Atherosclerosis, 61 (1986) l- 6
`Elsevier Scientific Publishers
`Ireland, Ltd.
`
`ATH 03785
`
`Causes of Death in Patients with Familial Hypercholesterolemia
`
`H. Mabuchi ‘, S. Miyamoto 2, K. Ueda 3, M. Oota 4, T. Takegoshi
`T. Wakasugi 1 and R. Takeda 1
`’ Second Department of Internal Medicine, Kanarawa University School of Medicine, Kanazawa;
`’ Department of Internal Medicine, Hokuriku Hospital, Kanarawa;
`3 Department of Internal Medicine, Komatsu Municipal Hospital, Komatsu;
`4 Department of Internal Medicine, Takaoka Municipal Hospital, Takaoka; and
`5 Department of Internal Medicine, Fukui Prefectural Hospital, Fukui (Japan)
`
`5,
`
`(Received 14 January,
`(Accepted 3 February,
`
`1986)
`1986)
`
`Summary
`
`(FH) died
`of familial hypercholesterolemia
`and 41 out of 527 heterozygotes
`Five out of 15 homozygotes
`during
`the past 10 years. Sudden death or heart
`failure was the cause of death
`in each of the 5 deceased
`homozygotes.
`Twenty heterozygotes
`died of myocardial
`infarction,
`9 of sudden death, and 1 died after AC
`bypass
`surgery. Thus, 30 heterozygotes
`(73.2%) died of coronary
`heart disease
`(CHD). The mean age of
`death was significantly
`younger
`in male heterozygotes
`(54 years)
`than
`in the females
`(68 years).
`in Japan.
`Rate of death
`from CHD
`in heterozygotes was 11 times higher
`than
`in the general population
`Rate of death
`from pancreas
`cancer
`in FH was significantly
`higher
`than
`in the general population.
`These
`results
`suggest
`that FH is highly associated with pancreas
`cancer as well as CHD.
`
`Key words: Causes of death - Coronary heart disease - Familial hypercholesterolemia
`
`by a Scientific Research Grant of
`This work was supported
`the Education Ministry of Japan
`(No. 59480198) and grants
`for
`Primary Hyperlipidemia
`Research
`Projects
`of
`the Welfare
`Ministry of Japan.
`to Hiroshi Mabuchi, M.D., Sec-
`requests
`Address
`reprint
`ond Department
`of Internal Medicine, Kanazawa University
`School of Medicine, Takara-machi
`13-1, Kanazawa,
`Ishikawa
`920, Japan.
`bypass; CHD
`aortocoronary
`Abbreuiations: AC = bypass,
`= coronary
`heart disease; FH = familial hypercholesterolemia;
`LDL = low-density
`lipoprotein;
`SCPK = serum
`creatinine
`phosphokinase;
`SGOT =
`serum glutamic
`oxaloacetic
`trans-
`aminase; SLDH = serum
`lactate dehydrogenase.
`
`Introduction
`
`is one of
`(FH)
`hypercholesterolemia
`Familial
`the most common
`inherited
`disorders
`in Japan
`[l]
`as well as in Western
`countries
`[2], occurring
`in
`approximately
`one out of 500 people. FH
`is char-
`acterized
`by a defect
`in
`low density
`lipoprotein
`(LDL) metabolism
`and
`is frequently
`associated
`with premature
`coronary
`heart disease
`(CHD)
`[2].
`We have studied
`the causes of death
`in FH pa-
`tients,
`and have compared
`the findings with
`the
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`
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`of Japan where CHD
`population
`general
`uncommon
`as a cause of death. We suggest
`addition
`to CHD,
`hypercholesterolemia
`associated with cancer of the pancreas.
`
`is still
`that in
`is also
`
`Patients and Methods
`
`to the following
`according
`FH was diagnosed
`two criteria:
`(1) primary
`hypercholesterolemic
`pa-
`tients
`(arbitrarily
`above 230 mg/dl
`in any
`age
`group) with
`tendon
`xanthomas,
`and
`(2) primary
`hypercholesterolemic
`patients with
`and without
`tendon
`xanthomas
`in a first-degree
`relative
`of
`familial
`hypercholesterolemic
`patients.
`The diag-
`nosis
`of homozygous
`FH was made
`in hyper-
`cholesterolemic
`patients with generalized
`xantho-
`mas whose parents
`had been proven
`to have het-
`erozygous FH.
`
`was
`infarction
`of myocardial
`The diagnosis
`3 criteria were
`the
`following
`accepted
`when
`fulfilled:
`(1) characteristic
`clinical history,
`(2) serial
`changes
`in ECG suggesting
`or proving myocardial
`infarction
`(Q-waves) or injury
`(ST elevations),
`and
`(3) transient
`increase
`of SGOT, SCPK or SLDH.
`The causes of death were based
`on autopsy
`studies,
`hospital
`records
`or
`interviews with
`the
`attending
`doctors. Sudden
`death was recorded
`if
`death
`occurred within
`15 min
`of
`the onset
`of
`symptoms with no specific cause. Malignancy
`cases
`were confirmed
`by surgical operation
`or autopsy.
`Serum
`cholesterol
`and
`triglyceride
`levels were
`determined
`by enzymatic methods.
`used for
`The x*-test was a statistical
`procedure
`comparing
`FH with
`the general
`population.
`The
`unpaired
`r-test was used
`to compare male
`and
`female FH patients.
`
`? ?Normal
`Ezzl Heterozygous
`Familial
`Hypercholesterolemia
`Homozygous
`Familial
`Hypercholesterolemia
`
`200
`
`400
`
`600
`
`800
`
`1000
`
`cmg/dll
`Fig. 1. Distributions of serum cholesterol levels in normal subjects, and in heterozygous and homozygous patients with familial
`hypercholesterolemia.
`
`SERUM CHOLESTEROL
`
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`TABLE 1
`
`DETAILS OF PATIENTS WITH HOMOZYGOUS
`
`FAMILIAL HYPERCHOLESTEROLEMIA
`
`3
`
`Sex
`(F/M)
`
`M
`F
`F
`F
`M
`
`Age
`(yr)
`
`16
`22
`31
`42
`18
`
`26
`11
`
`Serum
`cholesterol
`(mg/dl)
`900
`730
`609
`610
`781
`
`726
`123
`
`Serum
`triglyceride
`(w/dl)
`300
`237
`126
`180
`189
`
`206
`66
`
`Cause of
`death a
`
`Heart
`SD
`SD
`SD
`Heart
`
`failure
`
`failure
`
`Autopsy
`
`No
`No
`No
`No
`Yes
`
`NO.
`
`Patient
`
`Y.E.
`M.I.
`K.Y.
`K.M.
`S.T.
`
`1
`2
`3
`4
`5
`
`Mean
`SD
`
`a SD = Sudden death.
`
`TABLE 2
`
`DETAILS OF MALE PATIENTS WITH HETEROZYGOUS
`
`FAMILIAL HYPERCHOLESTEROLEMIA
`
`No.
`
`Patient
`
`Age
`(yr)
`
`Serum
`cholesterol
`(mg/dl)
`
`Serum
`triglyceride
`(mg/dl)
`
`ECG
`findings a
`
`1.0.
`Y.O.
`T.K.
`Y.O.
`T.K.
`H.Y.
`Y.K.
`S.N.
`T.N.
`K.E.
`M.M.
`R.I.
`K.W.
`K.M.
`H.T.
`K.O.
`W.M.
`ST.
`SM.
`S.T.
`S.M.
`SM.
`K.I.
`A.N.
`T.S.
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`
`Mean
`SD
`
`43
`33
`51
`63
`64
`43
`36
`59
`47
`42
`57
`59
`54
`48
`47
`58
`73
`32
`69
`75
`49
`65
`44
`63
`72
`
`54
`12
`
`378
`307
`395
`355
`346
`335
`300
`324
`500
`350
`468
`295
`308
`400
`378
`376
`308
`483
`415
`302
`306
`450
`423
`281
`280
`
`363
`65
`
`153
`82
`163
`57
`134
`
`122
`
`78
`212
`260
`303
`118
`192
`146
`133
`85
`115
`112
`230
`
`356
`
`161
`80
`
`++
`_
`++
`+
`++
`++
`
`++
`++
`++
`ii
`++
`+
`+
`++
`+
`++
`++
`++
`
`+
`++
`++
`++
`++
`
`Cause
`of
`death’
`
`Autopsy
`
`MI
`Accident
`MI
`SD
`Ca of kidney
`SD
`SD
`MI
`SD
`SD
`Stroke
`MI
`Ca of pancreas
`Ca of esophagus
`MI
`AC-bypass
`MI
`MI
`MI
`Ca of pancreas
`Ca of pancreas
`MI
`SD
`MI
`MI
`
`surgery
`
`Yes
`No
`No
`No
`Yes
`No
`No
`Yes
`No
`No
`No
`No
`No
`No
`No
`No
`No
`No
`Yes
`Yes
`No
`No
`No
`No
`Yes
`
`Achilles
`tendon
`thickness b
`(mm)
`16
`10
`10
`17
`22
`
`16
`
`9
`14
`13
`9
`
`15
`15
`
`10
`
`9
`15
`
`13
`4
`
`- = Normal, + = Angina pectoris with more than 1 mm flat ST-segment
`* ECG findings:
`with abnormal Q-wave.
`h Normal value
`in Japanese
`’ MI = myocardial
`infarction:
`
`subjects; 6.3 + 0.2 mm (mean + SEM).
`SD = sudden death; Ca = cancer.
`
`depression,
`
`+ + = Myocardial
`
`infarction
`
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`TABLE 3
`
`DETAILS OF FEMALE PATIENTS WITH HETEROZYGOUS
`
`FAMILIAL HYPERCHOLESTEROLEMIA
`
`No.
`
`Patient
`
`Age
`(Yr)
`
`Serum
`cholesterol
`(mg/dI)
`
`Serum
`triglyceride
`(mg/dI)
`
`ECG
`findings a
`
`Cause
`of
`death
`
`MI
`MI
`Ca of gallbladder
`Stroke
`MI
`MI
`MI
`MI
`SD
`SD
`SD
`MI
`Stroke
`MI
`MI
`Stroke
`
`Autopsy
`
`Yes
`Yes
`No
`Yes
`Yes
`No
`Yes
`Yes
`No
`No
`No
`No
`No
`Yes
`No
`No
`
`Achilles
`tendon
`thickness b
`@ml
`16
`18
`18
`14
`
`15
`
`12
`18
`22
`
`11
`
`16
`4
`
`++
`++
`+
`++
`++
`++
`++
`++
`++
`++
`+
`++
`
`++
`++
`+
`
`64
`113
`162
`107
`84
`104
`227
`78
`97
`143
`250
`193
`112
`211
`148
`95
`
`137
`57
`
`323
`326
`362
`557
`398
`332
`353
`373
`279
`390
`318
`349
`312
`343
`256
`319
`
`349
`67
`
`62
`69
`61
`63
`64
`73
`61
`71
`54
`72
`77
`63
`73
`85
`74
`70
`
`68
`8
`
`C.H.
`T.S.
`A.N.
`T.S.
`M.S.
`M.U.
`M.N.
`Y.M.
`F.K.
`S.A.
`R.K.
`M.K.
`N.T.
`K.T.
`S.N.
`S.S.
`
`1
`2
`3
`4
`5
`6
`7
`8
`9
`10
`11
`12
`13
`14
`15
`16
`
`Mean
`SD
`
`a,b,c See Table 2.
`
`Results
`
`During the past 10 years, 15 homozygotes and
`527 heterozygotes
`of FH were examined
`in
`Kanazawa University Hospital and its affiliated
`hospitals. Their serum cholesterol
`levels, including
`
`TABLE 4
`
`SEX, AGE, SERUM CHOLESTEROL
`CAUSES OF DEATH,
`HETEROZYGOUS
`FAMILIAL HYPERCHOLESTEROLEMIA
`
`Values are given as means f SD.
`
`family members, are shown in
`those of unaffected
`Fig. 1. Their
`trimodal distributions
`of serum
`cholesterol
`levels
`are evident. Mean
`serum
`cholesterol
`levels ( f SD) of unaffected
`subjects
`(n = 173) heterozygotes
`of FH
`(n = 527) and
`homozygotes of FH (n = 15) were 179 k 26, 338 k
`
`AND TRIGLYCERIDE
`
`LEVELS
`
`IN 41 PATIENTS WITH
`
`Cause of death
`
`infarction
`Myocardial
`Sudden death
`Death after AC bypass
`Stroke
`Cancer
`Accident
`
`Mean f SD
`
`No. of
`case
`
`M
`
`11
`6
`1
`1
`5
`1
`
`25
`
`F
`
`9
`3
`0
`3
`1
`0
`
`16
`
`Age
`(yrl
`
`M
`
`58+13
`46+
`58
`57
`58*11
`33
`
`54*12
`
`9
`
`Serum
`cholesterol
`(mg/dl)
`M
`
`362 f 70
`377 f 72
`376
`468
`332+42
`307
`
`F
`
`8
`
`5
`
`69+
`68512
`_
`69f
`61
`_
`
`F
`
`339*
`329+
`
`39
`56
`
`396* 140
`362
`
`Serum
`triglyceride
`(mg/dIl
`M
`
`175 * 85
`68*15
`146
`212
`179+84
`82
`
`F
`
`136 f 61
`163k79
`_
`105+
`162
`_
`
`9
`
`68*
`
`8
`
`363 + 65
`
`349f
`
`67
`
`161 f 80
`
`137 f 51
`
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`Other Diseases
`
`Accident
`
`Coronary Heart Direose
`
`Non.coronary
`Heart Direcise
`
`Stroke
`
`GetlCWCd
`Population
`in Japon
`
`GelleNd
`Population
`in England
`B Wales
`patients with familial
`Fig. 2. Causes of death
`in heterozygous
`hypercholesterolemia,
`and in the general populations
`of Japan,
`and England
`and Wales.
`
`neterorygous
`Familial
`Hypercholesterolemia
`
`respectively.
`63 and 713 & 122 mg/dl,
`failure was the cause of
`Sudden death or heart
`death
`in each of the 5 deceased
`homozygotes
`of
`FH (Table 1). Case Y.E. died of heart
`failure due
`to acquired
`stenosis of the aortic
`root. Case S.T.
`died of heart
`failure due to supravalvular
`stenosis
`and
`ischemic
`cardiomyopathy.
`Their average
`age
`at death was 26 years, with an average
`serum
`cholesterol
`level of 726 mg/dl.
`of FH died
`Forty-one
`of the 527 heterozygotes
`during
`the past 10 years (Tables 2 and 3). Autop-
`sies were performed
`in 13 cases
`(32%). Twenty
`patients
`died of myocardial
`infarction,
`9 of sud-
`den death,
`and 1 patient
`died after AC bypass
`surgery. Thus, 30 patients
`(73.2%) died of CHD.
`Four heterozygotes
`(10%) died of strokes. Out of 6
`patients who died of cancer, 3 died of cancer of
`the pancreas. The mean age at death was signifi-
`cantly
`younger
`in male heterozygotes
`(54 years)
`than
`in female heterozygotes
`(68 years) (P < 0.001)
`(Table 4).
`of
`in heterozygotes
`from CHD
`Rates of death
`in
`FH (73.2%) was 10.9 and 2.8 times higher
`than
`(6.7%, P < 0.005)
`the general population
`of Japan
`[3], and
`in England
`and Wales
`(26.6%
`[4], P <
`O.OOS), respectively. The percentage
`of deaths
`from
`strokes
`and cancer
`in FH was not
`significantly
`different
`from
`that
`in the general population
`(Fig.
`2). However, death
`from pancreatic
`cancer
`(7.5%)
`in FH was significantly
`higher
`than
`in the general
`population
`(1.2%) in Japan
`[3,4].
`
`5
`
`Discussion
`
`is highly
`that FH
`accepted
`is commonly
`It
`associated with CHD
`[2]. In homozygous
`FH,
`coronary
`arterial
`stenosis and aortic supravalvular
`stenosis
`caused
`by atherosclerotic
`changes were
`demonstrated
`through
`angiographies
`and autop-
`sies
`[5-71. The
`life expectancy
`of homozygous
`patients with FH
`is known
`to be limited
`to their
`second or third decades,
`the cause of death always
`being
`atherosclerotic
`cardiovascular
`diseases
`[1,2,7], as our present
`study
`indicates.
`is
`of CHD
`As
`for heterozygotes,
`the onset
`in
`reported
`to occur 10 years earlier
`in men
`than
`women
`[8]. In the present
`study,
`the mean age at
`death
`from CHD
`in 18 male heterozygotes
`(mean
`f SD; 54 + 13) was significantly
`lower
`than
`that
`in female heterozygotes
`(69 -t_ 8). The present
`study
`made no attempt
`to lower serum
`lipid concentra-
`tions and
`there were no significant
`differences
`in
`serum
`cholesterol
`and
`triglyceride
`levels
`in male
`and
`female patients.
`Therefore,
`some other
`risk
`factors might have produced
`the difference
`in ages
`of death
`in males and
`females,
`as is true of the
`general population.
`there were more cardio-
`that
`Heiberg
`showed
`vascular deaths
`in 172 males and 164 females with
`xanthomatosis
`than
`in the general population
`[IO].
`The groups with myocardial
`infarction
`and
`sud-
`den death combined
`accounted
`for 75 and 80% of
`the deaths
`in males and
`females,
`respectively.
`In
`the present
`study,
`the incidence
`of cardiovascular
`deaths
`in FH was 10.9
`times higher
`than
`the
`general
`population
`of
`Japan.
`[3]. Although
`myocardial
`infarction
`of FH is more frequent
`and
`appears
`earlier
`than
`in the general population,
`the
`greatest
`difference
`is found
`in
`the proportion
`of
`sudden
`deaths.
`Jensen
`et al. [ll]
`reported
`that
`32(51.6%) out of 62 deceased members
`died of
`manifest
`coronary
`disease and 10(16.1%) died sud-
`denly.
`In
`the present
`study 20(48.8%) out of 41
`died of myocardial
`infarction
`and 9(22.0%) died
`suddenly. Death
`from cerebrovascular
`disease
`is
`reported
`to be less frequent
`in xanthomatosis
`pa-
`tients
`than
`in the general population
`[lo]. In
`the
`present
`study no difference was observed
`in death
`from cerebrovascular
`disease
`in patients with FH
`and
`in the general population
`of Japan.
`A number
`of reports have been published
`
`indi-
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`6
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`serum
`between
`relationship
`a possible
`eating
`cholesterol levels and increased mortality of cancer
`[12]. Dietary
`fat
`intake
`is positively correlated
`with cancer mortality
`rates. There is also a posi-
`tive correlation between mortality from CHD and
`cancer. Some epidemiological
`studies revealed an
`inverse
`relationship
`between
`serum cholesterol
`levels and colon cancer mortality, especially
`in
`male patients [13]. On the basis of present knowl-
`edge, however, it may be concluded
`that the limi-
`tation of dietary
`fat and cholesterol
`intake
`is a
`prudent public health measure for the prevention
`of both coronary heart disease and cancer [12].
`Rates of pancreatic cancer in all malignancies
`in
`Japan increased from 0.8% in 1950 to 8.7% in 1982
`in men and from 0.5% to 6.2% in women, while
`death from coronary heart disease increased from
`9.9 to 41.6 per 100000 people [3], and total fat
`intake increased from 18 g/day
`to 58 g/day dur-
`ing this period [14]. Up to this time, there have
`been no other reports suggesting a relationship
`between serum cholesterol
`levels and cancer of the
`pancreas. Although the Watanabe heritable hyper-
`lipidemic
`(WHHL)
`rabbit, an animal model of
`human FH, shows histological changes of chronic
`pancreatitis
`[15], the process
`in which hyper-
`cholesterolemia produces cancer of the pancreas is
`not presently known. Thus, FH is highly associ-
`ated with early death from premature coronary
`heart disease, and it is additionally suggested that
`hypercholesterolemia
`is related
`to cancer of the
`pancreas.
`
`References
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