UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Whipple病

Authors
Michael D Apstein, MD
Thomas Schneider, MD, PhD
Section Editor
Stephen B Calderwood, MD
Deputy Editor
Allyson Bloom, MD
Translators
罗凌玉, 主治医师

引言

GH Whipple在1907年对一名36岁的临床医生的病征进行了描述：“体重和体力逐渐降低、粪便主要含中性脂肪和脂肪酸、不明确的腹部征象以及特殊的多关节炎[1]。”该患者最终死于这种进展性疾病；Whipple将其称为肠性脂肪营养不良，因为他观察到患者“淋巴间隙有大量的中性脂肪和脂肪酸”堆积。1949年该病被重新命名为Whipple病，这是基于对该病必要条件的描述，即黏膜固有层中巨噬细胞的积聚，并且这些巨噬细胞内含有过碘酸希夫染色(periodic acid-Schiff, PAS)强阳性物质[2]。早在Whipple最初报道该病时，感染性病因就曾被怀疑过，但直到1952年才有抗生素治疗成功的案例报道[3]。

自从Whipple病被首次报道后，人们对Whipple病组织学、免疫学及其治疗的科学认识已有所进步，并且于1991年确认了其病原体。现已知该病的病因是Tropheryma whipplei[来自希腊语“trophe”(营养)和“eryma”(障碍)，根据该病营养吸收障碍的特征]，这是一项应用基于编码其16S核糖体RNA的DNA序列识别微生物的新技术得出的发现。T.Whipplei与许多其他经土壤传播的放线菌密切相关[4,5]。

微生物学

1907年，当Whipple在患者的黏膜下层和巨噬细胞中发现大量的“杆状生物体”时，他就怀疑过该病存在一种感染原。随后在1960-1992年之间，许多研究者运用精密的光学和电子显微镜鉴定出一种革兰氏阳性、非抗酸、PAS阳性杆状菌，该杆菌有细胞壁包围的特征性的3薄层浆膜结构。

应用聚合酶链反应(polymerase chain reaction, PCR)可在5例Whipple病患者的肠道和淋巴组织中发现一种独特的细菌16S核糖体RNA，而这在10例对照患者中则没有[5]。该技术通过PCR、利用编码所有细菌16S核糖体RNA的DNA所共有的短DNA序列(引物)来扩增DNA；它可以用于在新鲜或福尔马林固定的肠道和淋巴组织[5]、Whipple葡萄膜炎中的玻璃体液[6]、外周血[7]、心脏瓣膜[8]、脑脊液(cerebrospinal fluid, CSF)[9]、滑液和滑膜组织中Tropheryma whipplei的检测[10]。

这些资料表明了T.Whipplei这种与放线菌相关的革兰氏阳性杆菌引起了Whipple病。该微生物的培养直到一份报道称T.Whipplei在细胞培养中增殖才获得成功；细胞内生长的实现需要由白细胞介素-4(interleukin-4, IL-4)介导的外周血单核细胞的失活[11]。不幸的是该培养技术不能被重现[12]。

                 

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: 2017-06 . | This topic last updated: 2016-03-18.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
References
Top
  1. Whipple GH. A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues. Bull Johns Hopkins Hosp 1907; 18:382.
  2. BLACK-SCHAFFER B. The tinctoral demonstration of a glycoprotein in Whipple's disease. Proc Soc Exp Biol Med 1949; 72:225.
  3. PAULLEY JW. A case of Whipple's disease (intestinal lipodystrophy). Gastroenterology 1952; 22:128.
  4. Wilson KH, Blitchington R, Frothingham R, Wilson JA. Phylogeny of the Whipple's-disease-associated bacterium. Lancet 1991; 338:474.
  5. Relman DA, Schmidt TM, MacDermott RP, Falkow S. Identification of the uncultured bacillus of Whipple's disease. N Engl J Med 1992; 327:293.
  6. Rickman LS, Freeman WR, Green WR, et al. Brief report: uveitis caused by Tropheryma whippelii (Whipple's bacillus). N Engl J Med 1995; 332:363.
  7. Lowsky R, Archer GL, Fyles G, et al. Brief report: diagnosis of Whipple's disease by molecular analysis of peripheral blood. N Engl J Med 1994; 331:1343.
  8. Wendler D, Mendoza E, Schleiffer T, et al. Tropheryma whippelii endocarditis confirmed by polymerase chain reaction. Eur Heart J 1995; 16:424.
  9. Cohen L, Berthet K, Dauga C, et al. Polymerase chain reaction of cerebrospinal fluid to diagnose Whipple's disease. Lancet 1996; 347:329.
  10. O'Duffy JD, Griffing WL, Li CY, et al. Whipple's arthritis: direct detection of Tropheryma whippelii in synovial fluid and tissue. Arthritis Rheum 1999; 42:812.
  11. Schoedon G, Goldenberger D, Forrer R, et al. Deactivation of macrophages with interleukin-4 is the key to the isolation of Tropheryma whippelii. J Infect Dis 1997; 176:672.
  12. Swartz MN. Whipple's disease--past, present, and future. N Engl J Med 2000; 342:648.
  13. Raoult D, Birg ML, La Scola B, et al. Cultivation of the bacillus of Whipple's disease. N Engl J Med 2000; 342:620.
  14. Raoult D, La Scola B, Lecocq P, et al. Culture and immunological detection of Tropheryma whippelii from the duodenum of a patient with Whipple disease. JAMA 2001; 285:1039.
  15. Maiwald M, von Herbay A, Fredricks DN, et al. Cultivation of Tropheryma whipplei from cerebrospinal fluid. J Infect Dis 2003; 188:801.
  16. Renesto P, Crapoulet N, Ogata H, et al. Genome-based design of a cell-free culture medium for Tropheryma whipplei. Lancet 2003; 362:447.
  17. Raoult D, Fenollar F, Birg ML. Culture of T. whipplei from the stool of a patient with Whipple's disease. N Engl J Med 2006; 355:1503.
  18. Masselot F, Boulos A, Maurin M, et al. Molecular evaluation of antibiotic susceptibility: Tropheryma whipplei paradigm. Antimicrob Agents Chemother 2003; 47:1658.
  19. Boulos A, Rolain JM, Raoult D. Antibiotic susceptibility of Tropheryma whipplei in MRC5 cells. Antimicrob Agents Chemother 2004; 48:747.
  20. Boulos A, Rolain JM, Mallet MN, Raoult D. Molecular evaluation of antibiotic susceptibility of Tropheryma whipplei in axenic medium. J Antimicrob Chemother 2005; 55:178.
  21. Raoult D, Fenollar F, Rolain JM, et al. Tropheryma whipplei in children with gastroenteritis. Emerg Infect Dis 2010; 16:776.
  22. Ehrbar HU, Bauerfeind P, Dutly F, et al. PCR-positive tests for Tropheryma whippelii in patients without Whipple's disease. Lancet 1999; 353:2214.
  23. Street S, Donoghue HD, Neild GH. Tropheryma whippelii DNA in saliva of healthy people. Lancet 1999; 354:1178.
  24. Zinkernagel AS, Gmür R, Fenner L, et al. Marginal and subgingival plaque--a natural habitat of Tropheryma whipplei? Infection 2003; 31:86.
  25. Maibach RC, Dutly F, Altwegg M. Detection of Tropheryma whipplei DNA in feces by PCR using a target capture method. J Clin Microbiol 2002; 40:2466.
  26. Dutly F, Altwegg M. Whipple's disease and "Tropheryma whippelii". Clin Microbiol Rev 2001; 14:561.
  27. Amsler L, Bauernfeind P, Nigg C, et al. Prevalence of Tropheryma whipplei DNA in patients with various gastrointestinal diseases and in healthy controls. Infection 2003; 31:81.
  28. Fenollar F, Puéchal X, Raoult D. Whipple's disease. N Engl J Med 2007; 356:55.
  29. Fenollar F, Trani M, Davoust B, et al. Prevalence of asymptomatic Tropheryma whipplei carriage among humans and nonhuman primates. J Infect Dis 2008; 197:880.
  30. Schöniger-Hekele M, Petermann D, Weber B, Müller C. Tropheryma whipplei in the environment: survey of sewage plant influxes and sewage plant workers. Appl Environ Microbiol 2007; 73:2033.
  31. Fenollar F, Mediannikov O, Socolovschi C, et al. Tropheryma whipplei bacteremia during fever in rural West Africa. Clin Infect Dis 2010; 51:515.
  32. Dobbins WO III. Whipple's Disease, Charles C Thomas, Springfield 1987.
  33. Bai JC, Mota AH, Mauriño E, et al. Class I and class II HLA antigens in a homogeneous Argentinian population with Whipple's disease: lack of association with HLA-B 27. Am J Gastroenterol 1991; 86:992.
  34. Olivieri I, Brandi G, Padula A, et al. Lack of association with spondyloarthritis and HLA-B27 in Italian patients with Whipple's disease. J Rheumatol 2001; 28:1294.
  35. Martinetti M, Biagi F, Badulli C, et al. The HLA alleles DRB1*13 and DQB1*06 are associated to Whipple's disease. Gastroenterology 2009; 136:2289.
  36. Bentley SD, Maiwald M, Murphy LD, et al. Sequencing and analysis of the genome of the Whipple's disease bacterium Tropheryma whipplei. Lancet 2003; 361:637.
  37. Li W, Fenollar F, Rolain JM, et al. Genotyping reveals a wide heterogeneity of Tropheryma whipplei. Microbiology 2008; 154:521.
  38. Marth T, Roux M, von Herbay A, et al. Persistent reduction of complement receptor 3 alpha-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple's disease. Clin Immunol Immunopathol 1994; 72:217.
  39. Ectors N, Geboes K, De Vos R, et al. Whipple's disease: a histological, immunocytochemical and electronmicroscopic study of the immune response in the small intestinal mucosa. Histopathology 1992; 21:1.
  40. Marth T, Neurath M, Cuccherini BA, Strober W. Defects of monocyte interleukin 12 production and humoral immunity in Whipple's disease. Gastroenterology 1997; 113:442.
  41. Marth T, Kleen N, Stallmach A, et al. Dysregulated peripheral and mucosal Th1/Th2 response in Whipple's disease. Gastroenterology 2002; 123:1468.
  42. Schneider T, Stallmach A, von Herbay A, et al. Treatment of refractory Whipple disease with interferon-gamma. Ann Intern Med 1998; 129:875.
  43. Ectors NL, Geboes KJ, De Vos RM, et al. Whipple's disease: a histological, immunocytochemical, and electron microscopic study of the small intestinal epithelium. J Pathol 1994; 172:73.
  44. Bai JC, Sen L, Diez R, et al. Impaired monocyte function in patients successfully treated for Whipple's disease. Acta Gastroenterol Latinoam 1996; 26:85.
  45. Moos V, Schmidt C, Geelhaar A, et al. Impaired immune functions of monocytes and macrophages in Whipple's disease. Gastroenterology 2010; 138:210.
  46. Maiwald M, von Herbay A, Persing DH, et al. Tropheryma whippelii DNA is rare in the intestinal mucosa of patients without other evidence of Whipple disease. Ann Intern Med 2001; 134:115.
  47. Desnues B, Lepidi H, Raoult D, Mege JL. Whipple disease: intestinal infiltrating cells exhibit a transcriptional pattern of M2/alternatively activated macrophages. J Infect Dis 2005; 192:1642.
  48. Desnues B, Ihrig M, Raoult D, Mege JL. Whipple's disease: a macrophage disease. Clin Vaccine Immunol 2006; 13:170.
  49. Desnues B, Raoult D, Mege JL. IL-16 is critical for Tropheryma whipplei replication in Whipple's disease. J Immunol 2005; 175:4575.
  50. Moos V, Kunkel D, Marth T, et al. Reduced peripheral and mucosal Tropheryma whipplei-specific Th1 response in patients with Whipple's disease. J Immunol 2006; 177:2015.
  51. Durand DV, Lecomte C, Cathébras P, et al. Whipple disease. Clinical review of 52 cases. The SNFMI Research Group on Whipple Disease. Société Nationale Française de Médecine Interne. Medicine (Baltimore) 1997; 76:170.
  52. Lagier JC, Lepidi H, Raoult D, Fenollar F. Systemic Tropheryma whipplei: clinical presentation of 142 patients with infections diagnosed or confirmed in a reference center. Medicine (Baltimore) 2010; 89:337.
  53. Alzahrani AS, Al Sheef M. Severe primary hyperparathyroidism masked by asymptomatic celiac disease. Endocr Pract 2008; 14:347.
  54. Vital Durand D, Gérard A, Rousset H. [Neurological manifestations of Whipple disease]. Rev Neurol (Paris) 2002; 158:988.
  55. Mori K, Ando I, Kukita A. Generalized hyperpigmentation of the skin due to vitamin B12 deficiency. J Dermatol 2001; 28:282.
  56. Riemer H, Hainz R, Stain C, et al. Severe pulmonary hypertension reversed by antibiotics in a patient with Whipple's disease. Thorax 1997; 52:1014.
  57. Elkins C, Shuman TA, Pirolo JS. Cardiac Whipple's disease without digestive symptoms. Ann Thorac Surg 1999; 67:250.
  58. Cremniter J, Bauer T, Lortat-Jacob A, et al. Prosthetic hip infection caused by Tropheryma whipplei. J Clin Microbiol 2008; 46:1556.
  59. Louis ED, Lynch T, Kaufmann P, et al. Diagnostic guidelines in central nervous system Whipple's disease. Ann Neurol 1996; 40:561.
  60. Matthews BR, Jones LK, Saad DA, et al. Cerebellar ataxia and central nervous system whipple disease. Arch Neurol 2005; 62:618.
  61. Gerard A, Sarrot-Reynauld F, Liozon E, et al. Neurologic presentation of Whipple disease: report of 12 cases and review of the literature. Medicine (Baltimore) 2002; 81:443.
  62. Panegyres PK, Edis R, Beaman M, Fallon M. Primary Whipple's disease of the brain: characterization of the clinical syndrome and molecular diagnosis. QJM 2006; 99:609.
  63. Gubler JG, Kuster M, Dutly F, et al. Whipple endocarditis without overt gastrointestinal disease: report of four cases. Ann Intern Med 1999; 131:112.
  64. Fenollar F, Lepidi H, Raoult D. Whipple's endocarditis: review of the literature and comparisons with Q fever, Bartonella infection, and blood culture-positive endocarditis. Clin Infect Dis 2001; 33:1309.
  65. Lepidi H, Fenollar F, Dumler JS, et al. Cardiac valves in patients with Whipple endocarditis: microbiological, molecular, quantitative histologic, and immunohistochemical studies of 5 patients. J Infect Dis 2004; 190:935.
  66. Geissdörfer W, Moos V, Moter A, et al. High frequency of Tropheryma whipplei in culture-negative endocarditis. J Clin Microbiol 2012; 50:216.
  67. Marín M, Muñoz P, Sánchez M, et al. Tropheryma whipplei infective endocarditis as the only manifestation of Whipple's disease. J Clin Microbiol 2007; 45:2078.
  68. Brouqui P, Raoult D. Endocarditis due to rare and fastidious bacteria. Clin Microbiol Rev 2001; 14:177.
  69. Dobbins WO 3rd. The diagnosis of Whipple's disease. N Engl J Med 1995; 332:390.
  70. von Herbay A, Ditton HJ, Maiwald M. Diagnostic application of a polymerase chain reaction assay for the Whipple's disease bacterium to intestinal biopsies. Gastroenterology 1996; 110:1735.
  71. Ramzan NN, Loftus E Jr, Burgart LJ, et al. Diagnosis and monitoring of Whipple disease by polymerase chain reaction. Ann Intern Med 1997; 126:520.
  72. Fenollar F, Raoult D. Molecular techniques in Whipple's disease. Expert Rev Mol Diagn 2001; 1:299.
  73. Fenollar F, Laouira S, Lepidi H, et al. Value of Tropheryma whipplei quantitative polymerase chain reaction assay for the diagnosis of Whipple disease: usefulness of saliva and stool specimens for first-line screening. Clin Infect Dis 2008; 47:659.
  74. Pron B, Poyart C, Abachin E, et al. Diagnosis and follow-up of Whipple's disease by amplification of the 16S rRNA gene of Tropheryma whippelii. Eur J Clin Microbiol Infect Dis 1999; 18:62.
  75. von Herbay A, Ditton HJ, Schuhmacher F, Maiwald M. Whipple's disease: staging and monitoring by cytology and polymerase chain reaction analysis of cerebrospinal fluid. Gastroenterology 1997; 113:434.
  76. Fenollar F, Amphoux B, Raoult D. A paradoxical Tropheryma whipplei western blot differentiates patients with whipple disease from asymptomatic carriers. Clin Infect Dis 2009; 49:717.
  77. Keinath RD, Merrell DE, Vlietstra R, Dobbins WO 3rd. Antibiotic treatment and relapse in Whipple's disease. Long-term follow-up of 88 patients. Gastroenterology 1985; 88:1867.
  78. Feurle GE, Marth T. An evaluation of antimicrobial treatment for Whipple's Disease. Tetracycline versus trimethoprim-sulfamethoxazole. Dig Dis Sci 1994; 39:1642.
  79. Marth T, Raoult D. Whipple's disease. Lancet 2003; 361:239.
  80. Feurle GE, Junga NS, Marth T. Efficacy of ceftriaxone or meropenem as initial therapies in Whipple's disease. Gastroenterology 2010; 138:478.
  81. Cooper GS, Blades EW, Remler BF, et al. Central nervous system Whipple's disease: relapse during therapy with trimethoprim-sulfamethoxazole and remission with cefixime. Gastroenterology 1994; 106:782.
  82. Schnider PJ, Reisinger EC, Berger T, et al. Treatment guidelines in central nervous system Whipple's disease. Ann Neurol 1997; 41:561.
  83. Fleming JL, Wiesner RH, Shorter RG. Whipple's disease: clinical, biochemical, and histopathologic features and assessment of treatment in 29 patients. Mayo Clin Proc 1988; 63:539.
  84. Schneider T, Moos V, Loddenkemper C, et al. Whipple's disease: new aspects of pathogenesis and treatment. Lancet Infect Dis 2008; 8:179.
  85. Feurle GE, Moos V, Schinnerling K, et al. The immune reconstitution inflammatory syndrome in whipple disease: a cohort study. Ann Intern Med 2010; 153:710.
  86. Feurle GE. Whipple's disease. Orphanet Encyclopedia 2004. http://www.orpha.net/data/patho/GB/uk-WhipplesDisease.pdf (Accessed on January 10, 2013).