A 76-year-old male was referred to the emergency department in May 2016 for significant unintentional weight loss of approximately 57 kg and associated chronic nonbloody watery diarrheal illness in the preceding 18 months. Medical history was notable for prostate cancer curatively treated in 2012, gout, a remote transient ischemic attack, osteoarthritis, and bilateral cataracts. In the months prior to presentation to Gastroenterology, an extensive medical workup performed as an outpatient was negative for prostate cancer recurrence, new malignancy, autoimmunity, or an identifiable malabsorption syndrome including celiac disease and pancreatic insufficiency.
The patient also noticed onycholysis in both his hands and feet (Figure 1), followed by hyperpigmentation of his hands (Figure 2), soles of his feet and legs, and abdomen. In addition to the nonbloody diarrhea, the patient reported a severe change in taste, early satiety, chronic heartburn, and nonspecific abdominal pain. He denied a history of fever, cough, night sweats, or abdominal pain. There was no family history of gastrointestinal malignancy or similar disorder.
Physical examination demonstrated profound cachexia with a weight of 50.9 kg and a BMI 16.5. Generalized sarcopenia was noted. The abdomen was scaphoid and nontender with no hepatosplenomegaly. Nonscarring alopecia was seen on the scalp, dystrophic nail changes were identified in both the hands (Figure 1) and feet, skin hyperpigmentation was noted primarily involving the palms (Figure 2), dorsal aspects of fingers, face, and limbs, as well as sexual pattern hair loss of the abdomen, groin, and axillary hair. No cervical, inguinal, or axillary lymphadenopathy was identified. The rest of the physical exam was unremarkable.
Complete blood count was notable for a mild normocytic anemia (hemoglobin 119 g/L (reference range, 130-175 g/L) and mild eosinophilia of 0.82 g/L (reference range, 0-0.35 g/L)). Serum albumin was low at 28 g/L (reference range, 35.0-55.0 g/L). Serum electrolytes platelet count, white count, renal, liver enzyme and function tests, lipase and total protein, serum immunoglobulins, CRP, and TSH were normal. PSA was undetectable. Autoantibodies, including antinuclear antibody, antineutrophil cytoplasmic antibody, and rheumatoid factor (RF) were undetectable as were serologic tests for HIV, hepatitis, syphilis, and Lyme disease. Serum protein electrophoresis exhibited a modest elevation in kappa free light chains (23.0 g/L) but a normal kappa/lambda ratio was not consistent with a monoclonal gammopathy. There were no extended nutrient deficiencies with lead, copper, zinc, B12, or iron. Fecal elastase, stool culture, C. difficile, ova and parasites, and fecal leukocytes were negative. Stool for occult blood was positive.
Abdominal computed tomography (CT) demonstrated extensive gastric and duodenal mucosal fold thickening (Figure 3).
Upper endoscopy demonstrated florid gastric and duodenal polyposis, with thickening of gastric folds and "carpet-like" semipedunculated gastric and duodenal polyps ranging from 5 mm to 20 mm (Figures 4(a) and 4(b)). Histologically, the duodenal polyps showed edematous mucosa with variably dilated and branching glands, foci of gastric foveolar metaplasia, and blunted or absent intestinal villi. The inflammatory cell content of the lamina propria was mildly increased with prominent eosinophils.
Where native intestinal-type surface epithelium remained, it showed a mild increase of intraepithelial lymphocytes and an occasional intraepithelial eosinophil. There was no subepithelial collagen deposition. The gastric polyps were also a characteristic of Cronkhite-Canada syndrome. The foveolar glands were elongated, irregular, and focally dilated. The lamina propria was widely expanded by edema with an infiltrate of eosinophils and mononuclear cells (Figures 5(a) and 5(b)). Helicobacter organisms were not identified in gastric or duodenal specimens. The involvement of the duodenum and gastric antrum in this process ruled out Menetrier's disease which is typically confined to the gastric body.
Based on these clinical, endoscopic, and histopathologic features, a diagnosis of Cronkhite-Canada Syndrome was made.
Due to near complete inability to take in enteral intake from severe early satiety and subjective global assessment of severe malnutrition, TPN was initiated in conjunction with a short course of methylprednisolone, followed by a tapering prednisone regimen starting at 50 mg per day. Azathioprine was also initiated at 75 mg daily. A jejunostomy tube was placed under radiological guidance to provide enteral nutrition, and a high protein formula was used for caloric requirements, as the patient was unable to take in more than a few tablespoons at a time.
Approximately six weeks after discharge, during the course of continued outpatient evaluation, the patient exhibited a worsening of his diarrheal illness accompanied by fever and progressive abdominal pain. Stool testing was positive for C difficile, and oral vancomycin was initiated with satisfactory clinical response. After several clinical relapses on vancomycin taper, the patient was advised by infectious diseases to continue suppressive vancomycin 125 mg PO daily.
Several months into steroid taper, the patient developed polyuria, polydipsia, and hyperglycemia which had not been present at higher steroid doses. Insulin was initiated with reversion to normoglycemia.
Despite adequate enteral caloric intake and immunosuppression, the patient continued to experience progressive weight loss, failure to thrive, and ongoing diarrhea (C. difficile toxin-negative). Based on a successful recent case report, off-label infliximab was employed. Typical induction and maintenance infusions of infliximab were initiated with a regimen of 5 mg/kg at weeks 0, 2, and 6 followed by maintenance regimen of 5 mg/kg every 8 weeks thereafter. Remicade level was within the accepted range at week 14. Azathioprine was initiated with infliximab, at the beginning of therapy to prevent antibody formation to the anti-TNF.
The patient did not have an immediate initial response, and due to nausea, azathioprine was discontinued after 3 months. Azathioprine metabolites showed a 6-thioguanine of 106 pmol/8 x 108 RBC in the nontherapeutic range (230-400) and an undetectable 6-methyl mercaptopurine, appropriate for combination therapy with infliximab. Therefore, azathioprine was discontinued.
At 4 months from induction, the patient began to have nail regrowth, improvements in taste, and a modest improvement in diarrhea and weight.
Eight months following induction therapy with infliximab, bowel hygiene was significantly improved with approximately two formed movements daily. The patient was able to resume eating and drinking, and weight had increased by 10 kg. The patient also noted an improved sense of taste. Physical examination showed hair regrowth on the scalp, abdomen, and axillary and pubic regions in addition with improved proximal nail bed health. Hyperpigmentation was globally improved (Figure 2(b)). Laboratory values were within normal range.
Repeat upper endoscopy 9 months after initiation of anti-TNF showed notable improvement in gastric distention; however, there was persistent polyposis and no obvious pathological improvement in inflammatory cell infiltrate.