Faculty Bibliography

Ductular reaction (DR) is observed in virtually all liver diseases in both humans and rodents. Depending on the injury, DR is confined within the periportal area or invades the parenchyma. On severe hepatocellular injury, invasive DR has been proposed to arise for supplying the liver with new hepatocytes. However, experimental data evidenced that DR contribution to hepatocyte repopulation is at the most modest, unless replicative capacity of hepatocytes is abrogated. Herein, we proposed that invasive DR could contribute to operating hepatobiliary junctions on hepatocellular injury. We used the choline-deficient ethionine-supplemented mouse model of hepatocellular injury and human liver samples to evaluate the hepatobiliary junctional role of the invasive form of DR. We showed that choline-deficient ethionine-supplemented-induced DR expanded as biliary epithelium into the lobule and established new junctions with the canaliculi. By contrast, no new ductular-canalicular junctions were observed in mouse models of biliary obstructive injury exhibiting noninvasive DR. Similarly, in humans, an increased number of hepatobiliary junctions were observed in hepatocellular diseases (viral, drug induced, or metabolic) in which DR invaded the lobule but not in biliary diseases (obstruction or cholangitis) in which DR was contained within the portal mesenchyme. In conclusion, our data in rodents and humans support that invasive DR plays a hepatobiliary junctional role to maintain structural continuity between hepatocytes and ducts in disorders affecting hepatocytes.

Idiopathic non-cirrhotic portal hypertension (INCPH) is a rare vascular liver disease that has attained a new interest in recent years. It is characterized by clinical signs of portal hypertension in the absence of cirrhosis or severe fibrosis and any known cause of portal hypertension. Since much uncertainty exists about INCPH pathophysiology and no definite diagnostic tests are available, liver biopsy is an essential tool to achieve a definite diagnosis. Unfortunately, the histological diagnosis of INCPH is not always straightforward, since the characteristic lesions are unevenly distributed, vary greatly in their severity and are often very subtle, and not all are necessarily present in a single case. Furthermore, specifically for the characteristic portal vessel changes observed in INCPH, the terminology and definition is ambiguous, which adds complexity to the already complex clinical-pathological scenario. An international study group of liver pathologists and hepatologists pursued a consensus on nomenclature for the portal vascular lesions of INCPH. Such standardization may assist pathologists in the recognition of such lesions and will possibly facilitate further advancement in this field.

BACKGROUND & RATIONALE/OBJECTIVE:High-mobility group box-1 (HMGB1) is a damage-associated molecular pattern (DAMP) increased in response to liver injury. Since HMGB1 is a ligand for the receptor for advanced glycation end-products (RAGE), we hypothesized that induction of HMGB1 could participate in the pathogenesis of liver fibrosis via RAGE cell-specific signaling mechanisms. RESULTS:) and RAGE neutralization prevented liver fibrosis. Lastly, we identified that HMGB1 stimulated HSC migration and signaled via RAGE to upregulate Collagen type I expression by activating the pMEK1/2/pERK1/2/pcJun signaling pathway. CONCLUSION/CONCLUSIONS:hepatocyte and KC-derived HMGB1 participates in the pathogenesis of liver fibrosis by signaling via RAGE in HSC to activate the pMEK1/2/pERK1/2/pcJun pathway and increase Collagen type I deposition.

In this new era of successful long term suppression of hepatitis B viral replication and consistent eradication of hepatitis C virus the necessity for routine pre-treatment biopsies has often been eliminated. Thus, whether there is utility to perform liver biopsy in chronic viral hepatitis is undergoing re-examination. In response to these changing needs, we have developed a new staging system, the Beijing Classification, for assessment of biopsy specimens from patients with chronic viral hepatitis. The most important novelty of the Beijing Classification is that it includes not only extent (stage) of fibrosis, but the quality of fibrosis, namely if the specimen shows predominantly regressive vs. progressive features (or is indeterminantly balanced between the two), the P-I-R score. This histologic distinction between regressive and progressive fibrosis, while invoked in this particular setting of chronic viral hepatitis, may have applicability to all forms of chronic liver disease. Thus, the review contains a description of the concepts of regression and progression with the aim of empowering pathologists to apply them in histopathologic-clinical correlation research as well as in the specific clinical setting for which it was developed. Also, in light of changing clinical needs, grading of necroinflammatory activity and staging of fibrosis are simplified into three point scales. These simplifications should aid the general diagnostic pathologist in being comfortable and confident in assessing biopsy specimens as the criteria for their distinction are far more precise, with significantly reduced "gray zones" of prior grading/staging systems.

Cirrhosis has been traditionally viewed as an irreversible, end-stage condition. Eighteen years ago, Wanless, Nakashima, and Sherman published a study that was based on the concept that hepatic architecture is under constant remodeling in the course of chronic liver diseases, even during their most advanced stages; depending on the balance between injury and repair, the histologic changes might be progressing or regressing. These authors described in detail the morphologic features of regressing cirrhosis, identified a set of histologic features of regression that they called the "hepatic repair complex," and provided convincing morphologic evidence that incomplete septal cirrhosis represents regressed cirrhosis. In the years that followed publication of this pioneering article, a number of clinical studies with performance of pre- and post-treatment liver biopsies provided abundant evidence that cirrhosis can regress after successful therapy of chronic hepatitis B, chronic hepatitis C, autoimmune hepatitis, and genetic hemochromatosis. Evidence for other chronic liver diseases may also be provided in the future, pending ongoing studies. Successful therapy allows resorption of fibrous septa, which can be followed by loss of nodularity and architectural improvement; however, many vascular lesions of cirrhotic livers are not thought to regress. Cases of cirrhosis that are considered more likely to improve than others include those of recent onset, with relatively thin fibrous septa and mild vascular changes. Histologic examination of liver biopsy specimens from patients with chronic liver diseases provides the opportunity to appreciate the features of the hepatic repair complex on a routine diagnostic basis; however, interpretation is often difficult, and can be aided by immunohistochemical stains. Clinicopathologic correlation is essential for a meaningful assessment of such cases. For many patients, cirrhosis is not an end-stage condition anymore; therefore, use of the term "cirrhosis" has been challenged, almost 200 years after its invention. However, regression of cirrhosis does not imply regression of molecular changes involved in hepatocarcinogenesis; therefore, surveillance for hepatocellular carcinoma should be continued in these patients.

Primary liver carcinomas with both hepatocytic and cholangiocytic differentiation have been referred to as "combined (or mixed) hepatocellular-cholangiocarcinoma." These tumors, although described over 100 years ago, have attracted greater attention recently because of interest in possible stem cell origin and perhaps because of greater frequency and clinical recognition. Currently, due to lack of common terminology in the literature, effective treatment and predictable outcome data have been challenging to accrue. This paper represents a consensus document from an international community of pathologists, radiologists, and clinicians who have studied and reported on these tumors and recommends a working terminology for diagnostic and research approaches for further study and evaluation. It is recommended that diagnosis is based on routine histopathology with hematoxylin and eosin; immunostains are supportive, but not essential for diagnosis. FOOTNOTE AT END OF ABSTRACT* The authors of this manuscript met in November 2015 and 2016 at the initiative of Drs. Theise and Brunt. The term combined HCC-CCA (cHCC-CCA) was agreed upon.