) in addition to the complete blood count (EBM 32120, €0.50 each) enables early and promising intervention with minimal effort and prevents progression to irreversible liver damage.
To increase practicality, laboratories should also regularly report the calculated FIB-4 score when requesting this combination of laboratory parameters.

Anchor early detection in health examination guidelines
In addition to the indication-specific DMPs, the Federal Joint Committee's health examination guideline should also include regular screening for the presence of MASLD. According to Section 2 of the guideline, the stated goal is the "early detection of diseases of public health significance," coupled with the requirement that "suspected cases identified are thoroughly diagnosed, identified diseases are treated promptly, and changes in health-damaging behaviors are initiated early" (21). Early detection of fatty liver disease would be ideally suited to fulfilling this self-imposed goal.

Include elastography in the GKV service catalogue
A further obstacle to the early detection of MASLD is that the transient elastography procedure is not a standard service provided by statutory health insurance. The Federal Joint Committee (G-BA) confirms in principle that elastography is suitable for "monitoring the progression and reducing the frequency of liver biopsies" and has included elastography in the scope of services for certain liver diseases within the guidelines for outpatient specialist care (ASV) pursuant to Section 116b of the German Social Code (SGB V) (22).
For the inclusion of new laboratory services in the Uniform Assessment Standard (EBM), which regulates the billing of outpatient medical services under the statutory health insurance system in Germany, a resolution of the Assessment Committee (BA) is required. However, an application to initiate such a procedure can be submitted not only through the BA's supporting organizations, but also through professional medical associations, medical societies, and associations of manufacturers of diagnostic services and medical devices (23).
In conclusion, despite its high diagnostic value, liver biopsy is not suitable for broad-based diagnostics or screening due to the complexity, invasiveness, and associated risks. After risk stratification using the recommended NFS and FIB-4 scores, routine follow-up diagnostics are only feasible with a noninvasive diagnostic procedure. The inclusion of transient elastography in the standard service catalog of statutory health insurance (SHI) would therefore enable early detection and treatment of liver changes.