The Submucous Coat #

The submucous coat is a layer of strong but loose areolar tissue with some elastic fibres, lying between the muscularis mucosae and the muscularis externa; it is rich in mast cells, macrophages, lymphocytes, eosinophilic leucocytes and plasma cells. It forms a bed in which the vessels and nerves break up before entering the mucous membrane; consequently it contains arteries, veins, lymphatics and Meissner's nerve plexuses. The plexuses form part of the autonomic nervous system and contain postganglionic sympathetic fibres as well as pre- and postglanglionic parasympathetic fibres. The nerve cells are all parasympathetic.

Stomach

In the stomach the submucous layer does not contain any glands. It is wider than that of the duodenum and extends into the rugae of the stomach, forming the core of each "mucosal" fold. A gastric mucosal fold, in other words, consists of a central core of submucous tissue (constituting the major part of the fold), with a layer of mucosa on each surface.

During injection of the submucous lymphatic plexus of the pyloric region, Jamieson and Dobson (1907) found that fluid ran most readily in an orad direction; however, it also filled a plexus on the orad side of the pyloric ring, and spread into the duodenal plexus. This was ascribed to well-marked continuity of the gastric and duodenal submucous lymphatic plexuses. The findings differ from those of Horton (l928, l931) who investigated the spread of India ink injected into the submucous layer of the pyloric part of the stomach. While it spread out in all directions from the needle point, it was halted at the pyloric ring, none passing into the submucosa of the duodenum. To Horton (l928, l931) this indicated a complete block between the submucous coat of the stomach and that of the duodenum.

Williams (l962) examined aspects of the mucosa and submucosa of the pyloro-duodenal junction in 48 fresh post-operative partial gastrectomy specimens. The gastric submucosa contained loosely knit connective tissue and was found to be considerably wider than that of the duodenum. The muscularis mucosae on the gastric side was clearly visible as a thin, continuous band closely applied to the mucosa, thickening as it approached the pylorus. At the pyloric ring it split up, sending fibres into the mucosa, and finally petering out in a washer-like band of fibrous tissue applied to the muscular ring; in this way the mucosa was firmly bound to the muscle. Injection of India ink into the submucosal layer of the stomach showed that its flow was halted abruptly at the pylorus, none passing into the submucosa of the duodenum; the band of fibrous tissue was the point at which the flow stopped. This point was situated either at the apex of the pyloric muscular ring, or on the duodenal or gastric aspect of the ring. According to Williams (l962) these findings as well as those of Horton (l928, l931) confirmed the fact that the gastric mucosa was firmly bound to the muscle at the "sphincter", and that there was no direct communication between the submucosal compartments of the stomach and the duodenum. (Comment: the sphincter was equated with the pyloric ring).

Duodenum #

The submucous coat of the duodenum is appreciably narrower than that of the stomach; it also differs from the gastric submucosa in that it contains glands, viz. the duodenal glands of Brunner. (Comment: As a possible link between Brunner's glands and transpyloric extension of gastric carcinoma cannot be excluded, as described in Chapter 33, they will be discussed in some detail). Vasoactive intestinal peptide (VIP), substance P and met-enkephalin immunoreactive neuronal elements are present in the duodenal submucosa (vide infra).

Brunner's glands are small acino-tubular glands in the submucosa of the duodenum. Their deep, secretory portions consist of branched and coiled tubules which extend to the circular muscularis externa. Their ducts pierce the muscularis mucosae to open on the luminal surface of the mucosa, in the depths of the crypts between the intestinal glands. Brunner's glands are composed of tall cuboidal cells with dark basal nuclei and a clear cytoplasm, their glandular portions extending into the ducts.

In the majority of subjects they commence at the pyloro-duodenal junction and are most numerous in the first part of the duodenum, gradually decreasing in number toward the third and fourth parts. Occasionally they extend into the upper part of the jejunum; in exceptional cases some Brunner's glands may be present in the pyloric sphincteric cylinder. Horton (l928) examined 84 anatomical specimens and found that they commenced abruptly at the distal portion of the pyloric "sphincter" in all subjects except one; in this single instance they extended for a distance of 8.0 mm across the "sphincter" into the stomach.

Landboe-Christensen (l944) examined the proximal delimitation of the Brunner gland area in 53 anatomical specimens of various age groups. It was found that the border might lie: (1) on the duodenal steep, i.e. the almost perpendicular duodenal side of the pyloric ring, (2) at the top of the ring itself and (3) on the sloping gastric side of the ring. The border between Brunner's glands and pyloric mucosa might run in a regular circle, might be wavy or dentate, or might present one or more tongues or linear extensions. The border might be sharp but in some cases there was a narrow transitional zone, usually on the duodenal side of the ring. Occasionally scattered or solitary islets of Brunner's glands were seen in the pyloric mucosa. In the age group of 25 years and under, the border was on the duodenal side of the ring in half the cases; as age advanced, the border tended to spread on to the pyloric ring and in subjects over 50 years of age the pyloric ring was crossed by Brunner islets in up to four-fifths of the cases. The border also tended to become less sharp with advancing age.

Brunner's glands produce a mucous secretion which forms a protective lining on the duodenal mucosa, preventing epithelial damage by chemical or mechanical trauma (Florey and Harding l934; Griffith and Harkins l956). The mucin secreted has a high bicarbonate content, rendering it alkaline and affording further protection against acid gastric chyme (Griffith and Harkins l956). However, it is possible that the alkaline secretion in the duodenum originates from the surface epithelium and not from Brunner's glands (Flemström and Garner l984). In man Brunner's glands have been shown to contain and secrete epidermal growth factor (EGF) (Elder et al. l978; Heitz et al. l978), a peptide comprising 53 amino acids (Gregory l975). EGF is also produced in the submandibular salivary glands (Hollenberg l979). Mouse EGF is chemically similar to human urogastrone, a polypeptide prepared from urine (Elder et al. l978). Mouse EGF and human urogastrone are closely related structures and seem to be identical in biologic activity; physical data on human EGF suggest that the material is urogastrone (Elder et al. l978).

Both polypeptides have a number of biologic effects in common, including inhibition of gastric acid secretion and a cytoprotective effect on the gastroduodenal mucosa. Intraduodenal as well as intragastric instillation of EGF prevents the development of experimental duodenal and gastric ulcers in the rat (Kirkegaard et al l983). Both substances are powerful mitogens, causing epithelial proliferation and keratinization of squamous epithelial cells in tissue cultures (Elder et al. l978). Experimental intragastric installation of EGF increases the synthesis and contents of DNA and RNA in the gastroduodenal mucosa (Dembinski et al. l982). It was suggested that EGF and urogastrone might have a role in the control of gastric secretion as well as in mucosal growth and the known rapid turnover of cells lining the gut (Elder et al. l978).

By means of immunohistochemical studies in the rat Kirkegaard et al (l98l) demonstrated a dense network of vasoactive intestinal polypeptide (VIP) immunoreactive nerve fibres around the acini of Brunner's glands as well as small ganglia with VIP immunoreactive nerve-cell bodies close to the glands. Intravenous infusions of VIP increased bicarbonate, protein and mucin output from the Brunner's glands, and it was suggested that physiological secretion from these glands might be stimulated by the VIP nerves. Ferri et al. (l984) studied the innervation of Brunner's glands in humans in specimens obtained during gastrectomy for gastric or extragastric carcinoma. In the duodenal submucosa numerous VIP and substance P nerve fibres were noted in the ganglia of Meissner's plexus and in the internodal strands. VIP immunostaining also revealed a rich supply of fibres at the periphery of Brunner's glands, but only a few of these were seen to enter the glands and reach the acinar cells. Nerve bundles immunostained for met- enkephalin ran in the internodal strands of the duodenal submucosa and formed dense networks in occasional ganglia. The study showed that in cases of gastric carcinoma in man, the Brunner's glands did not have the rich supply of VIP containing nerves as was the case in rats.

Immunohistochemical studies in the rat showed that as in man, EGF was almost exclusively present in the secretory cells of Brunner's glands (Kirkegaard et al. l984). It was shown that VIP stimulated secretion of EGF and bicarbonate from Brunner's glands, an effect which was inhibited by somatostatin. According to Kirkegaard et al. (l984) the mechanism controlling Brunner's gland secretion was complex and not fully elucidated. The autonomic nervous system, local factors and a hormonal mechanism were probably all involved.

According to Skov Olsen et al. (l985) evidence has accumulated to show that cholinergic, adrenergic and VIP-containing nerves innervate and thereby influence the secretion from Brunner's glands. They confirmed the presence of VIP containing nerves in these glands in the rat. The influence of the sympathetic nervous system and adrenergic agonists on basal and VIP stimulated flow rate and secretion of EGF from Brunner's glands was studied. It was confirmed that the sympathetic nervous system had an inhibitory effect on Brunner's gland secretion. Chemical sympathectomy increased the flow rate and output of EGF (but depleted the glands of EGF) whereas the alpha-adrenergic agonist noradrenaline inhibited the secretion. VIP was found to increase Brunner's gland secretion and total output of EGF; VIP probably also increased the synthesis of EGF.

Fuse et al. (l990) determined the thickness of Brunner's glands in surgically resected duodenal ulcer specimens and normal controls. The maximum mean thickness in controls was l.54 ± 0.38 mm; in duodenal ulceration it varied widely from 0.5 to 5.0 mm. In most duodenal ulcer cases the glands were thickest within 1.0 cm of the centre of the ulcer; in a small minority of cases of duodenal ulceration the layer of Brunner's glands remained diffusely thin. It was concluded that Brunner's glands became hyperplastic in duodenal ulceration, especially near the ulcer; this was probably a defense mechanism against acid and peptic digestion. In cases of healed duodenal ulceration Brunner's glands were thin at the centre of the scar; this histological finding corresponded to the depressed, scarred area observed endoscopically, and suggested decreased mucosal resistance.

Discussion #

The fact that the submucosa of the first part of the duodenum is much narrower than that of the stomach, and that it contains multiple Brunner's glands which pierce the muscularis mucosae (thus virtually attaching the mucosa to the muscular layer), means that its inherent ability to move is much less than that of the submucosa of the pyloric sphincteric cylinder. This may be of some importance in transpyloric prolapse of gastric mucosa (Chap. 38). It probably also accounts for the fact that normally duodenal mucosal folds are smaller, and less mobile, than mucosal folds of the pyloric sphincteric cylinder.

Brunner's glands have been shown to become hyperplastic in duodenal ulceration; this was considered to be a defense mechanism against digestion by acid gastric juice.

In a few cases of pyloric adenocarcinoma, where extension into the duodenum had occurred, we have noted that Brunner's glands were not infiltrated (Chap. 33). The question arises whether this signifies that Brunner's glands, by virtue of their secretions or some other mechanism, act as a biological or anatomical barrier preventing further spread of gastric carcinoma down the duodenum; this aspect will be discussed in more detail in Chapter 33.

References #

1. Dembinski A, Gregory H, Konturek SJ, et al. Trophic action of epidermal growth factor on the pancreas and gastroduodenal mucosa in rats. J Physiol l982, 325, 35-42.
2. Elder JB, Williams G, Lacey E, et al. Cellular localization of human urogastrone - epidermal growth factor. Nature l978, 271, 466-467.
3. Ferri GL, Botti P, Biliotti G, et al. VIP, substance P and metenkaphalin immunoreactive innervation of the human gastrodudodenal mucosa and Brunner's glands. Gut l984, 25, 948-952.
4. Flemström G, Garner A. Some characteristics of duodenal epithelium. In: Mucus and Mucosa. Pitman, London l984. Ciba Foundation Symposium 109, 94-108.
5. Florey HW, Harding HE. Further observations on the secretion of Brunner's glands. J Path Bact l934, 39, 255-276.
6. Fuse Y, Tsuchihashi Y, Takamasu M, et al. Thickness of Brunner's glands and its clinical significance in duodenal ulcer disease. Scand J Gastroenterol l990, 25, 165-172.
7. Gregory H. Isolation and structure of urogastrone and its relationship to epidermal growth factor. Nature l975, 257, 325-327.
8. Griffith CA, Harkins HN. The role of Brunner's glands in the intrinsic resistance of the duodenum to acid-pepsin digestion. Ann Surg l956, 243, 160-172.
9. Heitz PU, Kasper M, Van Noorden S, et al. Immunohistochemical localization of urogastrone to human duodenal and submandibular glands. Gut 1978, 19, 408-413.
10. Hollenberg MD. Epidermal growth factor - urogastrone, a polypeptide acquiring hormonal status. Vitam Horm l979, 37, 69-110.
11. Horton BT. Pyloric musculature, with special reference to pyloric block. Amer J Anat l928, 41, 197-225.
12. Horton BT. Pyloric block with special reference to the musculature, myenteric plexus and lymphatic vessels. Arch Surg l931, 22, 438-462.
13. Jamieson JK, Dobson JF. The lymphatic system of the stomach. Lancet l907, 1, 1061-1066.
14. Kirkegaard P, Lundberg JM, Poulsen SS, et al. Vasoactive intestinal peptidergic nerves and Brunner's gland secretion in the rat. Gastroenterology l98l, 8l, 872-878.
15. Kirkegaard P, Skov Olsen P, Poulsen SS, et al. Epidermal growth factor inhibits cystamine induced duodenal ulcers. Gastroenterology l983, 85, 1277-1283.
16. Kirkegaard P, Skov Olsen P, Poulsen SS, et al. Exocrine secretion of epidermal growth factor from Brunner's glands: stimulation by VIP and acetylcholine. Regulatory Peptides l983, 7, 367-372.
17. Kirkegaard P, Olsen PS, Nexo E, et al. Effect of vasoactive intestinal polypeptide and somatostatin on secretion of epidermal growth factor and bicarbonate from Brunner's glands. Gut l984, 25, 1225-1229.
18. Landboe-Christensen E. The duodenal glands of Brunner in man: their distribution and quantity. Acta Path Microbiol Scand l944, Suppl 52, ll-267.
19. Skov Olsen P, Poulsen SS, Kirkegaard P. Adrenergic effects on secretion of epidermal growth factor from Brunner's glands. Gut l985, 26, 920-927.
20. Williams I. Closure of the pylorus. Brit J Rad l962, 35, 653-670.