AIDS Res Hum Retroviruses. 2013 Mar;29(3):423-8.

Pancreatic insufficiency in HIV: is it possible?

Ethel Zimberg Chehter, Marcelo Rodrigues Bacci, Ruda Alessi, Pedro D’Oria, Felipe Chicoli, Nicole Salloto, Fabio Luiz Maximiano, and Fernando Luiz Afonso Fonseca

Department of Gastroenterology, Faculdade de Medicina do ABC, Santo André, Brazil.

 

Abstract  

Pancreatic involvement in AIDS is very important and common, but there are few studies in the literature concerning the pancreas in AIDS. Therefore, our research involves an important issue in the pancreatic field. The objective of the study was to evaluate the profile of HIV-infected patients with probable exocrine pancreatic insufficiency and its relation to the degree of human immunodeficiency virus (HIV) infection. This is a cross-sectional study carried out at Faculdade de Medicina do ABC in partnership with the basic health care unit Vila Guiomar in Santo André. We selected 118 individuals divided into four groups (a control group and three other groups composed of AIDS patients, separated according to CD4 levels); participants had an interview, completed a questionnaire, and had laboratory and imaging tests. The only clinical variables with significant differences among the studied groups were the use of highly active antiretroviral therapy (HAART), the incidence of opportunistic infections, the administration of chemoprophylaxis, and weight loss. There were no differences in the amylase, lipase, and steatocrit dosages among the groups. Levels of fecal elastase 1 were lower in the HIV patient groups (2, 3, and 4) when compared with the control group, although all of them showed average levels that were much higher than the cutoff point (200 lg/g). Only nonalcoholic individuals showed a relationship between diarrhea and alterations in elastase levels. A relationship between the use of HAART and exocrine pancreatic insufficiency in different phases of HIV infection could not be verified.

PMID: 23088671

 

Supplement:

Presently there are about 35.3 (32.2-38.8) millions of people living with HIV and 2.3 (1.9-2.7) millions of new cases reported in 2012, in a worldwide scale. These data reflects a decline of 33% of new cases in comparison with 2001. At the same time there is a reduction in the death cases with 1.6 (1.4-1.9) millions in 2012 against 2.3 (2.1-2.6) millions in 2005  [1].  Nevertheless the HIV infection has global proportions. The gastrointestinal tract (GIT) plays an important role in the HIV infection, both in transmission, as a reservoir and in lymphocyte depletion [2].  Among the organs of the GIT that are affected by HIV infection we highlight the pancreas.

Initially only a few number of studies concerned the participation of the pancreas until the year 2000 when our group published a study in which the histological pattern of the pancreas in AIDS was set. In this work, fulfilled in 1995, in the era before the use of potent antivirals (High Active Anti Retroviral Therapy – HAART), we prospectively studied pancreas obtained from autopsy of 109 deceased patients with AIDS. The results were: The mean age of AIDS patients was 37 years; 80% were male; 60% were white; 21% were alcoholic. All patients with AIDS had normal blood amylase, blood glucose, and pancreatic ultrasound. Histological findings were: acinar atrophy (60%), few zymogen granula in acinar cytoplasm (52%), abnormalities in acinar nucleus (65%), pancreatic steatosis (66%), and focal necrosis (17%). Immunohistochemistry revealed: mycobacteriosis (22%), toxoplasmosis (13%), cytomegalovirus (9%), Pneumocystis carinii (jiroveci) (9%), and HIV p24 antigen in macrophage cytoplasm (22%). As discussion and conclusion we defined pancreatic involvement in AIDS is very frequent (90%) and is usually asymptomatic. Morphological changes showed three patterns of pancreatic alterations: `nutritional-like’, inflammatory and both of these together. The `nutritional-like’ pattern (atrophy, few zymogen granula and steatosis) may be due to many factors such as nutritional characteristics (Kwashiorkor-like) induced by the HIV infection or related to the HIV virus itself [3]. Figure 1,2,3,4

normal pancreas fig1

Fig 1 – Normal pancreas

pancreas of aids fig2Fig 2 – AIDS pancreas

 

nuclear displasia like fig3

Fig 3 –  Nuclear displasia-like

Pancreatic steatosis fig 4

Fig 4 – Steatosis in parenchima

To deepen these histological aspects we conducted an electron microscopy study that led us to confirm the aspects of the protein-energy malnutrition (PEM), which were the edematous form of kwashiorkor like [4]. Figure 5,6

normal pancreas in electron microscopy fig 5

Fig 5 – Normal pancreas in electron microscopy

Pancreas in aids electron microscopy fig6

Fig 6 – AIDS pancreas in electron microscopy

Then, we proposed the following hypothesis: if these patients have a depletion of zymogen granula, could they develop a malabsorption syndrome by an exocrine pancreatic insufficiency?

Following this line of thought, Carrocio et al. investigated the exocrine pancreatic function in children suffering from malabsorption syndrome due to HIV infection. Forty seven children with HIV infection without apparent pancreatic disease and 45 sex and age matched healthy controls.  Pancreatic function was evaluated by measuring elastase 1 concentration and chymotrypsin activity in stools by ELISA and colorimetric methods, respectively. Intestinal function was evaluated by measuring fat and protein loss by the steatocrit method and by faecal α1 antitrypsin concentration. 14 (30%) had abnormal pancreatic function tests: seven had isolated elastase activity deficiency, three isolated chymotrypsin deficiency, and four pancreatic deficiencies in both enzymes. Patient enzyme values were significantly lower than those of controls. Low faecal pancreatic enzymes were not associated with symptoms. Twelve children had steatorrhoea and four had increased α 1 antitrypsin. Steatorrhoea was significantly associated with reduced faecal pancreatic enzymes. There was a significant negative correlation between elastase 1 concentration and steatocrit. Children with pathological faecal elastase 1 or chymotrypsin values did not differ from the other HIV infected children with respect to nutritional and immunological status, stage of HIV disease, presence of opportunistic infections, or drug administration. They concluded that abnormal pancreatic function tests are a frequent feature of pediatric HIV infection; this condition is associated with steatorrhea, which probably contributes to the disease [5].

Afterwards, Carrocio et al., following this hypothesis, executed a work in adult patients, studying thirty-five HIV-infected patients (30 male, 5 female: mean age +/- standard deviation, 33.6 +/- 7.2 years) and 51 sex- and age-matched controls without gastroenterologic diseases were studied. In all subjects fecal elastase 1 (EL-1) was assayed, and fecal fat excretion was evaluated with the steatocrit test. They found nineteen of 35 (54%) HIV-infected patients showed subnormal EL-1 values, whereas all the controls had normal values; furthermore, EL-1 values were significantly lower in patients than in controls: mean (95% confidence intervals), 207 (164 – 251) microg/g versus 312 (291-332) microg/g (P < 0.0001). Increased fecal fat excretion was observed in almost all (25 of 35) HIV-infected patients, and an inverse but not significant correlation was found between fecal EL-1 and steatocrit values. No association was found between reduced fecal EL-1 and the severity of HIV disease or nutritional and immunologic status. Opportunistic infections and drug administration had no influence on EL-1 concentrations in stools. The final conclusion was that a reduced exopancreatic function is frequent in HIV-infected patients but does not seem to be a major factor contributing to fat malabsorption [6].

In favor of this exocrine pancreatic insufficiency, his group made a pilot study, in which the patients were treated with pancreatic enzymes and concluded that this pilot, open-label study showed that pancreatic enzyme supplementation therapy is highly effective in reducing faecal fat loss in human immunodefciency virus-infected patients with nutrient malabsorption [7]. I

In that same hypothesis line, we supposed that these HIV infected patients could present exocrine pancreatic insufficiency manifestations, so we did a better stratification using CD4 rates.

For that was necessary a pattern for exocrine pancreatic insufficiency: faecal elastase. Since this exam was not available in Brazil, we executed its standardization. Bronzatti de Oliveira CG et al. did this standardization in 2008. [8].Figure 7.

curva roc fig7

Fig 7 – ROC curve of stardatization fecal elastase 1 in Brazil

 

Then, we could accomplish our study: the main idea was divided by phase of HIV infection (CD4 groups), and our hypothesis was that patients with lower CD4 levels would have less zymogen granula and by that a higher chance of developing signs of pancreatic involvement. Furthermore it would be done a screening for pancreas disease through the serum dosage of lipase, amylase, glucose, besides research for faecal fat, through steatocrit and more specifically through pancreatic elastase’s function and imaging through abdominal ultrasonography in ambulatory patients. For the differential diagnosis of diarrhea we did a feces exam looking for parasites and also culture. Through research of d-xylose we could withdraw diarrheas from enteral cause. During anamnesis we investigated alcoholism, smoking history and regarding HIV we investigated the use of antivirals, opportunists infections and the use of others drugs. In spite of all research we concluded that HIV infected patients, regardless CD4 count, wouldn’t present clinical or laboratorial signs of exocrine pancreatic insufficiency [current article – AIDS Res Hum Retroviruses. 2013 Mar;29(3):423-8] Table 1,2,3.

tab1

tab2

tab3

We hypothesize that these negative results could be due to that these were outpatients, in good clinical conditions and mostly of them in current usage of antivirals. So, how would be the pancreas in the post-HAART era? Could these drugs normalize the pancreas? Could the discovered histological modifications, such as depletion of zymogen granula, pancreatic atrophy, steatosis and nuclear dysplasia, disappear?

Therefore we accomplished the study in the HAART era. In 20 performed autopsies we were able to compare it with pancreas without HAART. This study showed that the pancreas in HAART era had greater rate of atrophy in acinars cells and a significantly higher decrease in zymogen granula, without clinical symptoms. Another important finding was abnormalities in Langerhans islets in this group [9]. Figure 8,9

pancreas in heart era fig8

Fig 8 – Pancreas with atrophy and few zymogen granule.

langherhans islests in haart era fig9

Fig 9 – Abnormal Langerhans islets in HAART pancreas

 

References:

1. UNAIDS: Report on the global AIDS epidemic. ; 2013 [http://www.unaids.org/globalreport].

2.Chehter EZ, Nunez MRZ. Digestive Mnifestations of AIDS. In: Mincis M. Gastroenterology and Hepatology. São Paulo Brasil , Casa da Leitura Médica 2008;   1173-1205.

3. Chehter EZ, Longo MA, Laudanna AA, et al: Involvement of the pancreas in AIDS: a prospective study of 109 post-mortems. AIDS 2000, 14:1879–1886.

4. Chehter EZ, Duarte MIS, Takakura CFH, et al: Ultrastructural Study of the Pancreas in AIDS. Pancreas 2003, 26(2):153–159.

5. Carroccio A, Fontana M, Spagnuolo MI, Zuin G, Montalto G, et al.: Pancreatic dysfunction and its association with fat malabsorption in HIV infected children. Gut 1998;43: 558–563.

6. Carroccio A, Di Prima L, Di Grigoli C, et al. Exocrine pancreatic function and fat malabsorption in human immunodeficiency virusinfected patients. Scand J Gastroenterol 1999;34:729–734.

7. Carroccio A, Guarino A, Zuin G, et al. Efficacy of oral pancreatic enzyme therapy for the treatment of fat malabsoption in HIV-infected patients. Aliment Pharmacol Ther 2001;15: 1619–1625.

8. de Oliveira CG, Fonseca FLA, Salotto NS, Chicoli FA, Doria PL, et al.: Validation of fecal elastase-1 determination using immunoenzymatic assay in HIV-infected patients. J Clin Lab Anal 2008;22:286–290.

9.  Barbosa  AG, Chehter EZ, Bacci  MR, Mader AA,  Fonseca FLA . AIDS and the pancreas in the HAART era: a cross sectional study. Intl Arch of Medicine 2013, 6:28. doi:10.1186/1755-7682-6-28

Acknowledgements: Our thanks to the graduation students from ABC Medical School Fernando Beani Margeotto and Carolina Novaes Perniqueli for their contribution to this study.

 

Contact:

Ethel Zimberg Chehter, MD,

Division of Gastroenterology, Department of Medicine

ABC Medical School

Avenida Príncipe de Gales, 821 – Bairro Príncipe de Gales

Santo André – São Paulo, SP 09060-650

Brazil

chehter.ops@terra.com.br

Telephone: +55-11-99962-9456 Fax: +55-11-44368739

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