Reactive human bile ductules express parathyroid hormone‐related peptide

Abstract

Various cholestatic liver diseases as well as regeneration after submassive necrosis are accompanied by a striking increase in the number of bile ductules. These reactive bile ductules are thought to arise either from proliferation of pre-existing bile ductules or bile ductule-related facultative stem cells, or from ductular metaplasia of hepatocytes. Recently, we found that reactive bile ductules display neuro-endocrine features, and speculated that the substance(s), produced in the neuro-endocrine granules, might play a role in their growth and/or differentiation through an autocrine or paracrine pathway. Parathyroid hormone-related peptide has been shown to be encoded by a growth factor-regulated gene that may play a role in cell growth and differentiation. We studied the immunohistochemical expression of this peptide in human liver, including three normal biopsies, 11 cases of cholestatic liver disease, six cases of focal nodular hyperplasia and three cases of regenerating liver. In regenerating liver, primary biliary cirrhosis, primary sclerosing cholangitis and partial or intermittent obstruction, the majority of reactive ductular cells expressing neuro-endocrine markers also expressed parathyroid hormone-related peptide. In focal nodular hyperplasia, a smaller number of bile ductular cells expressed the peptide. These findings suggest that parathyroid hormone-related peptide is localized in bile ductular cells and may indicate a role for this hormone in the growth and/or differentiation of human reactive bile ductules.

Comparison of liver progenitor cells in human atypical ductular reactions with those seen in experimental models of liver injury

“…148 It is hypothesized that bile acids may stimulate growth of primitive liver ''stem'' cells, while also promoting differentiation of more mature liver and bile duct cells. 149 The detection of neuroendocrine markers, such as parathyroid hormonerelated peptide, 47,150 in biliary cells indicates that reactive bile ductular cells may have an autocrine or paracrine effect in the control of liver cell proliferation and differentiation, 47 perhaps controlling the expression of the biliary phenotype. 150 Atypical ductular cells may also contribute factors, such as TGF-␤, that lead to transformation of perisinusoidal Ito cells into myofibroblasts [151][152][153] and the eventual development of fibrosis leading to cirrhosis.…”

“…149 The detection of neuroendocrine markers, such as parathyroid hormonerelated peptide, 47,150 in biliary cells indicates that reactive bile ductular cells may have an autocrine or paracrine effect in the control of liver cell proliferation and differentiation, 47 perhaps controlling the expression of the biliary phenotype. 150 Atypical ductular cells may also contribute factors, such as TGF-␤, that lead to transformation of perisinusoidal Ito cells into myofibroblasts [151][152][153] and the eventual development of fibrosis leading to cirrhosis. 21 During fetal development in animals [154][155][156][157][158][159][160][161][162] and humans, 7,163-167 bile ducts and hepatocytes both originate from a common ''bipolar'' hepatoblast.…”

Liver stem cells: when the going gets tough they get going

“…In man, PTHrP is expressed in reactive bile ductules of cholestatic and regenerating liver (Roskams et al 1993a), as well as by cholangiocarcinomas (Roskams et al 1993b). As growth factors such as EGF can rapidly induce PTHrP synthesis in cultured ductular cells, PTHrP could be a member of the early response gene family, and the peptide may have an autocrine role in bile ductular reactions (Roskams et al 1995).…”

The amazing universe of hepatic microstructure†

“…95,96 The early, transient expression of the extracellular matrix component tenascin showed that ductular reaction represents a pacemaker for progressive fibrosis in chronic cholestasis, analogous to the fibrosis-inducing role of interface hepatitis in chronic inflammation. 97,98 The study by Dr. Vanstapel and colleagues on S100 protein in ductules, 99 and the results by Dr. Roskams and colleagues on ductular expression of neuroendocrine markers 100,101 (Fig. 8) focused more on type III ductular reaction, emphasizing the existence in human liver of progenitor cells [100][101][102] with a multidrugresistant phenotype, which is of high importance in regeneration and carcinogenesis.…”

“…97,98 The study by Dr. Vanstapel and colleagues on S100 protein in ductules, 99 and the results by Dr. Roskams and colleagues on ductular expression of neuroendocrine markers 100,101 (Fig. 8) focused more on type III ductular reaction, emphasizing the existence in human liver of progenitor cells [100][101][102] with a multidrugresistant phenotype, which is of high importance in regeneration and carcinogenesis. 103,104 Further investigations by Dr. Roskams's team revealed expression of neuroendocrine markers in coproliferating hepatic stellate cells as well, leading to the concept of a neuroendocrine compartment in the liver and its neuroregulation.…”