Lessons from practice Low attenuation lymphadenopathy on computed tomography leading to diagnosis of Whipple disease

Clinical record

A 48‐year‐old man of Eastern European origin presented to our hospital in Adelaide, Australia with a 3‐month history of increasing diarrhoea 8–10 times per day, cramping abdominal discomfort and weight loss of 8 kg. The patient had returned 3 months previously from his annual 6‐week holiday in Croatia. He had also been recently admitted to hospital with acute pulmonary oedema of uncertain aetiology, and had a 5‐year history of seronegative polyarthralgia and lethargy. He had been noted to have abdominal lymphadenopathy with splenomegaly on a computed tomography (CT) scan of the abdomen 3 years earlier, for which investigations with BCR‐ABL genetic analysis and serum protein electrophoresis showed no evidence of a lymphoproliferative disorder.

On examination, there was no abdominal tenderness or distension. Neither was there palpable lymphadenopathy, skin changes, rash or evidence of arthropathy. He had a chronic microcytic anaemia with a haemoglobin level of 114 g/L (reference interval [RI], 135–175 g/L), an elevated C‐reactive protein level of 168.2 mg/L (RI, < 8.0 mg/L) and a white cell count of 5.88 × 10⁹/L (RI, 4.0–11.0 × 10⁹/L). His electrolyte and liver enzyme levels were normal.

A CT scan of his abdomen had been performed one week before this presentation, for re‐assessment of his lymphadenopathy. While the mesenteric and retroperitoneal lymph node enlargement and splenomegaly remained stable over 3 years, it was noted that the lymph nodes were of abnormally low fat density attenuation (Box 1). Given this, the differential diagnosis was broadened from haematological malignancy to include atypical infection and rarer causes such as Whipple disease. Gastroenterology consultation was requested.

On enteroscopy and colonoscopy, ulceration with white plaque‐like lesions was identified throughout the gastrointestinal tract consistent with the endoscopic appearance of Whipple disease (Box 2 and Box 3) The duodenum and terminal ileum were affected, as was the colon from the sigmoid to the caecum with rectal sparing. The oesophagus and stomach were not affected and the jejunum was not examined. Histology and immunohistochemistry from biopsy samples revealed periodic acid–Schiff–diastase staining, supporting a diagnosis of Whipple disease (Box 4), and Tropheryma whipplei polymerase chain reaction results were positive.

Antibiotic therapy commenced with 2 g ceftriaxone for 2 weeks, extended to 4 weeks after a transoesophageal echocardiogram identified a small mitral valve vegetation. The patient's gastrointestinal symptoms resolved within 48 hours of treatment. After 4 weeks, his antibiotic therapy was changed to oral sulfamethoxazole–trimethoprim for 12 months (standard therapy for this condition). The patient had total resolution of his symptoms within 2 weeks of starting therapy and remained symptom free at the time of writing (12 months after starting therapy).

Discussion

Whipple disease is a rare multisystem condition caused by infection by the gram‐positive bacillus Tropheryma whipplei. While the organism is ubiquitous, the actual incidence of Whipple disease is exceedingly low at one per million people, with our patient fitting the highest risk demographic profile.1 Susceptibility to infection is thought to be genetic, resulting in cell mediated and macrophage immune defect, as yet incompletely understood.1,2 The clinical presentation of this disease is non‐specific and diagnosis is therefore difficult and often delayed. The earliest manifestation is arthralgia, followed by gastrointestinal symptoms some months or years later. Our patient's history of polyarthralgia and a recent admission with pulmonary oedema may be attributable to Whipple disease.

If left unrecognised and untreated, the disease is progressive and can be fatal;3 timely recognition and treatment is therefore crucial. Standard treatment is 2–4 weeks of ceftriaxone followed by one year of trimethoprim–sulfamethoxazole, and relapse rates are 17–35%.4 Anaemia and malnutrition are found in almost all cases, while less common complications include endocarditis, myocarditis, skin hyperpigmentation, dementia, confusion and cerebellar ataxia, with neurological involvement usually manifesting late in the disease process.

Whipple disease is classically described in the radiology literature by its features on barium small bowel follow‐through studies.5,6 However, with technical advances and increasing availability of CT and magnetic resonance imaging, small bowel barium contrast studies are becoming less frequently performed and unlikely to be utilised unless there is pre‐existing clinical suspicion for specific small bowel pathology.

Low attenuation lymphadenopathy is a recognised feature of Whipple disease on CT imaging,5,6 although the literature is scarcer, presumably due to relatively less frequent use of cross‐sectional imaging in the past. The low fat density of the lymph nodes is thought to be a consequence of lymphatic obstruction and intranodal deposition of fat.4 It is important to consider other important disease processes that could produce this appearance, including the more commonly encountered coeliac disease, as well as abdominal tuberculosis. Other intestinal opportunistic infections, lymphoma and metastases are also considerations.

Box 1 – Computed tomography scan showing abnormally enlarged, low attenuation retroperitoneal lymph nodes (arrows) approaching the density of the adjacent abdominal fat

---

Box 2 – Endoscopic image of the duodenum demonstrating the classic white plaque appearance of Whipple disease

---

Box 3 – Colonoscopic image of the ascending colon demonstrating the classic white plaque appearance of Whipple disease

---

Box 4 – High power microscopic view of a duodenal biopsy demonstrating extensive PAS‐D staining of macrophages

---

PAS‐D = periodic acid–Schiff–diastase. Whipple disease diagnosis is supported by PAS‐D staining (magenta) of macrophages on intestinal tissue. Magnification, × 20.