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Worth a Second Look

Tyler M. Berzin, M.D., Norton J. Greenberger, M.D., Bruce D. Levy, M.D., and Joseph Loscalzo, M.D., Ph.D.
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert clinician, who responds to the information, sharing his or her reasoning with the reader (regular type). The authors commentary follows.

A 72-year-old man presented to his primary care physician for evaluation of fatigue and weight loss. Over the prior 8 months, the patient had lost 16 kg (35 lb) from a baseline weight of 82 kg (180 lb). During the same period, he began having up to 10 loose stools per day, which he described as voluminous and watery. The loose stools improved with fasting, and the urge to defecate did not awaken him from sleep. There was no history of blood in the stool, fever, chills, or rash. This patient has chronic diarrhea, a term that has been variably defined but that typically refers to increased stool volume, decreased stool consistency, or both over a period of at least 4 weeks. The large-volume, watery diarrhea raises concern about noninflammatory processes, which often affect the small bowel. Acute, noninflammatory diarrhea is most commonly caused by viral pathogens. However, the long-standing bowel symptoms and the associated substantial weight loss are inconsistent with a viral gastroenteritis. The persistent watery diarrhea raises concern about a secretory or osmotic (alimentary) diarrhea. Osmotic diarrhea is characterized by improvement with fasting, stool volume of less than 1 liter per day, and the presence of a stool osmotic gap (>100 mOsm per kilogram). Secretory diarrhea typically persists during fasting (commonly interrupting sleep) and is of larger volume (1 liter per day), and the stool osmotic gap is usually less than 50 mOsm per kilogram. Common causes of osmotic diarrhea include osmotically active substances such as sorbitol, lactose, and magnesium, but weight loss and other constitutional symptoms are not common in this setting. In addition, numerous medications, most commonly antibiotics, can cause diarrhea, so a careful review of medications is important. The diarrhea and weight loss may also suggest malabsorption. Some cases of infectious diarrhea may have both osmotic and secretory features because damage to the normal absorptive epithelial lining can result in an increased luminal osmotic load, and inflammatory cytokines may act as secretagogues in the bowel. The patient also reported a poor appetite, with early satiety and a reduced ability to taste foods. He had no nausea, abdominal pain, or flushing. Hypogeusia can be caused by mucositis, oral infections, and other abnormalities of the mucosal surface. Zinc and copper deficiencies are also believed to cause hypogeusia in some patients. Early satiety can suggest impaired gastric motility or obstructive lesions such as a tumor or stricture in the stomach or small bowel. The patients medical history included hypothyroidism after a thyroidectomy for Graves disease, hypertension, hyperlipidemia, and osteopenia. Medications included
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From the Clinical Pathological Conference Series, Department of Medicine, Brigham and Womens Hospital, and Harvard Medical School both in Boston. Address reprint requests to Dr. Levy at Brigham and Womens Hospital, Harvard Institutes of Medicine Bldg., Ave. Louis Pasteur (HIM855), Boston, MA 02115, or at blevy@partners.org. N Engl J Med 2012;366:463-8.
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betaxolol, lisinopril, atorvastatin, ezetimibe, hydrochlorothiazide, potassium, levothyroxine, aspirin, and meloxicam. He had no known drug allergies. He was a retired electrical engineer and lived at home with his wife. He had a remote history of smoking and had drunk 5 oz (approximately 150 ml) of scotch daily before quitting 1 year earlier. Excessive levothyroxine could potentially explain diarrhea and weight loss, but no other symptoms of hyperthyroidism are described. None of the patients other medications are likely to explain diarrhea and weight loss. The differential diagnosis remains broad. The patient could have a disorder of the stomach, small intestine, or large intestine. Diseases affecting the small bowel, such as celiac sprue or Crohns disease, are a particular concern. Information was not provided on the patients ethnic background, but this could help determine the likelihood of celiac sprue, which is fairly common in northern Europe but rare in Southeast Asia and Africa. Celiac sprue can be manifested atypically in older persons, who sometimes present only with fatigue and anemia, often leading to a delay in diagnosis. Microscopic or lymphocytic colitis should also be considered, but neither of these disorders generally causes this degree of weight loss. On physical examination, the patient appeared thin and tired. His height was 168 cm (5 ft 6 in.), and his weight was 66 kg (145 lb). The temperature was 36.7C (98.0F), the blood pressure 120/64 mm Hg, and the heart rate 60 beats per minute. The oxygen saturation was 98% while the patient was breathing ambient air. The oropharynx was moist, without lesions or hyperpigmentation. The neck was supple, with a well-healed thyroidectomy scar and without palpable masses or lymphadenopathy. The lungs were clear on auscultation, and the cardiac examination was normal. The jugular venous pressure was not elevated. The abdomen was soft, nondistended, and nontender, with normal bowel sounds. The liver span measured 8 cm by percussion along the midclavicular line, the spleen was not palpable, and there was no ascites. The extremities were warm and well perfused, with 3+ soft, pitting edema of the legs bilaterally. Skin examination revealed no rash. The neurologic examination was notable for diminished sensation of pinprick and vibration in the distal lower extremities bilaterally as well as the absence of ankle reflexes. The rectal examination revealed normal sphincter tone, a normal
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prostate, and brown stool that was Hemoccultpositive. The 3+ peripheral edema is a striking feature on examination. Congestive heart failure and severe liver disease are two common causes of peripheral edema, but they appear to be less likely causes in this case, given the normal jugular venous pressure and the absence of stigmata of chronic liver disease, such as spider angiomata and ascites. Venous or lymphatic obstruction in the pelvis can also cause bilateral lower-extremity edema. The nephrotic syndrome, gastrointestinal protein loss, and malabsorption should also be considered. The presence of a peripheral neuropathy raises the possibility of vitamin B12 deficiency, which could result from small-bowel disease. Measurements of serum calcium, albumin, cholesterol, iron, carotene, and zinc levels and coagulation should be ordered to assess the patient for malabsorption, as should a stool-fat determination. Testing for tissue transglutaminase antibodies and measurement of the total IgA level are appropriate to investigate the possibility of celiac sprue. The fact that the patients watery diarrhea improves with fasting argues against conditions causing secretory diarrhea. The white-cell count was 9920 per cubic milli meter, with 72% neutrophils, 17% lymphocytes, 6% monocytes, and 5% eosinophils. The hematocrit was 26.8% (decreased from 34.5% 1 year earlier), with a mean corpuscular volume of 86.9 fl and red-cell distribution width of 13.3%. The platelet count was 598,000 per cubic millimeter. A peripheral-blood smear showed moderately hypochromic erythrocytes. The serum sodium level was 136 mmol per liter, potassium 3.3 mmol per liter, chloride 103 mmol per liter, bicarbonate 24 mmol per liter, blood urea nitrogen 44 mg per deciliter (16 mmol per liter), creatinine 1.28 mg per deciliter (113.2 mol per liter), glucose 104 mg per deciliter (5.8 mmol per liter), and calcium 6.5 mg per deciliter (1.6 mmol per liter). Serum aminotransferase and alkaline phosphatase levels were normal. The albumin level was 2.8 g per deciliter, and the total protein level was 6.0 g per deciliter. The prothrombin time and partial-thromboplastin time were normal. The iron level was 13 g per deciliter (2.3 mol per liter), total iron-binding capacity 353 g per deciliter (63 mol per liter), and ferritin 10 ng per milliliter. The thyrotropin level was 1.72 mIU per liter. Vitamin B12 and folate lev-

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els were normal. The total 25-hydroxyvitamin D level was low, at 15 ng per milliliter, with a 25-hydroxyvitamin D3 level of 15 ng per milliliter and undetectable 25-hydroxyvitamin D2. The zinc level was 28 g per deciliter (4.3 mol per liter) (normal range, 60 to 120 g per deciliter [9.2 to 18.4 mol per liter]). Levels of vitamin A, vitamin E, niacin, copper, and lead were all within normal ranges. The transglutaminase IgA antibody level was normal, at 1.0 unit per milliliter (normal range, 0.0 to 6.9), and the total IgA level was also normal. A stool-fat test was not done. The normal level of thyrotropin excludes hyperthyroidism as a cause of weight loss. The patient has deficiencies in iron, vitamin D, and zinc, a pattern suggestive of disease within the duodenum, jejunum, or both. Given the hypoalbuminemia, there is probably protein malabsorption or frank protein-losing enteropathy due to gastrointestinal mucosal disease. Patients with IgA deficiency may have a false negative result on the tissue transglutaminase test, but in this patient, the total IgA level is normal, making celiac disease very unlikely. Autoimmune enteropathy is a syndrome rarely reported in adults, but it can cause watery diarrhea and malabsorption, often associated with antienterocyte antibodies. Eosinophilic enteritis is a diagnostic consideration even in the absence of peripheral eosinophilia. The next step is to perform upper endoscopy and colonoscopy, obtaining biopsy specimens from the stomach, small intestine, and colon. Although disease limited to the colon would not explain malabsorption, a colonoscopy is still warranted in a patient with severe diarrheal symptoms, weight loss, and Hemoccult-positive stool. The patient was referred for upper endoscopy, which revealed enlarged folds extending from the stomach to the beginning of the jejunum, with multiple nonbleeding erosions. Two sets of biopsy specimens taken from the stomach and duodenum were negative for cancer, celiac disease, Whipples disease, and eosinophilic gastroenteritis. There was evidence of chronic active gastritis. Stains for Helicobacter pylori were negative. There was mild stromal edema and loss of glands, which were considered to be nonspecific findings, possibly related to gastritis or healing erosions. The patient declined colonoscopy, having undergone a routine screening colonoscopy 1 year earlier; the

prior study revealed diverticulosis but was limited by inadequate bowel preparation. Computed tomography (CT) of the abdomen confirmed diverticulosis but showed no obvious abnormalities of the small bowel and no evidence of lymphadenopathy. The findings from the gastric and duodenal biopsies do not explain the patients symptoms. The enlarged folds seen throughout the stomach and duodenum, however, help to focus the differential diagnosis. Giant gastric folds can be seen in Mntriers disease, a poorly understood condition characterized by gastric mucous-cell hyperplasia. The clinical manifestations of Mntriers disease are protean, and malabsorption can be due to small-bowel involvement with dilated lacteals. Large gastric folds may also be present in eosinophilic enteritis, gastrinomas, and gastric lymphoma, but these are less likely, given the biopsy results. I would request a second review of the endoscopic-biopsy specimens. Otherwise, upper endoscopy should be repeated to obtain additional biopsy specimens that can be assessed for the conditions mentioned above. Inflammatory conditions, such as eosinophilic gastroenteritis, can have patchy distributions, and lymphoma can also be missed if biopsy sampling is not adequate. The previous, incomplete colonoscopy should also be repeated to look for a source of the occult blood loss. The patient preferred symptom management over additional diagnostic testing, and for the next several months, he was followed closely by a nutritionist and a gastroenterologist. Antidiarrheal agents were prescribed, as well as protein and multivitaminmultimineral supplements, including zinc, vitamin D, and calcium. His weight stabilized but did not increase, and his diarrhea improved only marginally. Zinc, vitamin D, and calcium levels all normalized. Follow-up evaluation by his gastroenterologist revealed new, patchy alopecia with depigmentation of the remaining scalp hairs, as well as onycholysis and yellow discoloration of his nails (Fig. 1). The development of skin and hair abnormalities provides an important clue to the diagnosis. Zinc deficiency has been reported to be associated with hypogeusia or dysgeusia, ectodermal changes, and diarrhea, but I would expect improvement, not worsening, after zinc supplementation. This
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Figure 1. Fingernail Onycholysis and Discoloration. (Photograph courtesy of Drs. Joanna Gibson and Elizabeth Morgan.)

patients clinical course of early gastrointestinal symptoms and associated evidence of malabsorption, with the delayed appearance of ectodermal findings, is typical of the CronkhiteCanada syndrome, a rare condition involving epithelial abnormalities in the gastrointestinal tract and skin. Repeat endoscopy and colonoscopy with assessment of biopsy specimens are appropriate to establish this diagnosis. Upper endoscopy and colonoscopy were repeated. Upper endoscopy revealed prominent folds throughout the stomach and duodenum. Colonoscopy revealed prominent mucus-secreting polypoid folds with intermittent erosions throughout the colon and terminal ileum (Fig. 2A and 2B). A video-capsule endoscopic study revealed a nodular and polypoidappearing small bowel with erythematous and edematous mucosa throughout. Biopsy specimens were obtained from the stomach, duodenum, terminal ileum, and colon. The duodenal-biopsy specimen showed villous blunting, stromal edema, and scattered dilated crypts (Fig. 3A and 3B). Biopsy specimens from the terminal ileum and colon revealed hamartomatous polyps with stromal edema and cystic dilatation of glands throughout the entire sampled mucosa (Fig. 4A and 4B).

Figure 2. Two Colonoscopic Views of the Cecum. Panel A shows innumerable polypoid-appearing folds in the cecum. Panel B shows the same area from a different angle.

dose of 30 mg daily, and protein and multivitamin multimineral supplementation was continued. There was moderate improvement in his abdominal discomfort and diarrhea within several weeks after the start of treatment; however, hypoalbuminemia persisted, and the patient was unable to gain weight. Vertebral compression fractures related to diffuse bone loss developed. Total parenteral nutrition was begun. One year after diagnosis, the patient was admitted to the hospital with lethargy and respiratory failure. The patients family Hamartomatous polyps with extensive stromal chose comfort-care measures, and the patient died edema are characteristic findings in the Cronkhite shortly after admission. Canada syndrome. In other syndromes with gastrointestinal hamartomatous polyps, such as juvenile polyposis, the intervening mucosa typically C om men ta r y appears normal. Glucocorticoids are commonly used, although their benefit is uncertain. The initial clinical evaluation centered on the patients watery diarrhea and malabsorption. The The patient received a diagnosis of the Cronkhite laboratory findings of hypoalbuminemia, hypoCanada syndrome. Prednisone was prescribed at a kalemia, and hypocalcemia all supported a mal-

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Figure 3. Specimens from Duodenal Biopsy. Panel A (hematoxylin and eosin) shows blunted villous architecture, stromal edema, acute and chronic inflammatory infiltrates, and haphazard gland distribution with scattered dilated crypts. Panel B (hematoxylin and eosin) shows the same area at higher magnification. (Photomicrographs courtesy of Drs. Joanna Gibson and Elizabeth Morgan.)

Figure 4. Specimens from Biopsy of the Sigmoid and Descending Colon. Panel A (hematoxylin and eosin) shows cystically dilated crypts with epithelial serration, stromal edema with acute and chronic inflammatory infiltrates, and surface erosion or ulceration in the sigmoid colon. Panel B (hematoxylin and eosin) shows similar features, at higher magnification, in the descending colon. (Photomicrographs courtesy of Drs. Joanna Gibson and Elizabeth Morgan.)

absorptive process. Initial endoscopy was nondiagnostic but revealed mucosal abnormalities. After a nondiagnostic initial evaluation, the patient chose to pursue symptom management rather than further diagnostic testing. He was treated supportively for several months, until the development of ectodermal changes prompted additional evaluation; studies that were previously nondiagnostic were repeated and ultimately confirmed the diagnosis. The cause of the CronkhiteCanada syndrome is unknown, and the clinical course is widely variable. The syndrome was first reported in 1955 by Cronkhite and Canada, who described two patients with a clinical syndrome of gastrointestinal polyposis with hair loss, hyperpigmentation, and nail atrophy.1 A subsequent case series of 55 patients yielded the typical findings of this disorder,
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which include hamartomatous polyps throughout the stomach, small bowel, and colon; ectodermal changes, including alopecia, onychodystrophy, and hyperpigmentation; onset in adulthood and absence of family history of polyposis; and the eventual development of diarrhea and weight loss.2 Diarrhea, weight loss, and abdominal pain are the most common presenting symptoms, and hypogeusia is frequently reported. The Cronkhite Canada syndrome also causes a protein-losing enteropathy, leading to hypoalbuminemia and edema. Ectodermal changes may appear later in the disease course, contributing to delayed diagnosis. A variety of gastrointestinal lesions have been described in this disorder in addition to hamar467

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tomatous polyps, including inflammatory polyps, serrated adenomas, and traditional adenomas. Among surviving patients with the Cronkhite Canada syndrome, there is an increased risk of gastric and colon cancer,3,4 but data are limited regarding the magnitude of the risk. Appropriate intervals for screening endoscopy and colonoscopy are undefined. At the time of the publication of the initial case series, 55% of the identified patients had died, although the interval between symptom onset and death was not reported.2 The majority of patients died from complications directly or indirectly attributable to malnutrition and dehydration, including severe cachexia, anemia, pulmonary embolism, and sepsis. Data to guide treatment are limited to case reports and reports on case series, which describe variable clinical responses to glucocorticoids, with some cases in which gastrointestinal and dermatologic abnormalities almost completely resolved within several months after the start of therapy.5-7 Improvement in diarrhea and other symptoms has been described after gastric or colonic resection of
References
1. Cronkhite LW Jr, Canada WJ. General-

involved mucosa, although usually in conjunction with medical therapies.6 Disease remission has also been reported after H. pylori eradication or acid-suppressive therapy.8-10 Spontaneous remissions have also been described.11 The widely variable clinical course and response to treatment in patients with the CronkhiteCanada syndrome raises the question of whether this syndrome represents a single disease or more than one distinct entity. This case illustrates one of the central challenges in establishing the diagnosis of the Cronk hiteCanada syndrome: the early gastrointestinal symptoms have a wide variety of potential causes, whereas the typical ectodermal findings may appear late in the course of the disease. In this patient, the clinical findings of persistent diarrhea, weight loss, anemia, and evidence of malabsorption but without an established diagnosis clearly warranted a second look.
Dr. Greenberger reports receiving consulting fees from Lighthouse Learning, a medical content company that is not supported by pharmaceutical grants, and from the TIMI (Thrombolysis in Myocardial Infarction) Study Group. No other potential conflict of interest relevant to this article was reported.

ized gastrointestinal polyposis; an unusual syndrome of polyposis, pigmentation, alopecia and onychotrophia. N Engl J Med 1955;252:1011-5. 2. Daniel ES, Ludwig SL, Lewin KJ, Ruprecht RM, Rajacich GM, Schwabe AD. The Cronkhite-Canada syndrome: an analysis of clinical and pathologic features and therapy in 55 patients. Medicine (Baltimore) 1982;61:293-309. 3. Yashiro M, Kobayashi H, Kubo N, Nishiguchi Y, Wakasa K, Hirakawa K. Cronkhite-Canada syndrome containing colon cancer and serrated adenoma lesions. Digestion 2004;69:57-62. 4. Katayama Y, Kimura M, Konn M. Cronkhite-Canada syndrome associated

with a rectal cancer and adenomatous changes in colonic polyps. Am J Surg Pathol 1985;9:65-71. 5. Johnson GK, Soergel KH, Hensley GT, Dodds WJ, Hogan WJ. Cronkite-Canada syndrome: gastrointestinal pathophysiology and morphology. Gastroenterology 1972;63:140-52. 6. Ward EM, Wolfsen HC. Pharmacological management of Cronkhite-Canada syndrome. Expert Opin Pharmacother 2003;4:385-9. 7. Goo YS, Lee YC, Shin MS, Kim WH, Kim H, Park IS. A case of Cronkhite-Canada syndrome involving the entire gastrointestinal tract. Endoscopy 2001;33:385. 8. Okamoto K, Isomoto H, Shikuwa S, Nishiyama H, Ito M, Kohno S. A case of

Cronkhite-Canada syndrome: remission after treatment with anti-Helicobacter pylori regimen. Digestion 2008;78:82-7. 9. Ward E, Wolfsen HC, Ng C. Medical management of Cronkhite-Canada syndrome. South Med J 2002;95:272-4. 10. Allbritton J, Simmons-OBrien E, Hutcheons D, Whitmore SE. CronkhiteCanada syndrome: report of two cases, biopsy findings in the associated alopecia, and a new treatment option. Cutis 1998;61:229-32. 11. Peart AG Jr, Sivak MV Jr, Rankin GB, Kish LS, Steck WD. Spontaneous improvement of Cronkhite-Canada syndrome in a postpartum female. Dig Dis Sci 1984;29: 470-4.
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