Lipemia Retinalis

Etiology

Heyl, in 1880 described a case of lipemia retinalis (LR) in detail.[2] Vinger and Sachs described different grades of LR in 1970.[3] There are five classes of lipid transport molecules or lipoprotein. These are chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) and their sizes are 100 to 1000 nm, 34 nm, 27 nm, 22 nm, and 5 to 12 nm respectively. Smaller lipoprotein molecules do not scatter light and are transparent. Chylomicrons are the largest lipoprotein macromolecules. Most of the dietary triglyceride is transported from intestine to the systemic circula­tion via chylomicrons. Chylomicrons are normally rapidly removed from the plasma. It is likely the high proportion of triglycerides in chylomicrons, which leads to the association of raised triglyceride levels and lipemia retinalis. If a sample of hyperlipidemic serum is allowed to stand, chylomicrons form a hazy surface layer. Circulating blood with a high level of chylomicrons gives the appearance of lipemia retinalis due to the light scattering effect of the chylomicrons in the retinal vessels.[4] Hypertriglyceridemia (HTG) can be primary familial or secondary to other diseases. Multiple genes responsible for abnormal triglyceride metabolism, causing HTG has been identified.[1] The initial changes of LR occur in the peripheral retinal vessels, and gradually the changes progress to involve the entire fundus.[3] HTG and chylomicronemia may lead to severe diseases like acute pancreatitis. However, in chylomicronemia, the whole blood is turbid and appears milky compared to fat embolism (after fracture of long bones) where there are large colorless globules in the blood that can cause vascular blockages leading to different retinal manifestations like Purtscher-like retinopathy.[2][5]

Chylomicronemia has been noted to occur when the plasma triglyceride level is higher than 1000 mg/dl.[6] Chylomicronemia syndrome is defined by the presence of 1 or more of the following, along with chylomicronemia[6]:

• Eruptive xanthoma
• Lipemia retinalis
• Abdominal pain and/or pancreatitis

However, some authors consider a triglyceride level of 2000 mg/dl as a lower cutoff while defining chylomicronemia and chylomicronemia syndrome.[7] According to these authors (Brunzell and Bierman), features of chylomicronemia syndrome included[7]:

• Lipemia retinalis in 23%
• Flushing with alcohol in 25%
• Documented pancreatitis in 28%
• Eruptive xanthoma in 40%
• Objective dyspnea in 46%
• Abdominal pain and/or pancreatitis in 63%
• Recent memory loss in 85% of patients

Elevation of plasma triglycerides is the main etiology of LR. HTG can be familial or secondary to other diseases.  

Familial HTG occurs due to:

• The presence of endogenous circulating lipoprotein lipase ( LPL ) inhibitor
• Deficiency of LPL
• Deficiency of apoprotein of LPL i.e., APOC-II. LPL deficiency is an autosomal recessive transmission due to a number of LPL gene mutations like Asp9Asn, Gly188Glu, Pro207Leu, Asp250Asn, Asn291Ser, Ser447X, Pro214Ser, and others.[8] 

Secondary causes of HTG include[9]:

• Uncontrolled type 1 or type 2 diabetes mellitus
• Endocrine disorders (obesity, metabolic syndrome, hypothyroidism, hypercortisolism)
• Medications (corticosteroids, estrogen, antipsychotics (clozapine and olanzapine), antidepressants, rosiglitazone, thiazides, beta-blockers, bile acid sequestrants, sirolimus, antiretroviral therapy,13-cis-retinoic acid, tamoxifen)
• Pregnancy
• Renal disease (nephrotic syndrome, renal failure, renal dialysis)
• Liver disease (acute hepatitis)
• Dietary intake (high in saturated fats and carbohydrates, excessive alcohol intake)
• Systemic diseases (Human immunodeficiency virus infection, acute spinal cord injury, anorexia nervosa, organ transplant, sarcoidosis, systemic lupus erythematosus, myeloma)

Epidemiology

Though the exact epidemiology of lipemia retinalis is not known, that of the associated risk factors have been mentioned. The deficiency of lipoprotein lipase results in familial HTG and high levels of chylomicrons in the serum. The incidence of LPL deficiency is less than 1 in 1 million.[10] LR may also be one of the manifestations of familial combined hyperlipidemia, which has a prevalence of 1% to 2% in the general population.[11] National Health and Nutrition Examination Survey reports from 2001 and 2006 mention that approximately 1.7% of the total U.S. population, or 3.4 million Americans, were estimated to have severe HTG (500 to 2,000 mg/dl). Individuals with severe HTG tended to be men (75.3%), non-Hispanic whites (70.1%) and aged 40 to 59 years (58.5%). Diabetes and hypertension were associated with 14% and 31.3% of cases of HTG, respectively.[12]

Pathophysiology

Hyperlipidemia without accompanying hypertriglyceridemia does not present lipemia retinalis.[13] The ocular findings result from light scatter induced by the triglyceride-laden chylomicrons in the plasma.[14] Chylomicronemia occurs when plasma triglycerides exceed more than 1000 mg/dl. Lipemia retinalis is always associated with elevated plasma triglycerides more than 2,000 mg/dL.[4][7] 

At triglyceride levels of:

• 2500 to 3499 mg/dL- the peripheral vessels look creamy and thin
• 3500 to 5000 mg/dL- posterior pole vessels have a creamy color
• At levels more than 5000 mg/dL, the fundus has salmon-color. Differentiation of retinal arteries and veins may be difficult by color (both have creamy color). Though clinical differentiation of the retinal artery and vein is difficult in such cases, the caliber of the vessel may give a clue.[1]

Histopathology

The creamy appearance of the retinal vessels is due to the presence of triglyceride-laden chylomicrons in the plasma. Optical coherence tomography (OCT) scan through the retinal vessels gives evidence of the enlarged caliber of retinal vessels and back shadowing due to the presence of hyperreflective material inside the vessel lumen.[15] Extravasated lipid materials may represent as hyperreflective dots in the retinal layers.[15]

History and Physical

The patient is visually asymptomatic and lipemia retinalis is most often detected during a routine ophthalmic workup or workup of a referral case related to lipid abnormalities. Neonates and infants have been diagnosed as LR during screening and treatment for retinopathy of prematurity (ROP ).[16][17] A few case reports have described abdominal pain and gastrointestinal disorders as the presenting symptoms of hyperlipidemia in infants. These infants were found to have lipemia retinalis.[18]  There may be a family history of hyperlipidemia due to various enzymatic and genetic disorders as mentioned above. Several secondary causes of HTG need to be ruled out by careful history and physical examination.

The physical examination should be done to look for evaluation of the cardiovascular system, the integumentary system, the abdomen, and the eye. Examination of the cardiovascular system includes the examination of heart sounds, carotid or renal bruits, and peripheral pulses. Characteristic skin lesions include xanthomas which are small yellowish papules, with an erythematous base, appearing predominantly on the buttocks and elbows due to deposition of large amounts of chylomicron triglycerides in cutaneous histiocytes. [19] Abdominal examination needs to be done for the assessment of hepatosplenomegally[18] and to rule out pancreatic disease. Ophthalmic evaluation should include the examination of the peri-orbital area, anterior segment, and posterior segment examinations.

• Examination of the periorbital area may reveal:
  • Xanthelasma,
  • Tuberous palpebral xanthomas
• Anterior segment findings, though rare, include:
  • Conjunctival xanthomas,
  • Corneal arcus senilis, and arcus juvenilis,
  • Lipid keratopathy,
  • Anterior chamber lipemia[20]
  • Iris xanthomas[3] 
• The dilated fundoscopic exam is needed for the diagnosis and staging of LR. 
• Additional rare posterior segment findings of hyperlipoproteinemia include:
  • retinal xanthomas[21]
  • choroidal xanthomas
  • Adult-onset Coat disease[3]

Evaluation

Laboratory evaluation of the fasting lipid profile is needed to diagnose HTG. The blood specimen for laboratory evaluation is lipemic, with a creamy white lipid layer seen in a standing tube of blood.[22] Turbid serum is due to the presence of chylomicrons in the plasma.[20] Genetic evaluation can be done to look for a number of LPL gene mutations.[8] Fundoscopy is needed for the diagnosis of LR, and fundus photography is helpful in the documentation and followup of the patients. Optical coherence tomography (OCT) scan of the retina in LR can indicate the indirect presence of chylomicrons in the retinal vessels.[15] Pretreatment decrease in amplitude of photopic and scotopic a and b waves have been documented in ERG. However, post-treatment reversal of these waves has been noted.[23] Fluorescein and indocyanine angiography testing are unremarkable.

Treatment / Management

Lipemia retinalis is sometimes transient and resolves within hours.[4] However, a prompt reversal of hyperlipidemia is the key to a better prognosis. Various measures can achieve this.(B3)

Dietary Restriction and Primary Prevention

Strict adherence to a low-fat diet without breast milk supplementation may be effective in treating infants with severe lipemia retinalis associated with HTG.[24] Reduction and control of serum triglyceride levels will prevent LR from developing. Correction of the lipid levels may reverse the abnormal findings within one week.(B3)

Medical Treatment

No treatment is required for the lipemia retinalis itself. However, LR is an important ocular sign of a life-threatening but easily treatable metabolic disorder. The treatment is to reduce the serum triglyceride levels to below 500 mg/dl. This can be accomplished by a number of medical treatments for lowering triglyceride and cholesterol. Several lipid-lowering drugs are used to treat HTG. First-line triglyceride-lowering medications include fibric acid derivatives (fibrates) and n-3 polyunsaturated fatty acids (i.e., fish oil).[25] Fibrates reduce triglycerides by 50%. The use of fibrates is contraindicated in those with hepatic or renal dysfunction.[26] N-3 polyunsaturated fatty acids reduce triglycerides by 50%, with little effect on other lipid fractions.[27] Gastrointestinal symptoms are the major side effects of this class of drugs. Nicotinic acid can decrease triglyceride levels by 15% to 35%.[28] Strict glycemic control is needed in patients with LR and diabetes.[9](A1)

Surgical Treatment

Surgery is not specifically indicated for the treatment of lipemia retinalis. However, exchange transfusion has been used in the setting of severe hypertriglyceridemia to reduce triglycerides in the acute setting.[29] Ileal bypass surgery has demonstrated improvement in all lipid parameters but should be reserved for refractory cases.[30]

Differential Diagnosis

The differential for lipemia retinalis includes 1) leukemia[2], 2) advanced diabetic eye disease with sclerotic vessels, 3) intravascular calcification of retinal vessels secondary to renal failure and hyperparathyroidism[31] 4) retinal branch retinal artery or vein occlusion, 5) hypertensive retinopathy, and 6) diffuse choroidal hemangioma (tomato catsup fundus seen in patients with diffuse hemangioma may resemble salmon fundus in LR). In leukemia, the veins are reddish pale, while the arteries are pale yellow. In lipemia, arteries and veins are of the same color and can be differentiated only by caliber. The veins are of a larger caliber.[2] In intravascular calcification secondary to renal failure or hyperparathyroidism, the disordered renal parameters, and parathyroid hormone level may be helpful in the proper diagnosis. On cursory exam, retinal vasculitis may be a differential, but vasculitis is usually segmental and associated with perivascular infiltrates and evidence of intraocular inflammation.

Staging

Staging of lipemia retinalis was given by Vinger and Sachs, which is as follows[3]:

• Grade I (early LR)- White and creamy appearance of peripheral retinal vessels
• Grade II (moderate LR)- Creamy colored vessels extending towards optic disc
• Grade III (marked LR)- Salmon colored retina, all vessels having a milky color

Prognosis

Retinal changes secondary to lipemia retinalis improve once serum triglyceride levels are normalized. Visual acuity is neither or minimally affected but improves well after the correction of the HTG. Reduced photopic and scotopic responses in electroretinogram are noted to improve after the correction of HTG.[23] These patients are at increased systemic risk for coronary artery disease, myocardial infarction and stroke, and increased ophthalmic risk for retinal artery and vein occlusions and retinal ischemia. So they should be followed up and monitored regularly.

Complications

Systemic complications of lipidemia retinalis due to hyperlipidemia include cardiovascular diseases, systemic hypertension, acute myocardial infarction, and stroke. Chylomicronemia may be associated with acute pancreatitis, abdominal pain, hepatosplenomegaly, dyspnea, and recent memory loss.

Ophthalmic complications are less frequently reported. These include retinovascular occlusions, retinal ischemia, causing neovascularization and vitreous hemorrhage.