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• HIV enteropathy
  Philip A Batman
  Published on: 18 April 2016

• Published on: 18 April 2016

  HIV enteropathy

  • Philip A Batman, Histopathologist
  • Other Contributors:
    • Moses S. Kapembwa

  Dear Editor

  Re: My Approach. An approach to duodenal biopsies

  We read with interest the section in this review of duodenal pathology describing AIDS enteropathy. However, the histological description of the lesion by Serra and Jani ¹ does not accurately reflect the majority of literature on the subject and the comments regarding pathogenesis are confused.

  The pathogenesis of villous at...

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  Dear Editor

  Re: My Approach. An approach to duodenal biopsies

  We read with interest the section in this review of duodenal pathology describing AIDS enteropathy. However, the histological description of the lesion by Serra and Jani ¹ does not accurately reflect the majority of literature on the subject and the comments regarding pathogenesis are confused.

  The pathogenesis of villous atrophy in the small intestinal mucosa of many patients infected with HIV (HIV enteropathy), and the significance of reduced mucosal absorptive surface area in the aetiology of diarrhoea, remain controversial in spite of two decades of investigation.² The bowel is one system which merits further study in AIDS.³ The paper of Serra and Jani describes villous atrophy with crypt hypoproliferation, and yet also details a hyper-regenerative crypt response to villous atrophy mediated by cytokine effects.

  Villous atrophy in the small intestine of patients infected with HIV has indeed been associated with both hyperproliferative^4-8 and hypoproliferative^9-11 activity in crypts. There is also some evidence based on studies of primates infected with Simian Immunodeficiency Virus that a hyperproliferative enteropathy may evolve into a hypoproliferative state later in the course of the disease.¹² Furthermore, there is confusion regarding whether changes in crypt cell kinetics are a regenerative response to enterocyte shedding and villous collapse, or whether they cause villous shortening.¹³ The changes in mucosal structure observed in HIV enteropathy bear some similarities to the lesion of coeliac disease, although severe villous atrophy is seen rarely in HIV-infected patients. Coeliac disease is mediated by a T cell response in the intestinal lamina propria mounted against antigenic gluten peptides.¹⁴ A response to damage and loss of villous enterocytes, increased proliferation of crypt epithelial cells induced by local growth factors, mucosal response to luminal nutrients, and increased degradation of the extracellular matrix support of the villous structure all may contribute to the mucosal changes observed in an enteropathy.^{13 14} It is not clear whether these phenomena are causally linked, and if so, which are primary or secondary events. There is evidence from fetal explant experiments, however, that crypt cell hyperplasia induced by mucosal T cell activation is the primary mucosal response and that this precedes villous atrophy.^{15 16} More recently we have shown that hyperplasia affects both transit and stem cells of the crypt epithelium in patients infected with HIV.¹⁷

  A close correlation is present in the small bowel mucosa of patients infected with HIV between crypt hypertrophy and reduced villous surface area. ^{4 5} This structural relationship in the crypt/villus unit indicates either that crypt elongation encroaches on villous height, or that villous collapse stimulates crypt hyperplasia. Crypt hypertrophy is the mucosal response of human fetal explants to HIV infection, indicating that accelerated crypt kinetics is the driving force in the pathogenesis of villous atrophy in the intestine of AIDS patients.18 Crypt cell hyperplasia is the primary mucosal lesion in this enteropathy, driving immature enterocytes onto the sides of villi and reducing absorptive villous surface area by shifting the crypt/villus junction in a luminal direction.

  The contribution of this pathology to the malabsorption and weight loss these patients suffer is as yet unclear. There is a strong correlation between fat malabsorption and jejunal villous atrophy in HIV positive patients in the absence of enteropathogens. Whilst this tructural-functional relationship in the crypt/villus unit accounts for diarrhoea and weight loss in some of the patients, it is important to recognise that factors other than enteropathy may be responsible for these symptoms in others, such as exocrine pancreatic insufficiency,¹⁹ gut autonomic neuropathy ²⁰ and drug therapy.

  References

  1. Serra S, Jani P A. An approach to duodenal biopsies. J Clin Pathol 2006; 59: 1133-1150. 2. Kotler D P, Gaetz H P, Lange M, Klein E B, Holt P R. Enteropathy associated with the Acquired Immunodeficiency Syndrome. Ann Intern Med 1984; 101: 421 - 428. 3. Levy J A. HIV and the Pathogenesis of AIDS; 2nd Edition, Preface. 1998. ASM Press. 4. Batman P A, Miller A R O, Forster S M, Harris J R W, Pinching A J, Griffin G E. Jejunal enteropathy associated with human immunodeficiency virus infection: quantitative histology. Journal of Clinical Pathology 1989; 42: 275 - 281. 5. Batman P A, Kapembwa M S, Miller A R O, et al. HIV Enteropathy: Comparative Morphometry of the Jejunal Mucosa of HIV infected patients resident in the United Kingdom and Uganda. Gut 1998; 43: 350 – 355. 6. Kotler D P, Francisco A, Clayton F, Scholes J V, Orenstein J M. Small intestinal injury and parasitic diseases in AIDS. Ann Intern Med 1990; 113: 444 - 449. 7. Greenson J K, Belitsos P C, Yardley J H, Bartlett J G. AIDS enteropathy: occult enteric infections and duodenal mucosal alterations in chronic diarrhoea. Ann Intern Med 1991; 114: 366 - 372. 8. Heise C, Dandekar S, Kumar P, Duplantier R, Donovan R M, Halsted C H. Human immunodeficiency virus infection of enterocytes and mononuclear cells in human jejunal mucosa. Gastroenterology 1991; 100: 1521 - 1527. 9. Ullrich R, Zeitz M, Heise W, L'age M, Höffken G, Riecken E O. Small intestinal structure and function in patients infected with Human Immunodeficiency Virus (HIV): Evidence for HIV-induced enteropathy. Ann Intern Med 1989; 111: 15 - 21. 10. Anonymous. HIV-Associated Enteropathy. Lancet 1989; 2: 777 – 778. 11. Ullrich R, Riecken E O, Zeitz M. HIV-Induced Enteropathy. Immunol Res 1991; 10: 456 – 464. 12. Zeitz M, Ullrich R, Schneider T, Kewenig S, Hohloch K, Riecken E O. HIV/SIV Enteropathy. Ann NY Acad Sci 1998; 859: 139 – 148. 13. Wong W M, Wright N A. Cell Proliferation in Gastrointestinal Mucosa. J Clin Pathol 1999; 52: 321 – 333. 14. Sollid L M. Molecular Basis of Coeliac Disease. Annu Rev Immunol 2000; 18: 53 – 81. 15. MacDonald T T, Spencer J. Evidence that activated mucosal T cells play a role in the pathogenesis of enteropathy in human small intestine. J Exp Med 1988; 167: 1341 - 1349. 16. Ferreira R da C, Forsyth L E, Richman P I, Wells C, Spencer J, MacDonald T T. Changes in the rate of crypt epithelial cell proliferation and mucosal morphology induced by a T-cell-mediated response in human small intestine. Gastroenterology 1990; 98: 1255 - 1263. 17. Batman P A, Kotler D P, Kapembwa M S, Booth D, Potten C S, Orenstein J M, Scally A J, Griffin G E. HIV Enteropathy: Crypt stem and transit cell hyperproliferation induces villous atrophy in HIV/Microsporidia-infected jejunal mucosa. AIDS; in press. 18. Batman P A, Fleming S C, Sedgwick P M, MacDonald T T, Griffin G E. HIV infection of human foetal intestinal explant cultures induces epithelial cell proliferation. AIDS 1994; 8: 161 – 167. 19 Kapembwa M.S, Fleming S.C, Griffin G.E, Caun K, Pinching A.J, Harris J.R.W.

  Fat absorption and exocrine pancreatic function in human immunodeficiency virus infection. Quarterly Journal of Medicine 1990; 273: 49 – 56. 20 Batman P A, Miller A.R.O, Sedgwick M.P, Griffin G.E.G. Autonomic denervation in jejunal mucosa of homosexual men infected with HIV. AIDS 1991; 5:1247 – 1252.

  P A Batman, MD FRCPath, Consultant Histopathologist, Bradford Teaching Hospitals Foundation Trust, UK M S Kapembwa, PhD FRCP, Consultant Physician, Northwick Park Hospital, UK

  The authors have no competing interest

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  Conflict of Interest:
  None declared.

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