Diverticular Perforation: A Fatal Complication to Forestall in Cushing Syndrome

Abstract

Context

Patients taking exogenous glucocorticoids are at risk for gastrointestinal (GI) complications, including peptic ulcer disease with perforation and gastric bleeding. However, little is known about the GI comorbidity in patients with endogenous hypercortisolemia.

Case Descriptions

We describe six patients with endogenous Cushing syndrome (CS) who developed sudden perforation of colonic diverticula necessitating urgent exploratory laparotomy. Most of these patients shared the following features of CS: skin thinning, severe hypercortisolemia (24-hour urinary free cortisol ≥10 times the upper limit of normal), ectopic secretion of ACTH, and severe hypokalemia. At the time of diagnosis of diverticular perforation (DP), these patients had minimal signs of peritonitis and lacked fever or marked leukocytosis. The diagnosis of DP was established by having a low threshold for obtaining an imaging study for evaluation of nonspecific abdominal pain.

Conclusions

Patients with CS can develop spontaneous surgical abdomen with rapid decompensation within hours. Prompt recognition is critical in the successful treatment of these patients.

We describe six patients with Cushing syndrome who developed spontaneous surgical abdomen from perforation of sigmoid diverticula, suggesting underlying predisposition.

Exposure to supraphysiologic doses of exogenous glucocorticoids is associated with gastrointestinal (GI) complications such as peptic ulcer disease, gastrointestinal hemorrhage, duodenal ulcer, and colonic diverticular perforation (DP) (1). However, little is known about GI complications in endogenous hypercortisolism caused by Cushing syndrome (CS). We present six patients with CS who developed sudden DP that necessitated surgical intervention.

Case Descriptions

Six hypercortisolemic patients had DP necessitating surgical treatment (Table 1). All were Caucasian; half were female. The median age at perforation was 57 years (range 31 to 80 years). All patients had some common features of CS, including weight gain, edema, weakness, and skin atrophy. The latter manifested as easy bruising and skin thinning (patients 1, 2, and 6) or as wide, purplish striae (patients 3, 4, and 5).

Table 1.

CS Features in Six Patients Presenting With DP

Patient	Age (y)	Sex	Highest UFC (μg/24 h)a	Cause of CS	Skin Atrophy	Hypokalemia	Time From Onset of CS Symptoms to Perforation (mo)
Patient 1	80	Female	2029.3	Lung carcinoid	Yes (easy bruising)	Yes	~36
Patient 2	60	Female	26,350	Metastatic islet cell carcinoma	Yes (easy bruising)	Yes	~36
Patient 3	31	Male	470	Cushing disease	Yes (striae)	No	20
Patient 4	52	Female	859	Lung carcinoid	Yes (striae)	Yes	4
Patient 5	67	Male	1350	Ectopic ACTH (not localized)	Yes (striae)	No	10
Patient 6	51	Male	4910	Metastatic thymic carcinoma	Yes (easy bruising)	Yes	4

^aNormal range: 3.5 to 45.0; to convert to Système Internationale units, multiply by 27.59.

Biochemical evaluation confirmed severe hypercortisolism: 24-hour urinary free cortisol (UFC) was 10 to 300 times the upper limit of normal and ranged from 470 µg every 24 hours (12,967 nmol every 24 hours, patient 3) to 26,350 µg every 24 hours (726,944 nmol every 24 hours, patient 2), with a median UFC of 1689.65 µg every 24 hours (46,617 nmol every 24 hours). Hypokalemia was present in four patients on presentation. Five patients had ectopic secretion of ACTH based on inferior petrosal sinus sampling (patients 1, 2, 4, 5, and 6). The ectopic source of ACTH was confirmed by histologic evaluation in four of these patients but remained occult in patient 5. The final patient had Cushing disease confirmed by surgical pathology. All patients were ultimately cured of CS after transsphenoidal resection of pituitary tumor (patient 3) or removal of the ectopic source of ACTH (patients 1 and 4) or by bilateral adrenalectomy done because of either metastases (patients 2 and 6) or occult tumor (patient 5).

DP occurred during active hypercortisolism in all patients. The presentation of DP was atypical in terms of clinical features, leukocytosis and fever (Table 2). On the day of diagnosis of DP, patients’ temperature was ≤37.4°C and white blood cell (WBC) count was ≤14 × 10⁹/L. WBC count was mildly elevated in three, normal in one, and suppressed in another (data not available for one) patient. The mild WBC elevations were present before the perforation and were considered to represent the effect of hypercortisolism on demargination of WBCs.

Table 2.

Clinical Presentation and Treatment of Diverticular Perforation in Patients With CS

Patient	Symptom	Peritoneal Signsa	Fever Present?	WBC (×109/L)	Necessitated Surgery or Surgical Findings	Surgical Complications
Patient 1	Abdominal pain	No	No	5.06	Acute DP and serositis	None
Patient 2	Abdominal pain	No	No	13.9	Sigmoid resection with colostomy	• Colostomy dehiscence necessitating revision
						• Septic shock
						• Pelvic abscess necessitating surgical drainage
Patient 3	Rectal bleeding and abdominal pain	Yes	No	13.0	Acute and chronic inflammation of left colon and retroperitoneal tissue with focal abscess	• Poor wound healing
						• Wound dehiscence necessitating multiple surgical debridements
Patient 4	Abdominal pain and constipation	Yes	No	2.91	Barium and pus in abdominal cavity; acute diverticulitis with rupture and abscess formation	None
Patient 5	No	Yes	No	11.3	Acute sigmoid diverticular rupture complicated by a pericolic abscess	None
Patient 6	Abdominal pain	NA	NA	NA	Partial colon resection with colostomy	Poor wound healing

Abbreviation: NA, not available.

^aOn abdominal examination (distension, tympany, rebound tenderness).

The pattern of abdominal pain and physical examination findings was variable. Three patients presented with abdominal pain, but physical examination did not suggest DP. In one of these patients, the diagnosis was clear after she rapidly deteriorated and developed rebound tenderness and guarding (patient 1); in others, the diagnosis was made after free air was seen under the diaphragm on x-ray (which evolved into a surgical abdomen with rebound tenderness and guarding in patients 2 and 5). The other three patients presented in a more typical fashion, with hypotension (patient 3) or pain and a distended, tympanic or silent abdomen (patients 3, 4, and 6). Three patients had a current or known diagnosis of diverticulosis: one perforated spontaneously during a diagnostic barium enema, another had a barium enema 2 weeks before DP, and the third had a more distant diagnosis.

All operations involved a partial resection of the sigmoid colon, with colostomy. Despite hypercortisolemia, three patients had an uncomplicated postoperative course. However, patient 2 developed dehiscence of the colostomy that necessitated revision and subsequently had leakage around the anastomosis, necessitating additional surgery. Patient 3 also had dehiscence necessitating debridement, and patient 6 had poor wound healing.

Discussion

We describe six patients with co-occurrence of CS and perforation of colonic diverticulum. Although the association of exogenous glucocorticoid administration and DP is well established, there are few reports of DP in endogenous CS. Of the four previous case reports, all patients were older adults (aged 60 to 79 years) and two were male (2–5). As in our series, two of the four had an atypical presentation with minimal abdominal findings. Although the etiology was evenly divided between ectopic ACTH secretion and Cushing disease, all had severe hypercortisolemia, as was seen in our patients. Hypercortisolism was demonstrated by a single result in each patient, including a 24-hour UFC that was 30 times normal (4), a basal cortisol of 35.3 µg/dL (974 nmol/L) (5), another basal cortisol of 51.9 µg/dL (1432 nmol/L) (3), and an abnormal cortisol after dexamethasone 8 mg of 94 µg/dL (2593 nmol/L) (2).

Prompt diagnosis of DP is extremely important, because it is associated with a mortality rate of ≤39% (6). Taken together, the previous and current cases suggest that clinicians should have a low threshold for suspecting DP in severely hypercortisolemic patients, regardless of etiology of hypercortisolism or patient’s age and sex, recognizing that the absence of a “typical” surgical abdomen does not exclude the diagnosis. The immunocompromised state associated with severe hypercortisolism also may provide clues to the presence of diverticulitis and risk of perforation. One report compared patients with diverticulitis who were or were not immunocompromised; perforation rates were higher in those exposed to supraphysiologic doses of steroid, those who were malnourished or uremic, those who were receiving cytotoxic chemotherapy, or those who had known immunodeficiency syndrome (6). A review of these factors may help identify particularly high-risk patients (Table 3).

Table 3.

Proposed Risk Factors for Colonic Perforation in Patients With Hypercortisolemia

Proposed Risk Factors for Colonic Perforation in Hypercortisolemia
1. Severe hypercortisolemia
2. Preexisting diverticula
3. History of diverticulitis
4. Hypokalemia
5. Constipation
6. Older age
7. Malnutrition
8. Uremia
9. Immunodeficiency

Although diverticulosis is common, only ~20% of patients become symptomatic, and a smaller minority (1% to 2%) develop complications such as abscess, perforation, and fistula formation (7). Perforation of diverticulitis results from severe inflammation of the bowel wall with resultant necrosis (7). Although our patients had evidence of bowel inflammation on imaging, surgical inspection, or pathology, none developed systemic features of inflammation such as pyrexia or marked leukocytosis, and the findings on abdominal examination were disproportionate to the underlying pathology (Table 2).

Why do hypercortisolemic patients present with DP in an atypical way? Because glucocorticoids inhibit many initial events in an inflammatory response, it seems biologically plausible that hypercortisolemia might inhibit the early clinical signs of DP (8). If this hypothesis is correct, waiting for signs of a surgical abdomen could lead to missing an important therapeutic window.

An underlying biological link between hypercortisolemia and DP has been hypothesized but not confirmed (2). The effects of glucocorticoids on skin may provide insight into the effect on intestinal mucosa. At supraphysiologic concentrations, glucocorticoids markedly suppress DNA synthesis and cell proliferation in human embryonic skin fibroblast cultures. This suppression is mirrored in vivo by decreased collagen synthesis (9), increased bruising and disorganized dermal collagen at bruising sites, decreased skin thickness, and development of striae in people exposed to chronic supraphysiologic glucocorticoids (10).

Decreased synthesis of collagen and DNA in hypercortisolemic patients may decrease intestinal fold thickness and intestinal fibroblast reparative activity (5) and result in tissue fragility (3). Other proposed mechanisms for gastrointestinal perforation in CS include hypokalemia-induced constipation resulting in increased intraluminal pressure (2), decreased turnover of intestinal mucosal cells, and less bowel lymphoid tissue, decreasing resistance to bacterial invasion.

Conclusion

Diverticular disease is common, and perforation is an unusual but potentially fatal complication in hypercortisolemic patients. When treating such patients, physicians should demonstrate awareness of this risk through proper management of malnutrition, uremia, hypokalemia, and constipation and early detection and aggressive management of diverticulitis and rapid identification and treatment of DP.

Glossary

Abbreviations:

CS

Cushing syndrome

DP

diverticular perforation

GI

gastrointestinal

UFC

urinary free cortisol

WBC

white blood cell