Parenchymal innervation of normal and cirrhotic human liver: a light and electron microscopic study using monoclonal antibodies against the neural cell-adhesion molecule.

Abstract

Hepatic innervation participates in the control of sinusoidal blood flow and in the regulation of certain metabolic functions of the liver. The study of the distribution of hepatic nerves has been hampered by the lack of adequate markers. We therefore tested the value of the neural cell-adhesion molecule (NCAM) as a probe for the study of parenchymal nerves in the normal and cirrhotic human liver. Four antibodies against various epitopes of NCAM were tested by light and electron microscopic immunohistochemistry: Leu19, ERIC-1, VC1.1, and HNK-1. Their reactivity was compared with that of antibodies against the following neural cell markers: S100 protein, neurofilaments, and neuron-specific enolase (NSE). The tissue reactivity of anti-NCAM antibodies was variable, suggesting a microheterogeneity of the NCAM molecule in the normal liver. Clones Leu19 and ERIC-1 proved to be the most sensitive of the anti-NCAM antibodies. Their sensitivity was superior to that of the antibodies directed against the other neural cell markers tested. In the normal liver, both Leu19 and ERIC-1 demonstrated a heterogeneous distribution of nerve fibers inside the hepatic lobule. Intralobular nerve fibers predominated in Zone 1. This might contribute to the constitution of distinct zonal microenvironments inside the hepatic lobule. In cirrhosis, no nerve fiber was detected inside parenchymal nodules; no nerve plexus was visible at the contact of proliferating neoductules. These alterations might contribute to the pathogenesis of the hemodynamic and metabolic disorders observed in cirrhosis.

Ontogeny of human intrahepatic innervation

“…PGP9.5-, NSE-, synaptophysin, S-100 and N-CAM-immunoreactive nerve fibers were identified in hepatic acini, along sinusoidal walls, in the space of Disse and in the walls of a few terminal hepatic veins. The intra-acinar distribution of nerve fibers was denser in zone 1 in accordance with previous studies [22,29]. The close relationship of intra-acinar nerve fibers with hepatocytes may reflect their influence in the regulation of carbohydrate and lipid metabolism [26], while nerve fiber distribution in portal tracts is likely related to their hemodynamic actions [20].…”

“…While rat and mouse livers have only limited intrasinusoidal innervation, the livers of man and guinea pig show rich intra-acinar innervation [3,4,13,14,19,20]. In human adult liver, afferent and efferent nerve aminergic and peptidergic fibers are distributed unevenly in the acini running along the sinusoidal walls, predominating in the periportal region [29] but also extending to the terminal hepatic venules [4]. Nerve fibers are identified within the space of Disse, between hepatocytes and in close contact with perisinusoidal, endothelial and Kupffer cells [3,4,20].…”

Negative feedforward control of body fluid homeostasis by hepatorenal reflex

“…Immunohistochemical studies have shown that the nerve fibers in the liver parenchyma are reduced or nearly completely absent in cirrhotic liver disease, whereas the nerve fibers in the portal tracts and fibrous septae remain prominent. [74][75][76] These observations are consistent with an impaired Na + -sensitive hepatorenal reflex, but are not consistent with hepatorenal-baroreflex-induced excitation of renal sympathetic nerve activity, because Figure 8 Responses of renal sympathetic nerve activity and urinary Na + excretion to high-NaCl food intake (20 g kg À1 boiled rice containing 0.4 g kg À1 body weight NaCl) given at time 0. Control: sham-operated control dogs.…”

Expression of neural cell adhesion molecule (N-CAM) in perisinusoidal stellate cells of the human liver

“…Previous immunohistological studies using human liver specimens have shown that N-CAM is positive in nerve fibers, NK cells, and proliferating bile ductules (Roskams et al 1990;Scoazec et al 1993;Volpes et al 1993).…”

“…In the liver, N-CAM-positive structures thus far known are nerve fibers and NK cells (Scoazec et al 1993). Nerve fibers are distributed in the portal area and in the liver lobule, making synapses with perivascular smooth muscle cells, stellate cells, and hepatocytes (Bioulac-Sage et al 1990).…”