Standardized MASLD Management in Japan: Non-Invasive Diagnosis and Treatment Experience Centered on CK-18

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the leading cause of chronic liver disease in Japan, with a prevalence rate of 33.7% in 2020 projected to climb to 44.8% by 2040. Obesity, type 2 diabetes, and metabolic syndrome are further driving up the disease burden. A non-invasive, standardized, and widely accessible diagnostic and treatment pathway will be the core breakthrough for standardized MASLD management. Japan has built a mature non-invasive management system with cytokeratin 18 fragments (CK-18 M30/M65) as its key cornerstone, providing a replicable model for the world. 

(Embedded Figure 1 in the original web page: MASLD epidemiology and future incidence projections (Japan))

■ Japan's Three-Step NILDA (Non-Invasive Liver Disease Assessment) Strategy

Japan has established a relatively mature three-step NILDA (Non-Invasive Liver Disease Assessment) strategy for MAFLD:

First-line screening: rapid risk stratification using the FIB-4 score;

Second-line refined assessment: for patients with indeterminate FIB-4 (1.3–2.67), non-invasive markers — including ELF (Enhanced Liver Fibrosis), COL4-7S (serum type IV collagen 7S), and CK-18 — are used for further determination, reducing risk and avoiding unnecessary referrals;

Third-line confirmation: high-risk patients (FIB-4 > 2.67 or abnormal second-line indicators) are referred to hepatology departments, where advanced imaging such as VCTE (Vibration-Controlled Transient Elastography) and MRE (Magnetic Resonance Elastography) confirms the treatment plan and follow-up strategy. (Embedded Figure 2 in the original web page: ideal management pathway for patients with MASLD/MASH)

The core objective is to fill the FIB-4 "gray zone" with non-invasive markers such as CK-18, turning "indeterminate" into "determinable," substantially improving stratification efficiency — a key step toward standardized non-invasive management.

图2.MASLD/MASH患者理想管理路径

The expert consensus "Noninvasive Strategies for Metabolic Dysfunction-Associated Steatotic Liver Disease Assessment and Referral in Japan" clarifies the irreplaceable core value of CK-18 in MASLD management, running through the entire process of diagnosis — stratification — monitoring:

MASL/MASH can be diagnosed using CK-18;

CK-18 is an effective marker for assessing MASH as a liver function indicator;

CK-18 can reflect the effects of various treatments by assessing liver function;

CK-18 can diagnose high-risk MASH;

The combination of CK-18 and FIB-4 indicators is very useful for diagnosing MASH. 

(Embedded Figure 3 in the original web page: clinical value of CK-18)

As early as January 2024, the Japanese government included cytokeratin 18 fragments in medical insurance coverage for the auxiliary diagnosis of non-alcoholic steatohepatitis (NASH), supporting the popularization of the non-invasive diagnostic system through concrete insurance policy — setting a replicable clinical model for full-process MASLD management worldwide. 

(Embedded Figure 4 in the original web page: CK-18 included in the scope of medical insurance payment as an auxiliary diagnostic indicator for MASH)

The clinical experience accumulated in Japan offers highly valuable lessons for MASLD management in China. China has up to 400 million MASLD patients, and clinical practice still faces challenges such as insufficient screening, unclear stratification, and non-standardized management. Incorporating CK-18 into the standardized MASLD screening pathway, promoting medical insurance coverage, and improving the tiered diagnosis and treatment system are key levers for achieving early screening, early diagnosis, and early treatment of MASLD in China.

As a specific marker of hepatocyte apoptosis, CK-18 — validated through Japanese clinical practice — has become a core tool for standardized non-invasive MASLD management. Its dual value of "diagnostic stratification + therapeutic monitoring" not only refines Japan's patient-centered MASLD management pathway, but also provides a pragmatic reference for China to build a localized and standardized MASLD prevention and treatment system.

References:

[1] amada Y, Sumida Y, Takahashi H, Ishiba H, Kawanaka M, Tada T, Yoneda M, Imajo K, Seko Y, Fujii H, Nakajima A. Noninvasive strategies for metabolic dysfunction-associated steatotic liver disease assessment and referral in Japan. World J Gastroenterol. 2026 Jan 14;32(2):114097.

[2] Seko Y, Yamaguchi K. Management of MASLD/MASH: challenges, innovations, and the future of patient-centered care in Japan. J Gastroenterol. 2026 Apr 15.

[3] https://www.srl-group.co.jp/assets/pdf/news/testing/2024-001.pdf