Unveiling Familial Hypercholesterolemia-Review, Cardiovascular Complications, Lipid-Lowering Treatment and Its Efficacy.

Familial hypercholesterolemia (FH) is a genetic disorder primarily transmitted in an autosomal-dominant manner. We distinguish two main forms of FH, which differ in the severity of the disease, namely homozygous familial hypercholesterolemia (HoFH) and heterozygous familial hypercholesterolemia (HeFH). The characteristic feature of this disease is a high concentration of low-density lipoprotein cholesterol (LDL-C) in the blood. However, the level may significantly vary between the two mentioned types of FH, and it is decidedly higher in HoFH. A chronically elevated concentration of LDL-C in the plasma leads to the occurrence of certain abnormalities, such as xanthomas in the tendons and skin, as well as corneal arcus. Nevertheless, a significantly more severe phenomenon is leading to the premature onset of cardiovascular disease (CVD) and its clinical implications, such as cardiac events, stroke or vascular dementia, even at a relatively young age. Due to the danger posed by this medical condition, we have investigated how both non-pharmacological and selected pharmacological treatment impact the course of FH, thereby reducing or postponing the risk of clinical manifestations of CVD. The primary objective of this review is to provide a comprehensive summary of the current understanding of FH, the effectiveness of lipid-lowering therapy in FH and to explain the anatomopathological correlation between FH and premature CVD development, with its complications.

Update on Sitosterolemia and Atherosclerosis.

PURPOSE OF REVIEW: The purpose of this review was to summarize important and updated information on sitosterolemia. Sitosterolemia is an inherited lipid disorder consisting of high levels of plasma plant sterols. This sterol storage condition is caused by biallelic loss-of-function genetic variants in either ABCG5 or ABCG8, leading to increased intestinal absorption and decreased hepatic excretion of plant sterols. Clinically, patients with sitosterolemia usually exhibit xanthomatosis, high levels of plasma cholesterol, and premature atherosclerotic disease, but presentation can be highly heterogeneous. Therefore, recognition of this condition requires a high level of suspicion, with confirmation upon genetic diagnosis or through measurement of plasma phytosterols. Treatment of sitosterolemia with both a plant sterol-restricted diet and the intestinal cholesterol absorption inhibitor ezetimibe can reduce efficiently the levels of plasma plant sterols, consisting in the first-line therapy for this disease. RECENT FINDINGS: Since hypercholesterolemia is often present in individuals with sitosterolemia, it is important to search for genetic variants in ABCG5 and ABCG8 in patients with clinical criteria for familial hypercholesterolemia (FH), but no variants in FH implicated genes. Indeed, recent studies have suggested that genetic variants in ABCG5/ABCG8 can mimic FH, and even when in heterozygosis, they may potentially exacerbate the phenotype of patients with severe dyslipidemia. Sitosterolemia is a genetic lipid disorder characterized by increased circulating levels of plant sterols and clinically manifested by xanthomatosis, hematologic disorders, and early atherosclerosis. Awareness about this condition, a rare, but commonly underdiagnosed and yet treatable cause of premature atherosclerotic disease, is imperative.

New diagnosis of diabetes and severe hyperlipidemia at 3 months postpartum presenting as florid diabetic retinopathy and eruptive xanthomas.

A 33-year-old woman presented to the Emergency Department at 3 months postpartum with a 2-day history of a partial left sixth cranial nerve palsy, and several weeks' history of bilateral blurred vision and papular skin lesions. Brain imaging and ultrasound of the carotid and vertebral arteries were all normal. Investigations revealed severe hyperlipidemia and a venous blood glucose level of 19.6 mmol/L despite a negative result on a 75-g oral glucose tolerance test at 32 weeks of pregnancy. Fundus photography demonstrated bilateral severe proliferative diabetic retinopathy with lipemia retinalis. The skin lesions were consistent with xanthomas on biopsy. The partial left sixth cranial nerve palsy and the bilateral rapidly progressive diabetic retinopathy were likely secondary to peripheral ischemia from serum hyperviscosity and displacement due to severe hyperlipidemia. The rapid progression of symptoms was likely triggered by a postpartum diet high in saturated fats in the context of presumed genetic predisposition.

HYPERLIPIDEMIA AND XANTHOMATOSIS IN YELLOW-FOOTED ROCK WALLABIES (PETROGALE XANTHOPUS) UNDER MANAGED CARE.

Xanthomas are localized lipid deposits in organs with associated granulomatous inflammation. Xanthomatosis is a rare condition in both human and veterinary medicine and is often linked to inherited or acquired dyslipidemias. Three female yellow-footed rock wallabies (Petrogale xanthopus) at a single institution were diagnosed via biopsy with cutaneous xanthomas secondary to hypertriglyceridemia and hypercholesterolemia, and an additional two female yellow-footed rock wallabies were diagnosed with xanthomas at a second institution. All cases presented with cutaneous masses at the haired skin and paw pad junctions of the extremities, and/or mucocutaneous junctions of the face or urogenital tract. The clinically affected individuals were overconditioned or obese, had lipemic serum, and had elevations in blood cholesterol and triglyceride levels. When full lipid panels were performed, inverse high- and low-density lipoprotein fractions were observed. Six other individuals at the first institution had identical husbandry but were of more appropriate body condition, were normolipidemic, and had no xanthomas. One of the affected animals was also concurrently diagnosed with hepatic lipidosis via liver biopsy. Pedigree review and evaluation for underlying endocrine diseases such as hypothyroidism were performed. Because all affected animals were found to be related, a genetic predisposition is possible but requires further investigation. Consideration for the predisposition of some individuals for obesity, hyperlipidemia, and subsequent xanthoma formation should be factored in the husbandry and medical management of this species.

Eruptive Xanthoma With Dermal Mucin Deposition.

ABSTRACT: Xanthomas present clinically as eruptive, tuberoeruptive, tuberous, tendinous, or planar forms. Among these, eruptive xanthoma (EX) is characterized by sudden development of multiple, red-to-yellow papules, each less than 5 mm in diameter, on the extensor surface of the extremities and the buttock area. EX is often associated with severe hypertriglyceridemia, underlying diabetes, obesity, or excessive alcohol intake. Histologically EX is characterized by foamy cells, which are lipid-laden macrophages surrounded by lymphoid cells, histiocytes, and neutrophils; however, mucin deposition is not a typical feature. Herein, we report a rare case of xanthoma with diffuse, abundant mucin deposition.

Clinical presentation, imaging and response to interferon-alpha therapy in Erdheim-Chester disease: case-based review.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis associated with BRAFV600E mutations in more than 50% of cases and presenting with 95% with skeletal lesions. However, cutaneous, pulmonary, large vessels and central nervous system involvement can also occur. We report a case of a 25-year-old woman who was admitted in 2018 for exploration of diffuse bone pain and rashes on the face. Her current symptoms had started 14 months earlier and consisted of bone pain, affecting the legs. She had periodic low-grade fever, asthenia and xanthelasma-like papules appeared on face. At admission, physical examination showed bilateral and symmetrical long bone pain, especially in the knees and multiple xanthelasma-like papules around the eyelids, cheeks and chin. Laboratory tests revealed elevated erythrocyte sedimentation rate and C-reactive protein. Magnetic resonance (MR) imaging showed multiple mixed bone lesions with a hyperintensive MR signal on PD FS and hypointense signal on T1of the femur and tibia. Bone scintigraphy indicated bilateral and symmetrical metaphyseal and diaphyseal increased uptake. Abdominal computed tomography (CT) scan showed infiltration of the perirenal fat. Biopsy of the skin revealed histiocytic infiltration, which was CD68-positive and CD100-positive, confirming the diagnosis of ECD. Patient was treated with interferon-α (IFN-α) plus methylprednisolone. After 6 months of treatment her clinical condition partly improved: a reduction of pain on visual analogue scale (VAS) scale, significant decrease of methylprednisolone dose and specific dynamics according to bone MR imaging data, however, no change in symptoms attributed to skin rash was noted. We also provide the literature review results of IFN-α treatment efficacy in Erdheim-Chester disease involving the skin and musculoskeletal system with MR imaging changes.

Diffuse (Generalized) Plane Xanthoma Misdiagnosed as Carotenoderma: Usefulness of Reflectance Confocal Microscopy.

Diffuse (generalized) plane xanthoma is a rare normolipemic xanthomatosis, frequently associated with multiple myeloma and monoclonal gammopathy. Its clinical presentation is well described, and in most cases, clinical suspicion is immediate. Rarely, it can clinically present with a diffuse and uniform yellowish discoloration, and in this context, several investigations are required to identify the correct diagnosis. We describe a case characterized by progressive diffuse yellow-orange discoloration lasting about 3 years and classified as carotenoderma in which reflectance confocal microscopy addressed the diagnosis and drove the correct selection of the biopsy site. Definitive diagnosis of diffuse (generalized) plane xanthoma was confirmed later by histological examination.

Verruciform xanthoma in a patient with recessive dystrophic epidermolysis bullosa: Case report and literature review.

Verruciform xanthoma (VX) is a rare finding thought to be caused by epidermal damage from trauma or inflammation and has been reported in a limited number of patients with recessive dystrophic epidermolysis bullosa (RDEB). Herein, we describe a 20-year-old woman with RDEB who developed a large, verrucous, pink plaque on the posterior thigh that was histologically proven to be a VX. We review cases of VX in patients with RDEB and summarize the clinical features, pathophysiology, and management principles.

Verruciform xanthoma in recessive dystrophic epidermolysis bullosa and keratitis-ichthyosis-deafness syndrome: Report of two cases and a review of the literature.

Verruciform xanthoma is a benign, wart-like lesion that can clinically mimic squamous cell carcinoma. We describe two teenage patients with severe genodermatoses, recessive dystrophic epidermolysis bullosa (RDEB), and keratitis-ichthyosis-deafness (KID) syndrome, respectively, each found to have plaques suspicious for malignancy, later demonstrated on histopathologic examination to be verruciform xanthoma. We discuss the connection between these severe genodermatoses and the suspected pathophysiology of verruciform xanthoma. In addition, we highlight the importance of recognizing verruciform xanthoma as a clinical mimicker of squamous cell carcinoma, for which patients with RDEB and KID syndrome are at increased risk.

Lipodystrophies-Disorders of the Fatty Tissue.

Lipodystrophies are a heterogeneous group of physiological changes characterized by a selective loss of fatty tissue. Here, no fat cells are present, either through lack of differentiation, loss of function or premature apoptosis. As a consequence, lipids can only be stored ectopically in non-adipocytes with the major health consequences as fatty liver and insulin resistance. This is a crucial difference to being slim where the fat cells are present and store lipids if needed. A simple clinical classification of lipodystrophies is based on congenital vs. acquired and generalized vs. partial disturbance of fat distribution. Complications in patients with lipodystrophy depend on the clinical manifestations. For example, in diabetes mellitus microangiopathic complications such as nephropathy, retinopathy and neuropathy may develop. In addition, due to ectopic lipid accumulation in the liver, fatty liver hepatitis may also develop, possibly with cirrhosis. The consequences of extreme hypertriglyceridemia are typically acute pancreatitis or eruptive xanthomas. The combination of severe hyperglycemia with dyslipidemia and signs of insulin resistance can lead to premature atherosclerosis with its associated complications of coronary heart disease, peripheral vascular disease and cerebrovascular changes. Overall, lipodystrophy is rare with an estimated incidence for congenital (<1/1.000.000) and acquired (1-9/100.000) forms. Due to the rarity of the syndrome and the phenotypic range of metabolic complications, only studies with limited patient numbers can be considered. Experimental animal models are therefore useful to understand the molecular mechanisms in lipodystrophy and to identify possible therapeutic approaches.

Eruptive xanthomas in a patient with soft-drink diabetic ketosis and apolipoprotein E4/2.

Soft-drink diabetic ketosis, characterized by acute onset ketosis induced by excessive ingestion of sugar-containing drinks, is often seen in obese, young patients, even with undiagnosed type 2 diabetes. We herein report a 15-year-old obese patient with the apolipoprotein E4/2 phenotype, in whom eruptive xanthomas lead to a diagnosis of soft-drink diabetic ketosis. He developed multiple asymptomatic yellowish papules on the auricles, back, buttocks and the extensor surfaces of the elbows and knees. He initially visited a dermatology clinic and his blood triglyceride and HbA1c levels were found to be 6,490 mg/dL and 16.5%, respectively. He was referred to our hospital for treatment of hyperglycemia and hypertyriglyceridemia. On admission, he had ketonuria and increased blood levels of 3-hydroxybutylate and acetoacetate. He habitually drank 1-3 litters of sweet beverages daily to quench his thirst. Therefore, "soft-drink diabetic ketosis" was diagnosed. Severe hypertriglyceridemia was considered to have been a consequence of impaired insulin action and his apolipoprotein E4/2 phenotype. We treated the diabetic ketosis and hypertriglyceridemia with intensive insulin therapy and a fat-restricted diet. At discharge, he no longer required insulin therapy and his blood glucose levels were controlled with metformin and voglibose. Along with amelioration of the hyperglycemia, triglyceride levels decreased to 247 mg/dL without administration of anti-hyperlipidemia agents. The eruptive xanthoma lesions gradually diminished in size and number and eventually disappeared by 12 months. This case provides an instructive example of eruptive xanthomas serving as a sign of severe dysregulation, not only of lipid, but also glucose, metabolism.

Familial Chylomicronemia Syndrome: A Clinical Guide For Endocrinologists.

OBJECTIVE: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder caused by mutations in lipoprotein lipase, resulting in accumulation of chylomicrons in plasma and hypertriglyceridemia. Elevated triglycerides cause several complications in patients, the most serious being episodes of acute pancreatitis. This review focuses on expert guidance and opinion from an experienced lipidologist and endocrinologist as well as a current review of the literature, as there are no specific guidelines on FCS. METHODS: Discussion of expert guidance and opinion review of current literature. RESULTS: To date, there is no pharmacologic treatment for affected patients, and management options primarily include adoption of an extremely restricted, very-low-fat diet, along with avoidance of certain medications and alcohol. Endocrinologists often diagnose and manage patients with metabolic disorders, including patients with high triglyceride levels, but rare diseases like FCS can be missed or poorly evaluated due to knowledge gaps about disease state. Given endocrinologists' role in the treatment of lipid disorders, it is important that they understand the clinical signs and symptoms of FCS to correctly diagnose patients. Patients with FCS can be identified based on a defined clinical criteria and a thorough review of medical history, after excluding differential diagnoses and secondary factors. Typical manifestations include hypertriglyceridemia characterized by lipemic serum, history of abdominal pain, and acute/recurrent pancreatitis. Secondary factors to be excluded are pregnancy, alcohol abuse, uncontrolled diabetes, and use of certain medications. CONCLUSION: FCS is a rare, inherited lipid disorder disease that often goes underdiagnosed and unmanaged. This review provides a summary of clinical characteristics of FCS that can be potentially used to screen patients in an endocrinologist's office and direct them to the appropriate standard of care. ABBREVIATIONS: apoB = apolipoprotein B; apoC-III = apolipoprotein CIII; ASO = antisense oligonucleotide; FCS = familial chylomicronemia syndrome; HTG = hypertriglyceridemia; LPL = lipoprotein lipase; LPLD = lipoprotein lipase deficiency.

Planar xanthomas secondary to post-transplantation cholangiopathy in a 16-month-old boy.

Planar xanthomas in children represent rare dermatologic findings associated with abnormalities in lipid metabolism. While planar xanthomas in Alagille's syndrome have been well described in the literature, there have been no cases reported of eruptive xanthomas in pediatric liver transplant patients. Herein we report a case of a 16-month-old boy status post-liver transplantation who presents with planar xanthomas secondary to cholangiopathy. A brief review of xanthomas and the related literature is also provided.

Bilateral xanthomas of tendoachilles in a slow learner adolescent - A rare case report of van bogaert scherer epstein disease.

Van Bogaert Scherer Epstein Disease is a rare autosomal recessive condition involving abnormal deposition of cholesterol and cholestanol in various parts of body, various clinical symptoms manifest on different age group, significantly neurological impairment in late presentation. We are reporting a slow learner young lady presented with bilateral painless ankle swelling, our initial clinical impression were torn Achilles tendon or Haglund's deformity. On further detail history taking, it leads us towards this disease and confirmed with biopsy. A proper history taking and assessment can easily diagnose this condition, early treatment can perhaps change the fate of these unfortunate patients.