Article ID: 25-00024
The patient was a 40-year-old woman who initially presented with ascites in September 2016. She was observed for suspected fatty liver disease and IgA nephropathy. In April 2023, she was admitted to the hospital after sustaining a self-inflicted injury. She presented with ascites and impaired liver and kidney function. A liver biopsy revealed no significant fibrosis, and she was diagnosed with idiopathic portal hypertension (IPH). The ascites did not improve with diuretics or paracentesis. A colonoscopy revealed multiple hyperplastic polyps, and a protein leakage scintigraphy identified protein leakage from the sigmoid colon. This led to a diagnosis of Cronkhite-Canada syndrome (CCS). She presented with characteristic skin symptoms of CCS, including nail atrophy and taste disturbances. Prior to the onset of symptoms, she reported experiencing psychological stress. Steroid therapy improved the ascites and pleural effusion, and the liver dysfunction gradually improved. This case suggests that an autoimmune background may have triggered or exacerbated the IPH and that CCS should be considered in the differential diagnosis of refractory ascites.
Idiopathic portal hypertension (IPH), a rare condition characterized by portal hypertension without cirrhosis, has recently been classified as a subtype of portosinusoidal vascular disease (PSVD)1,2). PSVD may be associated with multiple factors, including autoimmune diseases, infections, medications, and genetic predisposition3). Cronkhite-Canada syndrome (CCS) is a rare, nonhereditary condition involving multiple hamartomatous polyps, skin atrophy, hair loss, pigmentation abnormalities, and protein-losing enteropathy4). The onset of CCS may be associated with triggers such as stress, and its association with autoimmune abnormalities has been reported5-8). In this report, we present a rare case of a patient with CCS and IPH who presented with refractory ascites.
The patient was a 40-year-old woman. In September 2016, she visited a local clinic because of abdominal distension. She was referred to our hospital after ascites were detected. She was diagnosed with suspected fatty liver and immunoglobulin A nephropathy. Hepatic dysfunction and renal impairment were noted. However, a histological evaluation was not performed, and she was managed with diuretics. In April 2023, she was brought to the hospital after a self-inflicted injury and was admitted to the gastroenterology department. She presented with pleural effusion, ascites, hepatomegaly, and hepatic and renal dysfunction. On admission, her body mass index was 15.8, indicating severe malnutrition. She also had nail atrophy and taste disturbances. No skin pigmentation or hair loss was noted. She reported a history of psychological stress, suggesting a possible association with the onset of CCS. Blood tests revealed anemia, hypoalbuminemia, mildly elevated liver enzymes, and elevated inflammatory markers (Table 1). Serological tests for autoimmune liver disease, including antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and anti-mitochondrial antibody (AMA), were all negative. In addition, serum levels of immunoglobulin G (IgG) and immunoglobulin G4 (IgG4) were within normal limits. These findings did not support a diagnosis of autoimmune hepatitis, IgG4-related disease, or other immune-mediated liver disorders. CT scans revealed pleural effusion, ascites, and hepatomegaly. The liver had multiple nodular regenerative hyperplasia (NRH) lesions (Fig. 1). Upper endoscopy revealed F1RC0 esophageal varices and gastropathy related to portal hypertension (Fig. 1). The liver biopsy revealed no specific findings for chronic liver disease at stages A0 and F1. The diagnosis was IPH (Fig. 2). Splenomegaly was mild, and thrombocytopenia (110,000/μL) was present. The hepatic venous pressure gradient was not measured;however, secondary causes such as portal vein thrombosis or Budd-Chiari syndrome were excluded. Ascites tap and diuretics failed to improve the patient’s condition, and renal function deteriorated. During a colonoscopy performed for further investigation, multiple polypoid polyps were identified from the transverse colon to the sigmoid colon (Fig. 3). A mucosal biopsy revealed chronic inflammation with edema, as well as lymphocyte and plasma cell infiltration. The polyps exhibited cystic glandular duct dilatation, neutrophil infiltration, and fibrotic changes (Fig. 3). Protein leakage scintigraphy revealed accumulation from the sigmoid colon, which led to a diagnosis of CCS (Fig. 4).
We initiated immunosuppressive therapy with prednisolone at a dosage of 30 mg/day, which rapidly reduced ascites and pleural effusion and improved liver dysfunction. Portal hypertension symptoms have not worsened.
Hematology and biochemistry test results at the time of admission
γ-GPT, gamma-glutamyl transpeptidase;Alb, albumin;ALP, alkaline phosphatase;ALT, alanine aminotransferase;ANA, antinuclear antibody;AMA, anti-mitochondrial antibody;APTT, activated partial thromboplastin time;AST, aspartate aminotransferase; Ba, basophil;BUN, blood urea nitrogen;CK, creatine kinase;Cl, chlorine;Cre, creatinine;CRP, C-reactive protein;D-Bil, direct bilirubin;eGFR, estimated glomerular filtration rate;Hb, hemoglobin;HBs, hepatitis B surface;HCV, hepatitis C virus;Ht, hematocrit;K, potassium;LDH, lactate dehydrogenase;M2BPGi, Mac-2 binding protein glycosylation isomer;Na, sodium;Plt, platelet;PT, prothrombin time;RF, rheumatoid factor;T-Bil, total bilirubin;WBC, white blood cell.
Computed tomography (CT) images of the chest and abdomen and images obtained during upper gastrointestinal endoscopy. (a) Bilateral pleural effusions. (b, c) Ascites accumulation on the hepatic surface and in the pelvic cavity, as well as hepatomegaly, are noted. (d) Esophageal varices, classified as F1RC0. (e) Portal hypertensive gastropathy is detected.
Liver biopsy findings. (a) Hematoxylin and eosin staining (40× magnification). (b) Silver staining (40× magnification). A0 and F1 without evidence of advanced fibrosis are identified.
Colonoscopy findings. (a, b, c) The loss of normal vascular patterns and multiple elevated lesions with adherent white plaques are visible from the transverse colon to the sigmoid colon.
Histopathology of the colonic mucosa and polyps. (d, e, f) Mild infiltrations of lymphocytes and plasma cells within an edematous and fibrotic stroma, which are indicative of nonspecific chronic inflammation, are detected in the colonic mucosa. Colonic polyps appear as cystically dilated glands containing mucus and neutrophils scattered within the lesion. The stroma of the polyps has marked inflammatory cell infiltration (primarily plasma cells and lymphocytes), edema, fibrous proliferation, and increased capillary formation. These findings indicate hamartomatous (i.e., juvenile-like) polyps.
Protein-losing enteric scintigraphy image. Tracer accumulation is detected from the descending colon to the sigmoid colon.
Cronkhite-Canada syndrome (CCS) is a rare disease involving the growth of multiple non-neoplastic polyps in the gastrointestinal tract. It is accompanied by distinctive skin symptoms, such as nail atrophy, hair loss, and pigmentation changes, as well as taste disorders4). In this patient, nail atrophy and taste disorders were observed. CCS causes chronic diarrhea and hypoalbuminemia. Its etiology remains unclear;however, psychological and physical stress may have a role in its onset5-8). In this patient, hypoalbuminemia due to intestinal protein leakage, a characteristic of CCS, was considered a contributing factor to the ascites. Furthermore, idiopathic portal hypertension (IPH), which is specific to CCS, complicated the present case. The combined pathophysiology of both conditions may have complicated the treatment of ascites and hypoalbuminemia. Chronic inflammation and malnutrition associated with CCS may influence portal blood flow and microcirculation, potentially contributing to the onset or exacerbation of noncirrhotic portal hypertension (i.e., IPH)9).
Ascites caused by portal hypertension is primarily caused by increased hydrostatic pressure resulting from elevated portal pressure. However, the addition of low colloid osmotic pressure associated with CCS likely contributed to the refractory nature of the condition. IPH is a rare disease characterized by portal hypertension without cirrhosis. Recent studies have suggested that autoimmune mechanisms or chronic microvascular lesions around the portal vein may be involved in its pathogenesis1,2). In this case, the patient presented with esophageal varices, portal hypertension-associated gastropathy, and noncirrhotic portal hypertension (NRH). A liver biopsy revealed features typical of IPH without advanced fibrosis (i.e., F1).
Steroids are effective in treating CCS, with reports indicating that more than 85% of patients respond to prednisolone at a dose of 30 mg/day or higher5). Given the possibility that CCS is an autoimmune disease, shared immunological mechanisms between CCS and IPH are plausible. In this patient, steroid therapy resolved ascites and pleural effusion, thereby providing important evidence of an underlying autoimmune abnormality in CCS.
These results imply that the pathophysiologies of CCS and IPH may influence each other. However, cases of coexisting CCS and IPH are extremely rare, and further research is needed to clarify their interrelationship. Elucidating the effects of intestinal inflammation and hypoalbuminemia in CCS patients on portal blood flow and liver function may lead to improved treatment strategies. An integrated approach combining nutritional therapy, inflammation control, and immunosuppressive therapy may be effective.
In the present case, the patient was diagnosed with CCS along with clinical and histological findings consistent with IPH. Imaging and laboratory data revealed no evidence of cirrhosis or chronic liver disease, and liver histology showed preserved lobular architecture without significant fibrosis or inflammation. These findings support a diagnosis of non-cirrhotic portal hypertension, fulfilling the current diagnostic criteria for IPH.
Notably, corticosteroid therapy targeting CCS led to an improvement not only in gastrointestinal symptoms but also in signs of portal hypertension, including ascites and splenomegaly. This raises the possibility that portal hypertension may have been, at least in part, secondary to systemic inflammation, intestinal protein loss, or hemodynamic alterations associated with CCS. Although a direct pathophysiological link between CCS and portal hypertension has not been well established, this case suggests that the two conditions may have interacted, either coincidentally or mechanistically. Thus, our case may represent not only a rare coexistence of CCS and IPH but also a potential example in which inflammatory changes in CCS contributed to the development or exacerbation of portal hypertension.
Considering the possibility of refractory ascites due to an underlying autoimmune disease, we investigated and discovered the presence of Cronkhite-Canada syndrome. Cronkhite-Canada syndrome should be considered in the differential diagnosis of patients presenting with refractory ascites.
Jun Wada, Kana Tamazawa, Kenta Ueda, Sayuri Watanabe, Kohei Suzuki, Masato Aizawa, Yuki Nakajima, Goro Shibukawa, Kazutomo Togashi, and Hiromasa Ohira declare that they have no conflicts of interest.
All procedures performed in this study adhered to the ethical standards outlined in the 1964 Declaration of Helsinki and its subsequent amendments.
Informed consent was obtained from all participants included in the study.
The authors appreciate the endoscopy medical staff and ward staff of Fukushima Medical University Hospital for their assistance with the care of this patient.
