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.

INTRODUCTION/BACKGROUND:"Acute-on-Chronic-Liver Failure (ACLF)" entered hepatology practice by the end of the 20th century. Although we lack precise and universally agreed definitions, acute decompensation of chronic liver disease with jaundice and deranged clotting, multi-organ failure and high, short-term mortality are hallmarks of the syndrome. Timely recognition and and treatment, including urgent liver transplantation, may save the life of certain patients. The diagnosis and management are mostly based on clinical features, but some have suggested to incorporate histopathology (liver biopsy). This may add to the differentiation between acute and chronic disease, primary and concomitant etiologies, and identify prognostic determinants. Areas covered. A review of the literature on ACLF and the outcome of the discussions at a topical international meeting on specific histopathological aspects of diagnosis and prognosis of the syndrome. Expert commentary. There is a lack of standardized descriptions of histopathological features and there is limited prospective experience with the role of pathology of ACLF. It is important for the clinical hepatologist to understand the potential and limitations of (transjugular) liver biopsy in ACLF and for the pathologist to help address the clinical question and recognise the histopathological features that help to characterize ACLF, both in terms of diagnosis and prognosis.

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.

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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.