Cerebral cholesterol granuloma in homozygous familial hypercholesterolemia

Abstract

A 45-year-old Chinese-Canadian woman presented with chemosis of several years' duration. As a teenager the patient had noticed corneal arcus and thickening of her Achilles tendons. At age 20 she was found to have a fasting total cholesterol level of 18.0 (normal < 5.2) mmol/L and a low-density lipoprotein (LDL) cholesterol level of 15.4 (normal < 3.4) mmol/L. On the basis of these findings and a family history of hypercholesterolemia in both parents and premature coronary artery disease in her father, homozygous familial hypercholesterolemia (FH) was diagnosed. The initial treatment was with bile acidbinding resins, followed by the addition of hydroxymethylglutaryl coenzyme A reductase inhibitors, or statins, when she was 29. She has been intolerant of fibrates and niacin, both of which caused rashes. At age 30, angina pectoris necessitated coronary artery bypass grafting, and she has since remained free of cardiovascular symptoms. At age 40, carotid ultrasound imaging, conducted after carotid bruits were detected, revealed more than 95% and 50%-79% stenoses of the left and right carotid arteries respectively. She began taking 325 mg of ASA daily and has remained free of neurologic symptoms. Her total cholesterol level and LDL cholesterol level fell to 10.1 and 8.2 mmol/L respectively after she began taking 80 mg of atorvastatin and 4 g of colestipol daily, and her Achilles tendon xanthomas also shrank over time. Her lipoprotein (a) level was elevated at 0.44 (normal < 0.3) g/L. Her sitosterol level was 2.4 (normal ≤ 5.0) µg/mL, and her homocysteine level was 8.0 (normal < 12.1) µmol/L); her ApoE genotype (ε3/ε3) was also normal. The patient's high-density lipoprotein cholesterol level was 0.8 (normal > 0.9) mmol/L on no lipid therapy and has ranged between 0.6 and 1.1 mmol/L with atorvastatin and colestipol therapy; her triglyceride level was 2.7 (normal < 2.3) mmol/L at baseline and has ranged from 1.4 to 3.6 mmol/L with therapy.A genomic DNA sequence analysis showed that she was homozygous for proline-to-leucine substitution at residue 644 of the LDL receptor known as FH-Zambia 1 or FHGujerat, 2 which has not been reported in Canada. 3 This mutation is associated with slowed maturation and attenuated cell-surface expression of LDL receptors 4 but does not abolish receptor function. Partial LDL receptor function appears to explain the patient's responsiveness to therapy, which was better than expected for most patients with homozygous FH. The addition of 10 mg daily of ezetimibe to the atorvastatin and colestipol therapy lowered the patient's LDL cholesterol level to 6.9 mmol/L. When colestipol was discontinued, this level decreased further to 5.9 mmol/L, which suggests an enhanced response to combination statin-ezetimibe therapy in the absence of bile acid-binding resin. Fig. 1 shows the sites of action of medications taken by the patient. We are considering LDL apheresis to further decrease LDL levels.Ophthalmologic examination revealed bilateral chemosis and conjunctival redness with no ocular hypertension ...

Intracranial Cholesterol Granuloma in a Cat

“…72(11): 1475-1478, 2010 Cholesterol granulomas (CGs) are known as well circumscribed, non neoplastic lesions, resulting from a chronic inflammatory reaction to continuous deposition of cholesterol crystals [10]. In human beings, a diagnosis of CG has been established in several sites throughout the body, comprising the intracranial localisation [4,13,20].In veterinary medicine, the development of an intracranial cholesterol granuloma has been described as an incidental, asymptomatic finding at necropsy in 20% of older horses and the choroid plexus of fourth and lateral ventricles represented the preferential location of the so-called "cholesteatoma of the choroid plexus" [9]. Sporadic descriptions of identical intracranial lesions have been reported in other animals, such as meerkats (Suricata suricatta sp., family Herpestidae) [2,21,22] A 4 year-old neutered male cat was presented at the "Malpensa" Veterinary Clinic (Samarate, Italy) with a 5-month history of progressive weakness, ataxia and depression.…”

“…72(11): 1475-1478, 2010 Cholesterol granulomas (CGs) are known as well circumscribed, non neoplastic lesions, resulting from a chronic inflammatory reaction to continuous deposition of cholesterol crystals [10]. In human beings, a diagnosis of CG has been established in several sites throughout the body, comprising the intracranial localisation [4,13,20].…”

Diagnostic Exercise

“…Local recurrent microhemorrhages are again considered as a plausible underlying mechanism, but the possible role of dyslipidemia and hypercholesterolemia has also been speculated. 1,3,4,11 The overall results of the immunohistochemical evaluation-including expression of MHC-II and CD18 in the large round/polygonal and multinucleate cells associated with the cholesterol clefts, along with the presence of a spindle cell component characterized by expression of vimentin, S100, and NSE-may support interesting speculations on the histogenesis of cholesterol cleft-rich masses in the feline brain. Recruitment and proliferation of MHC-IIand CD18-positive dendritic cells associated with variable numbers of arachnoid cells from the leptomeninges might be hypothesized as a mechanism underlying a local response to the accumulation of cholesterol crystals.…”

“…Recently, coexistence of intraventricular meningioma and cholesterol granuloma of the choroid plexus was reported in a cat. 9 The occurrence of cholesterol granulomas in the brain has been described in several other species, including human, 4 horse, 7 dog, 5 and meerkat. 1 Equine cholesterol granuloma of the choroid plexus is a wellknown age-related condition affecting up to 20% of old horses.…”

LDLR promoter variant and exon 14 mutation on the same chromosome are associated with an unusually severe FH phenotype and treatment resistance

“…There are reports of treated 26 and untreated 27 homozygous FH patients living well beyond the expected lifespan; however, whether the patients in these reports had genetically confirmed homozygous FH is unclear. In contrast, one intriguing case report described an FH patient with a myocardial infarction at age 26 and markedly elevated, statin-resistant LDL cholesterol; the patient had two heterozygous LDLR mutations in exons 6 and 9 in cis.…”