HIGH ALTITUDE MEDICINE & BIOLOGY

Volume 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 altitude. High Alt. Med. Biol. 9:2427, 2008.The objective of this study was to determine whether
altitude hypoxia favors the development of diabetic retinopathy (DR) in healthy type 1 diabetic
climbers with tight glycemia control. The retinas of 7 type 1 diabetic climbers with a history of
stays at high altitude were studied through nonmydriatic chamber retinography (Ffo-CNM). The
retinographies were performed before and after a 7143 m peak expedition. One of the subjects
presented evidence of DR prior to the ascent, in addition to a microhemorrhage afterward; the
rest of the retinographies were normal. Fine glycemia management and adequate acclimatization are not the only cautions for diabetics going to altitude; an ophthalmologic exam beforehand is also recommended.
Key Words: diabetes; altitude; high altitude retinopathy; diabetic retinopathy; hypoxia

INTRODUCTION

conditions. Even if diabetic climbers showed a

normal incidence of HAR, such an event could
increase the likelihood of visual impairment.
Increasing the risk for development of retinopathy is a major concern for diabetic
climbers going to high altitude. The aim of this
study is to observe the state of the retina of
climbers with both extensive experience at high
altitude and well-controlled diabetes.

iabetic retinopathy appears in the majority of patients who have had type 1 diabetes mellitus for more than 20 yr (Watkins,
2003). On the other hand, retinal hemorrhages,
which in general are asymptomatic and inconsequential, are frequently observed in climbers
who ascend above 3500 m (Frayser et al., 1970;
Botella de Maglia and Martinez-Costa, 1998).
There is no information on whether high altitude (HA) contributes to or aggravates the retinal microangiopathy of diabetes, and no research has addressed the effect of high altitude
retinopathy (HAR) in such patients. HAR and
the vascular proliferation of DR are responses
to different types of tissue hypoxia, so there
could be a synergistic effect between the two

1Institut

MATERIAL AND METHODS

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

dEstudis de Medicina de Muntanya (IEMM), Barcelona, Spain.

de FisiologiaBiologia. Universitat de Barcelona, Barcelona, Spain.

2Departament

24

DIABETIC RETINOPATHY AT HIGH ALTITUDE

average duration was 14.6 yr (926 yr). The

climbers did not have significant medical antecedents or a previous diagnosis of diabetic
retinopathy nor antecedents of serious high altitude pathology. On other expeditions, they
had shown good metabolic control with very
flexible diabetes treatment and strict control of
glycemia (Admetlla et al., 2001; Admetlla et al.,
2003). They all had excellent management and
understanding of diet, exercise, and insulin
treatment and a tight control of glycemia
throughout the time they have been diabetic.
At altitude, their insulin management and
glycemia monitoring are mostly the same; for
instance, they self-monitor capillary blood glucose 7 times per day on average, as has been
described elsewhere (Leal, 2005). Previously to
the present expedition, the subjects had lived
for an average of 24.7 days above 5000 m (646
days), and the maximum individual altitude
reached ranged from 6000 to 8201 m. In this expedition they spent the first 4 days in the advanced base camp (4100 m), with an ascent to
5300 m on day 3. The participants in the study
spent an average of 5 days above 5350 m (27
days), and the total time above 5000 m averaged 29.7 days (851 days). Three of the 7 subjects reached the summit (7134 m), two reached
6750 m, and the other two stayed at 5350 m.
All participants were asked to undergo a bilateral nonmidriatic retinography (Ffo-CNM)
and a determination of glycosilated hemoglobin (HbA1c) with their usual medical team,
both before and after the expedition. Blood
samples and the retinographies were taken less
than 3 weeks before the departure of the expedition and a maximum of 2 weeks after returning home. Since the alpinists are resident
in different countries, these studies were done
in different laboratories. After the expedition,
they sent by e-mail all the images and the laboratory results (pre and post) to the authors;
these images were then examined by two independent specialists without access to patients identification data.
Ffo-CNM allows obtaining images of the
fundus by using a digital camera without
pharmacological midriatic agents. We choose
to use Ffo-CNM because it is a noninvasive
method, is widely available and is used to detect DR in many primary care settings (Sender

25

Palacios et al., 2003). To detect possible metabolic disorders during the expedition, the
HbA1c was measured. The Lake Louise score
was not measured systematically.
All subjects were informed about the objective of the study and the experimental protocol. The study was performed with their informed consent and in accordance with the
recommendations of the Declaration of
Helsinki.

RESULTS
The diabetic climbers did not express any
complaint related to high altitude illnesses except in one case. Subject 3 presented with an
episode of neurological impairment with ataxia
and disorientation at 5350 m clinically diagnosed as high altitude cerebral edema; no papilledema at fundoscopy was observed. This
episode improved with descent. The HbA1c in
all cases, and both before and after the expedition, was within the normal values for the
laboratories. The HbA1c variation was 0.5%
(0-0.8). For two participants, Ffo-CNM photographs were obtained only before the ascent.
Five of the subjects showed no anomalous results. In subject number 5, a single image compatible with a microaneurism was observed in
the photograph taken prior to the expedition.
Only in subject number 6 was a microhemorrhage observed in the post-expedition photograph that was not seen in the prior photos.
This subject presented five images of microaneurism both before and after the expedition;
therefore pre-existing background retinopathy
was diagnosed.
In none of the six other diabetic climbers
were images suggestive of background retinopathy or hemorrhage observed either before
or after the expedition.

COMMENTARY
The retina is the most metabolically active
tissue in the organism and is thus highly sensitive to decreases in the oxygen supply, either
from disease related systemic hypoxemia or
from exposure to high altitude. Hypoxia in-

LEAL ET AL.

26

creases retinal blood flow, which can lead to

microhemorrhages or, at sea level, vascular
proliferation (Arjamaa and Nikinmaa, 2006). It
is well known that virtually all the body tissues
constitutively express hypoxia-inducible factor
(HIF) which in hypoxia is not degraded as at
normal oxygen partial pressure. In these conditions HIF acts as a regulator protein coordinating the expression of multiple genes, including several implicated in angiogenesis
such as those for vascular endothelial factor
(VEGF) and erythropoietin (EPO) (Pugh and
Ratcliffe, 2003).
At high altitude, hypoxia induces vascular
engorgement, retinal hemorrhages and vascular tortuosity. Several pathophysiological explanations have been reported in previous reviews (Brtsch and Roach, 2001; Morris et al.,
2006), being increased blood flow and endothelial permeability the main determining factors in HAR development. There have been no
reported links between altitude hypoxia and
angiogenesis in humans, but such an association was reported in a study of mice subjected
to chronic hypoxia (Shortt et al., 2004).
In the development of DR, hyperglycemia
has the earliest and most critical role, since it
increases the blood flow, enlarges the endothelial wall, and liberates vascular growth factors. Basal membrane thickening can contribute to vascular occlusion, increasing the retinal
hypoxia and thus causing accumulation of HIF1, and a concomitant increase in the local concentration of VEGF and EPO, both powerful
angiogenic factors (Cai and Boulton, 2002), although EPO also has a neuroprotective role in
retinal cells (Arjamaa and Nikinmaa, 2006).
High levels of EPO have been detected in the
vitreous humor of DR patients (Katsura et al.,
2005). However, no relationship has been
found with plasma EPO levels, thus supporting the hypothesis of local production (Watanabe et al., 2005).
This study shows that, in spite of the long
history of diabetes in the subjects and the number of days spent at high altitude, they did not
develop persistent retinal damage, except for
one participant who showed five microaneurisms diagnosed as minimal background
diabetic retinopathy. This subject had the
longest history of diabetes, the longest time

spent above 5000 m, and the highest altitude

reached; as a result, it is difficult in this case to
determine the role of each of these factors in
the development of retinopathy.
Our study has several limitations: the number of subjects is small, the retinographies and
the HbA1c determinations were performed in
different laboratories and, moreover, the five
postascent retinographies were taken 2 weeks
after ascent, which could have been too late to
detect fresh HAR. In spite of these limitations,
our results indicate that strict control of
glycemia and correct acclimation can be protective factors in the development of HAR/DR
in diabetic climbers.
Nevertheless, the factors causing high altitude hemorrhagic retinopathy may enhance
the pathogenic effect under normoxic conditions of the vasoactive factors appearing in
other retinal disorders. As a result, we recommend that diabetic climbers undergo a careful
ophthalmologic examination, as well as a
retinography, before every ascent to high altitude. As proliferative changes may be a significant risk for loss of vision, and background retinopathy is a relative contraindication for high
altitude exposure (Mader and Tabin, 2003), we
recommend that decisions to undertake this activity be carefully considered.

ACKNOWLEDGMENTS
The authors are grateful to ADIQ, Alpinisti
Diabetici in Quota (www.adiq.org), and the
IDEA2000 (www.idea2000.org) groups, and especially to Marco Peruffo, the expedition chief,
for their support and collaboration. We also
thank Beatriz Barragn and Jordi Espins for
their technical contribution to retinal image
evaluation. We acknowledge Robin Rycroft
(SAL-UB) for his technical advice in editing the
manuscript.

DISCLOSURE
The present study does not put authors Leal,
Admetlla, Viscor, or Ricart in any conflict of interest either among themselves or with third
parties.

DIABETIC RETINOPATHY AT HIGH ALTITUDE

REFERENCES
Admetlla J., Leal C., and Ricart A. (2001). Management of
diabetes at high altitude. Brit. J. Sports Med. 35:282283.
Admetlla J., Leal C., and Ricart A. (2003). Diabetes mellitus and mountain sports. In: Health and Height. G. Viscor, A. Ricart, and C. Leal, eds. Pubicacions de la Universitat de Barcelona, Barcelona; pp. 229236.
Arjamaa O., and Nikinmaa M. (2006). Oxygen-dependent
diseases 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 altitude retinal hemorrhages in the expeditions to 8,000 meter
peaks: a study of 10 cases. Med. Clin. (Barc.) 110:457461.
Cai J., and Boulton M. (2002). The pathogenesis of diabetic retinopathy: old concepts and new questions. Eye.
16:242260.
Frayser R., Houston C.S., Bryan A.C., Rennie I.D., and
Gray 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., and
Nishigori H., et al. (2005). Erythropoietin is highly elevated in vitreous fluid of patients with proliferative diabetic 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 altitude
with preexisting ocular conditions. High Alt. Med. Biol.
4:419430.

27
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 angiogenesis by hypoxia: role of the HIF system. Nat. Med.
9:677684.
Sender Palacios M.J., Maseras Bover M., Vernet Vernet
M., Larrosa Saez P., de la Puente Martorell M.L., and
Foz Sala M. (2003). Application of a method for the
early detection of diabetic retinopathy in primary
health care. Rev. Clin. Esp. 203:224229.
Shortt A.J., Howell K., OBrien C., and McLoughlin P.
(2004). Chronic systemic hypoxia causes intra-retinal
angiogenesis. J. Anat. 205:349356.
Watanabe D., Suzuma K., Matsui S., Kurimoto M., Kiryu
J., Kita M., Suzuma I., Ohashi H., Ojima T., and Murakami T., et al. (2005). Erythropoietin as a retinal angiogenic 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 final
form July 27, 2007.