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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 3 791-796
Copyright © 1997 by The Endocrine Society

Clinical Studies

Characterization of a New Case of Autoimmune Type I Hyperlipidemia: Long-Term Remission under Immunosuppressive Therapy1

Valerie Pruneta, Philippe Moulin2, Florence Labrousse, Pierre-Jean Bondon, Gabriel Ponsin and Francois Berthezene

Laboratoire de Métabolisme des Lipides (V.P., P.M., G.P.), Service d’Endocrinologie et des Maladies de la Nutrition (F.L., F.B.), and Laboratoire de Biochimie (P.B.), Hôpital de l’Antiquaille, Lyon, France

Address all correspondence and requests for reprints to: Dr. Valérie Pruneta, Laboratoire de Métabolisme des Lipides, Hôpital de l’Antiquaille, 1 rue de l’Antiquaille, 69005 Lyon, France.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Only a few cases of type I hyperlipidemia occurring in patients with autoimmune disease have been reported. We describe the case of a 35-yr-old woman suffering from severe type I hyperchylomicronemia. A combination of various hypolipidemic treatments, including strict hypolipidemic dietary therapy and administration of fibrates or n-3 fatty acids, was inefficient. Because of a history of familial autoimmunity, we introduced an immunosuppressive therapy that resulted in consistent long term and stable remission. Two attempts to reduce the immunosuppressor dose resulted in major relapses. To explain the defect of chylomicron hydrolysis, we investigated the postheparin plasma lipase activities. Hepatic triglyceride lipase activity was normal, whereas that of lipoprotein lipase (LPL) was reduced to about 30% of normal. Immunosuppressive therapy resulted in a complete and durable normalization of LPL activity. Using Western blot analysis, we found in the plasma of the patient a circulating IgG specifically directed against LPL, which became undetectable during immunosuppressive therapy. Western blot analysis revealed that the whole circulating anti-LPL autoantibody was bound to chylomicrons. Proteins extracted from patient’s chylomicrons were able to induce a dose-related inhibition of LPL activity in vitro, whereas that of hepatic triglyceride lipase remained unchanged.

These data constitute the first description of autoimmune hyperchylomicronemia due to an exclusive defect of LPL activity, and they show that a complete remission has been obtained after immunosuppressive therapy. Finally, our finding that the anti-LPL autoantibody is bound to chylomicrons emphasizes their previously unrecognized ability to transport LPL, already described for other lipoprotein fractions.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
TYPE I HYPERLIPIDEMIA is characterized by a major hypertriglyceridemia due to an exclusive accumulation of chylomicrons in plasma (1). This infrequent lipoprotein phenotype is associated with a decrease in the ability of lipoprotein lipase (LPL; EC 3.1.1.34) to hydrolyze the tri-glycerides (TG) transported in chylomicrons and very low density lipoproteins (VLDL). Several reports have shown that type I hyperlipidemia generally results from gene mutations that may affect either LPL or apolipoprotein C-II (apo C-II), its physiological activator (2, 3). In contrast, secondary type I hyperlipidemia is extremely rare (4).

The concept of autoimmune hyperlipidemia was first proposed by Beaumont in 1970 (5, 6). Only a few reports have described the occurrence of type I hyperchylomicronemia in an autoimmune context (7, 8, 9). However, in two of these studies, no attempt was made to characterize the specificity of the interaction between autoantibodies and plasma lipases (7, 8). More recently, a patient was reported to develop autoimmune type I hyperchylomicronemia in association with idiopathic thrombocytopenic purpura and Graves’ disease (9). In this case, the hyperchylomicronemia was attributed to the presence of well characterized autoantibodies directed against both LPL and hepatic triglyceride lipase (HTGL), identified as IgA.

We have diagnosed a case of severe autoimmune type I hyperchylomicronemia that was not associated with any other autoimmune disease despite a familial context of autoimmunity. In the present study we describe the characterization and the circulating form of the autoantibody responsible for the hyperchylomicronemia together with the effects of immunosuppressive therapy.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Case report

A 35-yr-old woman (D.E.; 52 kg; 162 cm) was admitted to our lipid clinic for recurrent major hypertriglyceridemia that resisted dietary treatment. She had a lipid phenotype of type I hyperlipidemia characterized by the presence in fasting samples of abundant chylomicrons together with normal VLDL abundance. A routine plasma lipid measurement showed no abnormalities when she was 26 yr old. She gave a history of poorly documented increase in the plasma TG concentration dating from several years, accompanied by recurrent episodes of undiagnosed abdominal pain. After admission, she needed iterative plasmapheresis for major bursts of hypertriglyceridemia (TG, >50 mmol/L) during the first months of follow-up (Fig. 1Go).



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  		Figure 1. Evolution of plasma TG as a function of treatment: fenofibrate (300 mg/day; {blacksquare}), n-3 fatty acids (1.8 g/day; ), or azathioprine (0–100 mg/day; {square}). During the first 2 months of azathioprine treatment, prednisolone was additionally administered to the patient at a dose of 20 mg/day.

 
An apo C-II deficiency was excluded on the basis of three considerations. Firstly, she had an elevated apo C-II level (Table 1Go). Secondly, fresh plasma exchanges had no hypolipidemic effect. Finally, her plasma had a normal ability to activate control LPL in vitro. No common causes that could induce a decrease in plasma lipolytic activity were found; she had no diabetes (fasting plasma glucose, 4.5 mmol/L), and her thyroid function was normal (plasma TSH, 1.1 mIU/L). She was not treated with any drug known to interact with lipoprotein metabolism. Her alcohol consumption was low. Her first degree family members (parents and two sisters) were normocholesterolemic (4.9 ± 0.3 mmol/L) and normotriglyceridemic (0.77 ± 0.13 mmol/L). However, there was a familial history of autoimmune diseases. Her father had pernicious anemia, Graves’ disease, and insulin-dependent diabetes, and her sister had Graves’ disease. In the patient, screening for autoantibodies was negative, except for a low and transient titer of antibody against striated muscle (1:30 by ELISA; normal, <1:20) and against thyroid peroxidase (170 U/mL by RIA; normal, <100 U/mL).


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  		Table 1. Plasma lipid and apolipoprotein concentrations

 
A strict low fat diet (lipids <15%) and subsequent introduction of fenofibrate (300 mg/day) were unable to consistently maintain the TG concentration under 10 mmol/L. As fibrates are often ineffective in lowering TG in patients with severe hyperchylomicronemia, we introduced a treatment of n-3 fatty acids (1.8 g/day) that was inefficient. Previous to the threatening recurrences of major hyperchylomicronemia, we introduced an immunosuppressive therapy combining azathioprine (100 mg/day) and prednisolone (20 mg/day; Fig. 1Go). A consistent long term remission was obtained that persisted despite the interruption of prednisolone after 2 months. In contrast, when azathioprine was tentatively reduced to 25 mg/day from month 30, a recurrence occurred about 7 months later. Another recurrence was observed 15 days after the patient stopped the treatment (month 68) on her own. This dramatic recurrence, complicated by acute pancreatitis, was controled by plasmapheresis and reintroduction of the immunosuppressive treatment.

Plasma samples

All blood samples were collected after a 12-h fast. Control hyperchylomicronemic plasma samples were obtained from three diabetics (one man and two women) with secondary type V hyperchylomicronemia. After separation of chylomicrons by centrifugation at 35,000 x g for 1 h, VLDL, low density lipoprotein (LDL), and high density lipoprotein (HDL) were separated by sequential ultracentrifugation (10). Concentrations of total cholesterol and TG were measured using commercial kits (Biomérieux, Marcy-l’Etoile, France). Total protein concentrations in lipoproteins were determined by the method of Lowry et al. (11). Apo A-I and apo B-100 were determined by RIAs and apo C-II by immunonephelometry.

For measurements of postheparin lipolytic activity (PHLA), blood samples were collected 15 min after iv injection of heparin (LEO, Saint Quentin-en-Yvelines, France; 50 IU/kg BW). Plasma was immediately separated by centrifugation and stored at -70 C until use.

Partial purification of human LPL and HTGL

Four milliliters of postheparin plasma (PHP) were mixed with 500 µL heparin-Sepharose CL-6B (Pharmacia, Uppsala, Sweden) and incubated for 1 h at 4 C in 0.1 mol/L phosphate buffer, pH 7.2, containing 0.15 mol/L NaCl, 1 mmol/L ethylenediamine tetraacetate, 10% glycerol, and 10% diethyl p-nitro phenylphosphate. After two washes, the slurry was packed into a column and submitted to two additional washes. HTGL and LPL were then eluted with 0.8 and 1.3 mol/L NaCl, respectively (12).

Human LPL was also prepared from adipose tissue. Subcutaneous abdominal adipose tissues (200 mg) were homogenized at 4 C in 2 mL 0.2 mol/L Tris buffer, pH 7.5, containing 3% Triton X-100, 1% lauroylsarcosine, 0.15 mol/L NaCl, and 1 mmol/L phenylmethylsulfonylfluoride, using a Polytron homogenizer (Kinematica AG, Littan, Switzer-land). The homogenate was briefly sonicated at 4 C and centrifuged at 15,000 x g for 20 min (13). The LPL-containing protein supernatant was used for Western blot analysis.

Western blot analysis

HTGL and LPL prepared from PHP or adipose tissue were submitted to 8% or 10% PAGE in the presence of SDS, as described by Laemmli (14). The proteins were then transferred onto a nitrocellulose membrane (Bio-Rad, Hercules, CA) according to the procedure of Towbin et al. (15). After saturation of the nonspecific binding capacity, the blots were incubated for 1 h with total plasma or chylomicrons at a 1:100 dilution in TSE buffer [0.05 mol/L Tris-HCl (pH 7.4), 0.15 mol/L NaCl, and 1 mmol/L ethylenediamine tetraacetate] containing 0.01% Tween-20. After three washes with TSE containing 0.1% Tween-20, a horseradish peroxidase-conjugated goat antihuman IgG (Fc specific; Sigma Chemical Co., St. Louis, MO) was used as the secondary antibody at a 1:1000 dilution. Detection was performed by a chemiluminescent method (ECL, Amersham, Arlington Heights, IL).

Assay of PHP lipolytic activities

The measurements of plasma lipase activities were performed as previously described (16) with slight modifications. Briefly, for total PHLA, 20 µL PHP were mixed with 300 µL Tris-HCl buffer [0.2 mol/L Tris (pH 8.6), 0.15 mol/L NaCl, and 35 g/L fatty acid-free BSA (Sigma Chemical Co.)] containing 36 µL heat-inactivated (45 min at 50 C) human plasma as an additional source of apo C-II. The reaction was initiated by the addition of 100 µL of a TG emulsion containing 15 mmol/L triolein (Sigma) and 0.45 µCi/mL glycerol tri-[1-14C]oleate (Amersham), prepared by sonication under standardized conditions (eight 15-s periods at 15-s intervals, 4 C) in a 50 g/L solution of arabic gum (Sigma). After incubation at 37 C for 1 h under continuous shaking, fatty acid extraction was performed as described by Borensztajn et al. (17). The samples were then counted for [1-14C]oleate radioactivity, and the enzyme activities were expressed as micromoles of free fatty acids released per h/mL PHP. For direct measurement of LPL activity, HTGL was inactivated by preincubation with a specific goat anti-HTGL antiserum. For direct measurement of HTGL, heat-inactivated plasma was omitted from the incubation buffer, and LPL was inhibited by the addition of NaCl to a final concentration of 1 mol/L.

The question of whether a protein transported by the patient’s chylomicrons might inhibit LPL and/or HTGL activities was addressed as follows. Control PHP was preincubated for 1 h at 4 C in the presence of increasing amounts of chylomicron proteins, previously extracted from the patient’s plasma or from those of subjects with type V hypertriglyceridemia according to (18). PHLA as well as LPL and HTGL activities were then measured as described above.

All determinations were run in duplicate. Using a standard PHP, the interassay coefficients of variation for LPL and HTGL activities were 4.5% (n = 8) and 6.8% (n = 9), respectively. For both assays, the intraassay variability was less than 1.5%. When separately determined, the sums of LPL and HTGL activities corresponded to an average of 94 ± 4.1% of total PHLA.

Statistical methods

Results are expressed as the mean ± SD. Data from the patient were considered significantly different from normal when they were outside the 95% confidence limit of a control population.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The plasma lipid and apolipoprotein concentrations of the patient are shown in Table 1Go. For the sake of clarity, only data obtained in the absence of treatment or after 80 months of immunosuppressive therapy are shown. Without immunosuppressive therapy, the lipid phenotype of the patient was that of type I hyperlipidemia. The accumulation of chylomicrons, which represented about 90% of the total plasma TG, was associated with an increase in the concentration of plasma apo C-II similar to that observed in subjects with type V hyperlipidemia (Table 1Go). The patient’s VLDL-TG levels were 60% lower than those in type V subjects. She had low levels of LDL (0.19 mmol/L), HDL2 (0.08 mmol/L), and HDL3 (0.18 mmol/L) cholesterol. Immunosuppressive therapy induced normalization of the plasma TG concentration (Fig. 1Go), and no more prominent abnormalities of plasma lipoprotein concentrations were observed. The efficiency of the treatment was further evidenced by the measurement of TG concentrations in the postprandial state. Four hours after a normal meal, her total plasma TG concentration was 2.0 mmol/L, whereas that in chylomicrons was 0.93 mmol/L (not shown).

Collective consideration of these data was highly suggestive of the putative existence of an autoantibody able to inhibit plasma lipase activity. Consistent with this hypothesis, untreated patient LPL activity was 72% lower than that in controls, whereas it was normalized during treatment. No abnormality of HTGL activity was observed (Table 2Go). The question of whether the inhibition of LPL activity occurred through its direct interaction with an autoantibody was investigated by the use of Western blot. After SDS-PAGE, human LPL and HTGL were transferred onto nitrocellulose and incubated with the patient’s plasma (Fig. 2Go). A specific Ig interacting with LPL was detected only when the patient was not treated. It was characterized as an IgG. No signal associated with partially purified HTGL was observed (Fig. 2Go, lane 3). No Ig able to interact with lipases was detected in plasma either from patients with another autoimmune disease (Hashimoto’s thyroiditis, thyroid peroxidase antibody titer, >10,000 U/mL; n = 7) or from hyperchylomicronemic subjects presenting secondary type V hyperlipidemia (n = 8). The patient’s specific anti-LPL antibody became undetectable after immunosuppressive therapy even at a low plasma dilution (1:10).


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  		Table 2. Lipoprotein lipase and hepatic triglyceride lipase activities in postheparin plasma from the patient and from normolipidemic control subjects

 


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  		Figure 2. Detection of anti-LPL autoantibody in plasma. A, 15 µg protein homogenates from human adipose tissue (lanes 1 and 4), 10 µg LPL obtained from human PHP (lanes 2 and 5), or 10 µg HTGL from human PHP (lanes 3 and 6) were subjected to a 8% SDS-PAGE. After transfer onto nitrocellulose, the blots were incubated with either the patient’s plasma (lanes 1–3) or type V hypertriglyceridemic subject’s plasma (lanes 4–6) and then exposed to peroxidase-labeled antihuman IgG antibody. B, Nitrocellulose-bound human LPL (0.8 µg), kindly provided by Dr. U. Beisiegel (Hamburg, Germany) and Dr. G. Olivecrona (Umea, Sweden), was incubated with patient’s plasma as described above.

 
When chylomicrons were separated from plasma, the anti-LPL autoantibody was exclusively recovered in the chylomicron fraction (Fig. 3AGo). No IgG was detectable in any chylomicrons other than those obtained from the untreated patient (Fig. 3BGo). Incubation of the chylomicrons in acidic conditions (0.1 mol/L glycine-HCl, pH 2.5) resulted in dissociation of the anti-LPL IgG from chylomicrons in a time-dependent manner (Fig. 4Go).



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  		Figure 3. Detection of anti-LPL autoantibody in chylomicrons. A, Nitrocellulose-bound human LPL was incubated with patient’s plasma at a 1:100 dilution (lane 1), isolated chylomicrons at a 1:200 (lane 2) or a 1:100 dilution (lane 3), chylomicron-free plasma fraction at a 1:100 dilution (lane 4), chylomicrons from a type V hyperchylomicronemic subject (lane 5), or a chylomicron-free plasma fraction from the same subject (lane 6). After incubation, the blots were exposed to peroxidase-labeled antihuman IgG antibody. The signal (58 kDa) corresponds to LPL detected by the patient’s IgG. B, Fifteen micrograms of chylomicron proteins from the patient (lane 1) or from type V hyperchylomicronemic subjects (lanes 2–4) were submitted to 10% SDS-PAGE, transferred onto nitrocellulose, and directly exposed to peroxidase-labeled antihuman IgG antibody (Fc specific). The signal (55 kDa) correspond to the direct detection of the IgG heavy chain.

 


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  		Figure 4. Release of anti-LPL IgG from chylomicrons. Patient’s chylomicrons were incubated in a glycine-HCl buffer (pH 2.5 for 30 or 60 min) and reisolated by centrifugation. Proteins (15 µg) obtained from untreated chylomicrons (lane 1), from chylomicrons treated for 30 and 60 min (lanes 2 and 3, respectively), or released in the infranatant after 30 and 60 min (lanes 4 and 5, respectively) were submitted to a 10% SDS-PAGE, transferred onto nitrocellulose, and exposed to peroxidase-labeled antihuman IgG antibody.

 
The patient’s anti-LPL autoantibody gave no immunoreactivity against bovine LPL, but a low immunoreactivity was observed against porcine pancreatic lipase. When nitrocellulose-bound human LPL was incubated with patient’s chylomicrons at a 1:100 dilution in the presence of various amounts of porcine pancreatic lipase ranging from 0–500 µg/mL, the binding of the autoantibody to LPL was competitively inhibited (not shown).

The functional properties of the anti-LPL IgG were established by incubating control PHP in the presence of increasing amounts of proteins extracted from patient’s chylomicrons. This procedure induced a dose-related inhibition of PHLA that was entirely due to the specific inhibition of LPL, whereas HTGL activity remained unaffected (Fig. 5Go).



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  		Figure 5. Inhibition of lipolytic activity of control postheparin plasma by proteins extracted from chylomicrons. Control postheparin plasma was preincubated for 1 h at 4 C with proteins extracted either from patient’s chylomicrons ({square}) or from chylomicrons isolated from three individual type V hypertriglyceridemic plasmas (•, {blacktriangleup}, and {blacksquare}). The samples were then assayed in duplicate for total PHLA, HTGL, and LPL activities. For the patient, the mean of three independent experiments is presented. For one of the controls ({blacksquare}), LPL activity was measured indirectly by subtraction of HTGL from PHLA.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We report a new case of autoimmune hyperchylomicronemia in a patient who had no evidence of other autoimmune disease despite a familial history of autoimmunity. Hypolipidemic drugs had no consistent effect, but the patient was cured after introduction of immunosuppressive therapy combining azathioprine and prednisolone. The interruption of prednisolone treatment after 2 months had no deleterious effect, but there were two major recurrences when azathioprine doses were tentatively reduced. This confirms the autoimmune origin of the patient’s hyperchylomicronemia, although the contribution of mild additional defects in her TG-rich lipoprotein metabolism cannot be ruled out, because her triglyceridemia remained slightly out of the normal range after effective immunosuppression. To our knowledge, our observation constitutes the first example of recovery from a severe autoimmune hyperchylomicronemia obtained by immunosuppressive therapy. Pauciullo et al. reported a hypolipidemic effect of glucocorticoid therapy in a patient with lupus erythematosus (8). However, they considered that the normalization of triglyceridemia was attributed to a glucocorticoid-mediated increase in LPL gene expression.

In an attempt to characterize the metabolic basis of this hyperlipidemia, we identified the presence of an IgG directed against LPL. In vitro, this IgG dramatically reduced the LPL-mediated lipolysis of TG, thereby demonstrating the putative role of this autoantibody in the development of the patient’s hyperchylomicronemia. No detectable immunoreactivity directed against other lipases, including hormone-sensitive lipase, HTGL, and bovine LPL, could be detected. Only a low level of immunoreactivity was observed against porcine pancreatic lipase. Among the rare reports concerning autoimmune type I hyperchylomicronemia (7, 8, 9), only that by Kihara et al. has described in detail the differential activities of LPL and HTGL (9). Their observation differs from ours because the autoantibody that they characterized was an IgA clearly directed against both LPL and HTGL. Thus, the specificity of our patient’s autoantibody for LPL appears unusual, inasmuch as this enzyme belongs to a family that shares a high degree of sequence homology (19, 20, 21). From a theoretical viewpoint, the antibody could either directly block a site necessary for the action of the enzyme or mask it through steric hindrance. Two putative binding epitope localizations could explain the specificity of the LPL-autoantibody interaction. The first might be the area surrounding the catalytic pocket of the enzyme, whereas the second might be near the site of apo C-II binding. Both hypothesis are tenable, as LPL is distinguished from HTGL by subtile changes in polar amino acids in the lid located over the catalytic site, and, on the other hand, LPL but not HTGL, activity depends on apo C-II (22).

Interestingly, the whole circulating anti-LPL antibody was recovered in the chylomicron fraction. This strongly suggests that in hyperchylomicronemia, the bulk of circulating LPL may be bound to chylomicrons, which is not surprising in view of the recent finding that LPL may interact with other lipoproteins (23, 24, 25). One aspect that was not directly studied in our work is the possibility that a large noncirculating pool of anti-LPL IgG was bound to LPL on the surface of the endothelial cells along the vascular bed (26). In fact, this possibility appears very likely for two reasons. Firstly, the LPL-mediated lipolysis, which was inhibited in our patient, is believed to be due only to the endothelium-bound enzyme, as circulating LPL is in an inactive monomeric form (27, 28). Secondly, we found that the threshold dilution for the detection of anti-LPL IgG was 1:1000 for postheparin plasma, whereas it was 1:300 for preheparin plasma, clearly indicating that a pool of anti-LPL antibody was released from the endothelium as a consequence of heparinization.

Several reports have shown that besides its TG hydrolysis activity, LPL might promote the clearance of chylomicron remnants by the LDL receptor-related protein (29, 30, 31). Thus, in addition to its ability to inhibit lipolysis, the anti-LPL autoantibody might reduce the LPL-facilitated clearance of chylomicrons, thereby favoring the patient’s hyperchylomicronemia by two different mechanisms.


   Acknowledgments
 
We are indebted to Dr. U. Beisiegel (Hamburg, Germany) and Dr. G. Olivecrona (Umea, Sweden) for generously providing membrane-bound human LPL, to Dr. S. Griglio (Paris, France) for the gift of goat anti-human HTGL antiserum, to Dr. J. L. Peix (Lyon, France) for his cooperation in obtaining human adipose tissue, to Dr. G. Deleage (Lyon, France) for comparison of lipases structure, to Drs. A. Sassolas and R. Cartier (Lyon, France) for apo C-II measurement, and to Mrs. T. Duc and C. Ammerich for expert technical assistance.


   Footnotes
 
1 Presented in part at the 18th Annual Meeting of the European Lipoprotein Club, Tutzing, September 1995. This work was supported by grants from INSERM, the Hospices Civils de Lyon, and Fournier Laboratories. Back

2 Recipient of a fellowship from INSERM and Hospices Civils de Lyon. Back

Received July 23, 1996.

Revised November 13, 1996.

Accepted December 2, 1996.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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