Metabolik Disfonksiyonla İlişkili Karaciğer Hastalıklarında Yeni Kavramlar: MAFLD ve MASH

Öz

Metabolik disfonksiyonla ilişkili steatohepatit (MASH) önceki adıyla alkolsüz steatohepatit (NASH), NAFLD/MASLD kökeninden gelişen inflamasyonla ve karaciğerde fibrozis ile karakterize olan oldukça önemli ve kronik karaciğer hastalıklarından biridir. MASH obezite, tip 2 diabetes mellitus, dislipidemi gibi metabolik bozukluklarla güçlü bir şekilde ilişki göstermektedir. Hastalık karaciğer dokusunda fibrozis ve skarlaşmanın artmasıyla siroza ilerleyebilir ayrıca hepatoselüler karsinoma (HCC) gibi ciddi karaciğer komplikasyonlarına zemin hazırlayabilir. Bu bağlamda dünya çapında yaklaşık %25'ten fazla insanı etkileyerek küresel çapta giderek yaygınlaşan agresif bir karaciğer hastalığıdır. 2023 yılında yayımlanan konsensüs sonucunda değişen terminolojiyle birlikte NAFLD yerine metabolik disfonksiyonla ilişkili steatotik karaciğer hastalığı (MASLD); NASH yerine ise metabolik disfonksiyonla ilişkili steatohepatit (MASH) terimleri şeklinde güncellenmiştir. Bu yenilik hastalığın metabolizmayla olan ilişkisini vurgulayarak "alkol dışı" tanımının sebep olduğu damgalamayı ortadan kaldırmıştır. Yeni terminolojiyle birlikte tanı kriterlerinde de çeşitli değişiklikler meydana gelmiştir ve tanının daha net olması sağlanmıştır. MASH kompleks bir hastalık olduğundan patogenezi oldukça karmaşıktır. Hepatik lipid birikimi sonucu lipotoksik etkiler, ROS sonucu oksidatif stresin artışı, kas ve kalp üzerine sistemik etkileri ve bağırsak mikrobiyotası hastalığın patogenezini etkileyen faktörlerden yalnızca birkaçıdır. Günümüzde yapılan araştırmalarda GWAS kullanımı sonucu hastalığın prognozunda çeşitli varyantların (SNP'lerin) rol oynadığı belirlenmiştir. PNPLA3, TM6SF2, GCKR, HSD17B13 ve MBOAT7 gibi SNP'lerin hastalık gelişimiyle ilişkili olabileceği keşfedilmiştir. Hastalığın ilerleyişinde yalnızca genetik değil aynı zamanda epigenetik faktörlerin, farklı sinyal yolaklarının da etkili olduğu belirlenmiştir. Bu derlemede, MASH'in güncel sınıflandırması, hücresel ve moleküler mekanizmaları hastalığın patogenezi literatür verileri doğrultusunda ele alınmıştır.

Anahtar Kelimeler

• MASH
• HCC
• yağlı karaciğer
• genetik
• epigenetik

New concepts in metabolic dysfunction-associated liver diseases: MAFLD and MASH

Öz

Metabolic dysfunction-associated steatohepatitis (MASH), formerly termed non-alcoholic steatohepatitis (NASH), is a significant chronic liver disease that arises from metabolic dysfunction-associated steatotic liver disease (MASLD, previously NAFLD). It is characterized by hepatic inflammation and fibrosis and is strongly associated with metabolic disorders such as obesity, type 2 diabetes mellitus, and dyslipidemia. Progressive fibrosis and scarring of the liver tissue can lead to cirrhosis and predispose individuals to severe complications, including hepatocellular carcinoma (HCC). Affecting more than 25% of the global population, MASH represents an increasingly prevalent and aggressive liver disease worldwide. In 2023, a consensus redefined the terminology to better reflect the metabolic underpinnings of the disease: NAFLD was renamed MASLD, and NASH was updated to MASH. This revision not only emphasizes the metabolic drivers of the condition but also removes the stigma associated with the term “non-alcoholic.” Additionally, the new terminology introduced refinements in diagnostic criteria, enabling a more precise and standardized diagnosis. MASH has a complex and multifactorial pathogenesis. Contributing mechanisms include lipotoxic effects from hepatic lipid accumulation, increased oxidative stress driven by reactive oxygen species (ROS), systemic effects on extrahepatic tissues such as muscle and heart, and alterations in the gut microbiota. Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) that influence disease susceptibility and progression, including variants in PNPLA3, TM6SF2, GCKR, HSD17B13, and MBOAT7. Beyond genetic determinants, epigenetic modifications and diverse signaling pathways are also critical to disease development and progression. This review provides an overview of the updated classification of MASH and explores its cellular and molecular mechanisms of pathogenesis based on current literature.

Anahtar Kelimeler

• MASH
• HCC
• fatty liver
• genetics
• epigenetics

Kaynakça

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