From the origin of NASH to the future of metabolic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide. Understanding the pathological and molecular hallmarks from its first description to definitions of disease entities, classifications and molecular phenotypes is crucial for both appropriate clinical management and research in this complex disease. We provide an overview through almost two hundred years of clinical research from the beginnings as a nebulous disease entity of unknown origin in the 19th century to the most frequent and vigorously investigated liver disease today. The clinical discrimination between alcohol-related liver disease and NAFLD was uncommon until the 1950s and likely contributed to the late acceptance of NAFLD as a metabolic disease entity for long time. Although the term 'fatty liver hepatitis' first appeared in 1962, it was in 1980 that the term 'non-alcoholic steatohepatitis' (NASH) was coined and the histopathological hallmarks that are still valid today were defined. The 2005 NASH Clinical Research Network scoring was the first globally accepted grading and staging system for the full spectrum of NAFLD and is still used to semiquantify main histological features. In 2021, liver biopsy remains the only diagnostic procedure that can reliably assess the presence of NASH and early fibrosis but increasing efforts are made towards non-invasive testing and molecular classification of NAFLD subtypes.

Keywords: fatty liver; fibrosis; genetics; molecular pathology; obesity.

Figure 1

Venus figurines of obese women. (A) Venus of Willendorf. The figurine is estimated to have been created around 30 000 BC in the Austrian Danube Valley near Krems and is displayed at the Museum of Natural History, Vienna, Austria (Natural History Museum Vienna, with permission) (B) Neolithic Venus figurine. Clay naturalistic figurine of a seated obese woman from Farsala, Thessaly (Athanassakeion archaeological museum of Volos, Greece with permission of the Hellenic Ministry of Culture and Sports/Archaeological Resources Fund) middle Neolithic period 5800–5300 BC.

Figure 2

Historical pathology specimen of a fatty liver from T. Frerichs, Atlas of Pathological Anatomy (Part I, 1861) (A) ‘fatty liver of an advanced grade’. Massive steatosis sparing the vincinity of the central veins; (B) cut surface with pale-yellow parenchyma; (C) after removal of the fat by boiling in ether, only meshes formed by the vessels remain.

Figure 3

Numbers of annual PubMed/MEDLINE references for the term ‘NASH’ from 1980 to 2019. References were identified for the search term ‘NASH’ (excluding author names), accessed on 8 April 2020. NASH, non-alcoholic steatohepatitis.

Figure 4

Histology of steatosis and non-alcoholic steatohepatitis (NASH). (A) Macrovesicular steatosis. The hepatocytes are distended by large fat droplets; chromotrope-aniline blue, x200. (B) NASH characterised by ballooned hepatocytes with lightly stained cytoplasm, some of them containing indistinct cytoplasmic inclusions resembling Mallory-Denk bodies (MDBs; arrows); H&E stain, x200. (C) NASH with ballooned hepatocytes, some of them containing MDBs (arrows) most hepatocytes are surrounded by pericellular fibrosis (blue RIMs around hepatocytes); chromotrope-aniline blue stain x200. (D, inset) Immunohistochemistry using antibodies to sequestosome1/p62 reveals p62-containing MDBs (red), x200.

Figure 5

Timeline of major developments in the field of NAFLD over the past 200 years. Major landmarks in the field until 2000 are shown with solid lines and black font, while developments after 2000 that cannot yet be viewed in a historical context are shown in dashed lines and lighter font. NAFLD, non-alcoholic fatty liver disease.