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Optometry & Vision Science:
doi: 10.1097/OPX.0b013e3182223683
Case Report

Subconjunctival Hemorrhages: Presenting Sign for Hereditary Hemochromatosis

Tong, Judy W. H.*; Sawamura, Mark H.*

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Jarnagin Primary Care Service, Chronic Care Service, Eye Care Center, Southern California College of Optometry, Fullerton, California (JWHT, MHS)

Received January 4, 2011; accepted April 18, 2011.

Judy Tong, Southern California College of Optometry, 2575 Yorba Linda Blvd., Fullerton, California 92831, e-mail:

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Background. Hereditary hemochromatosis (HH) is a common hereditary disorder that primarily afflicts patients of Northern European descent. A single mutation of the HFE gene results in unregulated dietary iron uptake with the potential to deleteriously affect multiple organ systems including the eye. If HH is suspected, a screening test measuring transferrin saturation is initially obtained. Confirmation of this disorder is accomplished with genetic testing and liver biopsy. Treatment should commence immediately and undergo venesection (phlebotomy) treatments 2 to 4 times a year for the remainder of the patient's life.

Case Report. The following is a case of a 54-year-old male of Scottish-German descent who was evaluated for a subconjunctival hemorrhage (SCH). A review of the patient's record disclosed that he had 12 previous episodes of SCH over a 10-year period. He was undergoing a comprehensive evaluation for HH due to the recent diagnosis of this condition in his older brother. Hematologic analysis showed that our patient had a serum ferritin level 4 to 5 times higher than normal (1340 μg/L) and a homozygous recessive profile of the HFE gene. Once under maintenance venesection therapy, the frequency of the SCH diminished.

Conclusions. HH must be considered a differential diagnosis in cases of recurrent SCH. Coupled with the recognition of characteristic physical signs and symptoms of HH, hematologic analysis and genetic testing may further aid in diagnosis. With early detection and treatment, the optometrist can make a significant impact on the life expectancy of the patient.

This case report highlights a 54-year-old male of Scottish-German descent who presented with multiple episodes of subconjunctival hemorrhages (SCH). It also introduces the importance of hematologic screening and genetic testing in elucidating his underlying systemic condition of hereditary hemochromatosis (HH). HH is a hereditary disease first described by Sheldon1 in 1935. HH-related genetic mutations is characterized by an increase in iron absorption leading to iron deposition in the liver, spleen, skeletal muscle, and bone marrow. As the disease progresses, manifestations of arthropathy, diabetes mellitus, hypogonadism, endocrinopathies, liver cirrhosis, hepatic cellular carcinoma, cardiovascular disease, and skin pigmentation may develop.2, 3 Hematologic studies of our patient showed marked elevation of serum ferritin level at the time of the SCH. Genetic testing revealed a homozygous recessive gene pattern for HFE (High Fe or high iron). The frequency of subsequent SCH presentations dramatically diminished with venesection. This is the first article to report a possible link between recurrent SCH and iron overload seen with HH, and the role hematologic studies and genetic testing may play in optometric practice to alter the clinical course of this hereditary disease.

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A 54-year-old male of Scottish-German descent presented for a red eye evaluation. A review of the chart revealed that he was previously treated for 12 episodes of SCH that occurred over a 10-year period. The SCH appeared in both eyes independently with a greater predilection for the left eye (Fig. 1). The patient denied any ocular trauma, excessive valsalva activity, history of systemic hypertension, surgical procedures, or use of anti-coagulants. Assessment of visual acuity, neurological pupil testing, extraocular motility, ocular bruits, intraocular tensions, blood pressure, and retinal vascular structures were otherwise normal. As a result of his older brother being recently diagnosed with a condition known as HH, the patient was recommended to obtain a series of blood and genetic tests for HH and the HFE gene, respectively. Though the patient felt well, his initial blood tests showed that his serum ferritin level was 1340 μg/L which is between 4 and 5 times higher than normal. Even at this dangerously high level, he was asymptomatic and exhibited no constitutional or systemic signs of the condition other than the recurrent SCH.

Figure 1
Figure 1
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The initial (induction) phase of management required the patient to undergo venesection (phlebotomy) treatments once every 2 weeks for the first year. Thereafter, once his iron level reached normal values, maintenance venesection was scheduled on a 3-month basis. While adjusting to this maintenance phase, the patient experienced three more episodes of SCH. The first incident occurred 4 weeks before the planned venesection. The subsequent bouts took place because the patient was long overdue for the preplanned blood withdrawal.

The patient's brother elder by 4 years was the first member (proband) of the family to obtain genetic testing for the HFE gene. Genetic analysis showed that he possessed the homozygous recessive gene. On direct inquiry, the patient's brother confirmed his affliction with bronzed skin hyperpigmentation and atypical arthritis, which are characteristic traits of HH. However, he denied ever having a single episode of SCH. Subsequent evaluation of the brother's ocular health was unremarkable. Other family members who demonstrate the mutant gene for HFE and its variants include the patient's father, younger sister, son, and niece. His mother and daughter both are normal. The patient's grandfather succumbed to liver disease that was believed to be secondary to undiagnosed HH (Fig. 2).

Figure 2
Figure 2
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The term hemochromatosis may often be used to describe patients with abnormally elevated iron stores that result in impending tissue pathology. More specifically, HH is restricted to cases in which the primary cause is due to gene mutation, specifically to the HFE gene, that alters iron homeostasis. HH is an underdiagnosed condition that is recognized when patients present with significant signs and symptoms in the late stages of the disease. It is one of the most common genetic disorders in people of northern European descent, afflicting up to 8 per 1000 persons. Adams et al.4 found in a large population-based screening study (HEIRS Study) in North America, that 4.4 per 1000 whites were homozygous with two copies of the mutant hemochromatosis HFE gene. Other racial groups exhibited lower prevalence rates of homozygosity: Hispanics (2.7 per 1000 persons), blacks (1.4 per 1000 persons), Native Americans (1.1 per 1000 persons), Pacific Islanders (0.12 per 1000 persons), and Asians (3.9 per 10 million persons). In addition, most of the individuals with homozygosity for the HFE gene also had elevated serum iron levels. Heterozygosity or one copy of the mutant HFE gene occurs at a rate of 9% in North America, regardless of race, making it one of the most common genetic abnormalities. Prevalence in Europe for homozygosity and heterozygosity for the HFE gene is 0.4 and 9.2%, respectively.5 It was once believed that women were afflicted with HH less than males as a result of iron loss during menstruation and pregnancy. However, Moirand et al.6 found that age-matched patients from the two genders demonstrated similar hepatic iron concentrations.

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In 1996, Feder et al.7 isolated what is now known as the HFE gene in 85% of the patients with HH. HFE is the human hemochromatosis gene that encodes the HFE protein and is abbreviated from the words High Fe (iron). There are about 30 allelic variants of the HFE gene that have been identified to date.8 In population screenings and familial screenings of probands with HH, C282Y homozygotes, and C282Y and H63D compound heterozygotes comprise 90% or more of all the HH cases with the other 10% accounting for the rarer forms of iron overload syndromes. The C282Y sequence variant evolved from a transition at nucleotide 845 leading to a substitution of tyrosine for cysteine. A mutation at nucleotide 187 created a substitution of histidine for aspartate at nucleotide 63 resulting in the H63D mutant variant.7, 8

HH follows the traditional Mendelian autosomal recessive inheritance pattern whereby the afflicted individual must inherit a copy of the recessive gene from each parent to manifest the disease. Our patient along with his father and two siblings underwent specific genetic testing for the HFE gene. All tested positive with a genotype of C282Y homozygosity. Other members in the family were also tested. His daughter and two nieces did not harbor the mutant gene. However, genetic testing of his son and one niece demonstrated a compound C282Y and H36D heterozygote genotype. Compound heterozygotes exist, and in this event an offspring inherits a C282Y mutated copy from one parent and a H36D mutated copy from the other parent. Inferences can be made through studying the pedigree that our patient's mother, spouse, and brother in law must be carriers of either the mutant C282Y gene or H36D gene. The highest risk of iron loading occurs in males with the C282Y homozygous genotype. Our patient and each one of his siblings are all afflicted with HH and manifest varying phenotypic signs of iron overload. Variability in the combination of genotypes of the two leading mutated HFE gene (C282Y and H36D) imparts a less severe form of HH with a range of phenotypic presentations and penetrance.9 Such is the case with his son and niece who are asymptomatic and have relatively normal plasma transferrin saturation and ferritin levels.

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Characterized by the loss of homeostatic regulation of plasma iron, patients can manifest a host of physical ailments caused by the deposition of excess iron in hepatic and non-hepatic tissues. In unaffected patients, iron balance is regulated by the epithelium of the intestine, in which about 1 to 2 mg of iron is absorbed from the diet on a daily basis. Absorbed iron attaches to plasma transferrin, which transports it to the tissues, and binds to receptors on cell surfaces. Iron is then used to synthesize heme and non-heme proteins or stored as ferritin-bound iron in tissues. Patients with HH lose the negative feedback mechanism of intestinal iron absorption, resulting in excessive gastrointestinal uptake of iron. The disease is often asymptomatic until middle-age when chronic iron over-absorption transitions to iron overload, and then to organ damage. Overaccumulation of iron is deposited in a non-specific fashion in such tissues as the joints, skin, heart, pancreas, liver, and gonadotropin secreting cells of the anterior pituitary gland. Iron stores can vary up to 10-fold in patients before the conversion of iron accumulation to iron overload. Heredity, dietary intake, alcohol consumption, blood loss, or blood donation are all negative influences upon the progression of the disease. However, large cross-sectional studies have also demonstrated that 25 to 35% of C282Y homozygotes have normal serum ferritin levels and thus, never develop iron-overload–related pathology.10

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Ocular Manifestation of HH

SCH is a common condition (2.9%) encountered in ophthalmic practice.11 Characterized by the leakage of small conjunctival blood vessels into the potential space between the conjunctiva and episclera, it creates a flat area of bleeding that is alarming to patients. The hemorrhage may vary in size and most often, presents unilaterally. An extensive search of the medical literature produced no reported cases of SCH associated with HH. Our patient had recurrent SCHs, without the most commonly associated systemic conditions; hypertension, diabetes, arteriosclerosis, or chronic anticoagulant therapy. The proposed pathophysiology of the SCHs in this patient might be the spontaneous rupture of conjunctival aneurysms that have been previously documented in patients with HH. Hudson12 examined five postmortem eyes with biopsy-confirmed hemochromatosis and noted conjunctival fusiform and berry microaneurysms and the presence of retinal microaneurysms. It was noted that two of the five patients also had diabetes, whereas two others were borderline glucose intolerant. Hoisen et al.13 also reported a case of a 61-year-old patient with similar appearing microaneurysms in the bulbar conjunctiva, pigmentation in the perilimbal area, and a light brown horizontal ellipsoid opacity in the cornea. Other anterior segment findings of significance included iron-containing granules at the level of the anterior stroma causing diffuse grayish clouding of the entire cornea as described by Urrets-Zavalia and Katz.14 Similarly, Lazzaro et al.15 also reported similar findings of anterior corneal and conjunctival pigmentation in a patient with hemochromatosis. Davies et al.16 observed conjunctival pigmentation in 29% of 44 white hemochromatosis patients. Biopsy of the conjunctiva showed melanin pigment in the basal layers of the epithelium and trace amounts of iron. In addition, the investigators noted the presence of pigment confined to the cutaneous side of the mucocutaneous junction of the eyelid in nine of the patients. Pathological analysis revealed melanin pigmentation only. Interestingly, the amount of lid pigmentation diminished when patients underwent venesection treatments.16, 17 Postmortem studies of two of the patients revealed minute traces of free iron in the corneal epithelium and non-pigmented epithelium of the ciliary body.

In our case, the patient presented numerous times with conjunctival hemorrhages, but never when the eye was quiet to observe the presence of aneurysms. In addition, the recurrent hemorrhages presented a dozen times before the diagnosis of HH and only three times after the diagnosis was made when the patient was overdue for venesection treatment. The relative lack of reporting of ocular signs may be due to the variability in phenotypic presentation and effective penetrance of C282Y homozygotes developing iron overload related clinical signs and symptoms despite elevated ferritin levels (MacLaren Study). It is feasible that sub-conjunctival hemorrhages may present more frequently in HH; however, it may be assumed by the examining practitioner that the etiology may be due to more frequently observed benign causes such as HH-related diabetes, valsalva, systemic vascular disease, anti-coagulant therapy, or is idiopathic. In addition, laboratory testing is rarely ordered for singular events but may be considered if the recurrence rate of SCH is deemed significant to the practitioner. However, there are no universal practice standards to identify when the frequency rate for recurrence is aberrant. Even so, the clinician may order a battery of tests such as bleeding times (prothrombin time and activated partial thromboplastin time), CBC with differential and protein C and S to assist uncovering additional etiologies (Table 1), but rarely a transferrin saturation test.

Table 1
Table 1
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Non-Ocular Manifestation of HH

Additionally, patients with HH manifest a plethora of physical signs and symptoms as the disease progresses to iron-overload related disease. Large control-matched screening studies have identified non-specific symptoms such as arthralgia, apathy, lethargy, palpitations, weight loss, weakness, abdominal pain, and fatigue as the symptoms.18 As a result, many patients with HH have an initial working diagnosis of arthritis and chronic fatigue syndrome until additional pathognomonic clinical signs appear. The Hemochromatosis and Iron Overload Screening (HEIRS) Study investigators discovered in previously diagnosed C282Y homozygotes and newly diagnosed homozygotes with elevated serum ferritin levels, that the most common signs and symptoms based on overall age-adjusted odds ratios (OR) were skin hyperpigmentation (OR 4.7), swelling or tenderness of the second and third metacarpophalangeal (MCP) joints (OR 4.2), and chronic fatigue (OR 2.8).19 In the longitudinal Melbourne Collaborative Cohort study, 203 C282Y homozygotes were identified (108 women, 95 men) and followed closely to determine the conversion to iron overload-related disease over an average of 12 years.20 Within the study period, 28% of the men developed definite iron overload-related disease, in contrast to 1% of the women. In men, the most common clinical symptoms and signs were arthritis (52%), chronic fatigue (24%), and liver disease (17%). In women, it was arthritis (35%). Arthropathy may be the initial presenting sign, particularly in the second and third MCP joints of the hands. A little known, non-specific sign called the “Iron-Salute” in which the patient with HH is instructed to create a closed fist produces mild tenderness and limitation of flexion of the second and third MCP joints. A positive sign appears as bony swelling of these specific joints and the inability of these two digits to completely curl inwards. Other joints such as the shoulder, hip, knee, ankle, and wrist are also commonly afflicted locations and may bring forth quality of life issues. Male patients with serum ferritin levels in excess of 1000 μg/L are more likely to present with MCP joint disease.

Individuals who are homozygous for the C282Y mutation, may have normal iron stores through the fourth decade of life. Sequential measurements of serum ferritin and transferrin saturation may exhibit change over time, alerting the physician of risk for iron-overload related disease. It is hypothesized that HH-related tissue injury occurs as excess iron generates oxyradicals that damage cell membranes.21 Multiple organ systems can be involved in the consequent tissue pathology (Table 2). Particularly in the liver, excess iron remains localized within the hepatocytes in early HH disease. Ultimately, the chronic deposition of iron can result in hepatic fibrosis and cirrhosis. Excessive alcohol consumption, chronic Hepatitis C viral infection, and obesity-related steatosis act as co-factors in the development of these hepatic changes in HH disease. Of significance, when serum ferritin levels are <1000 μg/L, the risk of cirrhosis and hepatocellular carcinoma is <1%. If identified early, and treatment instituted before cirrhosis occurs, the patient with HH can achieve normal life expectancy. However, patients with liver cirrhosis, even in the presence of complete iron depletion therapy, will have a shortened life expectancy and a high risk for hepatocellular carcinoma.22 The cause of death in patients with HH, in comparison with normal patients was found to be 13-fold more frequent in hepatic cirrhosis, 100- to 219-fold more frequent in hepatocellular carcinoma, and 306-fold more frequent in cardiomyopathy.22

Table 2
Table 2
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Diagnostic Tests

Our patient's diagnostic evaluation was comprised of a concurrent analysis of both hematologic and genetic testing. For others, a diagnostic algorithm specific for HH exists for disease confirmation, staging, and treatment planning.23, 24 Initially, a plasma transferrin saturation is checked as this biochemical marker is elevated.2 Transferrin saturation is a direct indicator of the amount of protein-bound iron in circulation. Current acceptable threshold limits from screening studies are >50% in males and >45% in females.25 An unsaturated iron binding capacity is an automated test that has similar sensitivity and specificity to transferrin saturation. Ferritin is bound to iron and elevation of this protein in the blood indirectly signifies the amount of iron stored in the body. Normative values for men is <300 μg/L and for women is <200 μg/L. With HH, mild, medium, and severe iron overload values are expected in the range of <500 μg/L, 500 to 1000 μg/L, and >1000 μg/L, respectively.26 Dangerously high levels of serum ferritin in the range of 1000 to 5000 μg/L are commonly encountered in males with homozygous C282Y HH.23, 27 In our patient, the preliminary ferritin level was found to be 1340 μg/L. Increased serum ferritin levels can also be seen in other conditions thus genetic testing and liver studies must be conducted. Genetic testing of the HFE gene for its mutations C282Y and H63D is necessary to establish the genotypic pattern and confirm the disease. However, studies indicate that most patients are treated based on the phenotypic expression of the iron overload. Historically the gold standard in definitively diagnosing HH is liver biopsy. Though less favored, liver biopsy can determine the magnitude of the iron content and confirm the histiopathic presence of hepatocellular carcinoma or cirrhosis. MRI of the liver can reveal moderate to severe iron overload without the invasive nature of a biopsy.28 Gandon et al.29 has shown that MRI studies can detect iron overload of >60 μmol/g with a sensitivity of 89%. Alustiza et al.30 in another study demonstrated a correlation coefficient of 0.94 between liver iron concentration and that of MRI-derived estimation of liver iron concentration. The decisive test of total body iron stores is through diagnostic phlebotomy. Individuals with symptomatic HH require removal of nearly two to four times more (5 to 20 g) iron compared with those that are presymptomatic before becoming iron depleted.25 Other blood tests that are commonly performed include aspartate aminotransferase to measure enzymes in the blood indicative of liver damage and a C reactive protein to determine the presence of confounding inflammatory disease.23, 26

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Treatment and Management

Therapeutic management of HH is primarily aimed at reducing the iron overload and circumventing irreversible damage to the liver, heart, and pancreas. The most effective treatment modality is still venesection.31 Venesection is recommended in patients that have reached stage 2 (Table 3) in the disease spectrum with increased transferrin saturation levels of >60% in men and >50% in women and plasma ferritin levels >300 μg/L in men and >200μg/L in women.

Table 3
Table 3
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Both the patients underwent immediate venesection on being definitively diagnosed with HH, and have benefited from long-term venesection therapy alone. Initially, the induction phase required blood withdrawal to be performed on a weekly basis. The volume of blood withdrawn follows the formula of 7 mL/kg of body weight with the upper limit never exceeding 550 mL per phlebotomy. Once serum ferritin level ≤50 μg/L and the transferrin saturation level <75% are reached, maintenance phlebotomies were performed every 1 to 4 months indefinitely.26, 32 Other therapies that are available if venesection is not effective or contraindicated include chelation and erythrocytophoresis. Chelating drugs such as deferoxamine (Desferal) and deferasirox (Exjade) remove iron from the bloodstream.26, 33 Erythrocytophoresis is a procedure that separates red blood cells from whole blood thus selectively reducing the amount of iron. Although there are no diet restrictions for patients with HH, steps should be taken to restrict or avoid consumption of foods or supplements that possess high levels of iron, promote iron absorption, or trigger release of stored iron. Such known substances include iron supplements, large quantities of vitamin C, red meat, animal fats, sugary foods, and raw shellfish. Interestingly, vitamin C (ascorbic acid) has been shown to promote iron absorption through the intestine and triggers the release of iron from storage sites. Ingestion of supplemental vitamin C should be limited to 200 mg/day34–36 Consumption of nuts, seeds, legumes, grain products, fruits, vegetables, tannin containing products (coffee, tea, chocolate, and red wines), and calcium have been proven to retard iron absorption.9

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Genetic testing, while somewhat novel, should be considered a common component in diagnostic evaluations. Practitioners have become immune to the presentation of SCH as they appear frequently within their patients. These hemorrhages are often assumed to be due to a benign condition or are idiopathic in nature. On the contrary, this case report of a patient with multiple recurrences of SCHs spanning over a 10-year period turned out to be the initial presentation of a hereditary based, hematological disease with potential lethal sequelae. In patients with recurring, unilateral or bilateral episodes of SCH, the practitioner should delve further into the personal and family histories, and initiate testing to rule out hematologic or heritable disease-related conditions. Although there are many known causes of systemic iron overload, genetic testing is necessary to confirm the insidious diagnosis of HH. Symptoms of skin pigmentary changes, arthralgia and fatigue may also point toward the diagnosis of HH. With early detection of HH, the practitioner may prevent irreversible end organ damage, and positively impact the morbidity and mortality of the patient and their family members.

Judy Tong

Southern California College of Optometry

2575 Yorba Linda Blvd.

Fullerton, California 92831


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subconjunctival hemorrhages; hereditary hemochromatosis; transferrin saturation; serum ferritin; venesection

© 2011 American Academy of Optometry


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