Serum lipids and risk of atherosclerosis in xanthelasma palpebrarum: A systematic review and meta-analysis.

BACKGROUND: The association between dyslipidemia and xanthelasma palpebrarum (XP) remains controversial, and no definite evidence has indicated atherosclerosis risk in patients with XP. OBJECTIVE: The present study was a systematic review and meta-analysis to elucidate the association of serum lipid profiles and risk of atherosclerotic diseases with XP. METHODS: We systematically searched for the eligible comparative studies published before April 15, 2019, in the databases of PubMed, Web of Science, Embase, and Cochrane Library. A random-effects model was used to calculate the standard mean difference with 95% confidence interval for each pooled estimate. RESULTS: The qualitative analyses included 15 case-control studies with 854 patients with XP. Compared with the controls, the patients with XP had significantly higher serum levels of total cholesterol and low-density lipoproteins, significantly higher apolipoprotein B levels, and relatively lower apolipoprotein A1 levels, and the carotid intima-media thickness was significantly higher. CONCLUSION: Patients with XP had significantly higher serum levels of atherogenic low-density lipoproteins and bore significantly higher risk of atherosclerosis than the controls. Careful monitoring and targeted intervention for prevention of cardiovascular diseases is essential for these patients.

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.

Association of Achilles tendon thickness and LDL-cholesterol levels in patients with hypercholesterolemia.

BACKGROUND: Achilles tendons are the most common sites of tendon xanthomas that are commonly caused by disturbance of lipid metabolism. Achilles tendon thickening is the early characteristic of Achilles tendon xanthomas. The relationship between Achilles tendon thickness (ATT) and LDL-C levels, and risk factors of ATT in patients with hypercholesterolemia, have thus far been poorly documented. METHODS: A total of 205 individuals, aged 18-75 years, were enrolled from March 2014 to March 2015. According to the LDL-C levels and the "Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults", all subjects were divided into 3 groups: normal group (LDL-C < 3.37 mmol/L, n = 51); borderline LDL-C group (3.37 mmol/L ≤ LDL-C ≤ 4.12 mmol/L, n = 50); and hypercholesterolemia group (LDL ≥ 4.14 mmol/L, n = 104). ATT was measured using a standardized digital radiography method and the results were compared among the 3 groups. The correlation between ATT and serum LDL-C levels was analyzed by Pearson's correlation, and the risk factors of ATT were determined by the logistic regression model. RESULTS: ATT in borderline LDL-C group was 8.24 ± 1.73 mm, markedly higher than 6.05 ± 0.28 mm of normal group (P < 0.05). ATT in hypercholesterolemia group was 9.42 ± 3.63 mm which was significantly higher than that of normal group (P < 0.005) and that of borderline LDL-C group (P < 0.05). There was a positive correlation between the serum LDL-C levels and ATT (r = 0.346, P < 0.001). The serum LDL-C level was a risk factor (OR = 1.871, 95% CI: 1.067-3.280) while the levels of HDL-C (OR = 0.099, 95% CI: 0.017-0.573) and Apo AI (OR = 0.035, 95% CI: 0.003-0.412) were protective factors of ATT. CONCLUSIONS: ATT might serve as a valuable auxiliary diagnostic index for hypercholesterolemia and used for the assessment and management of cardiovascular disease.

Long-Term Follow-Up of a Homozygous Familial Hypercholesterolemic Patient Receiving Regular Double Filtration Plasmapheresis - Case Report and Literature Review.

Homozygous familial hypercholesterolemia (HoFH) is a very rare condition (1 case per 1 million people) with a dismal outcome due to inevitable coronary artery disease that occurs when left untreated. Lipoprotein apheresis (LA), previously known as low-density lipoprotein (LDL) apheresis, is very effective in reducing LDL-cholesterol (LDL-C) if HoFH is refractory to aggressive drug therapy and diet control. In this study, we report a case with HoFH, who presented with xanthomata over the 4 limbs when she was 3 years old. When she was 11 years old, she began treatment with semi-selective LA with double filtration plasmapheresis (DFPP) once per week because HoFH was refractory to high-dose statin and diet control. LDL-C was reduced from 8.2 ± 0.9 to 2.69 ± 0.75 mmol/l (reduction rate = 67.3 ± 6.1%). The xanthomata over the 4 limbs were nearly completely resolved after 2 years of DFPP. Two years later, after the initiation of DFPP, we performed coronary angiography and echocardiography for regular checkup in the absence of chest pain, and the result was negative. To date (11 years after initiation of DFPP), she has not complained of any chest pain, shown intolerance to exercise, or exhibited ST-T change on electrocardiography. At the age of 20, multidetector computed tomography showed no significant stenosis over the coronary arteries. At the most recent follow-up visit, she was found to have good heart function and no xanthomata. LA is effective in the treatment of HoFH when drug therapy and diet control fail. With this treatment, pre-existing xanthomata can regress and coronary artery disease can be prevented.

PCSK9 R46L, lower LDL, and cardiovascular disease risk in familial hypercholesterolemia: a cross-sectional cohort study.

OBJECTIVE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a downregulator of the low density lipoprotein receptor. The aims of this cross-sectional cohort-study were to examine whether the PCSK9 R46L loss of function variant found in a cohort of familial hypercholesterolemia (FH) patients was associated with lower low density lipoprotein cholesterol, lower frequency of xanthomata, and cardiovascular risk. APPROACH AND RESULTS: We studied FH patients attending the IRCM (Institut de Recherches Cliniques de Montréal) Lipid Clinic and whose DNA genotyping was positive for a low density lipoprotein receptor mutation. The presence of the PCSK9 loss of function R46L missense variant was determined among a cohort of 582 FH patients by genotyping. Frequency of the R46L variant was 3%. Carriers had significantly lower low density lipoprotein cholesterol (11%, P=0.002), total cholesterol (9%, P=0.007), apolipoprotein B (10%, P=0.037), and non-high density lipoprotein (12%, P<0.001) concentrations compared with noncarriers. Furthermore, R46L carriers showed a decreased average number of xanthoma per individual compared with noncarriers (0.33 and 0.76, respectively; P<0.001). Importantly, the R46L genetic variant was associated with a significant 86% lower odd of presenting a cardiovascular event (odds ratio, 0.14; 95% confidence interval, 0.032-0.63; P=0.001). CONCLUSIONS: Even though the R46L variant was present in 3% of our FH population, carriers of this polymorphism showed attenuated effect of the low density lipoprotein receptor mutation on parameters, such as low density lipoprotein cholesterol, apolipoprotein B, total cholesterol, and non-high density lipoprotein. More importantly, this mutation is associated with a significant lower risk of cardiovascular disease compared with noncarriers. It is therefore likely that targeting PCSK9 in FH patients with novel anti-PCSK9 therapies will be useful in reducing cardiovascular risk in affected subjects.

Are normolipidaemic patients with xanthelasma prone to atherosclerosis?

BACKGROUND: When patients with xanthelasma are found to have normal lipid levels, dermatologists usually proceed with their treatment without further investigations. However, there is some evidence that normolipidaemic patients with xanthelasma (NPX) have a similar cardiovascular risk to hyperlipidaemic patients with xanthelasma (HPX). AIM: To evaluate the risk of atherosclerosis in Egyptian NPX compared with HPX and controls. METHODS: In total, 20 NPX, 20 HPX and 40 normolipidaemic controls were enrolled. All participants were matched for age and sex. Diabetes was an exclusion factor. Carotid ultrasonography was used to measure intima-media thickness (IMT). Other risk factors of atherosclerosis such as high blood pressure, obesity and smoking were also assessed, as well as atherosclerotic markers, including total leucocytic count (TLC), C-reactive protein and lipoprotein a. RESULTS: Although still within the normal range, total cholesterol and triglycerides were significantly higher in NPX compared with controls. IMT was significantly higher in NPX compared with controls, but lower than that of HPX. The increased IMT in NPX was not related to any of the studied risk factors. Apart from significantly higher body mass index and TLC, NPX showed no significant differences from controls for other risk factors of atherosclerosis or for atherosclerotic markers. CONCLUSION: NPX seem to have a higher risk of atherosclerosis independent of lipid concentrations, and should therefore be fully investigated in order to allow detection and early management of such risk.

Raised numbers of IgG4-positive plasma cells are a common histopathological finding in orbital xanthogranulomatous disease.

PURPOSE: To determine the relation of orbital xanthogranuloma with IgG4-related disease. METHODS: Retrospective consecutive case series over a period of 25 years. We searched our charts for histologically confirmed orbital xanthogranuloma. Patient files were reviewed for clinical and follow up data including presence or absence of systemic non-ophthalmic manifestations of IgG4 related disease. Slides were re-examined and histopathological classification was re-assessed. Sixteen cases of orbital xanthogranuloma were evaluated. Immunohistochemical stains for IgG and IgG4 were performed. Positive immunohistochemical staining required increased IgG4-positive plasma cells in the involved tissues scored as >50 per high-power field, with IgG4/IgG ratio >0.40. RESULTS: According to the criteria described above 8/16 (50%) cases showed increased numbers of IgG4-positive plasma cells in the specimens. Two of these patients may have had signs of systemic disease. CONCLUSION: Raised numbers of IgG4-positive plasma cells are a common finding in histopathological specimens of xanthogranulomatous disease of the orbit and are often not indicative for IgG4 related systemic disease.

Xanthelasma palpebrarum: a marker of premature atherosclerosis (risk of atherosclerosis in xanthelasma).

PURPOSE: To evaluate the association between xanthelasma palpebrarum (XP) and atherosclerosis by the measurement of carotid intima media thickness (CIMT). In addition, the concurrent association between metabolic syndrome, dyslipidaemia and dyslipoproteinaemia was also assessed. STUDY DESIGN: A cross-sectional study was conducted from January 2008 to April 2009 involving 40 patients of XP and an equal number of age, sex and body mass index matched controls. All study subjects underwent CIMT estimation by ultrasonography and were evaluated for metabolic syndrome (obesity, blood pressure, blood glucose, serum lipid profile), non-alcoholic fatty liver disease, apolipoprotein A1 and apolipoprotein B. RESULTS: The mean CIMT was significantly higher in XP patients as compared with controls. However, there was no correlation with the extent or the duration of the XP lesions. Prevalence of metabolic syndrome was similar in both groups while non-alcoholic fatty liver disease was more frequent in XP patients as compared with controls (p=0.001). The mean serum cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglyceride levels were similar in the two groups. However, there was significant increase in the mean pro-atherogenic apolipoprotein B and decrease in the anti-atherogenic apolipoprotein A1 levels in XP patients. CONCLUSIONS: Alteration in apolipoprotein levels (A1 and B) in XP patients may predispose to cutaneous and systemic deposition of lipids, including atherosclerosis. Therefore, XP patients irrespective of their lesion size or serum lipid levels should be screened using CIMT for detection of subclinical atherosclerosis.

Xanthelasma palpebrarum treatment with a 1,450-nm-diode laser.

BACKGROUND: Various treatments of xanthelasma palpebrarum have been studied, including surgical excision, treatment with chemicals, and ablative laser therapy, but these methods have some disadvantages. Recently, nonablative laser therapy has been proposed as a treatment for xanthelasma palpebrarum. OBJECTIVE: To investigate the efficacy and safety of a 1,450-nm-diode laser in the treatment of xanthelasma. MATERIALS AND METHODS: Sixteen patients were treated using a 1,450-nm-diode laser. Fluences of 12 J/cm(2) , a 6-mm spot size, and a dynamic cooling device setting of 20 to 30 ms were used. One to four treatments 4 to 6 weeks apart were given to each patient. Photographs were taken before each treatment session and 4 to 6 weeks after the last treatment. RESULTS: Two (12.5%), eight (50%), and four (25%) of the 16 patients were scored as having some (20-40% clearing), moderate (40-60% clearing), and marked (60-80% clearing) improvement, respectively. Focal mild transient hyperpigmentation was noted in five patients. Post-treatment local swelling lasted 3 to 4 days. CONCLUSION: The 1,450-nm-diode laser treatment is a new, valuable treatment option for xanthelasma palpebrarum, offering relatively mild side effects. Studies including long term follow up and a comparison with alternative treatment modalities are necessary to further assess the clinical utility of this treatment. The authors have indicated no significant interest with commercial supporters.

Exploration of differentially-expressed exosomal mRNAs, lncRNAs and circRNAs from serum samples of gallbladder cancer and xantho-granulomatous cholecystitis patients.

Gallbladder cancer (GBC) is the most common biliary tract malignancy worldwide. Although a growing number of studies have explored the mechanism of GBC, thus far, few molecules have been discovered that can be utilized as specific biomarkers for the early diagnosis and therapeutic treatment of GBC. Recent studies have shown that exosomes not only participate in the progression of tumors, but also carry specific information that can define multiple cancer types. The present study investigated the expression profiles of coding (or messenger) ribonucleic acids (mRNAs) and non-coding RNAs (ncRNAs, including long non-coding RNAs [lncRNAs] and circular RNAs [circRNAs]) in plasma-derived exosomes from GBC patients. Using high-throughput RNA sequencing and subsequent bioinformatic analysis, a number of differentially expressed (DE) mRNAs, lncRNAs, and circRNAs were identified in GBC exosomes, compared to their expressions in xantho-granulomatous cholecystitis (XGC) exosomes. Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) analyses were then conducted to investigate the potential functions of these DE RNAs. Furthermore, the interaction networks and competing endogenous RNA networks of these DE RNAs and their target genes were investigated, revealing a complex regulatory network among mRNAs and ncRNAs. In summary, this study demonstrates the diagnostic value of plasma-derived exosomes in GBC and provides a new perspective on the mechanism of GBC.

Xanthomatous Hypophysitis: A Case Report and Comprehensive Literature Review.

Purpose: Xanthomatous hypophysitis (XHP) is an extremely rare form of primary hypophysitis for which there is a lack of clinical experience. A comprehensive understanding of its clinical characteristics, diagnosis and treatment is needed. Methods: Here, we report a case study and conduct a systematic review of XHP. Thirty-six cases were included, and their clinical manifestations, endocrine assessment, imaging features, treatment and follow-up data were collected and analyzed. Results: The mean age at diagnosis was 39.1 years, and females were predominant (75.0%). The most common symptom was headache (68.6%), and 66.7% of female patients presented menstrual disorders. The most common pituitary dysfunction was growth hormone (GH) deficiency. More than half of patients exhibited central diabetes insipidus (CDI). The majority of patients had an imaging presentation of a cystic lesion with peripheral enhancement. Pituitary stalk thickening was observed in half of the patients. Total lesion resection was achieved in 57.1% of cases. The recurrence rate after partial resection and biopsy was significantly higher than that after total lesion resection (57.1% vs. 0.0%, P = 0.0147). The most common pituitary hormone abnormalities to resolve after surgery were hyperprolactinemia (100.0%) and GH deficiency (91.7%). The typical pathological feature was inflammatory infiltration of foamy histiocytes, which showed positivity for CD68. Conclusion: Diagnosis of XHP is difficult when relying on clinical symptoms and imaging features. Therefore, surgical histopathology is necessary. Based on the available evidence, total lesion resection is recommended for treatment. However, the long-term prognosis for this rare disease remains unclear.

Roles of Salmonella typhi and Salmonella paratyphi in Gallbladder Cancer Development.

BACKGROUND: Typhoid (Salmonella typhi and paratyphi) carriers and gall bladder cancer (GBC) are endemic in northern India. Results of previous studies about association of typhoid carriers with GBC are inconsistent. We studied antibodies against Salmonella typhi and paratyphi in serum samples of patients with GBC. METHODS: We performed modified Widal test for antibodies against Salmonella typhi (Vi and O) and Salmonella paratyphi (AO and BO) antigens in patients with GBC (n=100), xanthogranulomatous cholecystitis (XGC, n=24), chronic cholecystitis (CC, n=200) and healthy controls (HC, n=200). RESULTS: Serum antibodies against Salmonella were more frequently positive in GBC (22%) and XGC (29%), particularly in males in age ≥50 years (GBC: 47% and XGC: 50%) vs. HC (0) (p <0.01). Vi antibody was more common in GBC (13%, OR:9.8) and XGC (8%, OR:5.9) than HC (2%). O antibody was more common in GBC (8%, OR: 8.6) and XGC (8%, OR: 9.0) than HC (1%). O antibody was also more common in males with GBC (12%) than CC (1%) and HC (1%) (P=0.02 and p <0.001, respectively). AO (6%) and BO (4%) antibodies were detected in GBC, particularly in males, than HC (0), (p <0.01). Salmonella antibodies were more frequent in GBC with GS than those without GS (50% vs. 20%, OR=3.94, P=0.01). CONCLUSIONS: Salmonella carrier state was more common in GBC and XGC, particularly in elderly males than HC. The Vi antibody was more common in GBC and XGC than HC. Salmonella infection was more common in GBC with GS than those without GS.

Case report--papular xanthoma in a 10-year-old female with abnormal lipid profile.

Papular xanthoma is a rare normolipemic xanthomatous skin disease which primarily occurs in adults. While this rare disorder has been documented in children, all but one reported in the literature had a normal lipid profile. We report a 10-year-old girl with multiple papule xanthomas on her face that had an abnormal lipid profile. To our knowledge this is only the second reported case of papular xanthoma in the pediatric population with an abnormal lipid profile.

Practice of lipoprotein apheresis and short-term efficacy in children with homozygous familial hypercholesterolemia: Data from an international registry.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (hoFH) may cause life-threatening atherosclerotic cardiovascular disease in childhood. Lipoprotein apheresis (LA) is considered a pivotal treatment option, but data on its efficacy, safety and optimal performance are limited. We therefore established an international registry on the execution and outcomes of LA in HoFH children. Here we report LA policies and short-term outcomes. METHODS: We approached centers worldwide, involved in LA in children with hoFH for participation. We collected information on clinical and treatment characteristics on patients aged 0-19 years between November 2016 and November 2018. RESULTS: We included 50 children, treated at 15 sites. Median (IQR) LDL-C levels at diagnosis, on medication and on LA were 19.2 (16.2-22.1), 14.4 (10.8-16.7) mmol/L and 4.6 mmol/L, respectively. Median (IQR) time between diagnosis and start of LA was 2.8 (1.0-4.7) years. Six (12%) patients developed cardiovascular disease during that period. Most children received LA either weekly (43%) or biweekly (37%). Seven (17%) patients reached mean LDL-C levels <3.5 mmol/L, all of them treated at least weekly. Xanthomas were present in 42 (84%) patients at diagnosis and disappeared completely in 19 (45%) on LA. Side effects of LA were minor. There were significant differences in LA conduction between sites in terms of frequency, responsible medical specialities and vascular access. CONCLUSIONS: LA is a safe treatment and may effectively lower LDL-C in children with HoFH. However, there is room for improvement with respect to time of onset and optimization of LA therapy in terms of frequency and execution.

Normolipemic papuloeruptive xanthomatosis in a child.

Normolipemic papuloeruptive xanthomatosis is a very rare skin disorder. We report a child with yellowish papular eruptions on the face that rapidly merged into confluent plaques. Serum lipid profiles showed normolipemia. A diagnosis of normolipemic papuloeruptive xanthomatosis with no associated systemic disorders was made. The skin lesions involuted spontaneously during follow-up.