This review focuses on the hypothesis that biliary HCO 3− secretion in humans serves to maintain an alkaline pH near the apical surface of hepatocytes and cholangiocytes to prevent the uncontrolled membrane permeation of protonated glycine‐conjugated bile acids. Functional impairment of this biliary HCO 3− umbrella or its regulation may lead to enhanced vulnerability of cholangiocytes and periportal hepatocytes toward the attack of apolar hydrophobic bile acids. An intact interplay of hepatocellular and cholangiocellular adenosine triphosphate (ATP) secretion, ATP/P2Y‐ and bile salt/TGR5‐mediated Cl−/ HCO 3− exchange and HCO 3− secretion, and alkaline phosphatase–mediated ATP breakdown may guarantee a stable biliary HCO 3− umbrella under physiological conditions. Genetic and acquired functional defects leading to destabilization of the biliary HCO 3− umbrella may contribute to development and progression of various forms of fibrosing/sclerosing cholangitis. (HEPATOLOGY 2010)

Human cholangiocytes are continuously exposed to millimolar levels of hydrophobic bile salt monomers. We recently hypothesized that an apical biliary HCO À 3 umbrella might prevent the protonation of biliary glycine-conjugated bile salts and uncontrolled cell entry of the corresponding bile acids, and that defects in this biliary HCO À 3 umbrella might predispose to chronic cholangiopathies. Here, we tested in vitro whether human cholangiocyte integrity in the presence of millimolar bile salt monomers is dependent on (1) pH, (2) adequate expression of the key HCO À 3 exporter, anion exchanger 2 (AE2), and (3) an intact cholangiocyte glycocalyx. To address these questions, human immortalized cholangiocytes and cholangiocarcinoma cells were exposed to chenodeoxycholate and its glycine/taurine conjugates at different pH levels. Bile acid uptake was determined radiochemically. Cell viability and apoptosis were measured enzymatically. AE2 was knocked down by lentiviral short hairpin RNA. A cholangiocyte glycocalyx was identified by electron microscopy, was enzymatically desialylated, and sialylation was quantified by flow cytometry. We found that bile acid uptake and toxicity in human immortalized cholangiocytes and cholangiocarcinoma cell lines in vitro were pH and AE2 dependent, with the highest rates at low pH and when AE2 expression was defective. An apical glycocalyx was identified on cholangiocytes in vitro by electron microscopic techniques. Desialylation of this protective layer increased cholangiocellular vulnerability in a pH-dependent manner. Conclusion: A biliary HCO À 3 umbrella protects human cholangiocytes against damage by bile acid monomers. An intact glycocalyx and adequate AE2 expression are crucial in this process. Defects of the biliary HCO À 3 umbrella may lead to the development of chronic cholangiopathies.

The recent addition of immunoglobulin (Ig)G4-associated cholangitis (IAC), also called IgG4-related sclerosing cholangitis (IRSC), to the spectrum of chronic cholangiopathies has created the clinical need for reliable methods to discriminate between IAC and the more common cholestatic entities, primary (PSC) and secondary sclerosing cholangitis. The current American Association for the Study of Liver Diseases practice guidelines for PSC advise on the measurement of specific Ig (sIg)G4 in PSC patients, but interpretation of elevated sIgG4 levels remains unclear. We aimed to provide an algorithm to distinguish IAC from PSC using sIgG analyses. We measured total IgG and IgG subclasses in serum samples of IAC (n = 73) and PSC (n = 310) patients, as well as in serum samples of disease controls (primary biliary cirrhosis; n = 22). sIgG4 levels were elevated above the upper limit of normal (ULN = >1.4 g/L) in 45 PSC patients (15%; 95% confidence interval [CI]: 11-19). The highest specificity and positive predictive value (PPV; 100%) for IAC were reached when applying the 4× ULN (sIgG4 > 5.6 g/L) cutoff with a sensitivity of 42% (95% CI: 31-55). However, in patients with a sIgG4 between 1× and 2× ULN (n = 38/45), the PPV of sIgG4 for IAC was only 28%. In this subgroup, the sIgG4/sIgG1 ratio cutoff of 0.24 yielded a sensitivity of 80% (95% CI: 51-95), a specificity of 74% (95% CI: 57-86), a PPV of 55% (95% CI: 33-75), and a negative predictive value of 90% (95% CI: 73-97). Conclusion: Elevated sIgG4 (>1.4 g/L) occurred in 15% of patients with PSC. In patients with a sIgG4 >1.4 and <2.8 g/L, incorporating the IgG4/IgG1 ratio with a cutoff at 0.24 in the diagnostic algorithm significantly improved PPV and specificity. We propose a new diagnostic algorithm based on IgG4/IgG1 ratio that may be used in clinical practice to distinguish PSC from IAC. (Hepatology 2014;59:1954–1963)

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BACKGROUND: Racial differences in the treatment of men with localized prostate cancer remain poorly understood. This study examines whether hospital racial composition is associated with the type of treatment black and white men receive. METHODS: The authors performed a retrospective cohort study of men in Surveillance, Epidemiology, and End Results‐Medicare diagnosed with localized prostate cancer from 1995 to 2005 linked to hospital and census data. A total of 134,291 men were assigned to the hospital where they received care. Generalized estimating equations were used to determine whether hospital racial composition was associated with the receipt of definitive therapy and type of treatment. RESULTS: Black men were less likely to receive radiation and/or prostatectomy compared with white men (55.5% vs 63.7%, P < .001) and, among those who received definitive therapy, were less likely to undergo prostatectomy (27.5% vs 31.9%, P < .001). The percentage of black men who received their care at hospitals with a high proportion of black patients was 48.0%, compared with only 5.2% of white patients who received care in this subset of hospitals. Men were significantly less likely to receive definitive treatment (odds ratio, 0.81; 95% confidence interval, 0.74‐0.90) in hospitals with a high proportion of black patients compared with men seen at hospitals with fewer black patients. The association between hospital racial composition and treatment did not significantly differ by patient race. CONCLUSIONS: Hospital racial composition is consistently associated with the care that men receive for localized prostate cancer. Better understanding of the factors that determine where men receive care is an important component in reducing variation in treatment. Cancer 2011;. © 2011 American Cancer Society.

Immunoglobulin G4 (IgG4)‐related disease (IgG4‐RD) of the biliary tree and pancreas is difficult to distinguish from sclerosing cholangitis and biliary/pancreatic malignancies (CA). An accurate noninvasive test for diagnosis and monitoring of disease activity is lacking. We demonstrate that dominant IgG4+ B‐cell receptor (BCR) clones determined by next‐generation sequencing accurately distinguish patients with IgG4‐associated cholangitis/autoimmune pancreatitis (n = 34) from those with primary sclerosing cholangitis (n = 17) and CA (n = 17). A novel, more affordable, and widely applicable quantitative polymerase chain reaction (qPCR) protocol analyzing the IgG4/IgG RNA ratio in blood also achieves excellent diagnostic accuracy (n = 125). Moreover, this qPCR test performed better than serum IgG4 levels in sensitivity (94% vs. 86%) and specificity (99% vs. 73%) and correlates with treatment response (n = 20). Conclusions: IgG4+ BCR clones and IgG4/IgG RNA ratio markedly improve delineation, early diagnosis, and monitoring of IgG4‐RD of the biliary tree and pancreas. (Hepatology 2016;64:501‐507)

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Focal nodular hyperplasia (FNH) and hepatic adenoma (HA) represent the most frequent non-vascular benign liver tumors. They are often asymptomatic. The widespread use of high-resolution imaging modalities leads to an increase of incidental detection of FNH and HA. Physicians are thus increasingly confronted with these formerly rarely recognized conditions, stressing the need for concise but adequate information on the optimal clinical strategies for these patients. FNH is the most common non-vascular benign tumor of the liver. It probably arises as a polyclonal, hyperplastic response to a locally disturbed blood flow. It is typically found in asymptomatic women. Histologically, FNH can be described as a focal form of cirrhosis. Complications of FNH are extremely rare and surgical resection is generally not advised. HA is a rare monoclonal, but benign liver tumor primarily found in young females using estrogen-containing contraceptives. Although its exact etiology is unknown, a direct link between sex steroid exposure and the uncontrolled hepatocellular growth is suspected. Complications of HA are spontaneous bleeding and malignant transformation. Withdrawal of estrogen treatment and excision of large tumors (>5 cm) are established therapeutic strategies. In conclusion, although FNH and HA are reasonably well-described clinical and histopathological entities, their epidemiology and pathophysiology need to be further unraveled.