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INTRODUCTION

Diabetic retinopathy appears in the major-ity of patients who have had type 1 dia-betes mellitus for more than 20 yr (Watkins,2003). On the other hand, retinal hemorrhages,which in general are asymptomatic and incon-sequential, are frequently observed in climberswho ascend above 3500 m (Frayser et al., 1970;Botella de Maglia and Martinez-Costa, 1998).There is no information on whether high alti-tude (HA) contributes to or aggravates the reti-nal microangiopathy of diabetes, and no re-search has addressed the effect of high altituderetinopathy (HAR) in such patients. HAR andthe vascular proliferation of DR are responsesto different types of tissue hypoxia, so therecould be a synergistic effect between the two

conditions. Even if diabetic climbers showed anormal incidence of HAR, such an event couldincrease the likelihood of visual impairment.

Increasing the risk for development of reti-nopathy is a major concern for diabeticclimbers going to high altitude. The aim of thisstudy is to observe the state of the retina ofclimbers with both extensive experience at highaltitude and well-controlled diabetes.

MATERIAL AND METHODS

We collected data from 7 healthy type 1 di-abetic climbers, 5 men and 2 women (averageage, 36.2; range 2950) before and after an ex-pedition to a 7134-m peak. The average onsetof diabetes was at age 21.7 yr (1036) and the

HIGH ALTITUDE MEDICINE & BIOLOGYVolume 9, Number 1, 2008 Mary Ann Liebert, Inc.DOI: 10.1089/ham.2008.0125

Diabetic Retinopathy at High Altitude

CONXITA LEAL,1 JORDI ADMETLLA,1 GINS VISCOR,1,2 and ANTONI RICART1

ABSTRACT

Leal, Conxita, Jordi Admetlla, Gins Viscor, and Antoni Ricart. Diabetic retinopathy at high al-titude. High Alt. Med. Biol. 9:2427, 2008.The objective of this study was to determine whetheraltitude hypoxia favors the development of diabetic retinopathy (DR) in healthy type 1 diabeticclimbers with tight glycemia control. The retinas of 7 type 1 diabetic climbers with a history ofstays at high altitude were studied through nonmydriatic chamber retinography (Ffo-CNM). Theretinographies were performed before and after a 7143 m peak expedition. One of the subjectspresented evidence of DR prior to the ascent, in addition to a microhemorrhage afterward; therest of the retinographies were normal. Fine glycemia management and adequate acclimatiza-tion are not the only cautions for diabetics going to altitude; an ophthalmologic exam before-hand is also recommended.

Key Words: diabetes; altitude; high altitude retinopathy; diabetic retinopathy; hypoxia

1Institut dEstudis de Medicina de Muntanya (IEMM), Barcelona, Spain.2Departament de FisiologiaBiologia. Universitat de Barcelona, Barcelona, Spain.

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average duration was 14.6 yr (926 yr). Theclimbers did not have significant medical an-tecedents or a previous diagnosis of diabeticretinopathy nor antecedents of serious high al-titude pathology. On other expeditions, theyhad shown good metabolic control with veryflexible diabetes treatment and strict control ofglycemia (Admetlla et al., 2001; Admetlla et al.,2003). They all had excellent management andunderstanding of diet, exercise, and insulintreatment and a tight control of glycemiathroughout the time they have been diabetic.At altitude, their insulin management andglycemia monitoring are mostly the same; forinstance, they self-monitor capillary blood glu-cose 7 times per day on average, as has beendescribed elsewhere (Leal, 2005). Previously tothe present expedition, the subjects had livedfor an average of 24.7 days above 5000 m (646days), and the maximum individual altitudereached ranged from 6000 to 8201 m. In this ex-pedition they spent the first 4 days in the ad-vanced base camp (4100 m), with an ascent to5300 m on day 3. The participants in the studyspent an average of 5 days above 5350 m (27days), and the total time above 5000 m aver-aged 29.7 days (851 days). Three of the 7 sub-jects reached the summit (7134 m), two reached6750 m, and the other two stayed at 5350 m.

All participants were asked to undergo a bi-lateral nonmidriatic retinography (Ffo-CNM)and a determination of glycosilated hemoglo-bin (HbA1c) with their usual medical team,both before and after the expedition. Bloodsamples and the retinographies were taken lessthan 3 weeks before the departure of the expe-dition and a maximum of 2 weeks after re-turning home. Since the alpinists are residentin different countries, these studies were donein different laboratories. After the expedition,they sent by e-mail all the images and the lab-oratory results (pre and post) to the authors;these images were then examined by two in-dependent specialists without access to pa-tients identification data.

Ffo-CNM allows obtaining images of thefundus by using a digital camera withoutpharmacological midriatic agents. We chooseto use Ffo-CNM because it is a noninvasivemethod, is widely available and is used to de-tect DR in many primary care settings (Sender

Palacios et al., 2003). To detect possible meta-bolic disorders during the expedition, theHbA1c was measured. The Lake Louise scorewas not measured systematically.

All subjects were informed about the objec-tive of the study and the experimental proto-col. The study was performed with their in-formed consent and in accordance with therecommendations of the Declaration ofHelsinki.

RESULTS

The diabetic climbers did not express anycomplaint related to high altitude illnesses ex-cept in one case. Subject 3 presented with anepisode of neurological impairment with ataxiaand disorientation at 5350 m clinically diag-nosed as high altitude cerebral edema; no pa-pilledema at fundoscopy was observed. Thisepisode improved with descent. The HbA1c inall cases, and both before and after the expedi-tion, was within the normal values for the laboratories. The HbA1c variation was 0.5%(0-0.8). For two participants, Ffo-CNM pho-tographs were obtained only before the ascent.Five of the subjects showed no anomalous re-sults. In subject number 5, a single image com-patible with a microaneurism was observed inthe photograph taken prior to the expedition.Only in subject number 6 was a microhemor-rhage observed in the post-expedition photo-graph that was not seen in the prior photos.This subject presented five images of microa-neurism both before and after the expedition;therefore pre-existing background retinopathywas diagnosed.

In none of the six other diabetic climberswere images suggestive of background reti-nopathy or hemorrhage observed either beforeor after the expedition.

COMMENTARY

The retina is the most metabolically activetissue in the organism and is thus highly sen-sitive to decreases in the oxygen supply, eitherfrom disease related systemic hypoxemia orfrom exposure to high altitude. Hypoxia in-

DIABETIC RETINOPATHY AT HIGH ALTITUDE

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creases retinal blood flow, which can lead tomicrohemorrhages or, at sea level, vascularproliferation (Arjamaa and Nikinmaa, 2006). Itis well known that virtually all the body tissuesconstitutively express hypoxia-inducible factor(HIF) which in hypoxia is not degraded as atnormal oxygen partial pressure. In these con-ditions HIF acts as a regulator protein coordi-nating the expression of multiple genes, in-cluding several implicated in angiogenesissuch as those for vascular endothelial factor(VEGF) and erythropoietin (EPO) (Pugh andRatcliffe, 2003).

At high altitude, hypoxia induces vascularengorgement, retinal hemorrhages and vascu-lar tortuosity. Several pathophysiological ex-planations have been reported in previous re-views (Brtsch and Roach, 2001; Morris et al.,2006), being increased blood flow and endo-thelial permeability the main determining fac-tors in HAR development. There have been noreported links between altitude hypoxia andangiogenesis in humans, but such an associa-tion was reported in a study of mice subjectedto chronic hypoxia (Shortt et al., 2004).

In the development of DR, hyperglycemiahas the earliest and most critical role, since itincreases the blood flow, enlarges the endo-thelial wall, and liberates vascular growth fac-tors. Basal membrane thickening can contrib-ute to vascular occlusion, increasing the retinalhypoxia and thus causing accumulation of HIF-1, and a concomitant increase in the local con-centration of VEGF and EPO, both powerfulangiogenic factors (Cai and Boulton, 2002), al-though EPO also has a neuroprotective role inretinal cells (Arjamaa and Nikinmaa, 2006).High levels of EPO have been detected in thevitreous humor of DR patients (Katsura et al.,2005). However, no relationship has beenfound with plasma EPO levels, thus support-ing the hypothesis of local production (Watan-abe et al., 2005).

This study shows that, in spite of the longhistory of diabetes in the subjects and the num-ber of days spent at high altitude, they did notdevelop persistent retinal damage, except forone participant who showed five microa-neurisms diagnosed as minimal backgrounddiabetic retinopathy. This subject had thelongest history of diabetes, the longest time

spent above 5000 m, and the highest altitudereached; as a result, it is difficult in this case todetermine the role of each of these factors inthe development of retinopathy.

Our study has several limitations: the num-ber of subjects is small, the retinographies andthe HbA1c determinations were performed indifferent laboratories and, moreover, the fivepostascent retinographies were taken 2 weeksafter ascent, which could have been too late todetect fresh HAR. In spite of these limitations,our results indicate that strict control ofglycemia and correct acclimation can be pro-tective factors in the development of HAR/DRin diabetic climbers.

Nevertheless, the factors causing high alti-tude hemorrhagic retinopathy may enhancethe pathogenic effect under normoxic condi-tions of the vasoactive factors appearing inother retinal disorders. As a result, we recom-mend that diabetic climbers undergo a carefulophthalmologic examination, as well as aretinography, before every ascent to high alti-tude. As proliferative changes may be a signif-icant risk for loss of vision, and background ret-inopathy is a relative contraindication for highaltitude exposure (Mader and Tabin, 2003), werecommend that decisions to undertake this ac-tivity be carefully considered.

ACKNOWLEDGMENTS

The authors are grateful to ADIQ, AlpinistiDiabetici in Quota (www.adiq.org), and theIDEA2000 (www.idea2000.org) groups, and es-pecially to Marco Peruffo, the expedition chief,for their support and collaboration. We alsothank Beatriz Barragn and Jordi Espins fortheir technical contribution to retinal imageevaluation. We acknowledge Robin Rycroft(SAL-UB) for his technical advice in editing themanuscript.

DISCLOSURE

The present study does not put authors Leal,Admetlla, Viscor, or Ricart in any conflict of in-terest either among themselves or with thirdparties.

LEAL ET AL.

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REFERENCES

Admetlla J., Leal C., and Ricart A. (2001). Management ofdiabetes at high altitude. Brit. J. Sports Med. 35:282283.

Admetlla J., Leal C., and Ricart A. (2003). Diabetes melli-tus and mountain sports. In: Health and Height. G. Vis-cor, A. Ricart, and C. Leal, eds. Pubicacions de la Uni-versitat de Barcelona, Barcelona; pp. 229236.

Arjamaa O., and Nikinmaa M. (2006). Oxygen-dependentdiseases in the retina: role of hypoxia-inducible factors.Exp. Eye Res. 83:473483.

Brtsch P., and Roach R. (2001). Retinal hemorrhages. In:High Altitude: An Exploration of Human Adaptation.T.F. Hornbein and R.B. Schoene, eds. Marcel Dekker,New York, pp. 755758.

Botella de Maglia J., and Martinez-Costa R. (1998). High alti-tude retinal hemorrhages in the expeditions to 8,000 meterpeaks: a study of 10 cases. Med. Clin. (Barc.) 110:457461.

Cai J., and Boulton M. (2002). The pathogenesis of dia-betic retinopathy: old concepts and new questions. Eye.16:242260.

Frayser R., Houston C.S., Bryan A.C., Rennie I.D., andGray G. (1970). Retinal hemorrhage at high altitude. N.Engl. J. Med. 282:11831184.

Katsura Y., Okano T., Matsuno K., Osako M., Kure M.,Watanabe T., Iwaki Y., Noritake M., Kosano H., andNishigori H., et al. (2005). Erythropoietin is highly ele-vated in vitreous fluid of patients with proliferative di-abetic retinopathy. Diabetes Care. 28:22522254.

Leal C. (2005). Going high with type 1 diabetes. High Alt.Med. Biol. 6:1421.

Mader T.H., and Tabin G. (2003). Going to high altitudewith preexisting ocular conditions. High Alt. Med. Biol.4:419430.

Morris D.S., Somner J., Donald M.J., McCormick I.J.,Bourne R.R., Huang S.S., Aspinall P., and Dhillon B.(2006). The eye at altitude. In: Hypoxia and Exercise. R.Roach, P.D. Wagner, and P. Hackett, eds. Plenum Press,New York; pp. 249270.

Pugh C.W., and Ratcliffe P.J. (2003). Regulation of angio-genesis by hypoxia: role of the HIF system. Nat. Med.9:677684.

Sender Palacios M.J., Maseras Bover M., Vernet VernetM., Larrosa Saez P., de la Puente Martorell M.L., andFoz Sala M. (2003). Application of a method for theearly detection of diabetic retinopathy in primaryhealth care. Rev. Clin. Esp. 203:224229.

Shortt A.J., Howell K., OBrien C., and McLoughlin P.(2004). Chronic systemic hypoxia causes intra-retinalangiogenesis. J. Anat. 205:349356.

Watanabe D., Suzuma K., Matsui S., Kurimoto M., KiryuJ., Kita M., Suzuma I., Ohashi H., Ojima T., and Mu-rakami T., et al. (2005). Erythropoietin as a retinal an-giogenic factor in proliferative diabetic retinopathy. N.Engl. J. Med. 353:782792.

Watkins P.J. (2003). ABC of diabetesretinopathy. BMJ.326:924926.

Address reprint requests to:Dr. Conxita Leal

E-mail: cleal@camfic.org

Received March 22, 2007; accepted in finalform July 27, 2007.

DIABETIC RETINOPATHY AT HIGH ALTITUDE