Historical narrative from fatty liver in the nineteenth century to contemporary NAFLD - Reconciling the present with the past

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder worldwide. This historical narrative traces the evolution from basic descriptions of fatty liver in the nineteenth century to our contemporary understanding of NAFLD in the twentieth and twenty-first centuries. A detailed historiographic review of fatty liver from 1800s onwards was performed alongside a brief review of contemporary associations. Archived published literature dating back to the 1800s describe clinicopathological features of fatty liver. In the nineteenth century, doyens of medicine associated fatty liver with alcohol, malnutrition or wasting conditions, and subsequently adiposity, unhealthy diets and sedentary lifestyle. Microscopically, fatty liver was described when 5% or more hepatocytes were distended with fat. Recommendations to reverse fatty liver included reducing consumption of fat, sugar, starchy carbohydrates and alcohol, plus increasing physical exercise. Fatty liver was associated with liver fibrosis and cirrhosis in the late 1800s, and with diabetes in the early 1900s. The diagnostic labels NAFLD and non-alcoholic steatohepatitis (NASH) were introduced in the late 1900s. Metabolic dysfunction-associated fatty liver disease (MAFLD) was recently proposed to update the nosology of fatty liver, recognising the similar metabolic pathogenesis evident in individuals with typical NAFLD and those with heterogenous "secondary" co-factors including alcohol and other aetiologies. Fatty liver has emerged from being considered a disorder of nutritional extremes or alcohol excess to contemporary recognition as a complex metabolic disorder that risks progression to cirrhosis and hepatocellular carcinoma. The increasing prevalence of NAFLD and our growing understanding of its lifestyle and metabolic determinants justify the current exercise of re-examining the evolution of this common metabolic disorder.

Keywords: HCC, hepatocellular carcinoma; MAFLD; MAFLD, Metabolic dysfunction-associated fatty liver disease; NAFL, Non-alcoholic fatty liver; NAFLD, Non-alcoholic fatty liver disease; NAS, NAFLD activity score; NASH; Non-alcoholic fatty liver disease; T2DM, Type 2 diabetes mellitus; alcohol; cirrhosis; diabetes; diet; liver fibrosis; metabolic; metabolic dysfunction-associated fatty liver disease; non-alcoholic steatohepatitis; obesity.

Fig 1

Trend of annual fatty liver publications (1910–2019). After a slow rise in fatty liver publications from the mid-1960s onwards, there was an exponential rise from 1991, i.e. after introduction of the terms NASH and NAFLD and comparisons with alcohol-related liver disease.

Fig 2

Trend of annual NAFLD publications (1986–2019). Though the term ‘NAFLD’ was introduced in 1986, the exponential rise in NAFLD publications was most notable from 2000 onwards.

Fig 3

Excerpts from books depicting fatty liver from the 1800s. (A) George Budd. On diseases of the liver (1857). (B) Virchow R, Chance F. Cellular Pathology as based upon physiological and pathological histology. Twenty lectures delivered in the pathologic institute of Berlin (1858).

Fig 4

Contemporary adult non-alcoholic fatty liver (NAFL or simple steatosis), (H&E stain).

Fig 5

Contemporary adult non-alcoholic steatohepatitis (NASH) with fibrosis (Masson’s trichrome stain). (A) NASH with fibrosis (Masson’s trichrome stain). (B) NASH with cirrhosis (Masson’s trichrome stain).

Fig 6

Pathogenesis of fatty liver as described between the 1850s and 1970. Fatty liver was described as resulting from excessive fat delivery to the liver, increased hepatic lipogenesis, reduced hepatic fat excretion, or reduced hepatic fat oxidation.

Fig 7

Timeline summarising the evolution of fatty liver knowledge.