Whipple's disease

In 1907 George Hoit Whipple, pathologist John Hopkins Medical school, has in detail described ­ sectional ­ observation of the unknown person before disease. Clinically it was characterised by a serious diarrhoeia, cтeaтopeeй, a sharp weight loss and an anaemia. On dissecting substantial growth of lymph nodes, a polyserositis have been found. At histological research ­ diffusive accumulation of lipids is found in an intestine and ­ lymph nodes and at a coloration on Levaditi - set ­ of rhabdoid ­ microorganisms. G. Whipple has stated two versions about causes of illness: ­ the first - disturbance ­ of a metabolism of lipids in this connection it was offered to name disease the intestinal ­ lipodystrophy, the second - disease has an infectious parentage.

It is interesting, that G.Whipple has lived 98 years, has published 270 works, but it is more to this disease ­ did not come back. In 1934 it became the Nobel prize winner in the field of medicine; the award has been awarded for working out of preventive maintenance and treatment of a pernicious anaemia. However ­ now it to very few people is known, and name Whipple associates only with the disease open by it on the basis of ­ one sectional observation.

The following description of disease Whipple has appeared only in 23 years. By their 1950 was only 15. By 1988 reports on 1000 patients are published.

Aetiology and pathogenesis

In 1907 Whipple has paid attention to resemblance of microorganisms in the form of rods in ­ own plate of a duodenum with an acyanotic spirochete. Since 1960 the disease-producing factor many bacteria excreted in culture from a biopsy sample (corynebacteriimi, the L-form of a streptococcus, etc.) appeared. Only in 1991 R.Wilson and co-authors, and then in 1992 D.Realman and co-authors by means of polymerase chain reaction (PCR) ­ have secured the Gram-positive bacillus from stuffs of the infected tissues of the patient. Microorganisms are mostly defined ­ in macrophages, but found and in extracellular space­. The main and ­ distinctive line of a bacterium - trilateral the cellular side, well visible at a submicroscopy­. On phylogenetic data and morphology the open bacterium concerns Actinomyces. In honour of Whipple the prospective disease-producing factor has received name Tropheryma whipplii.

Despite new data about the infectious agent presumably causing disease,­ are still actual reasons about a possible role of the immunologic factors ­ allowing the originator to educe. Apparently, patients with the given disease do not have appreciable humoral ­ immune insufficiency though it is considered, that production of antibodies to its originator is low or is absent completely. Obviously, more appreciable role is played by the cellular immune answer.

There are data about quantitative and qualitative disturbances of production of lymphocytes: reduction of quantity of T lymphocytes and depression of activity of lymphocytic reaction to mitogens. At Whipple's disease function of macrophages is broken. By histological researches it is established, that Tropheryma whipplii collect in macrophages where they continue to propagate. It allows ­ to assume, that macrophages keep ability to a phagocytosis, but lose ability to a microorganism lysis.

At studying of an expression of cytokines in culture of the macrophages received at a duodenal biopsy at patient Whipple's disease, depression of production of an interleukine-12 and g-­ interferon has been shown­. However it is obscure, whether these changes are bound to dysfunction of macrophages or they grow out of T-cellular defect.

And, at last, new technological approaches have allowed to achieve a surviving and growth ­ intracellular ­pathogens in human phagocytes. With that end in view the culture of the bacteria identified ­ as Tropheryma whipplii, infected the human phagocytes deactivated ­ by an interleukine-4, interlejkinom-10 and dexamethasone. ­ The interleukine-4 (G.Schoedon and co-authors) has appeared the most effective deactivate the factor­.

Thus, for last years our knowledge about Whipple's disease has essential extended: first,­ the microorganism causing disease is secured and studied; secondly, Tropheryma whipplii it is cultivated in immunodeficient cellular medium.

Clinic

Still Whipple underlined multisystem character of clinical signs of disease. Usually disease begins at the age of 40 - 50 years. Among the diseased men prevail.

The symptoms bound to disturbances of digestion (a diarrhoeia, absorption disturbance, mass loss), are classical signs of disease and by the moment of an establishment of the diagnosis are observed at 85 % of patients. To typical symptoms carry: a combination of a diarrhoeia and other intestinal implications (polyexcrements, a steatorrhea, a creatorrhea, an amylorrhea) with disorder of all kinds of a metabolism. Accrue attrition of the patient up to a cachexia; the general delicacy, working capacity depression; sometimes there are alienations, an acidosis. Frequent signs are: a polyhypovitaminosis, an osteoporosis and even an osteomalacia, В12-фолиево-and an iron deficiency anaemia, trophic changes of a skin, fingernails, an atrophy of muscles, polyglandular insufficiency.

The skin becomes dry, is frequent places a hyper-pigmented, there are edemas owing to disturbance of an albuminous and vodno-electrolytic exchange, the hypodermic fat is educed weakly, a hair drops out, fragility of fingernails is raised.

Owing to deficiency of vitamins appear: at insufficiency of Thiaminum - paresthesias of a skin of arms and feet, onychalgias, a sleeplessness; niacin - a glossitis, pellagroid skin changes; Riboflavinum a cheilitis, an angular stomatitis; Acidum ascorbinicum - a staxis of gums, hemorrhages on a skin; vitamin A - disorder of twilight sight; vitamin В12, Acidum folicum, a gland-anaemia.

To the clinical signs bound to disturbance of an exchange of electrolytes, the tachycardia, an arterial hypotension, thirst, a xeroderma and tongue concern at deficiency of sodium; pains and delicacy in muscles, weakening of tendon jerks, disturbance of a warm rhythm, more often in the form of an extrasystole - at deficiency of a potassium - a positive symptom of the muscular platen owing to rising of nervimuscular excitability, sensation of a numbness of labiums and dactyls, an osteoporosis, sometimes an osteomalacia, fractures of bones, myotonia - at a calcium disadvantage.

Changes of endocrine organs show disturbance of a menstrual cycle, occurrence of an impotency, hypocorticoidism signs.

Within many months and even years ­ articulate pains or cardiovascular, neurologic and pulmonary implications can ­ precede alimentiry semiology­. Articulate ­ symptoms precede gastrointestinal at 67 % of patients. For articulate semiology the lesion of the basic peripheric joints and a loin, short-term relapsing ­ arthralgias, in the subacute season - oligoarthritises or the chronic polyarthrites reminding ­ a pseudorheumatism is characteristic­­. However the arthritis at Whipple's disease, except for rare cases, does not lead to deformation of joints or destructive changes.

Frequency of lesion CNS fluctuates from 10 to 50 %. An aphrenia, supranuclear an ophthalmoplegia, a myoclonia and their combinations - the most frequent symptoms. Appearance of neurologic symptoms ­ was considered as a sign of an end-stage of disease earlier. Now it is known, that ­ neurologic symptoms are possible and for lack of gastrointestinal semiology, without ­ an intestine lesion, and also after years after correctly spent treatment of the intestinal form ­ of disease.

The Cardiovascular semiology becomes perceptible at 20-25 % of patients. The most usual ­ clinical implication ­ Whipple's disease - an infectious endocarditis which amazes the mitral valve and yields negative results of tests on cultures of blood cells. Pericarditis attacks are usually asymptomatic and are taped only at an echocardiography.

The chronic tussis noted still Whipple, meets at 30-50 % of patients. ­ Uveites are quite often observed.

Disease streams chronically, years, with change of typical stages. At I stage there are ­ abenteric symptoms: a fever, a polyarthritis, on II - signs of a serious sprue. At III stage ­­ neurologic symptoms, cardial and system implications join a progressing weight loss and serious metabolic disorders a pancarditis, a polyserositis).

Diagnostics

Diagnostics is considerably complicated by that at the majority of patients precede intestinal symptoms or various abenteric implications accompany.

At patients it is considerably raised an ESR, haemoglobin level is lowered, the number of leucocytes and thrombocytes is enlarged. Concentration in blood serum of protein, iron, calcium, cholesterol simultaneously decreases. The hypoalbuminemia is bound to loss of considerable quantities of seralbumin through digestive tube pots, and also with disturbance of synthesis of albumins. Positive takes of functional absorption tests with a xylose, iodine-kalievoj of assay, assay with a load a glucose, etc. the steatorrhea Is characteristic: Adeps loss reaches 50/days

At endoscopic research the duodenum mucosa is hydropic, hyperemic, with thickened cords. A mucosa relief rough because of numerous slightly towering formations of light yellow colour. At a X-ray inspection, especially at a radiological computer tomography, the enlarged retroperitoneal, mediastinal lymph nodes, an ascites, a pleural or pericardiac exudate can be found.

Clinical, routine laboratory and tool data allow to suspect disease only. Definitive diagnostics is based on results histopathological, electronic-microscopic researches and use PCR for identification Tropheryma whipplii.

At light microscopy of the biopsy samples received from lean and a duodenum of uncured patients, the claviform villuses containing a considerable quantity of a lymph are taped. Are characteristic intra-and extracellular accumulation of Adeps in a small bowel mucosa, dilating of absorbent vessels. In own plate of a mucosa the invasion is found by the foamy macrophages containing beads with strong PAS-positive reaction. Sometimes in macrophages and extracellularly happen are visible Gram-positive bacillus similar little bodies. Massive infiltration of a mucous duodenum by PAS-positive macrophages is dostatoch th argument for diagnosis statement even without submicroscopy application.

Presence of PAS-positive macrophages testifies to system character Whipple's disease in variety of tissues and organs - in lymph nodes, a CNS, a neurolymph, heart, a stomach, an intestine, a liver, muscles, easy, a synovial membrane, an osteal brain.

Electronic-microscopic research finds in the struck tissues bacillus similar little bodies. The last represent cells in the form of rods with a trizonal cover, it is a lot of them in stand-at-ease in intercellular space and at the same time they are present in a cell. The submicroscopy has allowed to observe and process of destruction of bacteria in macrophages. PAS-positive beads represent the lysosomic stuff containing bacteria at different stages of destruction. Negative takes of research of biopsy samples from a small bowel can have some explanations: the stuff is taken from top, instead of from the inferior part of a duodenum or the patient already received antimicrobic treatment. With these cases to diagnostics can help PCR, allowing to identify Tropheryma whipplii.

Treatment

In first half of XX-th century Whipple's disease in 100 % of observations came to an end it is lethal. The report on the first successful application at it of antibiotics has appeared in 1952. This fact has received an explanation after 1960 when submicroscopy data have confirmed the assumption of an infectious aetiology of disease. For treatment Whipple's disease different antibiotics were used, but the greatest diffusion was received by preparations of a tetracycline number.

Tetracyclinum or its semisynthetic analogue is recommended to be applied Metacyclinum within 2-5 months. Then for remission maintenance it is necessary to pass on intermittent (till 9 months) therapy with preparation reception in day or 3 days in a week with a rest in 4 days.

Last years into practice of treatment Whipple's disease it is introduced Trimethoprim-Sulfamethoxazole (Biseptolum, Co-trimoxazole (Septrin)). The preparation is especially shown at cerebral lesions as it inpours through a blood-brain barrier.

At cerebral lesions the following scheme of therapy is recommended: 1,2 million Unit a benzylpenicillin (Penicillinum G) and 1 gramme of streptomycin a parenterally daily within 2 weeks with the subsequent appointment To-trimoksazola (Trimethoprimum - 160 mg and Sulfametoxazolum - 800 mg) twice a day within 1-2 years to negative take PCR and disappearance Tropheryma whipplii in biopsy samples from a duodenum. Parallel appointment of Acidum folicum prevents its deficiency - possible complication at such therapy. At cerebral forms difficultly giving in to treatment it is necessary to mean 2 more medicines well inpouring through a blood-brain barrier: rifampicin and Chloramfenicolum. However to their application at long treatment stirs possibility of development secondary resistances (rifampicin) or serious negative by-effects (Chloramfenicolum). In cases, refractory to an antibioticotherapia, g-interferon appointment is shown also.

Also including in a complex of pathogenetic therapy of glucocorticoids is justified. Glucocorticoids are prescribed in an initial dose of 20-30 mg/days, on reaching a positive effect the dose gradually decreases. The widespread scheme of appointment of glucocorticoids: Prednisolonum of 40-60 mg/sut, next weeks: 60, 40, 15, 10 mg, then 10 mg in a day (3 months)

If necessary spend symptomatic therapy:

1. A sprue and the Syndrome of insufficient digestion:
   • Dietetic therapy provides sufficient introduction of alimentary materials, especially animal proteins to 135 gramme, correction lipide and a lipometabolism
   • Correction of metabolic disturbances by introduction of admixtures for an enteroalimentation: nutrient admixtures, on structure similar to a chyme (Ovolact), parenteral introduction of proteins (albumins) and admixtures of amino acids, a hemotransfusion and plasmas, appointment of anabolic steroids (Nerobolum, Retabolilum, Silabolinum) for liquidation of albuminous insufficiency, normalisation of metabolic processes, neogenesis of a mucosa of an intestine
   • Correction of a vodno-electrolytic exchange (enteral and parenteral introduction dextrose salt solutions), metabolic acidosis and alkalosis correction, preventive maintenance of a secondary hyperaldosteronism (verospiron)
   • Correction of cavitary digestion and indemnification of pancreatic insufficiency are carried out by application of fermental preparations (Festalum, Panzynorm, Pancreatinum, Pancreatin, Kreon, etc.)
   • Iron deficiency correction (Ferrum Lek, Tardyferon, jectofer, etc.)
   • Correction deficiency vitamin (B1, В12, В6, folic, Acidum ascorbinicum)
   • Other methods of correction: restoration of membranes of an intestinal epithelium (essential phosphotides, hepatoprotectors - Legalonum, Carsil). There are data on positive influence of an adrenergic preparation of ephedrine, on application of Sodium nitritums, caffeine, Complamin with a view of absorption enriching in a small bowel
2. A diarrhoeia syndrome:
   • Retardation of an intestinal peristalsis (Reasek, Nospanum, a papaverine, Buscopan) and reduction of secretion of water and electrolytes in an intestine lumen (imodium, a loperamide)
   • Correction pH endoluminal medium by appointment adsorbing and neutralised organic acids of preparations (bismuth Sodium nitritum, Dermatolum, Tannalbin, white clay, denol, Smecta, Cholestyramine, etc.)

Treatment should be supervised by repeated biopsies of a mucous small bowel. As positive effect morphological character disappearance of macrophages serves.

At timely and active treatment an outcome of disease the congenial. Enriching of a clinical picture and biological indicators often happens rather impressing and descends within 7-14 days. However regression of histopathological deflections slow and not always the full.

Relapses even after correct treatment meet in 8-35 % of observations. The neurologic relapses which are badly giving in to therapy are especially dangerous. Usually they meet at initially not distinguished localisation of an infection contamination and treatment by preparations of the tetracycline number which are not passing through a blood-brain barrier. At use of Trimethoprimum-Sulfametoxazolum of relapses practically does not happen. Therapy at relapses does not differ from described above.

Clinical observation

In summary it would be desirable to result one, rather indicative clinical observation:

At patient N., 43 years, within last 5 years were observed arthralgias against a fervescence to 37,2-37,5°С. Since August there were inflations and attacks of pains in the top half of gaste, an indulgence of a chair, the patient has started to grow thin (for 10 months - on 20 kg). In November it was surveyed in regional hospital where at endoscopic research narrowing bulbous duodenal regions hydropic cords on an extent to the top third of descending part of a duodenum is revealed.

The originality of a clinical picture has caused appreciable diagnostic difficulties. Assumed a small bowel tumour, a pancreas tumour, the peptic ulcer of a duodenum complicated by a stenosis.

At entering complained of colicy pains in the top parts of a gaste, a nausea and vomiting at height of a painful syndrome, on chair indulgences, a weight loss, delicacy, arthralgias. At survey: the patient of a subnutrition (body mass - 63 kg at growth of 185 sm), a gaste is blown slightly up, in periumbilical to region were palpated the tumorous formation of density indistinctly delimited, moderately painful. At a X-ray inspection it is noticed, that cords of a mucosa of a small bowel are dilated, their elasticity is lowered. The top third of descending part of a duodenum throughout 3 sm practically completely is narrowed. However at an endoscopy all intestine is passed for the apparatus, but its side looks fallen asleep, inactive at inflating by air, for bulbous duodenal region the intestine lumen is narrowed by hydropic cords.

According to a computer tomography the duodenum is represented dilated, with sharply thickened sides, on a posterolateral side of descending part - regional defects of filling owing to the expressed edema mucous. Merging, they form soft tissue pathological formation; the hyperadenosis in a mesentery root is revealed also.

The circle of differential diagnostics included such diseases of a small bowel, as disease of the Cron, a lymphoma, a benign nodous lymphoid hyperplasia at the general variable an immunodeficiencyy, Whipple's disease.

At histological research are noted infiltration of own layer of a mucosa of a small bowel large РАS-позитивными by macrophages, dilating of absorbent vessels. At electronic-microscopic research in own layer of an intestinal mucosa similar little bodies are found the bacillus. Revealing of these specific morphological characters has given the chance to diagnose Whipple's disease with a lesion of a small bowel and lymph nodes of an abdominal lumen.

In hospital treatment by antibiotics (Rondomycinum on 0,3 grammes 2 times a day) was spent. On this background the condition of the patient was considerably enriched: there have completely passed abdominal pains, arthralgias, the body temperature was normalised. The patient is written out with the reference to continue constant reception of antibiotics. However in 3 months it has independently stopped treatment that has led to relapse. With suspicion on enteric impassability it is hospitalised in hospital on a residence where it is operated. At revision of an abdominal lumen it is revealed, that the descending part of a duodenum and proximal parts of a small bowel are narrowed by rasping, hydropic cords. The particulate enterectomy is executed. The postoperative season has become complicated peritonitis and pneumonia development that has led to mors of the patient. Results of autopsy have confirmed diagnosis Whipple's disease.

The given case illustrates bad awareness of doctors on this disease, and from here - an incorrect choice of medical tactics, as was in the given observation by the cause of a lethal outcome.