Severe Hypercholesterolemia Caused by Mesalazine Which Is a Key Drug of Ulcerative Colitis

Abstract

Drug-induced hypercholesterolemia is well known to cause side effects, such as secondary hypercholesterolemia. Many of these drugs are essential for long-term use and are difficult to replace; therefore, they are continued even when associated with hypercholesterolemia. Mesalazine is the first-line drug used for treating ulcerative colitis. We herein report a case of severe hypercholesterolemia following mesalazine administration in a patient with ulcerative colitis. In this case, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor was effective in dramatically improving severe hypercholesterolemia. Clinicians should therefore be aware of the possibility of severe hypercholesterolemia caused by mesalazine for educational purposes.

Introduction

Several factors are associated with an increased risk of hyperlipidemia. Modifiable risk factors include a diet high in saturated or trans fats, physical inactivity, smoking, and obesity (1). Abnormalities in lipid metabolism, such as those due to obesity or lifestyle-related diseases, rarely lead to severe hypercholesterolemia. Secondary causes of elevated low-density lipoprotein LDL-cholesterol include biliary obstruction, chronic kidney disease, type 2 diabetes mellitus, hypertension, and hypothyroidism (1). We sometimes examine patients with severe hypercholesterolemia, but many have familial hypercholesterolemia (FH).

Drug-induced hypercholesterolemia is also known to cause side effects, such as secondary hypercholesterolemia (2-4), diuretics, cyclosporine, and glucocorticoids can also contribute to elevated LDL-cholesterol levels (5). However, the mechanisms by which these drugs increase cholesterol concentrations remain largely unknown.

Mesalazine, also known as 5-aminosalicylic acid (5-ASA), is used to treat inflammatory bowel diseases including ulcerative colitis. Mesalazine is a first-line drug for treating mild-to-moderate ulcerative colitis; thus, it is difficult to change to another drug (6,7). There are many unknowns about the causes and treatment of ulcerative colitis, and it is important to get enough drugs to the site of the lesion (usually the mouth or rectal region).

In this report, we present a case of severe mesalazine-induced hypercholesterolemia. LDL-cholesterol levels were markedly elevated after treatment with mesalazine. In addition, the LDL-cholesterol level was dramatically decreased by treatment with rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor.

Case Report

A 58-year-old Japanese woman who had a 4-month history of ulcerative colitis was referred to our department with an elevated total cholesterol level of 703 mg/dL and LDL-cholesterol level of 582 mg/dL. Her medical history included a diagnosis of ischemic colitis (at 55 years of age). Three months previously, she started treatment with mesalazine Enteric-coated Tablets (3,600 mg three times a day) for ulcerative colitis. Her height, body weight, and BMI were 150.3 cm, 30.6 kg (Her weight was 43 kg before she suffered from ischemic colitis, and she lost 3 kg of body weight with her bout of ischemic colitis, and 13.6 kg with her bout of ulcerative colitis). Clinical FH signs [tendon xanthoma (on the backs of hands, elbows, knees, etc.) or xanthoma] were not present in this patient. The patient's vital signs were normal. We did not detect either Achilles tendon hypertrophy on radiography or intima-media thickness hypertrophy on carotid artery ultrasonography. She was admitted to the hospital, and Table 1 shows her fasting laboratory data. The fasting laboratory data about dyslipidemia were as follows: total cholesterol, 774 mg/dL; LDL-cholesterol, 581 mg/dL; high-density lipoprotein-cholesterol, 75 mg/dL; triglyceride, 158 mg/dL; remnant-like particle (RLP)-cholesterol, 53.0 mg/dL; Lipoprotein (a), 11 mg/dL, pre-heparin lipoprotein lipase (LPL), 78 ng/mL; apolipoprotein A-I, 165 mg/dL; apolipoprotein A-II, 18.7 mg/dL; apolipoprotein B, 399 mg/dL; apolipoprotein C-II, 7.6 mg/dL; apolipoprotein C-III, 22.7 mg/dL; apolipoprotein E, 16.2 mg/dL. Table 1 shows the details of her fasting laboratory data at that time. In addition, her lipoprotein fractions showed elevated MIDBAND fractions (33%) and lipoprotein-X was not detected (Supplementary material 1A). Abdominal ultrasonography revealed slightly prominent blood flow in the hepatic artery, but cholestasis was not detected (Supplementary material 1B). We examined the genetic testing of FH coding regions of FH-associated genes [LDL receptor (LDLR), proprotein convertase subtilisin/kexin 9 (PCSK9), LDLR adaptor protein 1 (LDLRAP1), and apolipoprotein B (APOB)] (BML, Tokyo, Japan), and no genetic mutations were detected.

Table 1.

The Fasting Laboratory Data in This Subject.

Variable	Result	Reference range	Variable	Result	Reference range
Peripheral blood			Dyslipidemia marker
White blood cells (/μL)	4,310	3,300-8,600	Total cholesterol (mg/dL)	774	142-248
Neutrophil (%)	72.7	52.0-80.0	LDL cholesterol (mg/dL)	581	65-139
Lymphocyte (%)	22.5	20.0-40.0	HDL cholesterol (mg/dL)	75	40-103
Red blood cells (×104/μL)	380	386-492	Triglyceride (mg/dL)	158	30-149
Hemoglobin (g/dL)	12.7	11.6-14.8	RLP-cholesterol (mg/dL)	53.0	0.0-7.5
Hematocrit (%)	37.0	35.1-44.4	Lipoprotein (a) (mg/dL)	11	0-40
Platelets (×104/μL)	17.9	15.8-34.8	pre-heparin LPL (ng/mL)	78
Blood biochemistry			apolipoprotein A-I (mg/dL)	165	126-165
Total protein (g/dL)	5.9	6.6-8.1	apolipoprotein A-II (mg/dL)	18.7	24.6-33.3
Albumin (g/dL)	3.6	4.1-5.1	apolipoprotein B (mg/dL)	399	66-101
Globulin (g/dL)	2.3	2.2-3.4	apolipoprotein C-II (mg/dL)	7.6	1.5-3.8
Total bilirubin (mg/dL)	1.2	0.4-1.5	apolipoprotein C-III (mg/dL)	22.7	5.4-9.0
AST (U/L)	21	13-30	apolipoprotein E (mg/dL)	16.2	2.8-4.6
ALT (U/L)	56	7-23	Phospholipid (mg/dL)	600	160-260
LDH (U/L)	252	124-222	Free fatty acid- (μEq/L)	511	140-850
ALP (U/L)	32	38-113	Free cholesterol (mg/dL)	219	30-60
γ-GTP (U/L)	66	9-32	EPA (μg/mL)	245.6	10.2-142.3
BUN (mg/dL)	15	8-20	DHA (μg/mL)	556.4	54.8-240.3
Creatinine (mg/dL)	0.47	0.46-0.79	AA (μg/mL)	781.8	135.7-335.3
Cholinesterase (U/L)	149	201-421	DHLA (μg/mL)	43.2	22.6-72.5
Uric acid (mg/dL)	2.4	2.6-5.5	Lipoprotein fractionation
Creatine kinase (U/L)	62	41-153	VLDL (%)	5	2-12
Amylase (μg/dL)	67	44-132	MIDBAND (%)	20
CRP (mg/dL)	<0.03	<0.14	LDL (%)	63	44-66
Sodium (mmol/L)	137	138-145	HDL (%)	12	27-50
Potassium (mmol/L)	3.8	3.6-4.8	Endocrinology marker and vitamin
Chloride (mmol/L)	102	101-108	TSH (μIU/mL)	1.651	0.400-6.000
IP (mg/dL)	3.5	2.7-4.6	FT3 (pg/mL)	1.38	2.50-4.20
Calcium (mg/dL)	8.7	8.8-10.1	FT4 (ng/dL)	0.54	0.80-1.60
Magnesium (mg/dL)	2.3	1.9-2.6	TRAb (IU/L)	<1.0	<1.0
Diabetes marker			TPOAb (IU/mL)	30.8	<16.0
Plasma glucose (mg/dL)	80	73-109	TgAb (IU/mL)	75.0	<28.0
Hemoglobin A1c (%)	5.6	4.9-6.0	Vitamin B1 (ng/mL)	16	24-66
Glycoalbumin (%)	19.0	12.4-16.3	Vitamin B2 (ng/mL)	101.8	66.1-111.4
IRI (μU/mL)	2.7	0.0-10.0	Vitamin B12 (pg/mL)	468	233-914

AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γ-GTP: gamma-glutamyltranspeptidase, BUN: blood urea nitrogen, CRP: C-reactive protein, IP: inorganic phosphorus, IRI: immunoreactive insulin, LDL: low-density lipoprotein, HDL: high-density lipoprotein, RLP: remnant like particle, LPL: lipoprotein lipase, EPA: eicosapentaenoic acid, DHA: docosahexaenoic acid, AA: arachidonic acid, DHLA: dihomogamma-linolenic acid, TSH: thyroid stimulating hormone, FT3: free triiodothyronine, FT4: free thyroxine, TRAb: thyrotropin receptor, TPOAb: anti-thyroid peroxidase antibodies, TgAb: anti-thyroglobulin antibody

Her thyroid hormone level slightly decreased (thyroid-stimulating hormone (TSH), 1.651 μIU/mL; free triiodothyronine 1.38 pg/mL; free thyroxine 0.54 ng/dL). As the thyroid function affects lipid metabolism, we started treatment with 25 μg of levothyroxine, and her thyroid hormone levels immediately improved. During the course of treatment for severe hypercholesterolemia, the thyroid hormones were stable with 25 μg thyroxine (Supplementary material 2). Mesalazine is a key drug used for the treatment of ulcerative colitis. Therefore, we were reluctant to discontinue mesalazine in the absence of UC remission of ulcerative colitis. We started therapy with rosuvastatin (2.5 mg/once a day) for severe hypercholesterolemia, while continuing treatment with mesalazine for ulcerative colitis. As such, the total cholesterol and LDL-cholesterol levels in this case had never been observed before, and there have been no previous reports of mesalazine-induced hypercholesterolemia, we examined each dyslipidemia marker at various times (Figure). The rosuvastatin dose was gradually increased to 10 mg/day and then decreased depending on the cholesterol levels. Once her LDL-cholesterol level improved, even small doses of statins did not exacerbate the patient's LDL-cholesterol levels. All lipid metabolism markers, not just LDL-cholesterol, improved with statin administration (Table 2). During the course of treatment for hypercholesterolemia with rosuvastatin, her ulcerative colitis repeatedly improved followed by exacerbations even with continued mesalazine administration. Twelve months after the start of statin (2.5 mg of rosuvastatin), steroid therapy (5 mg of prednisolone) was started. Prednisolone was gradually reduced to 2 mg and 1 mg every 1 month. During the course of prednisolone treatment for exacerbated ulcerative colitis, her dyslipidemia markers were stable and she continued with 2.5 mg of rosuvastatin.

Figure.

Clinical time course of the lipid parameters in this study After the diagnosis of ulcerative colitis, mesalazine was started at 3,600 mg/ three times a day for ulcerative colitis. Four months later, her total cholesterol and low-density lipoprotein (LDL)-cholesterol levels gradually increased; her elevated total cholesterol level was 703 mg/dL, and her LDL-cholesterol level was 582 mg/dL at 4 months later. Rosuvastatin (2.5 mg/once a day) was started for severe hypercholesterolemia, while continuing treatment with mesalazine. The rosuvastatin dose was gradually increased to 10 mg/day and then decreased depending on the cholesterol levels.

Table 2.

Time Course of Various Lipid Metabolism Markers after Rosuvastatin Therapy.

Dyslipidemia marker	Just before Rosuvastatin 0 mg	After 2 weeks Rosuvastatin 2.5 mg	After 2 months Rosuvastatin 10 mg	After 5 months Rosuvastatin 5 mg	Reference range
Total cholesterol (mg/dL)	774	630	246	195	142-248
LDL cholesterol (mg/dL)	581	460	82	50	65-139
HDL cholesterol (mg/dL)	75	76	129	117	40-103
Triglyceride (mg/dL)	158	228	57	78	30-149
RLP-cholesterol (mg/dL)	53.0	36.7	2.8	2.3	0.0-7.5
Lipoprotein (a) (mg/dL)	11	9	6	8	0-40
apolipoprotein A-I (mg/dL)	165	176	257	240	126-165
apolipoprotein A-II (mg/dL)	18.7	22.6	37.6	42.6	24.6-33.3
apolipoprotein B (mg/dL)	399	326	80	55	66-101
apolipoprotein C-II (mg/dL)	7.6	7.7	4.0	4.6	1.5-3.8
apolipoprotein C-III (mg/dL)	22.7	21.5	17.8	15.8	5.4-9.0
apolipoprotein E (mg/dL)	16.2	14.0	10.1	10.4	2.8-4.6
Phospholipid (mg/dL)	600	505	304	268	160-260

LDL: low-density lipoproteins, HDL: high-density lipoprotein, RLP: remnant like particle

Discussion

We herein report a case of severe hypercholesterolemia following mesalazine administration in a patient with ulcerative colitis. In general, LDL-cholesterol in the blood is processed in the liver. However, since the liver was unable or had a low ability to process LDL-cholesterol, as observed in patients with FH, the blood concentration of LDL-cholesterol is severely elevated. There are two types of FH: homozygous (HoFH) and heterozygous (HeFH). HeFH is usually caused by a single pathogenic variant in one of the four primary genes associated with FH: LDLR, which encodes APOB, PCSK9, and LDLRAP1. Therefore, the average LDL-cholesterol level is elevated by approximately 200-450 mg/dL (8). In contrast, HoFH is caused by biallelic pathogenic variants, generally in LDLR, and can present with significantly elevated LDL-cholesterol levels (450 to ＞1,000 mg/dL) (9-11). It is unlikely that the patient had FH because no FH-associated genetic mutations were detected. Nevertheless, in this case, her LDL-cholesterol level was elevated at 581 mg/dL, similar to that of HoFH. These results indicate that her liver was completely unable to temporarily process LDL-cholesterol, even with secondary drug-induced hypercholesterolemia.

Statins are widely recommended as the first-line treatment for hyperlipidemia and are used even in FH (12,13). Statins are competitive inhibitors of HMG-CoA reductase, which is the rate-limiting enzyme in cholesterol biosynthesis and decreases serum LDL-cholesterol levels. Although the biosynthesis of cholesterol and the cholesterol pool in hepatocytes decrease, the number of LDL receptors on the hepatic cell membrane increases. The increase in LDL receptors overcomes the increase in HMG-CoA reductase, thereby enhancing the LDL-cholesterol uptake and decreasing the serum cholesterol levels (14). In other words, the serum cholesterol-lowering effect of statins is due to an increase in LDL receptor expression rather than the inhibition of cholesterol biosynthesis in the liver. It is relatively selective in lowering serum LDL-cholesterol levels. In general, statins can reduce the LDL-cholesterol levels by approximately 20-65% (3). In this case, statins were effective in dramatically improving severe hypercholesterolemia, and this result means that any of the pathways in lipid metabolism through which statins act are abnormal. In addition, high LDL-cholesterol may decrease at some stage of expression of the LDL receptor, which we think is due to the effects of statins.

Secondary drug-induced hypercholesterolemia is not uncommon as a side effect, and several drugs, including antihypertensives, antihyperglycemics, antipsychotics, antiretrovirals, and immunosuppressants, have been reported to cause hypercholesterolemia, primarily elevated LDL-cholesterol (4). The largest drug classes that can increase the LDL-cholesterol levels are immunosuppressants, antineoplastic agents, antipsychotics, and antiretrovirals. As many of these drugs are essential for long-term use and are difficult to replace, there is an increased potential for cardiovascular risk. Determining the mechanisms of drug-induced dyslipidemia is difficult, and data from sophisticated human studies are limited. These drugs may cause drug-induced hypercholesterolemia directly or may be indirectly caused by other effects of the drug, such as weight gain (15). The mechanisms by which immunosuppressants induce dyslipidemia are reported to involve LDL metabolism and PCSK9, at least (16,17). mammalian target of rapamycin (mTOR) inhibitors are antineoplastic agents that increase cholesterol (18). mTOR is a central regulator of lipid metabolism and sterol regulatory element binding protein (SREBP), thus suggesting that mTOR inhibitor-induced dyslipidemia may be mediated by these mechanisms (19). The hypercholesterolemic effects of several antipsychotics are thought to be associated with increased SREBP2 activation due to INSIG-2 inhibition in murine models (20). Protease inhibitors, a class of antiretroviral drugs, have also been shown to stimulate the SREBP activity in the liver (21). Although it is unclear how hypercholesterolemia is induced by mesalazine, it is usually used for a long time, and it is difficult to replace this medication for ulcerative colitis. Moreover, in general, acute infections tend to decrease LDL-cholesterol levels, and the more severe the infection, the more pronounced the decrease in cholesterol levels (22,23). Therefore, it is known that as inflammation attenuates during anti-inflammatory drug treatment, the cholesterol levels return to normal (24,25). As this means that the improvement in inflammation increases cholesterol levels, many anti-inflammatory drugs seem to increase cholesterol levels. Therefore, in this case, the improvement in ulcerative colitis may be associated with an increase in the cholesterol level, at least in part. However, during the course of rosuvastatin treatment and after showing an improvement in her LDL-cholesterol levels, her ulcerative colitis exacerbated. Therefore, it is unlikely that the improvement in inflammation caused the hypercholesterolemia. Interestingly, there is a report that statins are useful as adjuvant therapy to mesalazine therapy for ulcerative colitis (26). This report showed that high doses of atorvastatin may attenuate inflammation and symptoms in patients with ulcerative colitis. In this case, it was difficult to replace mesalazine therapy for ulcerative colitis, and thus, it is thought that it is better to start statin therapy at an early stage when hypercholesterolemia develops.

This study has several strengths. To the best of our knowledge, this is the first case report of severe hypercholesterolemia caused by an abnormal secondary lipid metabolism following mesalazine administration. Clinicians should be aware of the possibility of severe hypercholesterolemia caused by mesalazine for educational purposes. Second, we observed elevated LDL-cholesterol levels equivalent to those of HoFH even in secondary hypercholesterolemia. Third, this case directly demonstrated the effectiveness of statins in treating hypercholesterolemia caused by secondary lipid metabolism abnormalities. However, this case report was also associated with several limitations. This is a case report of a single Japanese woman, which limits the generalizability and reliability of our findings. In addition, we believe that the results of this case are not necessarily applicable to Caucasians. However, in this case, we believe that mesalazine contributed to severe hypercholesterolemia, at least in part, given the pattern of elevated LDL-cholesterol levels. The mechanisms of the lipid metabolism are often unclear, and many factors (such as thyroid function and weight loss, and etc.) may have contributed to the elevated LDL-cholesterol levels in this case. Moreover, prednisolone therapy was initiated even after the patient achieved an improvement of dyslipidemia. As corticosteroids are known to influence lipid metabolism, we described the timing and dose of steroid treatment.

Taken together, we should keep in mind that mesalazine therapy for ulcerative colitis can cause severe hypercholesterolemia and significantly increase the LDL-cholesterol levels. Furthermore, this case suggests that secondary hypercholesterolemia with elevated LDL-cholesterol levels is similar to that of homozygous FH. We also believe that this case is important because it proves that statins are effective in treating hypercholesterolemia caused by secondary lipid metabolism abnormalities. Therefore, various lipid metabolic disorders must be checked during mesalazine treatment.

Informed consent was obtained from this patient for being included in the case report.

The authors state that they have no Conflict of Interest (COI).

Supplementary Material

Supplementary material 1. Lipoprotein fractions and the abdominal ultrasound.

A: Lipoprotein fractions. Lipoprotein fractions showed MIDBAND fractions were elevated (MIDBAND, 33%), and lipoprotein-X was not detected. B: The abdominal ultrasound. The abdominal ultrasound revealed slightly prominent blood flow in the hepatic artery, but cholestasis was not detected.