Keratin polypeptides 8 and 18 (K8/K18) are the cytoskeletal intermediate filament proteins of hepatocytes while K8/K18/K19 are the keratins of hepatobiliary ductal cells. Hepatocyte K8/K18 are highly abundant and behave as stress proteins with injury-inducible expression. Human association studies show that K8/K18 germline heterozygous mutations predispose to end-stage liver disease of multiple etiologies (Ϸ3 fold increased risk), and to liver disease progression in patients with chronic hepatitis C infection. These findings are supported by extensive transgenic mouse and ex vivo primary hepatocyte culture studies showing that K8 or K18 mutations predispose the liver to acute or subacute injury and promote apoptosis and fibrosis. Mutation-associated predisposition to liver injury is likely related to mechanical and nonmechanical keratin functions including maintenance of cell integrity, protection from apoptosis and oxidative injury, serving as a phosphate sponge, regulation of mitochondrial organization/function and protein targeting. These functions are altered by mutationinduced changes in keratin phosphorylation, solubility and filament organization/reorganization. Keratins are also the major constituents of Mallory-Denk bodies (MDBs). A toxin-induced K8>K18 ratio, and keratin crosslinking by transglutaminase-2 play essential roles in MDB formation. Furthermore, intracellular or cell-released K18 fragments, generated by caspase-mediated proteolysis during apoptosis serve as markers of liver injury. Therefore, K8 and K18 are cytoprotective stress proteins that play a central role in guarding hepatocytes from apoptosis. Keratin involvement in liver disease is multi-faceted and includes modulating disease progression upon mutation, formation of MDBs in response to unique forms of injury, and serving as markers of epithelial cell death. (HEPATOLOGY 2007; 46:1639-1649.)

BACKGROUND & AIMS Keratins 8 and 18 (K8/K18) provide anti-apoptotic functions upon liver injury. The cytoprotective function of keratins explains the over-representation of K8/K18 variants in patients with cirrhosis. However, K8/K18 variant-associated susceptibility to acute liver injury, which is well-described in animal models, has not been studied in humans. METHODS We analyzed the entire coding regions of the KRT8 and KRT18 genes (15 total exons and their exon-intron boundaries) to determine the frequency of K8/K18 variants in 344 acute liver failure (ALF) patients (49% acetaminophen-related) and two control groups [African-Americans (245 subjects) and previously-analyzed Caucasians (727 subjects)]. RESULTS There were 45 ALF patients with significant amino-acid-altering K8/K18 variants including 23 with K8 R341H and 11 with K8 G434S. K8 variants were significantly more common (total of 42 patients) than K18 variants (3 patients) (p<0.001). We found an increased frequency of variants in Caucasian ALF patients (9.1%) versus controls (3.7%) (p=0.01). K8 R341H was more common in Caucasian (p=0.01) and G434S was more common in African-American (p=0.02) ALF patients versus controls. Furthermore, Caucasians with K8/K18 variants were less likely to survive ALF without transplantation (p=0.02). K8 A333A and G434S variants associated exclusively with African-Americans (23% combined frequency in African-American but none in Caucasian controls; p<0.0001), while overall K18 variants were more common in non-Caucasian liver disease subjects compared to Caucasians (2.8% versus 0.6%, respectively, p=0.008). CONCLUSIONS KRT8 and KRT18 are important susceptibility genes for ALF development. The presence of K8/K18 variants predisposes to an adverse ALF outcome, and some variants segregate with unique ethnic/race backgrounds.

No abstract

No abstract