Eruptive xanthomas in a patient with soft-drink diabetic ketosis and apolipoprotein E4/2

Abstract

Soft-drink diabetic ketosis, characterized by acute onset ketosis induced by excessive ingestion of sugar-containing drinks, is often seen in obese, young patients, even with undiagnosed type 2 diabetes. We herein report a 15-year-old obese patient with the apolipoprotein E4/2 phenotype, in whom eruptive xanthomas lead to a diagnosis of soft-drink diabetic ketosis. He developed multiple asymptomatic yellowish papules on the auricles, back, buttocks and the extensor surfaces of the elbows and knees. He initially visited a dermatology clinic and his blood triglyceride and HbA1c levels were found to be 6,490 mg/dL and 16.5%, respectively. He was referred to our hospital for treatment of hyperglycemia and hypertyriglyceridemia. On admission, he had ketonuria and increased blood levels of 3-hydroxybutylate and acetoacetate. He habitually drank 1–3 litters of sweet beverages daily to quench his thirst. Therefore, “soft-drink diabetic ketosis” was diagnosed. Severe hypertriglyceridemia was considered to have been a consequence of impaired insulin action and his apolipoprotein E4/2 phenotype. We treated the diabetic ketosis and hypertriglyceridemia with intensive insulin therapy and a fat-restricted diet. At discharge, he no longer required insulin therapy and his blood glucose levels were controlled with metformin and voglibose. Along with amelioration of the hyperglycemia, triglyceride levels decreased to 247 mg/dL without administration of anti-hyperlipidemia agents. The eruptive xanthoma lesions gradually diminished in size and number and eventually disappeared by 12 months. This case provides an instructive example of eruptive xanthomas serving as a sign of severe dysregulation, not only of lipid, but also glucose, metabolism.

ERUPTIVE XANTHOMAS are benign lesions caused by lipid deposition in the skin, and are usually associated with severe hypertriglyceridemia [1]. In a retrospective study, eruptive xanthomas were seen in 8.5% of patients with severe hypertriglyceridemia (serum level >1,772 mg/dL) [2]. Eruptive xanthomas usually develop at the extensor surfaces of the extremities, buttocks, and back [3]. The pathological features of skin biopsies are scattered foci of foamy cells in the dermis. The foamy cells contain an abundance of triglycerides, which are derived from circulating triglyceride-rich lipoproteins [4].

Soft-drink diabetic ketosis has an acute onset and is induced by excessive ingestion of sugar-containing soft drinks in obese type 2 diabetic patients, and has most commonly been reported in Japanese subjects [5-7]. Soft-drink diabetic ketosis shows a male predominance, a tendency for obesity, family history of type 2 diabetes mellitus, and patients are generally negative for anti-glutamic acid decarboxylase (GAD) antibody. Excessive intake of sugar-containing soft drinks in patients with uncontrolled type 2 diabetes can lead to severe hyperglycemia, thereby transiently impairing insulin secretion, resulting in a state of glucose toxicity [8]. Both β-cell dysfunction and insulin resistance in individuals who are obese and have type 2 diabetes lead to severely impaired insulin action, thereby inducing ketosis. We herein report a 15-year-old obese patient in whom development of eruptive xanthomas was the first clue to diagnosing soft-drink diabetic ketosis.

Case Presentation

An obese 15-year-old Japanese male with no relevant past medical history presented with multiple asymptomatic yellowish papules on the auricles, back, buttocks, extensor surfaces of the elbows and knees that had appeared 2 weeks earlier. He visited a local dermatology clinic and complained that the eruptive papules were spreading. Laboratory tests revealed a triglyceride level of 6,490 mg/dL, glycated hemoglobin (HbA1c) level of 16.5%, glycosuria and ketonuria. Based on a diagnosis of diabetic ketosis and eruptive xanthomas associated with severe hypertriglyceridemia, he was referred to our hospital and emergently admitted for management of these metabolic disorders. The history taken on admission revealed that he had developed thirst and general malaise, associated with a 20 kg weight loss, starting 6 months prior to hospitalozation. He did not smoke or drink alcohol. He had no family history of either diabetes or hyperlipidemia.

His height was 180 cm, weight 96.2 kg (BMI: 29.7 kg/m²). His consciousness was clear but he showed moderate malaise. His blood pressure was 147/61 mmHg, pulse rate 93/min. As shown in Fig. 1, multiple yellowish papules, 4–5 mm in diameter, surrounded by an erythematous halo, were observed on the auricles, back, buttocks, the extensor surfaces of the elbows, knees and both Achilles tendons. As shown in the Table 1, laboratory examination revealed severe hyperglycemia of 460 mg/dL with HbA1c elevated to 16.0%. He had ketonuria and increased blood levels of both 3-hydroxybutylate and acetoacetate. Arterial blood gas analysis showed no metabolic acidosis. Anti-GAD antibody was negative. C-peptide levels revealed his insulin secretion capacity to be preserved. He had consumed 1–3 liters of sweet beverages daily until admission, in an effort to quench his thirst. The observations made in this case, taken together, indicated that he was suffering from “soft-drink diabetic ketosis” [5]. The blood triglyceride and total cholesterol levels were extremely elevated, having reached 5,449 mg/dL and 718 mg/dL, respectively (Table 2). As shown in Fig. 2, the appearance of the serum after an overnight standing test revealed a remarkable increase in chylomicrons in the upper layer and in very low density lipoprotein (VLDL) in the lower lay­er, indicating type V hyperlipidemia according to the Fredrickson classification [9]. Serum lipoprotein analyses assessed by polyacrylamide-gel electrophoresis with the Lipophor system (Joko, Tokyo, Japan) revealed the percentage area under the curve for VLDL to be increased (38%) and that for LDL to be decreased (10%) (Fig. 3A). Serum amylase and lipase levels were within the normal reference ranges and there was no evidence of acute pancreatitis. Thyroid stimulating hormone, triiodothyronine and thyroxin levels were also within their normal reference ranges (Table 1). ApoC-II, C-III, and E levels were markedly elevated (Table 2). The ApoE phenotype was revealed to be ApoE4/2 assessed by isometric electrophoresis with the Phenotyping ApoE IEF system (Joko, Tokyo, Japan). No extra bands were observed. Lipoprotein lipase (LPL) protein mass and LPL activity after intravenous heparin injection at a dose of 30 U/kg of body weight on day 9 after admission were within their normal reference ranges (Table 1). We screened 22 mutations of the LPL gene (W-14X / N43S / Int2+1 G→A / Y61X / G105R / G154V / G188E / I194T / V200A / D204E / A221X / C239X / R243C / R243H / A261T / F270L / C278R / N291del / S323C / A334T / W382X / Int8+2 T→C), which are commercially available at the BML, Inc. (Tokyo, Japan). These mutations were previously documented in Japanese population [10], but none were detected in our patient. Therefore, his sever hypertriglyceridemia was considered to be secondary to soft-drink diabetic ketosis in association with the effects of the ApoE4/2 phenotype.

Fig. 1

Eruptive xanthomas on the auricles and Achilles tendons at admission.

Table 1 Biochemical data

HbA1c	16.0%
Glucose	460 mg/dL
C-peptide	2.65 ng/mL
β-hydroxybutyric acid	724 μmol/L
Acetoactate	353 μmol/L
Anti GAD antibody	<5.0 U/mL
Amylase	32 U/L
Lipase	49 U/L
TSH	1.04 μU/mL
Free T3	2.49 pg/mL
Free T4	1.36 ng/dL
LPL (pre heparin)	44 ng/mL
LPL (post heparin)	210 ng/mL
LPL activity (post heparin)	7.1 μmol/L/hr
HTGL activity (post heparin)	8.2 μmol/L/hr
Apo-E phenotype	E4/2
Urinalysis
Glucose	(3+)
Protein	(–)
Ketone bodies	(2+)
Arterial blood gas analysis
pH	7.404
PO2	90.5 mmHg
PCO2	43.2 mmHg
HCO3–	26.5 mmol/L
Base Excess	1.9 mmol/L

Table 2 Time course of lipids and apolipoproteins

	admission		discharge
	day 1	day 9	day 22	3 months	8 months
Total cholesterol (mg/dL)	718	505	247	157	189
LDL cholesterol (mg/dL)	45	262	182	81	102
HDL cholesterol (mg/dL)	28	34	32	49	53
Triglycerides (mg/dL)	5,449	421	247	181	188
Apolipoprotein A-I (mg/dL)	106	—	—	130	150
Apolipoprotein A-II (mg/dL)	21.6	—	—	27.0	33.8
Apolipoprotein B (mg/dL)	114	—	—	69	90
Apolipoprotein C-II (mg/dL)	36.0	—	—	5.4	5.7
Apolipoprotein C-III (mg/dL)	91.2	—	—	14.1	15.7
Apolipoprotein E (mg/dL)	43.2	—	—	5.3	6.0

Fig. 2

The overnight serum standing test revealed a remarkable increase in chylomicrons in the upper layer and in VLDL in the lower layer.

Fig. 3

The serum lipoprotein analyses assessed by polyacrylamide-gel electrophoresis. The asterisk indicates the mid-band.

We managed the diabetic ketosis with intensive insulin therapy, and the hypertriglyceridemia with a fat-restricted diet (40 g of fat per day) (Fig. 4). The ketosis had fully resolved and blood glucose levels normalized. On day 7 after admission, 98 units of insulin (insulin aspart 78 U, insulin degludec 20 U) per day were needed to control blood glucose. Thereafter, while insulin doses were gradually tapered, 750 mg of metformin and 0.6 mg of voglibose were added in a stepwise fashion. Finally, insulin therapy was stopped on day 18 after admission. Along with the amelioration of hyperglycemia, blood triglyceride levels had markedly decreased to 247 mg/dL without the administration of any anti-hyperlipidemia agents by the time of discharge on day 22. Polyacrylamide-gel electrophoresis of lipoprotein revealed the presence of a mid-band at day 9 (Fig. 3B). Thereafter, although the li­poprotein pattern showed improvement at day 22 and 8 months, a small mid-band still existed (Fig. 3C, D), indicating impaired lipolysis of VLDL. Histological findings of biopsy specimens taken from the eruptions on the buttock showed scattered foci of foamy cells in the dermis, confirming the diagnosis of eruptive xanthomas (Fig. 5).

Fig. 4

The patient’s clinical course.

Fig. 5

Histological findings of a biopsy specimen from the buttock showed scattered foci of foamy cells in the dermis.

Eight months after discharge, diabetic conditions were well controlled (HbA1c 5.4%) with 2,250 mg/day of metformin. Triglyceride levels had further decreased to 188 mg/dL with a fat-restricted diet. Serum apoC-II, apoC-III and apoE levels were markedly decreased (Table 2). Interestingly, the eruptive xanthoma lesions persisted as pigmentations (Fig. 6), which then fully disappeared by 12 months after discharge.

Fig. 6

Eruptive xanthomas on the auricles and Achilles tendon at 8 months after discharge.

Discussion

Soft-drink diabetic ketosis is due to excessive ingestion of sugar-containing soft drinks by obese type 2 diabetic patients. The onset of soft-drink ketosis often triggers the diagnosis of type 2 diabetes [5-7]. Excessive sugar-containing soft drink consumption by patients with uncontrolled type 2 diabetes can reportedly lead to severe hyperglycemia, which in turn impairs insulin secretion and thereby leads to overproduction of ketone bodies [8]. To our knowledge, this is the first report describing a case in whom eruptive xanthomas were the first clue to the diagnosis of soft-drink diabetic ketosis. Therefore, he initially visited a local dermatology clinic. Thus, this case provides an instructive example of eruptive xanthomas being a sign of severe dysregulation, not only of lipid, but also glucose, metabolism.

Eruptive xanthomas, which are lipid depositions in the skin, are usually associated with severe hypertriglyceridemia [1] and are reportedly seen in 8.5% of patients whose triglyceride levels exceed 1,772 mg/dL [2]. The serum triglyceride level of our patient was actually 6,490 mg/dL. Primary causes of severe hypertriglyceridemia are known to be genetic mutations, such as LPL deficiency and ApoC-II deficiency, while secondary causes include uncontrolled diabetes mellitus, hypothyroidism, nephrotic syndrome, alcohol abuse and administration of certain medications (e.g., estrogens, corticosteroids, retinoid agents) [11]. Ketosis-prone diabetes is on occasion accompanied by hypertriglyceridemia [12-14]. There are several case reports documenting eruptive xanthomas with severe hypertriglyceridemia (>2,000 mg/dL) as well as uncontrolled diabetes mellitus (HbA1c >10%) [3, 15-19]. Most of these patients were relatively young (<40-year-old) and were obese (BMI >25 kg/m²). In our present patient, excessive ingestion of sugar-containing soft drinks may have caused such a severe impairment of insulin action as to lead to overproduction of ketone bodies. In addition, initial insulin therapy improved hypertriglyceridemia. Long-term glycemic control with metformin treatment lowered serum triglyceride levels and, eventually, eruptive xanthomas disappeared with no dermatological treatment or anti-hyperlipidemia agents having been administered. Thus, severely impaired insulin action is considered be a major cause of severe hypertriglyceridemia and eruptive xanthomas.

The mechanisms whereby impairment of insulin action increases triglyceride-rich lipoprotein are considered to be as follows. First, insulin suppresses the lipolysis of triglycerides to free fatty acids in adipose tissue. Because insulin action is decreased in type 2 diabetes mellitus, the inhibition of triglyceride lipolysis in adipose tissue is attenuated. Then free fatty acids are released into the circulation. Excessive flux of free fatty acids to the liver increases hepatic secretion of VLDL. Second, insulin stimulates the activity of sterol responsive element binding protein-1c (SREBP-1c), a transcription factor promoting the expressions of the enzymes required for fatty acid synthesis [20]. In obese patients with type 2 diabetes, while the suppressive effect of insulin on hepatic gluconeogenesis is impaired, the effect of insulin on hepatic lipogenesis is stimulated, a state referred to as selective insulin resistance [21]. This mechanism, which was proposed based on findings obtained with animal models, was shown to actually occur in human subjects with hepatic steatosis [22]. Additionally, hyperglycemia stimulates the activity of carbohydrate responsive element binding protein (ChREBP), a transcription factor that increases the expressions of the enzymes required for fatty acid synthesis [23]. Increased de novo lipo­genesis raises hepatic secretion of VLDL. Third, insulin stimulates LPL expression in adipocytes and increases LPL activity in blood. LPL hydrolyzes and removes triglyceride-rich lipoprotein from the circulation [24]. Type 2 diabetes patients with insulin resistance have lower LPL activity in plasma and impaired clearance of triglyceride-rich lipoprotein, leading to retention of chylomicrons and VLDL in blood [25]. In our patient, the plasma LPL activity measured after intravenous heparin injection was normal on day 9 after admission, when the triglyceride level was 421 mg/dL. We speculate that the initial insulin therapy restored LPL activity to within the normal range, along with normalization of glycemic control. Taken together, our observations suggest that marked impairment of insulin action induced by excessive ingestion of sugar-containing soft drinks may have resulted in both overproduction and impaired clearance of triglyceride-rich lipoprotein in this patient.

Although patients with type 2 diabetes often have lipoprotein abnormalities, especially elevated triglyceride-rich lipoproteins in blood [26], the extremely severe hypertriglyceridemia observed in our patient (6,490 mg/dL) is seemingly very rare. Therefore, we further searched for genetic factors possibly involved in hypertriglyceridemia and found this patient to have the ApoE4/2 phenotype. ApoE isoforms may impact blood triglyceride levels. ApoE is a protein constituting of the lipoprotein particle, which plays a key role in lipoprotein transport in blood. ApoE has 3 major isoforms, ApoE2, ApoE3, and ApoE4, which differ by amino acid substitutions at positions 112 and 158. ApoE3 is the most common isoform with a frequency of 84.6%, followed by ApoE4 with 11.7%, and ApoE2 with 3.7% in Japanese population [27]. ApoE3 is the parent form, which binds to low density lipoprotein receptor (LDLR) to mediate appropriate lipolytic processing and endocytosis of triglyceride-rich lipoprotein remnant particles. ApoE2 (Arg158Cys) exhibits impaired binding to LDLR and an inability to promote clearance of triglyceride-rich lipoprotein remnant particles. In contrast, ApoE4 (Cys112Arg) exhibits enhanced binding to the surface of triglyceride-rich lipoprotein particles and thereby impairs lipolytic processing of triglyceride-rich lipoprotein. Therefore, subjects with ApoE2 and ApoE4 isoforms are at greater risk of developing hyperlipidemia than subjects with the ApoE3 isoform [28]. In particular, apoE4 is speculated to play an important role in development of the type V hyperlipoproteinemia observed in this patient, because the association of the apoE4 isoform and type V hyperlipoproteinemia is widely accepted [29-33]. However, the molecular mechanism of this association remains to be elucidated, although the following mechanism was hypothesized [34]. ApoE molecules at the surface of triglyceride-rich lipoproteins anchor to endothelial proteoglycans and facilitate their interaction with endothelial LPL, resulting in lipolysis of triglyceride-rich lipoproteins and clearance of plasma triglycerides [35]. ApoC-II is an essential cofactor for LPL activation [36]. The AopE4 isoform has a greater affinity for VLDL [37] and this tight binding is considered to displace apoC-II and inhibit lipolysis of VLDL. In our patient, even after glycemic control had been achieved, polyacrylamide-gel electrophoresis of lipoprotein revealed that a small mid-band still existed. This finding indicates incomplete lipolysis of components of the VLDL-IDL-LDL cascade. When VLDL production is excessive, such as in the case of obesity, apoE4-carrying subjects may be susceptible to having type V hyperlipoproteinemia. In fact, obese apoE4-carrying subjects are reportedly predisposed to elevated plasma triglycerides [38, 39]. These reports are consistent with the type V hyperlipoproteinemia ob­served in our obese diabetic patient. With regard to the apoE2 isoform, carrying it was reported to be associated with higher triglyceride levels than apoE3 [39], although other reports have indicated the frequencies of the apoE2 isoform in patients with type V hyperlipoproteinemia to not be significantly increased, as compared with those with the apoE3 isoform [30, 31]. Therefore, we cannot rule out the possibility that the apoE2 isoform is involved in the development of dyslipidemia, observed in our patient, and in the existence of the mid-band on polyacrylamide-gel electrophoresis of his lipoprotein. However, the contribution of apoE2, if any, seems not to be as major as that of apoE4. In any case, further studies are required to elucidate the relationships between the apoE isoforms and the development of type V hyperlipoproteinemia.

There are 3 homozygous phenotype (ApoE2/2, ApoE3/3, ApoE4/4) and 3 heterozygous phenotype (ApoE3/2, ApoE4/2, and ApoE4/3). The ApoE4/2 observed in our patient is a rare phenotype. Serum triglyceride levels in subjects with ApoE4/2 were reported to be significantly higher than those in individuals with ApoE3/3 [39]. In fact, in our patient, the blood triglyceride level at discharge (247 mg/dL) was still not within the normal range (<150 mg/dL), while good glycemic control was achieved. Thus, the ApoE4/2 phenotype of our patient may be involved in the development of markedly severe hypertriglyceridemia, leading to the development of eruptive xanthomas.

In conclusion, markedly impaired insulin action induced by excessive soft-drink intake in combination with having the ApoE4/2 phenotype may have caused eruptive xanthomas in a young, obese, male, Japanese subject who had not been diagnosed as having diabetes. His main reason for consultation was the development of eruptive xanthomas. We should keep in mind that the development of eruptive xanthomas is a sign indicating severe dysregulation, not only of lipid, but also glucose, metabolism, even in patients not undiagnosed as having diabetes.

Disclosure

The authors have no conflicts of interest associated with this manuscript to declare.

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