Eruptive Xanthomata Research Articles

Analysis of a Chinese Pedigree With Familial Chylomicronemia Syndrome Reveals Two Novel LPL Mutations by Whole-Exome Sequencing

Familial chylomicronemia syndrome (FCS) is a rare monogenic autosomal recessive disease caused by loss-of-function mutations in genes involved in chylomicron breakdown through hydrolysis of triglycerides into free fatty acids. Patients are often diagnosed in early childhood with extremely high triglyceride levels and symptoms including abdominal pain, eruptive cutaneous xanthomata, hepatosplenomegaly, and significant cognitive, psychological, and social impairment. The most serious medical condition suffered by FCS patients is recurrent acute pancreatitis. Lipoprotein lipase (LPL) gene mutation accounts for majority of the known pathogenic mutations. Early diagnosis and strict low-fat diet are critical for successful management of the triglyceride concentration to lower the risk of pancreatitis. The true prevalence of FCS in China is unknown and here we report a Chinese female preterm neonate presented with an extremely high triglyceride level of 22.11 mmol/L on day 13 after birth. Clinical and laboratory workup including whole-exome sequencing revealed two novel compound heterozygous LPL mutations (c.406G > C and c.829G > C) that are co-segregated with her non-consanguineous parents, consistent with autosomal recessive inheritance. A diagnosis of FCS based on clinical, biochemical, and genetic ground was made to guide her management.

Co-occurrence of heterozygous CREB3L3 and APOA5 nonsense variants and polygenic risk in a patient with severe hypertriglyceridemia exacerbated by estrogen administration

We describe a case of a 36-year-old woman with severe hypertriglyceridemia likely caused by double heterozygosity of a known pathogenic APOA5 nonsense variant (p.Q275X) and a novel CREB3L3 nonsense variant (p.C296X) on a background of very strong polygenic susceptibility. Her clinical course worsened with development of eruptive xanthomata after oral administration of 2 mg estradiol twice daily for 2 weeks as part of a medical protocol for intrauterine embryo transfer following in vitro fertilization. Her triglyceride levels decreased to baseline and xanthomata resolved without treatment after discontinuation of hormonal therapy, which also resulted in termination of pregnancy. Before undergoing a second embryo transfer using her natural cycle and no exogenous hormones, the patient started combination therapy with eicosapentaenoic acid ethyl ester and gemfibrozil, leading to an ∼80% decrease in triglyceride levels. She continued treatment throughout pregnancy, which progressed to term with the delivery of healthy twins.

Lipoprotein X in autoimmune liver disease causing interference in routine and specialist biochemical investigations

AbstractPrimary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are chronic, immune-mediated diseases which may be associated with the presence of lipoprotein X (LpX). This is an abnormal lipoprotein resulting in marked elevation of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) concentration. LpX is rich in free cholesterol (FC) and phospholipids (PL) and low in esterified cholesterol (CE). We describe two cases with florid lipid stigmata and presence of LpX. A patient with PBC presented with itching and palmar xanthomata. TC = 55.5 mmol/L, direct LDL-C = 14.9 mmol/L, high-density lipoprotein cholesterol (HDL-C) = 0.5 mmol and triglycerides (TG) = 11.3 mmol/L. Lipoprotein electrophoresis (LPE) showed the presence of LpX. An apolipoprotein E (Apo E) phenotype and genotype reported E2E3 and E3E3 isoforms, respectively. A patient with PSC presented with itchy eruptive xanthomata. TC = 22.8 mmol/L, calculated LDL-C = 21.7 mmol/L, HDL-C = 0.2 mmol/L and TG = 1.6 mmol/L...

Metabolic surgery for the treatment of hypertriglyceridemia-related pancreatitis due to familial lipoprotein lipase deficiency

Familial lipoprotein lipase deficiency (LPLD) is an autosomal recessive disorder characterized by severely elevated serum triglyceride (TG) levels with an associated risk of recurrent pancreatitis. The prevalence is approximately 1–2 in 1,000,000 [1]. LPLD usually presents in childhood with severe hypertriglyceridemia (HTG) and associated episodes of abdominal pain, recurrent pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly [1]. Metabolic surgery, defined as surgery resulting in anatomic and functional changes with the goal of treating metabolic disorders [2], has been proposed as an effective treatment for severe HTG. Gastric bypass, as a bariatric surgery, has been shown to be highly effective for reducing plasma lipid levels in patients with hyperlipidemia [3,4]. Therefore, gastric bypass should be a viable treatment option for recurrent pancreatitis secondary to LPLDinduced HTG. To the best of the authors’ knowledge, this is the first report of a patient with LPLD undergoing laparoscopic mini-gastric bypass (LMGB) as a metabolic surgery for the treatment of intractable HTG-related pancreatitis.

Familial lipoprotein lipase deficiency: a case of compound heterozygosity of a novel duplication (R44Kfs*4) and a common mutation (N291S) in the lipoprotein lipase gene

Familial lipoprotein lipase (LPL) deficiency (FLLD) is a rare autosomal recessive genetic disorder caused by homozygous or compound heterozygous mutations in the LPL gene. FLLD individuals usually express an impaired or non-functional LPL enzyme with low or absent triglyceride (TG) hydrolysis activity causing severe hypertriglyceridaemia. Here we report a case of FLLD in a 29-year-old man, who initially presented with eruptive cutaneous xanthomata, elevated plasma TG concentration but no other co-morbidities. Subsequent genetic testing of the patient revealed compound heterozygosity of a novel duplication (p.R44Kfs*4) leading to a premature stop codon in exon 2 and a known mutation (N291S) in exon 5 of the LPL gene. Further biochemical analysis of the patient's postheparin plasma confirmed a reduction of total lipase activity compared with his heterozygous father carrying the common N291S mutation and to a healthy control. Also the patient showed increased (1.85-fold) activity of hepatic lipase (HL), indicating a functional link between HL and LPL. In summary, we report a case of FLLD caused by compound heterozygosity of a new duplication and a common mutation in the LPL gene, resulting in residual LPL activity. With such mutations, individuals may not receive a diagnosis before classical FLLD symptoms appear later in adulthood. Nevertheless, early diagnosis and lipid-lowering treatment may favour a reduced risk of premature cardiovascular disease or acute pancreatitis in such individuals.

Lipoprotein X in a patient with cholestasis and hypertriglyceridaemia

Hypertriglyceridaemia is an established cause of acute pancreatitis and responds to insulin therapy in addition to lipid lowering medication. We report a case of severe hypertriglycaeridemia of 149 mmol/L in a 36-year-old man with type 2 diabetes who presented to the surgical ward with abdominal pain due to pancreatitis and developed acute cholestasis, jaundice and eruptive xanthomata. His triglycerides improved to 3.8 mmol/L with sliding scale insulin within two weeks of in-hospital stay. However, his total cholesterol remained raised at 23.7 mmol/L. The lipoprotein electrophoresis confirmed the presence of lipoprotein X associated with bile obstruction, which contributed to an increase in total cholesterol. The total cholesterol normalized on improvement of his cholestasis.

Dystrophic xanthomatization as a type of Wolf's isotopic response: Eruptive xanthomata at a herpes zoster site

To the Editor: A 58-year-old man presented with a 5-day history of multiple clustered yellowish papules on his left ear and neck. According to the patient, he experienced an episode of herpes zoster 2 months before presentation over the same region, leaving residual atrophic scars and hyperpigmentation.

Protocolo diagnóstico de las hipertrigliceridemias

Protocol diagnosis of hypertriglyceridemiaThe serum triglyceride concentration can be stratified as normal (< 150mg/dl), borderline-high (150–200mg/dl), high (200–499mg/dl) and very high (> 500mg/dl). Both inherited and acquired disorders of triglyceride metabolism have been identified. Hypertriglyceridemia should be studied by means of a complete evaluation. These include personal history (drugs, concomitant diseases, lifestyle, familial history), physical examination (obesity, eruptive xanthomata, lipemia retinalis, xanthomata palmare striatum) and laboratory test (levels of HDL-c, LDL-c, renal and hepatic function, thyroid hormones). In patients with mild-to-moderate hypertriglyceridemia, the global cardiovascular risk must be evaluated. Triglycerides are independently associated with coronary heart disease risk. In patients with severe hypertriglyceridemia, the major risk to avoid is pancreatitis.

Xanthomata and diabetes in an adolescent with familial dysbetalipoproteinemia 9 yr after valproate-induced pancreatitis

A 14-yr-old girl presented with eruptive xanthomata and hypertriglyceridemia. This rare presentation led to diagnoses of diabetes and familial dysbetalipoproteinemia. Type 1 diabetes is a common childhood illness often presenting in adolescence. However, this patient's past medical history revealed valproate-induced severe acute pancreatitis with necrosis at the age of 5 yr. Diabetes, in this case, developed 9 yr later as a result of inadequate pancreatic tissue to support increasing insulin requirements during growth and adolescence. Diabetes was discovered only after the appearance of cutaneous eruptive xanthomata, which appeared due to the previously undiagnosed genetic dyslipidemia. Although the relationship between xanthomata, hypertriglyceridemia, and diabetes may be well known in adults, in children, xanthomata are very rarely the presenting feature of diabetes of any cause. The patient was treated with insulin which induced rapid resolution of hypertriglyceridemia and gradual disappearance of xanthomata. This case acknowledges the rarity of diabetes presenting with xanthomata in adolescence, highlights the importance of searching for an underlying dyslipidemia in such a case, and presents diabetes as a long-term complication of acute pancreatitis in children.

Incidence of pancreatitis, secondary causes, and treatment of patients referred to a specialty lipid clinic with severe hypertriglyceridemia: a retrospective cohort study

BackgroundSevere hypertriglyceridemia (HTG) is one cause of acute pancreatitis, yet the level of plasma triglycerides likely to be responsible for inducing pancreatitis has not been clearly defined.Methods and ResultsA retrospective cohort study was conducted on patients presenting non-acutely to the Healthy Heart Program Lipid Clinic at St. Paul's Hospital with a TG level > 20 mM (1772 mg/dl) between 1986 and 2007. Ninety-five patients with TG > 20 mM at the time of referral were identified, in who follow up data was available for 84. Fifteen patients (15.8%), with a mean outpatient TG level of 38.1 mM, had a history of acute pancreatitis. Among 91 additional patients with less severe HTG, none had a history of pancreatitis when TG were between 10 and 20 mM. Among patients with TG > 20 mM on presentation, 8 (8.5%), with a mean TG level of 67.8 mM, exhibited eruptive xanthomata. A diet high in carbohydrates and fats (79%) and obesity (47.6%) were the two most frequent secondary causes of HTG at initial visit. By 2009, among patients with follow up data 53% exhibited either pre-diabetes or overt Type 2 diabetes mellitus. Upon referral only 23 patients (24%) were receiving a fibrate as either monotherapy or part of combination lipid-lowering therapy. Following initial assessment by a lipid specialist this rose to 84%, and remained at 67% at the last follow up visit.ConclusionsThese results suggest hypertriglyceridemia is unlikely to be the primary cause of acute pancreatitis unless TG levels are > 20 mM, that dysglycemia, a diet high in carbohydrates and fats, and obesity are the main secondary causes of HTG, and that fibrates are frequently overlooked as the drug of first choice for severe HTG.

Severe hypertriglyceridemia is related to episodes of epididymitis

Severe hypertriglyceridemia can lead to hepatospleomegaly, eruptive xanthomata, and dysfunction of several organ systems, including acute pancreatitis. In this study, we describe acute epidydimitis reoccuring in a case of Fredrickson type I hyperlipoproteinemia. We believe this to be the second published report and the first in a child with severe hypertriglyceridemia and acute epidydimitis. The etiology of the hypertriglyceridemia was confirmed by the measurement of the enzymatic activity of post—heparin lipoprotein lipase (LPL) (undetectable) and demonstration of compound heterozygosity with gene mutations at Gly188Glu and D250N.

Severe Hypertriglyceridaemia as a result of Familial Chylomicronaemia

Lipoprotein lipase deficiency causes severe hypertriglyceridaemia due to chylomicronaemia, and leads to recurrent and potentially life-threatening pancreatitis. This disorder can only be managed by dietary fat restriction as drugs are ineffective. We review the experience with familial chylomicronaemia in patients who attended the lipid clinics at Groote Schuur Hospital and Red Cross Children's War Memorial Hospital in Cape Town. Criteria for inclusion were an initial plasma triglyceride concentration of >15 mmol/l and a typical type I Fredrickson hyperlipidaemia pattern on plasma lipoprotein electrophoresis. A total of 29 patients were seen over 25 years. The mean age of presentation was 10 years, but ranged from 0 to 43 years. The modes of presentation differed: pancreatitis (N=16), eruptive xanthomata (N=2), coincidental detection of hypertriglyceridaemia (N=2), screening relatives (N=7), and after death from pancreatitis (N=1). Plasma triglycerides responded rapidly and dramatically to dietary fat restriction, and some patients sustained good control of the hyperlipidaemia. The onset of pancreatitis was earlier in patients of Indian ancestry, suggesting a genotype/phenotype interaction within this disorder. Genetic work-up indicated founder effects in the Afrikaner and Indian patients. Lipaemic plasma should be taken seriously at all ages, and necessitates work-up at specialised clinics where the diagnosis of chylomicronaemia or type I hyperlipidaemia facilitates appropriate dietary management that can prevent pancreatitis. South African Medical Journal Vol. 98 (2) 2008: pp. 105-108

Eruptive xanthomata in insulin‐treated type 2 diabetes

Eruptive xanthomata in insulin‐treated type 2 diabetes

Hypertriglyceridemia and Hypercholesterolemia Induced by L-Asparaginase

Hypertriglyceridemia and Hypercholesterolemia Induced by L-Asparaginase

Milky Serum:

Milky serum (Figure 1) was often noted during blood letting in the seventeenth century, and later reported in association with diabetes mellitus, abdominal pain and eruptive xanthomata.1, 2 The latter are papules with yellow centres that appear over extensor surfaces and are a clinical clue to severe hypertriglyceridemia. As the plasma triglyceride levels climb above 20 mmol/l, there is the likelihood of acute pancreatitis, often resulting in admission to the surgical ward with abdominal pain where the significance of the underlying metabolic abnormality may be missed. So it was with this 37 year old lady who presented to the surgical department with non-specific abdominal pain thought to be acute appendicitis. Suspicion that all was not as it seemed was aroused when the pathology department telephoned to say that they couldn't analyse the blood sample because of grossly lipaemic plasma. The nursing staff had also noted heavy glycosuria, so medical opinion was sought. The patient was not known to have diabetes, but her admission blood glucose was 13.1 mmol/l. Multiple eruptive xanthomata were noted over the elbows and back (Figure: 2a & 2b). A subsequent lipid analysis revealed a total cholesterol of 43 mmol/l and triglycerides of 55 mmol/l. The HbA1c was 10.5% (normal < 6.4%). Her body mass index was 24.9, but over the proceeding few months she had lost about 5 kgs in weight, and reported mild polyuria and polydipsia. Her mother who had type 2 diabetes and hyperlipidemia died from a myocardial infarction at the age of 46 years. Her father had a stroke at the age of 52, and had high blood cholesterol. Our patient was initially treated with intravenous fluids and insulin, and her abdominal pain settled without surgical intervention. A low fat diet was started to limit chylomicron formation and the cholesterol fell to 10 mmol/l and the triglycerides to 17.6 mmol/l over 12 weeks without any drug therapy. At this stage she was lost to follow up when she moved away. Diabetes frequently accompanies the type V hyperlipoproteinemia phenotype that is characterised by elevated levels of chylomicrons and VLDL, both of which compete for the same clearance pathway (lipoprotein lipase).3 Overproduction of hepatic VLDL in those with diabetes overloads the system, resulting in milky serum following meals that may last for days rather than hours. Initial treatment by diet is usually effective, but restriction to as little as 10 grams fat/day may be necessary. Hypoglycaemic agents and fibrates may also be required.4

Eruptive xanthomata in uncontrolled diabetes

with a two-week history of worsening symptoms of thirst, polyuria and lethargy presented to the admissions department feeling generally unwell. Five days previously he had visited his general practitioner who had made a diagnosis of diabetes mellitus and treated the patient for a presumed urinary tract infection. The patient had an otherwise unremarkable medical history, he did not take any regular medications or abuse alcohol and his grandfather was the only family member with type 2 diabetes. The patient had small, yellow nodules located across his torso and upper arms (figure 1). He said that these nodules, ranging from 2–4 mm in diameter, had appeared over the preceding week or so. The rest of the examination, including fundoscopy, was normal. Routine blood biochemistry was undertaken: liver and thyroid function tests as well as urea and creatinine were normal. Abnormal results included a random glucose sample of 22.5 mmol/L, sodium 120 mmol/L and total cholesterol 24.7 mmol/L. Subsequent testing found that his high density lipoprotein (HDL) cholesterol was 2.2 mmol/L, triglycerides were 96.0 mmol/L and upon close inspection, the serum was noticeably lipaemic; and the lipid content was clearly visible after settling the specimen bottle in the fridge (figure 2). The patient commenced insulin therapy (Humalog Mix 25; 36 & 18 units) and was seen by both the diabetes nurse specialist and the dietitian for education and advice. After six weeks he was seen in the Outpatients Clinic and his blood biochemistry had improved: total cholesterol 7.8 mmol/L, HDL cholesterol 1.1 mmol/L, triglycerides 19.4 mmol/L and HbA1C 6.6%. Eruptive xanthomata or xanthoma diabeticorum appear in patients who have greatly elevated serum triglycerides, very low density lipoproteins (VLDLs) and chylomicrons. The lesions themselves consist of mainly triglycerides and small amounts of cholesterol. In severe cases, fundoscopy may reveal lipaemia retinalis, when blood vessels of the retina appear milky due to exudation of abnormal triglyceride-rich plasma. The low sodium in this patient was a spurious result due to

SCALP PAIN AND HYPERLIPIDAEMIA

SUMMARYAcute pancreatitis and eruptive xanthomata are the only recognised direct complications of severe hyperthglyceridaemia, although peripheral neuropathy has been described in patients with hyperlipidaemia. We describe a patient with mixed hyperlipidaemia presenting with severe scalp pain and eruptive xanthomata. Both resolved with treatment. We suspect that high triglyceride concentration can affect the function of sensory nerve fibres.

Lipoproteins modify the macrophage uptake of triacylglycerol emulsion and of zymosan particles by similar mechanisms.

The uptake of lipids and formation of foam cells are key events in atherosclerosis and in eruptive xanthomata formation in primary hyperchylomicronemia. Here we have compared the influence of low density lipoprotein (LDL), oxidized LDL (oxLDL), high density lipoprotein (HDL), and delipidated HDL (apoHDL) on the uptake by macrophages of zymosan (an insoluble fraction of yeast cell walls) and of triglyceride-rich emulsion (EM) particles that resemble chylomicrons, but, like zymosan, are equally devoid of protein components. Zymosan internalization is known to occur through unspecific phagocytosis, whereas natural chylomicrons are taken up by several specific lipoprotein receptors. We found that phagocytosis is not promoted as much by oxLDL as by normal LDL. HDL-coated zymosan was found to be inert and apoHDL slightly enhanced phagocytosis. LDL and apoHDL promoted the uptake of EM while oxLDL and HDL significantly inhibited the uptake. Therefore, the data support that HDL, and not apoHDL, particles inhibit EM uptake. We concluded that by using lipoprotein-coated zymosan particles, we could demonstrate different biological effects of LDL, oxLDL, HDL, and apoHDL on macrophage phagocytosis and that this method could be useful to delineate components of the various lipoproteins important for the propagation or inhibition of the formation of foam cells.

Dysbetalipoproteinaemia and eruptive xanthomata expressed in an APO-E2, E2 HIV patient on protease inhibitors

Dysbetalipoproteinaemia and eruptive xanthomata expressed in an APO-E2, E2 HIV patient on protease inhibitors

Gene-based therapeutic strategies for Human Lipoprotein Lipase (LPL) deficiency: Rationale and prospects for alteration of atherogenic risk

Lipoprotein lipase (LPL) plays a critical role in the regulation of total body lipoprotein and energy metabolism. This is evident in patients presenting with significant morbidity from profound hypertiglyceridemia due to complete LPL deficiency, such as infantile onset failure to thrive, hepatosplenomegaly, eruptive xanthomata, lipemia retinalis and chronic progressive pancreatitis. In addition, gene mutations leading to partial LPL deficiency may be common in the population and carriers often present with combined hyperlipidemia and hypercholesterolemia, which would be predicted to increase atherogenic risk. Conventional therapy by diet or lipid-lowering agents is often ineffective. The development of an alternative gene transfer-based therapy to potentiate LPL activity in patients with either complete or partial LPL deficiency would represent a major advance for persons suffering from this disorder. We report the current status of our efforts to develop and test a comprehensive series of vectors and delivery systems for LPL gene transfer and expression in somatic cells in vitro, and ultimately in vivo, in a well-characterized naturally occurring feline model with LPL deficiency.