Rectal wall contractility in healthy subjects and in patients with chronic severe constipation.

OBJECTIVE: The aim of this study was to identify differences in rectal wall contractility between healthy volunteers and patients with chronic severe constipation. SUMMARY BACKGROUND DATA: Whether motor function of the rectum contributes to slow-transit constipation is unknown. Measurements of rectal contractility have been performed traditionally with perfused catheters or microtransducers. The rectal barostat is a new technique that quantifies the volume of air within an infinitely compliant intrarectal bag maintained at constant pressure; decreases in bag volume therefore reflect increases in rectal muscular contractility (tone). Increases in volume reflect decreased contractility. METHODS: Fifteen healthy volunteers (ten women and five men; mean age, 36 years) and eight patients (seven women and one man; mean age, 44 years) were studied. Barostat recordings were made for 1 hour before and after a meal. Randomly, neostigmine (0.5 mg) or glucagon (1 unit) was then given intravenously. After 1 hour, the other medication was given. RESULTS: The fasting rectal volume was similar in the patient and control groups (113 +/- 7 mL vs. 103 +/- 4 mL, respectively; p > 0.05). Compared with controls, constipated patients had a significantly lower reduction in rectal volume after a meal (constipated, 35 +/- 8% vs. controls, 65 +/- 7%; p < 0.05) and after neostigmine administration (constipated, 39 +/- 6% vs. controls, 58 +/- 6%; p < 0.05). Moreover, constipated patients had a smaller increase in rectal volume after glucagon administration than did controls (28 +/- 6% vs. 64 +/- 18%, respectively; p < 0.05. CONCLUSIONS: Changes in rectal wall contractility in response to feeding, a cholinergic agonist, and a smooth muscle relaxant were decreased in constipated patients. These findings suggest that an abnormality of rectal muscular wall contractility is present in constipated patients.

Parameters of anorectal and colonic motility in health and in severe constipation.

Anorectal function and colonic transit was assessed in 17 severely constipated patients and 15 age-matched controls. The constipated patients were divided into those who had "immobile perineum" (perineal descent < or = 1.0 cm during attempted defecation) and those who had a normal descent (> 1.0 cm) of the perineum. When constipation was accompanied by an immobile perineum, patients had impaired balloon expulsion, impaired and delayed artificial stool expulsion, decreased straightening of the anorectal angle, decreased descent of the pelvic floor with defecation, and prolonged rectosigmoid colon transit compared with the patients with constipation who had a mobile perineum and with normal controls. The mobile-perineum group differed from controls only in colon transit times, having prolonged total colon transit. Anal sphincter resting pressures, immediate artificial stool expulsion, resting anorectal angles, and electromyography of the external anal sphincter and puborectalis did not differentiate the constipated patients from the controls. We concluded that descent of the perineum of < 1 cm was associated with impaired expulsion, an adynamic anorectal angle, and slowed distal colon transit. This simple sign of pelvic floor function distinguished constipated patients with disordered expulsion from constipated patients with normal pelvic floor function. These patients may respond poorly to surgery and conventional management and would therefore be candidates instead for pelvic floor retraining. Accurate characterization and appreciation of pelvic floor dysfunction in patients with severe chronic constipation may improve the selection for and results of surgical and nonsurgical intervention.

Relationship between anal canal tone and rectal motor activity.

The anal sphincters facilitate fecal continence by maintaining a pressure barrier; whether proximal contractile events influence this barrier is unknown. The aim of this study was to determine whether a relationship exists between anal canal pressures and rectal motor activity. A fully ambulatory system for prolonged pressure recording was developed. In 12 healthy subjects (seven males and five females; mean age, 35 years; range, 22-43 years), a flexible transducer catheter (outside diameter, 4.5 mm) was introduced endoscopically such that sensors were 2, 3, 8, 12, 18, and 24 cm from the anal orifice. Twenty-four-hour spontaneous motor activity was stored in a 2.5-megabyte portable recorder for later transfer to a Microvax II for computerized analysis and display. Mean anal canal pressure was calculated, and rectal motor complexes (RMCs) were characterized. Mean and canal resting pressure was 75 +/- 12 mmHg. During sleep, anal pressures displayed cyclic decreases (mean periodicity, 1.6 hours; range, 1-4 hours), during which the mean +/- SD pressure trough was 15 +/- 4 mmHg (range, 8-21 mmHg). RMCs were identified in all subjects: mean frequency, 16 per 24 hours (range, 12-22 per 24 hours); duration, 15.3 minutes (range, 8-35 minutes); contractile frequency, two to three per minute; mean peak amplitudes, 58 +/- 18 mmHg; and periodicity, 78 +/- 24 minutes (range, 35-265 minutes). Importantly, an RMC was invariably accompanied by a rise in mean anal canal pressure and contractile activity such that pressure in the anal canal was always greater than pressure in the rectum. Anal canal relaxations never occurred during an RMC. Motor activities of the rectum and of the anal canal may be related; the onset of rectal contractions was accompanied by increased resting pressure and contractile activity of the anal canal. This temporal relationship represents an important mechanism preserving fecal continence.

Dysplasia in chronic ulcerative colitis: implications for colonoscopic surveillance.

Mucosal dysplasia has been used as a marker for patients with chronic ulcerative colitis considered to be most at risk of developing cancer, and its identification is the basis for colonoscopic surveillance programs. To evaluate the reliability of this premise, colectomy specimens from two groups of patients who had undergone surgery for chronic ulcerative colitis (50 with cancer and 50 without) were retrieved. The groups were matched by age, sex, duration of disease, disease extent, and symptoms at the time of surgery. Using a standard technique of multiple random biopsies, we utilized the standard colonoscopic biopsy forceps to obtain four biopsies from mucosa that was not macroscopically suspicious for dysplasia or cancer in eight defined regions in each of the 100 colon specimens. This technique mimicked exactly the methods used in our clinical surveillance program. All 3,200 biopsies were evaluated blindly by one pathologist for presence and grade of dysplasia. Twenty-six percent of colons with an established cancer harbored no dysplasia in any biopsy from any region in the colon. While an overall association between the presence of cancer and high-grade dysplasia was detected (relative risk = 9.00; 95 percent CI of 2.73-29.67), the sensitivity and specificity of random colonic biopsies to detect concomitant carcinoma were 0.74 and 0.74, respectively. These findings prompt concern that reliance on random biopsies, obtained during colonoscopic surveillance, may be misplaced.

Effect of somatostatin on adenylate cyclase activity in normal and neoplastic thyroid tissue.

Thyroid stimulating hormone (TSH) and other substances increase adenylate cyclase (AC) activity and growth of normal and neoplastic thyroid tissue. Factors that inhibit cAMP may provide targeted therapy to tumors dependent on cAMP for growth. Somatostatin has been reported to inhibit the growth of gastrinomas and carcinoid tumors. We therefore studied the effects of somatostatin on basal, TSH, pertussis toxin, and forskolin stimulated adenylate cyclase activity in normal and neoplastic thyroid tissue from 19 patients. Adenylate cyclase (AC) activity was determined by the conversion of alpha 32P-ATP to 32P-cAMP in pmoles/mg protein/30 minutes in an 8000 x g particulate fraction rich in thyroid plasma membranes. TSH (300 mU/ml) and forskolin (100 mM) (a diterpine that directly stimulates the catalytic unit of AC) increased AC activity in normal and neoplastic thyroid tissue. The AC stimulation was greater in the neoplasms (p less than 0.01). Somatostatin (5 x 10(-6)M) decreased basal and TSH stimulated AC activity below basal levels in both normal and neoplastic thyroid tissue (including papillary, follicular, and medullary carcinomas). The inhibition of AC by somatostatin was greater in neoplastic tissue (p less than 0.025). Pertussis toxin (which blocks the inhibitory guanyl nucleotide regulatory protein) was able to partially reverse the effect of somatostatin. Somatostatin partially inhibited forskolin stimulated AC activity. Somatostatin inhibits basal and TSH stimulated AC activity in both normal and neoplastic human thyroid tissue, with a greater effect on neoplasms. These studies establish that somatostatin blocks a major regulator of thyroid growth and provides the rationale for the use of somatostatin analogs in the treatment of thyroid cancers.

Reoperative thyroid surgery.

BACKGROUND: Patients with thyroid cancer are sometimes denied repeat thyroid operations for fear of an increased risk of complications. METHODS: We therefore reviewed our experience in 114 patients with benign or malignant thyroid tumors who underwent 116 thyroid reoperations with or without other procedures. All patients had undergone at least one prior thyroid operation and 16 patients had undergone from two to four thyroid operations before referral. The initial histologic diagnosis before reoperation was thyroid carcinoma in 79 patients, papillary carcinoma in 47 patients, follicular carcinoma in 17 patients, medullary carcinoma in 9 patients, and Hürthle cell carcinoma in 6 patients. Benign disease was present in 35 patients. In 62 patients with cancer, reoperations were performed because of suspected persistent or recurrent disease; one of these patients underwent two reoperations by us. In 17 patients reoperation was to complete total thyroidectomy, primarily so that radioactive iodine could be used to scan for and treat metastatic disease. RESULTS: Among the 116 reoperations, 102 were completion total thyroidectomy, 8 were near-total or subtotal thyroidectomy, and 6 were completion lobectomy. Histologic examination at reoperation revealed thyroid carcinoma in 51 cases (64%) among the 79 patients who had undergone 80 operations for previous thyroid cancer. Recurrent or persistent cancer was present in 49 of 63 (78%) reoperations for patients with papillary, medullary, and Hürthle cell cancer but in only 2 of 17 (12%) patients with follicular cancer. Cancer also occurred in 8 cases (22%) of the 36 reoperations in 35 patients who initially had benign lesions. Complications included one permanent and one transient palsy of the recurrent laryngeal nerve; both occurred on the side of a previous partial or subtotal lobectomy. Other complications included temporary hypoparathyroidism in four patients, seromas in two patients, and a keloid in one patient. CONCLUSIONS: This study documents that reoperations can be performed with minimal morbidity. Thus patients should not be denied the chance to undergo removal of a persistent tumor or the remnant normal thyroid tissue because of the fear of complications.

Role of oxygen free radicals in the etiology of pouchitis.

Transient mucosal ischemia may cause oxygen-derived free radical production by xanthine oxidase, precipitating pouchitis after ileal pouch-anal anastomosis. Our aim, therefore, was to determine the effect of allopurinol, a xanthine oxidase inhibitor, in patients with acute and chronic pouchitis. Acute pouchitis was characterized clinically by sporadic episodes of increased frequency and decreased viscosity of stools, hematochezia, fever, malaise, and pelvic pain, which resolved promptly with treatment. Chronic pouchitis patients required continuous treatment to remain asymptomatic and invariably developed the signs and symptoms of pouchitis within one week following cessation of therapy. Eight patients with acute pouchitis were treated with allopurinol (300 mg p.o. b.i.d.) during the episode. Fourteen patients with chronic pouchitis had their standard antibiotic therapy discontinued while still asymptomatic; they were then given allopurinol (300 mg p.o. b.i.d.) for 28 days. Acute pouchitis resolved promptly in four of eight patients. Seven of the 14 patients with chronic pouchitis responded completely with no recurrence of symptoms during treatment. Allopurinol either terminated an episode of acute pouchitis or prevented pouchitis from recurring in 50 percent of patients. These data support a role for mucosal ischemia and oxygen free radical production in the etiology of pouchitis.

Epidemiology of large bowel cancer.

Results from epidemiologic studies have provided insights into the etiology of large bowel cancer. Markedly diverse incidences of colorectal cancer exist in various parts of the world and within different regions of a given country. Studies of migrant populations have revealed a role for environmental factors, particularly dietary, in the etiology of colorectal cancers. Genetic factors and inflammatory bowel disease also place certain individuals at increased risk. Sedentary lifestyle, cholecystectomy, and ureterosigmoidostomy may also increase the risk of developing large bowel cancer.

The reasons for failure in parathyroid operations.

Primary hyperparathyroidism occurs in about 1 in every 700 individuals. We analyzed our experience with 81 patients with persistent or recurrent hyperparathyroidism who were treated at the University of California, San Francisco, and the Veterans Administration Medical Center, San Francisco, from January 1979 through September 1988. In the 89 reoperations performed, the following six reasons or combination of reasons were responsible for the failed initial operation: (1) in 50 patients, there were multiple abnormal glands (30 hyperplastic and 20 second adenoma); (2) in 40 patients, the tumor was located in an ectopic position (22 mediastinal, 9 deep-seated cervical, 7 intrathyroidal, and 2 undescended); (3) in 17 patients, there were supernumerary parathyroid glands; (4) in 12 patients, the abnormal parathyroid glands were found in normal locations and the tumors were missed because of surgeon inexperience; (5) in 4 patients, failure was due to metastatic parathyroid cancer; and (6) in 4 patients, failure was due to errors on frozen section examinations. Preoperative localization studies usually identified the abnormal parathyroid tumor(s) prior to reoperations and were helpful in these patients. Knowledge of the reasons for failed parathyroid operations and the usual and unusual sites where parathyroid tumors are situated as well as a complete exploration should decrease the frequency of failed parathyroid operations. Localization studies are helpful for identifying these often elusive tumors.

Deoxyribonucleic acid cytometry helps identify parathyroid carcinomas.

It may be difficult in some patients with parathyroid tumors to distinguish between parathyroid carcinoma and parathyroid adenoma on the basis of clinical and histopathological findings. Patients initially diagnosed as having a parathyroid adenoma have subsequently occasionally developed metastases, and thereby their tumor was proven to be a carcinoma. To determine whether the nuclear DNA content would correlate with the clinical course and pathology of parathyroid tumors DNA cytometry was performed on parathyroid carcinomas (9 patients), histologically atypical adenomas (10 patients), adenomas associated with severe hypercalcemia [serum calcium, greater than or equal to 13.0 mg/dL (greater than or equal to 3.24 mmol/L); 11 patients], typical benign adenomas (11 patients), and incidentally removed normal parathyroid glands (6 patients). Sections were cut from the original paraffin-embedded surgical specimens and stained for nuclear DNA using the azure A Feulgen reaction. Nuclear DNA stain content was measured using an integrating image cytometer, and the results were plotted as histograms. Adjusted optical density (AOD) values were measured (in arbitrary units) to estimate the DNA content of whole nuclei in the specimens. The mean nuclear DNA content in the parathyroid carcinomas [24.6 +/- 2.1 (+/- SE) AOD] was significantly greater than that in the three groups of parathyroid adenomas (P less than 0.005, by unpaired t test) and in the normal parathyroid glands (P less than 0.0005). The mean nuclear DNA content in the atypical adenomas (15.8 +/- 1.6 AOD), profoundly hypercalcemic adenomas (16.8 +/- 1.3 AOD), and typical adenomas (16.0 +/- 1.1. AOD) were similar, and all were significantly greater than that in the normal parathyroid glands (11.5 +/- 0.7 AOD, P less than 0.05). Five distinct DNA histogram patterns were present in the parathyroid specimens from these 47 patients. Four of the 9 parathyroid carcinomas had an aneuploid DNA pattern, an abnormal pattern not found in any of the other groups; 2 of these tumors were originally diagnosed as atypical parathyroid adenomas. Both patients developed recurrent disease, and 1 died from a hepatic metastasis. Therefore, DNA cytometry provides valuable information in differentiating some parathyroid carcinomas from adenomas and diagnosing certain parathyroid carcinomas before the appearance of grossly invasive or metastatic tumor.

Diagnosis of recurrent hyperparathyroidism: comparison of MR imaging and other imaging techniques.

Several reports have indicated good results with MR imaging of hyperparathyroidism. However, its use in recurrent hyperparathyroidism has not been assessed separately. Thirty patients with recurrent hyperparathyroidism were evaluated by MR with both T1- and T2-weighted images. Twenty-six and 23 of these patients, respectively, also had thallium-201 scintigraphy and high-resolution sonography. For the 28 patients who eventually had surgical exploration and histologic evidence of adenoma (21 cases) or hypoplasia (seven cases), MR accurately located abnormal parathyroid glands in 75% evaluated prospectively and 89% evaluated retrospectively. Scintigraphy located 68% prospectively and 76% retrospectively. Sonography detected 57% prospectively and 67% retrospectively. For patients undergoing three studies, the prospective and retrospective detection rate was significantly better (p less than .05) for MR compared with sonography but was not significantly different for MR and scintigraphy. MR detected three of four mediastinal adenomas evaluated prospectively and retrospectively. One false-positive case was seen with MR, one with scintigraphy, and one with sonography. Thus, MR can be used to locate abnormal parathyroid tissue at a rate equal to or better than scintigraphy or sonography.

Localization of parathyroid glands.

Parathyroid localization tests are helpful for all patients with primary hyperparathyroidism before parathyroid exploration, and they are essential for patients who have had previous parathyroid or thyroid operations. The selection of specific localization tests depends on whether the patient is undergoing an initial or a reoperative procedure, as well as on the availability of the specialized equipment and expertise of the physicians and technicians performing and interpreting these studies.

Localizing studies in patients with persistent or recurrent hyperparathyroidism.

Preoperative localizing studies are essential for patients with persistent or recurrent hyperparathyroidism requiring reoperation, because of loss of normal tissue planes and because the hyperfunctioning parathyroid tissue that remains is more likely to be situated in an ectopic position. The value of noninvasive and invasive localizing techniques was evaluated in 59 consecutive patients undergoing reoperation for persistent (40 patients) or recurrent (19 patients) hyperparathyroidism. Magnetic resonance imaging was performed in 17 patients; 11 results (65%) were positive, 3 (18%) were negative, and 3 (18%) were false-positive. Ultrasonography was performed in 52 patients; 29 (56%) were positive, 16 (31%) were negative, and 7 (13%) were false-positive. Computed tomography was performed on 41 patients; 19 (46%) were positive, 16 (39%) were negative, and 6 (15%) were false-positive. Thallium chloride 201-technetium 99m pertechnetate scans were used in 39 patients; 19 (49%) were positive, 11 (28%) were negative, and 9 (13%) were false-positive. One or more of these noninvasive tests was positive in 78% of the cases. Highly selective venous catheterization with measurement of immunoreactive parathyroid hormone concentration localized the abnormal parathyroid gland in 20 of 28 patients (71%) overall and in 8 of the 14 patients (57%) whose tumors were not identified by the noninvasive techniques. Since false-positive results were common, a combination of localizing studies was helpful in identifying the abnormal gland. Fifty-three of the 59 patients (90%) were successfully treated at the initial reoperation and three were successfully treated at a second reoperation. Advances in parathyroid localization have contributed to the improved surgical results in patients with persistent or recurrent hyperparathyroidism.

Parathyroid carcinoma versus parathyroid adenoma in patients with profound hypercalcemia.

The metabolic manifestations and operative findings in 10 patients with a diagnosis of parathyroid carcinoma were analyzed to determine whether they differ from those in patients with parathyroid adenomas and similar degrees of hypercalcemia. Two groups of patients with parathyroid adenomas were used for comparison. Group A consisted of eight patients with "atypical" benign adenomas (mean preoperative level of serum calcium: 13.4 mg/dl); group B consisted of 13 patients with benign typical adenomas--all with preoperative serum calcium levels greater than or equal to 13.0 mg/dl (mean: 14.2 mg/dl). The patients with carcinoma (mean preoperative level of serum calcium: 15.3 mg/dl) had a frequency of osteoporosis and osteitis fibrosa cystica (50%) comparable with that of group A (33%) and group B (62%). Seventy percent of the patients with carcinoma had renal disease (nephrolithiasis, nephrocalcinosis, or impaired renal function), whereas only 38% of group A and 15% of group B had similar disorders. The patients with carcinomas had the highest frequency of combined bone and renal disease (50% versus 14% in group A and 15% in group B). Anemia, peptic ulcer disease, and hypertension occurred with similar frequencies in the three groups. Three patients with recurrent parathyroid carcinoma died of profound hypercalcemia, renal failure, or cardiac arrhythmia. In general, although patients with parathyroid carcinomas have more profound metabolic abnormalities than do patients with primary hyperparathyroidism, the metabolic manifestations in patients with parathyroid carcinoma are comparable with those in patients with parathyroid adenomas and profound hypercalcemia. Furthermore atypical adenomas share many anatomic and histopathologic features with parathyroid carcinomas, and distinguishing between the two is sometimes possible only in cases of tumor recurrence.

Parathyroid hormone: before and after parathyroidectomy.

The clinical value of measuring serum immunoreactive parathyroid hormone (iPTH) for the diagnosis of primary hyperparathyroidism is sometimes debated, and the clinical significance of an elevated postoperative serum iPTH level is unknown. Therefore we studied 141 consecutive patients with primary hyperparathyroidism before and after parathyroidectomy to determine the clinical value of measuring serum iPTH by a mid-region-specific radioimmunoassay. Eighty-eight percent of the patients with primary hyperparathyroidism had an absolute increase in the level of serum iPTH (greater than 40 microliter Eq/ml) before surgery, and the remaining patients had an inappropriately increased level of serum iPTH for the simultaneous serum calcium level. Preoperative serum iPTH level correlated positively with serum calcium level and parathyroid tumor size. Postoperative elevation of serum iPTH level was common (as high as 40%) and was associated with higher preoperative levels of blood urea nitrogen, serum creatinine, and alkaline phosphatase and larger tumors. An elevated postoperative serum iPTH level without hypercalcemia did not indicate a failed parathyroidectomy, whereas negative parathyroid exploration and postoperative hypercalcemia were the best predictors of persistent hyperparathyroidism. We conclude that preoperative serum iPTH measurement is a very sensitive diagnostic test for primary hyperparathyroidism, but postoperative serum iPTH measurement is not a good predictor for persistent or recurrent hyperparathyroidism.

Epidermal growth factor receptors in parathyroid tumors.

Hyperparathyroidism is caused by parathyroid adenomas, hyperplastic parathyroid glands, or rarely parathyroid carcinoma. Membrane receptors to epidermal growth factor (EGF), a growth-stimulating polypeptide, have been shown in other endocrine tissues such as thyroid, breast, and ovary, but not in parathyroid glands. Therefore we studied abnormal parathyroid glands from fourteen patients for the presence of EGF receptors. The binding of radioiodine-labeled EGF to the crude membrane fractions was studied using competitive inhibition with unlabeled EGF. In ten patients with solitary parathyroid adenomas, seven adenomas had no EGF binding, three had low affinity EGF binding with dissociation constants (Kd) of 28 to 148 nM and maximal specific binding (Bmax) of 285 to 1944 fmole/mg protein. In two patients with multiple adenomas, a high affinity EGF binding with Kd of 0.28 to 2.8 nM and Bmax of 6.7 to 43 fmole/mg protein was found. In one patient with hyperplastic parathyroid glands secondary to renal failure, a high affinity EGF binding with Kd of 1.7 nM and Bmax of 18 fmole/mg protein was found. In one patient with persistent hyperparathyroidism following a successful renal transplant (tertiary hyperparathyroidism), a low affinity EGF binding with Kd of 25 nM and Bmax of 219 fmole/mg protein was found. The binding of EGF did not correlate with the preoperative serum calcium or PTH levels. Thus, hyperplastic parathyroid glands (either primary or secondary) have high affinity EGF receptors whereas solitary parathyroid adenomas do not.