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.

The cytoplasmic hepatocyte inclusions, Mallory-Denk bodies (MDBs), are characteristic of several liver disorders, including alcoholic and nonalcoholic steatohepatitis. In mice, MDBs can be induced by long-term feeding with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) for 3 to 4 months or rapidly reformed in DDC-induced then recovered mice by DDC refeeding or exposure to a wide range of toxins for only 5 to 7 days. The molecular basis for such a rapid reinduction of MDBs is unknown. We hypothesized that protein changes retained after DDC priming contribute to the rapid MDB reappearance and associate with MDB formation in general terms. Two-dimensional differential-in-gel-electrophoresis coupled with mass spectrometry were used to characterize protein changes in livers from the various treatment groups. The alterations were assessed by real-time reverse-transcription polymerase chain reaction and confirmed by immunoblotting. DDC treatment led to pronounced charged isoform changes in several chaperone families, including Hsp25, 60, 70, GRP58, GRP75, and GRP78, which lasted at least for 1 month after discontinuation of DDC feeding, whereas changes in other proteins normalized during recovery. DDC feeding also resulted in altered expression of Hsp72, GRP75, and Hsp25 and in functional impairment of Hsp60 and Hsp70 as determined using a protein complex formation and release assay. The priming toward rapid MDB reinduction lasts for at least 3 months after DDC discontinuation, but becomes weaker after prolonged recovery. MDB reinduction parallels the rapid increase in p62 and Hsp25 levels as well as keratin 8 cross-linking that is normally associated with MDB formation. Conclusion: Persistent posttranslational modifications in chaperone proteins, coupled with protein cross-linking and altered chaperone expression and function likely contribute to the "toxic memory" of DDC-primed mice. We hypothesize that similar changes are important contributors to inclusion body formation in several diseases. (HEPATOLOGY 2008;48:931-942.)

Dental extraction is probably safe for patients with thrombocytopenia: the standard of care is a guide for clinical decision making related to platelet transfusion. Phillip SoWayne State University School of Medicine, phillip.cj.so@gmail.com Recommended Citation So P. Dental extraction is probably safe for patients with thrombocytopenia: the standard of care is a guide for clinical decision making related to platelet transfusion.

Background In the USA, uncontrolled hypertension contributes to 1000 deaths a day. However, little is known about the quality of hypertension management in family medicine resident clinics. Objectives To examine rates of documentation and treatment of elevated blood pressure, and to identify missed opportunities to address hypertension. Study design A cross-sectional chart review of 1011 adult patient visits between 2 January and 4 February 2013 was performed in a resident-run federally qualified health centre. For patients with elevated blood pressure at time of visit, we noted whether or not the residents had documented a diagnosis or discussion of hypertension and the presence or absence of a treatment plan. We compared these rates with those from a national sample of primary care physicians. Results 262/1011 (26%) of adult patients had elevated blood pressure at time of visit. Of those, 115/262 (44%) had documentation and a plan for treatment, 79/262 (30%) had documentation but no plan, and 68/262 (26%) had neither documentation nor plan. Nationally, 45% of patients are diagnosed and treated compared with 44% of study visits with documentation and treatment. Conclusions Fewer than half of visits of patients with elevated blood pressure resulted in both documentation and a treatment plan. Nevertheless, these rates are comparable to national providers. Elevated blood pressure was more likely to be missed during acute visits and in patients with less elevated blood pressure.