Management strategy and novel ophthalmological findings in neonatal severe hypertriglyceridemia: a case report and literature review.

BACKGROUND: Neonatal severe hypertriglyceridemia is rarely reported in the literature and there is no consensus for hypertriglyceridemia management at this age group. METHODS: The index case is a 4-week-old male infant with severe hypertriglyceridemia accidentally discovered during a circumcision surgery. His clinical and genetic characteristics and his successful management strategy are described. Furthermore, a detailed ophthalmological examination of the proband was conducted at 3 and 6 months of age using Fourier-domain-optical coherence tomography. RESULTS: Triglycerides level at presentation was extremely high 33,727 mg/dL (380.8 mmol/L). Two sessions of exchange blood transfusion on two consecutive days successfully reduced triglycerides to 382 mg/dL (4.3 mmol/L) with no adverse effects. The infant was discharged 3 days later. At discharge, the mother was advised to continue breastfeeding together with a medium-chain triglycerides formula. Satisfactory growth parameters and lipid profile values were obtained for a follow-up duration of 5 months with no reported attacks of acute pancreatitis. Lipoprotein lipase deficiency was confirmed by the detection of the LPL homozygous pathogenic variant c.805G > A; p.(Glu269Lys). Early corneal and macular lesions were detected and persisted on follow-up despite relatively good lipemic control. CONCLUSION: This case highlights the importance of the early discovery of severe hypertriglyceridemia during the neonatal period, which is needed for prompt management and prevention of severe complications. Rationalized breastfeeding can be tolerated within the diet plan of the disease with satisfactory outcomes. To our knowledge, it is the first study reporting early corneal and macular affection by severe hypertriglyceridemia in a neonate. Prolonged follow-up is needed to determine the extent of ophthalmological lesions.

Familial hypertriglyceridemia: an entity with distinguishable features from other causes of hypertriglyceridemia.

BACKGROUND: Familial hypertriglyceridemia (FHTG) is a partially characterized primary dyslipidemia which is frequently confused with other forms hypertriglyceridemia. The aim of this work is to search for specific features that can help physicians recognize this disease. METHODS: This study included 84 FHTG cases, 728 subjects with common mild-to-moderate hypertriglyceridemia (CHTG) and 609 normotriglyceridemic controls. All subjects underwent genetic, clinical and biochemical assessments. A set of 53 single nucleotide polymorphisms (SNPs) previously associated with triglycerides levels, as well as 37 rare variants within the five main genes associated with hypertriglyceridemia (i.e. LPL, APOC2, APOA5, LMF1 and GPIHBP1) were analyzed. A panel of endocrine regulatory proteins associated with triglycerides homeostasis were compared between the FHTG and CHTG groups. RESULTS: Apolipoprotein B, fibroblast growth factor 21(FGF-21), angiopoietin-like proteins 3 (ANGPTL3) and apolipoprotein A-II concentrations, were independent components of a model to detect FHTG compared with CHTG (AUC 0.948, 95%CI 0.901-0.970, 98.5% sensitivity, 92.2% specificity, P < 0.001). The polygenic set of SNPs, accounted for 1.78% of the variance in triglyceride levels in FHTG and 6.73% in CHTG. CONCLUSIONS: The clinical and genetic differences observed between FHTG and CHTG supports the notion that FHTG is a unique entity, distinguishable from other causes of hypertriglyceridemia by the higher concentrations of insulin, FGF-21, ANGPTL3, apo A-II and lower levels of apo B. We propose the inclusion of these parameters as useful markers for differentiating FHTG from other causes of hypertriglyceridemia.

The Regulatory Role of Nuclear Factor Kappa B in the Heart of Hereditary Hypertriglyceridemic Rat.

Activation of nuclear factor-κB (NF-κB) by increased production of reactive oxygen species (ROS) might induce transcription and expression of different antioxidant enzymes and also of nitric oxide synthase (NOS) isoforms. Thus, we aimed at studying the effect of NF-κB inhibition, caused by JSH-23 (4-methyl-N (1)-(3-phenyl-propyl)-benzene-1,2-diamine) injection, on ROS and NO generation in hereditary hypertriglyceridemic (HTG) rats. 12-week-old, male Wistar and HTG rats were treated with JSH-23 (bolus, 10 µmol, i.v.). After one week, blood pressure (BP), superoxide dismutase (SOD) activity, SOD1, endothelial NOS (eNOS), and NF-κB (p65) protein expressions were higher in the heart of HTG rats compared to control rats. On the other hand, NOS activity was decreased. In HTG rats, JSH-23 treatment increased BP and heart conjugated dienes (CD) concentration (measured as the marker of tissue oxidative damage). Concomitantly, SOD activity together with SOD1 expression was decreased, while NOS activity and eNOS protein expression were increased significantly. In conclusion, NF-κB inhibition in HTG rats led to decreased ROS degradation by SOD followed by increased oxidative damage in the heart and BP elevation. In these conditions, increased NO generation may represent rather a counterregulatory mechanism activated by ROS. Nevertheless, this mechanism was not sufficient enough to compensate BP increase in HTG rats.

Divergent responses of the liver to increased delivery of glucose or fatty acids: implications for the pathogenesis of type IV hyperlipoproteinemia.

This study examines the patterns of response of primary cultures of hamster hepatocytes to increased delivery of glucose or oleate. Increased glucose in the medium produced: (1) increased triglyceride in the cells and the medium; (2) no change in cholesterol ester in the cells or the medium; (3) no change in apo B100 secreted into the medium; (4) more apo B100 particles within the VLDL range with an increase in the VLDL triglyceride to apo B100 ratio. By contrast, increased oleate in the medium resulted in: (1) increased triglyceride in the cells and the medium; (2) increased cholesterol ester in the cells and the medium; and (3) increased apo B100 secreted into the medium. Important differences in the intracellular metabolism of triglyceride and cholesterol ester were also documented. Under all circumstances, there was substantially more radiolabelled triglyceride (overall eight times more) in the cell than in the medium, indicating that up to 90% of the newly synthesized triglyceride enters the cellular pool rather than being secreted with apo B100. By contrast, almost half of the newly synthesized cholesterol ester molecules were secreted with apo B100, pointing to an equal probability of entering the cell storage pool as opposed to being secreted. The data establish therefore two patterns of response of the liver to increased triglyceride synthesis depending on whether the substrate drive is glucose or oleate.

Structural changes in the aorta of the hereditary hypertriglyceridemic rat.

Structural changes in the ascending thoracic aorta of hereditary hypertriglyceridemic (hHTG), insulin-resistant, and hypertensive rats were studied using transmission electron microscopy. Normotensive Wistar rats were used as controls. The most-pronounced morphological changes were observed in the tunica intima. Endothelial cells of hHTG rats formed a continual layer around the whole circumference. Subendothelial space was enlarged. Some endothelial cells were delaminated from the subendothelial space by big lipid droplets that were often present in the subendothelial space, and the endothelial cells bulged out towards the lumen. Big electron-lucent lipid droplets were present in the majority of the endothelial cells and occupied the main part of the cytoplasm. Degenerative microvesicular and membranous material was present in the cytoplasm. Increased numbers of vesicles of Golgi apparatus and cisternae of endoplasmic reticulum were found. Similar morphological alterations, but in less-extended form, were observed in smooth muscle cells. The organization and orientation of smooth muscle cells were essentially intact. In muscle cells, lipid droplets were localized in close relation to Golgi complex and in dilated cisternae of the sarcoplasmic reticulum. Lipid droplets, degenerative material, myelin figures, myelinoid membranes, and vesicular components were also sporadically found in the intercellular space among muscle cells. This pilot morphological investigation provides further arguments for a thorough and more-focused electron microscopy study of conductance arteries of the hHTG rats.

[Successful treatment of eruptive xanthomatosis with the antilipemic agents acipimox]. / Erfolgreiche Behandlung einer eruptiven Xanthomatose mit dem Lipidsenker Acipimox.

A 51-year-old male patient with histologically confirmed eruptive xanthomatosis is presented. Routine and special laboratory examinations showed complex disturbances of carbohydrate and lipid metabolism, the latter taking the form of classic hyperlipoproteinaemia type IV. Combined oral antilipaemic drugs including acipimox (methylpyrazine carboxylic acid analogue of nicotinic acid) and a low-fat diet resulted in regression of the skin symptoms and normalization of the serum lipid levels.

Long-term follow-up of a paediatric case of lipoprotein glomerulopathy.

A paediatric case of lipoprotein glomerulopathy, a new kidney disease characterized by glomerular lipoprotein thrombi, is reported. The patient had massive proteinuria from the age of 8 years, when the nephrotic syndrome was first detected. This was resistant to conventional treatment for more than 10 years. During the course of the disease, the hyperlipidaemia characteristic of hyper-pre-beta-lipoproteinaemia and elevation of apoprotein E persisted, and renal function gradually deteriorated. The renal histopathological findings from four biopsies were essentially the same, with storage of beta-lipoprotein in dilated, balloon-like glomerular capillary lumina. However, the number of glomeruli showing global sclerosis increased and tubulo-interstitial changes progressed in parallel with the gradual clinical deterioration. As in other cases reported in Japan some familial involvement has been noted.

Cell-mediated immune response in patients with type IIa, type IIb and type IV primary hyperlipoproteinaemia.

Plasma lipoproteins inhibit immune function. Polymorphonuclear cell (PMN) and monocyte activities, and pokeweed mitogen (PWM)-driven B cell differentiation in patients with type IIa, type IIb and type IV primary hyperlipoproteinaemia were evaluated. Evidence is provided for a selective impairment of these functional capacities in type IIa and type IIb hyperlipoproteinaemic patients, while immune responsiveness is unaffected in type IV primary hyperlipoproteinaemia. The data suggest a specific immune dysfunction in patients with type IIa and type IIb primary hyperlipoproteinaemia.

Hypertrophy of liver peroxisomes in type II and type IV hyperlipoproteinemia.

A morphometric study on liver biopsies from patients with primary hyperlipoproteinemia (IIa n = 4, IIb n = 7, IV n = 7) and in controls (n = 7) was performed by light and electron microscopy. We found hypertrophy of peroxisomes in all subjects with hyperlipoproteinemia. As none of our patients had been given lipid-lowering drugs, this increase in volume seems to be due to hyperlipoproteinemia. Hypertrophy of peroxisomes in hyperlipoproteinemia may constitute a response of the hepatocyte to a disturbed metabolic state. Alterations of peroxisomes in hyperlipoproteinemia may thus occur prior to any lipid-lowering therapy.

Fenofibrate and human liver. Lack of proliferation of peroxisomes.

In rodents fenofibrate shares with other triglyceride-lowering agents the potential to increase the liver peroxisome population. It was therefore of interest to look for this effect in hyperlipoproteinemic patients receiving this drug. Light and electron microscopy of liver biopsies from a group of 10 patients treated with fenofibrate and from another group of 15 receiving diet only, show no morphological difference between both groups. In contrast with the rodent data the morphometric study reveals no significant changes in the number (fenofibrate group: 7.96 10(10) cm-3; group receiving diet alone: 8.41 10(10) peroxisomes/cm3 of liver tissue) or in the size (fenofibrate group: Diameter = 0.53 +/- 0.07 micrometer--group receiving diet alone: 0.50 +/- 0.06) of peroxisomes. The difference between our results and those obtained consistently in rodents may be due to the relatively low dose in man and/or a species-dependent difference in enzyme content of liver peroxisomes, itself related to an apparent difference in the way in which lipids are handled.

The liver and primary type IV hyperlipoproteinaemia: a pathological study.

We studied the histological structure of the livers of 36 patients presenting type IV primary hyperlipoproteinaemia. Electron microscopy revealed dilation of the smooth endoplasmic reticulum and rough endoplasmic reticulum as well as the presence of giant mitochondria containing para-crystalline inclusions. Steatosis was present in all type IV hyperlipoproteinaemic patients regardless of their weight or nutritional sensitivity (to alcohol or carbohydrate). The ultrastructural modifications observed by electron microscopy indicate an increased synthesis of very-low-density lipoproteins by the hepatocytes. An alteration in excretion cannot be ruled out with certainty even though the microfilamentary microtubular system was intact, since the qualitative and functional modifications in this system may be undetectable by electron microscopy.

A case of xanthoma tendinosum associated with Fredrickson's type 4 hyperlipoproteinaemia.

Primary xanthoma tendinosum is a very rare condition. The cases so far reported in the literature (200) have been standardised and linked to Fredrickson's type 2 or type 3 hyperlipoproteinaemia. The case reported here, however, is allied to Fredrickson's type 4 hyperlipoproteinaemia.

Retinal vascular abnormalities in the hyperlipidaemias.

Previous studies have suggested an association between hyperlipidaemia and retinal venous and arterial occlusion. To investigate this association further, the retinal arterial vasculature was studied by fluorescein angiography in forty hyperlipidaemic subjects, and clinical examination and biochemical investigations, including lipid profile, were performed in 99 patients with retinal vein occlusion and forty patients without retinal vein occlusion as a comparison group. Retinal arterial abnormalities were found on fluorescein angiography in eight patients with combined hypercholesterolaemia and hypertriglyceridaemia (type IV and V hyperlipidaemia). However no abnormalities were found in patients with familial hypercholesterolaemia (type II). Fluorescein angiography was repeated after 6 months hypolipidaemic therapy in four of the patients with retinal arterial abnormalities. Progression of retinal vascular closure was observed in two patients with poor hyperlipidaemic control and improvement in two other patients with good hyperlipidaemic control. There was a significantly higher incidence of hyperlipidaemia (P less than 0.001) and glucose intolerance (P less than 0.05) in the retinal vein occlusion group when compared to the control group, and a higher incidence of hypertension in patients with either central or branch retinal vein occlusion than in the normal population. We conclude that retinal arterial abnormalities occur in type IV and V hyperlipidaemias and that both central and branch retinal vein occlusion are associated with similar risk factors to large vessel disease.

Ultrastructural aspects of normolipidemic xanthomatosis.

Electron microscopic aspects in ten cases of normolipidemic cutaneous xanthomatosis have been investigated. Two additional types IV and V hyperlipoproteinaemic xanthomatosis have also been included. Ultrastructural findings in all cases were similar. Abundant histiocytic cells with numerous intracytoplasmic lipid vacuoles, lysosomes, and myelin-figures, were the striking features. Moreover, in older lesions microfilaments and lipid vacuoles were found in some fibroblastic cells, as well as long space collagen around them. In some specimens we observed: giant multinucleated histiocytic cells, crystalline cleft-like spaces in histiocytes and some mastocytes with lipidic crystals in the extracellular space, as well as lipid vacuoles in Schwann cells, endothelial cells and pericytes. Rod-shaped tubulated bodies were found in some endothelial cells, with multiple basal vascular laminae. In xantelasma palpebrarum and in disseminate plane xanthoma the histiocytary foamy cells adopted a perivascular arrangement, as in hyperlipoproteinemic xanthomatosis. We concluded that ultrastructural aspects of different xanthomatosis are fairly similar as a consequence of the large amount of intracytoplasmic lipids accumulated in xanthomatosus cells. In xanthelasma palpebrarum and in disseminated plane xanthoma this cell phase is reached by similar pathways to those for hyperlipoproteinemic xanthomatosis, whilst in xanthoma disseminatum and juvenile xanthogranuloma the pathways seem to be different. A classification of normolipidemic xanthomatosis is also provided.