AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Lecithin-cholesterol acyltransferase (LCAT) is an enzyme bound to high-density lipoproteins (HDLs) and low-density lipoproteins in the plasma. LCAT catalyzes the formation of cholesterol esters in lipoproteins as follows:

unesterified cholesterol + phosphatidylcholine ® cholesterol ester + lysophosphatidylcholine

The 2 familial forms of LCAT deficiency are termed familial LCAT deficiency (complete LCAT deficiency) and fish eye disease (partial LCAT deficiency). Familial LCAT deficiency, first reported in 1967 in a Norwegian family, is characterized by the absence of LCAT activity towards HDL and low-density lipoprotein. Fish eye disease, initially described in 2 families of Swedish origin, is characterized by the absence of LCAT activity towards HDL only.

Both familial LCAT deficiency and fish eye disease are autosomal recessive disorders caused by mutations of the LCAT gene. Because only one LCAT gene has been discovered, certain mutations of the LCAT gene result in familial LCAT deficiency, whereas other mutations of the gene cause fish eye disease.

Pathophysiology

The clinical manifestations of LCAT deficiency are probably due to a defect in LCAT-mediated cholesterol ester formation and, therefore, accumulation of unesterified cholesterol in certain tissues, such as the cornea, kidneys, and erythrocytes. Fish eye disease is characterized by partial reduction of LCAT and only manifests with progressive corneal opacification.

Frequency

International

Both familial LCAT deficiency and fish eye disease are rare. More than 30 families, consisting of at least 60 patients, with familial LCAT deficiency have been reported worldwide. Approximately 20 patients with fish eye disease have been documented in the world literature.

Mortality/Morbidity

• The major morbidity and mortality of familial LCAT deficiency is related to renal failure.
• In fish eye disease, the major morbidity is corneal opacities causing visual impairment.
• These individuals have low HDL levels, and, generally, premature atherosclerosis is uncommon. This may be due to the intact ability of plasma from persons with LCAT deficiency to remove cholesterol from cells as compared with plasma from healthy persons. However, several documented cases of premature atherosclerosis have been reported in patients with familial LCAT deficiency or fish eye disease.

Race

• A detailed analysis of ethnicity is difficult because of the rarity of this disease. Most of the reports are from western and northern Europe, but series have also been received from Japan, Algeria, and Australia.

Age

• Most patients are diagnosed during adulthood.
• Only a few cases have been diagnosed during the symptom-free teenage years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• In patients with familial LCAT deficiency, symptoms are related to anemia, corneal opacities, renal insufficiency, and atherosclerosis (rarely). Corneal opacities may be severe enough to require corneal transplantation for the restoration of vision. Family history may reveal similar clinical features in siblings.
• In patients with fish eye disease, symptoms typically include corneal opacities and atherosclerosis (~30% of cases). Family history also may be positive for similar manifestations.

Physical

• Familial LCAT deficiency
• • Corneal opacities: The corneal lesions consist of minute grayish dots throughout the corneal stroma. The corneal opacities are more prominent in the periphery, develop in early childhood, and can be easily detected in the second decade of life. Papilledema with impaired ocular blood supply, leading to functional visual loss, has also been reported.
  • Anemia
  • Signs of renal insufficiency, including hypertension
  • Signs of atherosclerosis in some cases
  • Xanthelasma (may be seen in end-stage disease)
  • Hepatomegaly, splenomegaly, and lymphadenopathy: Generally, these are not present despite the accumulation of lipid-laden foam cells.
• Fish eye disease
• • Corneal opacities: Their appearance is similar to the eyes of a boiled fish. The degree of corneal opacification is more severe in persons with fish eye disease, resulting in visual impairment at an early age.
  • Signs of atherosclerosis in some cases
  • Hepatomegaly, splenomegaly, and lymphadenopathy: Generally, these are not present despite the accumulation of lipid-laden foam cells.

Causes

The exact location of the mutations of the LCAT gene cannot yet be used to predict the clinical or biochemical manifestations of either familial LCAT deficiency or fish eye disease.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Apolipoprotein (apo)A-I/apoC-III/apoA-IV deficiency
apoA-I deficiency
Combined apoA-I/apoC-III deficiency
Familial dyslipidemia
Familial hypoalphalipoproteinemia
Tangier disease

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Familial LCAT deficiency
• • CBC count: Normochromic normocytic anemia with anisopoikilocytosis, target cells, stomatocytes, and hematological evidence of hemolysis may be present.
  • Urinalysis: Proteinuria is commonly detected during the second or third decade of life. Less common findings include hyaline and granular casts and red blood cells.
  • In some patients, laboratory evidence of progressive renal insufficiency, such as increased plasma BUN, increased plasma creatinine, and decreased creatinine clearance
  • Low concentrations of HDL cholesterol (generally <10 mg/dL)
  • High concentrations of plasma unesterified (free) cholesterol
  • Low concentrations of plasma cholesterol ester
  • Elevated very low-density lipoprotein and triglyceride levels
  • Negligible plasma LCAT activity: Plasma fails to esterify radioactive cholesterol in exogenous apo A-I–containing liposomes.
  • Negligible plasma cholesterol esterification rate: Plasma fails to esterify radioactive cholesterol in endogenous lipoproteins.
• Fish eye disease
• • No anemia upon CBC count
  • No proteinuria upon urinalysis
  • No laboratory evidence of renal insufficiency
  • Low concentrations (10% of normal) of HDL cholesterol
  • High concentrations of unesterified (free) cholesterol in HDL
  • Low concentrations of cholesterol ester in HDL, but normal in very low-density lipoprotein and low-density lipoprotein
  • Elevated very low-density lipoprotein and triglyceride levels
  • Negligible LCAT activity in HDL
  • Normal plasma cholesterol esterification rate
  • Failure of plasma to esterify radioactive cholesterol in exogenous lipoproteins or HDL, but not in low-density lipoprotein

Imaging Studies

Imaging is not beneficial in diagnosis.

Other Tests

A definitive diagnosis requires mutational analysis of the LCAT gene and a functional analysis of the mutated gene product.

Histologic Findings

Foam cells are found in the biopsy specimens from the bone marrow, kidneys, and spleen. Sea-blue histiocytes by Giemsa staining are found in the bone marrow and spleen. Postmortem studies showed atherosclerotic changes of the aorta and arteries in some patients with familial LCAT deficiency and fish eye disease.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Symptomatic treatment for anemia, renal insufficiency, and atherosclerosis is indicated.

• LCAT gene therapy or liver transplantation theoretically would be a treatment of choice to correct the underlying pathophysiology, but neither procedure has been reported.
• Short-term whole blood or plasma transfusion has been tried to replace the LCAT enzyme in some patients with familial LCAT deficiency, but it did not correct anemia, proteinuria, or lipoprotein abnormalities.
• Renal replacement by dialysis is necessary in those individuals who develop kidney failure.

Surgical Care

• Kidney transplantation is indicated in patients with familial LCAT deficiency and renal failure.
• Corneal transplantation is indicated in patients with corneal opacities with severely reduced vision.

Consultations

• Endocrinologist: Consultation should allow accurate diagnosis and dietary therapy to improve the abnormal lipid findings of hypertriglyceridemia and low HDL.
• Ophthalmologist: Schedule follow-up to monitor visual acuity, the presence of papilledema, and the need for interventions such as corneal transplantation.
• Nephrologist: Consultation is useful in the staging and replacement of kidney function if the kidneys become compromised by LCAT deficiency.

Diet

Restriction of fat intake may be advisable in patients with familial LCAT deficiency, but no evidence supports its potential benefits.

Activity

Because of the small but measurable risk of atherosclerosis in persons with LCAT deficiency, exercise, under the guidance of a physician, theoretically would have a role in prevention of this complication.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Because of the rarity of LCAT deficiency, pharmacologic therapy has not been specifically studied in a systematic fashion.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Familial LCAT deficiency
• • Monitor renal function. This includes monitoring blood pressure, plasma BUN and creatinine values, 24-hour urine protein levels, and creatinine clearance.
  • Monitor visual acuity.
• Fish eye disease: Corneal opacities may impair visual function.

Complications

• Renal failure
• Reduced vision from corneal opacities
• Premature atherosclerosis
• Anemia

Prognosis

• Renal transplantation has been reported to be successful in some patients with familial LCAT deficiency, but it does not reverse the serum lipoprotein abnormalities or correct the anemia.
• The risk of premature atherosclerosis associated with both familial LCAT deficiency and fish eye disease is only modestly increased.

Patient Education

For excellent patient education resources, visit eMedicine's Cholesterol Center and Statins Center. Also, see eMedicine's patient education articles High Cholesterol, Cholesterol FAQs, and Atorvastatin (Lipitor).

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• The clinical and biochemical features of LCAT deficiency and fish eye disease are highly variable.
• Measurements of plasma LCAT activity and the plasma cholesterol esterification rate and genetic testing for LCAT gene mutations are not routinely performed in most laboratories.
• Referrals to experts in lipoprotein research are often required to make a definitive diagnosis.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Bérard AM, Clerc M, Brewer B, Santamarina-Fojo S. A normal rate of cellular cholesterol removal can be mediated by plasma from a patient with familial lecithin-cholesterol acyltransferase (LCAT) deficiency. Clin Chim Acta. Dec 2001;314(1-2):131-9. [Medline].
• Elkhalil L, Majd Z, Bakir R, et al. Fish-eye disease: structural and in vivo metabolic abnormalities of high-density lipoproteins. Metabolism. May 1997;46(5):474-83. [Medline].
• Hirano K, Kachi S, Ushida C, Naito M. Corneal and macular manifestations in a case of deficient lecithin: cholesterol acyltransferase. Jpn J Ophthalmol. Jan-Feb 2004;48(1):82-4. [Medline].
• Kuivenhoven JA, Pritchard H, Hill J, et al. The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. J Lipid Res. Feb 1997;38(2):191-205. [Medline].
• Mertens A, Verhamme P, Bielicki JK, et al. Increased low-density lipoprotein oxidation and impaired high-density lipoprotein antioxidant defense are associated with increased macrophage homing and atherosclerosis in dyslipidemic obese mice: LCAT gene transfer decreases atherosclerosis. Circulation. Apr 1 2003;107(12):1640-6. [Medline].
• Pritchard PH, Hill JS. Genetic disorders of lecithin:cholesterol acyltransferase. In: Betterridge J, Illingworth R, Sheperd J, eds. Lipoproteins in Health and Disease. 799-814. ed. London, England: Hodder and Stoughton; 1999:799-814.
• Santamarina-Fojo S, Hoef J, Assmann G. Lecithin: cholesterol acyltransferase deficiency and fish-eye disease. In: Wonsiewicz M, Noujaim S, Boyle P, eds. The Metabolic and Molecular Bases of Inherited Disease. 8^th ed. New York, NY: McGraw-Hill; 2001:2817-33.

Article Last Updated: Sep 18, 2007