Whipple's disease

Pigmented
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Diagnosis and reasoning

This middle aged gentleman has presented with chronic watery diarrhea - a very common condition which may be due to a myriad of causes. The first step in his evaluation should be to determine if the diarrhea is organic or functional in origin (keeping in mind that the majority of such cases are functional). In this patient's case, the profound weight loss (of over 5 kg) strongly suggests an organic cause, as does the predominantly nocturnal nature of the diarrhea. The organic causes of chronic diarrhea can be broadly classified into inflammatory conditions (such as Crohn's disease), malabsorptive conditions (such as giardiasis, coeliac disease and Whipple’s disease), and secretory conditions (such as diabetes, adrenal insufficiency, and hypo-or-hyperthyroidism). In most patients, differentiating between these etiologies requires a systematic and at times protracted workup. However, this patient's examination reveals a valuable clue which helps short-circuit the diagnostic pathway: the presence of generalized hyperpigmentation. Very few etiologies causing chronic diarrhea give rise to generalized hyperpigmentation; in this patient, the two most plausible are Whipple’s disease and adrenal insufficiency. A diagnostic workup initially aimed at these two etiologies is perhaps the most efficient way forward. First of all, note that Whipple's disease gives rise to a malabsorptive diarrhea, while that of Adrenal insufficiency is secretory in origin. Thus the stool analysis showing increased fecal fat (i.e. malabsorption) is a pointer towards Whipple's disease; the hypoalbuminemia coupled with examination findings of peripheral edema and bilateral pleural effusions provide further supportive evidence in this regard. Note also that adrenal insufficiency is typically associated with hyponatremia and hyperkalemia; the mild hyponatremia and hypokalemia in this patient is more suggestive of chronic electrolyte loss secondary to the diarrhea. Estimation of morning cortisol definitively rules out adrenal insufficiency by demonstrating levels which are unambiguously normal. The diagnosis of Whipple's disease requires endoscopy and biopsy of the duodenal mucosa. This is justifiable now in this patient, and reveals consistent histopathological findings, clinching the diagnosis. Antibiotics are the mainstay of treatment in patients with Whipple's disease. Steroids, dietary restrictions and surgical resection have no place in the management.


Discussion

Whipple’s disease is a chronic multisystemic disease caused by the gram-positive, PAS-positive bacterium Tropheryma whipplei. It is rare, with an annual incidence of less than 1 per 1,000,000 individuals; white, middle aged males are preferentially affected. The disease mainly affects the small intestine, joints, cardiovascular system, and central nervous system; the clinical manifestations are believed to be secondary to infiltration of these tissues. Although Whipple’s disease has traditionally been regarded as a gastrointestinal disease, in the majority of cases it begins insidiously with arthropathy, while some patients may even present without gastrointestinal manifestations. The joint manifestations typically consist of migratory arthralgia or arthritis of the large joints. Key gastrointestinal symptoms include episodic watery diarrhoea or steatorrhoea accompanied by colicky abdominal pain; along with concomitant anorexia these lead to the full picture of a malabsorption syndrome with severe weight loss, weakness and general cachexia. Cardiac involvement is common and has been reported to be an important clinical sign. This includes cardiac murmurs, insufficiency of the aortic or mitral valve necessitating replacement, or culture negative endocarditis. Neurological manifestations are found in 10% to 40% of patients and are considered very serious, as irreversible damage may persist despite adequate treatment and elimination of the agent. CNS manifestations may first become apparent as a memory disorder, personality change, or dementia. Other common clinical signs include ophthalmoplegia, nystagmus, and myoclonia. Various cranial nerve symptoms, such as hearing loss and blurring of vision, have also been reported. Note that oculomasticatory myorhythmia (continuous rhythmic movements of the eye with mastication and convergence) is almost pathognomonic of the disease. Systemic symptoms are encountered in about half of patients and consist of intermittent, mostly low-grade fever and night sweats. Peripheral and abdominal lymphadenopathy is also common; mesenteric lymphadenopathy is identified frequently on radiographs but can also present as an abdominal mass. Skin hyperpigmentation, especially around the orbital and malar areas of the face, has also been reported. Patients with Whipple's disease are also at risk of Immune reconstitution inflammatory syndrome (IRIS). Due to its varied presentation, Whipple's disease mimics many other chronic inflammatory diseases and therefore, in combination with its rarity, the diagnosis is often delayed. Basic laboratory studies that suggest the presence of malabsorption is a useful screening test for Whipple’s disease. However, endoscopy and biopsy are essential for establishing the diagnosis. On endoscopy, the lesions of Whipple's disease are commonly described as pale yellow shaggy mucosal areas alternating with an erythematous, erosive or mildly friable mucosa in the duodenum or jejunum. Note however that these typical morphological changes are uncommon - duodenal biopsies should always be obtained if there is clinical suspicion of the disease. The histological features can be readily appreciated on standard hemotoxylin-eosin-stained sections as massive infiltration of the lamina propria by foamy macrophages. A periodic acid-Schiff (PAS) stain will confirm the suspected diagnosis. No tests are specific for the diagnosis except determining the presence of T. whipplei DNA through PCR. Note that this test is currently performed at only a few centers. Whipple's disease can be fatal if left untreated. The goals of management are to reduce morbidity, prevent complications, and eradicate the infection. Antibiotics are the mainstay of treatment. A general treatment proposal includes a primary (induction) treatment for 2 weeks with intravenous antibiotics which achieve high CSF levels, such as ceftriaxone. This is usually followed by 1-year (continuous) treatment with oral antibiotics (Trimethoprim-Sulfamethoxazole). Patients who have a relapse usually are treated for another 1 to 2 years. Once treated for a full year, the prognosis is usually good, with clinical remission occurring in approximately 70% of patients. Unfortunately, upto 30% to 40% of patients may relapse - this appears to be more common in those with CNS disease.


Take home messages

  1. Whipple’s disease is a potentially fatal condition which is often missed due to its rarity.
  2. Although generally considered a gastrointestinal disease, Whipple's disease often begins as an arthralgia or arthritis.
  3. The main symptom tetrad is arthralgia, weight loss, diarrhea with abdominal pain, and pigmentation.
  4. If treated properly and promptly with antibiotics, the prognosis is generally good.

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  1. Changing paradigms in Whipple’s disease and infection with Tropheryma whipplei: European Journal of Clinical Microbiology & Infectious Diseases, 2011
  2. Evaluation of Chronic Diarrhea: AAFP, 2011
  3. Tropheryma whipplei Infection: World J Gastroenterol., May 2009
  4. Whipple Disease Revealed by Lung Involvement: American College of Chest Physicians, June, 2012
  5. Whipple's disease: The Lancet, January 2003
  6. Whipple's disease: new aspects of pathogenesis and treatment: The Lancet Infectious Diseases, March 2008