The cytoskeleton comprises three filamentous systems: microfilaments, intermediate filaments, and microtubules. In epithelial cells, type I keratins such as keratin 18 (KRT18) and type II keratins such as keratin 8 (KRT8) polymerise to form the intermediate filaments. KRT18 and KRT8 represent the major keratins expressed in single-layered epithelia of the gastrointestinal tract including liver and pancreas.¹

Animal studies suggest KRT8 and KRT18 have a hepatoprotective role against mechanical and toxic injury.² Transgenic mice overexpressing mutant KRT18 display fragile hepatocytes with disrupted cytoskeleton filaments.³ These mice developed chronic hepatitis and were more susceptible to liver injury in comparison to mice overexpressing wild type KRT18.⁴ The viability of KRT8 null mice depends on the genetic background of the different mouse strains suggesting further genetic factors contribute to the resultant phenotype. For instance, in one mouse strain KRT8-deficient mice died during embryonic development due to extensive liver haemorrhage.⁵ However, in another strain 55% of the KRT8-deficient mice had a normal life expectancy but developed signs of inflammatory bowel disease and in some cases a mild inflammation of the liver.⁶ A recent report emphasises the importance of Keratin 8 for the formation of an intact placental barrier function for the viability of KRT8-deficient embryos. These findings argue in favour of an extraembryonic defect responsible for lethality of these embryos.⁷ Furthermore, KRT8 null mice showed an abnormal histological liver architecture and were more vulnerable to liver damage after exposure to hepatotoxic substances compared to wild type mice.^8–10

The above mentioned results support the hypothesis that keratin mutations might predispose humans to liver disease. Indeed, Ku et al described an association between two KRT8 mutations and cryptogenic cirrhosis. A heterozygous single base substitution involving a Gly to Cys at codon 62 (G62C) was found …