Low Fasting Serum Triglyceride Level as a Precocious Marker of Autoimmune Disorders

Silvia Iannello, MD, Antonina Cavaleri, MD, Paolina Milazzo, MD, Santi Cantarella, MD, Francesco Belfiore, MD

Disclosures

Medscape General Medicine. 2003;5(3) 

In This Article

Discussion

Previous data suggest an unexpected association between fasting low TG (and high FFA levels) and chronic interstitial lung disease or pulmonary fibrosis.[1] The data in this paper confirm a link between decreased TG levels and some other autoimmune diseases or allergic hyperreactivity syndromes. TG were found to be also low in patients with autoimmunity, who were also obese, when compared with the obese subjects without autoimmune disorder.

These data seem to be in contrast with epidemiologic studies showing that the Greenland population has low TG (perhaps as a result of high dietary intake of polyunsaturated fatty acids or PUFA n-3) and a low incidence of some chronic diseases, including some immune disorders such as thyrotoxicosis, bronchial asthma, multiple sclerosis, and psoriasis, in comparison with western European populations.[5]

The available data from literature concerning the relationships between TG or FFA and some different autoimmune or dysreactive disorders are summarized and discussed below.

(a) Concerning chronic autoimmune thyroiditis and (b) chronicthyreopathies without autoantibodies, plasma TG metabolism is very well known with reference to the advanced states of thyroid disease, when functional failure is well developed.[6] The reported changes include primarily a significant increase in cholesterol levels in the most severely hypothyroid patients as well as a graded increase in mean serum TG as thyroid failure increases.[7] The data in this paper seem to be the first observation of a TG decrease in the early stage of chronic autoimmune thyroiditis, before the appearance of thyroid failure.

(c) Concerning chronic active B or C hepatitis (in the initial stage, before the appearance of liver failure or cholestasis), available data are scanty. In a Japanese study,[8] among 4256 visitors to a Tokyo Health Control Center for their health examination, 463 asymptomatic subjects (11%) showed abnormal liver function including elevation of ALT value. Ultrasonography and HCV antibody measurement had been applied to 362 cases in order to screen the etiology of liver dysfunction. HCV antibody-positive hepatitis showed high levels of total protein, aminotransferases, and low levels of TG as well as of albumin, A/G, total cholesterol, gamma-GT, and cholinesterase.

(d) Concerning lupus-like syndrome and (e) SLE or rheumatoid arthritis, numerous literature data are available, some confirming results in this paper, others opposite. Data in this study seem to be confirmed in 2 clinical studies by Svenson and coworkers[9,10] and in a research study by Lakatos and Harsagyi.[11] In the former study, Svenson[9] prospectively analyzed serum lipids and lipoprotein patterns of 33 patients with active chronic inflammatory arthritides. Before any treatment, low TG concentration (both in very-low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) cholesterols) was found. In the other study by Svenson,[10] in 48 patients with untreated active rheumatoid arthritis, TG levels in VLDL and HDL were reduced by 10% to 30% and significantly correlated with inflammatory activity (C-protein reactivity [CPR]). The authors suggest that it is the degree of inflammatory activity that governs the altered lipoprotein metabolism in untreated active chronic inflammatory arthritides.[10] The relationships between CPR and VLDL indicate that the VLDL particles may be altered by the inflammatory process, and that the increased elimination may take place through the "scavenger pathway".[10] In patients with rheumatoid arthritis (26 men and 103 women), compared with TG values observed in controls (625 men and 749 women), Lakatos and Harsagyi[11] reported low TG level (with high LDL and low HDL cholesterol). This lipid pattern did not change when the patients were treated with steroidal or nonsteroidal anti-inflammatory drugs.

Other data, however, are at variance with results in this paper. In fact, increased TG levels were reported in patients with SLE (who had also depressed HDL and elevated VLDL cholesterol).[12,13] Ettinger and coworkers[14] also found high TG levels in 46 female patients with SLE. Elevated TG levels were suggested to result from the presence of autoantibodies to LPL (which occurred in 47% of SLE patients and in a similar percentage of patients with polymyositis or systemic sclerosis).[15] More recently, elevated TG levels (and other lipid abnormalities) were observed in 53 premenopausal (mean 34.5 years old) SLE patients and 45 controls; TG, as well as total cholesterol and LDL-cholesterol, were significantly correlated with proteinuria.[16] The authors concluded that proteinuria is a good predictor of dyslipoproteinemia in these patients.

The above observations on SLE and rheumatoid arthritis indicate that both high and low TG levels have been observed. These apparent contrasting findings could perhaps be explained by hypothesizing a different behavior of TG during the course of these disease, with low TG levels in the early stages and high TG levels in the advanced stages. This is supported by the very low TG level reported in the early stage (ninth day) of adjuvant-induced arthritis in rats.[17] It could be hypothesized that the development of SLE and rheumatoid arthritis (and perhaps other autoimmune diseases) is associated with a reduction in TG level, and that in the advanced stages of these diseases, appearance of antibodies toward LPL (which results in reduced TG clearance) and of proteinuria (which induces increased hepatic lipoprotein synthesis) is associated with an increase in TG levels.

(f) Concerning anamnestic allergy or atopic dermatitis/asthma, no data on the behavior of TG and FFA levels are available. The only finding marginally related to this study is the observation that in prepubertal and pubertal atopic patients, the proportions of linoleic acid in total plasma lipids and phospholipids were significantly increased and those of oleic acid reduced.[18] The n-3/n-6 fatty acid ratio of the TG fraction was also lower in atopic patients.[18] In these subjects, however, no significant decreases in the proportions of dihomo-gamma-linolenic acid and arachidonic acid were observed in plasma lipids, suggesting that delta-6-desaturase activity was not impaired in the atopic subjects.[18] This observation in atopia provides a good explanation for the beneficial effects of raising the n-3/n-6 ratio of dietary oils for suppressing allergic hyperreactivity or inflammatory process and repairing chronic fibrosing mechanisms in humans.

(g) With regard to other autoimmune diseases (scleroderma, APECED, urticaria or urticarial vasculitis, Reiter or Sjogren syndromes, ulcerative proctocolitis or Crohn's disease, and chronic multiple sclerosis or Guillain-Barré syndrome), only data concerning Sjogren disease are available. In 41 patients with primary Sjogren syndrome, docosahexaenoic acid was the EFA whose levels correlated (inversely) most closely with the clinical disease status.[19] Moreover, sigma n-3 EFA/sigma n-6 EFA ratios correlated significantly to the quantitative estimates of immunopathologic and clinical disease status.[19] These data are in agreement with current understanding of pro- and anti-immunoinflammatory roles of EFA.[19]

Concerning low TG level and autoimmunity, interesting data are reported in autoimmune diabetes. It is noteworthy that autoantibodies to glutamic acid decarboxylase (GAD) are considered the most useful marker for autoimmune diabetes.[20,21] GAD levels and their relationships with clinical features and pancreatic beta-cell function were studied in 140 young Chinese type 1 diabetic patients.[22] Patients who had antibodies to GAD had lower plasma TG and higher concentrations of plasma HDL-cholesterol as well as lower BMI and blood pressure.[22] In a large study on latent autoimmune diabetes in adults performed in western Finland, the prevalence of GAD was 9.3% among 1122 type 2 diabetic patients, 3.6% among 558 impaired glucose tolerance subjects, and 4.4% among 383 nondiabetic control subjects.[23] The GAD-positive patients (compared with GAD-negative subjects) had lower TG concentrations (1.40 ± 1.18 vs 1.75 /- 1.25 mmol/L, P = .003) as well as lower fasting C-peptide concentrations, insulin response to oral glucose, and blood pressure values.[23]

Possible role of polyunsaturated fatty acids (PUFA). Based on the observation of the low prevalence of lung disease among Greenland Eskimos as result of their diet high in PUFA, a protective role of the PUFA n-3 in lung disease is reported in an extensive review by Schwartz.[24] Incorporation of PUFA n-3 into lipid membranes lowers the production of inflammatory eicosanoids (a) through competition with arachidonic acid as a constituent of lipid membranes, (b) through competition with arachidonic acid as a substrate for prostaglandin-endoperoxide synthase (cyclo-oxygenase activity), and (c) through inhibition of the conversion of linolenic acid to arachidonic acid.[25] Gamma-linolenic acid has similar effects.[24] When PUFA n-3 are the substrate of the cyclo-oxygenase pathway (instead of arachidonic acid), they may modulate inflammatory activity, reducing leukotriene B4, which is a proinflammatory mediator responsible for production of eicosanoids and neutrophil recruitment.[24] Some data reported from the lung would suggest that inflammatory cells (neutrophils and macrophages) might affect TG metabolism. These cells contain much more arachidonic acid, which is accumulated in a large quantity into a TG pool.[26] The accumulation of arachidonic acid into TG could be a marker of cell activation, suggesting a central role of the TG pool in arachidonic acid metabolism of activated inflammatory cells.[26] Probably, in human inflammatory cells, TG is not only a storage site for arachidonic acid, but may also be an important regulator of arachidonic acid metabolism and eicosanoid biosynthesis.[27]

Fibrosing mechanism in autoimmune disease. Data in this study are in agreement with the previous published data about low TG in pulmonary fibrosis,[1] since most autoimmune disorders are fibrosing diseases that can evolve toward chronic interstitiopathy or pulmonary fibrosis.[28,29] Fibrosis is a pathologic process characterized by the replacement of normal tissue by mesenchymal cells and the extracellular matrix produced by these cells.[30] The sequence of events leading to fibrosis of an organ involves the subsequent processes of injury with inflammation and disruption of the normal tissue architecture, followed by tissue repair with accumulation of mesenchymal cells in the area of derangement.[30] Inflammatory cells (mainly mononuclear phagocytes), platelets, and endothelial cells (and, in pulmonary fibrosis, type II pneumocytes) play direct and indirect roles in tissue injury and repair.[30] In pulmonary fibrosis, several cytokines participate in the local injury and inflammatory reaction, such as interleukin (IL)-1, IL-8, monocyte chemotactic protein-1, and tumor necrosis factor-alpha.[30] Other cytokines are involved in tissue repair and fibrosis, such as platelet-derived growth factor (PDGF), insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-beta), and basic-fibroblast growth factor.[30] Recent data directly demonstrated how acute tissue injury in the lung, initiated by a highly proinflammatory cytokine, IL-1-beta, converts to progressive fibrotic changes.[31] TGF-beta1 has been reported to modify fibroblast growth factor-2 production in type II cells in the lung.[32] Interferon-gamma, a Th1 cytokine, downregulates the expression of TGF-beta1 and is a therapeutic agent in some diverse autoimmune diseases.[33] In several other autoimmune diseases (besides primary pulmonary fibrosis), these cytokines also play a key role in acute local injury/inflammatory reaction and chronic repair.[34,35]

It is noteworthy that the progress toward autoimmune chronic pulmonary fibrosis is especially associated with increased expression of pulmonary IGF-1, mainly in interstitial and alveolar macrophages.[36,37] In lungs of patients with idiopathic fibrosis, this growth factor is known to promote fibroblast proliferation and differentiation as well as to stimulate collagen synthesis by these cells.[38] The role for interstitial macrophages as a source of IGF-1 is crucial, and the level of expression of IGF-I by interstitial macrophages was related to the degree of disease severity.[38] In rheumatoid arthritis, synovium is characterized by the presence of a number of secreted cytokines (including IGF-1, PDGF, and TGF-beta) of activated lymphocytes, macrophages, and other cell types (such as fibroblasts and endothelial cells) that have a key role in the rheumatoid inflammatory process.[34] The activity of these cytokines appears to account for many of the features of rheumatoid synovitis as well as the systemic manifestations of disease.[34]

IGF-1, the mediator strongly implicated in fibroblast proliferation and collagen deposition, is also involved in TG clearance. Total IGF-1 levels are lower in patients with atherogenic lipid profile, so contributing to the development of atherosclerosis.[39,40] Age- and sex-adjusted fasting free IGF-1 levels were inversely correlated with serum TG (but showed no relation with most cardiovascular risk factors).[41] IGF-1 concentrations would be subnormal in obesity, a disease in which TG levels are increased.[42] In both healthy young men and type 2 diabetic patients, IGF-1 lowers fasting and postprandial TG (without affecting the metabolism of intestine-derived TG-rich lipoproteins after a high-fat meal in normal subjects) and increases FFA level, most probably by decreasing insulin secretion and production of VLDL particles and possibly by increasing their turnover.[43,44] Recombinant IGF-1 administered subcutaneously to healthy subjects or patients with type 2 diabetes causes a drop in plasma levels of TG and VLDL.[45] IGF-1 may be envisaged for cases of insulin resistance[45] or altered lipid profile in type 2 (noninsulin-dependent) diabetic patients.[43] On these grounds, an increased release of IGF-1 by different tissues might be the cause of the metabolic pattern (low TG and high FFA levels) occurring in some patients with autoimmune disease.

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