Deep vein thrombosis in a patient with Cronkhite-Canada syndrome: a complex case report

On August 16, 2018, a 58-year-old female was admitted to our hospital, complaining of a 2-month history of anorexia, abdominal distention exacerbated by food intake, watery diarrhea, malaise and 8-kg weight loss. She denied the diarrhea was related to the ingestion of lactose, gluten-containing food, or emotional changes, but mentioned intake of Chinese medicine before onset.

Physical examination revealed the patient was malnourished, with a body mass index (BMI) of 16.02 kg/m2, and the appearance of a chronic illness, including sparse hair, black-brown pigmentation of palms and feet, and dystrophic nails (Fig. 1A and B). Laboratory tests showed decreased white blood cells (3.11 × 109/L), complement C3 (497.9 mg/L), and albumin (37.6 g/L). Other blood parameters, including liver, renal, thyroid function, and tumor markers, were normal.

Fig. 1figure 1

Typical appearance changes of the patient before therapy (A-B) and after methylprednisolone-based comprehensive therapy (C-D)

Autoimmune assessments indicated a slight abnormality in patient’s anti-ds-DNA (20.8 IU/mL) and antinuclear antibody (titer 1:80, discrete speckle pattern), with all other tests within normal range, including antinuclear antibody profile, indicators for screening early rheumatoid disease, vasculitis, antiphospholipid-antibody syndrome, and autoimmune hepatitis.

Furthermore, the patient’s stool sample reviewed no occult blood, ova, or parasites. Gastroduodenal endoscopy revealed erosive gastritis and duodenitis with swollen and protruding gastric mucosa. Infection with H. pylori was excluded from the diagnosis by the rapid urease test and hematoxylin–eosin staining. the patient’s colonoscopy revealed edematous terminal ileum mucosa with inflammation, and multiple polypoid eminences were removed by endoscopic electronic resection and clamping. A video capsule and double-balloon endoscopy revealed atrophy with a mosaic and serrated appearance.

Malignancy was excluded by PET-CT, and toxicological testing was negative for heavy metal intoxication from herbal medicine. The patient denied any family history of gastrointestinal polyposis or malignancy, and she had no mutations in cancer-related genes, including APC, ATN2, BARD1, BRCA1, MSH, or and MUTYH tested by next generation sequencing.

CCS was given the clinical manifestation of gastrointestinal and ectodermal symptoms, massive polyps throughout the gastrointestinal tract, and the special pathological features. The patients was prescribed 3000 mg/day mesalazine with symptomatic and supportive treatment, including nutritional support (enteral nutrition powder), gastric mucosa protection (rabeprazole & teprenone), digestive enzyme supplementation (Combizym), gastrointestinal peristalsis regulation (trimebutine meleate) and intestinal flora modulation (live combined Bifidobacterium and Lactobacillus) (Fig. 2). The patient saw improvement in gastrointestinal symptoms and body weight following treatment.

Fig. 2figure 2

Time-dependent figure of disease progression and treatment

However, 1 year later, the patient was re-admitted to the hospital due to recurrent diarrhea, exaggerated weight loss, fever, lower extremity edema and foamy urine, and additional symptoms. A repeat gastroscopy and colonoscopy revealed aggravation of the mucosa edema and diffuse eruption of polyps in the stomach and colon (Fig. 3A and C). Additionally the patient’s video capsule endoscopy indicated atrophy with a nodular and serrated appearance of the small intestinal mucosa and diffuse polypoid lesions (Fig. 3E).

Fig. 3figure 3

Representative images of gastroscopy, colonoscopy and video capsule endoscopy. Before effective treatment, gastric antrum mucosa was swollen with scattered punctate pigmentation, dense granular and nodular uplift (A), a laterally developing tumor-like protrusion in the cecum, multiple polyps along the colon (C), and edema and atrophied of mucosa and villi of small intestine with mosaic and sawtooth signs and diffuse polypoid lesions (E). After methylprednisolone-based comprehensive therapy, both gastric and colonic mucosa became smooth and all polyps subsided (B, D), edema and atrophied mucosa and villi were reduced, and small intestine polypoid lesions disappeared (F)

Further histological examination revealed infiltration of mixed inflammatory cells, excessive stromal edema, sparse and shrinking villi and crypts, hyperplastic polyps in stomach, and tubular adenoma widespread from the cecum to the rectum (Fig. 4A and C). Nail atrophy worsened with exudation, and we then diagnosed the patient with a Candida glabrata infection. The microbiological culture of the stool further confirmed a salmonella infection. Laboratory tests for the inflammatory-related cytokines indicated normal levels of interleukin-6 (4.1 pg/mL) and ceruloplasmin (281 mg/L), with a decreased level of α1-acidglycoprotein(0.39 g/L). Additional laboratory tests showed hypoproteinemia (serum albumin 19.84 g/L) and massive proteinuria (24-h urine albumin 6.0 g/L). The patient’s anti-PLAR2 antibody was negative, and blood tests for hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV), and syphilis infections were negative.

Fig. 4figure 4

Representative histological photos of endoscopic biopsy specimens taken from the stomach and colon (Hematoxylin–eosin staining, original magnification × 100). Before effective treatment, there was chronic inflammation, extensive interstitial edema, gland expansion and hyperplastic polyps in stomach were present (A), inflammatory cell infiltration in the colonic mucosa was present, and tubular adenomas were widely distributed from the cecum to the rectum with or without low-grade intraepithelial neoplasia (C). After the methylprednisolone-based comprehensive treatment, only mild chronic inflammation was present in the gastric mucosa (B), and scattered tubular adenoma was present in the colon (D)

Given the patient’s hypoalbuminemia and proteinuria results, nephrotic syndrome diagnosis was certain. Because the patient had severe fluid loss and malnutrition due to watery diarrhea, a central venous catheter (CVC) placed in the left internal jugular vein to facilitate fluid infusion and parental nutrition. However, 6 days following insertion of CVC, the patient complained about neck pain and skin swelling. No coagulation function and serum protein electrophoresis abnormalities were found. However, Color-Doppler ultrasound detected thrombus formation of the left internal jugular vein involving the proximal end of left subclavian vein(Fig. 5A and B), A CT of the neck confirmed the findings and found excessive exudation in the interstitial space with inflammatory changes in the surrounding tissue around the venous thrombus (Fig. 6). Before and after the formation of the venous thrombus, the platelet level increased from 249 × 10^9/L to 316 × 10^9/L, international normalized ratio (INR) decreased from 1.03 to 0.94, and fibrinogen increased from 4.93 g/L to 6.15 g/L. However, there prothrombin time (12.7 s), activated partial thromboplastin time (43.3 s), thrombin time (14.2 s), and level of D-dimer (1010 ng/mL) did not change significantly. The CVC was immediately removed to avoid its influence on the DVT, and the patient was treated with empirical use of piperacillin and tazobactam (4.5 g, iv, q8h) and a fondaparinux sodium injection (0.5 ml, qd) to prevent further thrombosis. The patient had a relief of neck pain and skin swelling after treatment but relapsed later, therefore, the patient was given low molecular weight heparin (LMWH 0.4 ml, subcutaneous injection, q12h) and discharged with rivaroxaban (10 mg, qd).

Fig. 5figure 5

An ultrasound examination of the neck demonstrated low-density thrombus (white arrow) in the left internal jugular vein after catheterization of PICC (A) and Color Doppler imaging confirmed the blockage of blood flow (B). After adequate dose and duration of anti-coagulation, surveillance ultrasound detected that the thrombus (white arrow) remained stable in size with increased density in the left internal jugular vein (C), with no recovery of blood flow in Color Doppler image (D)

Fig. 6figure 6

CT scanning detected the PICC in the left subclavian vein and left internal jugular vein with thrombus formation. A few gas bubbles were seen along the left internal jugular vein Excessive exudation and inflammatory changes were seen in the interstitial space around the venous thrombus.

The patient was diagnosed as CCS complicated with infectious enteritis, nephrotic syndrome and jugular vein thrombosis. A comprehensive therapy consisting of methylprednisolone, mesalazine, anti-infection, anticoagulant treatment, and auxiliary nutritional support were provided. Two years later, the patient reached complete remission of gastrointestinal symptoms and was well-nourished with a BMI of 24.03 kg/m2.She had grown back a full head of glossy, black hair, had complete disappearance of pigmentation on her hands and feet, and regrowth of healthy nails (Fig. 1C and D). Hypoproteinemia and proteinuria returned to normal (serum albumin 41.7 g/L). On March 1, 2022, the patient received gastroscopy and colonoscopy, which showed a significant reduction in the number of polyps(Fig. 3B, D, and F), and pathological examination revealed only mild inflammation throughout the gastrointestinal tract and regeneration of the intestinal villi and crypts (Fig. 4B and D). The patient had no recurrence of neck pain or skin swelling. Surveillance ultrasound detected that the left internal jugular vein thrombosis still existed but remained stable in size with organization (Fig. 5C and D). The patient had regular followed-up appointments to monitor her long-term prognosis, including maintenance of remission, recurrence of CCS, and potential canceration of colonic polyps.

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