Background
Whipple disease (WD) is extremely uncommon with an incidence of less than 1 per million and fewer than 1,000 cases reported worldwide [1]. The disease is caused by Tropheryma whipplei, a Gram-positive bacillus ubiq- uitous in the environment. It is not known how people become infected with the bacteria although transmission is probably orofecal or oro-oral [2]. WD appears to pre- dominantly affect white males of European ancestry, aged 40-60 years, suggesting an underlying genetic predispo- sition to the disease [1,3]. Indeed, WD has been recently associated with human leukocyte antigen B27 haplotype [4].
The disease is a multisystemic process with four cardi- nal clinical manifestations: arthralgias, weight loss, diar- rhea, and abdominal pain [5].
Overall, intestinal symptoms are the most preva- lent among WD patients, followed by rheumatological symptoms [2]. Nevertheless, other organs are known to be potential targets for T. whipplei. Cardiac involvement is reported in up to 55% of cases, with pericarditis and blood culture-negative endocarditis being more frequent [1]. Skin hyperpigmentation is relatively common, being reported in up to 45% of WD cases [4]. Lymphadenopathy, predominantly of mesenteric and mediastinal nodes, has been reported up to 60% of cases making WD a differ- ential diagnosis for lymphoproliferative diseases [6]. Pulmonary involvement occurs in an estimated 30%-40% of patients with WD, mainly as pleural effusion, chronic cough, interstitial-lung disease-like presentation, and pulmonary hypertension [6]. Both ocular and neurolog- ical involvement are seen in less than 20% [7]. Kidney involvement was reported only on a few occasions and typically occurs late in the course of the disease [8-11].
The diagnosis of WD is made with a biopsy of the intestine and the identification of T. whipplei [12]. Current diagnostic criteria require positive results for periodic acid Schiff (PAS) positive foamy macrophages in the small bowel biopsy. If negative, diagnosis can also be reached by showing positive results in two of the following: i. PAS staining showing foamy macrophages in a biopsy speci- men of involved tissues; ii. PCR Detection of T. whipplei or detection of the specific 16S rRNA of the bacterium; and iii. Immunohistochemical staining with T. whipplei antibodies [12].
Without treatment, WD is ultimately fatal [1]. The basis of treatment is antibiotic therapy. Because of the possibility of central nervous system (CNS) involvement, the use of antibiotics that penetrate the blood-brain barrier is desirable [12]. One recommended regimen for the ini- tial phase is ceftriaxone 2 g daily or penicillin G 2 mil- lion units every 4 hours. The usual duration for the initial phase is 2 weeks, followed by the maintenance phase with trimethoprim 160 mg-sulfamethoxazole 800 mg twice daily for 12 months. Long courses are usually necessary to prevent relapses that can occur even years after treat- ment, with an estimated incidence of up to 30% of the cases [13].
Secondary amyloidosis is a late complication of chronic inflammatory disorders associated with a sustained acute- phase response [14]. Deposits of amyloid fibrils can lead to the disruption of structure and function of tissues and organs [14]. In WD, secondary amyloidosis has only been sporadically described [8-11,15-17]. This is, to our knowl- edge, the first report of secondary amyloidosis found in several digestive organs in a patient diagnosed with WD.
Case Presentation
A 56-year-old man with a 2 years-evolution of normo- cytic/normochromic anemia, under no daily medication, presented to the emergency room with complaints of diar- rhea of multiple watery stools per day, abdominal cramp- ing, skin darkening and a 14 kg unintentional weight loss (13% of patient total weight) within the previous month. There was no history of fever or night sweating. Physical examination revealed muco-cutaneous pallor and dehy- dration, diminished breath sounds with crackles, and symmetric lower limb edema. Neurological examination did not show signs suggestive of CNS affection. Blood tests on admission revealed a normocytic normochro- mic anemia (hemoglobin 11.4 g/dl, elevated reactive C protein (8.55 mg/dl), acute renal injury (creatinine 1.23 mg/dl), hyponatremia (129 mg/dl) and hypoalbumine- mia (2.1 mg/dl). Biochemical analysis of urine showed a proteinuria of 300 mg/dl. Human immune deficiency virus, hepatitis B/C virus, cytomegalovirus, and Epstein- Barr virus testing were negative. Autoimmune markers were also negative. Microbiological sampling of the stool and blood demonstrated no organisms on smear or cul- ture. Cutaneous biopsy shown irregular hyperplasia and melanic pigmentation of basal cells without inflammatory infiltrates. Abdominal computed tomography (CT) scan revealed multiple enlarged retroperitoneal lymph nodes and mild splenomegaly (Figure 1). At this stage, lymph- oproliferative disease could not be ruled out and a bone marrow biopsy was performed showing increased marrow iron suggestive of chronic disease, with no further clini- cally relevant findings. Biopsy of an inguinal lymph node was inconclusive. Thoracic CT scan revealed axillary and mediastinal lymphadenopathy and a small volume pleural effusion.
Abdominal-pelvic CT-scan in axial sections revealing multiple mesenteric and retroperitoneal adenopathies.
Upper endoscopy and colonoscopy were performed with standard biopsies. The histological findings were characteristic of WD. Microscopically, the duodenal biopsy featured a prominent infiltrate of plumped mac- rophages with granular cytoplasm which filled the lam- ina propria, distorting the overlying villous architecture (Figure 2). PAS stain highlighted these histiocytes packed with coarse granules in their cytoplasm (Figure 3). Histiocytes of identical appearance and epithelioid non-caseating microgranulomas were also identified in an involved regional lymph node (Figure 4). Ziehl-Neelsen stains were negative, excluding Mycobacterium avium-in- tracellulare. At this stage, a second attempt of lymph node biopsy was performed at a cervical node and T. whipplei was detected by PCR.
Duodenal biopsy featuring distortion of villous archi- tecture (hematoxylin-eosin, original magnification ×40). Inset: distension of villi due to macrophage infiltrates in the lamina propria (hematoxylin-eosin, original magnification ×100).
Expansion of the lamina propria by PAS-positive mac- rophages (original magnification ×400).
After diagnosis was established and due to previously known cardiovascular involvement in WD, a transthoracic echocardiogram was performed revealing a blood-culture negative endocarditis, with no stigmata of infective endo- carditis. Also, due to the initial finding of sub-nephrotic proteinuria, a work-up to further investigate patient renal function was established. Both 24-hours proteinu- ria and protein/creatinine ratio were 20-fold higher than the maximum of the normal range, reaching a proteinu- ria peak value of 9 g/24 hours during hospitalization. An urgent kidney biopsy was performed revealing glomeru- lar and arteriolar serum amyloid A deposits compatible with secondary amyloidosis (Figure 5). Similar findings were observed in colonic (Figure 6) and gastric mucosa biopsies.
Kidney biopsy with serum amyloid A deposits (Immu- nofluorescence, original magnification ×400).
Figure 6. Superficial subepithelial“band-like” amyloid deposits in large bowel biopsy (Congo red stain, original magnification ×100).
Before starting the patient on antibiotic therapy, a lumbar puncture was performed with cerebrospinal fluid showing inflammatory cell responses with no PAS- positive macrophages. We started the patient on a stand- ardized antibiotic regimen of ceftriaxone 2 g a day for the first 2 weeks and then trimethoprim/sulfamethoxaz- ole (TMP-SMX) 960 mg twice a day for 1 year. Clinical improvement was seen on the 7th day of treatment, with proteinuria decreasing to subnephrotic levels. Within 1 month of the planned year-long treatment regimen, com- plete resolution of abdominal complaints was obtained.
Discussion
WD is a chronic systemic infection caused by T. whip- plei, resulting in a variable clinical presentation, including intestinal and extra-intestinal symptoms [1].
It is known that T. whipplei is present in the environ- ment and has also been found in healthy carriers. A higher incidence of the infection among breeders and sewage workers has been reported, suggesting an occupational or environmental method of transmission [5]. In the case we report, the patient had no contact with livestock, residual water or sewers.
Diagnosis of WD is suspected most of the time on the basis of the appearance of gastrointestinal symptoms with rheumatologic manifestations usually preceding intestinal symptoms [2]. In hindsight, our patient had a presenta- tion consistent with WD: European male, fifth decade of life, with diarrhea, weight loss, and skin pigmentation. We were able to diagnose WD both from duodenal biopsies with PAS-positive macrophages and T. whipplei detected on a cervical lymph node.
Besides WD classic manifestations, cardiac disease may also occur. Patients with WD endocarditis usually have no previous heart disease and are most often apy- retic, with negative blood cultures [1]. This was the case of our patient who developed endocarditis without symp- toms or signs suggestive of cardiac disease.
Even less common WD presentations include pleu- ropulmonary, renal and endocrinological manifestations [6-13]. In the case we report, thoracic CT scan revealed a small volume pleural effusion and multiple axillary and mediastinal lymphadenopathies. Proteinuria was identi- fied at an early-stage and immunofluorescence of kidney biopsy samples revealing subepithelial type A amyloid deposits. Similar deposits were found in biopsy samples collected from gastric and colonic mucosa.
Aside from kidney [8,9,10,11,17], secondary amyloi- dosis in other locations in WD patients has only occa- sionally been described during life [14] and at autopsy [16,17]. Sander described the first link between WD and amyloidosis in a WD patient [17]. Farr et al. [15] reported a case of WD patient with amyloid fibers found in rectal and knee synovial. Schmid et al. [16] identified amyloid deposits in the heart of a WD patient that died suddenly of a heart attack. To the authors’ knowledge this is the first report of secondary amyloidosis affecting several diges- tive organs in the context of WD.
It is possible that the chronic inflammatory stimulus of WD works as a trigger for the development of secondary amyloidosis. In fact, Sander [17] proposed that the elabo- ration of amyloid might be induced by antigenic stimula- tion by the microorganisms found locally. The prognosis of secondary amyloidosis is poor with a median survival after diagnosis of 133 months [14]. However, successful treatment of the underlying inflammatory disease may be beneficial.
Further studies are needed in order to conclude a causal association between T. whipplei presence and amyloid deposits.