Anemia and Diabetic Retinopathy

Stanley R. Shorb, M.D.

Three patients (a 44-year-old woman, a 65­year-old man, and a 39-year-old woman) whohad had diabetes mellitus for an average of 17years had good vision and mild to moderatebackground diabetic retinopathy. These pa­tients developed severe iron deficiency anemiafrom varying causes and their conditions rap­idly progressed to a severe proliferative phasethat necessitated panretinal photocoagulationand pars plana vitrectomy in two cases.

DIABETIC RETINOPATHY is a major cause ofvisual loss in adults, and its proliferative formis the leading cause of new blindness in adults.Three adult patients with diabetes who initiallyhad mild to moderate background retinopathydeveloped moderate to severe iron deficiencyanemia for varying reasons. All three casesrapidly progressed to severe proliferative reti­nopathy. To my knowledge, little attention hasbeen paid to this potentially devastating combi­nation.

Case Reports

Case 1A 44-year-old woman was examined in May

1983 with bilateral background retinopathy anda hemoglobin level of 11 g/100 ml. She hadbeen diabetic for seven years. She began toexperience menorrhagia and within monthshad a hemoglobin level of 5.6 g/100 ml and ared blood cell count of 4,000,000/mm3

• Withinsix months florid proliferative diabetic retinop­athy developed bilaterally. There was no hy­pertension or nephropathy. Despite panretinalphotocoagulation bilateral vitreous hemor­rhage developed along with a traction retinaldetachment that involved the macula of her left

Accepted for publication June 3, 1985.Reprint requests to Stanley R. Shorb, M.D., 222 W.

Thomas Rd., Phoenix, AZ 85013.

eye. Pars plana vitrectomy in May 1984 im­proved her visual acuity from its preoperativelevel of 20/800 to 20/50. The patient underwenta hysterectomy and supplemental iron therapyand her hemoglobin level returned to12 g/100 ml. The retinopathy appears to havestabilized.

Case 2A 65-year-old man had had diabetes for 20

years. In November 1983 he had bilateral back­ground diabetic retinopathy with a visual acu­ity of R.E.: 20/30 and L.E.: 20/80. His hemoglo­bin level had decreased from 13 g/100 ml inJuly 1982 to 9.2 g/100 ml in April 1984 for un­known reasons. A normal total red blood cellcount was noted in 1982. Florid proliferativediabetic retinopathy developed bilaterallyabout the time the patient's hemoglobin levelreached its nadir. The patient underwent pan­retinal photocoagulation in his right eye inDecember 1983. He suffered a cerebrovascularaccident in that month and panretinal photoco­agulation was finally completed in May 1984. Inthe meantime, however, the left eye had devel­oped a vitreous hemorrhage that reduced visu­al acuity to less than 20/400. Six months laterthis was resolved surgically; at the same timehe underwent argon laser endophotocoagula­tion. His anemia has persisted at 9.5 g/100 mldespite iron therapy. The blood urea nitrogenlevel is 26 g/lOO ml.

Case 3A 39-year-old woman, examined in April

1983, had no significant diabetic retinopathydespite having had diabetes for 25 years.Her hemoglobin level at that time was13.7 g/lOO ml. She was admitted to the hospitalin April 1984 with a myocardial infarction;at that time her hemoglobin level was 13 g/100 ml. She was reported to have minor back­ground retinopathy at that time. In November1984 the hemoglobin level was 8.8 g/lOO ml andflorid proliferative retinopathy was present.The total red blood cell count was normal.Pametinal photocoagulation was done in De-

434 ©AMERICAN JOURNAL OF OPHTHALMOLOGY 100:434-436, SEPTEMBER, 1985

Vol. 100, No.3 Anemia and Diabetic Retinopathy 435

cember 1984. The iron deficiency is being treat­ed with supplemental iron, although the causeof her anemia was never detected.

Discussion

Although patients with diabetes are general­ly monitored closely, in many cases the bloodspecimens taken focus on blood glucose levelsand not on hemoglobin levels. Uncomplicateddiabetes does not manifest a reduced red bloodcell count. Current thinking holds that hypoxiacan cause the release of a vasoproliferativefactor (factor X). Therefore, it seems obviousthat anything that reduces the amount of oxy­gen reaching the diabetic retina necessarilyincreases the tendency to develop proliferativeretinopathy. Capillary nonperfusion is oftenseen in isolated areas in the diabetic patient'sangiogram and it is probably from these areasthat the vasoproliferative factor is released. Itseems possible, therefore, that in severe ane­mia the entire retina may be releasing thisfactor and that this "total release" may be whatcaused such a rapid and progressive course.

Anemia per se has been noted to cause a typeof retinopathy characterized by retinal hemor­rhages, cotton-wool spots, and, occasionally,hard exudates. Rubenstein, Yanoff, and Albert!found that severe anemia by itself rarely causedretinal hemorrhages, but when it is coupledwith severe thrombocytopenia 70% of patientsdeveloped retinopathy. They postulated thatan adequate number of platelets was necessaryto maintain capillary integrity. Although mypatients did not manifest thrombocytopenia,diabetes mellitus by itself can cause damage tothe capillary intraluminal wall and allow theanemia to manifest itself fully, causing an al­ready hypoxic retina to suffer a further de­crease in oxygen tension as a result of fluidaccumulation within the retina. Abadie,Lornbrail, and Passa" reported that sickle celltrait seems to be associated with diabetic reti­nopathy in newly diagnosed cases more oftenthan would normally be expected and that thetrait should be considered an additional riskfactor in diabetes. Other factors possibly relat­ed to the development of proliferative retinop­athy have been suggested. Little and Sacks"stated that rheologic factors are important andthat sludging of the microcirculation of theretina occurs in response to changes in theplasma proteins, particularly the cx2-globulins

and fibrinogens. The aforementioned proteinscause rouleaux formation of the red blood cellsthat in turn sludges the microcirculation." Mypatients, although suffering iron deficiency,had almost normal total red blood cell countsand therefore probably underwent this rou­leaux formation.

Large epidemiologic studies carried out inWisconsin identified various risk factors in dia­betes. Among the more important factors corre­lated with severity of retinopathy were dura­tion of disease, younger age at diagnosis,higher glycosylated hemoglobin levels, highersystolic blood pressure, and the presence ofproteinuria.' Anemia was not mentioned.West, Erdreich, and Stober.! in a study of 973diabetic patients, reviewed risk factors for reti­nopathy and nephropathy and identified high­er plasma glucose levels, a history of ketonuria,leanness, and younger age at onset. There wasno comment regarding the hematologic pa­tient." Similarly, a large study of Pima Indiansin Arizona failed to mention anemia as a possi­ble contributing factor in the development ofdiabetic retinopathy. 6 None of my patientswere pregnant but Moloney and Drury" notedthat pregnancy per se had an adverse effect onretinopathy, but again there was no mention ofanemia. Ditzel" mentioned anemic hypoxia as apossible cause of the microangiopathy of dia­betic retinopathy, but stated that as hemoglo­bin levels decrease the oxyhemoglobin dissoci­ation curve is shifted to the right of normal,leading to an improvement in oxygen delivery.However, he also pointed out that of the fivetypes of hypoxia (anemic, ischemic, hypoxic,stagnant, and affinity) the first three affect thearteriolar part of the microcirculation and thelatter two the venous part of the microcircula­tion. Signs of retinal ischemia such as cotton­wool spots are a sign of arteriolar or prearterio­lar ischemia and are thought to be associatedwith the release of vasoproliferative factor. Be­cause anemic hypoxia affects this portion of themicrocirculation, it too should be capable ofcausing the release of vasoproliferative factor.

My patients all had mild to moderate back­ground retinopathy when their hemoglobinlevels were in the normal range. Iron deficiencyand anemia produced proliferative retinopathywithin one year. This observation may be evenmore relevant in women who are still menstru­ating and more likely to develop iron deficien­cy. The pregnant diabetic woman should bemonitored carefully as should the diabetic pa­tient with renal failure because anemia is com-

436 AMERICAN JOURNAL OF OPHTHALMOLOGY September, 1985

mon in both of these clinical settings. Theophthalmologist should alert the primary phy­sician to the possibility of anemia whenever theproliferative phase develops.

References

1. Rubenstein, R. A., Yanoff, M., and Albert,D. M.: Thrombocytopenia, anemia, and retinal hem­orrhage. Am. J. Ophthalmol. 65:435, 1968.

2. Abadie, E., Lombrail, P., and Passa, P.: Is sicklecell trait an additional risk factor for diabetic angiop­athy? Diabetes Care 4:6559, 1981.

3. Little, H. 1., and Sacks, A. H.: Role of abnor­mal blood rheology in the pathogenesis of diabeticretinopathy. Trans. Am. Acad. Ophthalmol. Otolar­yngol. 83:522, 1977.

4. Klein, R., Klein, B. C. K., Moss, S. E., Davis,M. D., and Demets, D. 1.: The Wisconsin epidemio­logic study of diabetic retinopathy. Arch. Ophthal­mol. 102:520, 1984.

5. West, K. M., Erdreich, 1. J., and Stober, J. A.:A detailed study of risk factors for retinopathy andnephropathy in diabetes. Diabetes 29:501, 1980.

6. Knowler, W. C.; Bennett, P. H., and Ballintine,E. J.: Increased incidence of retinopathy in diabeticswith elevated blood pressure. N. Engl. J. Med.302:645, 1980.

7. Moloney, J. B. M., and Drury, M. I.: The effectof pregnancy on the natural course of diabetic reti­nopathy. Am. J. Ophthalmol. 93:745, 1982.

8. Ditzel, J.: Affinity hypoxia as a pathogeneticfactor of microangiopathy with particular referenceto diabetic retinopathy. Acta Endocrinol. 94:39, 1980.