Severe Hyperlipidemia Research Articles

Asparaginase-associated concurrence of hyperlipidemia, hyperglobulinemia, and thrombocytosis was successfully treated by centrifuge/membrane hybrid double-filtration plasmapheresis

Asparaginase-associated concurrence of hyperlipidemia, hyperglobulinemia, and thrombocytosis is a rare complication requiring aggressive lipoprotein apheresis, but no one of currently available lipoprotein apheresis methods can simultaneously resolve the 3 abnormalities. Herein, we reported a construction of double-filtration plasmapheresis (DFPP) using a combination of centrifugal/membranous plasma separation techniques to successfully treat a patient with hyperlipidemia, hyperglobulinemia, and thrombocytosis. A male presented with severe hyperlipidemia, hyperglobulinemia, and thrombocytosis during asparaginase treatment for NK/T-cell lymphoblastic lymphoma and was scheduled to receive lipoprotein apheresis. To simultaneously remove lipoproteins, immunoglobulin, and deplete platelets from blood, a centrifuge/membrane hybrid DFPP was constructed as following steps: plasma and part of platelets were separated first from whole blood by centrifugal technique and then divided by a fraction plasma separator into 2 parts: platelets and plasma components with large size, which were discarded; and those containing albumin, which were returned to blood with a supplement of extrinsic albumin solution. DFPP lasted 240 minutes uneventfully, processing 5450-mL plasma. The concentrations of plasma components before DFPP were as follows: triglycerides 38.22 mmol/L, total cholesterols 22.98 mmol/L, immunoglobulin A (IgA) 15.7 g/L, IgG 12.7 g/L, and IgM 14.3 g/L; whereas after treatment were 5.69 mmol/L, 2.38 mmol/L, 2.5 g/L, 7.7 g/L, and 0.4 g/L, respectively. The respective reduction ratio was 85.1%, 89.6%, 83.9%, 39.4%, and 96.9%. Platelet count decreased by 40.4% (from 612 × 109/L to 365 × 109/L). Centrifuge/membrane hybrid DFPP can simultaneously remove lipoproteins, immunoglobulin, and deplete platelets, with a success in treatment of asparaginase treatment-induced hyperlipidemia, hyperglobulinemia, and thrombocytosis, and may be useful for patients requiring DFPP but with particular situations.

Abstract 547: A Novel Abetalipoproteinemia Missense Mutation Highlights the Importance of N-terminal β-barrel in Microsomal Triglyceride Transfer Protein Function

Background: The use of microsomal triglyceride transfer protein (MTP) inhibitors is limited to severe hyperlipidemias due to associated hepatosteatosis. Comprehensive knowledge about the structure-function of MTP might help design new molecules that avoid steatosis. Characterization of mutations in MTP causing abetalipoproteinemia (ABL) have revealed that the central α-helical and C-terminal β-sheet domains are important for protein disulfide isomerase (PDI) binding and lipid transfer activity. Our aim was to identify and characterize ABL mutations in the N-terminal region to understand the function of this domain. Methods and Results: We identified a novel missense mutation (D169V) in a 4-month old Turkish male with severe signs of ABL. To study the effect of this mutation on MTP function, we created mutants via site directed mutagenesis. Although D169V was expressed in the endoplasmic reticulum and interacted with apoB17, it was unable to bind PDI, transfer lipids, and support apoB secretion. Computational modeling suggested that D169 could form an internal salt bridge with K187 and K189. Mutagenesis of these lysines to leucines abolished PDI heterodimerization, lipid transfer, and apoB secretion, without affecting apoB binding. Further, mutants with preserved charges (D169E, K187R, K189R) rescued these activities. Conclusions: D169V is detrimental because it disrupts an internal salt bridge leading to loss of PDI binding and lipid transfer activities; however, it does not affect apoB-binding. We propose that future inhibitors should avoid this region of the N-terminal domain.

Green tea polyphenol epigallocatechin-3-gallate ameliorates insulin resistance in non-alcoholic fatty liver disease mice.

Epigallocatechin-3-gallate (EGCG) is a major polyphenol in green tea. In this study, we investigated the effects of EGCG on insulin resistance and insulin clearance in non-alcoholic fatty liver disease (NAFLD) mice. Mice were fed on a high-fat diet for 24 weeks. During the last 4 weeks, the mice were injected with EGCG (10, 20 and 40 mg·kg(-1)·d(-1), ip). Glucose tolerance, insulin tolerance and insulin clearance were assessed. After the mice were euthanized, blood samples and tissue specimens were collected. Glucose-stimulated insulin secretion was examined in isolated pancreatic islets. The progression of NAFLD was evaluated histologically and by measuring lipid contents. Insulin-degrading enzyme (IDE) protein expression and enzyme activity were detected using Western blot and immunocapture activity assays, respectively. The high-fat diet significantly increased the body weight and induced grade 2 or 3 liver fatty degeneration (steatosis, lobular inflammation and ballooning) accompanied by severe hyperlipidemia, hyperglycemia, hyperinsulinemia and insulin resistance in the model mice. Administration of EGCG dose-dependently ameliorated the hepatic morphology and function, reduced the body weight, and alleviated hyperlipidemia, hyperglycemia, hyperinsulinemia and insulin resistance in NAFLD mice. Furthermore, EGCG dose-dependently enhanced insulin clearance and upregulated IDE protein expression and enzyme activity in the liver of NAFLD mice. EGCG dose-dependently improves insulin resistance in NAFLD mice not only by reducing body weight but also through enhancing the insulin clearance by hepatic IDE. The results suggest that IDE be a potential drug target for the treatment of NAFLD.

Lipodystrophies: adipose tissue disorders with severe metabolic implications.

Lipodystrophy encompass a group of heterogeneous disorders consisting in marked reduction, absence, and/or the redistribution of adipose tissue. Lipodystrophy is frequently complicated with severe insulin resistance, diabetes, hyperlipidemia, and fatty liver. Anatomically, lipodystrophies can be partial or generalized. Etiologically, they can be congenital or acquired. Lipodystrophy diagnosis can be challenging, and it has been suggested that partial forms can be easily misdiagnosed as common central obesity with associated metabolic syndrome. Conventional insulin-sensitizing approaches usually fail to fully ameliorate insulin resistance in lipodystrophic patients. Leptin replacement is an approved therapy for the metabolic complications of congenital generalized lipodystrophy. Novel nutritional interventions are promising complementary approaches for treating lipodystrophy metabolic complications.

Skin lesions in the form of eruptive xanthomasas a first manifestation of severe hyperlipidemia complicated by acute pancreatitis in a patient with newly diagnosed type 2 diabetes

Skin lesions in the form of eruptive xanthomasas a first manifestation of severe hyperlipidemia complicated by acute pancreatitis in a patient with newly diagnosed type 2 diabetes

Hyperlipidemia and statins affect neurological outcome in lumbar spine injury.

The disabling pathophysiologic effects of lipid and neuroprotective effects of statins have recently been demonstrated for acute spinal cord injuries in animal models. This large scale population-based study aimed to investigate the effect hyperlipidemia and the use of statins in patients with lumbar spine injury. The National Health Insurance Research Database of Taiwan was used to identify patients with lumbar spine injury. A total of 2844 patients were grouped into three: no hyperlipidemia, hyperlipidemia using low-dose of statins (≤90 of the defined daily dosage (DDD)), and severe hyperlipidemia using high-dose of statins (>90 DDD). A Cox multiple regression model was used to compare the incidence rates of disability among the three groups. The results showed that patients with hyperlipidemia appeared a higher risk of permanent disability (adjusted HR = 1.38, p = 0.28). In subgroup analysis, patients with severe hyperlipidemia had a higher risk of disability (adjusted HR = 3.1, p < 0.004), whereas hyperlipidemia using low-dose statins had a similar risk of permanently disability (adjusted HR = 0.83, p = 0.661). Hyperlipidemia adversely affected the neurological outcomes of lumbar spinal injury. Statins may have the potential to reverse this higher risk of disability. However, this beneficiary effect of statins only existed in patients using a lower dose (≤90 DDD).

Human apolipoprotein B transgenic SHR/NDmcr-cp rats show exacerbated kidney dysfunction.

Nephropathy frequently co-occurs with metabolic syndrome in humans. Metabolic syndrome is a cluster of metabolic diseases including obesity, diabetes, hypertension, and dyslipidemia, and some previous studies revealed that dyslipidemia contributes to the progression of kidney dysfunction. To establish a new nephropathy model with metabolic syndrome, we produced human apolipoprotein B (apoB) transgenic (Tg.) SHR/NDmcr-cp (SHR-cp/cp) rats, in which dyslipidemia is exacerbated more than in an established metabolic syndrome model, SHR-cp/cp rats. Human apoB Tg. SHR-cp/cp rats showed obesity, hyperinsulinemia, hypertension, and severe hyperlipidemia. They also exhibited exacerbated early-onset proteinuria, accompanied by increased kidney injury and increased oxidative and inflammatory markers. Histological analyses revealed the characteristic features of human apoB Tg. SHR-cp/cp rats including prominent glomerulosclerosis with lipid accumulation. Our newly established human apoB Tg. SHR-cp/cp rat could be a useful model for the nephropathy in metabolic syndrome and for understanding the interaction between dyslipidemia and renal dysfunction in metabolic syndrome.

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Objectives Alterations in lipoprotein metabolism have been proposed as a possible pathophysiologic factor for preeclampsia. Elevation of very low density lipoproteins (VLDL) and predominance of atherogenic small dense low density lipoproteins (sdLDL) have been demonstrated in preeclampsia. Heparin-mediated-extracorporeal-LDL-precipitation (H.E.L.P.)-apheresis is an established method for lipoprotein removal and regeneration of endothelial function in severe hyperlipidemia. Wang et al. (2006) successfully used H.E.L.P.-apheresis in a pilot study to prolong preeclamptic pregnancies. We investigated alterations in the lipidprofile and the effects of H.E.L.P.-apheresis in the prolongation of hypertensive pregnancies. Methods Six patients with early pregnancy complicated by hypertension were treated with H.E.L.P.-apheresis. Blood was collected before and after apheresis and subjected to ultracentrifugation for determination of lipid parameters. Results A total of 23 apheresis treatments (2–6 per patient) were performed without severe complications. Within apoB-containing lipoproteins, VLDL (−58%) and sdLDL (L5: −65% and L6: −68%) were removed at highest proportion. Cholesterol was reduced by 32% and triglycerides by 44%. Soluble fms-like tyrosine kinase-1 (sFlt-1) and placenta-growth-factor (PlGF) were not removed by H.E.L.P. Pregnancies continued for 4–14 days and lung maturation was successfully initiated before termination of pregnancy by caesarean section. Conclusions H.E.L.P.-apheresis appears to preferentially address atherogenic lipoproteins, relevant to preeclampsia. Disclosures C. Contini: None. B. Konig: None. F. Markfeld-Erol: None. M. Kunze: None. S. Zschiedrich: None. H. Prompeler: None. G. Putz: None. K. Winkler: Commercial Interest: BBraun Melsungen AG provided the H.E.L.P.-system; Research Support: BBraun Melsungen AG; Speaker: BBraun Melsungen AG.

Adiponectin is essential for lipid homeostasis and survival under insulin deficiency and promotes β-cell regeneration.

As an adipokine in circulation, adiponectin has been extensively studied for its beneficial metabolic effects. While many important functions have been attributed to adiponectin under high-fat diet conditions, little is known about its essential role under regular chow. Employing a mouse model with inducible, acute β-cell ablation, we uncovered an essential role of adiponectin under insulinopenic conditions to maintain minimal lipid homeostasis. When insulin levels are marginal, adiponectin is critical for insulin signaling, endocytosis, and lipid uptake in subcutaneous white adipose tissue. In the absence of both insulin and adiponectin, severe lipoatrophy and hyperlipidemia lead to lethality. In contrast, elevated adiponectin levels improve systemic lipid metabolism in the near absence of insulin. Moreover, adiponectin is sufficient to mitigate local lipotoxicity in pancreatic islets, and it promotes reconstitution of β-cell mass, eventually reinstating glycemic control. We uncovered an essential new role for adiponectin, with major implications for type 1 diabetes.

Vitamin D Repletion Needed for Resolution of Steatohepatitis

Introduction: Bile acid (BA) activation of the farnesoid X receptor inhibits small heterodimer protein (SHP) decreasing BA synthesis from cholesterol and promoting choleresis. Vitamin D (vit D) also inhibits SHP, thus also lowering serum cholesterol (CHOL) and serum BAs. An association between 25-OH vit D deficiency and non-alcoholic fatty liver disease has been reported. A 44-year-old African man with a history of, obesity, hypertension, and hyperlipidemia presented for the evaluation of jaundice. Three years prior, the patient presented similarly after an alcohol binge. Labs revealed a severe cholestatic hepatitis and hyperlipidemia (Table). Twenty-five vit D levels were undetectable, PTH was 9 times normal, and 1-25 vit D was low. Alcohol levels were zero. Liver biopsy showed moderate acute and chronic steatohepatitis, diffuse cholestasis, and focal necrosis. Abstinence was advised and oral vit D and calcium supplements were given. Bilirubin normalized within 1 month, but alkaline phosphatase (ALK) remained elevated. Oral vit D was continued. The patient was lost to follow-up for 2 years. He returned, again complaining of jaundice, abdominal pain, and nausea after several days of drinking. Blood alcohol level was zero. On exam, the patient was obese, very dark-skinned, and icteric. There were no stigmata of chronic liver disease. Labs revealed a severe cholestatic hepatitis (Table T=0). Total CHOL was >1,000 and PTH was 339. Liver biopsy showed moderate to severe macro and microvesicular steatosis, with mild steatohepatitis and cholestasis. Ursodiol and budesonide were started to induce choleresis. Another course of ergocalciferol was given to replete his vit D. By month 5, BILI and ALT had normalized. ALK remained slightly elevated. PTH was now normal at 56.9. Total 25-OH vit D was also normal at 61. Repeat liver biopsy revealed minimal to no steatosis, minimal pericellular fibrosis, and mild chronic steatohepatitis. We believe that our patient had alcoholic steatohepatitis superimposed on NASH. Our patient had severe vit D deficiency. Choleresis and mobilization of hepatic fat was aided by total body vit D repletion, as indicated by normalized PTH levels. Serial liver biopsies confirmed improvement of severe steatohepatitis.Table 1

Bexarotene-Induced Dyslipidemia and Central Hypothyroidism in a Patient With Sezary Syndrome

We report a patient with Se zary syndrome ( cutaneous T-cell lymphoma) who developed severe central hypothyroidism and mixed hyperlipidemia due to the bexarotene treatment (a synthetic retinoid analog with specific affinity for retinoid X receptor used in the treatment of Sezary syndrome). The other pituitary functions were found to be normal. These are rare adverse effects of bexarotene treatment and there are a few case reports in literature. Management of the adverse events could be done by nicotinic acid or f e nofibrates, statins and L-thyroxin replacement. In this case we managed the patient by nicotinic acid , statin and L-thyroxin for 2 years. J Endocrinol Metab. 2014;4(4):115-117 doi: http://dx.doi.org/10.14740/jem222w

Neonatal Glycogen Storage Disease Ia

Glycogen storage disease Ia (GSD Ia) is an autosomal recessive inborn error of carbohydrate metabolism that is caused by a deficiency of the enzyme glucose-6-phosphatase, leading to disturbed glycogenolysis and gluconeogenesis. Patients with GSD Ia are dependent on supplementary exogenous sources of glucose and suffer severe fasting hypoglycemia, lactic acidosis, hyperuricemia, and hyperlipidemia. The primary objective in treatment is to prevent hypoglycemia either by frequent meals, consumption of uncooked cornstarch, continuous gastric drip feeding, or glucose infusion.

Quetiapine-Induced Hyperglycemic Crisis and Severe Hyperlipidemia: A Case Report and Review of the Literature

Quetiapine, dispensed as Seroquel, has become 1 of the 100 most commonly prescribed medications in the United States in the past 10 years. It has fewer extrapyramidal side effects than first-generation antipsychotics, but it has been associated with low to moderate weight gain, hyperlipidemia/hypercholesterolemia, and new-onset diabetes, with half of these cases manifesting as diabetic ketoacidosis (DKA). We present a case of a middle-aged man who developed diabetes mellitus (DM) manifesting as hyperglycemic crisis and severe reversible hyperlipidemia. Literature on antipsychotic-associated metabolic adverse effects and clinical recommendations is presented.

Methyl Substitution of a Rexinoid Agonist Improves Potency and Reveals Site of Lipid Toxicity

(2E,4E,6Z,8E)-8-(3′,4′-Dihydro-1′(2′H)-naphthalen-1′-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid, 9cUAB30, is a selective rexinoid that displays substantial chemopreventive capacity with little toxicity. 4-Methyl-UAB30, an analogue of 9cUAB30, is a potent RXR agonist but caused increased lipid biosynthesis unlike 9cUAB30. To evaluate how methyl substitution influenced potency and lipid biosynthesis, we synthesized four 9cUAB30 homologues with methyl substitutions at the 5-, 6-, 7-, or 8-position of the tetralone ring. The syntheses and biological evaluations of these new analogues are reported here along with the X-ray crystal structures of each homologue bound to the ligand binding domain of hRXRα. We demonstrate that each homologue of 9cUAB30 is a more potent agonist, but only the 7-methyl-9cUAB30 caused severe hyperlipidemia in rats. On the basis of the X-ray crystal structures of these new rexinoids and bexarotene (Targretin) bound to hRXRα-LBD, we reveal that each rexinoid, which induced hyperlipidemia, had methyl groups that interacted with helix 7 residues of the LBD.

Emerging Therapeutic Approaches to Treat Dyslipidemia

Statins are safe, efficacious and the cornerstone of cardiovascular disease prevention strategies. A number of add-on therapies with complementary actions on the plasma lipid profile have been tested in large scale trials to see if they give incremental benefit. In particular, the 'HDL hypothesis' - that raising this lipoprotein will promote reverse cholesterol transport and reduce cardiovascular risk - has been examined using drugs such as dalcetrapib and niacin. So far, results have been negative, and this has raised questions over the nature of the association of HDL with atherosclerosis, and whether statins reduce cardiovascular risk through multiple mechanisms. There is still an unmet clinical need especially in those patients who cannot tolerate statins and those with severe hyperlipidemia, and so new therapeutic approaches have been developed. These show significant promise in terms of LDL-cholesterol lowering but significant challenges include cost, route of administration (subcutaneous injection) and side effects. Testing in major outcome trials will be required to demonstrate their clinical utility.

Remission of generalized erythematous granuloma annulare after improvement of hyperlipidemia and review of the Japanese literature

Granuloma annulare has been associated with systemic disease including diabetes mellitus. We report a case of a 62-year-old Japanese woman with generalized erythematous granuloma annulare who showed remission after substantial improvement in hyperlipidemia following a strict lipid-lowering diet. The lesion appeared in the lower abdomen one year before current presentation and subsequently spread to other areas of the trunk despite treatment with topical steroid and oral epinastine hydrochloride. Physical examination showed a well-demarcated erythematous plaque measuring 10 cm in diameter with fine scales on the left abdomen, and slightly indurated pinkish plaques of up to 5 cm in diameter on the right side of the abdomen and axillae. Clinical laboratory tests showed mild glucose intolerance (HbA1c 6.2%), mild liver dysfunction (AST: 86 IU/L, ALT: 76 IU/l), slight hypercholesterolemia (total cholesterol: 235 mg/dl), and severe hyperlipidemia (triglyceride: 962 mg/ml). Histopathological examination of the lesions showed homogenization of collagen fibers and granulomatous infiltrates between fibers in the upper and middle dermis. A diagnosis of generalized erythematous granuloma annulare was established based on the clinical and histopathological findings, especially with the distribution on more than one anatomic site. A lipid-lowering diet for three months resulted in major improvement of hyperlipidemia and remission of the skin lesions.A review of generalized erythematous granuloma annulare in the Japanese literature indicated a well-known association of granuloma annulare with diabetes mellitus, however, the relation with hyperlipidemia was described only recently. This case suggests a possible relationship between granuloma annulare and hyperlipidemia, with possible improvement of granuloma annulare with a lipid-lowering diet.

Usefulness of lipid apheresis in the treatment of familial hypercholesterolemia.

Lipid apheresis is used to treat patients with severe hyperlipidemia by reducing low-density lipoprotein cholesterol (LDL-C). This study examines the effect of apheresis on the lipid panel and cardiac event rates before and after apheresis. An electronic health record screen of ambulatory patients identified 11 active patients undergoing lipid apheresis with 10/11 carrying a diagnosis of FH. Baseline demographics, pre- and postapheresis lipid levels, highest recorded LDL-C, cardiac events, current medications, and first apheresis treatment were recorded. Patients completed a questionnaire and self-reported risk factors and interest in alternative treatment. There were significant reductions in mean total cholesterol (−58.4%), LDL-C (−71.9%), triglycerides (−51%), high-density lipoprotein (HDL) cholesterol (−9.3%), and non-HDL (−68.2%) values. Thirty-four cardiac events were documented in 8 patients before apheresis, compared with 9 events in 5 patients after apheresis. Our survey showed a high prevalence of statin intolerance (64%), with the majority (90%) of participants indicating an interest in alternative treatment options. Our results have shown that lipid apheresis primary effect is a marked reduction in LDL-C cholesterol levels and may reduce the recurrence of cardiac events. Apheresis should be compared to the newer alternative treatment modalities in a randomized fashion due to patient interest in alternative options.

Bexarotene-Induced Dyslipidemia and Central Hypothyroidism in a Patient With Sezary Syndrome

We report a patient with Se zary syndrome ( cutaneous T-cell lymphoma) who developed severe central hypothyroidism and mixed hyperlipidemia due to the bexarotene treatment (a synthetic retinoid analog with specific affinity for retinoid X receptor used in the treatment of Sezary syndrome). The other pituitary functions were found to be normal. These are rare adverse effects of bexarotene treatment and there are a few case reports in literature. Management of the adverse events could be done by nicotinic acid or f e nofibrates, statins and L-thyroxin replacement. In this case we managed the patient by nicotinic acid , statin and L-thyroxin for 2 years. J Endocrinol Metab. 2014;4(4):115-117 doi: http://dx.doi.org/10.14740/jem222w

Skin lesions in the form of eruptive xanthomasas - a first manifestation of severe hyperlipidaemia

The presence of eruptive xanthomas is associated with lipid disorders, particularly hypertriglyceridaemia. Intensified hypertriglyceridaemia >10 mmol/l (880 mg%) is a major risk factor for acute pancreatitis. The presented case concerns a 40-year-old man with skin lesions in the form of eruptive xanthomas, accompanied by hypertriglyceridaemiae, complicated by acute pancreatitis, and diagnosed with type 2 diabetes with glycated haemoglobin 9.7 g/dl. Seeding of skin lesions appeared 2–3 months before hospitalization and was observed in the direction of molluscum contagiosum.

Significance of Histological Crescent Formation in Patients with Diffuse Proliferative Lupus Nephritis

Background: Although crescentic nephritis is not rare in diffuse proliferative lupus nephritis (DPLN), little is known about the clinicopathological features in DPLN with crescents worldwide. This study was undertaken to investigate the clinicopathological features and outcome of Chinese DPLN patients with different degrees of crescents. Methods: 520 DPLN patients with more than 10% histological crescents (cDPLN) were enrolled in this retrospective study. They were divided into three groups: group 1 (10%≤ crescents <25%, n = 240), group 2 (25%≤ crescents <50%, n = 160), and group 3 (crescents ≥50%, n = 120). Another 100 patients without histological crescents were enrolled as a control group. Clinicopathological features, treatment responses, and outcomes were compared among the four groups. Results: There were 450 (86.6%) females and 70 (13.4%) males with an average age of 31.7 ± 11.4 years. Compared with the control group, cDPLN patients had shorter lupus nephritis duration (20.7 ± 34.1 vs. 30.4 ± 48.9 months), higher prevalence of rapidly progressive glomerulonephritis syndrome (21.8%), and gross hematuria (26.7%). Laboratory findings indicated more severe hypoproteinemia, hyperlipidemia, and renal insufficiency; heavier proteinuria and microscopic hematuria; higher tubular injury parameters, and lower serological activity in crescentic groups. Histologically, cDPLN patients have severe glomerular and tubulointerstitial lesions as well as extensive leukocyte infiltration together with a lesser degree of immune complex deposition. The proportion of death, end-stage renal disease, and treatment failure correlates positively with the degree of histological crescents. Conclusions: cDPLN patients with acute onset and short disease duration mostly show severe renal manifestations, less extrarenal organ involvement, lower serological activity, serious capillary necrosis, severe tubulointerstitial inflammation, atrophy and fibrosis, prominent leukocyte infiltration, less glomerular immune complex deposition, poor treatment response, and worse renal outcome.