Innervation of the Liver: Morphology and Function

Liver 1996: 16: 151-160 Printed in Denmark. All rights reserved

Copyright 0 Munksgaard 1996

LIVER ISSN 0106-9543

Invited Review

Innervation of the liver: morphology and function

Tiniakos DG, Lee JA, Burt AD. Innervation of the liver: morphology and function. Liver 1996: 16: 151-160. 0 Munksgaard, 1996

Abstract: Although it has been known for many years that the liver receives a nerve supply, it is only with the advent of immunohistochemistry that this innervation has been analysed in depth. It is now appreciated not only that many different nerve types are present, but also that there are significant differences between species, especially in the degree of parenchymal innervation. This has stimulated more detailed investigation of the innervation of the human liver in both health and disease. At the same time, functional studies have been underlining the important roles that these nerves play in processes as diverse as osmoreception and liver regeneration. This article briefly reviews current understanding of the morphology and functions of the hepatic nerve supply.

That the liver receives an innervation was known to the Roman physician Galen. He described the hepatic division of the vagus nerve as “a very small nerve inserted into the liver”. He explained that the nerve was small “because the liver does not move like a muscle or need extra sensation like the intestine” (1). It is only during the last few decades that research in “neuro-hepatology” (2) has indicated that he was wrong on both accounts.

In most mammalian species, large nerve bundles can be identified at the hilum of the liver forming two separate but intercommunicating plexuses in close apposition to the portal vein and the hepatic artery (3). These bundles contain sympathetic fibres from T7-TlO via the coeliac ganglia, and parasympathetic nerves from posterior and anterior vagi; in some species parasympathetic fibres may also be derived from the right phrenic nerve. The nerve plexuses also contain afferent nerves, the projections of which have been well documented in the rat using the techniques of retrograde and anterograde tracing (4, 5) . The possibility of an enterohepatic nerve plexus has recently been raised (6), but the anatomical basis for this remains to be determined.

A large number of physiological and pharmaco- logical studies have indicated that the motor (effer-

0. G. Tiniakos’, J. A. Lee2 and A. 0. Burt3 ‘Department of Pathology, University of Patras, Greece, ‘Department of Pathology, University of Sheffield, UK, and 3Department of Pathology, University of Newcastle upon Tyne, UK

Key words: liver - nerves - innervation Prof. A. D. Burt, Department of Pathology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK Received 19 September, accepted for publication 1 22 November 1995

ent) innervation plays important roles in intrahepatic haemodynamic and bile flow regulation (7- lo), control of carbohydrate and lipid metabolism (7, 8, 11-15), and parenchymal cell regeneration (16-19), while the sensory (afferent) supply may be involved in osmoreception, ionoreception, barore- ception and in the control of hepatic metabolic receptors (20-30). However, the intrahepatic distribution of the different nerve fibre types has been con- troversial. The purpose of this review is to summa- rize the findings of morphological studies of hepatic innervation and to consider structure-function rela- tionships.

lntrahepatic innervation: animal livers

Several early investigators used metal impregnation methods (gold, silver or osmium-based histochemical techniques) to study the distribution of intrahepatic fibres. Pfluger (31) was the first to suggest that nerves may be present within the liver sinusoids, di- rectly innervating parenchymal cells. When Kupffer (32) stumbled upon his stellate cells using gold chloride, his initial intention had been to identify nerve fibres. In contrast to Pfliiger, he and others (33) were unable to identify any intra-sinusoidal

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nerves. However, several investigators subsequently supported the observations of Pfliiger (34,354. It is likely that these disparate results were due to lack of sensitivity and specificity of the methods used for the demonstration of nerve fibres; for example, several of the metal compounds applied are now known to bind to extracellular matrix components.

More convincing evidence in favour of the presence of intra-sinusoidal nerve fibres came from scanning (36, 37) and transmission electron microscopic studies (37, 38). However, neither metal impregnation methods nor electron microscopy could establish the precise nature of such fibres.

Histochemical studies

Early studies dealing with the topography of sympathetic innervation in mammalian liver used one of two fluorescence histochemical methods to identify adrenergic nerves: (i) the Falck-Hillarp technique (39) and (ii) the glyoxylic-acid technique (40). Both methods are accepted as being capricious and their specificity and sensitivity have been questioned by some authors (4 1). The catecholamine neurotransmitters are present within dense core vesicles which can be seen along the length of post-ganglionic sympathetic axons, but which are found in greatest abundance within varicosities close to nerve terminals. The enzymes responsible for production of noradrenaline are synthesized within neuronal cell bodies and transported to terminal varicosities by axoplasmic flow (42).

Ungviry & Donith were the first to apply fluorescence histochemistry to study hepatic innervation (43). Using the Falck-Hillarp technique, they identified catecholamine-containing nerve fibres within portal tracts of dogs, cats, guinea-pigs, rats and mice. However, they failed to demonstrate any intra- sinusoidal fibres, even in animals pre-treated with the mono-amine oxidase inhibitor nialamide to en- hance catecholamine accumulation in peripheral nerves. Skarring & Bierring (36) and Reilly et al. (44) were also unable to identify intra-sinusoidal sympathetic nerves in rat liver using both the Falck- Hillarp and glyoxylic acid methods. However, Anu- friev et al. (45) demonstrated adrenergic fibres along sinusoidal walls in guinea-pig liver, an observation subsequently confirmed by others (46-48). Intra-sinusoidal fibres were not identified in the livers of cats, dogs or rats. Further evidence in favour of in- ter-species variation in the distribution of intrahepatic nerves was provided by Mogimzadeh et al. (47) who demonstrated considerable variation in the levels of chemically detectable noradrenaline between different animals; the biochemical results cor- related well with their histochemical observations.

lmmunohistochemical studies

The development of immunohistochemical techniques has led to a considerable advance in our abil- ity to detect and characterize specific types of nerves in the liver. Burt et al. (49) identified adrenergic nerves by the demonstration of fibres containing the catecholamine synthesis enzymes, tyrosine hydroxylase (TH) and dopamine P hydroxylase (DPH). It was found that in guinea-pig and rat liver, abundant adrenergic fibres are present within portal tracts. The majority of fibres within large nerve bundles of hilar portal tracts were TH-positive suggesting that adrenergic nerves constitute the principal fibre type in mammalian liver. Adrenergic nerves were frequently observed in close apposition to hepatic artery branches, but rarely around portal vein branches or bile ducts. Dopaminergic nerves were localized around hepatic arteries in guinea pig, rat and also human liver (49,50).

Immunohistochemistry has confirmed that there are marked intra-species differences in the degree of intra-sinusoidal innervation. In rat liver, only occa- sional periportal fibres can be identified. In guinea- pig liver, however, TH-positive and DPH-positive fibres extend from the portal tracts into the parenchyma and are identified in both periportal and pe- rivenular zones as well as within the walls of hepatic vein radicles.

Many autonomic nerves contain not only classi- cal neurotransmitters but also regulatory peptides such as neuropeptide tyrosine (NPY) and its C- flanking neuropeptide C-PON, calcitonin gene-related peptide (CGRP), somatostatin, vasoactive intestinal polypeptide (VIP), enkephalin and bombe- sin (51-55); some of these peptides may act as co- transmitters. Effector nerves that are peptidergic but neither adrenergic nor cholinergic are thought to exist (56). However, NPY and C-PON are mainly found in sympathetic adrenergic fibres (51, 57) whereas VIP is thought to be associated with parasympathetic cholinergic fibres. Within the peripheral nervous system, substance P and CGRP are largely restricted to afferent sensory fibres (54,58).

NPY-positive nerves have been identified in the extrahepatic biliary tract and also in intrahepatic nerves of guinea pig, dog, monkey and human liver and C-PON has also been identified (49, 59, 60). NPY has been shown to have direct vasoconstrictor properties but it may also act as a co-transmitter, po- tentiating the effects of noradrenaline (61) and ATP, both of which are released from sympathetic nerve endings (2). In the liver, the distribution of NPY- positive and C-PON-positive fibres closely resem- bles that of TH-positive fibres (49). Also, TH and NPY can be co-localized within individual intra-si-

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Innervation of the liver

cells; Ito cells) or parenchymal cells at these sites represent synaptic clefts, although no membrane specializations have yet been identified on either hepatic stellate cells or parenchymal cells. Nobin et al. (75) also reported close contacts between nerves and Kupffer cells, but this was refuted by others (77). Since stellate cells may act as pericytes in the liver and have been shown to contract in response to a number of vasoactive agonists (79), it is possible that neural control of these cells might be involved in the regulation of sinusoidal blood flow in vivo (77). The recent observation that the isolated perfused liver can support portal pressure oscilla- tions (80) is consistent with this hypothesis, although the site (or sites) of control remains to be established.

Fluorescence histochemistry has been used in a few studies to identify adrenergic nerves in human liver (37, 39, 47). This was substantiated in further studies in which the histochemical data were supported by chemical measurements of noradrenaline showing high concentrations in human liver (75). In general, tissue noradrenaline levels correlate well with the extent of sympathetic innervation (81). Up- take of the dopamine analogue, 5-hydroxydopamine has also been demonstrated in nerve fibres at the ultrastructural level, a property believed to be restricted to sympathetic nerves (75). In their compar- ative study, Moghimzadeh et al. (47) showed that the sinusoids of humans and other primates were as densely innervated as those of the guinea-pig. Amenta et al. (82) demonstrated acetylcholineste- rase-containing fibres in human liver using the method of Kamovsky & Roots. Fibres were identified within portal tracts along sinusoidal walls; their distribution was unaltered after in vitro incubation with 6-hydroxydopamine suggesting that they are cholinergic parasympathetic fibres.

Several groups have used immunohistochemical methods to study the distribution and the nature of intrahepatic nerves in human liver. Mann et al., using antibodies to NSE and enzymes involved in the catecholamine synthesis, showed that 60% of the non- myelinated axons supplying the hepatic parenchyma and virtually all those supplying the vasculature ap- peared to be sympathetic (83). Similarly, Feher et al. (84) demonstrated NPY-containing noradrenergic perivascular nerve fibres using antibodies to NPY, TH and DPH. Miyazawa et al. (85) demonstrated intra-sinusoidal fibres using antibodies to S- 100 protein and NSE; fibres immunoreactive for NPY and VIP were also observed but such peptidergic nerves were found in lower density. Ding et al. observed a dense NPY-immunoreactive nerve network surrounding the hepatocytes; the nerve terminals were found close to endothelial cells of blood vessels and

nusoidal fibres. There is evidence that some intrahepatic NPY-ergic fibres may be short post-ganglionic sympathetic fibres whose ganglia are present at the liver hilum, although the possible existence of NPY- ergic fibres which do not contain TH, and are therefore not adrenergic, cannot be excluded (62, 63). In the dog, the liver, rather than the gut, has been shown to be the major source of NPY during sympathetic nerve stimulation (64).

Hepatic afferent fibres travel with the vagus and splanchnic nerves and project centrally to the tractus solitarius (4, 65). In guinea-pig and rat liver, nerve fibres containing the regulatory peptides CGRP and substance P are present around blood vessels and bile duct radicles within portal tracts, but are not detectable within the sinusoids (66-70). CGRP- and substance P-containing nerves are also present around lymphatic capillaries in the interlobular con- nective tissue of the rat liver (71). As both peptides are commonly found in primary afferent neurons in the peripheral nervous system, these observations are presumptive evidence of the presence of sensory nerves in guinea-pig and rat liver. However, it should be noted that CGRP may be present at low concentration in some motor neurons (72). Never- theless, chemical denervation studies (68) as well as the numerous functional studies referred to else- where in this article provide strong evidence for the sensory nature of at least some intrahepatic CGRP- and substance P-positive fibres. In feline liver, substance P- and somatostatin- immunoreactive nerve fibres are identified in portal tracts, while somatostatinergic nerves are also noted in the hepatic lob- ules along the sinusoidal endothelial cells and hepatocyte walls (73). It has recently been observed that galanin is released by the liver during sympathetic stimulation, although the significance of this finding awaits further study (74).

lntrahepatic innervation: human liver

There have been relatively few studies dealing with innervation of the human liver. Portal nerve bundles are readily identified with a distribution similar to that observed in rat and guinea-pig liver. Intra-sinusoidal nerves have been described in several transmission electron microscopic studies (32, 75-78). Fibres are identified within the space of Disse and within recesses between parenchymal cells; some are accompanied by a surrounding Schwann cell. In all of these studies, close contact has been noted between nerve fibres and sinusoidal cells or parenchymal cells; points of contact frequently involve nerve varicosities within which dense-core vesicles could be seen. Bioulac-Sage et al. (77) have suggested that indentations of hepatic stellate cells (fat-storing

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in the space of Disse (86). Terada & Nakamura also demonstrated S- 100- and NSE-positive intra-sinusoidal fibres, but were unable to immunolocalize peptidergic nerves in their material (87). Ueno et al. identified substance P-positive fibres within sinusoidal walls (88). Carlei et a l . demonstrated NPY-, substance P- and VIP-positive fibres around vessels from the liver hilum, but no attempts were made to investigate the intrahepatic distribution of these peptidergic nerves (62). Intrahepatic nerves containing these and other neuropeptides (glucagon, glucagon- like peptide, somatostatin, gastridcholecystokinin C-terminus, neurotensin, galanin, and serotonin were recently demonstrated in human material (89).

Burt et al. showed that although parenchymal nerve fibres could be identified using a polyclonal anti-S-100 protein antibody, intra-sinusoidal nerves were more readily demonstrable using an anti-PGP 9.5 antibody (90) (Fig. 1). Unlike PGP 9.5, S-100 protein is not present within the axoplasm of nerves but is a component of surrounding Schwann cells. Transmission electron microscopic studies have previously demonstrated that intra-sinusoidal fibres in human liver may only partly be surrounded by Schwann cell processes (38). It is not surprising, therefore, that the density of PGP 9.5-positive fibres is greater than that of S-100-positive fibres.

We have recently used an immunohistochemical method to study the development of nerves in the human fetal liver (91, 92). A few neurofilament- containing fibres were detected at the hilum as early as 8 weeks, but portal tract innervation was not observed before 12 weeks. There is a progressive increase in the density of fibres (detected using anti-

Fig. 1. PGP 9.5 immunoreactivity in intrahepatic nerves of adult human liver. (a) A fibre (arrows) extends from a portal tract along the sinusoids. (b) fibres are also present in ac- inar zone 3 (THV, terminal hepatic vein).

bodies to PGP 9.5, S-100 protein, NSE and neurofilament) towards term (Fig. 2) although intrasinusoi- dal fibres appear late in gestation. Galaninergic and somatostatinergic fibres were observed from 22 weeks gestation, but were not present at term; de- velopmental regulation of neuropeptides may play a role in morphogenesis and control of physiological processes peculiar to the fetus.

Altered hepatic innervation in disease

Alterations to the distribution of intrahepatic nerves in rat liver following CC1,-induced acute necrosis (93) and partial hepatectomy (94) have previously been studied. However, the distribution of intrahepatic nerves in rat liver differs from that in the hu-

Fig. 2. PGP 9.5-positive fibres in a week 28 fetal liver.

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proliferation in this situation, there may be insuffi- cient nerve growth factors to stimulate ingrowth of Schwann cells and neurons into regenerative nodules.

man and these studies are therefore of only limited relevance for understanding the changes occurring in human liver disease. Using fluorescence and en- zyme histochemistry, UngvBry & DonBth (95) and Akiyoshi (48) examined changes occurring to intrahepatic innervation in guinea-pig liver following common bile duct ligation. Although U n g v h & DonBth demonstrated an increase in both adrenergic and cholinergic fibres in portal tracts and in fibrous septa (70), Akiyoshi found that cholinergic nerves were mainly affected (48). Abundant acetyl- cholinesterase-positive fibres could be seen in fibrous septa six weeks after operation. However, no alterations in the pattern of innervation within the parenchymal nodules was detected.

In keeping with these animal studies, Honjo & Hasebe (96) demonstrated increased numbers of myelinated nerve fibres in areas of fibrosis in human cirrhosis. In their immunohistochemical study, Mi- yazawa et al. (85) showed that in chronic active hepatitis, there was an apparent proliferation of S- 100 and NSE-positive fibres within developing fibrous septa. However, in contrast to previous animal studies, a decrease in the density of fibres within developing nodules in cirrhotic liver was noted. Lee et al. have further demonstrated that there is virtually a complete absence of intra-sinusoidal nerve fibres in established cirrhosis (97), irrespective of the aetiol- ogy of the liver disease. These results were confirmed by Scoazec et al. (78) using immunoelec- tron-microscopy and antibodies to the neural cell- adhesion molecule, NCAM, and by Kanda et al. using antibodies to synaptophysin (98). Jaskiewicz et al. also observed absence of parenchymal fibres in cirrhotic nodules (99). Observations in pre-cirrhotic chronic liver disease suggested that intra-sinusoidal fibres may be reduced in density prior to the development of established cirrhosis (90). The mechanisms responsible for the loss of intra-sinusoidal fibres in cirrhosis remain uncertain. Miyazawa et al. (85) suggest that in evolving cirrhosis nerve fibres may degenerate, possibly as a result of the primary liver insult. The observation of either normal or ap- parently increased nerve fibre density in various forms of acute liver injury suggests that other mechanisms may be involved (90,99, 100). However, the apparent increased fibre density noted in acute hepatitis could reflect parenchymal collapse in bridging necrosis rather than true nerve proliferation. In chronic liver disease, nerves may be damaged by progressive fibrosis within the space of Disse. Thus nodular regeneration, an essential feature for the development of established cirrhosis, may contribute to sinusoidal denervation. One may speculate that although there is a continued source of growth factors stimulating parenchymal and sinusoidal cell

Nerves in the transplanted liver

Several recent studies have investigated the intrinsic innervation of the transplanted human liver (101- 103). These have shown that parenchymal nerve fibres disappear shortly after orthotopic liver transplantation, while the disappearance of portal fibres is less rapid; the latter, however, are undetectable by six weeks. Reinnervation of some portal tracts may take place as early as 32 weeks post-transplant (1 02), but the majority of the liver appears to remain denervated (101, 103). Reinnervation of the hepatic parenchyma does not occur, even though abnor- mally large nerve bundles may be seen in fibrous septa and major portal tracts after transplantation. Despite the enhanced expression of HLA class I1 antigens on large nerve bundles in the transplanted liver, little cellular rejection of these structures is noted (104). The origin of the reappearing intrahepatic nerve fibres in the transplanted liver is still under investigation; they may represent projections of extrinsic nerves or they may result from proliferation of intrinsic hepatic nerves from intrahepatic ganglia at the hilum.

Increased blood flow has been reported in the denervated liver following transplantation ( 105) and this may be due to loss of normal vasomotor tone. However, the absence of major physiological distur- bances and clinical effects following liver transplantation clearly cannot be attributed to the survival or rapid regeneration of autonomic nerve fibres.

Functional aspects It is clear from the data summarized above that the liver receives an extensive innervation. The nerves are present in portal tracts and in the parenchyma and are closely apposed not only to vessels, but also to hepatocytes and sinusoidal cells. Furthermore, the nerve types present show a morphology consistent with numerous other observations indicating that they serve sensory (afferent) as well as regulatory metabolic and motor (efferent) functions. Early controversies concerning whether or not the liver receives an innervation have therefore now given way to discussion of the relative proportions of the various neural subtypes, whether they have discernably different distributions within the liver and what the precise functions of these nerves are.

The fact that hepatic innervation is not necessary for life is clearly shown by the observation that the

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liver can be transplanted successfully, even though minimal regeneration of nerves occurs (101-103). Nevertheless, the fact that other mechanisms can compensate for hepatic denervation should not be taken to indicate that hepatic nerves are of little im- portance under normal circumstances. The heart, for example, also receives little reinnervation for several months following transplantation (1 06), but few would deny the functional role of cardiac nerves.

The motor functions of hepatic nerves are the least problematic to understand. Until quite recently it was generally thought that regulation of blood flow through the liver was passive, and that the major influence was exerted by the extrahepatic splanchnic circulation (1 07). However, increasing evidence indicates that the hepatic nerves may play the predominant role in portal haemodynamic regulation. For example, stimulation of nerve bundles entering the liver causes noradrenaline release associated with decreased flow and increased portal pressure (108). Under basal conditions, the large blood pressure drop between the portal vein and hepatic vein is divided approximately equally between the portal vein to the terminal hepatic venule and across the sinusoids (109). Thus, there is ample scope for the innervation of portal structures, sinusoids and hepatic vein radicles to influence liver blood flow. The observation of haemodynamic os- cillations in isolated perfused liver (80) demon- strates that the components necessary to regulate blood flow are present in the liver and an increasing number of functional studies are beginning to clar- ify the role of this regulation (8, 9, 110). The absence of parenchymal innervation in cirrhosis (90, 97-99) has been suggested to account for some of the observed abnormalities of portal blood flow occurring in this condition. However, direct evidence for this remains scarce since it is difficult to control the effects of the anatomical disorganisation caused by cirrhosis. Perhaps not surprisingly, one study found little correlation between anatomical changes and the presence of portal hypertension (99).

There is evidence that efferent hepatic nerves may also influence carbohydrate metabolism, lipid metabolism, parenchymal regeneration and even plasma protein synthesis (7, 8, 11, 15, 11 1). In functional studies it is often difficult to distinguish between a direct effect on these variables and a sec- ondary effect mediated by alterations in blood flow. Even if overall flow and pressure remain con- stant, it is difficult to exclude the possibility that re- gional variations may be influencing the results. Nevertheless, the demonstration of parenchymal innervation by morphologists - with sinusoidal and peri-hepatocytic ramifications - indicates that the anatomic substrate for direct modulation of metabo-

lism and regeneration exists in the liver. Several studies suggest that signal propagation between hepatocytes via gap junctions may be an important step in the transduction of neurally-mediated metabolic effects (14, 112). In species such as the rat, where there are nerve fibres only in the immediate periportal area, gap junction signalling could provide a mechanism by which portal/periportal efferents might influence hepatocyte function across the acinus. A further mechanism by which efferent nerves may modulate liver cell metabolism has recently been suggested (1 13). Hepatic stellate cells have been shown to have a, adrenoreceptors and exposure of these cells in v i m to noradrenaline leads to the release of PGF,, and PGD,. These prostanoids in turn stimulate glycogenolysis in cul- tured hepatocytes via receptors that have recently been cloned. This sympathetic innervation of stellate cells could modulate liver cell function via a paracrine mechanism.

Although there has been evidence for neural sensory receptors in the liver for many years (20, 114- 116), they have only recently attracted more wide- spread interest (21-30). The anatomical studies described above have provided ample evidence for many neural subtypes which are likely to serve sensory functions, while physiological studies have provided evidence for receptors sensitive to osmolality, specific ions, glucose, specific amino acids and pressure. From a design standpoint it seems logical that the liver should have sensory receptors since it is exposed to the nutrient and solute load entering the body from the gut before this reaches the systemic circulation. One might predict that under certain circumstances stimulation of hepatic sensors could usefully be involved in the afferent arm of feedback mechanisms which may, for example, modulate water intake, glomerular filtration rate, natriuresis, appetite or gastric emptying - and in- deed there is evidence for all of these (26, 29, 117- 120). Furthermore, the blood brought to the liver by the hepatic artery contains important information on the concentrations of nutrients in the systemic blood. Again one could speculate that hepatic sensory afferents might be involved in the control of glucose and amino acid levels. Currently there is strong evidence for the involvement of hepatic afferents in glucose homeostasis (121). There appear to be several control mechanisms including modulation of pancreatic insulin secretion (1 22, 123), modulation of the effects of insulin (124) and glucose (25) on the liver and transmission of a glucagon- stimulated satiety signal to the brainstem (125). The description of further metabolic-neural feedback loops seems certain as interest in this area intensi- fies.


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Conclusions

Recent research has proven Galen wrong on all his suggestions about hepatic innervation. The liver does receive an extensive innervation. It might not “move like a muscle”, but it does contain contractile elements which have an important role to play in the regulation of portal haemodynamics. And it seems that the liver not only has sensation of several different kinds, but makes considerably better use of it than was previously thought. However, we should not be complacent. It is likely that future work will significantly refine our current understanding of the structure and functions of the hepatic nerves.

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Innervation of the Liver: Morphology and Function