Ocular Manifestations of Hemochromatosis and Iron-Overloaded States

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Article initiated by:

Jacob Winters, MD, Samyuktha Ratnam Melachuri

All contributors:

Jill Wells, MD, Jacob Winters, MD

Assigned editor:

Armin R. Afshar, MD, MBA, MAS

Review:

Assigned status Update Pending

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Hemochromatosis and iron overloaded states as well as the treatment of these conditions can have significant visual implications. We hope this article can further clinician awareness as well as identification and management of such symptoms.

Hemochromatosis and Iron-Overloaded States

Introduction

The deposition of iron in ocular structures has been described in several clinical studies, most case reports or series, since the early 1900’s. Many studies have reported ocular changes associated with hereditary hemochromatosis and other iron overloaded states, including patients with anemia with iron overload secondary to transfusion dependence. In addition to the disease itself, the treatment of the disease (i.e. chelation) has also been implicated in visual loss.

Etiology

In hereditary hemochromatosis, intestinal iron absorption is significantly increased due to a HFE gene mutation, and causes deposition of iron in the liver, skin, pancreas, joints, and heart. As these organs accumulate with iron, their function diminishes. Acquired hemochromatosis occurs from hemolysis or multiple transfusions. Unlike hereditary hemochromatosis, iron first deposits in reticuloendothelial cells. Soon, the reticuloendothelial system becomes saturated, leading to similar systemic manifestations as hereditary hemochromatosis. The main clinical features of hemochromatosis include pigmentation of the skin, cirrhosis of the liver, diabetes mellitus due to pancreatic deposition, and hypogonadism.

Excess iron has potential to cause oxidative damage. Increased accumulation of iron is believed to contribute to age-related macular degeneration. A study by Menghini et al. assessed for drusen and other retinal changes in patients with hereditary hemochromatosis. They concluded that increased intestinal iron absorption and increased blood iron concentration are not risk factors for the early development of retinal degenerative changes.

Diagnosis

Physical examination

Conjunctiva

Brown pigmentation has been detected in the conjunctiva, confined to the area adjacent to the limbus, encroaching onto the cornea. The pigment was most noticeable along the inferior border of the limbus, extending to the medial aspect of the globe. In the conjunctiva, the deposits of pigment may appear in a radial striation by the intervening lymphatic channels. Fusiform and berry aneurysms were noted in a few patients’ conjunctiva.

Cornea

In 1971, Lazzaro et al.  noted corneal iron deposition as “a multitude of minute refringent dots in the anterior third of the corneal stroma” in their case study.

Currently, there are four established types of corneal iron "lines": Hudson-Stahli lines, Stocker lines, Fleischer rings, and Ferry lines. All are located in the corneal epithelium and can been seen best with cobalt blue or red-free filters on slit lamp examination. The formation of these iron lines is not entirely understood; however, various hypotheses have been proposed, including tear film pooling/desiccation, basal cell migration, and increased expression of transferrin or lactoferrin receptor expression in stressed basal epithelial cells. 

Hudson-Stahli lines are seen in the elderly at the junction of the middle and lower thirds of the cornea. They are horizontal and form at the location where the upper and lower lid meet.

Stocker lines are seen in pterygia and are located distal to the leading edge of the pterygium. They are generally vertical and form when the pterygium is stable (i.e. not actively growing).

Fleischer rings are seen in keratoconus and are seen at the circumference of the base of the cone.

Ferry lines can be seen with filtering blebs from glaucoma surgery and appear as a golden-brown line the distal edge of the bleb and is thought to positively correlated with the height of the bleb.

Retina

Several studies have reported microaneurysms along the main retinal vessels and retinal hemorrhages, changes overall similar to diabetic retinopathy.

A unique case report described a patient who presented with bilateral progressive blurry vision and recent onset of photopsias and headaches. Upon fundus examination, the patient was found to have a symmetric bull's eye maculopathy with photoreceptor loss and retinal pigment epithelium transmission defects in the area of speckled hyper- and hypo-pigmentation. Additional testing via full field and multifocal electroretinograms demonstrated generalized rod and cone dysfunction. Further systemic work-up revealed low ceruloplasmin, mildly decreased serum copper and zinc levels, and low urinary copper. The patient's low serum ceruloplasmin may have increased the amount of redox-active ferrous iron and increased retinal iron toxicity resulting in the observed retinopathy.

Zerbib et al. reported a patient with pigmentary epithelial atrophy and irregularities of the retina, focal interruption of the ellipsoid zone, a thin retina in the foveolar region, and a thickened choroid. Full-field electroretinogram showed a decrease of rods and cones activity.

Optic Nerve

Bilateral, sequential, non-arteritic anterior ischemic optic neuropathy has been seen in patients with hemochromatosis as the sole risk factor (i.e. no pre-existing vasculopathic disease).

Interestingly, many patients with anemias (e.g. hemolytic anemia, thalassemia) become secondarily iron-overloaded due to transfusion dependence and other complications of their disease.

Additionally, Baba et al. reported a case of a 14-year-old with underlying hereditary hemolytic anemia with unstable Christchurch hemoglobin who presented with bilateral visual loss due to optic canal stenosis secondary to hyperostosis of the calvarium due to extramedullary hematopoiesis. The authors reported significant improvement in visual acuity after neurosurgical decompression of the optic canal.

Diagnostic procedures

Obtain iron studies, particularly serum transferrin saturation and serum ferritin, to diagnose hemochromatosis. Optical coherence tomography can be used to assess pathological retinal changes. Utilize full-field electroretinogram to check the function of patient cones and rods. Slit-lamp can reveal pigment deposition in the conjunctiva, cornea, uvea, lens, and retina.

Differential diagnosis

Corneal pigmentation deposition is also seen in lysosomal diseases, Wilson disease, amyloidosis, multiple myeloma, and cystinosis. Fundus exam may show retinal changes similar to diabetic retinopathy.

Regarding Chelation Therapy

Importantly, one must consider the treatment of the disease (i.e. chelation therapy) as a cause for visual symptoms in patients with hemochromatosis and other iron overloaded states. Lakhanpal et al. reported several patients with presumed retrobulbar optic neuropathy given patients’ central scotomas, decreased night vision, and decreased color vision. Notably, 12/16 (75%) of the eyes examined regained vision.

Additionally, Simon et al. reported the case of a 29-year-old woman with beta-thalassemia complicated by life-long transfusion dependence who experienced onset of night blindness, peripheral visual field loss, and decreased color vision two weeks after the initiation of intravenous deferoxamine (Desferal, desferrioxamine). Ten weeks prior to presentation, patient had initiated intravenous deferoxamine therapy due to ferritin level of >5000. While her visual acuity was mostly preserved (20/20 right eye, 20/40 left eye), she had a relative afferent pupillary defect (RAPD) and markedly diminished color vision bilaterally.

In fact, some have even suggested more thorough monitoring of ophthalmologic monitoring of patients on chelation therapy. Ng et al. reported a case of a 74-year-old woman with myelofibrosis on subcutaneous deferoxamine who presented with reduced visual acuity, reduced color vision, and reduced peripheral vision with a normal slit lamp exam. However, optical coherence tomography (OCT) of the retinal nerve fiber layer (RNFL) showed a thickened RNFL. Thus, early recognition of visual symptoms of those on deferoxamine may only be available via non-invasive ophthalmologic testing such as OCT and formal visual field testing.

Management and Prognosis

The treatment of patients with ocular manifestations of hemochromatosis and iron overloaded states is to treat the underlying condition, which is often done with chelation therapy.

The cutaneous pigmentation of patients with hemochromatosis usually reduces with phlebotomy. It has been hypothesized that iron deposited in cutaneous tissues may favor the deposition of melanin by increasing the progressive oxidation of the amino acid tyrosine, similar to normal melanogenesis. Patients with hemochromatosis that were either untreated or only partially treated had the most marked ocular pigmentation. Overall, normalization of serum ferritin levels via serial phlebotomy has shown to halt the progression of retinopathy and reduce ocular pigmentation.

Clinical Relevance

Ocular manifestations of hemochromatosis may cause visual changes such as diminished visual acuity due to pathological changes in the cornea and retina.