At a Glance

The presence of corneal opacities, markedly reduced high-density lipoprotein (HDL) levels, hypertriglyceridemia with reduced or normal low-density lipoprotein (LDL) levels, and increased very low-density lipoprotein (VLDL) levels may be indicative of familial LCAT deficiency (FLD) or fish-eye disease (FED). These rare disorders are caused by different mutations in the LCAT gene that result in the complete absence (FLD) or reduced levels (FLD and FED) of LCAT in the plasma. The FED phenotype tends to be milder than that of FLD.

The action of LCAT accounts for the synthesis of most of the plasma cholesteryl ester (CE), and the reduced or abolished LCAT-mediated cholesterol esterification in LCAT deficiency leads to defective HDL maturation with accumulation of nascent pre-beta HDL. The overall composition, size, and shape of the plasma lipoproteins are seen to be grossly abnormal because of the absence of cholesteryl esters. Foam cells and membrane-bound vesicles, which appear to be composed of cholesterol and phospholipid, accumulate in many tissues, including the cornea, kidneys, liver, spleen, bone marrow, and arteries. The often pale, cloudy cornea is due to cholesterol accumulation but does not typically interfere with vision.

Those FLD mutations that cause very severe defects in LCAT activity may lead to hemolytic anemia (hemoglobin levels at about 10-11 g/dl) and kidney failure. Renal disease is the major cause of morbidity and mortality in patients with FLD. Proteinuria can develop in childhood and progresses to nephrotic syndrome by the fourth or fifth decade of life. Eventually, these patients develop hypertension and end-stage renal disease.

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Some studies have shown a modest but significant increased incidence of cardiovascular disease in patients with LCAT deficiency, although findings are inconsistent regarding the relationship between LCAT and cardiovascular disease in the general population. The role of LCAT in the pathogenesis of atherosclerosis is still not fully understood, although it may be modified by diet and by other lipoprotein-modifying proteins in the reverse cholesterol transport pathway.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Both FED and FLD patients can have normal to elevated total cholesterol (TC) and triglycerides (TG), and both present with a similar low level of HDL-cholesterol (HDL-C). FLD subjects have a much lower ratio of CE/TC because of their greater reduction in LCAT activity.

This is also reflected in the much lower cholesterol esterification ratio (CER) usually found in FLD compared to FED. The CER assay is a measure of LCAT activity based on endogenous lipoproteins and is performed by adding radiolabeled cholesterol to plasma and then ascertaining the rate of CE formation. LCAT mass can be variable, depending on whether the genetic mutation mainly affects the enzyme activity or the mass.

One of the most useful tests to identify LCAT deficiency is CE/TC ratio, which is calculated following the measurement of free cholesterol in plasma. In patients with FLD, free cholesterol accumulates and the percentage of cholesterol esters is typically very low. Unaffected individuals have % cholesterol ester values in the 60-80% range. Severely affected FLD patients have very low values (often <25%), and FED patients have mildly decreased values in the 50-60% range.

Lysophosphatidylcholine is markedly reduced in FLD and can be measured in reference laboratories using LC-MS/MS technology to aid in the diagnosis of FLD.(Table 1)

Table 1
FLD (range) Reference range FED (range)
TC (mg/dL) 173 (89-323) 120-280 186 (64-253)
TG (mg/dL) 605 (85-1480) 40-250 146 (60-408)
HDL-C (mg/dL) 8 (0-16) 30-250 9 (0-27)
ApoA-1 (mg/dL) 39 (36-48) 90-190 42 (29-45)
CE/TC 0.06 (0.06-0.49) 0.67-0.71 0.46 (0.57-0.65)
CER (nmol/mL/h) 1 (0-16) 40-80 51 (25-74)
LCAT mass (ug/mL) 0.5 (0-2.6) 3.8-6.6 3.5 (0-4)

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Liver diseases can result in reduced concentrations of cholesterol esters in plasma. If using % cholesterol ester or CE/TC ratio to investigate the possibility of LCAT deficiency, liver disease should be ruled out prior to making a diagnosis.

What Lab Results Are Absolutely Confirmatory?

The diagnosis of FLD is confirmed by a virtual absence of plasma LCAT activity in patients presenting with hypoalphalipoproteinemia, anemia, proteinuria, or renal disease. The diagnosis of FED is confirmed by finding a partial deficiency of LCAT activity in the plasma of patients presenting with corneal opacities and marked hypoalphalipoproteinemia.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Reliable LCAT activity assays are not prevalent, and laboratory measures most commonly used to diagnose LCAT deficiency include total cholesterol, triglycerides, HDL-C, free, cholesterol, and the cholesterol ester to total cholesterol ratio (or % cholesterol ester value). In addition, decreased lysophosphatidylcholine values can be used to aid in the diagnosis of LCAT deficiency.