Document Vj5awo9a0YyY13ELG55yLqjRN

CHAPTER 235 PEPTIC ULCER 1239 FLEISERD. KFSSLER F Endoscopic YAG laser therapy for carcinoma of the esophagus: A new form of palliative treatment. Gastroenterology 85:600. 1983 GELmno M et al: Isosorbide dinitrate and nifedipinc treatment of achalasia: A chemical. manomemc and radionuclide evaluation. Gastroenterology 83:%3. 1982 GOYALRK: Disorders of the circopharyngeus muscle. Otolaryngol Clin North Am 17:115. 1984 KELSEN D Chemotherapy of esophageal cancer. Semin Oncol 11:159. 1984 KIKENDALLJW et al: Pill-induced esophageal injury--case repons and review of the medical literamre. Dig Dis Sci 28174. 1983 LEICHMANL et al: Roperative chemotherapy and radiation therapy for patients with cancer of the esophagus: A potentially curative approach. J Clin Oncol 2:75. 1984 MCDONALDGB et al: Esophageal infections in immunosuppressed patients after marrow transplantation. Gastroenterology 88:1 I 1 1, 1985 SPECHLER SJ. COYALRK: Barrett's Esophagus: Parhophvsiology. Diagnosis and Trement. New Yo&. Elsevier. 1985 TRIER JS. BJORKMANDJ: Esophageal. gasmc and intestinal candidiasis. Am J Med n : 3 9 . 1984 VAMUPPEN G . HELLEMANJS: Treatment of achalasia and related motor disorders. Gastroenterology 79144, 1980 glands in the body and fundus of the stomach. can secrete hydrogen ions at a concentration 3 million times that found in blood. Hydrogen ions are secreted into the gastric lumen by a proton pump mechanism involving a specific hydrogen-potassium adenosine triphosphatase (H',K'-ATPase) located on the microvilli of the secretory canaliculi of the parietal cells. The estimated concentration of HCI secreted directly by parietal cells is approximately 160 mM. Each secreted hydrogen ion (H') is accompanied by a chloride ion (Cl-). With increased gastric hydrogen ion secretion, there is a reciprocal decrease in sodium ion secretion. For each hydrogen ion secreted into the gastric lumen, one bicarbonate ion (HC0,-) is returned via the gastric venous circulation. accounting for the alkaline tide. which reflects directly the magnitude of gastric H secretion. Bicarbonate is released from carbonic acid; the latter is generated from carbon dioxide by parietal cell carbonic anhydrase. The twotomponent hypothesis for secretion of gastric juice proposes that parietal cells secrete pure HCI. which is mixed (in various proportions) with nonparietal cell alkaline secretions, similar in ionic composition to extracellular fluid. 235 PEPTlC ULCER Multiple chemical, neural, and hormonal factors participate in regulation of gastric acid secretion. Acid secretion is stimulated by gastrin and by cholinergic postganglionic vagal fibers via muscarinic JAMES E. McGUIGAN receptors on parietal cells. Gastrin, the most potent known stimulant of gastric acid secretion, is present in cytoplasmic secretory granules The termpeptic ulcer is used to refer to a group of ulcerative disorders in gastrin cells (or G cells) which are interspersed singly or in small of the upper gastrointestinal tract which appear to have in common clusters among other epithelial cells principally in the mid and deeper the participation of acid-pepsin in their pathogenesis. The major portions of the antral pyloric glands. Gastrin, as most, if not all, the forms of peptic ulcer are chronic duodenal and gastric ulcer. The gastrointestinal regulatory peptides, is present in multiple molecular Zollinger-Ellison syndrome, which is caused by gastrin-releasing forms (Fig. 235-1). The major form of tissue gasmn is heptadeca- tumors (gastrinomas), may also be considered a form of peptic ulcer. peptide gastrin (G-17) which contains 17 amino acid residues. Gastrin Although our present knowledge of the etiology of peptic ulcer is II is the form of gastrin in which the tyrosyl residue at position 12 incomplete, information from studies in humans and in experimental is sulfated, and gastrin I is the nonsulfated form. Approximately two- animals indicates that acid-pepsin is crucial for development of peptic ulcer. The presence or absence of peptic ulcer is determined by the delicate interplay between aggressive factors (secreted gastric acid and pepsin) and defensive factors (mucosal resistance). Peptic ulcer is produced when the aggressive effects of acid-pepsin dominate the protective effects of gastric or duodenal mucosal resistance. Why do not all humans develop peptic ulcer? The normal capacity of gastric and proximal duodenal mucosa to resist the corrosive effects of acidpepsin is extraordinary and unique. This resistance to acid-pepsin is not shared by other tissues-hence the susceptibility of the esophageal mucosa to injury when exposed to refluxed gastric juice and the fiequent ulceration of the small intestine at the site of surgical attachment to actively secreting gastric mucosa. Much has been learned concerning the mechanisms regulating gastric secretion and about a variety of factors which appear important in the development of peptic ulcer. Consideration of gastric physiology provides an understandingof some elements responsible for producing peptic ulcer as well as a rational basis for its treatment. thirds of circulating serum gastrin consists of a larger molecular species of gastrin, namely, "big gastrin." or G-34. This species of gastrin contains 34 amino acids, the carboxyl-terminal 17 of which are identical with heptadecapeptide gastrin and may also be present in sulfated (G-34 II) or nonsulfated (G-34I) forms. Although G-17 has a shorter half-life than G-34, on a molar basis circulating (3-17 is approximately as potent as G-34 in stimulatinggastric acid secretion. More than 90 percent of antral mucosal gastrin is in the form of G-17. Gastrin is also present in duodenal mucosa, the highest concentration being in the most proximal duodenum (approximately 10 percent of the antral concentration). The mucosal concentration of gastrin and the proportion as G- 17 decrease with progression down the duodenum. The effects of gastrin and the vagus on gastric acid secretion are intimately related. Vagal stimulation increases gastric acid secretion by (1) directly stimulating parietal cells, (2) stimulating release of gastrin into the circulation. and (3) lowering the parietal cell threshold for response to circulating gastrin concentrations. There is also evidence that certain vagal branches or fibers inhibit gastrin release. GASTRIC PHYSIOLOGY RELATED TO PEPTIC ULCER Histamine is present in large concentrations in mast cells in the lamina propria of the parietal cell-containing regions of the gastric mucosa. Histamine-containingmast cells are located in close proximity to parietal cells, with a ratio of one mast cell to every two or three The gastric mucosa possesses an extraordinary capacity to secrete parietal cells. For many years views have differed on the importance acid. Parietal (oxyntic) cells secrete hydrochloric acid by a process of histamine in stimulating gastric acid secretion; some suggested involving oxidative phosphorylation. Parietal cells, located in mucosal that histamine is the "final common pathway" for cholinergic and FIGURE 235-1 Amino acid sequences of selected gastrin peptides. all of which contain the common C-terminal pentapeptide amide. (*Tyrosyl is sulfated in gasm`n I1 and nonsulfated in gastrin I molecules.) Big Gastrin (G34) Heptadecapeptide Gastrin (G17) Minigastrin (G 441 C-Terminal Pentapeptide ~Iu-Leu-Gly-Pro-Gln-Gly-Pro-Pro-His-Leu-Val-Ala-Asp-Pro-Ser-Lys-Lys-Gln-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu-Glu-AlaT'y-rGly-TrpMet-AspPhe-NH? ~lu-Gly-Pro-Trp-Leu-Glu-Glu-Glu-Glu-Glu-Ala-T~r'-Gly-Trp-Met-Asp-Phe-NH, TrpLeu-Glu-Glu-Glu-Glu-Glu-Ala-Ty* r-Gly-Trp-Met-Asp-Phe-NH? Gly-Trp-Met-Asp-Phe-NH, 1240 PART SEVEN DISORDERS OF THE GASTROlNTESTlNALSYSTEM gastrin stimulation of parietal cell acid secretion. while others were duodenum. Reduction of the intragastric pH to 3.0 produces partial skeptical about any role for histamine in the acid secretory process. inhibition of gastrin release; further reduction to pH 1.5 or below Interest in the role of histamine in acid secretion was renewed by blocks the release of gastrin to almost all stimuli. There is evidence the discovery of H-2-receptor antagonists which competitively inhibit that somarosrutin is involved in the inhibition of gastrin Elease the action of histamine on H-2 receptors (located on gastric parietal, produced by acid in the gastric lumen. Somatostatin is present in cardiac atrial. and uterine smooth-muscle cells). These drugs exert high concentrations in antral mucosal endocrine cells (D cells) which negligible effect on H-1 receptors, which are readily inhibited by possess cytoplasmic processes that extend to neighboring gastrin conventional antihistamines. H-?-receptor antagonists (e.g., cimeti- cells. The action of somatostatin in inhibiting gastrin release appears dine and ranitidine) inhibit both basal acid secretion and secretory to be mediated by its local (paracrine) effects on gastrin cells. The responses to feeding, gastrin, histamine, hypoglycemia. and vagal cytoplasmic processes of somatostatin cells also extend to intimate stimulation. Most data support the conclusions that (1) histamine contact with parietal and other cells in the acid-secreting portions of plays an important role in stimulating gastric acid secretion, and that the stomach. Somatostatin is believed to reduce gastric acid secretion (2) histamine acts in concert with gastrin and cholinergic activity on by inhibiting gastrin release and by directly inhibiting parietal cell parietal cells, which bear receptors for histamine, gastrin. and secretion. Acid in the duodenum also inhibits gastric acid secretion; acetylcholine. but that (3) there is still uncertainty as to whether this may be secondary to stimulating the release of secretin and/or histamine is the final common effector molecule in the stimulation other peptides capable of inhibiting gastric acid secretion. Secretin of parietal cell secretion. is a linear polypeptide containing 27 amino acids bearing structural Food ingestion is the major physiologic stimulus of gastric acid similarities to glucagon. Secretin is released from endocrine cells (S secretion. Traditionally, gastric acid secretion has been classified into cells) in the mucosa of the small intestine in response to mucosal three phases-cephalic, gastric, and intestinal. This classification is acidification. Fat in the duodenum also inhibits gastric acid secretion; of some value in examining the multiple factors which regulate gastric gastric inhibitory peptide (GIP) has been proposed as a candidate for acid secretion. The cephalicphuse represents the gastric acid secretory this enterogastrone action; however, this effect for GIP remains to response to the sight, smell, taste, and anticipation of food. The be proved. The mechanisms by which hyperglycemia or intraduodenal gastric phuse is induced by the presence of food in the stomach. The hyperosmolality inhibit gastric acid secretion are not known. Addi- intestinal phuse is due to the entry or presence of food within the tional peptides identified in the mucosa of the gastrointestinal tract lumen of the small intestine. Although these three phases are which have the capacity to inhibit gastric acid secretion include convenient for considering the diverse contributions to gastric acid glucagon-like peptides (e.g., glicentin), vasoactive intestinal peptide secretion, each phase is complex and not necessarily due to a single (VIP), and urogastrone; the latter appears to be structurally and stimulatory control mechanism. functionally identical with epidermal growth factor. Vasoactive The cephalic phase appears to be mediated primarily by the vagus, intestinal peptide, which is located in neurons, is unlikely to inhibit which increases gastric acid secretion by stimulation of parietal cells gastric acid secretion as a circulating hormone, since it is inactivated directly and to a lesser extent by stimulating the release of gastrin during its portal passage thmugh the liver. The extent to which these into the circulation. The gastric phase results from stimulation of peptides contribute to the regulation of gastric acid secretion is not chemical and mechanical receptors in the gastric wall by luminal clear. contents. Mechanical distention of the stomach stimulates gastric acid The proteolytic effects of pepsins and the corrosive effects of acid secretion but results in little, if any, gastrin release; this mechanical appear to be integral components in the tissue injury which leads to effect is inhibited by atropine and appears to be mediated by vagal peptic ulceration. Acid catalyzes the cleavage of inactive pepsinogen reflexes. Food in the stomach promotes gastric acid secretion by molecules to active pepsins and also provides the appropriate pH increasing gastrin release, principally due to the prorein content and required for pepsin activity. Pepsin activity is substantially reduced the producrs of protein digestion contained in the meal; oral glucose above pH 4.0, and these enzymes are irreversibly inactivated at and fat cause slight increases in serum gastrin but do not stimulate neutral or alkaline pH. There are a variety of pepsinogens and pepsins gastric acid secretion. Food in the proximal small intestine stimulates in gastric juice. Pepsinogens (and their corresponding active pepsins) the intestinal phase of gastric acid secretion. A peptone meal (which have been classified by immunochemical techniques as either PG I contains partially hydrolyzed meat protein) introduced into the small (pepsinogens 1 through 5 ) or PG I1 (pepsinogens 6 and 7). Pepsinogen intestine stimulates gastric acid secretion but not gastrin release. It I is present in chief and mucous cells in the body and fundus of the has been proposed that food in the small intestine induces release of stomach. Pepsinogen D is located in cells of the pyloric glands, an intestinal hormone, presumably a polypeptide, which stimulates Brunner's glands of the duodenum, mucous cells of the gastric cardiac gastric acid secretion. This substance is believed to be distinct from glands, and the same cells in which PG I is found. Both PG I and gastrin and, unlike gastrin. appears to be degraded substantially PG II are present in plasma, while only PG I can be detected in during its portal transit through the liver. urine. A high degree of correlation exists between serum concentra- Ingestion of both caffeine-containing and caffeine-free coflee tions of PG I and maximal gastric acid secretion. In general, agents stimulates gastric acid secretion: both forms of coffee stimulate gastrin which stimulate gastric acid secretion also stimulate pepsinogen release. Ingestion of ethanol and ethanol-containing beverages stim- secretion. Cholinergic action is particularly potent in promoting ulates gastric acid secretion. Specifically, ingestion of 5 and 10% pepsinogen secretion. Secretin, although it inhibits gastric acid ethanol solutions and 10% bourbon whiskey results in prompt secretion, stimulates pepsinogen secretion. stimulation of gastric acid secretion without increasing gastrin release; Parietal cells also secrete intrinsicfactor. Agents which stimulate however. white wine stimulates both gastric acid secretion and gastrin gastric acid secretion also lead to secretion of intrinsic factor. release. Furthermore. intravenous ethanol stimulates gastric k i d The precise mechanisms whereby the normal stomach and duo- secretion, suggesting that both systemic and local mechanisms are denum resist the corrosive effects of acid-pepsin (Le., mucosal involved. Intravenous calcium stimulates acid secretion and produces resistance) have not been defined. A variety of factors have been minimal increases in serum gastrin levels. Oral calcium has been proposed as potential contributors to mucosal resistance. Gastric reported to stimulate gastric acid secretion dkcctly, i.e., without an mucus, secreted by gastric mucous cells, is present in solution in increase in serum calcium or gastrin concentrations. Except in patients gastric juice and as an insoluble mucus gel layer which coats the with gastrinoma, hypercalcemia is usually not associated with acid mucosal surface of the stomach. It has been suggested that gusfric hypersecretion or increases in serum gastrin. mucus may play a role in mucosal defense against injury, and thus Inhibition of gastric acid secretion can be produced by several in preventing peptic ulceration. Mucus secretion is enhanced by mechanisms. Acid secretion may be inhibited by acid in the stomach mechanical or chemical initation and by cholinergic stimulation. or duodenum, by hyperglycemia, or by hypertonic fluids or fat in the Gastric mucus is a large polymeric glycoprotein (2 x 106 mol wt) CHAPTER 235 PEPTIC ULCER 1241 containing four subunits connected by disulfide bridges. Depolymerization of the glycoprotein subunits of mucus, which may be produced by peptic digestion or disruption of disulfide bonds. renders the glycoprotein incapable of forming a viscous gel. When intact, this mucus gel serves as an unstirred layer which permits ionic diffusion but is impermeable to penetration by macromolecules such as pepsin (34,000 mol wt). Bicarbonate ions are secreted by gastric surface epithelial cells (nonparietal cells) and enter the unstirred layer of mucus gel; this mechanism facilitates the development of a microenvironment with a substantial hydrogen ion gradient between the gel opposing the gastrin luminal contents (more acid) and the gel surface facing and in intimate contact with the apical surfaces of gastric mucosal cells (more alkaline). Pepsin secreted into the gastrin lumen is denied reentry by the impermeable mucus gel, thereby potentially protecting the mucosal cells from proteolytic injury. Gastric mucus also contains glycoprotein blood group substances. Approximately three-fourths of the population secrete gastric juice containing these AB(H) substances and those individuals are referred to as secretors. Normally the gastric luminal epithelial cell surfaces and intercellular tight junctions provide an almost completely impermeable barrier to back-diffusion of hydrogen ions from the lumen. This gastric mucosal barrier may participate in mucosal resistance to acid-peptic ulceration. This barrier may be interrupted by various agents including bile acids, salicylates. alcohol, and weak organic acids, thus permitting buck-diffusion of hydrogen ions from the lumen to intra- and intercellular sites. Such back-diffusion may result in cellular injury, release of histamine from mast cells. further stimulation of acid secretion, damage to small blood vessels, mucosal hemorrhage, and superficial ulceration. Interruption of the gastric mucosal barrier may be responsible (at least in part) for the hemorrhagic erosive gastritis associated with salicylate and ethanol ingestion and may also contribute to other forms of gastric mucosal injury. However, the relationship between the gastric mucosal barrier and mucosal resistance to chronic peptic ulcer has not been completely elucidated. Decreased mucosal blood pow, accompanied by backdiffusion of available hydrogen ions, also appears to contribute to gastric mucosal damage. Maintenance of normal mucosal blood flow is an essential component of mucosal resistance to injury. Promglundins are present in abundant quantities in the gastric mucosa. Various prostaglandins, particularly those of the E series, have been shown to inhibit gastric mucosal injury due to a wide variety of agents. It is possible that endogenous prostaglandins contribute to mucosal resistance and may thereby have a "cytoprotective" function. Mild mucosal injury or irritation may induce prostaglandin synthesis, thereby potentially enhancing mucosal resistance to injury, a concept referred to as adoptive cyroprotection. Other mucosal factors, some of which are genetic, but which have not been clearly defined, apparently contribute to the ability of the gastric mucosa to resist or permit the development of peptic Ulceration. MEASUREMENT OF GASTRIC ACID SECRETION Since HCI secretion by the stomach appears to be an important factor in the production of peptic ulcer disease, measurement of basal and stimulated gastric acid secretion may be of value in the assessment u f peptic ulcer patients. In general, basal and stimulated acid outputs in females are approximately two-thirds to three-fourths those found in males. The range of values for normal subjects is extremely broad and overlaps substantially with those found in patients with duodenal ulcer, gastric ulcer, and even the Zollinger-Ellison syndrome. Mean basal acid output (BAO) in normal males without known ulcer disease is about 1.5 to 2.0 meq/h. In duodenal ulcer patients mean basal acid output averages from 4 to 6 meq/h, again with a wide degree of variation. Patients with gastric ulcer tend to have gastric acid secretory rates which are normal or even slightly less than those of normal subjects. Measurement of gastric acid output is not helpful in either diagnosing peptic ulcer or excluding it. Thus measuring gastric acid secretion is clearly not necessary in all patients with duodenal ulcer. However, detection of gastric acid hypersecretion is of value when the Zollinger-Ellison syndrome is suspected. Measurement of gascric acid output is useful to detect achlorhydria, as found in patients with pernicious anemia. Since patients with benign gastric ulcer virtually always secrete some acid, pentagastrin-fast achlorhydria in a patient with a gastric ulcer almost always indicates malignancy. Measurement of gastric acid secretion is indicated in the search for the c a w of ulcer recurrence after surgery for peptic ulcer. In order to measure gastric acid output, a radiopaque gastric tube is passed so that its tip is located in the most dependent portion of the stomach. With the patient in a reclining or semirecumbent position on the left side, the position of the tube is verified by fluoroscopy. Gastric contents are aspirated and discarded. Basal gastric acid secretions are then collected in four consecutive 15-min intervals to determine the I-h basal acid output. Secretion volume and acid concentration (titrated with 0.1 N sodium hydroxide to pH 7.0 or calculated by formula from the pH of the aspirated gastric juice) are measured, and acid output is expressed as milliequivalents per hour. A variety of substances have been used to stimulate maximal acid output (MAO) by the stomach. These have included histamine, beruzole (Histalog)-a structural analogue of histamine-and pentagastrin (Peptavlon). Histamine, the first standard stimulant to be used for gastric acid secretory testing, requires the simultaneous administration of an antihistaminic agent (H-I-receptor antagonist) to inhibit untoward systemic side effects. Betazole possesses fewer undesired side effects of histamine and does not require the concomitant administration of an antihistamine. Pentagastrin (N-tert-butyloxycarbonyl-P- Ala-Try-Met-Asp-Phe-NHJ contains the biologically active carboxyl-terminal tetrapeptide amide portion of the gastrin molecule and is currently the preferred and most commonly used agent to induce maximal acid secretion. Following collection of basal acid secretion gastric juice is collected for four additional consecutive 15min periods after the subcutaneous injection of pentagastrin (6 pg/ kg). The M A 0 is the expression of the milliequivalents of acid aspirated during the 1 h after pentagastrin administration. Peak acid output (PAO) is calculated by combining the two highest consecutive 15-min acid outputs following pentagastrin injection and multiplying by 2. DUODENAL ULCER GENERAL CONSIDERATIONS Duodenal ulcer is a chronic and recurrent disease. The ulcer is usually deep and sharply demarcated. It tends to penetrate through the submucosa and often into the muscularis propria. The ulcer floor contains no intact epithelium and usually consists of a zone of eosinophilic necrosis resting on a base of granulation tissue surrounded by variable amounts of fibrosis. The ulcer bed may be clear or contain either blood or a proteinaceous exudate with entrapped erythrocytes and acute and chronic inflammatory cells. More than 95 percent of duodenal ulcers occur in the first portion of the duodenum. and approximately 90percent of these are located within 3 cm of the junction of the pyloric and duodenal mucosa. Duodenal ulcers are usually round or oval, but they may be irregular or elliptic. They are usually less than 1 cm in diameter. Rarely, duodenal ulcers may be extremely large (3 to 6 cm in diameter) and may be mistaken radiographically forthe entire duodenal bulb. These giant ulcers often escape radiologic detection and are usually identified directly by endoscopy or at surgery or postmortem examination. The absolute prevalence of duodenal ulcer in the population is not known. Estimates have ranged from 6 to 15percent. This variation may be related to the populations examined, differences in study design and diagnostic methods (e.g.. endoscopy vs. radiological examination), and perhaps to actual changes or differences in frequency of duodenal ulcer disease. The best current estimates suggest 1250 PART SEVEN DISORDERS OF THE GASTROlNTESTlNAL SYSTEM most common single hematologic defect after peptic ulcer surgery and may result from either blood loss (e.g., with persistent or recurrent ulcer) or from iron malabsorption. Patients with gastric resection malabsorb dietary iron but have normal absorption of iron salts; therefore they will respond favorably to treatment with therapeutic oral iron preparations. Folate deficiency may result from either reduced dietary intake or impaired folate absorption. Except for the anemia produced by blood loss in association with early recurrent ulcer disease, the development of anemia after peptic ulcer surgery is gradual, usually occurring several years postoperatively. The nature of the anemia after ulcer surgery should be clarified by determination of the red blood cell morphology and by measurements of serum iron, folate, and vitamin B,*. Irun or folate deficiency may be treated by oral replacement. Vitamin B,2 deficiency should be treated with monthly intramuscular injections of the vitamin. OSTEOMALACIA AND OSEOPOROSIS Osteoporosis and osteomalacia may develop after partial or complete gastrectomy but occur rarely after vagotomy and pyloroplasty. Osteomalacia is extremely frequent following gastrojejunostomy or Billroth 11 anastomosis. These bone changes are believed to result from malabsorption of calcium and vitamin D. Patients may develop bone pain and have pathologic fractures. The incidence of bone fractures in men following gastric resection has been estimated to be almost twice that of control subjects of similar age. Reduced bone density requires years to develop and can be identified by x-ray. Patients with osteomalacia usually have increased levels of serum alkaline phosphatase and may have reduced serum calcium concentrations. These patients should be treated by supplemental oral vitamin D and calcium. In fact, the frequency of osteoporosis and osteomalacia after partial or complete gastrectomy is sufficiently great that treatment with vitamin D and calcium should probably be instituted and continued indefinitely in these patients, especially females, following gastric resection. GENERAL MALABSORPTION (See Chap. 237) Mild, chemically demonstrable steatorrhea is common in patients after ulcer surgery. Weight loss is more common after partial gastric resection than with vagotomy without resection and occurs in approximately 60 percent of patients in whom a portion of the stomach has been removed. The major cause of weight loss after peptic ulcer surgery is reduced food intake. On a 100-9 fat diet, loss of stool fat seldom exceeds 15 g per day (normal individuals, less than 7 g per day). The causes of maldigestion and malabsorption after peptic ulcer surgery include rapid gastric emptying, reduced dispersion of food in the stomach. reduced bile concentrations in the gut lumen, increased rate of transit of the meal through the small intestine, and reduced or delayed pancreatic secretory responses to feeding. Steatorrhea and weight loss, sometimes accompanied by vitamin B,, malabsorption, may develop as a result of bacterial overgrowth, especially in patients with afferent loop bacterial stasis. Overt symptoms and other manifestations of malabsorption appearing after surgery for peptic ulcer may also be due to other preexisting conditions, including latent celiac sprue and chronic pancreatitis. CARCINOMA A-ER PARTIAL GASTRECTOMY Several studies have documented an increased incidence of adenocarcinoma of the stomach in duodenal ulcer patients following partial gastric resection and after vagotomy and drainage without resection. This usually develops 10 or more years after ulcer surgery. The possibility of carcinoma of the stomach should be considered when abdominal symptoms, which may be similar to or distinct from those due to the original ulcer, appear many years after apparently successful surgery. ZOLLINGER-ELLISON SYNDROME (GASTRINOMA) In 1955 Zollinger and Ellison described the syndrome which bears their names, Le., ulcer disease of the upper gastrointestinal tract, marked increases in gastric acid secretion, and nonbeta islet-cell tumors of the pancreas. ETIOLOGY AND PATHOGENESIS Zollinger and Ellison. in their original description of the syndrome. suggested that the ulcer disease in these patients resulted from liberation of a secretagogue from the islet-cell tumors which accounted for the often enormously increased rates of gastric acid secretion. Their proposal was proved correct when in 1960 extracts of Zollinger-Ellison (2-E) tumors were shown to stimulate gastric acid secretion. Subsequently. it was found that the pancreatic tumors contained gastrin and that large amounts of this hormone were released into the circulation, producing the pathophysiologic characteristics of the syndrome. These gastrin-containing tumors are, therefore, now referred to as gustrinomus. Gastrin has been demonstrated in these tumors by chemical isolation of polypeptides with amino acid compositions and peptide mapping patterns identical with those of human gastrin molecules. In addition, large amounts of gastrin have been demonstrated by radioimmunoassay in gastrinomas and in serums of patients with the Z-E syndrome. Most gastrinomas are found within the pancreas. Multiple, apparently primary, tumors are common. Pancreatic gastrinomas may be single or multiple and may vary in size from 2 mm to more than 20 cm in diameter. In from one-half to two-thirds of patients multiple gastrinomas are present within the pancreas; however, more than half of these are not identified at surgery. Pancreatic gastrinomas are most common in the body or tail of the pancreas. Approximately 13 percent of patients with this syndrome have tumors in the wall of the proximal duodenum. Gastrinomas have also been located less commonly in other sites, including the hilum of the spleen and very rarely in the stomach. Primary gastrinomas, surrounded by lymphoid tissue, have been found in proximity to the pancreas, proximal duodenum, and spleen. These may be confused with, but are distinct from, metastasis to regional lymph nodes. In rare instances, the Z-E syndrome has resulted from ectopic gastrin-containing tumors, e.g., parathyroid and ovarian adenomas. Many, and when sought for, most, gastrinsecreting islet-cell tumors have been found to contain multiple hormones, which may or may not be released, but are usually clinically silent. These have included adrenocorticotropic hormone, glucagon, insulin, pancreatic polypeptide. and. vasoactive intestinal peptide. The absolute frequency of multiple hormones contained in or released by these tumors is not known. Approximately one-third of patients with gastrinomas have increases in serum concentrations of pancrenric polypeptide. About t w o - t h i i are histologically or biologically malignant, and about half have spread to the liver when the tumor is identified. Malignant gastrinomas usually grow slowly. From one-half to two-thirds of patients with gastrinomas have metastases, most commonly to regional lymph nodes and liver; spread may also be to peritoneal surfaces, spleen. bone, skin, or mediastinum. Gastrinomas have light-microscopic similarities to carcinoid tumors and may be mistaken for carcinoid tumors, especially when arising from the mucosa of the small intestine or stomach. Pancreatic isletcell hyperplasia occurs in approximately 10 percent of patients with the Z-E syndrome. Hyperplasia of the islets, accompanying recognizable or unidentified gastrinoma. appears to be an association or a consequence rather than a cause of excess gastrin release, since gastrin is not present in the hyperplastic tissue. In most gastrinomas approximately 90 to 95 percent of gastrin is in the form of heptadecapeptide gasmn ((2-17 or little gasmn), with most of the remainder being big gastrin (G-34).In contrast, approximately two-thirds of circulating gastrin in gastrinoma patients is G34; most of the remainder of circulating gastrin is G-17. However, smaller amounts of even larger forms of gastrin and smaller gastrin fragments can be detected in the serum. The parietal cell mass is substantially expanded to from three to six times normal, secondary to the trophic effects of gastrin on parietal cells. In from 20 to 25 percent of patients with the Z-E syndrome. the gastrinoma is a component of the multiple endocrine neoplasia type I (MEN-I) syndrome, an autosomal dominant disorder with a high degree of penetrance and great variability in expressivity. Patients with MEN-I may have hyperplasia, adenomas, or carcinoma involving the parathyroid glands, pancreatic islets, and pituitary: the organs CHAPTER 235 PEFTIC ULCER I251 involved are in that order of frequency. Hyperparathyroidism is present in 87 percent of patients with the MEN-I syndrome. and gastrinoma is present in approximately half of these patients (see chap. 334). While the true incidence of the Z-E syndrome is not known, estimates are that it accounts for 0.1 to 1 percent of peptic ulcers. The Z-E syndrome may occur at any age. but initial manifestations are most common between ages 30 and 60. CLINICAL FEATURES From 90 to 95 percent of patients with gastrinomas develop ulceration of the gastrointestinal tract at some point during the course of their disease. Profound gastric hypersecretion is found in most, but not all, patients. Symptoms are often similar to those seen in patients with typical peptic ulcer disease. However, the ulcer symptoms may be more fulminant, progressive, and persistent, and usually respond poorly to usual medical and surgical peptic ulcer treatment programs. The anatomic site of the ulcers in patients with gasmnoma is similar, but not identical, to that of patients with common types of peptic ulcer. About 75 percent of gastrinoma patients have ulcers in the first portion of the duodenum or in the stomach; these are usually single, but may be multiple. When multiple ulcers occur, they are frequently located not only in the first portion of the duodenum, but also in the remainder of the duodenum or even the jejunum. In one large series, 14 percent of the ulcers were found in the duodenum beyond its first portion, and 11 percent in the jejunum. Prompt recurrence of ulcer, often with hemorrhage or perforation, after peptic ulcer surgery without total gastrectomy (in which the Z-E syndrome had not been recognized) is characteristic of gastrinoma. Diarrhea occurs in about 40 percent of patients, and about 7 percent of patients with gastrinoma may have diarrhea in the absence of ulcer disease. The diarrhea is due to the outpouring of large amounts of hydrochloric acid into the proximal duodenum and can be reduced or eliminated by aspiration of gastric juice. The excessive acid has been shown to reduce the pH within the lumen of the proximal and distal jejunum to as low as 1 and 3.6, respectively. Inflammatory changes may develop in the mucosa of the small intestine, presumably secondary to the injurious effect of the increased amounts of acid and pepsin. Steatorrhea, which is less common than diarrhea, appears to result from inactivation of pancreatic lipase by the large concentration of acid in the proximal small intestine and from decreases in luminal bile acids. The decrease in bile acid concentration of the intraluminal contents is caused by precipitation of the major bile acids at low pH. This leads to impaired micelle formation which, in turn, reduces the intestinal absorption of fatty acids and monoglycerides (see Chap. 237). Vitamin BI2rnalabsorption, not correctable by addition of intrinsic factor, has been detected in some patients with the Z-E syndrome. Although the secretion of intrinsic factor appears normal, the reduced pH within the gut interferes with intrinsic factor mediation of vitamin B,, absorption. This can be corrected by neutralization of the intestinal contents. The mechanism by which low pH in the gut interferes with intrinsic factor action is not known. Diarrhea in patients with gastrinoma is invariably accompanied by gastric acid hypersecretion. (This does not occur in patients with common duodenal ulcer with similar rates of hypersecretion of gastric acid; the reason for this difference is not known.) Severe diarrhea is also seen with other nonbeta islet-cell tumors of the pancreas, which are usually associated with hyposecretion of gastric acid or even achlorhydria [pancreatic cholera or WDHA (watery diarrhea, hypokalemia. and achlorhydria) syndrome]. In most cases, the pancreatic cholera syndrome appears to be due to tumor release of VLP (see Chaps. 334 and 255). DIAGNOSIS The presence of a gastrinoma should be suspected in patients with a compatible clinical history, especially in those with evidence of marked acid hypersecretion. Two-thirds of gastrinoma patients have basal gastric acid outputs (BAO) which exceed 15 meq/h. In some instances the basal output may be greater than 100 meq/h. However, as stated earlier, there is substantial overlap in the rates of gastric acid secretion among patients with gastrinoma, duodenal ulcer, and normal subjects. Gasmnoma patients often have basal acid output rates which are greater than 60 percent of those induced by maximal stimulation (MAO). In most normal subjects and duodenal ulcer patients basal acid secretory rates are less than 60 percent of maximal secretion. However, because of frequent patient variations, with exceptions to these guidelines by patients with gastrinomas and common duodenal ulcers, the use of the BAO/MAO ratio is of no value in the certain identification of gastrinoma patients. Some radiographic features may suggest and support the diagnosis of the Z-E syndrome. Large mucosal folds may be demonstrated in the stomach, duodenum, and, in some instances. the jejunum. The lumen of the stomach and small intestine often contains large amounts of fluid. Radiographic features of most ulcers in these patients, except when they are multiple or distal in location, are similar to the common peptic ulcer. Arteriography is of limited value in identifying patients with gastrinoma; primary tumors or hepatic metastases demonstrated at surgery have been identified in only from 20 to 30 percent of gastrinoma patients. Some reports suggest that computerized axial tomography may be of slightly greater value in identifying primary or metastatic gastrinoma. Endoscopic retrograde pancreaticoduodenography (ERCP) has not proved to be of assistance in the diagnosis or exclusion of pancreatic gastrinomas. A small number of duodenal wall gastrinomas have been identified and confirmed histologically by duodenoscopy. The diagnosis in a patient with clinical features consistent with the Z-E syndrome depends upon the demonstration of increased serum gastrin levels by radioimmunoassay. Fasting serum gastrin levels in normal subjects and patients with typical duodenal ulcer average approximately 40 to 50 pg/mL and usually do not exceed 150 pg/mL. Patients with gastrinoma almost always have fasting serum gastrin levels which are greater than 200 pg/mL and have been reported as high as 450,000 pg/mL. Approximately half of these patients have fasting serum gastrin levels which are less than lo00 Pg/d. Several provocative tests have been used to evaluate patients with possible gastrinoma, especially in those who do not exhibit pronounced hypergastrinemia (i.e., serum gastrin greater than 1000pg/mL). These tests utilize the measurement of serum gastrin levels in response to intravenous calcium infusion, secretin injection, or ingestion of a standard test meal (see Table 235-1). In the recrcrin injection resr, secretin (Kabi secretin, 2 units per kilogram) is given intravenously over 30 to 60 s. (Boots secretin is approximately one-sixth as potent as Kabi secretin prepared by the Karolinska Institute. Stockholm. Boots secretin should not be used, since it contains large amounts of gastrin-like material which is immunoreactive with antibodies to gastrin and, therefore, can spuriously increase serum gastrin concentrations.) Gastrin is measured in serum samples obtained before injection of secretin and at 5-min intervals thereafter for 30 min. In normal individuals and patients with common duodenal ulcer, secretin produces either no change or small reductions or small increases in serum gastrin levels. In contrast, in gastrinoma patients intravenous secretin induces substantial increases in serum gastrin. The gastrin levels increase promptly, usually at 5 min, (and virtually always by 10 min), by at least 200 pg/mL. The calcium infurion test involves constant 3-h intravenous infusion of calcium gluconate (5 mg calcium per kilogram per hour). Serum samples for gastrin measurements are obtained before and at 30-min intervals for 4 h after initiation of infusion. In gastrinoma patients serum g a s h concentrations usually increase above the basal serum gastrin by at least 50 percent or by more than 400 pg/mL. The third provocative test involves the feeding of a standard meal; gastrin is measured in serum samples obtained before the meal and at 1.5-min intervals for 90min. In gastrinoma patients peak serum gastrin levels do not increase (or increase minimally) and do not reach values 50 percent greater than fasting levels (see Table 235-1). The secretin injection test is the provocative test of greatest value CHAPTER 285 UEGALOBLASIC ANEMIAS 1501 the posterior and lateral columns undergo demyelination, and the Laboratory examination will reveal hypergastrinemia and pentagastrin- cerebrum itself. Signs and symptoms include numbness and pares- fast achlorhydria as well as the hematologic and other laboratory hesias in the extremities (the earliest neurologic manifestations), abnormalities discussed below in "Diagnosis." weakness, ataxia, and poor finger coordination. There may be Through appropriate replacement therapy, patients with pernicious sphincter disturbances. Reflexes may be diminished or increased. anemia should experience complete and lifelong comction of all The Romberg and Babinski signs may be positive, and position sense abnormalities which are due to vitamin BI2deficiency, except to the a d vibration sense are usually diminished. Disturbances of mentation extent that irreversible changes in the nervous system may have will vary from mild initability and forgetfulness to severe dementia occurred prior to treatment. These patients, however, are unusually or frank psychosis. It should be emphasized that occasionally neu- subject to gastric polyps and have about twice the normal incidence rologic disease may occur in a patient with a normal hematocrit. of cancer of the stomach. In view of the latter complication, patients In the usual patient, in whom hematologic problems predominate, should be followed with frequent stool guaiac examinations together the blood and bone marrow show characteristic megaloblastic changes with further diagnostic studies when indicated. which are described under "Diagnosis" below. The anemia may be very severe-hematocrits of 15 to 20 are not infrequent-but is surprisingly well tolerated by the patient because it develops so slowly. Postgastrectomy Following total gastrectomy or extensive damage to gastric mucosa as, for example, by ingestion of comsive agents, megaloblastic anemia may develop because the source of intrinsic factor has been removed. In such patients the absorption of orally Pernicious anemia The most common cause of vitamin BIZdeficiency in temperate climates is pernicious anemia, in which intrinsic factor secretion ceases owing to atrophy of the gastric mucosa. It is most frequently seen in individuals of northern European descent and is much less common in southern Europeans, blacks, and Orientals. Men and women are equally affected. It is a disease of the elderly, administered vitamin BIZis impaired. Megaloblastic anemia may also follow partial gastrectomy, but the incidence is lower than after total gastrectomy, in which vitamin BIZmalabsorption occurs in 100 percent of patients. The cause of vitamin B I Zdeficiency after partial gastrectomy may be intestinal over,gowth of bacteria, but it does not always respond to antibiotics. the average patient presenting near age 60; it is rare under 30, intestinal organisms The macrocytic anemia seen in association although typical pernicious anemia can be seen in children under 10 with intestinal strictures, diverticula, anastomoses, and "blind loops" (juvenile pernicious anemia). Inherited conditions in which a histo- may be attributed to colonization of the small intestine by large logically normal stomach secretes either an abnormal intrinsic factor masses of bacteria which divert vitamin BIZfrom the host. Steatorrhea or none at all will cause vitamin BIZdeficiency which appears in may also be seen under these circumstances, because bile salt infancy or early childhood. metabolism is disturbed when the intestine is heavily colonized with On the basis of incomplete evidence, pernicious anemia is currently bacteria. Hematologic responses have been observed after adminis- thought to be caused by an autoimmune reaction against gastric tration of oral antibiotics such as tetracycline and ampicillin. parietal cells. There is considerable evidence for immunologic ab- Megaloblastic anemia is seen, in Scandinavia especially, in persons normalities in pernicious anemia. The incidence of pernicious anemia harboring the tapeworm D. larum. The anemia has been attributed to is substantially increased in patients with other diseases thought to competition by the worm for vitamin BIZ.Destruction of the worm be of immunologic origin, including Graves' disease, myxedema. eliminates the problem. thyroiditis, idiopathic adrenocortical insufficiency, vitiligo, and hypoparathyroidism. Patients with pernicious anemia also have abnormal circulating antibodies related to their disease: 90 percent have antiparietal cell antibody while 60 percent have anti-intrinsic factor antibody. Antiparietal cell antibody is also found in 50 percent of patients with gastric atrophy without pernicious anemia as well as in 10 to 15 percent of an unselected patient population, but anti-intrinsic factor antibody is usually absent from these patients. Relatives of patients with pernicious anemia show an increased incidence of the disease, and even clinically unaffected relatives may have antiintrinsic factor antibody in their serum. A final point supporting an immunologic basis forpernicious anemia is the fact that corticosteroids have been reported to reverse the disease both pathologically and clinically. The destruction of parietal cells in pernicious anemia is thought to be mediated by the cellular immune system. Humoral factors such as anti-inmnsic factor antibody probably have little role in the pathogenesis of the disease, a view supported by the observation that pernicious anemia is unusually common in patients with agamrnaglobulinemia. Pathologically, the most characteristic finding in pernicious anemia is gastric atrophy which involves only the acid- and pepsin-secreting ileal abnormalities Vitamin B,,deficiency is commonly found in tropical sprue, while it is an unusual complication of nontropical sprue (gluten-sensitive enteropathy; see Chap. 237). Virtually any disorder which compromises the absorptive capacity of the distal ileum can result in vitamin BIZdeficiency. Specific entities include regional enteritis, Whipple's disease, and tuberculosis. Segmental involvement of the distal ileum by disease can cause megaloblastic anemia without any other manifestations of intestinal malabsorption such as steatorrhea. Vitamin BIZmalabsorption is also seen after ileal resection. The Zollinger-Ellison syndrome (intense gastric hyperacidity due to a gastrin-secreting tumor) may cause vitamin BIZmalabsorption by acidifying the small intestine. This will retard the transfer of the vitamin from R binder to intrinsic factor and will impair the binding of the vitamin Blz-IF complex to the ileal receptors. Chronic pancreatitis may also cause vitamin B,,malabsorption by impairing the transfer of the vitamin from R binder to intrinsic factor. This abnormality can be detected by tests of vitamin BIZabsorption (see below, Schilling test), but it is invariably mild and never causes clinical vitamin BIZdeficiency. Finally, there is a rare congenital disorder, described by Imerslund, in which a selective defect in vitamin B,, absorption is accompanied by proteinuria. portion of the stomach; the antrum is spared. Other pathologic FOLIC ACID DEflClENCY Patients with folic acid deficiency are changes, which are secondary to the deficiency of vitamin B,,, include more apt to be malnourished than those with vitamin B,2 deficiency. megaloblastoid alterations in the gastric and intestinal epithelium and Accordingly. they are likely to appear wasted. The gastrointestinal the neurologic changes described above. The abnormalities in the manifestations are similar to, but may be more widespread and more gastric epithelium are evident as cellular atypia in gastric cytology severe than those of, pernicious anemia. Diarrhea is often present, specimens. a finding which must be carefully distinguished from the and cheilosis and glossitis are also encountered. However, in conIrast cytologic abnormalities seen in gastric malignancy. to vitamin B,z deficiency, neurologic abnormalities do not occur. The clinical manifestations are primarily those of vitamin BIZ The hematologic manifestations of folic acid deficiency are the deficiency, as described above. The disease is of insidious onset and same as those of vitamin BIZdeficiency. Folic acid deficiency can progresses slowly. An additional physical finding is the tendency of generally be attributed to one or more of the following factors: patients with pernicious anemia to be fair-haired or prematurely gray. increased demand for folate, inadequate intake. and malabsorption. I502 PART NINE HENATOLOGY AND ONCOLOGY Inadequateintake Folic acid malnutrition is commonly encountered megaloblastic changes in folate and vitamin BI2deficiency might among a number of groups. Alcoholics frequently become folate- have a similar biochemical origin. deficient because their main source of caloric intake is in the form 3 Nitrous oxide. Nitrous oxide inhalation causes the destruction of of alcoholic beverages. Distilled spirits are virtually devoid of folic endogenous vitamin BIZ.As ordinarily used, this anesthetic does acid, while beer and wine do not contain enough of the vitamin to satisfy the daily requirement. In addition, alcohol may interfere with not destroy enough of the vitamin to cause clinical manifestations. Repeated or protracted exposure, however, may lead to a mega- folate metabolism. Narcotic addicts are also prone to become folate- loblastic anemia. Fatal megaloblastic anemia has been reported in deficient because of malnutrition. Many indigent and elderly individ- patients with tetanus who were given nitrous oxide continuously uals who subsist primarily on canned foods or "tea and toast" and for weeks. occasional teenagers whose diet consists of soft drinks and potato 4 Others. A number of drugs antagonize folate by mechanisms which chips develop folate deficiency. are poorly understood but are thought to involve an effect on increaseddemand Tissues with a relatively high rate of cell division such as the bone marrow or gut mucosa have a large requirement for folate. Therefore, patients with chronic hemolytic anemias or other causes of very active erythropoiesis may become deficient if their absorption of the vitamin by the intestine. In this category are certain anticonvulsants [phenytoin (Dilantin), primidone (Mysoline)] and phenobarbital (Luminal). Megaloblastic anemia induced by these agents is mild. high folate requirement is not met by dietary intake. Likewise, a pregnant woman may become deficient in folic acid because of the high demand of the developing fetus. Folate deficiency may also occur during the growth spurts of infancy and adolescence. OTHER Hereditary Megaloblastic anemia may be seen in several hereditary disorders. It is a regular feature of orotic aciduria, a defect in pyrimidine metabolism which is also characterized by retarded growth and development as well as the excretion of large amounts Malabsorption Folic acid deficiency is a common accompaniment of tropical sprue. Both the gastrointestinal symptoms and malabsorp tion are improved by the administration of either folic acid or antibiotics by mouth. Patients with nontropical sprue (gluten-sensitive enteropathy) may also develop significant folic acid deficiency which parallels other parameters of malabsorption. Similarly, alcohol-related folate deficiency may be due in part to malabsorption. In addition, other primary small-bowel disorders are sometimes associated with vitamin deficiency. These entities are all discussed in Chap. 237. DRUGS Next to deficiency of folate or vitamin BIZ, the most common cause of megaloblastic anemia is drug ingestion. Drugs which cause megaloblastic anemia do so by interfering with DNA synthesis, either directly or by antagonizing the action of folate. They can be classified as follows: of orotic acid, and which is due to a deficiency of orotidylic decarboxylase and phosphorylase. Megaloblastic anemia has been reported in a single case of the Lesch-Nyhan syndrome, a condition resulting from a deficiency of hypoxanthine-guanine phosphoribosyltransferase whose clinical manifestations include gout, mental retardation, and self-mutilation. It has also been described in methylmalonic aciduria due to a defect in the biosynthesis of the two metabolically active alkyl cobalamins, though it is not seen in methylmalonic aciduria due to methylmalonyl CoA mutase deficiency. Congenital folate malabsorption causes megaloblastic anemia, accompanied by ataxia and mental retardation. Megaloblastic anemia has been reported to accompany the congenital deficiency of other folatemetabolizing enzymes including formiminotransferase, dihydrofolate reductase, and Wmethyltetrahydrofolate reductase. These deficiencies are less well documented than is congenital folate malabsorption. I Direct inhibitors of DNA synthesis. The drugs in this category are used in the treatment of malignancy. Their efficacy depends on their ability to disrupt DNA synthesis. They include purine analogues (&thioguanine, azathioprine, 6-mercaptopurine), pyrimidine analogues (5-fluorouracil, cytosine arabinoside), and certain other drugs which interfere with DNA synthesis by a variety of mechanisms (hydroxyurea. procarbazine). 2 Folate antugonisrs. The most toxic of these is methotrexate, an exceedingly powerful inhibitor of dihydrofolate reductase which is used in the treatment of certain malignancies. Much less toxic, but Megaloblastic changes as well as multinuclearity of red blood cell precursors are seen in the m m w of certain patients with congenital dyserythropoietic anemia, a group of inherited disorders characterized by mild to moderate anemia presenting at any age and pursuing a benign course. Transcobalamin II deficiency, as well as the congenital abnormalities in vitamin B,, absorption described previously, causes pronounced deficiencies in vitamin B,, in infancy or early childhood, with all the accompanying manifestations. Megaloblastic anemia is not seen in hereditary transcobdamin I deficiency. still capable of inducing a megaloblastic anemia, are several weak dihydrofolate reductase inhibitors which are used to treat a variety of nonmalignant conditions. These include pentamidine, uimethoprine, triamterene, and pyrimethamine. The megaloblastic changes in methotrexate poisoning appear to result from the following sequence of events. In methotrexatepoisoned cells, the methylation of dUMP to dTMP is grossly impaired. As a consequence, the phosphorylation of dUMP to dUTP, normally a very minor reaction, becomes a major route of dUMP metabolism. The capacity of a highly specific dUTP pyrophosphatase to degrade dUTP back to dUMP is exceeded under these conditions, and dUTP accumulates in the cell. This dUTP is incorporated into newly synthesized DNA, because DNA Acquired idiopathic anemia Some patients with acquired sideroblastic anemia and other forms of refractory anemia show megaloblastic erythropoiesis. Megaloblastic changes are restricted to the red blood cell series; large granulocyte precursors and giant metamyelocytes are not seen (seebelow). Both are associated with an increased incidence of acute leukemia. Megaloblastic changes are seen in erythremic myelosis and acute erythroleukemia (di Guglielmo) where red blood cell precursors are prominently involved. Here, the marrow is characterized by bizarre erythroid maturation, with multinuclearity and multipolar mitotic figures in the red blood cell precursors. Erythremic myelosis is discussed further in Chap. 292. polymerase cannot distinguish between dUTP and the closely DIAGNOSIS The finding of significant macrocytosis [mean corpus- related normal substrate, d?Tp. As a result, defective strands of cular volume (MCV) > 96 fl] suggests the presence of a megaloblastic DNA are produced in which T is partly replaced by U. The U- anemia. Other causes of macrocytosis include hemolysis, liver disease, containing regions of these defective strands are recognized by a alcoholism, hypothyroidism, and aplastic anemia. If the macrocytosis specific repair system. which excises them and attempts to replace is marked (MCV > 110 fl), the patient is much more likely to have them with normal DNA. In methotrexate-poisoned cells, however, a megaloblastic anemia. The reticulocyte count is low, and the there is so much dUTP and so little d " P that the new DNA is leukocyte and platelet count may also be decreased, particularly in also likely to be defective. It is this futile cycle of faulty replication. severely anemic patients. The blood smear (Fig. A5-2) demonstrates error excision. faulty repair. etc., which explains the megaloblastic marked anisocytosis and poikilocytosis, together with macroovalo- pattern of DNA synthesis in methotrexate-poisoned cells. The cytes which are large. oval. fully hemoglobinized erythrocytes typical I852 PART TEN ENDOCRINOLOGY A?4D METABOLISM stein syndrome to only occasional patients with the infertile male external genitalia are well developed and the patients masculinize syndrome. The patients with a negative family history are believed normally at puberty, it is assumed that during the critical stage of to be the result of new mutations. embryonic sexual differentiation the fetal testes produced a normal Hormone dynamics are similar in all disorders of the androgen amount of androgen. However. miillenan regression does not occur receptor. Plasma testosterone levels and rates of testosterone produc- for one of three possible reasons: failure of the fetal testis to produce tion by the testes are normal or higher than normal. The elevated miillenan-inhibiting substance. poor timing of the release of rniillerian- rate of testosterone production is caused by the high mean plasma inhibiting substance, or failure of the tissues to respond to this level of LH, which in turn is due to defective feedback regulation hormone. To minimize the chance of tumor development and to caused by resistance to the action of androgen at the hypothalamic- maintain virilization, a primacy or staged orchiopexy should be pituitary level. Elevated LH concentration is probably responsible performed. Malignancy in the uterus or vagina has not been described, also for the increased estrogen production by the testes (see Chap. and because the vasa deferentia are closely associated with the broad 330). (In normal men most estrogen is derived from peripheral ligaments, the uterus and vagina should be left in place to avoid formation from circulating androgens, but when plasma LH is elevated disruption of the vasa deferentia during removal and consequently to the testes secrete significant amounts of estrogen into the circulation.) preserve possible fertility. Thus, resistance to the feedback regulation of LH secretion by circulating androgen results in elevated plasma LH levels, and this in turn results in the enhanced secretion of both testosterone and estradiol by the testes. Gonadotropin levels rise even higher (and menopausal symptoms may develop) when the testes are removed. indicating that gonadotropin secretion is under partial regulatory control. Presumably, in the steady state and in the absence of an androgen effect, estrogen done regulates LH secretion. a control that is purchased at the expense of an elevated plasma estrogen concentration for a male. The hormonal changes in the infertile male syndrome are similar to those in the other receptor disorders but less marked. Some men with this syndrome do not have an elevation of plasma LH or plasma testosterone. Feminization in these disorders is the result of two interlocking phenomena. First, androgens and estrogens have antagonistic effects at the peripheral level, and virilization occurs in normal men when the ratio of androgen to estrogen is 100 to 1 or greater; in the absence of androgen action the cellular effect of estrogen is unopposed. Developmental defects of the male genitalia HYPOSPADIAS Hypospadias is a congenital anomaly in which the urethra terminates in an abnormal position along the midline of the ventral surface of the penis at some site between the normal urethral meatus and the perineum. This malformation is often associated with some degree of ventral contraction and bowing of the penis (chordee). The disorder occurs in 0.5 to 0.8 percent of male births in the United States. It is common to categorize hypospadias as glandular (involving the glans penis), penile. or perineoscrotal. Since penile development is mediated by androgens, it is assumed that hypospadias results from some defect in earlier androgen formation or androgen action during embryogenesis. Indeed hypospadias occurs in most disorders of male sexual differentiation. A rare cause of hypospadias is maternal ingestion of progestational agents early in pregnancy. However, the known causes (single gene defects, chromosomal abnormalities, and maternal drug ingestion) at best can account for only about one-fourth of cases, and the etiology of most remains unknown. The management is surgical. Second, the production of estradiol is greater than that of the normal male (although less than that of the normal female). Variable degrees of androgen resistance coupled with variably enhanced estradiol production result in different degrees of defective virilization and enhanced feminization in the four clinical syndromes. Each of these four syndromes is the result of an abnormality of the androgen receptor. Initially fibroblasts cultured from the skin of some subjects with complete testicular feminization were shown to have a near absence of high-affinity dihydrotestosterone binding. Subsequently, other individuals with complete testicular feminization as well as subjects with incomplete testicular feminization, Reifenstein syndrome, and the infertile male syndrome have been found to have either a decreased amount of an apparently normal receptor or a qualitatively abnormal androgen receptor. Receptor-positive resistance. A category of androgen resistance that does not appear to involve either the Sa-reductase or the androgen receptor was first identified in a family with the syndrome of testicular feminization. Subsequent patients have been described with a variety of phenotypes ranging from incomplete testicular feminization to findings similar to those in the Reifenstein syndrome. The hormonal profile is similar to that seen in the receptor disorders. The site of the molecular abnormality in these patients is unclear. It could be due to defects of the androgen receptor too subtle to be detected by the usual assay. If the defect is truly distal to the receptor. there could be failure of generation of specific messenger RNA or an abnormality of RNA processing. Indeed. the disorder may represent a heterogeneous group of molecular abnormalities. Management depends on the phenotype. CRYPTORCHIDISM The normal descent of the testis is perhaps the most poorly understood portion of male sexual differentiation, both in regard to the nature of the forces that result in the movement and to the hormonal factors that regulate the process. In anatomic terms testiculardescent can be divided into three phases: (1) transabdominal movement of the testis from its site of origin above the kidney to the inguinal ring, (2) formation of the opening in the inguinal canal (processus vaginalis) through which the testis exits the abdominal cavity, and (3) actual movement of the testis through the inguinal canal to its permanent site in the scrotum. This entire process occurs over a 6- to 7-month period during gestation. beginning at about the sixth week and not completed in some normal individuals until after birth. Whatever its involvement, androgen is probably not the sole hormone responsible for normal descent. Failure of any of the above anatomic events can be responsible for the failure of descent of one or both testes that occurs in 3 percent of full-term males and 30 percent of premature male infants. Cryptorchidism can be classified as intraabdominai, retractile (intermittently in the groin), obstructed (permanently in the groin), and high scrotal. Most are retractile and descend permanently by 6 weeks to 3 months of age so that the incidence of failure of descent in late teenagers is only 0.6 to 0.7 percent. It is this latter category that requires intervention. The cryptorchid testis functions p r l y after puberty, but the extent to which maldescent is the result of an abnormality of the testis or the cause of abnormal function is unknown. Two g e n e d theories have been advanced as to the etiology-inadequate intraabdominal pressure and deficient endocrine function of the testis either because of deficient testosterone synthesis or inadequate formation Persistent milllerian duct syndrome Men with this disorder have of miillenan-inhibiting substance. Indeed, hereditary defects that normal penile development but have in addition bilateral fallopian result in inadequate development of intraabdominal pressure or tubes, a uterus, and an upper vagina, and variable development of inadequate development of the testes themselves can cause cryptor- the vas deferens. The subjects commonly present with inguinal hernias chidism. As is true for hypospadias, however, the known causes of which contain the uterus, and cryptorchidism is common. Most have cryptorchidism constitute only a small fraction of the cases, and the uninformative family histones, but several pairs of siblings have been etiology in most remains to be identified. Two complications of described in whom the condition must be inherited either as an cryptorchidism are important: spermatogenesis cannot occur at the autosomal recessive or an X-linked recessive mutation. Because the temperature of the abdominal cavity, and it is therefore necessary to CHAPTER W MSORMRS AFFECnNG MULTIPLEENOOCRlW SYSTEMS I853 correct the process as early as possible to allow possible fertility. However. the fact that infertility is common in men who have been treated for unilateral as well as bilateral cryptorchidism suggests that maldescent is usually the consequence rather than the cause of the testicular malfunction. There is also a greater frequency of malignancy in undescended testis, and all should be surgically corrected for this to pituitary dysfunction such as headaches, visual field defects, and secondary amenorrhea. and ( 5 ) multiple lipomas of the skin. A minority (probably <IO percent) come to medical attention with acromegaly, Cushing's syndrome. nonfunctional thyroid adenomas. hyperthyroidism. hepatomegaly (due to metastatic liver disease). or Rushing (associated with the carcinoid syndrome). reason (see Chap. 297). Parathyroid involvement in MEN I may be asymptomatic for prolonged periods. although most patients eventually show some REFERENCES signs of hyperparathyroidism. Tumors of the islet cells may elaborate excessive insulin or gasmn. Insulinomas cause hypoglycemia (Chap. DE LA CHAPELLE A: The etiology of maleness in XX men. Hum Genet 58:105, 1981 DoNAnoe PK et al: M u d gonadal dysgenesis. pachogcmsisand management. J Pediau Surg 14287. 1979 EDMANCD et al: Embryonic testicular regression: A clinical spectrum of XY agonadal individuals. Obsta Gynecol49208. 1977 GEORGE FW,WIWN JD: Sexual differentiation. in Campbell's Texrbook 4 Urology. 5th 4, PC Walsh et aJ (cds).Philadelphia. Saunden. 1986. pp 1804-1818 GORDONDL et al: parhologic testicular findings in Klincfeltcr's syndrome. 47.XXY vs 46.XYl47.XXY. Arch Intern Med 130:726. 1972 G M m N JE et al: Congenital absence of the vagina. The Mayer-Rokitansky-Kuer- Hauscr syndrome. Ann lntcrn Med 85:224, 1976 -, WILSONJD: Disorder of sexual differentianon, in CumpbeN's Textbook of Urology.5th ed. FC Walsh et al (eds).fiiladclphia, Saunden. 1986. pp 1819-1855 GRUMBACMHM, CONTEFA: Disorders of sexual differentiation. in Williams' Texrbmk of Endocrinology, 7th ed,ID Wilson, DW Foster (eds). Philadelphia, Saunden. 1985. pp 312-401 LEONARD JM et al: The classification of Klinefelter's syndrome, in Generic Mechanism of Sexual Development. HL Vallet, IH Porter (eds). New York. Academic, 1979 MCD~NOUGfHf i et d:Phenotypic and cytogenetic findings in eighty-two patienu with ovarian failurc-changing trends. Fcrtil Steril 28:638. 1977 NEW M et ak Congenital adrenal hyperplasla and related conditions. in Metabolic Baris oflnherired Disease. 5th ed. JB Stanbury et al (eds). New Yo&. McGraw-Hill, 1983. pp 973-1000 S I H R ~ Nk Disorders of Sexual Differenriarim.New York. Academic, 1976, p 466 -: Gonadal dysgenesis and sex chromosome abnormalities: Phc~pic-Laryotypic correlations. in Generic Mechonimrr of Sexual Dcvelopmcnr, HL Vallet. M Porter (eds).New Yo&, Academic, 1979 -et al: XY gonadal dysgenesis: Genetic heterogeneity b& upon clinical observations. H-Y antigen stam and segregation analysis. Hum Genet 58:91. 1981 VAN NIEKERIWCA: True hermaphralitism. Pediatr Adolesc EndoCrinol 8530, 1981 WIWN JD et al:The androgen resistance syndromes: Sa-Reducme deficiency. testicular fetniniition and related disorden, in The Metabolic Baris of hherited Disease. 5th ed. IB Stanbuy et al(eds). New York, McGraw-Hill, 1983, pp 1UO1-1026 Z\HW et al: Mixed gonadal dysgenesis. A case report and review of the world litcrarurr. Acta EndocMol Suppl 197:3, 1975 329). whereas excess gastrin secretion causes the Zollinger-Ellison syndrome with its multifocal or atypically located ulcers and massive hypersecretion of gastric acid. Symptoms may be identical with those of ordinary peptic ulcer. but there is a higher incidence of complications, including perforation, bleeding, and obstruction. Diarrhea is frequent, often with steatorrhea. Radiographic findings include giant gastric rugae, duodenal nodularity, ectopic ulcers in the esophagus, lower duodenum, and jejunum. and intestinal hyperperistalsis. Associated endocrine abnormalities consistent with the MEN syndrome are present in over one-quarter of patients with the Zollinger-Ellison syndrome and in half of the first-degree relatives of such patients. MEN I should be considered in a patient with the Zollinger-Ellison syndrome even when no other endocrine abnormalities are apparent. Islet-cell tumors may also produce glucagon. vasoactive intestinal polypeptide (VIP), prostaglandins, adrenocorticotropic hormone (ACTH), parathyroid hormone. antidiuretic hormone (ADH), serotonin, somatostatin, calcitonin. and pancreatic polypeptide (also see Chap. 329). Glucagonomas cause hyperglycemia. weight loss, stomatitis, and a peculiar skin rash called necrorizingmigratory erythema. VIP and prostaglandins have been implicated in the watery diarrhea (pancreatic cholera) syndrome sometimes seen in MEN I. Cushing's syndrome may be due to an adrenal adenoma or may occur as a consequence of ectopic ACTH production by an islet tumor or a thymic carcinoid. Some adrenal adenomas produce aldosterone or adrenal androgens. Involvement of the thyroid gland is uncommon in MEN I, but goiter. simple adenoma, and thyroiditis have all been reported. Other features of MEN I include small-intestinal and bronchial carcinoid tumors, schwannomas. thymomas, multiple li- pomas, inclusion cysts, and cutaneous leiomyomas. Patients with MEN I may develop symptoms at any age. but the 334 condition presents rarely in childhood or after the age of 60. Affected DISORDERS AFFECTING MULTIPLE individuals may demonstrate multiple endocrine system involvement ENDOCRINE SYSTEMS simultaneously, or months to years may elapse between the discovery of one adenoma and the appearance of the next. Once the diagnosis R. NEIL SCHIMKE is established, the patient must be surveyed periodically for appearance of new facets of the syndrome. By the same token, all first-degree relatives should be studied. A reasonable approach for screening Multiple endocrine gland hyper- or hypofunction can result from mechanisms other than a primary abnormality in the hypothalamicpituitary axis. While not common, certain of the conditions that affect multiple endocrine systems are inherited and thus have significance out of proportion to their frequency. relatives at risk is as follows: (1) review history for symptoms of peptic ulcer disease. hypoglycemia, renal calculi, lipomas, or hypopituitarism; (2) examine for multiple lipomas: (3) assay serum calcium, phosphorus, prolactin. and gastrin. Upper gastrointestinal series and sella turcica x-rays have proved of no value as screening tests. Serum pancreatic polypeptide determinations may be useful in SYNDROMES WITH MULTISYSTEM HYPERFUNCTION centers where the assay is available. The fundamental lesion in MEN I is unknown. Some have considered the basic abnormality to be in the islet cells with their extensive capability for hormone synthesis, attributing changes in the MULTIPLE ENDOCRINE NEOPLASIA, TYPE I (MEN I) This disor- other glands to secondary effects of islet hormone hypersecretion. der, also termed the Werner syndrome, comprises tumors or hyper- Others have classified MEN I as a neurocrestopathy implicating faulty plasia of the parathyroids, pancreatic islet cells, pituitary, adrenal differentiation or regulation of the embryonic neural crest, which is cortex, and thyroid. The clinical presentation is variable, depending the anlage of at least part of the endocrine system. The endocrine on which of the potentially affected glands is hyperfunctioning at the components of the neural crest have been classified into a subsystem time of diagnosis, About two-thirds of patients have adenomas of of APUD cells, so named because of their capacity for amine two or more endocrine systems, and one-fifth develop tumors of three precursor uptake and decarboxylation. The evidence supporting the Or more systems. contention that all APUD cells are derived from neural crest is not The majority of affected subjects present with one of the following strong; instead. cells of diverse origin probably develop similar problems: (1) peptic ulcer and its complications. (2) hypoglycemia, ch;iracteristics; i.e., they represent a structural-functional conver- (3) hypercalcemia and/or nephrocalcinosis, (4) complaints referable gence. 1 i II i I 1854 PART TEN ENDOCRINOLOGY AND METABOLISM The pituitary and parathyroid tumors in MEN I are usually benign, removal of the tumor and in concert with selective venous catheter- but pancreatic tumors are frequently malignant. Surgical removal of ization may be utilized to locate distant metastases that are surgically the affected gland is the usual therapy, although standard radiation accessible. Neither standard radioiodine nor x-ray therapy is helpful techniques may be employed for the pituitary tumors, and homer- in disseminated medullary thyroid cancer, and chemotherapy has gocryptine is useful in prolactinomes. Hyperparathyroidism may be been of limited value (see Chap. 324). The pheochromocytomas are ! due to a single adenoma, but diffuse hyperplasia of more than one usually benign and are also treated surgically. Unresectable malignant gland is more common. In some centers selective venous catheter- pheochromocytoma requires long-term sympathetic blockade. A new !i I ization with measurement of serum parathyroid hormone levels can radiopharmaceutical, meru-iodobenzyl guanidine, shows promise as be used to differentiate between those possibilities. Since new both a diagnostic and a therapeutic agent. I ! 1 adenomas may arise in normal glands left after removal of an adenoma (and since second operations are difficult because of scar formation), some have advocated removal of all the parathyroid glands with MULTIPLEENDOCRINENEOPLASIA,TYPE 111(MEN111OR IlB) MEN III also consists of medullary thyroid carcinoma and pheochromo- I transplantation of extirpated fragments into the thigh or foreann, cytoma, but affected individuals have striking dysmorphic features i~ I where they can be easily removed should hyperparathyroidism recur. Successful transplantation obviates the need for long-term therapy of such as neuromas of the,conjunctival, labial, and buccal mucosa, the tongue, the larynx, and the gastrointestinal tract; hence the alternate hypoparathyroidism. In hypergasmnemia due to islet-cell lesions, designation of the condition as the mucosal neuroma syndrome. Other I total gastrectomy has been used to prevent recurrent peptic ulcers, physical findings include enlarged corneal nerves, "blubbery" lips, I and in rare cases distant metastases have regressed after this procedure. Histamine-2-receptor antagonists are efficacious in controlling the soft-tissue prognathism, and a habitus resembling that seen in the Marfan syndrome with hypotonia, lax joints, kyphoscoliosis, genu 1i hyperacidity and diamhea seen with hypergastrinemia. valgus, and pes cavus. The patients may have cafk au lait spots or a diffuse lentiginous type of skin pigmentation along with cutaneous ! MULTIPLEENDOCRINENEOPLASIA,TYPE I1 (MENI1OR IIA) MEN neuromas or neurofibromas. Megacolon may occur. 11,also known as the Sippfe syndrome, consists of pheochromocytoma MEN III and MEN 11 appear to be distinct syndromes. For I (frequently bilateral and occasionally extraadrenal). medullary thyroid example, both parathyroid hyperplasia and production of hormones carcinoma (MTC), and, in about half of the reported cases, parathyroid other than calcitonin by MTC are rare in MEN JII. The mean survival hyperplasia. MEN II can be related more directly to abnormal neural of patients with MEN 111is around 30 years compared with 60 years ! crest development than can MEN I, since both the adrenal medulla for those with MEN 11, suggesting a more malignant course in the and the parafollicular or C cells of the thyroid originate in neural former disorder, although histologically the thyroid tumors appear to ! crest. However, there is no evidence that the parenchymal component be identical. As with MEN 11treatment of the medullary carcinoma of the parathyroid glands are so derived. The parafollicular cell is surgical. The unusual physical features of MEN Dl should elaborates calcitonin, the primary marker of medullary carcinoma of immediately suggest the diagnosis of underlying thyroid malignancy. the thyroid. MTC is not common, comprising less than 10 percent MTC has been documented in asymptomatic children with MEN III, of thyroid malignancies. At least 10 percent of MTC cases are i familial, usually appearing as a component of MEN II or MEN III (see below). Medullary carcinoma may also occur in families without I other associated endocrine dysfunction; this form is also transmitted and C-cell hyperplasia has been found at operation as early as 15 months of age. Clinically, the associated pheochromocytomas behave as expected (Chap. 326). 1 as an autosomal dominant trait. MTC may present as a thyroidal McCUNE-ALBRIGHT SYNDROME This condition is characterized ii ! mass or be clinically silent and undetectable by palpation or radioiodine by the triad of polyostotic fibrous dysplasia, cafk au lait spots. and scanning. The diagnosis is usually established by immunoassay of isosexual precocity, the latter occurring predominantly but not exclu- serum calcitonin, provided ectopic sites of calcitonin production can sively in females. The isosexual precocity may be hypothalamic in iI be excluded, e.g., breast, lung, and pancreatic islet-cell tumors. origin, but gonadotropin-independent ovarian function has been Occasionally, basal serum calcitonin levels are borderline in at-risk implicated in some cases (see Chap. 331). Cushing's syndrome, i individuals, and measurement of plasma levels after calcium-penta- gigantism or acromegaly, and hyperprolactinemia may also occur in gastrin infusion can be used to establish the diagnosis. MTC may on affected patients. The Cushing's syndrome may result from abnormal occasion secrete substances other than calcitonin, including ACTH, ACTH production or adrenal adenomas. Nodular toxic goiter and prolactin, serotonin, VIP, histamine, and various prostaglandins, pheochromocytoma have also been reported. The bone lesion resem- resulting in a confusing array of symptoms. bles that seen in hyperparathyroidism, and parathyroid hyperplasia The pheochromocytoma of MEN I1 may produce the classic signs has been described histologically but not clinically. The condition is of catecholamineexcess as described in Chap. 326 or be asymptomatic. usually sporadic, but pedigrees compatible with autosomal dominant Approximately 7 percent of patients who present with pheochromo- inheritance have been seen. The cause of the condition is unknown cytomas also have MTC. Symptoms of hyperparathyroidism rarely (see Chap. 339). bring the patient with MEN 11to initial clinical attention. Examination of cells from both the MTC and the pheochromo- SYNDROMES WITH MULTISYSTEM HYPOFUNCTION cytoma components of MEN 11using X-linked gene markers has led to the conclusion that the inherited defect produces multiple clones POLYGLANDULAR DEFICIENCY SYNDROME (SCHMIDT SYN- of abnormal cells; tumors then develop from a second mutation in DROME) (See also Chaps. 324 and 325) The prototype of a the abnormal clone, accounting for the appearance of varying clinical polyglandular deficiency state is the Schmidt syndrome, originally patterns. Other tumors in MEN II include gliomas, glioblastomas, described as the presence of both Addison's disease and lymphocytic and meningiomas, all of which may be derived from the neural crest. thyroiditis in a single patient. This syndrome has subsequently been The age of the patient at the time of diagnosis varies from 2 to expanded to include any combination of adrenal insufficiency, lym- 67 years. C-Cell hyperplasia of the thyroid may precede development phocytic thyroiditis, hypoparathyroidism, and gonadal failure. Dia- of malignancy by many years, making early screening studies for betes mellitus is a frequent accompaniment. The manifestations may calcitonin elevation mandatory in all family members at risk. The be so extensive as to simulate panhypopituitazisrn;rarely. hue pituitary only effective therapy for MTC is surgical removal of the entire deficiency has been described. The lirst evidence of endocrinopathy thyroid, as the tumor is probably always multifocal in origin. Limited generally appears in adult life. The most significant laboratory feature, node dissection is often indicated since the cancer may progress in addition to the low levels of circulating hormones, is the presence slowly despite an aggressive histologic appearance, and prolonged of antibodies to one or more endocrine glands. The antibodies may survival is seen in patients with known metastatic disease. Serum be directed against a clinically normal gland, but with time hypo- calcitonin levels can be used to assess completeness of surgical function usually supervenes. Additional evidence for an immune