The official journal of the Japan Atherosclerosis Society andthe Asian Pacific Society of Atherosclerosis and Vascular Diseases

Review

J Atheroscler Thromb, 2021; 28: 883-904. http://doi.org/10.5551/jat.RV17054

Current Diagnosis and Management of Primary Chylomicronemia
Hiroaki Okazaki 1, Takanari Gotoda 2, Masatsune Ogura 3, Shun Ishibashi 4, Kyoko Inagaki 5, Hiroyuki Daida 6,
Toshio Hayashi 7, Mika Hori 8, Daisaku Masuda 9, Kota Matsuki 10, Shinji Yokoyama 11 and Mariko Harada-Shiba 12
on behalf of the Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable
Disease of the Ministry of Health, Labour and Welfare of Japan †1

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Department of Metabolic Biochemistry, Faculty of Medicine, Kyorin University, Tokyo, Japan3
Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
4
Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University,
Tochigi, Japan
5
Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Nippon Medical School, Tokyo, Japan
6
Faculty of Health Science, Juntendo University, Juntendo University Graduate School of Medicine, Tokyo, Japan
7
School of Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan
8
Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
9
Department of Cardiology, Health Care Center, Rinku Innovation Center for Wellness Care and Activities (RICWA), Rinku
General Medical Center, Osaka, Japan10
Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
11
Institute for Biological Functions, Chubu University, Aichi, Japan
12
Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
2†

The Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable Disease of the Ministry of
Health, Labour and Welfare of Japan: Mariko Harada-Shiba (Department of Molecular Pathogenesis, National Cerebral andCardiovascular Center Research Institute, Osaka, Japan), Shun Ishibashi (Division of Endocrinology and Metabolism, Department
of Internal Medicine, School of Medicine, Jichi Medical University, Tochigi, Japan), Shinji Yokoyama (Institute for Biological
Functions, Chubu University, Aichi, Japan), Hitoshi Shimano (Department of Internal Medicine (Endocrinology and Metabolism),
Faculty of Medicine University of Tsukuba, Tsukuba, Japan), Koutaro Yokote (Department of Endocrinology, Hematology andGerontology, Chiba University Graduate School of Medicine, Chiba, Japan), Hideaki Bujo (Department of Clinical-Laboratory andExperimental-Research Medicine, Toho University Sakura Medical Center, Chiba, Japan), Shizuya Yamashita (Rinku General
Medical Center, Osaka, Japan), Kazuhisa Tsukamoto (Department of Internal Medicine, Teikyo University, Tokyo, Japan), Toshio
Hayashi (School of Health Sciences, Nagoya University Graduate School of Medicine, Nagoya, Japan), Katsunori Ikewaki (Divisionof Neurology, Anti-Aging, and Vascular Medicine, Department of Internal Medicine, National Defense Medical College, Saitama,
Japan), Takanari Gotoda (Department of Metabolic Biochemistry, Faculty of Medicine, Kyorin University, Tokyo, Japan), Kazushige
Dobashi (Department of Pediatrics, School of Medicine, University of Yamanashi, Yamanashi, Japan), Yoshihiro Miyamoto (Open
Innovation Center, National Cerebral and Cardiovascular Center, Osaka, Japan), Misa Takegami (Department of Preventive
Medicine and Epidemiology, National Cerebral and Cardiovascular Center, Osaka, Japan), Yoshiki Sekijima (Department ofMedicine (Neurology & Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan), Yasushi Ishigaki (Division of
Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan), Hiroaki
Okazaki (Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan),Atsushi Nohara (Ishikawa Prefectural Central Hospital, Kanazawa, Japan), Shingo Koyama (Division of Neurology and Clinical
Neuroscience, Department of Internal Medicine III, Yamagata University Faculty of Medicine, Yamagata, Japan), Kyoko Inagaki(Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Nippon Medical School, Tokyo, Japan), Koh
Ono (Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan), Masahiro Koseki(Division of Cardiovascular Medicine, Department of Medicine, Osaka University Graduate School of Medicine, Osaka, Japan),
Hiroyuki Daida (Faculty of Health Science, Juntendo University, Juntendo University Graduate School of Medicine, Tokyo, Japan),
Manabu Takahashi (Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University,
Tochigi, Japan), Kimitoshi Nakamura (Department of Pediatrics, Kumamoto University Graduate School of Medical Sciences,
Kumamoto, Japan), Takashi Miida (Department of Clinical Laboratory Medicine, Juntendo University Graduate School of
Medicine, Tokyo, Japan), Masa-aki Kawashiri (Department of Cardiovascular Medicine, Graduate School of Medical Sciences,
Kanazawa University, Kanazawa, Japan), Tetsuo Minamino (Department of Cardiorenal and Cerebrovascular Medicine, Faculty of
Medicine, Kagawa University, Kagawa, Japan), Sachiko Okazaki (Division for Health Service Promotion, The University of Tokyo,
Tokyo, Japan), Hayato Tada (Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences,
Kanazawa, Japan), Jun Wada (Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University

883

Okazaki et al .

Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan), Masatsune Ogura (Division of Lipid
Metabolism, Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute,
Osaka, Japan), Hirotoshi Ohmura (Department of Cardiovascular Medicine, School of Medicine, Juntendo University, Tokyo,
Japan), Mika Hori (Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University, Nagoya,Japan), Kota Matsuki (Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki,
Japan), Masashi Yamamoto (Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of
Medicine, Chiba, Japan), Yasuo Takeuchi (Division of Nephrology, Kitasato University School of Medicine, Kanagawa, Japan),
Atsuko Nakatsuka (Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate
School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan), Daisaku Masuda (Department of Cardiology,
Health Care Center, Rinku Innovation Center for Wellness Care and Activities (RICWA), Rinku General Medical Center, Osaka,
Japan), Satoshi Hirayama (Department of Clinical Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo,
Japan), Masayuki Kuroda (Center for Advanced Medicine, Chiba University Hospital, Chiba University, Chiba, Japan), Takashi
Yamaguchi (Center of Diabetes, Endocrinology and Metabolism, Toho University Sakura Medical Center, Chiba, Japan), Takeyoshi
Murano (Clinical Laboratory Program, Faculty of Science, Toho University, Chiba, Japan).

Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation ofchylomicrons in plasma. The levels of plasma triglycerides (TGs) typically range from 1,000 - 15,000 mg/dL or
higher.
PCM is caused by defects in the lipoprotein lipase (LPL) pathway due to genetic mutations, autoantibodies,or unidentified causes. The monogenic type is typically inherited as an autosomal recessive trait with loss-offunction mutations in LPL pathway genes (LPL, LMF1, GPIHBP1, APOC2, and APOA5). Secondary/environmental factors (diabetes, alcohol intake, pregnancy, etc.) often exacerbate hypertriglyceridemia (HTG).
The signs, symptoms, and complications of chylomicronemia include eruptive xanthomas, lipemia retinalis,
hepatosplenomegaly, and acute pancreatitis with onset as early as in infancy. Acute pancreatitis can be fatal andrecurrent episodes of abdominal pain may lead to dietary fat intolerance and failure to thrive.
The main goal of treatment is to prevent acute pancreatitis by reducing plasma TG levels to at least lessthan 500-1,000 mg/dL. However, current TG-lowering medications are generally ineffective for PCM. The only
other treatment options are modulation of secondary/environmental factors. Most patients need strict dietary fat
restriction, which is often difficult to maintain and likely affects their quality of life.
Timely diagnosis is critical for the best prognosis with currently available management, but PCM is often
misdiagnosed and undertreated. The aim of this review is firstly to summarize the pathogenesis, signs,
symptoms, diagnosis, and management of PCM, and secondly to propose simple diagnostic criteria that can bereadily translated into general clinical practice to improve the diagnostic rate of PCM. In fact, these criteria are
currently used to define eligibility to receive social support from the Japanese government for PCM as a rare andintractable disease.
Nevertheless, further research to unravel the molecular pathogenesis and develop effective therapeuticmodalities is warranted. Nationwide registry research on PCM is currently ongoing in Japan with the aim ofbetter understanding the disease burden as well as the unmet needs of this life-threatening disease with poor
therapeutic options.
Key words: Chylomicronemia, Triglyceride, Pancreatitis, Diagnostic criteria, Treatment guide

1. Definition of Chylomicronemia
Chylomicrons (CMs) are intestine-derived
lipoproteins that transport dietary fat to peripheral

tissues 1). CMs are usually quickly cleared from plasma
after an overnight fast. The hallmark ofchylomicronemia is persistent elevation of CMs in thefasting state ( ＞ 12h). Plasma triglyceride (TG) levels

Address for correspondence: Hiroaki Okazaki, Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1
Hongo, Bunkyo-ku, Tokyo 113–8655, Japan
E-mail: hokazaki-tky@umin.ac.jp
Received: March 17, 2021
Accepted for publication: March 20, 2021
Copyright©2021 Japan Atherosclerosis Society
This article is distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

884

Diagnosis and Management of Chylomicronemia

Fig. 1. Molecular basis of primary chylomicronemia
Lipoprotein lipase (LPL) hydrolyzes triglycerides (TGs) in TG-rich lipoproteins (TGRLs), such as very low-density lipoproteins (VLDLs) andchylomicrons (CMs) to liberate free fatty acids (FFAs), which are utilized by peripheral tissues (e.g., muscle, heart, and adipose tissues). Activity of LPL is regulated by a quaternary structure (monomer/dimer/oligomer) as well as by multiple LPL-pathway proteins 210-212). LMF1 isrequired for the synthesis of LPL in parenchymal cells of these peripheral tissues. GPIHBP1 is a transmembrane protein that tethers LPL on
the endothelial cell surface to provide a platform for TG hydrolysis. GPIHBP1 captures LPL in the subendothelial (interstitial) space of
peripheral tissues, transports LPL from the subendothelial surface to the luminal surface of endothelial cells by transcytosis, and anchors LPL
on the luminal surface facing the bloodstream to facilitate lipolysis. For the hydrolytic activity of LPL, two apolipoproteins, apoC-II andapoA-V, are required. ApoC-II is necessary for the enzymatic activity of LPL. ApoA-V primarily enhances the interaction between TGRL and
LPL by forming TGRL-apoA-V-GPIHBP1-LPL complex via its dual binding affinity to TGRL and GPIHBP1. Defects in LPL pathway proteins (LPL, LMF1, GPIHBP1, apoC-II, apoA-V) due to genetic mutations or autoantibodies cause primary chylomicronemia (PCM). LPL
activity can be measured after releasing LPL from the luminal surface into the circulation by i.v. injection with heparin.
Abbreviations: apoA-V, apolipoprotein A-V; apoC-II, apolipoprotein C-II; GPIHBP-1, glycosylphosphatidylinositol-anchored high-density
lipoprotein-binding protein 1; LMF1, lipase maturation factor 1.

in chylomicronemia typically range from 1,000 to
15,000 mg/dL or higher 2). As CMs start toaccumulate in plasma when TG levels increase to morethan 500 - 1,000 mg/dL 1), it is practical to screen andsuspect chylomicronemia if plasma TGs ＞ 1,000 mg/
dL 2, 3).

energy source in peripheral tissues, or stored as TGs in
adipose tissues, or re-esterified and secreted as very
low-density lipoprotein (VLDL)-TG by the liver.
CMs are converted to CM remnants after TG
hydrolysis by LPL and then cleared from plasma
through endocytosis mainly by the liver.

2. Metabolism of Chylomicrons

3. Molecular Basis of Chylomicronemia

CMs are produced by the intestine after a mealand secreted into the circulation 1). Their synthesis
requires apoB-48 protein, which is transcribed fromthe edited mRNA of APOB, and microsomal
triglyceride transfer protein (MTTP), which
incorporates dietary TGs into CMs. More than 90%
of lipids in CMs are TGs (derived from dietary fatty
acids and TGs), which are hydrolyzed by lipoprotein
lipase (LPL) on the endothelial cell surface of
peripheral tissues (muscle, heart, adipose tissue, etc.)
to liberate free fatty acids (FFAs). FFAs are used as an

Plasma levels of CMs are affected by primary factors
as well as secondary factors 2, 4, 5). Primary factors consistof defects in the proteins that metabolize CMs, such as
LPL and its related proteins (apolipoprotein(apo)C-II,
apoA-V, glycosylphosphatidylinositol-anchored highdensity lipoprotein-binding protein 1 (GPIHBP1),
lipase maturation factor 1 (LMF1)) (Fig. 1). Secondary
factors include conditions that impair CM metabolism,
such as poor control of diabetes, excessive alcohol
intake, and pregnancy. In primary chylomicronemia(PCM), chylomicronemia usually persists even after885

Okazaki et al .

management of secondary factors. PCM is caused by
defects in LPL pathway genes (LPL, APOC2, APOA5,GPIHBP1, LMF1) due to genetic mutations orpresence of autoantibodies against LPL pathway
proteins (GPIHBP1, LPL, and apoC-II) 6-9).
4. Complications of Chylomicronemia
Chylomicronemia is a risk factor for acutepancreatitis 10). Although the underlying mechanisms
are not fully understood, the widely acceptedhypothesis is that an excess of FFAs derived fromlipolysis of chylomicron-TG by pancreatic lipase
damages pancreatic acinar cells or endothelial cells ofpancreatic capillaries, leading to activation of
inflammatory processes 11). In addition, high levels ofplasma CM may increase the viscosity of pancreatic
microcirculation and impair pancreatic blood flow,
further exacerbating inflammation. Genetic predisposition
may also contribute to the pathogenesis 12).
Based on this hypothesis, it is generally believedthat chylomicronemia per se induces pancreatitis and,
therefore, reducing plasma CM levels should lower therisk of pancreatitis 10). The widely accepted treatment
goal is to reduce plasma TG levels to at least less than
1,000 mg/dL 2, 4, 5, 12-14).
5. Primary Factors of Chylomicronemia
Five genes (LPL, LMF1, GPIHBP1, APOC2,
APOA5) have been identified as the causative genes ofmonogenic chylomicronemia (Fig. 1) 4, 5). All of them
are required for the normal function of LPL.
Homozygous, compound heterozygous, or double
heterozygous loss-of-function mutations of these LPL
pathway genes usually cause monogenic
chylomicronemia with an autosomal recessive mode ofinheritance 15). Heterozygous mutations or pathologicalvariants in HTG-susceptible genes, including thosefor hepatic lipase (HL) and apolipoprotein E, mayalso predispose to chylomicronemia 3, 5, 16-18).
Loss-of-function mutations in LPL-pathway
genes have been identified in only less than 30-40% of
patients suspected of monogenic chylomicronemia 19, 20).
In some cases, autoantibodies against LPL pathway
proteins can cause PCM. Additional genetic factors or
unknown causes may also underlie PCM.
• LPL (LPL deficiency, OMIM: 238600): LPL is
the most common causative gene of monogenic
chylomicronemia. More than 220 pathogenic variantsin LPL have been described (missense, nonsense,
splicing variants, insertion/deletion of nucleotide(s),deletion/duplication/insertion/rearrangement of886

exon(s)) 2, 4, 15, 20-22). A list of mutations in LPL has been
comprehensively summarized in exon-intron diagramsby Rabacchi C et al. and Rodrigues R et al. 20, 22). LPL
activity is usually tested in post-heparin plasma taken
10-15 min after iv. heparin injection (10-60 IU/kg
body weight) 4, 23).
• LMF1 (LMF1 deficiency, OMIM: 246650):
LMF1 encodes LMF1, a transmembrane chaperone
protein of parenchymal cells (muscle, adipose tissues,etc.). LMF1 is localized to the endoplasmic reticulum
and is required for proper synthesis and secretion of
LPL and HL. In addition to nonsense mutations thatwere originally reported, several other mutations,
including missense loss-of-function mutations, havebeen identified in LMF1 24-29).
• GPIHBP1 (GPIHBP1 deficiency, OMIM:
615947): GPIHBP1 encodes GPIHBP1, a transmembraneprotein that tethers LPL on the endothelial cell surface
to provide a platform for TG hydrolysis 30, 31). GPIHBP1
captures LPL in the subendothelial (interstitial) spaceof peripheral tissues (skeletal muscles, heart, adipose
tissues, etc.), transports LPL from the subendothelial
surface to the luminal surface of endothelial cells bytranscytosis, and anchors LPL on the luminal surface
facing the bloodstream to facilitate lipolysis. So far, atleast 23 pathogenic mutations in GPIHBP1 have beenreported in severe HTG patients, including thosecausing total GPIHBP1 deficiency 21, 32-36). Mutations
in GPIHBP1 are comprehensively summarized in theexon-intron diagram by Rabacchi et al. 35). GPIHBP1
deficiency may be differentiated from LPL deficiency
in that LPL activity or protein in post-heparin plasma
is not totally lacking in GPIHBP1 deficiency 37).
• APOC2 (apoC-II deficiency, OMIM: 207750):
APOC2 encodes apoC-II, a co-factor required for LPL
activity. APOC2 is the second most common causative
gene of monogenic chylomicronemia. At least 24
mutations have been reported worldwide 2, 4, 5, 38-41),
and are comprehensively summarized in the exonintron diagram by Wolska et al. 41). In some cases,
plasma levels of apoC-II have been severely decreased
but are detected with apparently normal electrophoretic
patterns (so-called hypoapoC-II) 42-45). In apoC-II
deficiency, symptoms often develop at an older age(13-60 years) than in LPL deficiency 1, 4). As apoC-II
deficient patients tend to be subjected to strict fat
restriction at an older age, they may have poorer
dietary adherence and more frequent episodes of acutepancreatitis in adulthood than LPL deficient patients,
often accompanied by high VLDL levels 2).
• APOA5 (apoA-V deficiency, OMIM: 144650):
APOA5 encodes apoA-V, a co-factor of LPL thatenhances interaction between LPL and TG-richlipoproteins (TGRLs) 46, 47). ApoA-V has dual bindingDiagnosis and Management of Chylomicronemia

affinity for both TGRL and GPIHBP1, thereby
forming the TGRL-apoA-V-GPIHBP1-LPL complex
to facilitate lipolysis 31, 48, 49). So far, at least 21
mutations in APOA5 have been reported, which arecomprehensively summarized in exon-intron diagramsby Albers et al. 50-53). In most cases, severe HTG
develops later in life due to the combinatorial effects
of primary (genetic) and secondary factors (aging,diabetes, pregnancy, HIV therapy, etc.) 53). The
underlying molecular mechanisms of apoA-V deficient
HTG in terms of gene-environmental interactions has
only begun to be elucidated 54, 55).
• Autoantibodies against LPL pathway proteins:
Autoimmune chylomicronemia due to autoantibodies
against LPL pathway proteins (GPIHBP1, LPL,
apoC-II) has been reported 6-9) . Autoimmune
chylomicronemia may be complicated by otherautoimmune diseases and be ameliorated by steroid or
immune-suppressive therapy.
6. Secondary Factors of Chylomicronemia
The following factors have been reported toinduce chylomicronemia 3-5, 13, 35, 56-61). Among them,excess alcohol consumption and diabetes mellitus are
the two most common factors associated with severe
HTG 18, 62, 63).
Pregnancy is another important factor that can
induce chylomicronemia. Hormonal changes during
pregnancy result in hyperlipidemia even in healthy
subjects, as a physiological response to ensure nutrient
supply to the fetus 64-66). Plasma TG levels progressively
increase in healthy subjects by 2- to 4-fold 67), andmarkedly increase in subjects with PCM 68-74).
Pregnancy increases TGRL (VLDL) production anddecreases TGRL clearance 75-78).
• Lifestyle-related factors: Dietary factors suchas excessive alcohol intake, high-fat diet, highcarbohydrate diet rich in fructose and other simple
sugars. Less exercise and excessive intake of total
calories, particularly in subjects who are overweight,
have metabolic syndrome, or diabetes mellitus.
• Pathophysiological conditions: Pregnancy,
obesity, metabolic syndrome, anorexia nervosa,glucose intolerance, diabetes mellitus with insulin
resistance or insulin deficiency, endocrine diseases
such as hypothyroidism, acromegaly, Cushing’s
syndrome, Nelson’s syndrome, glycogen storage
diseases, amyloidosis, renal disease (nephrotic
syndrome, proteinuria, uremia, glomerulonephritis,etc.), liver disease, autoimmune disorders,lipodystrophies, Weber-Christian disease, multiple
myeloma, paraproteinemia, and lymphoproliferative

disorders, etc.
• Medications: Glucocorticoids, oral estrogens(contraceptives, postmenopausal replacement
therapies), clomiphene, tamoxifen, exogenous
testosterone; retinoids such as isotretinoin, bexarotene;
immunosuppressants and anticancer drugs such as
sirolimus, cyclosporine A, tacrolimus, capecitabine,
cyclophosphamide, asparaginase; antihypertensives
such as thiazides, loop diuretics, non-selective β-blockers; bile acid-sequestrants; antiviral drugs suchas entecavir, ritonavir and other antiretroviral proteaseinhibitors; second-generation antipsychotics (atypicalantipsychotics), such as dozapine, clozapine,olanzapine, risperidone, quetiapine; antidepressantssuch as mirtazapine, venlafaxine; selective serotonin
reuptake inhibitors (sertraline, etc.); anticonvulsants,
such as valproate; anesthetic drugs, such as propofol.
7. Classification of Chylomicronemia
Chylomicronemia was formerly classified as type
1 and 5 hyperlipoproteinemia (HLP) in theFredrickson classification (WHO classification) 5, 79),
where increased plasma lipoproteins are CM for type
1 and CM+VLDL for type 5 HLP. However,differentiation of type 1 and type 5 HLP is often
difficult because of considerable overlaps inphenotypes and genetic backgrounds 3, 5, 17).
Differentiation of monogenic from polygenic
chylomicronemia is also difficult 80). Even whenmonogenic chylomicronemia is suspected, causative
mutations have been identified in less than 30-40% 19, 20).
For practical reasons, we prefer to use the term
PCM, which is defined as a condition with persistentelevation of TG ＞ 1,000 mg/dL even after
management of secondary factors. The term familial
chylomicronemia syndrome (FCS) is not used here, as
monogenic chylomicronemia is typically autosomal
recessive, and most cases are sporadic, without a family
history. The term “familial” may confuse both patientsand doctors, and may lead to underdiagnosis 3, 81).
8. Prevalence of Chylomicronemia
The prevalence of severe HTG (TG ＞ 10 mmol/
L (885 mg/dL)) is estimated at ~1 in 600 in North
America 5). In a population of 440,240 subjects in theUS, severe HTG (886-2,000 mg/dL) and very severe
HTG ( ＞ 2,000 mg/dL) were observed in 0.15% and0.014%, respectively 36).
The monogenic type of chylomicronemia is veryrare and its frequency is estimated at 1 to 2 per million
in the general population 1, 4, 5). The most common
causative gene is LPL, followed by other LPL pathway
887

Okazaki et al .

genes (APOC2, GPIHBP1, APOA5, and LMF1) 5, 15, 53).
Severe HTG is more often due to polygenic
causes 3, 82). Dron et al. reported that the etiology ofsevere HTG (TG ＞ 10 mmol/L (885 mg/dL)) ismonogenic in 1.1%, polygenic in 46%, andgenetically unidentified in the rest of cases 83). Anotherstudy identified monogenic causes in 0.96% of
patients with very severe HTG (TG ＞ 20 mmol/L(1770 mg/dL)) recorded at least once during regular
medical care 22).
9. Prevalence of HTG-Induced
Acute Pancreatitis
Regardless of the underlying etiology of HTG,
the risk of acute pancreatitis increases as TG levels
increase, particularly when they exceed 1,000 - 2,000
mg/dL 84).
HTG is the third leading cause (5-38%) of acutepancreatitis after alcohol and gallstones 1, 12, 85-87). HTG
is the leading cause (25~50%) of acute pancreatitis
during pregnancy 12, 74, 88), which is most often seen in
the third trimester (19%, 26%, 53% in the 1st, 2nd,
and 3rd trimester, and 2% in postpartum period) 89).
The frequency of HTG-induced acute pancreatitis inpregnancy is estimated as 1 in 1000-12,000
pregnancies 14, 73, 74).
Risk of acute pancreatitis increases by ~4% for
every 100 mg/dL increase in plasma TG 56, 84, 87, 90, 91).
According to the 2010 Endocrine Society guidelines,
HTG can be classified into mild HTG (150-199 mg/dL), moderate HTG (200-999 mg/dL), severe HTG(sHTG, 1000-1999 mg/dL), or very severe HTG(vsHTG, ＞ 2000 mg/dL). The prevalence ofpancreatitis in sHTG and vsHTG is about 10% and20%, respectively 5, 13, 14, 87, 92).
Clinically, it remains difficult to predict if a
HTG patient will develop acute pancreatitis or not.
Some patients do not develop acute pancreatitis evenat TG levels higher than 30,000 mg/dL 1, 2).
Conversely, patients can develop acute pancreatitis at
TG levels of 5-10 mmol/L (442-885 mg/dL) 93). The
underlying etiology of monogenic chylomicronemia
seems to confer a potent risk of acute pancreatitis 53, 94-96).
Compared to normolipidemic individuals, the risk ofacute pancreatitis increased by 16-fold, 56-fold, and361-fold in HTG (5-9 mmol/L (442-796 mg/dL))
without LPL deficiency, HTG ( ＞ 9 mmol/L (796 mg/dL)) without LPL deficiency, and HTG ( ＞ 9 mmol/L(796 mg/dL)) with LPL deficiency (geneticallyconfirmed), respectively 94). Greater cumulative
exposure of HTG to the pancreas due to genetic
causes may impose higher pancreatitis risk 53, 94-97)(See
sections 12 and 16(B) for other suggested risk factors
888

of acute pancreatitis among HTG subjects).
10. Signs, Symptoms, and Complications of
Chylomicronemia
Depending on the severity of the mutation, signs,
symptoms, and complications of chylomicronemia
may manifest as early as in infancy, in childhood, orlater in life 4, 95).
• Abdominal pain, fat intolerance, failure to
thrive: Abdominal pain affects ~60% of monogenic
chylomicronemia patients and can be mild toincapacitating 4, 95, 96). Recurrent episodes of abdominal
pain may lead to dietary fat intolerance and failure to
thrive. Body weight may be lower because of restricted
food intake.
• Pancreatitis: Acute pancreatitis can be severe,
recurrent, and life-threatening 1, 4, 95). Acute pancreatitis
may lead to chronic pancreatitis and diabetes.
Irrespective of its etiology, severe HTG should be
carefully monitored for the possible complications ofpancreatitis. Compared to polygenic chylomicronemia,
monogenic chylomicronemia is associated with ahigher risk of acute pancreatitis and tends to manifest
severe phenotypes 86, 94, 95). According to a survey oflipidologists, ~67% of monogenic patients were
hospitalized for acute pancreatitis vs. ~14% of
polygenic patients 95, 96). It should be noted that highlevels of plasma TG may interfere with assays ofplasma pancreatic enzymes (lipase, amylase), resulting
in falsely low levels 2, 98-100). HTG-induced acutepancreatitis should not be misdiagnosed due toapparently low serum levels of pancreatic enzymes.
• Lipemic plasma: Lipemic plasma (milkylooking plasma) is characterized by a creamy CM layer
floating above the bottom layer, after leaving serum
standing overnight in a refrigerator (the “refrigerator”
test) 1). In type 5 HLP, the bottom layer contains
VLDLs and has a lactescent appearance. In type 1
HLP, the bottom layer is clear without apparent
VLDL accumulation. Type 1 HLP is more frequently
observed than type 5 in monogenic chylomicronemia 19).
(See reference by Yuan G et al. for a photograph oflipemic plasma 56).)• Eruptive xanthomas: Eruptive xanthomas
affect 10-50% of the monogenic type 95, 96). They
appear when plasma TG levels increase to more than
2,000 mg/dL as yellow papules on the skin of thetrunk, buttocks, and extremities (extensor surfaces of
the arms and knees) as a result of TG uptake bymacrophages (see references by Nayak KR et al. andYuan G et al. for photographs) 2, 4, 56, 101). Along with
reduction in plasma TG levels, they graduallyDiagnosis and Management of Chylomicronemia

Table 1. Diagnostic criteria for primary chylomicronemia
A. Entry Criterion:
A1 and A2 with exclusion of differential diagnosis in E
A1) Plasma TG level ≧ 1,000 mg/dL (after fasting for 12 hours or longer)
A2) Presence of chylomicrons in serum (from appearance of supernatant cream layer after allowing serum to stand for 24 hours or longer
at 4℃, ultracentrifugation, or electrophoresis (agarose gel, polyacrylamide gel, or HPLC))
B. Clinical manifestations (major (B1-B4) and minor (B5, B6))
B1) Recurrent episodes of abdominal pain and/or acute pancreatitis
B2) Eruptive xanthomas
B3) Lipemia retinalis
B4) Hepatomegaly and/or splenomegaly
B5) Dyspnea
B6) Neurological symptoms (cognitive impairment, memory impairment, depression, etc.)
C. Laboratory findings
C1) LPL activity and/or protein in post heparin plasma, adipose tissue, or macrophages is absent or markedly decreased ( ＜ 10% of
normal subjects)
C2) Plasma apoC-II is absent or markedly decreased ( ＜ 10% of normal subjects)
C3) Plasma apoA-V is absent or markedly decreased ( ＜ 10% of normal subjects)
C4) Autoantibodies against LPL, heparin, apoC-II, or GPIHBP1.
D. Genetic test
Identification of causative mutation(s) in LPL, APOC2, GPIHBP1, LMF1, or APOA5
E. Differential diagnosis
Type 3 hyperlipidemia, familial combined hyperlipidemia (FCHL), and secondary hyperlipidemia due to following: excess alcohol
intake, nephrotic syndrome, anorexia nervosa, pregnancy, diabetes mellitus, lipodystrophies, Weber-Christian disease, hypothyroidism,
acromegaly, Cushing’s syndrome, Nelson’s syndrome, multiple myeloma, systemic lupus erythematosis, malignant lymphoma,
sarcoidosis, etc.; medications such as estrogens, steroids, diuretics, β-blockers, antipsychotics including selective serotonin reuptake
inhibitors (SSRIs), retinoids such as isotretinoin, antiretroviral protease inhibitors, immunosuppressants, etc.
<Diagnosis>
Definite: Entry criterion (A) associated with at least one item from C or D
Probable: Entry criterion (A) associated with at least one item from B1-B4
Possible: Entry criterion (A) with or without item(s) from B5-B6

disappear over several weeks to a few months 2).
• Lipemia retinalis: Lipemia retinalis affects~40% of the monogenic type 95, 96) and is characterized
by retinal blood vessels with a milky appearance (apale pink color) on fundoscopy (see references by
Kumar J et al. and Yuan G et al. for photographs) 56, 102).
Vision is not impaired. It is usually visible whenplasma TG levels increase to more than 4,000 mg/
dL 2).
•H e p a t o m e g a l y a n d s p l e n o m e g a l y :Hepatomegaly and splenomegaly affect 10-50% of themonogenic type 95, 96) as a result of TG uptake bymacrophages and other cell types in these tissues 1, 4).
Both conditions are reversible and rapidly improve
within a week, along with reduction in plasma TG
levels 2).
• Other symptoms (fatigue, dyspnea, andneurological symptoms): Other clinical symptoms
include fatigue, dyspnea, and neurological symptoms 1)
such as memory impairment (transient memory loss),cognitive impairment, mild dementia, cloudy thought,

brain fog, neurosis, irritability, anxiety, anddepression 4, 95, 103-107). Neurological symptoms affect~8% of the monogenic type 95). Although little is
known about the underlying mechanisms of these
symptoms, large surveillance studies among
chylomicronemia patients have shown that they
dominantly and adversely affect patients’ quality oflife and increase the burden of the disease 104-107).
11. Diagnosis of Chylomicronemia
Undertreatment and underdiagnosis ofchylomicronemia are one of the major risks for acutepancreatitis 84, 87). In order to achieve early diagnosis
and treatment for chylomicronemia, simple diagnostic
criteria that can be readily translated into generalpractice are required.
Based on TG levels that lead to suspicion ofchylomicronemia (TG ＞ 1,000 mg/dL), clinicalmanifestations and the available data on diagnostic
tests, here we propose diagnostic criteria for PCM
889

Okazaki et al .

(Table 1).
It should be noted that PCM is geneticallyconfirmed in less than 30-40% of patients suspectedof monogenic chylomicronemia 19, 20). Therefore, wehave set three categories (definite, probable, andpossible) so that PCM patients will not be missed
even without a genetic diagnosis.
To achieve timely diagnosis and improve thediagnostic rate of PCM, screening of plasma TG levelsin the following settings will be helpful. Clinicians
across multiple disciplines, such as primary care
physicians, gastroenterologists, gynecologists, andother doctors who have occasionally encountered
severe HTG patients, should consult lipidologists
concerning further diagnostic tests for chylomicronemia.
• Health checkup or opportunistic blood test: Allpatients who have TG levels of more than 1,000 mg/
dL in universal lipid screening 108) or a routine clinic
visit should be suspected of chylomicronemia 96, 109).
• Acute abdomen (including pancreatitis):Those who have acute abdomen or are suspected ofpancreatitis should have their plasma TG levels
measured 96). Plasma TG should be measured as earlyas possible after the onset of abdominal pain, as TG
levels rapidly decrease within 24-48 hours of onset 110).
• Pregnancy: Many cases of monogenic
chylomicronemia have been discovered in the third
trimester of pregnancy 111-118). HTG-induced acutepancreatitis in pregnancy can be lethal to both motherand fetus 119). Gestational HTG may also increase therisk of hyperviscosity syndrome 120), pre-eclampsia 121),
fetal macrosomia, and fetal pancreatitis-related
complications (in-utero fetal death, preterm labor, andprematurity) 66). Pregnant women who are suspected ofpancreatitis should be tested for plasma TG. Pregnant
women at high-risk for HTG-induced acutepancreatitis may benefit from plasma TG screening
and monitoring on a weekly basis 122). Such patients
include: those with HTG or pancreatitis prior to or
during pregnancy; high predisposition for HTGinduced acute pancreatitis due to diabetes mellitus,
obesity, hypertension, hypothyroidism, renal disease,liver disease, family history of HTG, alcohol
consumption, and medications that cause HTG;HTG with abdominal pain or other symptoms typicalto chylomicronemia 84, 87, 122)(See sections 12 and16(B) for suggested risk factors of acute pancreatitis
among HTG patients).
• Family members of chylomicronemia
patients: Evaluation of plasma TG levels in family
members is beneficial for early diagnosis andmanagement of possible complications 96).

890

12. Features for Suspecting
Monogenic Chylomicronemia
Clinical features that lead to suspicion of monogenic
chylomicronemia have been suggested by previous studies
and in expert opinions, but further validation in various
cohorts is required 2-5, 15, 18, 53, 80, 96, 109, 123, 124). These features
may be useful not only for indicating the likelihood ofmonogenic chylomicronemia but also for predicting ahigher risk of pancreatitis 53, 86, 94-96):• Intractable, severe HTG (TG ＞ 10 mmol/L or
1,000 mg/dL)• Fasting severe HTG on multiple occasions• Very severe HTG• No history of normal to mild plasma TG
levels ( ＜ 200 mg/dL)• Severe HTG with no secondary factors (except
for pregnancy and oral estrogens)• Severe HTG with pregnancy• No response (TG decrease ＜ 20%) tohypolipidemic agents• Severe HTG with type 1 rather than type 5
HLP• History of recurrent abdominal pain or acutepancreatitis• Younger age at onset• Lower body mass index (BMI)• Eruptive xanthomas• Lipemia retinalis• Hepatosplenomegaly• Consanguinity
On the other hand, the polygenic type ofchylomicronemia is more frequently associated withsecondary/environmental factors, such as high-alcohol
intake, diabetes mellitus, hypertension, and obesity 2, 18, 96).
13. Treatment of Chylomicronemia
The treatment goal of chylomicronemia is tolower plasma TG levels enough to reduce the risk ofpancreatitis. Data from large healthcare databases
suggest that sustained HTG ( ＞ 500 mg/dL) increases
the risk of pancreatitis (hazard ratio 1.79 [CI 95%:
1.10-1.28]) 125) and lowering TG from ＞ 500 mg/dL
to less than 200 mg/dL can reduce the incidence ofacute pancreatitis from 1.1 to 0.4 per 100 person-year(adjusted OR 0.45 [CI 95%: 0.34-0.60]) 126). Due tothe rareness of the disease, there have been no
randomized control trials (RCTs) to determine
treatment TG targets for prevention of pancreatitis.
Mainly based on clinical experience, the opinion ofDiagnosis and Management of Chylomicronemia

experts is to recommend maintaining plasma TG levels
below 500-1,000 mg/dL to prevent pancreatitis 2, 4, 5, 12-14).
A) Control of Secondary Factors
Comorbid conditions that aggravate chylomicronemia
should be thoroughly evaluated in order to rule themout. If any are present, they should be managed
adequately. Bodyweight reduction, reduced calorie
intake, and increased energy expenditure throughregular physical exercise may help reduce plasma TG
levels, particularly in overweight subjects. Regularphysical exercise may also help in the non-obese 93, 127).
Bodyweight should be carefully controlled as reboundweight gain might elicit pancreatitis 13).
B) Dietary Therapy
Strict dietary control is currently the primary
treatment modality for chylomicronemia, although it
is often insufficient and difficult to maintain in thelong term 128, 129). Children and adolescents should be
carefully monitored to ensure proper growth anddevelopment. Adjustment of social life might be achallenge throughout life 104-107).
• Fat restriction: The mainstay of dietary
treatment is a low-fat diet. Restriction of total dietary
fat to ＜ 15-20 g per day ( ＜ 10-15 % of total energy
intake) is usually required to reduce plasma CMs andprevent pancreatitis 128, 129). Under fat restriction,adequate intake of essential fatty acids (EFA; 2-4% ofdaily calories) and fat-soluble vitamins (A, D, E, andK) should be ensured to avoid deficiency. Signs andsymptoms typical of EFA deficiency include:
inadequate growth in pediatric patients, dry or dull
hair, dry or scaly skin, skin lesions, particularly raised
bumps on the skin, soft and brittle nails, and impaired
wound healing 129). Food sources of EFAs include
soybeans, tofu, flaxseeds, walnuts, and chia seeds foralpha-linolenic acid (ALA) and whole grains forlinoleic acid (LA).
• Medium-chain triglycerides (MCTs): In avery-low-fat diet, MCTs containing fatty acids of ≦10 carbon atoms in length may be used to provide
sufficient calories in meals or infant formula 4, 36, 128, 129).
MCTs are absorbed directly into the circulation via
the CM-independent pathway. MCTs may help
reduce plasma TG levels 130). In order to avoid possible
adverse effects (diarrhea, abdominal pain, etc.), MCTs
should be introduced slowly. The safety of long-term
MCTs is not established and patients should be
carefully monitored for possible complications such as
hepatotoxicity. MCTs should not be confused withcoconut oil, which contains lauric acid (C12) andother long-chain fatty acids 129).
• Carbohydrate restriction: Restriction ofcarbohydrates, particularly fructose and other simple
and refined carbohydrates, is advisable for patientswith increased VLDL levels such as those withdiabetes mellitus, metabolic syndrome, and obesity. As
both CMs and VLDLs are substrates for LPL, reduced
production of VLDLs due to carbohydrate restriction
enhances the catabolism of CMs by LPL 131). In cases
where carbohydrate intake needs to be adequate, suchas in pregnancy-associated HTG, carbohydrate iv may
be a better therapeutic choice, as oral carbohydrate
intake may produce a greater rise in plasma TG thancarbohydrate iv 122, 132).
• Alcohol restriction: Alcohol intake should be
restricted 4, 128, 129).
C) Lipid-Lowering Medications
Current lipid-lowering medications (fibrates, n-3
polyunsaturated fatty acids (PUFAs), niacin, etc.)
generally have little to no TG-lowering effects inpatients with PCM, as they lower plasma TGs mainly
by enhancing the LPL pathway and reducing VLDL
levels. Treatment with n-3 PUFA or fish oil may be
useful for lowering TG and preventing pancreatitis as
suggested in patients with APOA5 mutations 21).
However, the effect of n-3 PUFAs needs to bemonitored carefully, as their effectiveness has only
been suggested by small studies without controls 3, 5).
Fish oil supplements may increase the production ofchylomicrons and are contraindicated according to an
expert opinion 4). In patients with autoantibodies
against LPL pathway proteins (GPIHBP1, LPL,
apoC-II), immune-suppressive agents may ameliorate
HTG as well as the comorbid autoimmune diseases 7).
14. Treatment of HTG-Induced
Acute Pancreatitis
The clinical course of HTG-induced acutepancreatitis may be more severe than acute pancreatitis
due to other causes in terms of complications andmortality rates 12, 14, 133, 134), but more controlled studies
are required to produce firm evidence. Meta analysisof acute pancreatitis is difficult due to theheterogeneity of scoring systems for its severity 86).
A) Standard Care for Acute Pancreatitis
Treatment of HTG-induced acute pancreatitis isbased on standard care, including cessation of oral
food intake, admission to hospital, intravenous
hydration, hypocaloric parenteral nutrition avoiding
excess calories and glucose infusions, pain
management, prophylactic antibiotics, and proteaseinhibitors 12, 130, 135). Any precipitating factors should betreated appropriately (e.g., insulin treatment for891

Okazaki et al .

diabetes). Patients should be carefully monitored fordevelopment of pancreatic complications (necrosis,
abscesses, etc.).
B) Specific Therapy for HTG-Induced Acute
Pancreatitis
When patients can tolerate, oral TG-lowering
medications (fibrates, n-3 PUFAs, niacin, etc.) may be
administered 12, 130, 135). MCTs may help reduce plasma
TG levels as well as the risk of pancreatitis 130). With afew exceptions, current TG-lowering medications are
not based on the etiology of chylomicronemia. In
apoC-II deficiency, infusion of normal human plasma
containing apoC-II can greatly reduce plasma TG
levels, and plasmapheresis has been suggested as atreatment of choice for pancreatitis due to apoC-II
deficiency 4, 58).
C) Management of Chronic Pancreatitis
As acute pancreatitis can lead to chronic
complications, patients with a history of it are better
monitored for complications such as chronicpancreatitis, pancreatic pseudocysts, pancreatic
insufficiency, steatorrhea, and insulin-dependent
diabetes mellitus 4, 86). Although chronic complications
are not invariably associated with HTG-induced acutepancreatitis 136), they are not uncommon despite
modern medical care 95).
D) Other Therapeutic Options for HTG-Induced
Acute Pancreatitis• Insulin (should be individualized): Insulin
therapy is advised in patients with diabetes mellitus.
Insulin stimulates LPL activity, thereby reducing
plasma TG levels. Administration of insulin or insulin
plus glucose may be considered in non-diabetic
patients in the case of severe HTG-induced acutepancreatitis 14, 137-139). Detailed protocols for insulin/
glucose administration have been summarizedelsewhere 137, 139).
• Heparin (not usually recommended): Heparin
infusion has been used as a therapeutic option but is
not usually recommended as a monotherapy intreatment guides by experts 12, 14). Heparin transiently
increases plasma LPL levels by releasing LPL from theendothelial cell surface, which temporarily reduces
plasma TG levels. However, heparin can also deplete
LPL, causing a rebound increase in plasma TGs 140).
Heparin may increase the risk of pancreatic
hemorrhage when pancreatic necrosis is present 66).
•H e p a r i n p l u s i n s u l i n ( s h o u l d b e
individualized): Combination of heparin and insulin
may be a therapeutic option for severe HTG-induced
acute pancreatitis 14). Although heparin infusion alone892

is usually not advised, a recent study has suggested
that combination of heparin and insulin may beeffective 14). Evaluation in RCTs is awaited.
• A p h e re s i s f o r H TG - i n d u c e d a c u t epancreatitis (should be individualized): In the acutesetting, apheresis (lipoprotein apheresis (LA),plasmapheresis, or plasma exchange (PEX), etc.) 141, 142)
can rapidly reduce plasma TG levels (40-80%) bydirectly removing TGRLs, as reported in case reports,case series, and multi-center studies 12, 14, 36, 57).
However, it is not proven whether rapid TG reduction
by apheresis leads to better clinical outcomes thanother therapeutic modalities in terms of pancreaticcomplications and mortality 59). Plasmapheresis iscostly, has only a transient TG- lowering effect (usuallyfor a day), and may have adverse reactions (e.g.,allergic reactions, anaphylactic shock, infusion-related
infections, thromboses, etc.) 14). A recent systematic
review and case-control studies indicated that whileplasmapheresis decreased plasma TG, it did notconclusively affect the morbidity or mortality of acutepancreatitis 14, 86). A recent RCT, the first one in HTGinduced acute pancreatitis, has demonstrated that
although plasma apheresis lowers plasma TG more
efficiently than insulin plus heparin, it is costly anddoes not lead to better clinical outcomes 143). In theguideline of the American Society for Apheresis (ASFA),
plasmapheresis is a category III indication with Grade
2C recommendation (“optimum role of apheresis
therapy is not established. Decision making should be
individualized”; “Weak recommendation, low-quality
or very low-quality evidence due to observational
studies or case series”) 144), and generally not recommended
by experts in treatment guides for chylomicronemia 4, 5).
Plasmapheresis may be a therapeutic option for: 1)
severe HTG-induced acute pancreatitis with persistent
TG elevation past the first 48-72h with no othertherapeutic choice 57, 59, 86, 120); 2) HTG-induced acutepancreatitis in pregnancy or postpartum with no othertherapeutic choice 14, 36, 74, 120, 145-149); or 3) severe HTGinduced acute pancreatitis with high levels of serum
lipase, hypocalcemia, lactic acidosis, worsening
inflammation or organ dysfunction 149, 150). However,such advice is experience-based, not evidence-based.
• Prophylactic apheresis to prevent HTGi n d u c e d a c u t e p a n c re a t i t i s ( s h o u l d b e
individualized): Prophylactic apheresis may be atherapeutic choice for preventing severe recurrent
HTG-induced acute pancreatitis but evidence for it islimited to several case reports of HTG-induced acutepancreatitis 12, 14, 57, 151-154) and gestational HTG-induced
acute pancreatitis 155, 156).

Diagnosis and Management of Chylomicronemia

15. Treatment of HTG and HTG-induced
Acute Pancreatitis in Pregnancy
There are currently no formal guidelines forgestational HTG and HTG-induced acute pancreatitis
due to the rarity of these conditions and insufficientevidence. The treatment approach for gestational
HTG and HTG-induced acute pancreatitis is wellsummarized by Wong et al. 66).
• Dietary therapy (restriction of dietary fat,
MCTs, n-3 PUFA): There have been reports ofsuccessful management of HTG and prevention of
HTG-induced acute pancreatitis during pregnancy
through early intervention with a low-fat or very-low
fat diet, MCTs, and n-3 fatty acids 4, 66, 113, 122, 149, 157-162).
For pregnant women at high-risk of pregnancyassociated pancreatitis, extreme fat restriction to ＜ 2g/day may be required during the 2nd and 3rdtrimesters for successful delivery 1, 4, 122, 159). Topicalapplication of sunflower oil or corn oil in pregnancy
with an extra-low-fat diet may help prevent EFA
deficiency 122, 129, 159). In pregnancy-induced HTG,
carbohydrate may need to be restricted, but anadequate amount should be taken. Carbohydrate iv
may be a better therapeutic choice during
carbohydrate restriction, as carbohydrate per os may
produce a greater rise in plasma TG than carbohydrateiv 122, 132). The risk of MCTs to the fetus is thought tobe low 66). The safety of maternal n-3 fatty acidsupplementation (DHA 2.2 g and EPA 1.1 g/day) forthe mother and the fetus has been confirmed througha RCT 66).
• TG-lowering medications (some arecontraindicated in Japan): There have been several
reports on the use of niacin, or fibrates (gemfibrozil
and fenofibrate) for pregnancy-associated HTG
66,120,122,159,163-166). However, the safety of niacin or
fibrate use during pregnancy has not been established,
and the use of fibrates during pregnancy iscontraindicated in Japan.
• Admission to hospital: For gestational HTG,
admission to hospital may be advised in the following
cases: suspected pancreatitis, persistent abdominal
pain, steep increase in plasma TG in the 3rd trimester,or TG ＞ 40 mmol/L (3540 mg/dL) 66, 122, 159).
Gestational acute pancreatitis is managed throughstandard care, which has been extensively reviewed by
Papadakis EP et al. 73).
•O t h e r t h e r a p e u t i c o p t i o n s : W h e nuncontrollable, further management may include:insulin, insulin pus glucose, insulin plus heparin, or
plasmapheresis 36, 66, 119, 120, 137-139, 149, 156, 161). In atreatment guide for gestational HTG, the use of

insulin is recommended only for hyperglycemic
pregnant women, and the use of heparin is notrecommended due to the paucity of clinical evidence 66).
16. Unanswered QuestionsA) Molecular Basis and New Therapeutic Modalities
Unraveling the molecular basis of chylomicronemia
may lead to the development of new therapeuticmodalities 167).
Emerging therapeutic targets for chylomicronemia
include: a microsomal triglyceride transfer protein(MTTP) inhibitor (lomitapide) 168-170); an APOB
antisense oligonucleotide (ASO) inhibitor(mipomersen) 171-173); APOC3 ASO inhibitors, e.g.,
volanesorsen 174), which has been approved by the
EMA for genetically confirmed chylomicronemia at
high-risk for pancreatitis 93); diacylglycerol O-acyltransferase
1 (DGAT1) inhibitors (AZD7687, LCQ908(Pradigastat)) 175-177); angiopoietin-like protein 3(ANGPTL3) inhibitors, e.g., ANGPTL3 ASOs
(IONIS-ANGPTL3-LRx) 178) and ANGPTL3 antibody(evinacumab) 179-182).
For these new therapies, potential adverse effects
need to be carefully evaluated, including fatty liverassociated diseases for lomitapide and mipomersen 168-170, 172)
as a consequence of their inhibition of VLDL
secretion; thrombocytopenia for volanesorsen 174);
gastrointestinal adverse effects (diarrhea, nausea, etc.)
for DGAT inhibitors 175-177), consistent with the factthat homozygous loss-of-function mutations of
DGAT1 cause a congenital diarrheal disorder(OMIM: 615863) 183).
Other agents under development include CAT2003, a niacin-eicosapentaenoic acid conjugate thatblocks sterol regulatory element-binding protein(SREBP). Inhibition of SREBP-1c has ameliorated
environment-induced severe HTG in mouse modelsof hyperlipidemia, including apoA-V deficient mice,by blocking secretion of large-sized VLDL particles 54, 55).
Orlistat, an inhibitor of intestinal lipase, may
help reduce TG levels in PCM 21, 184, 185) but may haveadverse effects such as oily stools and fat-soluble
vitamin insufficiency 128).
Treatment that targets a specific genetic cause of
PCM is not available. A gene therapy for LPL(alipogene tiparvovec) was approved by the EMA in
2012, but is costly and has been withdrawn from themarket 94, 186).
B) Risk and Management of CM-Related Complications
Not all patients with severe HTG manifest
pancreatitis. Suggested risk factors of acute pancreatitis
among HTG patients include underlying genetic
893

Okazaki et al .

etiology of monogenic type, underdiagnosis andundertreatment, younger age, higher baseline TG
levels, prior history of acute pancreatitis, male, alcoholuse, obesity, diabetes, hypertension, renal disease, liverdisease, and hypothyroidism 84, 87, 94, 95). Further
elucidation and validation of the risk factors andgenetic predisposition for HTG-induced acutepancreatitis is awaited 187-191). Understanding themolecular basis of HTG-induced acute pancreatitis isnecessary for developing diagnostic markers as well as
effective therapeutic modalities.
There has been controversy as to the atherogenicityof HTG, including chylomicronemia 136, 192, 193).
Although it remains uncertain whether HTG is acausal factor or a mere marker of atherosclerosis 3, 91, 194-196),
recent mendelian randomization studies haveindicated an association between risk of cardiovasculardiseases and variants in HTG-related genes, including
causative genes of chylomicronemia (APOA5, LPL,etc.) 197-199). Chylomicronemia, particularly when it ispolygenic, may be associated with higher risk ofcardiovascular diseases 53, 96, 200), which warrants further
studies.
C) Genotype-Phenotype Relationship of PCM
The genetic etiology of chylomicronemia may
influence the risk of complications such as pancreatitis
and atherosclerotic diseases 86, 94-96). The benefit, risk,
and cost-effectiveness of genetic testing for chylomicronemia
should be carefully evaluated 15, 109, 201-203). Some expert
reviews, which include the Consensus Panel report of
the European Atherosclerosis Society, do notrecommend routine genetic testing for severe HTG 3, 204).
D) Underdiagnosis and Undertreatment
Underdiagnosis of chylomicronemia is one of the
major risks for pancreatitis 84, 87). A web-based patient
survey reported that patients with chylomicronemia
typically visit 5 physicians (range, 1-30) on average before
receiving a final diagnosis of chylomicronemia 106, 107).
Owing to the variety of symptoms and complications,patients with chylomicronemia may visit not only
lipidologists and endocrinologists but also otherdiverse specialists, such as primary care physicians,
pediatricians, obstetricians, emergency physicians,
gastroenterologists, pancreatologists, and psychologists.
Simple diagnostic criteria as well as cooperation
among different medical specialists will be necessary
to achieve timely diagnosis and treatment.
E) Unmet Needs and Burden of Disease
Due to the rarity of the disease, the clinicalexperience of each doctor is limited. Large registrystudies 205, 206) as well as patient-oriented observational894

studies 104-107) from the patient’s perspective are usefulfor understanding the unmet needs and burden of thedisease from the physical, psychological, social, andfinancial viewpoints 104-107).
A recent web-based patient survey revealed
physical, emotional, and cognitive symptoms that are
relevant to patient’s quality of life but have not beenrecognized by physicians 207, 208), including abdominal
pain (41%), fatigue (23%), feeling sad/down/blue/
depressed (18%), difficulty in concentrating (16%),
impaired judgment (11%), brain fog (8%),
forgetfulness (8%), and recent memory loss (5%) 106, 107).
This survey also revealed actual handicaps felt at
school, in society, and work, and family-related
issues 106, 107).
Self-monitoring of plasma TG may be an unmet
need that could help patients with the long-term
management of the disease. It may enable patients toindividualize their low-fat diets, hopefully leading tofewer episodes of acute pancreatitis 209).
F) Support for Patients
The mainstay of the current treatment forchylomicronemia is dietary interventions. Supporting
information and materials for patients on diets will
help develop recipes and menu plans that would be
more enjoyable and sustainable. Information andsupport for patients can be found at FCS Foundation(www.livingwithfcs.org; www.facebook.com/
livingwithfcs), FCS Focus (fcsfocus.com), LPLD
Alliance (UK) (www.lpldalliance.org), the National
Organization for Rare Disorders (NORD) (https://rarediseases.org), and the Japan Intractable Diseases
Information Center (https://www.nanbyou.or.jp/
entry/4883). Supportive care from other healthcare
professionals, such as medical social workers andmental health professionals, will be necessary to
reduce the burden of the disease as well as to improve
the quality of life of patients with chylomicronemia 105-107).
Acknowledgments andNotice of Grant Support
This work has been supported by Health, Labourand Welfare Sciences Research Grant for Research on
Rare and Intractable Diseases (H30-nanji-ippan-003).
Conflicts of Interest
Atsushi Nohara has nothing to disclose. Hayato
Tada has nothing to disclose. Masatsune Ogura hasreceived honoraria from Amgen Inc., Astellas Pharma
Inc. Sachiko Okazaki has received scholarship grants
from Minophagen Pharmaceutical Co., Ltd., Kowa

Diagnosis and Management of Chylomicronemia

Company, Ltd. Koh Ono has nothing to disclose.
Hitoshi Shimano has nothing to disclose. Hiroyuki
Daida has received honoraria from Amgen Inc.,
Daiichi-Sankyo Co., Ltd., Kowa Co., Ltd., and MSD
K.K., Novartis Pharma K.K., Bayer Yakuhin, Ltd. andreceived clinical research funding from Canon Medical
Systems Corporation, Philips Japan, Ltd., Toho
Holdings Co., Ltd., Asahi Kasei Corporation, andInter Reha Co., Ltd. HD has also received scholarshipgrants from Nippon Boehringer Ingelheim Co., Ltd.,
Otsuka Pharmaceutical Co., Ltd., Sanofi K.K., MSD
K.K., Daiichi-Sankyo Co., Ltd., Pfizer Co., Ltd.,
Mitsubishi Tanabe Pharma Corp., Astellas PharmaInc., Takeda Pharmaceutical Co., Ltd., Teijin Pharma,
Ltd., Shionogi & Co., Ltd., Actelion Pharmaceuticals,Ltd., Actelion Ltd., Kowa Co., Ltd., Bayer Yakuhin,Ltd. HD has also courses endowed by companies,
including Philips Japan, Ltd., ResMed, Fukuda
Denshi Co., Ltd., and Paramount Bed Co., Ltd.
Kazushige Dobashi has nothing to disclose. Toshio
Hayashi has nothing to disclose. Mika Hori has
nothing to disclose. Kota Matsuki has nothing todisclose. Tetsuo Minamino has nothing to disclose.
Shinji Yokoyama has nothing to disclose. Mariko
Harada-Shiba has received stock holdings or options
from Liid Pharma, honoraria from Amgen Inc.,
Astellas Pharma Inc., Sanofi, and scholarship grants
from Aegerion Pharmaceuticals, Inc., Recordati Rare
Diseases Japan, and Kaneka Corporation. Katsunori
Ikewaki has nothing to disclose. Yasushi Ishigaki has
nothing to disclose. Shun Ishibashi has received
honoraria from Kowa Co., Ltd., and a scholarshipgrant from Ono Pharmaceutical Co., Ltd. Kyoko
Inagaki has nothing to disclose. Hirotoshi Ohmura
has nothing to disclose. Hiroaki Okazaki has received
scholarship grants from Minophagen PharmaceuticalCo., Ltd., Kowa Company, Ltd. Masa-aki Kawashiri
has nothing to disclose. Masayuki Kuroda has nothing
to disclose. Masahiro Koseki has received clinicalresearch funding from Kowa Company, Ltd., Rohto
Pharmaceutical Co., Ltd. Takanari Gotoda has
nothing to disclose. Shingo Koyama has nothing todisclose. Yoshiki Sekijima has nothing to disclose.
Manabu Takahashi has nothing to disclose. Yasuo
Takeuchi has nothing to disclose. Misa Takegami has
nothing to disclose. Kazuhisa Tsukamoto has received
honoraria from Bayer Yakuhin, Ltd., MSD Ltd.,
Takeda Pharmaceutical Company Ltd., andscholarship grants from Mitsubishi Tanabe Pharma
Corporation., Bayer Yakuhin, Ltd., Sanofi K.K.
Atsuko Nakatsuka has nothing to disclose. Kimitoshi
Nakamura has nothing to disclose. Satoshi Hirayama
has nothing to disclose. Hideaki Bujo has nothing todisclose. Daisaku Masuda has received clinical researchfunding from MSD K.K., Ono Pharmaceutical Co.,
Ltd., Takeda Pharmaceutical Co., Ltd., Kowa Co.,
Ltd. Takashi Miida has nothing to disclose. Yoshihiro
Miyamoto has nothing to disclose. Takeyoshi Murano
has nothing to disclose. Takashi Yamaguchi has
nothing to disclose. Shizuya Yamashita has received
honoraria from Kowa Company, Ltd., MSD K.K.
Masashi Yamamoto has nothing to disclose. Koutaro
Yokote has received honoraria from Kowa Company,
Ltd., MSD K.K., Astellas Pharma Inc., Mitsubishi
Tanabe Pharma Corp., Amgen K.K., Takeda
Pharmaceutical Company Limited, Sanofi K.K., Ono
Pharmaceutical Co., Ltd., AstraZeneca K.K., DaiichiSankyo Co., Ltd., Novartis Pharma K.K., Sumitomo
Dainippon Pharma Co., Ltd., Kyowa Kirin Co., Ltd.,
Pfizer Japan Inc., Novo Nordisk Pharma Ltd., Nippon
Boehringer Ingelheim Co., Ltd., Eli Lilly Japan K.K.,
Taisho Pharmaceutical Co., Ltd., Janssen
Pharmaceutical K.K., and received clinical researchfunding from Taisho Pharmaceutical Co., Ltd. KY has
also received scholarship grants from Mitsubishi
Tanabe Pharma Corp., Takeda Pharmaceutical Co.,
Ltd., MSD K.K., Pfizer Japan Inc., Novo Nordisk
Pharma Ltd., Taisho Pharmaceutical Co., Ltd., Kao
Corporation, Ono Pharmaceutical Co., Ltd., Eli Lilly
Japan K.K., Sumitomo Dainippon Pharma Co., Ltd.,
Nippon Boehringer Ingelheim Co., Ltd., DaiichiSankyo Co., Ltd., Teijin Pharma, Ltd., Shionogi Co.,
Ltd., Bayer Yakuhin, Ltd. Jun Wada has nothing todisclose.
References
1) Brunzell JD, Deeb SS. Familial lipoprotein lipase
deficiency, apoC-II deficiency, and hepatic lipase
deficiency. The metabolic and molecular bases ofinherited disease, 2001; 2: 2789-2816
2) Gotoda T, Shirai K, Ohta T, Kobayashi J, Yokoyama S,
Oikawa S, Bujo H, Ishibashi S, Arai H, Yamashita S,
Harada-Shiba M, Eto M, Hayashi T, Sone H, Suzuki H,
Yamada N, Research Committee for PrimaryHyperlipidemia, Research on Measures against
Intractable Diseases by the Ministry of Health, Labourand Welfare in Japan. Diagnosis and management oftype I and type V hyperlipoproteinemia. J Atheroscler
Thromb, 2012; 19: 1-12
3) Hegele RA, Ginsberg HN, Chapman MJ, Nordestgaard
BG, Kuivenhoven JA, Averna M, Borén J, Bruckert E,
Catapano AL, Descamps OS, Hovingh GK, Humphries
SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG,
Raal FJ, Ray KK, Santos RD, Stalenhoef AFH, Stroes E,
Taskinen M-RR, Tybjærg-Hansen A, Watts GF, Wiklund
O , Pa n e l E A S C . T h e p o l y g e n i c n a t u re o f
hypertriglyceridaemia: implications for definition,
diagnosis, and management. Lancet Diabetes
Endocrinol, 2014; 2: 655-666
4) Burnett JR, Hooper AJ, Hegele RA. Familial Lipoprotein
895

Okazaki et al .

Lipase Deficiency [Internet]. In: Adam MP, Ardinger
HH, Pagon RA, Wallace SE, Bean LJ, Stephens K,
Amemiya A, editors. GeneReviews®. Seattle (WA):
University of Washington, Seattle; 1993 [cited 2019 Oct28]. Available from: http: //www.ncbi.nlm.nih.gov/
books/NBK1308/
5) Brahm AJ, Hegele RA. Chylomicronaemia--current
diagnosis and future therapies. Nat Rev Endocrinol,
2015; 11: 352-362
6) Kihara S, Matsuzawa Y, Kubo M, Nozaki S, Funahashi
T, Yamashita S, Sho N, Tarui S. Autoimmune
hyperchylomicronemia. N Engl J Med, 1989; 320:
1255-1259
7) Beigneux AP, Miyashita K, Ploug M, Blom DJ, Ai M,
Linton MF, Khovidhunkit W, Dufour R, Garg A,
McMahon MA, Pullinger CR, Sandoval NP, Hu X,
Allan CM, Larsson M, Machida T, Murakami M, Reue
K, Tontonoz P, Goldberg IJ, Moulin P, Charrière S, Fong
LG, Nakajima K, Young SG. Autoantibodies against
GPIHBP1 as a Cause of Hypertriglyceridemia. N Engl J
Med, 2017; 376: 1647-1658
8) Inoue M, Kawamura M, Yamamoto H, Takahashi T,
Kihara S. Juvenile-onset systemic lupus erythematosus
with severe hypertriglyceridemia induced by antiapolipoprotein C-II antibody. Pediatr Int, 2019; 61:
201-203
9) Miyashita K, Lutz J, Hudgins LC, Toib D, Ashraf AP,
Song W, Murakami M, Nakajima K, Ploug M, Fong
LG, Young SG, Beigneux AP. Chylomicronemia fromGPIHBP1 autoantibodies. J Lipid Res, 2020; 61: 13651376
10) Havel RJ. Pathogenesis, differentiation and managementof hypertriglyceridemia. Adv Intern Med, 1969; 15:
117-154
11) Navina S, Acharya C, DeLany JP, Orlichenko LS, Baty
CJ, Shiva SS, Durgampudi C, Karlsson JM, Lee K, Bae
KT, Furlan A, Behari J, Liu S, McHale T, Nichols L,
Papachristou GI, Yadav D, Singh VP. Lipotoxicity causes
multisystem organ failure and exacerbates acutepancreatitis in obesity. Sci Transl Med, 2011; 3:
107ra110
12) Valdivielso P, Ramírez-Bueno A, Ewald N. Current
knowledge of hypertriglyceridemic pancreatitis. Eur JIntern Med, 2014; 25: 689-694
13) Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ,
Sacks F, Murad MH, Stalenhoef AFH, Endocrines o c i e t y. E v a l u a t i o n a n d t r e a t m e n t o f
hypertriglyceridemia: an Endocrine Society clinicalpractice guideline. J Clin Endocrinol Metab, 2012; 97:2969-2989
14) Rawla P, Sunkara T, Thandra KC, Gaduputi V.
Hypertriglyceridemia-induced pancreatitis: updated
review of current treatment and preventive strategies.
Clin J Gastroenterol, 2018; 11: 441-448
15) Hegele RA, Berberich AJ, Ban MR, Wang J, Digenio A,
Alexander VJ, D’Erasmo L, Arca M, Jones A, Bruckert E,
Stroes ES, Bergeron J, Civeira F, Witztum JL, Gaudet D.
Clinical and biochemical features of different molecularetiologies of familial chylomicronemia. Journal of
Clinical Lipidology, 2018; 12: 920-927.e4
16) Lewis GF, Xiao C, Hegele RA. Hypertriglyceridemia in896

the Genomic Era: A New Paradigm. Endocrine Reviews,
2015; 36: 131-147
17) Brown WV, Goldberg IJ, Young SG. JCL Roundtable:
Hypertriglyceridemia due to defects in lipoprotein lipase
function. J Clin Lipidol, 2015; 9: 274-280
18) Murase T, Okubo M, Ebara T, Mori Y. Severe
hypertriglyceridemia in Japan: Differences in causes andtherapeutic responses. J Clin Lipidol, 2017; 11: 13831392
19) Surendran RP, Visser ME, Heemelaar S, Wang J, Peter J,
Defesche JC, Kuivenhoven JA, Hosseini M, Péterfy M,
Kastelein JJP, Johansen CT, Hegele RA, Stroes ESG,
Dallinga-Thie GM. Mutations in LPL, APOC2,
APOA5, GPIHBP1 and LMF1 in patients with severe
hypertriglyceridaemia. J Intern Med, 2012; 272: 185196
20) Rabacchi C, Pisciotta L, Cefalù AB, Noto D, Fresa R,
Tarugi P, Averna M, Bertolini S, Calandra S. Spectrumof mutations of the LPL gene identified in Italy inpatients with severe hypertriglyceridemia.
Atherosclerosis, 2015; 241: 79-86
21) Chokshi N, Blumenschein SD, Ahmad Z, Garg A.
Genotype-phenotype relationships in patients with typeI hyperlipoproteinemia. J Clin Lipidol, 2014; 8: 287295
22) Rodrigues R, Artieda M, Tejedor D, Martínez A,
Konstantinova P, Petry H, Meyer C, Corzo D,
Sundgreen C, Klor HU, Gouni-Berthold I, Westphal S,
Steinhagen-Thiessen E, Julius U, Winkler K, Stroes E,
Vogt A, Hardt P, Prophet H, Otte B, Nordestgaard BG,
Deeb SS, Brunzell JD. Pathogenic classification of LPL
gene variants reported to be associated with LPL
deficiency. J Clin Lipidol, 2016; 10: 394-409
23) Nilsson-Ehle P, Schotz MC. A stable, radioactive
substrate emulsion for assay of lipoprotein lipase. J Lipid
Res, 1976; 17: 536-541
24) Péterfy M, Ben-Zeev O, Mao HZ, Weissglas-Volkov D,
Aouizerat BE, Pullinger CR, Frost PH, Kane JP, Malloy
MJ, Reue K, Pajukanta P, Doolittle MH. Mutations in
LMF1 cause combined lipase deficiency and severe
hypertriglyceridemia. Nat Genet, 2007; 39: 1483-1487
25) Cefalù AB, Noto D, Arpi ML, Yin F, Spina R, Hilden H,
Barbagallo CM, Carroccio A, Tarugi P, Squatrito S,
Vigneri R, Taskinen M-R, Péterfy M, Averna MR. NovelLMF1 nonsense mutation in a patient with severe
hypertriglyceridemia. J Clin Endocrinol Metab, 2009;
94: 4584-4590
26) Péterfy M, Bedoya C, Giacobbe C, Pagano C, Gentile
M, Rubba P, Fortunato G, Di Taranto MD.
Characterization of two novel pathogenic variants atcompound heterozygous status in lipase maturation
factor 1 gene causing severe hypertriglyceridemia. J Clin
Lipidol, 2018; 12: 1253-1259
27) Serveaux Dancer M, Di Filippo M, Marmontel O,
Valéro R, Piombo Rivarola MDC, Peretti N, Caussy C,
Krempf M, Vergès B, Mahl M, Marçais C, Moulin P,
Charrière S. New rare genetic variants of LMF1 gene
identified in severe hypertriglyceridemia. J Clin Lipidol,
2018; 12: 1244-1252
28) Liu Y, Xu J, Tao W, Yu R, Zhang X. A Compound
Heterozygous Mutation of Lipase Maturation Factor 1 isDiagnosis and Management of Chylomicronemia

Responsible for Hypertriglyceridemia of a Patient. J
Atheroscler Thromb, 2019; 26: 136-144
29) Chen W-W, Yang Q, Li X-Y, Shi X-L, Pu N, Lu G-T,
Tong Z-H, Chen J-M, Li W-Q. Identification of a novel
and heterozygous LMF1 nonsense mutation in an acutepancreatitis patient with severe hypertriglyceridemia,
severe obesity and heavy smoking. Lipids Health Dis,
2019; 18: 68
30) Ioka RX, Kang M-J, Kamiyama S, Kim D-H, Magoori
K, Kamataki A, Ito Y, Takei YA, Sasaki M, Suzuki T,
Sasano H, Takahashi S, Sakai J, Fujino T, Yamamoto TT.
Expression cloning and characterization of a novel
glycosylphosphatidylinositol-anchored high density
lipoprotein-binding protein, GPI-HBP1. J Biol Chem,
2003; 278: 7344-7349
31) Beigneux AP, Davies BSJ, Gin P, Weinstein MM, Farber
E, Qiao X, Peale F, Bunting S, Walzem RL, Wong JS,
Blaner WS, Ding Z-M, Melford K, Wongsiriroj N, Shu
X, de Sauvage F, Ryan RO, Fong LG, Bensadoun A,
Young SG. Glycosylphosphatidylinositol-anchored highdensity lipoprotein-binding protein 1 plays a critical rolein the lipolytic processing of chylomicrons. Cell Metab,
2007; 5: 279-291
32) Rios JJ, Shastry S, Jasso J, Hauser N, Garg A, Bensadoun
A, Cohen JC, Hobbs HH. Deletion of GPIHBP1
causing severe chylomicronemia. J Inherit Metab Dis,
2012; 35: 531-540
33) Adeyo O, Goulbourne CN, Bensadoun A, Beigneux AP,
Fong LG, Young SG. Glycosylphosphatidylinositolanchored high-density lipoprotein-binding protein 1
and the intravascular processing of triglyceride-richlipoproteins. J Intern Med, 2012; 272: 528-540
34) Patni N, Brothers J, Xing C, Garg A. Type 1
hyperlipoproteinemia in a child with large homozygous
deletion encompassing GPIHBP1. J Clin Lipidol, 2016;
10: 1035-1039.e2
35) Rabacchi C, D’Addato S, Palmisano S, Lucchi T,
Bertolini S, Calandra S, Tarugi P. Clinical and genetic
features of 3 patients with familial chylomicronemia due
to mutations in GPIHBP1 gene. J Clin Lipidol, 2016;
10: 915-921.e4
36) Chyzhyk V, Kozmic S, Brown AS, Hudgins LC, Starc
TJ, Davila AD, Blevins TC, Diffenderfer MR, He L,
Geller AS, Rush C, Hegele RA, Schaefer EJ. Extreme
hypertriglyceridemia: Genetic diversity, pancreatitis,
pregnancy, and prevalence. J Clin Lipidol, 2019; 13:
89-9937) Franssen R, Young SG, Peelman F, Hertecant J, Sierts
JA, Schimmel AWM, Bensadoun A, Kastelein JJP, FongLG, Dallinga-Thie GM, Beigneux AP. Chylomicronemia
with low postheparin lipoprotein lipase levels in thesetting of GPIHBP1 defects. Circ Cardiovasc Genet,
2010; 3: 169-178
38) Breckenridge WC, Little JA, Steiner G, Chow A, Poapst
M. Hypertriglyceridemia associated with deficiency of
apolipoprotein C-II. N Engl J Med, 1978; 298: 12651273
39) Yamamura T, Sudo H, Ishikawa K, Yamamoto A.
Familial type I hyperlipoproteinemia caused byapolipoprotein C-II deficiency. Atherosclerosis, 1979;
34: 53-6540) Okubo M, Toromanovic A, Ebara T, Murase T.
Apolipoprotein C-II Tuzla: a novel large deletion in
APOC2 caused by Alu-Alu homologous recombinationin an infant with apolipoprotein C-II deficiency. Clin
Chim Acta, 2015; 438: 148-153
41) Wolska A, Dunbar RL, Freeman LA, Ueda M, Amar
MJ, Sviridov DO, Remaley AT. Apolipoprotein C-II:
New findings related to genetics, biochemistry, and rolein triglyceride metabolism. Atherosclerosis, 2017; 267:
49-6042) Fojo SS, Beisiegel U, Beil U, Higuchi K, Bojanovski M,
Gregg RE, Greten H, Brewer HB. Donor splice site
mutation in the apolipoprotein (Apo) C-II gene (ApoC-IIHamburg) of a patient with Apo C-II deficiency. J
Clin Invest, 1988; 82: 1489-1494
43) Streicher R, Geisel J, Weisshaar C, Avci H, Oette K,
Müller-Wieland D, Krone W. A single nucleotide
substitution in the promoter region of theapolipoprotein C-II gene identified in individuals withchylomicronemia. J Lipid Res, 1996; 37: 2599-2607
44) Okubo M, Hasegawa Y, Aoyama Y, Murase T. A G+1 to
C mutation in a donor splice site of intron 2 in theapolipoprotein (apo) C-II gene in a patient with apo
C-II deficiency. A possible interaction between apo C-II
deficiency and apo E4 in a severely hypertriglyceridemic
patient. Atherosclerosis, 1997; 130: 153-160
45) Takase S, Osuga J, Fujita H, Hara K, Sekiya M, Igarashi
M, Takanashi M, Takeuchi Y, Izumida Y, Ohta K,
Kumagai M, Nishi M, Kubota M, Masuda Y, Taira Y,
Okazaki S, Iizuka Y, Yahagi N, Ohashi K, Yoshida H,
Yanai H, Tada N, Gotoda T, Ishibashi S, Kadowaki T,
Okazaki H. Apolipoprotein C-II deficiency with no rarevariant in the APOC2 gene. J Atheroscler Thromb,2013; 20: 481-493
46) Pennacchio LA, Olivier M, Hubacek JA, Cohen JC, Cox
DR, Fruchart JC, Krauss RM, Rubin EM. An
apolipoprotein influencing triglycerides in humans andmice revealed by comparative sequencing. Science, 2001;
294: 169-17347) van der Vliet HN, Sammels MG, Leegwater AC, Levels
JH, Reitsma PH, Boers W, Chamuleau RA.
Apolipoprotein A-V: a novel apolipoprotein associatedwith an early phase of liver regeneration. J Biol Chem,
2001; 276: 44512-44520
48) Merkel M, Loeffler B, Kluger M, Fabig N, Geppert G,
Pennacchio LA, Laatsch A, Heeren J. Apolipoprotein AV
accelerates plasma hydrolysis of triglyceride-richlipoproteins by interaction with proteoglycan-boundlipoprotein lipase. J Biol Chem, 2005; 280: 2155321560
49) Merkel M, Heeren J. Give me A5 for lipoproteinhydrolysis! J Clin Invest, 2005; 115: 2694-2696
50) Marçais C, Verges B, Charrière S, Pruneta V, Merlin M,
Billon S, Perrot L, Drai J, Sassolas A, Pennacchio LA,
Fruchart-Najib J, Fruchart J-C, Durlach V, Moulin P.
Apoa5 Q139X truncation predisposes to late-onset
hyperchylomicronemia due to lipoprotein lipase
impairment. J Clin Invest, 2005; 115: 2862-2869
51) Priore Oliva C, Pisciotta L, Li Volti G, Sambataro MP,
Cantafora A, Bellocchio A, Catapano A, Tarugi P,
Bertolini S, Calandra S. Inherited apolipoprotein A-V
897

Okazaki et al .

deficiency in severe hypertriglyceridemia. Arterioscler
Thromb Vasc Biol, 2005; 25: 411-417
52) Albers K, Schlein C, Wenner K, Lohse P, Bartelt A,
Heeren J, Santer R, Merkel M. Homozygosity for apartial deletion of apoprotein A-V signal peptide results
in intracellular missorting of the protein andchylomicronemia in a breast-fed infant. Atherosclerosis,
2014; 233: 97-103
53) D’Erasmo L, Di Costanzo A, Cassandra F, Minicocci I,
Polito L, Montali A, Ceci F, Arca M. Spectrum of
Mutations and Long-Term Clinical Outcomes in
Genetic Chylomicronemia Syndromes. Arterioscler
Thromb Vasc Biol, 2019; 39: 2531-2541
54) Okazaki H, Goldstein JL, Brown MS, Liang G. LXRSREBP-1c-phospholipid transfer protein axis controls
very low density lipoprotein (VLDL) particle size. J Biol
Chem, 2010; 285: 6801-6810
55) Takanashi M, Kimura T, Li C, Tanaka M, Matsuhashi A,
Yoshida H, Noda A, Xu P, Takase S, Okazaki S, Iizuka Y,
Kumagai H, Ikeda Y, Gotoda T, Takahashi M, Yagyu H,
Ishibashi S, Yamauchi T, Kadowaki T, Liang G, Okazaki
H. Critical Role of SREBP-1c Large-VLDL Pathway inEnvironment-Induced Hypertriglyceridemia of Apo AV
Deficiency. Arterioscler Thromb Vasc Biol, 2019; 39:373-386
56) Yuan G, Al-Shali KZ, Hegele RA. Hypertriglyceridemia:
its etiology, effects and treatment. CMAJ, 2007; 176:
1113-1120
57) Stefanutti C, Di Giacomo S, Vivenzio A, Labbadia G,
Mazza F, D’Alessandri G, Russi G, De Silvestro G,
Marson P. Therapeutic plasma exchange in patients withsevere hypertriglyceridemia: a multicenter study. Artif
Organs, 2009; 33: 1096-1102
58) Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui
MH, Ginsberg HN, Goldberg AC, Howard WJ,
Jacobson MS, Kris-Etherton PM, Lennie TA, Levi M,
Mazzone T, Pennathur S, American Heart Association
Clinical Lipidology, Thrombosis, and Prevention
Committee of the Council on Nutrition, Physical
Activity, and Metabolism, Council on Arteriosclerosis,
Thrombosis and Vascular Biology, Council on
Cardiovascular Nursing, Council on the Kidney in
Cardiovascular Disease. Triglycerides and cardiovasculardisease: a scientific statement from the American Heart
Association. Circulation, 2011; 123: 2292-2333
59) Click B, Ketchum AM, Turner R, Whitcomb DC,
Papachristou GI, Yadav D. The role of apheresis in
hypertriglyceridemia-induced acute pancreatitis: A
systematic review. Pancreatology, 2015; 15: 313-32060) Inayat F, Zafar F, Riaz I, Younus F, Baig AS, Imran Z.
Hypertriglyceridemic Pancreatitis: Is Insulin
Monotherapy A Feasible Therapeutic Option? Cureus,
2018; 10: e3461
61) Skulas-Ray AC, Wilson PWF, Harris WS, Brinton EA,
Kris-Etherton PM, Richter CK, Jacobson TA, Engler
MB, Miller M, Robinson JG, Blum CB, RodriguezLeyva D, de Ferranti SD, Welty FK, American Heart
Association Council on Arteriosclerosis, Thrombosis and
Vascular Biology; Council on Lifestyle andCardiometabolic Health; Council on Cardiovascular
Disease in the Young; Council on Cardiovascular and898

Stroke Nursing; and Council on Clinical Cardiology.
Omega-3 Fatty Acids for the Management ofHypertriglyceridemia: A Science Advisory From theAmerican Heart Association. Circulation, 2019; 140:e673-e691
62) Greenberg BH. Primary Type V Hyperlipoproteinemia:
A Descriptive Study in 32 Families. Ann Intern Med,
1977; 87: 526-534
63) Tada H, Kawashiri M-A, Nakahashi T, Yagi K, Chujo D,
Ohbatake A, Mori Y, Mori S, Kometani M, Fujii H,
Nohara A, Inazu A, Mabuchi H, Yamagishi M, Hayashi
K. Clinical characteristics of Japanese patients withsevere hypertriglyceridemia. J Clin Lipidol, 2015; 9:519-524
64) Basaran A. Pregnancy-induced hyperlipoproteinemia:
review of the literature. Reprod Sci, 2009; 16: 431-437
65) Ghio A, Bertolotto A, Resi V, Volpe L, Di Cianni G.
Triglyceride metabolism in pregnancy. Adv Clin Chem,
2011; 55: 133-153
66) Wong B, Ooi TC, Keely E. Severe gestational
hypertriglyceridemia: A practical approach for clinicians.
Obstet Med, 2015; 8: 158-167
67) Amundsen AL, Khoury J, Iversen PO, Bergei C, Ose L,
Tonstad S, Retterstøl K. Marked changes in plasma
lipids and lipoproteins during pregnancy in women withfamilial hypercholesterolemia. Atherosclerosis, 2006;
189: 451-457
68) Warth MR, Arky RA, Knopp RH. Lipid metabolism inpregnancy. II. Altered lipid composition in intermediage,
very low, low and high-density lipoprotein fractions. J
Clin Endocrinol Metab, 1975; 41: 649-655
69) Potter JM, Nestel PJ. The hyperlipidemia of pregnancy
in normal and complicated pregnancies. Am J Obstet
Gynecol, 1979; 133: 165-170
70) Salameh WA, Mastrogiannis DS. Maternal hyperlipidemia
in pregnancy. Clin Obstet Gynecol, 1994; 37: 66-77
71) Alvarez JJ, Montelongo A, Iglesias A, Lasunción MA,
Herrera E. Longitudinal study on lipoprotein profile,high density lipoprotein subclass, and postheparinlipases during gestation in women. J Lipid Res, 1996;
37: 299-308
72) Herrera E. Lipid metabolism in pregnancy and its
consequences in the fetus and newborn. Endocrine,
2002; 19: 43-55
73) Papadakis EP, Sarigianni M, Mikhailidis DP,
Mamopoulos A, Karagiannis V. Acute pancreatitis inpregnancy: an overview. Eur J Obstet Gynecol Reprod
Biol, 2011; 159: 261-266
74) Russi G. Severe dyslipidemia in pregnancy: The role oftherapeutic apheresis. Transfus Apher Sci, 2015; 53:
283-28775) Kekki M, Nikkilä EA. Plasma triglyceride turnover
during use of oral contraceptives. Metab Clin Exp, 1971;
20: 878-889
76) Schaefer EJ, Foster DM, Zech LA, Lindgren FT, Brewer
HB, Levy RI. The Effects of Estrogen Administration on
Plasma Lipoprotein Metabolism in Premenopausal
Females. The Journal of Clinical Endocrinology &Metabolism, 1983; 57: 262-267
77) Desoye G, Schweditsch MO, Pfeiffer KP, Zechner R,
Kostner GM. Correlation of hormones with lipid andDiagnosis and Management of Chylomicronemia

lipoprotein levels during normal pregnancy andpostpartum. J Clin Endocrinol Metab, 1987; 64: 704712
78) Lamon-Fava S, Diffenderfer MR, Barrett PHR, Wan
WY, Postfai B, Nartsupha C, Dolnikowski GG, Schaefer
EJ. Differential Effects of Estrogen and Progestin on
Ap o l i p o p ro t ei n B 1 0 0 a n d B 4 8 K i n e t i cs i n
Postmenopausal Women. Lipids, 2018; 53: 167-175
79) Fredrickson DS, Lees RS. A SYSTEM FOR
PHENOTYPING HYPERLIPOPROTEINEMIA.
Circulation, 1965; 31: 321-32780) Moulin P, Dufour R, Averna M, Arca M, Cefalù AB,
Noto D, D’Erasmo L, Di Costanzo A, Marçais C,
Alvarez-Sala Walther LA, Banach M, Borén J, Cramb R,
Gouni-Berthold I, Hughes E, Johnson C, Pintó X,
Reiner Ž, van Lennep JR, Soran H, Stefanutti C, Stroes
E, Bruckert E. Identification and diagnosis of patientswith familial chylomicronaemia syndrome (FCS): Expert
panel recommendations and proposal of an “FCS score.”
Atherosclerosis, 2018; 275: 265-272
81) Brown WV, Goldberg I, Duell B, Gaudet D. Roundtablediscussion: Familial chylomicronemia syndrome:
Diagnosis and management. J Clin Lipidol, 2018; 12:254-263
82) Brown WV, Gaudet D, Goldberg I, Hegele R.
Roundtable on etiology of familial chylomicronemia
syndrome. J Clin Lipidol, 2018; 12: 5-1183) Dron JS, Wang J, Cao H, McIntyre AD, Iacocca MA,
Menard JR, Movsesyan I, Malloy MJ, Pullinger CR,
Kane JP, Hegele RA. Severe hypertriglyceridemia is
primarily polygenic. J Clin Lipidol, 2019; 13: 80-88
84) Toth PP, Grabner M, Ramey N, Higuchi K. Clinical andeconomic outcomes in a real-world population ofpatients with elevated triglyceride levels. Atherosclerosis,
2014; 237: 790-797
85) Sekimoto M, Takada T, Kawarada Y, Hirata K, Mayumi
T, Yoshida M, Hirota M, Kimura Y, Takeda K, Isaji S,
Koizumi M, Otsuki M, Matsuno S, JPN. JPN
Guidelines for the management of acute pancreatitis:
epidemiology, etiology, natural history, and outcome
predictors in acute pancreatitis. J Hepatobiliary Pancreat
Surg, 2006; 13: 10-24
86) Carr RA, Rejowski BJ, Cote GA, Pitt HA, Zyromski NJ.
Systematic review of hypertriglyceridemia-induced acutepancreatitis: A more virulent etiology? Pancreatology,
2016; 16: 469-476
87) Rashid N, Sharma PP, Scott RD, Lin KJ, Toth PP. Severe
hypertriglyceridemia and factors associated with acutepancreatitis in an integrated health care system. J Clin
Lipidol, 2016; 10: 880-89088) Geng Y, Li W, Sun L, Tong Z, Li N, Li J. Severe acutepancreatitis during pregnancy: eleven years experiencefrom a surgical intensive care unit. Dig Dis Sci, 2011;
56: 3672-3677
89) Ramin KD, Ramin SM, Richey SD, Cunningham FG.
Acute pancreatitis in pregnancy. Am J Obstet Gynecol,
1995; 173: 187-191
90) Murphy MJ, Sheng X, MacDonald TM, Wei L.
Hypertriglyceridemia and acute pancreatitis. JAMA
Intern Med, 2013; 173: 162-164
91) Pedersen SB, Langsted A, Nordestgaard BG. Nonfasting

Mild-to-Moderate Hypertriglyceridemia and Risk of
Acute Pancreatitis. JAMA Intern Med, 2016; 176: 18341842
92) Scherer J, Singh VP, Pitchumoni CS, Yadav D. Issues inhypertriglyceridemic pancreatitis: an update. J Clin
Gastroenterol, 2014; 48: 195-203
93) Authors/Task Force Members, ESC Committee for
Practice Guidelines (CPG), ESC National Cardiac
Societies. 2019 ESC/EAS guidelines for the managementof dyslipidaemias: Lipid modification to reduce
cardiovascular risk. Atherosclerosis, 2019; 290: 140-205
94) Gaudet D, de Wal J, Tremblay K, Déry S, van Deventer
S, Freidig A, Brisson D, Méthot J. Review of the clinicaldevelopment of alipogene tiparvovec gene therapy forlipoprotein lipase deficiency. Atheroscler Suppl, 2010;
11: 55-6095) Gaudet D, Blom D, Bruckert E, Stroes E, Kastelein J,
John K, Malloy M, Moulin P, Retterstøļl K, Hughes S,
Tsimikas S, Witztum J. Acute Pancreatitis is Highly
Prevalent and Complications can be Fatal in Patientswith Familial Chylomicronemia: Results From a Surveyof Lipidologist. Journal of Clinical Lipidology, 2016; 10:
680-68196) Paquette M, Bernard S, Hegele RA, Baass A.
Chylomicronemia: Differences between familial
chylomicronemia syndrome and multifactorialchylomicronemia. Atherosclerosis, 2019; 283: 137-142
97) Zafrir B, Jubran A, Hijazi R, Shapira C. Clinical featuresand outcomes of severe, very severe, and extreme
hypertriglyceridemia in a regional health service. Journalof Clinical Lipidology, 2018; 12: 928-936
98) Fallat RW, Vester JW, Glueck CJ. Suppression of amylase
activity by hypertriglyceridemia. JAMA, 1973; 225:
1331-1334
99) Melnick S, Nazir S, Gish D, Aryal MR. Hypertriglyceridemic
pancreatitis associated with confounding laboratory
abnormalities. J Community Hosp Intern Med Perspect,
2016; 6: 31808
100) Singh A, Shrestha M, Anand C. Acute pancreatitis withnormal amylase and lipase--an ED dilemma. Am J
Emerg Med, 2016; 34: 940.e5-7101) Nayak KR, Daly RG. Images in clinical medicine.
Eruptive xanthomas associated with hypertriglyceridemia
and new-onset diabetes mellitus. N Engl J Med, 2004;
350: 1235
102) Kumar J, Wierzbicki AS. Images in clinical medicine.
Lipemia retinalis. N Engl J Med, 2005; 353: 823
103) Stefanutti C, Labbadia G, Morozzi C. Severe
hypertriglyceridemia-related acute pancreatitis. Ther
Apher Dial, 2013; 17: 130-137
104) Ahmad Z, Halter R, Stevenson M. Building a better
understanding of the burden of disease in familial
chylomicronemia syndrome. Expert Rev Clin
Pharmacol, 2017; 10: 1-3
105) Gelrud A, Williams KR, Hsieh A, Gwosdow AR,
Gilstrap A, Brown A. The burden of familial
chylomicronemia syndrome from the patients’perspective. Expert Rev Cardiovasc Ther, 2017; 15: 879887
106) Davidson M, Stevenson M, Hsieh A, Ahmad Z,
Crowson C, Witztum JL. The burden of familial
899

Okazaki et al .

chylomicronemia syndrome: interim results from the
IN-FOCUS study. Expert Rev Cardiovasc Ther, 2017;
15: 415-423
107) Davidson M, Stevenson M, Hsieh A, Ahmad Z, Roeters
van Lennep J, Crowson C, Witztum JL. The burden offamilial chylomicronemia syndrome: Results from theglobal IN-FOCUS study. J Clin Lipidol, 2018; 12: 898907.e2
108) Expert Panel on Integrated Guidelines for Cardiovascular
Health and Risk Reduction in Children and Adolescents,
National Heart, Lung, and Blood Institute. Expert panel
on integrated guidelines for cardiovascular health andrisk reduction in children and adolescents: summary
report. Pediatrics, 2011; 128 Suppl 5: S213-256
109) Buonuomo PS, Rabacchi C, Macchiaiolo M, Trenti C,
Fasano T, Tarugi P, Bartuli A, Bertolini S, Calandra S.
Incidental finding of severe hypertriglyceridemia inchildren. Role of multiple rare variants in genes affecting
plasma triglyceride. Journal of Clinical Lipidology, 2017;
11: 1329-1337.e3
110) Dominguez-Muñoz JE, Malfertheiner P, Ditschuneit
HH, Blanco-Chavez J, Uhl W, Büchler M, Ditschuneit
H. Hyperlipidemia in acute pancreatitis. Relationshipwith etiology, onset, and severity of the disease. Int J
Pancreatol, 1991; 10: 261-267
111) Watts GF, Morton K, Jackson P, Lewis B. Managementof patients with severe hypertriglyceridaemia during
pregnancy: report of two cases with familial lipoprotein
lipase deficiency. Br J Obstet Gynaecol, 1992; 99: 163166
112) Ma Y, Liu MS, Ginzinger D, Frohlich J, Brunzell JD,
Hayden MR. Gene-environment interaction in theconversion of a mild-to-severe phenotype in a patienthomozygous for a Ser172-->Cys mutation in the
lipoprotein lipase gene. J Clin Invest, 1993; 91: 19531958
113) Glueck CJ, Streicher P, Wang P, Sprecher D, Falko JM.
Treatment of severe familial hypertriglyceridemia during
pregnancy with very-low-fat diet and n-3 fatty acids.
Nutrition, 1996; 12: 202-205
114) Saravanan P, Blumenthal S, Anderson C, Stein R,
Berkelhammer C. Plasma exchange for dramatic
gestational hyperlipidemic pancreatitis. J Clin
Gastroenterol, 1996; 22: 295-298
115) Suga S, Tamasawa N, Kinpara I, Murakami H, Kasai N,
Onuma T, Ikeda Y, Takagi A, Suda T. Identification ofhomozygous lipoprotein lipase gene mutation in awoman with recurrent aggravation of hypertriglyceridaemia
induced by pregnancy. J Intern Med, 1998; 243: 317321
116) McGladdery SH, Frohlich JJ. Lipoprotein lipase andapoE polymorphisms: relationship to hypertriglyceridemia
during pregnancy. J Lipid Res, 2001; 42: 1905-1912
117) Bartha I, Dinya T, Seres I, Paragh G, Ross C, Hayden
MR, Biró S, Vargha G. Acute hypertriglyceridemic
pancreatitis during pregnancy due to homozygous
lipoprotein lipase gene mutation. Clin Chim Acta, 2009;
400: 137-138
118) Xie S-L, Chen T-Z, Huang X-L, Chen C, Jin R, Huang
Z-M, Zhou M-T. Genetic Variants Associated with
Gestational Hypertriglyceridemia and Pancreatitis. PLoS
900

ONE, 2015; 10: e0129488
119) Gürsoy A, Kulaksizoglu M, Sahin M, Ertugrul DT, Ozer
F, Tu t u n c u N B , D e m i r a g N G . S e v e r ehypertriglyceridemia-induced pancreatitis during
pregnancy. J Natl Med Assoc, 2006; 98: 655-657
120) Goldberg AS, Hegele RA. Severe hypertriglyceridemia in
pregnancy. J Clin Endocrinol Metab, 2012; 97: 25892596
121) Gallos ID, Sivakumar K, Kilby MD, Coomarasamy A,
Thangaratinam S, Vatish M. Pre-eclampsia is associatedwith, and preceded by, hypertriglyceridaemia: a metaanalysis. BJOG, 2013; 120: 1321-1332
122) Al-Shali K, Wang J, Fellows F, Huff MW, Wolfe BM,
Hegele RA. Successful pregnancy outcome in a patientwith severe chylomicronemia due to compound
heterozygosity for mutant lipoprotein lipase. Clin
Biochem, 2002; 35: 125-130123) Stroes E, Moulin P, Parhofer KG, Rebours V, Löhr J-M,
Averna M. Diagnostic algorithm for familial
chylomicronemia syndrome. Atheroscler Suppl, 2017;
23: 1-7
124) Tremblay K, Gaudet D, Khoury E, Brisson D.
Dissection of Clinical and Gene Expression Signaturesof Familial versus Multifactorial Chylomicronemia. J
Endocr Soc, 2020; 4: bvaa056
125) Christian JB, Arondekar B, Buysman EK, Johnson SL,
Seeger JD, Jacobson TA. Clinical and economic benefits
observed when follow-up triglyceride levels are less than
500 mg/dL in patients with severe hypertriglyceridemia.
J Clin Lipidol, 2012; 6: 450-461
126) Christian JB, Arondekar B, Buysman EK, Jacobson TA,
Snipes RG, Horwitz RI. Determining triglyceride
reductions needed for clinical impact in severe
hypertriglyceridemia. Am J Med, 2014; 127: 36-44.e1
127) Huffman KM, Hawk VH, Henes ST, Ocampo CI,
Orenduff MC, Slentz CA, Johnson JL, Houmard JA,
Samsa GP, Kraus WE, Bales CW. Exercise effects on
lipids in persons with varying dietary patterns-does dietmatter if they exercise? Responses in Studies of aTargeted Risk Reduction Intervention through Defined
Exercise I. Am Heart J, 2012; 164: 117-124
128) Williams L, Wilson DP. Editorial commentary: Dietary
management of familial chylomicronemia syndrome. J
Clin Lipidol, 2016; 10: 462-465
129) Williams L, Rhodes KS, Karmally W, Welstead LA,
Alexander L, Sutton L, patients and families living with
FCS. Familial chylomicronemia syndrome: Bringing tolife dietary recommendations throughout the life span. J
Clin Lipidol, 2018; 12: 908-919
130) Ewald N, Hardt PD, Kloer H-U. Severe hypertriglyceridemia
and pancreatitis: presentation and management. Curr
Opin Lipidol, 2009; 20: 497-504
131) Brunzell JD, Hazzard WR, Porte D, Bierman EL.
Evidence for a common, saturable, triglyceride removal
mechanism for chylomicrons and very low density
lipoproteins in man. J Clin Invest, 1973; 52: 1578-1585
132) DenBesten L, Reyna RH, Connor WE, Stegink LD. The
different effects on the serum lipids and fecal steroids ofhigh carbohydrate diets given orally or intravenously. J
Clin Invest, 1973; 52: 1384-1393
133) Deng L-H, Xue P, Xia Q, Yang X-N, Wan M-H. EffectDiagnosis and Management of Chylomicronemiaof admission hypertriglyceridemia on the episodes ofsevere acute pancreatitis. World J Gastroenterol, 2008;
14: 4558-4561
134) Nawaz H, Koutroumpakis E, Easler J, Slivka A,
Whitcomb DC, Singh VP, Yadav D, Papachristou GI.
Elevated serum triglycerides are independently associatedwith persistent organ failure in acute pancreatitis. Am J
Gastroenterol, 2015; 110: 1497-1503
135) Tsuang W, Navaneethan U, Ruiz L, Palascak JB, Gelrud
A. Hypertriglyceridemic pancreatitis: presentation andmanagement. Am J Gastroenterol, 2009; 104: 984-991
136) Kawashiri M, Higashikata T, Mizuno M, Takata M,
Katsuda S, Miwa K, Nozue T, Nohara A, Inazu A,
Kobayashi J, Koizumi J, Mabuchi H. Long-term courseof lipoprotein lipase (LPL) deficiency due tohomozygous LPL(Arita) in a patient with recurrent
pancreatitis, retained glucose tolerance, andatherosclerosis. J Clin Endocrinol Metab, 2005; 90:6541-6544
137) Mikhail N, Trivedi K, Page C, Wali S, Cope D.
Treatment of severe hypertriglyceridemia in nondiabetic
patients with insulin. Am J Emerg Med, 2005; 23: 415417
138) Khan R, Jehangir W, Regeti K, Yousif A.
Hypertriglyceridemia-Induced Pancreatitis: Choice ofTreatment. Gastroenterology Res, 2015; 8: 234-236
139) Inayat F, Zafar F, Baig AS, Chaudhry NA, Aslam A,
Khan ZH, Iqbal MJ. Hypertriglyceridemic Pancreatitis
Treated with Insulin Therapy: A Comparative Review of
34 Cases. Cureus, 2018; 10: e3501
140) Weintraub M, Rassin T, Eisenberg S, Ringel Y,
Grosskopf I, Iaina A, Charach G, Liron M, Rubinstein
A. Continuous intravenous heparin administration inhumans causes a decrease in serum lipolytic activity andaccumulation of chylomicrons in circulation. J Lipid
Res, 1994; 35: 229-238
141) Schuff-Werner P, Fenger S, Kohlschein P. Role of lipid
apheresis in changing times. Clin Res Cardiol Suppl,
2012; 7: 7-14142) Stefanutti C, Julius U. Treatment of primary
hypertriglyceridemia states--General approach and therole of extracorporeal methods. Atheroscler Suppl, 2015;
18: 85-94
143) He W-H, Yu M, Zhu Y, Xia L, Liu P, Zeng H, Zhu Y,
Lv N-H. Emergent Triglyceride-lowering Therapy With
Early High-volume Hemofiltration Against LowMolecular-Weight Heparin Combined With Insulin inHypertriglyceridemic Pancreatitis: A Prospective
Randomized Controlled Trial. J Clin Gastroenterol,
2016; 50: 772-778
144) Schwartz J, Winters JL, Padmanabhan A, Balogun RA,
Delaney M, Linenberger ML, Szczepiorkowski ZM,
Williams ME, Wu Y, Shaz BH. Guidelines on the use oftherapeutic apheresis in clinical practice-evidence-based
approach from the Writing Committee of the American
Society for Apheresis: the sixth special issue. J Clin
Apher, 2013; 28: 145-284
145) Thompson GR. Lipoprotein apheresis. Curr Opin
Lipidol, 2010; 21: 487-491
146) Ewald N, Kloer H-U. Treatment options for severe
hypertriglyceridemia (SHTG): the role of apheresis. Clin

Res Cardiol Suppl, 2012; 7: 31-35
147) Basar R, Uzum AK, Canbaz B, Dogansen SC,
Kalayoglu-Besisik S, Altay-Dadin S, Aral F, Ozbey NC.
Therapeutic apheresis for severe hypertriglyceridemia in
pregnancy. Arch Gynecol Obstet, 2013; 287: 839-843
148) Safi F, Toumeh A, Abuissa Qadan MA, Karaz R, AlAkdar
B, Assaly R. Management of familial hypertriglyceridemiainduced pancreatitis during pregnancy with therapeuticplasma exchange: a case report and review of literature.
Am J Ther, 2014; 21: e134-136
149) Gupta N, Ahmed S, Shaffer L, Cavens P, Blankstein J.
Severe hypertriglyceridemia induced pancreatitis inpregnancy. Case Rep Obstet Gynecol, 2014; 2014:
485493150) Newman CB, Blaha MJ, Boord JB, Cariou B, Chait A,
Fein HG, Ginsberg HN, Goldberg IJ, Murad MH,
Subramanian S, Tannock LR. Lipid Management inPatients with Endocrine Disorders: An Endocrine
Society Clinical Practice Guideline. The Journal of
Clinical Endocrinology & Metabolism, 2020; 105:
3613-3682
151) Piolot A, Nadler F, Cavallero E, Coquard JL, Jacotot B.
Prevention of recurrent acute pancreatitis in patientswith severe hypertriglyceridemia: value of regular
plasmapheresis. Pancreas, 1996; 13: 96-99
152) Hovland A, Hardersen R, Mollnes TE, Lappegård KT.
Selective whole blood lipoprotein apheresis to prevent
pancreatitis in drug refractory hypertriglyceridemia. JOP,
2010; 11: 467-469
153) Schaap-Fogler M, Schurr D, Schaap T, Leitersdorf E,
Rund D. Long-term plasma exchange for severe
refractory hypertriglyceridemia: a decade of experiencedemonstrates safety and efficacy. J Clin Apher, 2009; 24:
254-258154) Saleh MA, Mansoor E, Cooper GS. Case of familial
hyperlipoproteinemia type III hypertriglyceridemia
induced acute pancreatitis: Role for outpatient apheresis
maintenance therapy. World J Gastroenterol, 2017; 23:7332-7336
155) Niro J, Sapin V, Constantin J-M, Cotte B, Lebel A,
Roszyk L, R Eglizot null, Tauveron I, Jacquetin B,
Lémery D, Gallot D. [Management of gestational
hypertriglyceridemia by plasmapheresis]. Gynecol Obstet
Fertil, 2007; 35: 1133-1135
156) Sivakumaran P, Tabak SW, Gregory K, Pepkowitz SH,
Klapper EB. Management of familial hypertriglyceridemia
during pregnancy with plasma exchange. J Clin Apher,
2009; 24: 42-46
157) Mizushima T, Ochi K, Matsumura N, Ichimura M,
Ishibashi T, Tsuboi K, Harada H. Prevention of
hyperlipidemic acute pancreatitis during pregnancy withmedium-chain triglyceride nutritional support. Int J
Pancreatol, 1998; 23: 187-192
158) Athyros VG, Giouleme OI, Nikolaidis NL, Vasiliadis
TV, Bouloukos VI, Kontopoulos AG, Eugenidis NP.
Long-term follow-up of patients with acute
hypertriglyceridemia-induced pancreatitis. J Clin
Gastroenterol, 2002; 34: 472-475
159) Tsai EC, Brown JA, Veldee MY, Anderson GJ, Chait A,
Brunzell JD. Potential of essential fatty acid deficiency
with extremely low fat diet in lipoprotein lipase901

Okazaki et al .

deficiency during pregnancy: A case report. BMC
Pregnancy Childbirth, 2004; 4: 27
160) Greenberg JA, Bell SJ, Ausdal WV. Omega-3 Fatty Acidsupplementation during pregnancy. Rev Obstet Gynecol,
2008; 1: 162-169
161) Nelson-Piercy C, Crook MA. Severe hypertriglyceridemia
complicating pregnancy, management by dietaryintervention and omega-3 fatty acid supplementation.
Nutrition, 2009; 25: 1098-1099
162) Takaishi K, Miyoshi J, Matsumura T, Honda R, Ohba T,
Katabuchi H. Hypertriglyceridemic acute pancreatitis
during pregnancy: prevention with diet therapy andomega-3 fatty acids in the following pregnancy.
Nutrition, 2009; 25: 1094-1097
163) Saadi HF, Kurlander DJ, Erkins JM, Hoogwerf BJ.
Severe hypertriglyceridemia and acute pancreatitis
during pregnancy: treatment with gemfibrozil. Endocr
Pract, 1999; 5: 33-36
164) Abu Musa AA, Usta IM, Rechdan JB, Nassar AH.
Recurrent hypertriglyceridemia-induced pancreatitis inpregnancy: a management dilemma. Pancreas, 2006; 32:
227-228165) Hill AJ, Pacheco LD, Saade G, Hankins GDV. Familial
hypertriglyceridemia in pregnancy. Int J Gynaecol
Obstet, 2014; 125: 80-81
166) Lim R, Rodger SJ, Hawkins TL-A. Presentation andmanagement of acute hypertriglyceridemic pancreatitis
in pregnancy: A case report. Obstet Med, 2015; 8: 200203
167) Hegele RA, Tsimikas S. Lipid-Lowering Agents. Circ
Res, 2019; 124: 386-404
168) Cuchel M, Meagher EA, du Toit Theron H, Blom DJ,
Marais AD, Hegele RA, Averna MR, Sirtori CR, Shah
PK, Gaudet D, Stefanutti C, Vigna GB, Du Plessis
AME, Propert KJ, Sasiela WJ, Bloedon LT, Rader DJ,
Phase 3 HoFH Lomitapide Study investigators. Efficacy
and safety of a microsomal triglyceride transfer protein
inhibitor in patients with homozygous familial
hypercholesterolaemia: a single-arm, open-label, phase 3
study. Lancet, 2013; 381: 40-46
169) Sa c k s F M , St a n e s a M , He g e l e R A . Se ve rehypertriglyceridemia with pancreatitis: thirteen years’
treatment with lomitapide. JAMA Intern Med, 2014;
174: 443-447
170) Blom DJ, Averna MR, Meagher EA, du Toit Theron H,
Sirtori CR, Hegele RA, Shah PK, Gaudet D, Stefanutti
C, Vigna GB, Larrey D, Bloedon LT, Foulds P, Rader
DJ, Cuchel M. Long-Term Efficacy and Safety of theMicrosomal Triglyceride Transfer Protein Inhibitor
Lomitapide in Patients With Homozygous Familial
Hypercholesterolemia. Circulation, 2017; 136: 332-335
171) Raal FJ, Santos RD, Blom DJ, Marais AD, Charng M-J,
Cromwell WC, Lachmann RH, Gaudet D, Tan JL,
Chasan-Taber S, Tribble DL, Flaim JD, Crooke ST.
Mipomersen, an apolipoprotein B synthesis inhibitor,
for lowering of LDL cholesterol concentrations inpatients with homozygous familial
hypercholesterolaemia: a randomised, double-blind,placebo-controlled trial. Lancet, 2010; 375: 998-1006
172) Panta R, Dahal K, Kunwar S. Efficacy and safety of
mipomersen in treatment of dyslipidemia: a meta902

analysis of randomized controlled trials. J Clin Lipidol,
2015; 9: 217-225
173) Gryn SE, Hegele RA. Novel therapeutics in
hypertriglyceridemia. Curr Opin Lipidol, 2015; 26:484-491174) Witztum JL, Gaudet D, Freedman SD, Alexander VJ,
Digenio A, Williams KR, Yang Q, Hughes SG, Geary
RS, Arca M, Stroes ESG, Bergeron J, Soran H, Civeira F,
Hemphill L, Tsimikas S, Blom DJ, O’Dea L, Bruckert E.
Volanesorsen and Triglyceride Levels in Familial
Chylomicronemia Syndrome. N Engl J Med, 2019; 381:
531-542175) Denison H, Nilsson C, Löfgren L, Himmelmann A,Mårtensson G, Knutsson M, Al-Shurbaji A, Tornqvist
H, Eriksson JW. Diacylglycerol acyltransferase 1
inhibition with AZD7687 alters lipid handling andhormone secretion in the gut with intolerable side
effects: a randomized clinical trial. Diabetes Obes Metab,
2014; 16: 334-343
176) Meyers CD, Tremblay K, Amer A, Chen J, Jiang L,
Gaudet D. Effect of the DGAT1 inhibitor pradigastat
on triglyceride and apoB48 levels in patients withfamilial chylomicronemia syndrome. Lipids Health Dis,
2015; 14: 8
177) Meyers CD, Amer A, Majumdar T, Chen J.
Pharmacokinetics, pharmacodynamics, safety, andtolerability of pradigastat, a novel diacylglycerol
acyltransferase 1 inhibitor in overweight or obese, butotherwise healthy human subjects. J Clin Pharmacol,
2015; 55: 1031-1041
178) Graham MJ, Lee RG, Brandt TA, Tai L-J, Fu W, Peralta
R, Yu R, Hurh E, Paz E, McEvoy BW, Baker BF, PhamNC, Digenio A, Hughes SG, Geary RS, Witztum JL,
Crooke RM, Tsimikas S. Cardiovascular and Metabolic
Effects of ANGPTL3 Antisense Oligonucleotides. N
Engl J Med, 2017; 377: 222-232
179) Dewey FE, Gusarova V, Dunbar RL, O’Dushlaine C,
Schurmann C, Gottesman O, McCarthy S, Van Hout
CV, Bruse S, Dansky HM, Leader JB, Murray MF,
Ritchie MD, Kirchner HL, Habegger L, Lopez A, Penn
J, Zhao A, Shao W, Stahl N, Murphy AJ, Hamon S,
Bouzelmat A, Zhang R, Shumel B, Pordy R, Gipe D,
Herman GA, Sheu WHH, Lee I-T, Liang K-W, Guo X,
Rotter JI, Chen Y-DI, Kraus WE, Shah SH, Damrauer S,
Small A, Rader DJ, Wulff AB, Nordestgaard BG,Tybjærg-Hansen A, van den Hoek AM, Princen HMG,
Ledbetter DH, Carey DJ, Overton JD, Reid JG, Sasiela
WJ, Banerjee P, Shuldiner AR, Borecki IB, Teslovich
TM, Yancopoulos GD, Mellis SJ, Gromada J, Baras A.
Genetic and Pharmacologic Inactivation of ANGPTL3
and Cardiovascular Disease. N Engl J Med, 2017; 377:
211-221180) Gaudet D, Gipe DA, Pordy R, Ahmad Z, Cuchel M,
Shah PK, Chyu K-Y, Sasiela WJ, Chan K-C, Brisson D,
Khoury E, Banerjee P, Gusarova V, Gromada J, Stahl N,
Yancopoulos GD, Hovingh GK. ANGPTL3 Inhibitionin Homozygous Familial Hypercholesterolemia. N Engl
J Med, 2017; 377: 296-297
181) Ahmad Z, Banerjee P, Hamon S, Chan K-C, Bouzelmat
A, Sasiela WJ, Pordy R, Mellis S, Dansky H, Gipe DA,
Dunbar RL. Inhibition of Angiopoietin-Like Protein 3

Diagnosis and Management of Chylomicronemia

With a Monoclonal Antibody Reduces Triglycerides inHypertriglyceridemia. Circulation, 2019; 140: 470-486
182) Raal FJ, Rosenson RS, Reeskamp LF, Hovingh GK,
Kastelein JJP, Rubba P, Ali S, Banerjee P, Chan K-C,
Gipe DA, Khilla N, Pordy R, Weinreich DM,
Yancopoulos GD, Zhang Y, Gaudet D, ELIPSE HoFH
Investigators. Evinacumab for Homozygous Familial
Hypercholesterolemia. N Engl J Med, 2020; 383: 711720
183) Haas JT, Winter HS, Lim E, Kirby A, Blumenstiel B,
DeFelice M, Gabriel S, Jalas C, Branski D, Grueter CA,
Toporovski MS, Walther TC, Daly MJ, Farese RV.
DGAT1 mutation is linked to a congenital diarrheal
disorder. J Clin Invest, 2012; 122: 4680-4684
184) Nakou ES, Filippatos TD, Agouridis AP, Kostara C,
Bairaktari ET, Elisaf MS. The effects of ezetimibe and/or
orlistat on triglyceride-rich lipoprotein metabolism inobese hypercholesterolemic patients. Lipids, 2010; 45:445-450185) Blackett P, Tryggestad J, Krishnan S, Li S, Xu W,
Alaupovic P, Quiroga C, Copeland K. Lipoprotein
abnormalities in compound heterozygous lipoprotein
lipase deficiency after treatment with a low-fat diet andorlistat. J Clin Lipidol, 2013; 7: 132-139
186) Gaudet D, Méthot J, Déry S, Brisson D, Essiembre C,
Tremblay G, Tremblay K, de Wal J, Twisk J, van den
Bulk N, Sier-Ferreira V, van Deventer S. Efficacy andlong-term safety of alipogene tiparvovec (AAV1LPLS447X) gene therapy for lipoprotein lipase
deficiency: an open-label trial. Gene Ther, 2013; 20:361-369
187) Cohn JA, Friedman KJ, Noone PG, Knowles MR,
Silverman LM, Jowell PS. Relation between mutationsof the cystic fibrosis gene and idiopathic pancreatitis. N
Engl J Med, 1998; 339: 653-658
188) Schneider A, Barmada MM, Slivka A, Martin JA,
Whitcomb DC. Clinical characterization of patientswith idiopathic chronic pancreatitis and SPINK1
Mutations. Scand J Gastroenterol, 2004; 39: 903-904
189) Chen J-M, Férec C. Chronic pancreatitis: genetics andpathogenesis. Annu Rev Genomics Hum Genet, 2009;10: 63-87
190) Whitcomb DC. Genetic aspects of pancreatitis. Annu
Rev Med, 2010; 61: 413-424
191) Tremblay K, Dubois-Bouchard C, Brisson D, Gaudet D.
Association of CTRC and SPINK1 gene variants withrecurrent hospitalizations for pancreatitis or acuteabdominal pain in lipoprotein lipase deficiency. Front
Genet, 2014; 5: 90
192) Benlian P, De Gennes JL, Foubert L, Zhang H, Gagné
SE, Hayden M. Premature atherosclerosis in patientswith familial chylomicronemia caused by mutations in
the lipoprotein lipase gene. N Engl J Med, 1996; 335:
848-854193) Ebara T, Okubo M, Horinishi A, Adachi M, Murase T,
Hirano T. No evidence of accelerated atherosclerosis in a
66-yr-old chylomicronemia patient homozygous for thenonsense mutation (Tyr61-->stop) in the lipoprotein
lipase gene. Atherosclerosis, 2001; 159: 375-379
194) Maki KC, Guyton JR, Orringer CE, Hamilton-Craig I,
Alexander DD, Davidson MH. Triglyceride-lowering

therapies reduce cardiovascular disease event risk insubjects with hypertriglyceridemia. J Clin Lipidol, 2016;
10: 905-914
195) Shah NP, Cho L, Ahmed HM. Familial Chylomicronemia
Syndrome: Clinical Characteristics and Long-Term
Cardiovascular Outcomes. J Am Coll Cardiol, 2018; 72:
1177-1179
196) Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA,
Ketchum SB, Doyle RT, Juliano RA, Jiao L, Granowitz
C, Tardif J-C, Ballantyne CM, REDUCE-IT
Investigators. Cardiovascular Risk Reduction with
Icosapent Ethyl for Hypertriglyceridemia. N Engl J
Med, 2019; 380: 11-22
197) Musunuru K, Kathiresan S. Genetics of Common,
Complex Coronary Artery Disease. Cell, 2019; 177:
132-145198) Triglyceride Coronary Disease Genetics Consortium andEmerging Risk Factors Collaboration, Sarwar N, Sandhu
MS, Ricketts SL, Butterworth AS, Di Angelantonio E,
Boekholdt SM, Ouwehand W, Watkins H, Samani NJ,
Saleheen D, Lawlor D, Reilly MP, Hingorani AD,
Talmud PJ, Danesh J. Triglyceride-mediated pathways
and coronary disease: collaborative analysis of 101
studies. Lancet, 2010; 375: 1634-1639
199) Do R, Stitziel NO, Won H-H, Jørgensen AB, Duga S,
Angelica Merlini P, Kiezun A, Farrall M, Goel A, Zuk O,
Guella I, Asselta R, Lange LA, Peloso GM, Auer PL,
NHLBI Exome Sequencing Project, Girelli D, Martinelli
N, Farlow DN, DePristo MA, Roberts R, Stewart AFR,
Saleheen D, Danesh J, Epstein SE, Sivapalaratnam S,
Hovingh GK, Kastelein JJ, Samani NJ, Schunkert H,
Erdmann J, Shah SH, Kraus WE, Davies R, Nikpay M,
Johansen CT, Wang J, Hegele RA, Hechter E, Marz W,
Kleber ME, Huang J, Johnson AD, Li M, Burke GL,
Gross M, Liu Y, Assimes TL, Heiss G, Lange EM,
Folsom AR, Taylor HA, Olivieri O, Hamsten A, Clarke
R, Reilly DF, Yin W, Rivas MA, Donnelly P, Rossouw
JE, Psaty BM, Herrington DM, Wilson JG, Rich SS,
Bamshad MJ, Tracy RP, Cupples LA, Rader DJ, Reilly
MP, Spertus JA, Cresci S, Hartiala J, Tang WHW, Hazen
SL, Allayee H, Reiner AP, Carlson CS, Kooperberg C,
Jackson RD, Boerwinkle E, Lander ES, Schwartz SM,
Siscovick DS, McPherson R, Tybjaerg-Hansen A,
Abecasis GR, Watkins H, Nickerson DA, Ardissino D,
Sunyaev SR, O’Donnell CJ, Altshuler D, Gabriel S,
Kathiresan S. Exome sequencing identifies rare LDLR
and APOA5 alleles conferring risk for myocardial
infarction. Nature, 2015; 518: 102-106200) Tremblay K, Méthot J, Brisson D, Gaudet D. Etiology
and risk of lactescent plasma and severe hypertriglyceridemia.
J Clin Lipidol, 2011; 5: 37-44
201) Fu J, Kwok S, Sinai L, Abdel-Razek O, Babula J, Chen
D, Farago E, Fernandopulle N, Leith S, Loyzer M, Lu C,
Malkani N, Morris N, Schmidt M, Stringer R,
Whitehead H, Ban MR, Dubé JB, McIntyre A, Johansen
CT, Cao H, Wang J, Hegele RA. Western Database of
Lipid Variants (WDLV): a catalogue of genetic variants
in monogenic dyslipidemias. Can J Cardiol, 2013; 29:934-939202) Berberich AJ, Hegele RA. The role of genetic testing indyslipidaemia. Pathology, 2019; 51: 184-192
903

Okazaki et al .

203) Ng DM, Burnett JR, Bell DA, Hegele RA, Hooper AJ.
Update on the diagnosis, treatment and management ofrare genetic lipid disorders. Pathology, 2019; 51: 193201
204) Garg A, Garg V, Hegele RA, Lewis GF. Practicaldefinitions of severe versus familial hypercholesterolaemia
and hypertriglyceridaemia for adult clinical practice.
Lancet Diabetes Endocrinol, 2019; 7: 880-886
205) Steinhagen-Thiessen E, Stroes E, Soran H, Johnson C,
Moulin P, Iotti G, Zibellini M, Ossenkoppele B, Dippel
M, Averna MR, GENIALL Investigators. The role ofregistries in rare genetic lipid disorders: Review andintroduction of the first global registry in lipoprotein
lipase deficiency. Atherosclerosis, 2017; 262: 146-153
206) Ng DM, Hooper AJ, Bellgard MI, Burnett JR. The roleof patient registries for rare genetic lipid disorders. Curr
Opin Lipidol, 2018; 29: 156-162
207) Huang C-Q, Dong B-R, Wu H-M, Zhang Y-L, Wu J-H,
Lu Z-C, Flaherty JH. Association of cognitive
impairment with serum lipid/lipoprotein among
Chinese nonagenarians and centenarians. Dement
Geriatr Cogn Disord, 2009; 27: 111-116

904208) Morley JE, Banks WA. Lipids and cognition. J
Alzheimers Dis, 2010; 20: 737-747
209) Hauenschild A, Ewald N, Schnell-Kretschmer H,
Porsch-Oezcueruemez M, Kloer H-U, Hardt PD.
Successful long-term treatment of severe hypertriglyceridemia
by feedback control with lipid self-monitoring. Ann
Nutr Metab, 2008; 52: 215-220210) Lookene A, Zhang L, Hultin M, Olivecrona G. Rapid
subunit exchange in dimeric lipoprotein lipase andproperties of the inactive monomer. J Biol Chem, 2004;
279: 49964-49972
211) Beigneux AP, Allan CM, Sandoval NP, Cho GW, Heizer
PJ, Jung RS, Stanhope KL, Havel PJ, Birrane G,
Meiyappan M, Gill JE, Murakami M, Miyashita K,
Nakajima K, Ploug M, Fong LG, Young SG.
Lipoprotein lipase is active as a monomer. Proc Natl
Acad Sci USA, 2019; 116: 6319-6328
212) Gunn KH, Roberts BS, Wang F, Strauss JD, Borgnia
MJ, Egelman EH, Neher SB. The structure of helicallipoprotein lipase reveals an unexpected twist in lipase
storage. Proc Natl Acad Sci USA, 2020; 117: 1025410264