OVERVIEW
Whipple’s disease is a rare systemic disorder. The male-to-female incidence ratio is (4 to 8):1, with more cases occurring between the ages of 30 and 50, with a mean age of onset of 39 years. Clinical features include small intestinal malabsorption, fever, skin pigmentation, anemia, enlarged lymph nodes, arthritis, arthralgia, pleurisy, valvular endocarditis, and central nervous system symptoms.The disease was first reported by Whipple in 1907, who described its clinical features and the pathological changes in the small intestines and lymph nodes.
Etiology
Bacteria are now recognized as the main causative agent. Biopsy specimens from the small intestine during the active phase of the disease may reveal rod-shaped bacteria (gram-positive bacilli) as described by Whipple, in addition to rod-shaped bacteria, bacillus-like organisms, Streptococcus anisopliae, Streptococcus alpha-streptococcus, Haemophilus, and Borrelia burgdorferi-like bacilli.
Symptoms
Clinical symptoms are prolonged and intermittent, and a few patients may die within a few months. The vast majority have weight loss, fatigue, and fever. The severity of clinical manifestations depends on the organs involved and the duration of the disease.
1. Digestive system
Abdominal pain accounts for 82%, diarrhea 76%, occult bleeding 64%, ascites 15%, and abdominal mass 13%. Diarrhea is the main complaint of the patient, defecation 5 to 10 times a day, feces is watery, with a bad smell, for the fat diarrhea containing a lot of foam. Flesh and blood stools are rare, which may be related to hypoprothrombinemia caused by secondary malabsorption. Abdominal pain is the most common symptom, and the pain is spasmodic in nature and variable in location. Anorexia is more common than idiopathic steatorrhea and may be accompanied by dramatic wasting, which may lead to severe cachexia.
2. Joints
More than 2/3 of patients have arthritis. Arthritis is characterized by intermittent, wandering, sometimes lasting only 1 to 4 weeks, and both large and small joints can be involved. The affected joints show pain, redness, swelling and localized fever. Arthritic episodes are commonly characterized by polyarthritis, with occasional monoarticular episodes. The most frequently affected joints are wrist and knee joints, followed by metacarpophalangeal joints, metacarpophalangeal joints, ankle joints, spinal joints, hip joints, shoulder joints and elbow joints. A few patients may develop ankylosing spondylitis, which is characterized by lower back pain or limitation of spinal movement.
3. Eye and nervous system
Conjunctivitis, keratitis, uveitis, vitritis, supranuclear ophthalmoplegia and progressive encephalopathy may occur. Disorientation, memory loss and various signs of cerebral nerve palsy may also occur. These signs include ophthalmoplegia, nystagmus, and facial paralysis. Mental disorders and behavioral abnormalities may also occur. Wernick’s encephalopathy may occur later in the course of the disease. Peripheral neuritis is characterized by abnormal sensation or hypersensitivity of the extremities.
4. Circulatory system
Some patients may develop cardiac valvulopathy, and a systolic murmur may be heard in the mitral or aortic valve area. The tricuspid and pulmonary valves may also be involved. When fever is also present, the possibility of bacterial endocarditis should be considered. The possibility of secondary acute or subacute bacterial endocarditis is especially likely when a diastolic murmur is heard or when the nature of the systolic murmur changes. Some patients may develop pericarditis or pericardial effusion.
5. Other
More than half of the patients may have different degrees of fever, chills, mostly intermittent low fever, a few patients may be high fever, in the acute stage may be manifested as persistent high fever.
Examination
1. Laboratory examination
(1) Blood count and sedimentation Almost all patients have anemia, which can be hypo- or normochromic anemia or megaloblastic anemia.
(2) Stool examination Some patients have positive occult blood test. Due to steatorrhea, the stool stains positively with Sudan III.
(3) Biochemical examination Most patients have low blood calcium, decreased cholesterol and decreased carotene. When there is secondary adrenocortical insufficiency, 17-hydroxycorticosterone and 17-ketocortisol drop in 24-hour urine, blood potassium rises and blood sodium drops. Most patients may have hypoalbuminemia.
(4) Immunologic examination There may be a decrease in IgG, IgM, IgA, a decrease in the number of E-rosette formation, a decrease in the lymphoblastoid cell transformation rate, a negative rheumatoid factor, a negative LE cell, and a negative antinuclear antibody.
(5) Cerebrospinal fluid examination If the disease involves the nervous system, cerebrospinal fluid smear can be stained with PAS, and the diagnosis can be confirmed if there is a positive finding.
2. Imaging examination
(1) Barium examination of the digestive tract shows thickening of the mucosal folds of the duodenum and jejunum. Due to the enlargement of lymph nodes in the posterior abdominal wall, the duodenal loops may be enlarged, and the stomach and ureter may be displaced.
(2) CT and MRI can also be used to detect central neuropathy, and brain involvement may show areas of space-occupying sparing.
(3) Chest radiographs may show enlarged mediastinal or hilar lymph nodes, pulmonary fibrosis, and in a few patients, solid changes in the lobes of the lungs and pleural fluid.
(4) Bone and joint X-rays: Joints are mostly normal, occasionally there are bone invasion and narrowing of joint cavity, while joint stiffness is rare, sometimes sacroiliac arthritis can be shown, and spondylitis is rare.
3. Endoscopy
Small yellowish-white nodules or granules, 2-3 mm in size, are seen on the mucosa of the duodenum and jejunum, with increased mucosal fragility, similar to Candida albicans infection. These nodules are formed by collections of coarse villi filled with macrophages. Biopsy of the duodenal or jejunal mucosa, which reveals a macrophage infiltrate with PAS-positive granules, establishes the diagnosis.
4. Electron microscopy
Electron microscopy of the patient’s biopsy tissue reveals small rod-shaped bacilli, rod-shaped, with three membranes, measuring (1-2) µm x 0.2 µm, i.e., Whipplelii bacilli, within the macrophages, which is the gold standard for confirming the diagnosis. Electron microscopy also reveals degradation of bacteria within macrophages.
Diagnosis
The disease should be considered in seronegative patients with arthritis and relapsing rheumatism who develop enlarged lymph nodes, central nervous system symptoms, vitritis, or diarrhea. The diagnosis of the disease can be confirmed on the basis of the patient’s presentation of malabsorption syndrome and other organ system involvement, biopsy of lymph nodes and small intestinal mucosa, and the typical PAS-staining-positive macrophages with pathologic features of the small intestinal mucosa.
Differential diagnosis
1. Blind loop syndrome
From the perspective of malabsorption syndrome, this disease is easily confused with blind loop syndrome. However, the latter often has a history of abdominal surgery or other intestinal diseases, without joint symptoms and fever. If barium gastrointestinal examination reveals intestinal fistula, adhesion, short circuit of small intestine, etc., it will help to distinguish this disease.
2. Primary malabsorption syndrome
Compared with primary malabsorption syndrome, this disease is similar in intractable gastrointestinal symptoms, nutritional deficiencies due to malabsorption and vitamin deficiencies, but primary malabsorption syndrome does not have lymph node enlargement, arthritis, fever and cardiopulmonary changes. Small intestinal mucosal biopsy specimens were devoid of macrophages that stained positively for PAS in Whipple’s disease. Gastrointestinal barium meal examination also has obvious difference.
3. Lymphoma
Lymphoma is easily confused with Whipple’s disease when it presents with fever, enlarged lymph nodes, diarrhea and joint symptoms. However, in the former case, there are no PAS-staining positive macrophages in the small intestinal mucosa biopsy specimen. Gastrointestinal barium meal examination also has no X-ray manifestations of Whipple’s, so it is easy to distinguish the two.
4. Systemic sclerosis
Sometimes with malabsorption, diarrhea, abdominal pain as the main clinical manifestations, similar to Whipple’s disease, but there is no hyperpigmentation, and no response to antibiotic treatment, the skin pathology is typical of scleroderma. Small intestinal mucosa and lymph node biopsy specimens were also devoid of PAS-staining positive macrophages.
5. Addison’s disease
When Whipple’s disease presents with secondary adrenocortical insufficiency, care should be taken to differentiate it from primary Addison’s disease. Although both have hyperpigmentation, hypotension, and electrolyte imbalance, the latter has no gastrointestinal symptoms, no characteristic pathological changes and small bowel X-ray abnormalities, and no arthritis, lymph node enlargement, or cardiopulmonary manifestations.
Complications
The eye and nervous system may be complicated by conjunctivitis, keratitis, uveitis, vitritis, supranuclear oculomotor palsy with progressive encephalopathy. The circulatory system may be complicated by bacterial endocarditis. Hypotension, hyponatremia, hyperkalemia, and hypoglycemia may occur when secondary hypoadrenocorticism is present. Sometimes pleurisy with pleural fluid may also occur. Individual patients may develop nonspecific peritonitis, hypoproteinemic peritoneal effusion, and enlargement of the liver, spleen, and lymph nodes.
Treatment
1. Antibiotic treatment
With appropriate antibiotic treatment, the clinical symptoms of Whipple’s disease can be relieved quickly, and fever and arthritis can be controlled within a few days. Penicillin is preferred to be injected intramuscularly every 6 hours or erythromycin intravenously once/day. Other antibiotics such as chloramphenicol, ampicillin (ampicillin penicillin), doxycycline (doxycycline), and sulfamethoxazole are available. Use for a total of 7 to 14 days. After that it is changed to tetracycline in 4 oral doses. The above drugs can be used alone or in combination. When combined with bacterial endocarditis, large doses of effective antibiotics should be given intravenously until the infection is controlled.
2. Glucocorticoids
If secondary adrenal insufficiency occurs, replacement therapy should be given.
3. Others
If dehydration is severe, appropriate correction should be given, along with nutritional reinforcement, correction of hypoproteinemia, whole blood or plasma transfusion. Long-term malabsorption may cause vitamin K, vitamin B12, vitamin D and other vitamin deficiencies, as well as hypocalcemia, hypomagnesemia and hypokalemia, which should be supplemented appropriately.
4. For patients with combined bacterial endocarditis
In the course of treatment, once heart failure occurs, it should be controlled by intravenous injection of appropriate amount of digitalis (mao dihuang) preparation.
5. Joint pain can be treated with indomethacin.
Prognosis
In most patients, clinical symptoms disappear within weeks to months after adequate antibiotic treatment. Relapse may occur after discontinuation of therapy. Once recurrence occurs, antibiotic therapy may be reintroduced. In some cases, the clinical symptoms are prolonged and intermittent, and a few patients may die within a few months.
Prevention
1. Eliminate and reduce or avoid the morbidity factors, improve the living environment space, develop good living habits, prevent infection, pay attention to dietary hygiene, reasonable dietary allocation.
2. Pay attention to physical exercise, increase the body’s ability to resist disease, do not over-fatigue, over-consumption, quit smoking and drinking.
3. Early detection, early diagnosis and early treatment, set up confidence in overcoming the disease, and adhere to the treatment.