Retinal Lipemia

Key points at a glance

Key Points at a Glance

• Retinal lipemia is a rare fundus finding in which retinal blood vessels turn milky white to cream-colored due to hypertriglyceridemia.
• It generally appears when serum triglyceride levels exceed 2,500 mg/dL, but the absolute value alone may not always determine onset.
• Fundus changes begin in the periphery and progress to the posterior pole as levels rise.
• It is usually asymptomatic and often does not affect vision.
• Fundus findings disappear within days to weeks after normalization of serum triglyceride levels.
• Life-threatening metabolic abnormalities such as acute pancreatitis or cardiovascular disease may be hidden in the background, making systemic evaluation essential.
• Treatment is primarily medical lipid management; ophthalmic treatment is usually unnecessary.

1. What is Lipemia Retinalis?

Lipemia retinalis is a rare fundus finding in which retinal arteries and veins turn a creamy to milky white color due to a marked elevation of serum triglyceride levels. It was first described by Heyl in 1880 as “intraocular lipaemia” ⁴⁾.

This condition appears in association with hyperlipoproteinemia types I, III, IV, and V. Severe hypertriglyceridemia (500–2,000 mg/dL) is estimated to occur in about 1.7% of the US population. Approximately 23% of patients with severe hypertriglyceridemia are reported to develop this condition ⁴⁾.

The fundus findings themselves are reversible and disappear quickly when triglyceride levels normalize. However, because they can be a sign of fatal complications such as acute pancreatitis or cardiovascular events, early detection and systemic management are extremely important ³⁾.

2. Main Symptoms and Clinical Findings

Subjective Symptoms

Retinal lipemia is usually asymptomatic. Unless accompanied by vascular occlusion or retinal ischemia, it often does not affect vision.

• Asymptomatic: Most patients lack visual subjective symptoms. It is commonly discovered incidentally during fundus examination³⁾.
• Vision loss: Occurs in advanced cases or when complications are present. Vision loss has been reported in cases complicated by retinal ischemia¹⁾.
• Transient blurred vision: In cases such as those with dexamethasone during chemotherapy, transient vision loss may occur due to a rapid rise in triglycerides⁵⁾.

Clinical Findings

Retinal lipemia is classified into three grades based on triglyceride levels (Vinger & Sachs classification). Changes begin in the periphery and progress to the posterior pole.

Grade I (Mild)

TG level: 2,500–3,499 mg/dL

Peripheral vascular changes: Retinal vessels in the periphery appear milky white and narrow.

Posterior pole: Vessels at the posterior pole retain normal color.

Grade II (Moderate)

TG level: 3,500–5,000 mg/dL

Extension to the posterior pole: Milky-white changes extend to the peripapillary area.

Arteriovenous differentiation: The color difference between arteries and veins becomes somewhat indistinct.

Grade III (Severe)

TG level: >5,000 mg/dL

Salmon-pink fundus: The entire fundus appears salmon-pink.

Difficulty distinguishing arteries from veins: The milky-white arteries and veins are distinguished only by vessel diameter⁴⁾.

OCT may show hyperreflective, tortuous retinal vessels and hyperreflective dots in the inner nuclear layer and ganglion cell layer³⁾. These hyperreflective dots are thought to reflect intraretinal accumulation of chylomicrons and gradually disappear over several months after normalization of triglyceride levels.

Q Can retinal lipemia cause blindness?

A

This condition itself usually does not affect vision. However, persistent hypertriglyceridemia can lead to retinal arteriovenous occlusion and retinal ischemia, resulting in vision loss. There have been reports of irreversible vision loss due to lipid exudation, making early lipid management important⁴⁾.

3. Causes and Risk Factors

The direct cause of retinal lipemia is light scattering by chylomicrons rich in triglycerides in the plasma. This condition does not occur in hyperlipidemia without hypertriglyceridemia.

Primary (hereditary) causes

• Lipoprotein lipase (LPL) deficiency: Caused by pathogenic variants in the LPL gene. Homozygous forms result in complete loss of LPL activity, presenting with severe hypertriglyceridemia, acute pancreatitis, eruptive xanthomas, and hepatosplenomegaly ²⁾. Approximately 95% of familial chylomicronemia syndrome (FCS) cases are associated with LPL gene mutations ²⁾.
• ApoC-II deficiency: Deficiency of ApoC-II, the coenzyme of LPL.
• Others: APOA5, LMF1, GPIHBP1 gene mutations ²⁾.

Secondary causes

• Diabetes (especially poorly controlled type 2 diabetes): Reported to be associated in many cases¹⁾³⁾⁴⁾.
• Glucocorticoid administration: Systemic administration of drugs such as dexamethasone worsens lipid metabolism⁵⁾.
• History of total body irradiation: Hypertriglyceridemia as a late complication of childhood cancer treatment⁴⁾.
• Others: Obesity, excessive alcohol consumption, unhealthy dietary habits, hypothyroidism.

Even with similar triglyceride levels, there are individual differences in the development of retinal lipemia. It is speculated that differences in hematocrit levels and permeability of retinal and choroidal vessels are involved⁵⁾⁶⁾.

Prevention and daily care

• If you have been diagnosed with hypertriglyceridemia, continue dietary therapy and exercise.
• Avoid excessive intake of saturated fatty acids and carbohydrates, and aim for a balanced diet.
• If you have diabetes, strictly manage your blood sugar and undergo regular fundus examinations.
• Do not discontinue prescribed lipid-lowering medications on your own.

Q Can hereditary hypertriglyceridemia with retinal lipemia be cured?

A

Even if hereditary, strict low-fat diet and drug therapy can lower triglyceride levels and improve fundus findings ²⁾. However, in cases of complete LPL deficiency, response to standard lipid-lowering drugs is poor, and lifelong strict fat restriction is required.

4. Diagnosis and Examination Methods

Fundus Examination

Fundus examination under mydriasis is the basis of diagnosis. Confirm the milky-white to cream-colored changes in retinal arteries and veins, and perform staging based on the Clinical Findings section.

Blood Tests

• Fasting lipid profile: Perform immediately upon discovery of retinal lipemia. Serum triglyceride levels are usually elevated above 2,500 mg/dL.
• Related tests: Blood glucose, HbA1c, thyroid function, liver function, kidney function.

In severe hyperlipidemia, routine biochemical analysis may be impossible due to lipemic turbidity of the sample. In such cases, special processing (dilution, solvent addition) is required ⁴⁾.

Imaging tests

Test method	Main findings
Optical coherence tomography (OCT)	Vascular hyperreflectivity, inner layer hyperreflective dots
Fluorescein angiography	Usually no specific findings
Fundus autofluorescence	Increased fluorescence due to lipids

OCT shows hyperreflective dots in the inner nuclear layer and ganglion cell layer, in addition to dilated hyperreflective vessels ³⁾. Fluorescein angiography (FA) and indocyanine green angiography usually show no specific findings.

Near-infrared imaging and fundus autofluorescence have been reported to show increased reflectivity and hyperautofluorescence corresponding to lipid-filled vascular segments ¹⁾.

Electroretinography (ERG) may show reduced a-wave and b-wave amplitudes in both cone and rod responses.

Genetic Testing

When familial chylomicronemia is suspected, searching a lipid disorder-related gene panel including the LPL gene is useful ²⁾. The FCS score (Moulin criteria) can differentiate familial from multifactorial forms ²⁾.

Differential Diagnosis

• Branch retinal artery occlusion (BRAO) and branch retinal vein occlusion (BRVO): Vascular whitening is often localized and unilateral.
• Hypertensive retinopathy: Accompanied by hemorrhages and exudates.
• Diffuse choroidal hemangioma: Tomato ketchup fundus can resemble Grade III salmon-pink fundus.
• Leukemic retinopathy: Veins are pale red, arteries are pale yellow, with different color tones⁴⁾.
• Intravascular lipid aggregates: Segmental white intravascular lesions, different from typical retinal lipemia showing uniform milky-white changes. May be associated with retinal ischemia and poor prognosis¹⁾.

5. Standard Treatment

Ophthalmic treatment for retinal lipemia itself is unnecessary. The goal of treatment is to correct the underlying hypertriglyceridemia, and it is recommended to reduce serum triglyceride levels to below 500 mg/dL⁴⁾.

Medical Treatment

Basically, normalization of serum triglyceride levels through medical treatment is necessary.

Dietary and Lifestyle Improvements

A fat-restricted diet is the foundation of treatment. Limiting saturated fat intake, avoiding excessive carbohydrate consumption, and restricting alcohol are recommended.

Prairie et al. (2024) reported a case of a 55-year-old male (TG 3,141 mg/dL) who was treated with atorvastatin 40 mg and dietary and lifestyle modifications, resulting in a decrease in TG to 689 mg/dL after 3 months and complete resolution of retinal lipemia³⁾.

In infants with LPL deficiency, discontinuing breastfeeding and switching to a strict low-fat formula significantly reduces triglyceride levels ²⁾.

Pharmacotherapy

The main triglyceride-lowering drugs include the following.

• Fibrates: fenofibrate, bezafibrate, gemfibrozil, etc. They enhance LPL activity and reduce VLDL production ²⁾.
• Statins: atorvastatin, rosuvastatin, etc. At high doses, they lower triglycerides by up to approximately 50%.
• Omega-3 fatty acids: used as adjunctive therapy.
• Niacin: has a triglyceride-lowering effect.
• Insulin: particularly effective in diabetic hypertriglyceridemia. Insulin induces LPL activity and suppresses lipolysis from existing adipose tissue ¹⁾.

Christakopoulos (2023) reported that intravascular lipid aggregates disappeared one day after initiating insulin and atorvastatin in a 30-year-old man (TG 2,850 mg/dL)¹⁾.

Ortiz de Salido-Mencheca et al. (2021) reported that a 40-year-old man (TG 11,930 mg/dL) received atorvastatin 40 mg plus fenofibrate 200 mg along with insulin therapy, and after 12 days, TG decreased to 529 mg/dL and retinal lipemia disappeared⁴⁾.

Acute Phase Treatment

In cases of severe hypertriglyceridemia complicated by acute pancreatitis, rapid removal of triglycerides via plasmapheresis may be considered.

Precautions in Treatment

• Systemic administration of glucocorticoids (e.g., dexamethasone) can worsen lipid metabolism and acutely exacerbate well-controlled dyslipidemia⁵⁾. Regular monitoring of lipid levels is necessary during steroid use.
• In LPL complete deficiency (homozygous type), response to usual fibrates and statins is poor²⁾. Strict dietary fat restriction is the mainstay of treatment.
• Disappearance of retinal lipemia can be confirmed by fundus examination, but hyperreflective spots on OCT may persist for several months.

Q Which department should be consulted if retinal lipemia is diagnosed?

A

Ophthalmic treatment is usually unnecessary, but referral to internal medicine (lipid metabolism or endocrinology) is needed for evaluation and treatment of underlying hypertriglyceridemia. If diabetes is present, management by a diabetologist is also important.

6. Pathophysiology and Detailed Mechanism

The fundus findings in retinal lipemia are due to light scattering by chylomicrons rich in triglycerides in the plasma⁵⁾. Chylomicrons are large lipoproteins that transport triglycerides absorbed from the intestine; slightly smaller VLDL (very low-density lipoproteins) also participate in triglyceride transport but are thought to contribute less to fundus findings⁵⁾.

Mechanism of Lesion Progression

Peripheral retinal vessels have a smaller diameter than those of the posterior pole. In the early stage of triglyceride elevation, the light-scattering effect of chylomicrons first becomes visible in the thin peripheral vessels. As levels rise further, milky-white changes become apparent in the larger vessels of the posterior pole. Eventually, changes in the entire retina and choroidal vessels also contribute, causing the fundus to appear salmon pink ⁴⁾.

Factors of Individual Variation

The correlation between triglyceride levels and fundus findings is not absolute.

Lai & Chang (2021) compared the treatment response of two cases over a 5-year follow-up ⁶⁾. In one case, retinal lipemia persisted even at a TG level of 1,031 mg/dL, while in the other, the fundus normalized at a TG level of 4,660 mg/dL. It has been suggested that differences may involve history of splenectomy, duration of hypertriglyceridemia, age, and genetic factors.

Individual differences in hematocrit levels and retinal/choroidal vascular permeability are also thought to affect the threshold for onset ⁵⁾.

Hypertriglyceridemia and Retinal Ischemia

Hypertriglyceridemia increases plasma viscosity and is an independent risk factor for cerebral ischemia ¹⁾. When lipid aggregates in retinal vessels occupy the vascular lumen, they can cause a decrease in local hematocrit and a reduction in the hematocrit/viscosity ratio, potentially leading to retinal ischemia ¹⁾.

In the case reported by Christakopoulos (2023), OCT revealed a p-MLM (prominent middle limiting membrane) sign ¹⁾. This finding indicates perfusion failure at the level of the deep capillary plexus and is a precursor sign of macular ischemia and atrophy.

Molecular Pathogenesis of LPL Deficiency

LPL is localized on the vascular endothelial cells of adipose tissue, heart, and skeletal muscle, where it hydrolyzes triglycerides in chylomicrons and VLDL ²⁾. More than 250 pathogenic variants of the LPL gene have been reported to date ²⁾. Homozygous mutations result in complete loss of LPL activity and resistance to standard lipid-lowering drugs. Heterozygous mutations lead to only partial reduction in activity, and patients often respond to dietary therapy and fibrates ²⁾.

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7. Latest Research and Future Prospects (Investigational Reports)

For Patients: Please Read Carefully

The following content is currently under investigation or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Evaluation by Multimodal Imaging

Christakopoulos (2023) described for the first time multimodal imaging findings not previously reported, such as hyperreflectivity on near-infrared imaging, hyperautofluorescence on fundus autofluorescence, and the p-MLM sign on OCT, in intravascular lipid aggregates associated with hypertriglyceridemia ¹⁾. These findings may be useful for differentiating from typical retinal lipemia and assessing the risk of retinal ischemia.

Detection of Residual Lipid Deposits by OCT

Multiple cases have confirmed that hyperreflective foci in the inner retinal layers detected by OCT can persist for several months even after clinical normalization of vascular color tone ³⁾. If this finding reflects intraretinal accumulation of chylomicrons, OCT may serve as a long-term monitoring indicator of treatment efficacy.

Elucidation of genotype-phenotype associations

Ain et al. (2024) conducted a systematic literature review of three LPL gene variants: c.984G>T, c.337T>C, and c.724G>A ²⁾. Homozygous patients had the highest mean triglyceride levels (65.6–161.3 mmol/L) and a higher rate of acute pancreatitis, whereas heterozygous patients had relatively low mean triglyceride levels (11.4 mmol/L) and were often manageable with diet and fibrates. Genotype-based personalized treatment is expected in the future.

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8. References

1. Christakopoulos C. Multimodal retinal imaging of intravascular lipid in severe/extreme hypertriglyceridemia. Case Rep Ophthalmol Med. 2023;2023:6698239.
2. Ain Q, Cevc M, Marusic T, et al. Genetic and clinical characteristics of patients with lipoprotein lipase deficiency from Slovenia and Pakistan: case series and systematic literature review. Front Endocrinol. 2024;15:1387419.
3. Prairie ML, Rubino SM, Tang PH. Resolution of lipemia retinalis with lifestyle modification. J VitreoRetinal Dis. 2024;8(6):728-730.
4. Ortiz de Salido-Menchaca J, Tazon-Varela MA, de la Hera-Vegas D, et al. Retinal lipemia as expression of hyperchylomicronemia syndrome. Colomb Med (Cali). 2021;52(1):e7024059.
5. Wetzel B, Mylonas G, Puntus T, et al. Lipemia retinalis during chemotherapy with adjunctive glucocorticoid treatment in a patient with colon carcinoma. Retinal Cases Brief Rep. 2021;15:450-452.
6. Lai CC, Chang CH. Lipemia retinalis with different therapeutic responses: a report of two cases. Taiwan J Ophthalmol. 2021;11:405-407.