Metabolism of plasma triglycerides in

hypothyroidism and hyperthyroidism in man

Jeffrey J. Abrams, Scott M. Grundy, and Henry Ginsberg
Department of Medicine, Veterans Adnlinistration Medical Center and
University of California, San Diego, CA 92 161

thyroidism)on
plasma T C ; metabolism, we have
carried out a series of studies on turnover of chylomicrons and very low density lipoprotein-triglyceride
(VLDL-TG) in onegroup o f patients with hypothyroidism and in another with hyperthyroidism. Our
findings indicate that thyroid hormones have multiple
actions o n T G metabolism thatcaninfluencetheir
plasmaconcentrations.However,
in spite of these
actions, many patients in both categories of thyroid
dysfunction are able to compensate so a s t o maintain
plasma T G concentrations in the normal range.

METHODS

Patients

'Thirty-nine patients with thyroid dysfunction were

studiedonthe
SpecialDiagnostic
andTreatment
IJnit (metabolic unit), Veterans Administration Medical Center, San Diego, CA. Thyroid functional status
was defined by T, and TSH measurements in all patients. Twenty-six patients had hypothyroidism, and
13 had hyperthyroidism. In the former group of the
26, 5 patients were women; in the latter group,
all
were men. All the patients gave informed consentfor
the investigation.
F o r hypothyroid patients, ages ranged from 31 to
70
years (mean 54 years). Their admissionlevels of T,
Supplementarykey words very low density lipoprotein . lipoprotein lipase . hepatic triglyceride lipase
were consistently low (mean 1.3 f 0.22 pg/dl 5 SEMI).
On admission, plasma cholesterol averaged 300 f 16
T h e actions of thyroid hormones on plasma choles- mg/dl, and triglycerides were 266 2 37 mg/dl. Uric
terol concentrations are well-recognized. In contrast,
acid concentrations were occasionally elevated (mean
there are conflicting reports about the influence o f
7.4 0.36 mg/dl). Ten patients were less than 120%'
these hormones on the metabolism of plasma triglycof ideal weight (IW), and they were designated nonerides. Several workers have reported that patients
obese, hypothyroid patients. Their clinical characterwith hypothyroidismarepronetohypertriglyceridemia (1-8), possibly related to a decrease in lipoAbbreviations: VLDL-TG, very low density lipoprotein triglycprotein lipase (3, 4, 9). However, elevated plasma T G
eride; IW, idealweight; LPL, lipoprotein lipase; HTGL, hepatic
triglyceride lipase; LDL, low density lipoprotein; HDL, high density
hasbeenobserved
less consistently thanincreased
lipoprotein; FCR, fractional catabolic rate; FFA, free fatty acids.
concentrations of cholesterol (6, 10). To understand
All results in this paperare listed asmean 5 SEM unless
better the effects of thyroid disease (hypo- and hyperotherwise indicated.

Journal of LipidResearch

Volume 22, 1981

307

Downloaded from www.jlr.org by guest, on January 27, 2015

Abstract Studies on plasma triglycerides (TG) were perf'ormed in I O nonobese and 16 obese patients with hypothyroidismand
in 13 with hyperthyroidism.Nonobese,
hypothyroid patients generally had normal
levels of 'TG,
but obese patients often had hypertriglyceridemia. In most
hypothyroid patients I-thyroxine treatment lowered plasma
TC, and most hyperthyroidpatientshad
low TG.One
mechanisnlwherebythyroidhormonesmightdecrease
plasma T G could be t o increase lipoprotein lipase (LPL).
However, post-heparinLPL was not increased after therapy,
nor was it increased in hyperthyroid patients. In contrast,
low levels ofposthypothyroidpatientshadabnormally
heparin hepatic triglyceride lipase. In hypothyroid patients
withouthypertriglyceridemia,clearance
of chylomicrons
was normal. A few obese, hypothyroid patients with f'asting
hypertriglycel-idemia had low clearance of chylomicrons,
which may have been due in part to competition for re~novalof excess endogenous TG. Thus, 110 evidence was
obtainedfora
significant abnormality in chylomicron
metabolism in hypothyroidism.
Nonobese,
hypothyroid
patients had normal
synthesis and clearance of very l o w
densitylipoprotein(Vl,DL)-?C.Incontrast,VLDL-TG
synthesis was increased in 8 obese, hypothyroid patients,
andfractionalclearancerateswere
relatively low cornpared t o obese,euthyroid subjects. Instrikingcontrast,
hyperthyroidpatientshadremarkable
facility in clearing
V1,DL-TG.IThus,
TG m e t d b o h n is not grossly deranged in hypothyroidism,butthyroidhormonesapparently can promotecatabolism of VLDL. -Abrams, J. J.,
S. M. Grundy, and H. Ginsberg. Metabolism of plasma
triglycerides in hypothyroidismandhyperthyroidism
in
man. J . Lipid Res. 1981. 22: 307-322.

I'ABL~E1. (Xnical data (non-obese hypothyroicl patients)

Z r l n ~ i \ \ i o n l.tpi(i\
C'IN

I(lc;ll

Patient

.\gc

SC\

Height

hi

168
I66
169

69
ti I
66
6.5

Y,

8"
9"

47
60
60
54
.5 4
62
54
50
61

IO"

47

I'

2 I)
3b

4"

5"
60
7 r1

M
hl
h1
hl
hl
kl

\\Cl#ht

\\eight

f Ill

kii

1;

157

54

166
158
158
188
184
I ti2

10.5
I 05
I IO
1I O

I /

"

I /

XX
X8

112

ti9

1IX

I (;

(:hole\trr~~ll

l'llll\

llr,y/fll

lIl,~/dl

> IO0

>I O 0

3 6 .5
250

0.4
0
2.0

>1 0 0

1 .5x

100

189
2 9'1
24 7

2x3
114
!)i
1I6
2I O
I .?I2
I .i
1
I9 1
I .i
1
279

1.2
5.0
2.0
2.0
0.6

I IX

I 'iH

lll,~lfll

96
I OI
IO2

"

'1

00
76
5. 5
>1 0 0
> I 00

> IO0

253
28x4

:io4

210

\c

id

Ilrgldl

5.8
ti.4
5.11
6.4
6.8
6.0
"

:>.i

6.2
10.2
4.0

'l'hese patients were hospitalized for a p~-olongedperiod for detailed studies o f cholcsterol n~etaholisnl.
Patients 2 and 3 were hospitaliled for 21 prolonged period but did not undet-go cholestr~-olt)alanc-e9tutlies.
' Patient 5 was studied as an outpatient and hospitalired only for tests.
" Patient 7 was hospitalized tor 1 month i n the hypothyroid state. but w a s twated 215 at1 outpatient,

"

"

N o n e o f ' the patients i n either g~-ouphad clinical

'IABLE 2.

(:linical

dat;l

e\idence of gastrointestinal disorders,and none were

taking medication knorvn t o af'fect lipid or lipoprotein
metabolism.
'4 series of euthyroidsubjectspreviouslystudied
i n our laboratory has heen used to describe normal
values for each \,al-iableunder consideration. Char-actel-istics o f ' these control sul~jects are described s u b sequently with the discussion of each variahle.

Experimental design
Patients were atlnlittecl t o the hospital foI either
brief 01- prolonged periods depending
on whether
they underwentdetailedstudy
of theircholesterol
Inetabolism (see ;lccompanying paper; Ref. 1 1 ) . Those
(obese h~pothyroitl patients)
- \ d m i \ \ i o n l.ipi(l\

Idc.1l

Parienr

Age

SCX

VI

11"

12*
13'
14*
15"
16"
1 7"
18 h
19"
2 0''
2 1"

22*
23"
24"
25 r
2 6"

55
34

M
$1

70
50

60
45
48

hl
M
hl

61

64
31
59

L.1 I (

Height

\\clgllt

\\eight

'1 1

ISH

(:h<Jit'5lClO1

I(;

\<id

cm

k,?

c:

nr,qldl

Pnr h

nr,qldl

nqM1

lll,ql~ll

178
173
165
178
176
182
176
192
175
1 64
173

86

121

123

2.0
1.9
3.4
0 .1

27
>IOU

203

81
63
83
X9

238
194

8.2
6.2
11.2

96
86
Y7
90
X1

97
126
I13

44

198

57
55
57
52

h,i
M

180

168

I09
92

165

126

177

12.5

125
130
1Y 1
1 ?I1

132
133
136
147
150

158
1 ti0
176
2 52

59

297
437
256

0.8

>100

296

2.0
2.5
I.o
0
0
1.2
2.2
0.9

ti0

350
265
2 ti2
546

> I00

> 100
45

> 100
70
44
>1 0 0
88

150
I23

59 1
590
440

10.3
6.7
8.5

225

152

405
178
-52
200

4.2
9.7
7.5
7.8

385
2x8

0.9

77

419
329

1.6

>1 0 0

932

2.0

>1 0 0

2.58

'These patients were hospitalized f o r ;I prolonged period for. detailed s t u d y of cholesterol metaboli5tn.
These patients were hospitalized only for tests.
'' Patient 25 was hospitalized throughout the study hut did not untlet-go cholesterol halance studies.
"

I'

308

Journal of Lipid Research Volume 22, 1981

158

207
159
8:UI

7.0
8.8

6.2

Downloaded from www.jlr.org by guest, on January 27, 2015

istics andduration of hospitalization areshown i n

Table 1. The remaining 16 patients were greater than
120% IW, and clinical dataforthese
obese, hypothyroid patients are given
in Table 2. 'I'he division
betweennonobeseandobese
may he somewhat
arbitrary because varying amounts of ~nyxedernatous
fluid may be present in hypothyr-oid patients.
Among
the
13
hyperthyroid
patients,
a l l had
clinical evidence of their disease (Table 3). I n onl!
three was idealweightgreaterthan
120%. Plasma
concentrations of 7I'4 were consistently
increased
(mean 21 -+- 2 pugldl), and TSH was al~vayslow (mean
2.6 ? 0.2units).Theirplasmacholesterol
on aclmission averaged 158 ? 12 mg/dl, T G was 155 ? 13
mg/dl, and uric acid levels were 6.4 f 0.4 mg/dl.

Tr\BLE 3. Clinical data (hyperthyroidpatients)

\ h i \ \ i o n lipid\

Height

\Veighl

\\'right

1,

'I \H

(:h<)le\terol

1G

CI c
i
k i d

< 111

ki:

<y

Jrl,g/d/

l'JlIl,

Jlly/l//

r11,y/d/

wrq////

165
171
158
I82

.5 1
5x

32
19

4.0
2.0

91
148
1 :14
10:1

:3.0

147

.5 1
I I6
106
56
X2

6.3

2.0

189
134
21 I

1I O
1 ox
2.5 1

225
165
94

I x7

I85

111
II O

Itk'll

Palicnt Sex

\gr
YJ

2 7"
28 h
2 9f'

24

41

56
59

11

3 0 h

:3 1

3 I"

42
42

:4 2"
:4 :4c

3 I)

?A''
:4 ~3
3 6''

65
6s
2Y
34
3I
.5 5

J 7"
3 8"
30"

xr

:1I
11
kt
hl
11
11

178
181

67
74
73
76

179
172
162

81
-.

64
92

hl

l6J
180
1 x4

100

\I

177

98

F'If

I 3

6X

85

87
95
IO0

?6

1.4

103

22
I7

IO6

18

?.O

I4

2.0
3.7
4.3
2.2

I13
115
117
I19
12x
1s5
144

14

27
17
4?

3.0

12
I5

2 .o
3.4

I72

"

I l

70

3.8

7.2
5.0

6.2
5.X

5.9
8.0

4.2
4.6
7.2
7.9

Patient 27 \\':IS ho\l)itali/ed f o ~f u l l stud) but did not undel-go cholesterol balance s t ~ ~ d i e s .
trad abbre\ iaterl hosl'italizations hecause of theil- 11)I'erth~roidisn~
and did not undergo cholesterol h a l a ~ ~studies.
tr
' Thew patients \cere hospitali/etl for- a prolonged period for detailed studies o f cholesterol mct;holi\m.
,I p .'ulrrlt :16 \\;IS hosl)italired only f o t - tests.
"
/,

p .,ltlents
'

.4brarn.r, Grundy,

These patients were discharged t o be follonwl once

monthly as outpatients; when they reached euthyroid
status, which
usually
required2-3months,they
we~-e readmitted for study.
PPriod 11. During the second period of the study,
thepatientswererestabilized
a t their pretreatment
Lveight. Some changes in caloric intake usually were
needed hecause o f ' altered thyroid status. Othet-wise,
Period I1 \vas identical to Period I , and the same tests
tvere ca1-1-ied out.

Methodology
T h ~ r o i df 7 r ~ ~ c l i otpstS.
n
Thyroidfunction testswere
done routinely on admission of all patients; these includedplasmath).roxine
( T 4 ) , l-esin-T, uptake, 'I.l3
(ladioimmunoassa).),thyroidstimulatinghot-rnone
(.ISH), free T 4 index, and thyroid antibodies.
Also,
each patient had an 1 l 3 ' uptake and technetium scan
todefinetheirthyroid
s i x hettel-;thesedatawere
used to calculate the I I 3 ' dose in the cases o f ' hyperthyroidism. -I4and 'I'SH were repeated weekly during
hospitalization in bothhypo- and hyperthyroidpatients; these tests were done to confirm stable thyroid
function. and i n the case of hypothy~-oid patients,t o
monitor incr-etnental doses o t ' I-thyroxine.
Plcsmcr lipids. Total plasma cholesterol and
TC; were
ctetetnlinec-t on ;I Technicon Auto Analyxr (Model
11,
Technicon Instruments Corp., Tarrytown, X I ' ) (12, 13).
Post hrpnrin LPI, and HTGL c ~ t i ~ ~ i Post-heparin
ti~.~.
plasnla was obtained from blood drawn 15 min after
intravenous in.jection o f ' 60 I U/kg sodium heparin
(Riker Labs., Inc.) Subjects had been f'asting for 14 h r
prior t o sampling. Sanlples lvere cooled immediately
o n ice and centrifuged at4C for 30 min at 480 g. T h e

and G I T L J ~Triglyceride
P~~
metabolism in hypo- and hyperthyroidism

309

Downloaded from www.jlr.org by guest, on January 27, 2015

patients Ivho were and were not i n the hospital for

prolongedperiodsaredesignated
b y footnotes i n
Tables 1-3. Patients undergoing long-term hospitalization \ v e x given a repetitive dietof mixed solid f ' o o d
and liquid formula, 21s described in the companion
paper ( 1 1). 'Ihose admitted only for testing were o n
an a c t lib diet at home but rnaintained their weights
at constant levels throughout the study. The
following
descrihes the protocol of hospitalizedpatients. The
same secluence of investigation \ v a s carriedouton
patients adrnittecl only for tests except that some
of'
the patients did not undergo all of the tests.
Prriod I . T h e first month was ;I controlperiod.
During this period, the f'ollowing tests were carried
out: (lj thryoi(~f'unction tests (I-,and TSH) lveekly:
h ) plasma cholesterol and' I G twice weekly, and in the
last week o f ' hospitalization; c) clearanceofchylomicrons: d ) transport o f ' VI,L)L,-TC;; P ) plasma postheparin lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTCVL); and f j particle sizes of VLDL.
I n addition, several variables o f ' cholesterol and lile
acid metabolism were estimated
as described in the
accompanying paper ( 1 1).
7rucrtmorlt plmw. After Period I , hypothyroid patients
weretreated with I-thyroxine(SynthroidEj in srnall
incremental doses with titration against their serum
T S H levels. Thisphase usuallylasted
forabout 2
weeks, and af'ter the euthyroid state (normal TSH)
was achieved, patiellts were allowedto stabilize on the
maintenmce (lose for 2 Inore weeks before beginning
the next period.
After- their control period, hyperthyroid patients
1vel.e treated Lvith ','"I by the Nuclear Medicine Section
of the L'eterans .Zdministration Medical Center-.

310

Journal of Lipid Research

Volume 22, 1981

Downloaded from www.jlr.org by guest, on January 27, 2015

plasma was removed and recentrifuged for

30 rnin
interval after injection of [3H]glycerol. Each patient
at750gat
4C. Sampleswerethenimmediately
was given a regimen of fat-free formula throughout
assayed or stored at -70C u p t o 3 months befor-e
the study. Feedings were given every 3 hr around the
assay. LPL and HTGL activities were determined as
clock; they began 36 h r prior to injection of [3H]glycdescribed by Baginsky and Brown (14). For control.
erol and were continued for 48 h r following the inpost-heparin lipase activities were carried out in 16 jection. The diet contained 60% ofcalories
the
needed
normal men (ages20-50 years) and2 1 normal women to maintain the patients weight at a constant
level.
(ages 20-50 years).
In other words, 40% of weight-maintenance calories
ChTlomicron. clenrance rates were determined accord- in the form of fat
was withheld. Of the remaining
ing to Grundy and Mok (15). Briefly, subjects were
60% given to the patient, 45%
was in the form of
intubated with a single-lumen tube which was posicarbohydrate, and 15% was protein (as casein). Retioned in the duodenum. Fat(saffloweroil) was inmoval of fat from the diet was required to prevent
fused at a rate of 200 mg/kg per hr. Before infusion
contamination of the VLDL-TG fraction with intestiand after 21 5-hr equilibrated period, 10 ml of blood
nal chylomicron-TG, and caloric intake was reduced
was collected hourly for the next
5 hr. Plasma was
to prevent carbohydrate-induced hypertriglyceridemia
separatedandstoredat
4C. Chylomicronswere
( 1 7). On the other hand, maintenance of some
caloric
separatedfromotherlipoproteins
by preparative
intake was neededtopreventa
fall inVLDL-TG
ultracentrifugation through a saline layer (1.6 X 106
secondary to prolonged fasting (18). With the feeding
schedule chosen, VLDL-TG concentrations were con$-Inin in a Beckman SW-41 rotor). The lower layer i n
the centrifuge tubewas removed quantitatively through
stant throughout the study.
a pinhole in the bottom of the tube andwas analyzed
At time of injection, 300 PCi of [2-3H]glycerol
(New
for TC; and cholesterol. Chylomicron-1G was taken
EnglandNuclearCorporation,Boston,
MA) were
as the differences between pooled total T G a n d t h e
given intravenously, and blood samples were drawn
concentration in the infranatant, the latter designated at 15 min, 1.0, 1.5, 2.0, 2.5, 4, 5, 6, 7, 8, 11, 13, 15 hr
lipoprotein-IG,ornonchylomicron-TG. Ihe latter
and then every 3 h r u p to 48 hr. Blood samples conterm includes IGin VLDL, LDL, and HDL. For most
taining EDTA were immediately centrifuged at 3000
rpm for 20 min at 5C. T h e plasma was stored at 4C.
patients fasting TG includes T G in these three lipoVLDL was isolated by preparative ultracentrifugation
proteins with none in chylomicrons. In one patient
and specificactivities ofVLDL-TGwereestimated
( N o . lY), fastingchylomicronswerepresentanda
with VLDL-cholesterol,asrecentlydescribed
prespin was done t o remove chylomicrons. Inhis case,
(16).
the term tasting IC; refers to the IG contained i n
T h e specific activity curves of VLDL-TG following
the infranatant, ag,?in corresponding to X in VLDL,
the in-jection of [3H]glycerol have several components
LDL,, and HDL.
includingashortdelayperiodfollowed
by a rapid
After 5 h r o f fat infusion, concentrations o f total
upswing, a flatness at the top of the curve, a rapid,
plasma TG and chylomicron-TG became constant and linear decay for several hours followed
by a slow decay
remained s o throughoutthestudy.Assumingthat
(or tail) out t o 48 hr. The complexity of this curve
absorption of fat was complete, this finding indicates
requires a tnulticompartmentalmodelforanalysis.
that influx and removal ofchylomicron-TG were con- The major features of our model include a ) a delay
stant, i.e., 200 mg/kg per hr. From this value and the
pool at the synthetic site to explain the short retardaincrement i n chylomicron-TG, the residence time of
tion in upswing ofthe curve, 6 ) a fast-synthetic comT G in the chylomicron fraction could be calculated
partment to account for the sharp upswing and deas the reciprocal of the fractional catabolic rate (FCR),cline in the specific activity curve, c) a slow-synthesis
where FCR = input o f chylonkron-TG (200 mg/kg
compartment to explainthe tail of the curve, and
per hr) + plasma pool of chylomicron-TG (mg). T h e
d ) afour-stepdelipidationchainintheplasmato
residence time of chylomicron-TG w i l l be expressed
describe the flatness at the top of the curve. In our
in units of minutes (min).
previous report (16), evidence was provided to support ouI contention that the major portion
Rates of chylomicron clearance in hypothyroid and
of the
hyperthyroid patients were compared
with those o f
tail of the specific activity is d u e to a slow-synthesis
45 normal and hyperlipidemic subjects reported pre- compartment. Other factors that could contribute t o
the tail area slow-removalpathway in theplasma
viously ( 1.5).
compartment and exchange o f T G betweenVLDL
Trrmsfiort of VLDL-TG was estimated by multicomand other lipoproteins. Although it seems likely that
partmental analysis using the method of Zech et al.
both factors do exist, the report of Zech et al. (16)
(16).Thistechnique
involvedanalysis
of plasma
describes
our reasonsfor believing that their contribuVLDL-TG radioactivity data conducted over a 48-hr

RESULTS

Plasma lipids
Results for TG in plasma and VLDL are presented
along with post-heparin lipase activities for nonobese
and obese patients with hypothyroidism and hyperthyroid patients in Tables 4-6, respectively. In nonobese, hypothyroid patients, plasma total T G was alAbrams, Gmndy, and Ginsberg

Table 7 presents results for chylomicron clearance

in 9 hypothyroid patients with normotriglyceridemia.
T h e results for 2 1 euthyroid, normotriglyceridemic
patients are shown for comparison. In control suhjects, the risein chylomicron-TGaveraged49 k 6
mg/dl, and residence time was 6.5 ? 0.9 min. For the
untreated hypothyroid patients, the increasein chylomicron-TG was similar (27 ? 3 mg/dl), as was residence time (3.4 2 0.4 min). In these patients, therefore, their hypothyroidism did not delay chylomicron

Triglyceride metabolismin hypo- and hyperthyroidism

31 1

Downloaded from www.jlr.org by guest, on January 27, 2015

most always in thenormalrange(i.e.,

below 200
tions to the slowly-decaying component of the curves
mg/dl).
Likewise,
8
of
16
obese,
hypothyroid
patients
are small.
had
normal
TG.
Thus,
hypothyroidism
per
se,
espeT h e values calculated by multicompartmental analcially
in
the
absence
of
obesity,
rarely
induced
clinical
ysis includetransport(orsynthesis)andfractional
hypertriglyceridemia.Ontheotherhand,8obese
catabolic rates(FCR)ofplasmaVLDL-TG.
The
patients had elevated plasma TG, and in a few cases
plasma
mass
ofVLDL-TG
was calculated from
the increases were marked.
VLDL-TGconcentrationandtheestimatedplasma
Treatment of hypothyroid patients with T, genervolume. T h e latter was calculatedaspreviouslyreally caused a reduction of plasma TG, and mean values
ported (16) using the following equation:plasma
for both groups werelower after return toeuthyvolume (liters) = ideal weight X (0.045) + excess weight
roidism. Thus,thehypothyroidstateapparently
X (0.010). Ideal weightwas calculated from Standard
caused a slight increase in TG, but usually not to abMetropolitanLifeInsurance
tables (19), assuming
normally high levels. In some of those with marked
that all patients were of medium body frame.
Since patients ofthis study were ofdifferent heights hypertriglyceridemia (i.e., Nos. 16, 19, ZO),treatment
caused a distinct reduction of T G . Nevertheless, most
and weights, it was necessary to normalize the results
of those with striking elevations of TG did not norso that a meaningful comparison among the various
malize their lipids after treatment suggesting that
they
groups could be made. A common method for norhad
an
underlying
primary
hypertriglyceridemia
malizing VLDL-TG transport datais to express them
perhaps accentuated by obesity.
as mg/hr per kg of total body weight. However, as
As shown in Table 6, patients with hyperthyroidism
recently shown by Grundy et al. (20), calculation of
almost always had normal plasmaT G in the untreated
transport rates per kg total body weight may be misstate,and
values
were
essentially
unchanged by
leading. In obese subjects, it decreases the calculated
therapy.
transport t o inordinately low values, as compared to
absolute transports. In other words, dividing transPostheparin lipases
port by a large mass of adipose tissuecan obscure
real increases in production of VLDL-TG, a process
In both groups of hypothyroid patients (Tables 4
presumablyconfinedtothe
liver and intestine. T o
and 5), post-heparin LPL was in the normal range,
overcome this problem, Grundy et al. (20) proposed
and treatment did not produce a significant change.
that transport rates
be expressed as mg/hr per kg ideal T h e same was true for hyperthyroid patients (Table
weight. Their workshowedahighcorrelation
be6).Incontrast,HTGLappearedreduced
inboth
groups o f hypothyroidism: this conclusion is based
tween rates expressed in this way and absolute transport rates across a wide range of transport rates for
onthe following: a ) thesepatients,whoconsisted
subjects of all degrees of obesity.Forthis
mostly ofmen, haddistinctly lower valuesthan control
reason,
transport rates for VLDL-TG
will heexpressedas
men (see footnote e , Table 4): b ) treatment with T4
mg/hr per kg IW in the results section.
produced a highly significant increase in HTGL for
both groups (and for the combined data of all hypoParticle sizing of VLDL was performed by electron
thyroidpatients):and
microscopy as described by Groszek and Grundy(2 1).
c) hypothyroidpatientshad
VLDL was isolated by preparative ultracentrifugation
appreciably lower levels than untreated and treated
and, following negative staining with phosphotungstic
with hyperthyroidismpatients.Inthelattergroup,
acid, photographs were made on a Zeiss EM-10 elecvalues for HTGL were somewhat higher before than
tron microscope.Particle-size distributions were obaftertreatment
ofhyperthyroidism,butthediftained from electron micrographs using a 48-channel ferences were not statistically significant.
Zeiss TGZ-3 particle analyzer.
Chylomicron clearance

T A B L E 4. Plasma and VLDI, triglycerides and lipases (non-obese hypothyroid patients)

Postheparin1,ipoIytic..\ctivits

P;rtient"
-~

Pel-iod

f SU ( I t ) "

NI,!@

I
II

I (;

l'l~l\lll'l

VI.1)I. .I.(;

H.l'G1,

1.1'1.

~~

234 t 77
139 t 3 8

111,g

pmol FAlhrlml

Id/

1743.2

90

6.0
10.3

3.9

114k 2
I17 t 24

68
71

3.8
14.2

10.6
25.3

I
I1

87 2 18
76 t 1 1

49
41

4.7
10.5

8.6
12.0

I
I1

104 2 26
106 2 23

.5 9
61

150 t x9 (3)
92 ( 1 )

22.3
32.4

26.1

143 ? 18
1 I O f 18

96

24.0

I1

65

3X.0

12.8
17.7

I
II

13 1 t 30
I18 ( 1 )

89
104

16.9
18. 1

6.7
27.4

I 3 9 f 32
152 t 28

YO
102

24.7
28.1

16.3
10.6

178
162

21
27

I25
I10

20.0

11

21.8
26.7

I
I1

1% t 34
I:%) -+ 5 3

140
82

11.6
19.8

I 8.0

1.47 t I4
I 1 x -+ 9''

98 t 12
78 2 7"

14.9 t 2.8
21.6 t17.8
3.2"

14.1 2 2.6
t 2.7"

22.7

15.4 f 1.:1
16.8 t 1 . 0

6
7
8

11

9
10

Mean k SEM

I1

?
?

Normal Inen (11= 15Y

Nornlal wornen (11 = 2 I ) "

IO0
22.0
5'L

22.7

'r

f 2.1
14.0 t 1.2

14.4

" See footnotes i n '1'at)lr I <14 t o whether- patiettts wet-e stutlietl t o t - hr-ief o t - pt.olongetl periods
inpatients.
" Unless otherwiw intlic;Itetl, the d a t a t o t - mean t SI) represent six \;dues taken during the
last 3 weeks of each pe~-iotl;
if the patient WIS ;ttlmitted onl! for t a t s , the number i n parentheses
gives how many nmlsuretnenta \ c r ~ - enl;ltle.
L)
Iffct
' " > . ences
between Pet-iotls 1 (11)pothpt-oitl) and I 1 (eu&h)t.oicI)wet-e n o t significant a t
P < 0 . 0 5 by pait-ed atl;tl)sis.
" L)ifferetlte signiflc;lnt I)! paitxd an:tt\\i\ (I' < 0 . 0 . 5 ) .
" Ages l o r nol~mall l l C l l < I l l t l \ Y O I I l C I l IaIlgetl I'ronl 2 0 t o 50 \IS.

;L

(.

clearance. It1 contrast,theincrcrnent

i n non-chylomicron (lil~oprotein)-'I'<;was greater i n hypothyroid
patients than i n controls ('70 2 I O vs 'LO 2 10 Ing/dl);
likewise, cholester-ol concentrations tetltletl to increase
more i n the hypothyroid patients. 'l'rcattnento f ' h J . p o thyroidism had little ef'fect o n over;tll clearance of
chylomicron-'l'G which had been essetrli;dlJ. n o t m a l
hefbre thel-apy.
Chylomicr-on clearance d a t a 1 0 1 . hy1,el.tl.iglycel.idernic,hypothyroidpatients
;IIY g i w n i n Table 8;
the results are compared t o those o f ' 3 1 euthyroid
subjects \ v h o also had ele\atetl ~ 1 . G A. 1 1 o f ' this group
of hypothyroid patients were ot)esc. 'Il>cir responses
were variable. Two patients ( K o s . 17 and 1 9 ) had :I

312

Journal of Lipid Research

Voltttne 22, 1981

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II

normalclearance
of chylornicr-ons despite f'asting
hyper.tl.iglyceridemia. .Ihe ~-etnainder hadpr-olonged
residencetimes as was typical of manyeuthyroid,
hypeI-triglyceridenlic patients. A finding o f ' some interest MW t h a t nonchylomicrorl-~l.(; during duodenal
in contrast
infusion f'requently increasedmarkedly
l o o n l y small increments i n this same f ~ x t i o no f '
cuthyl-oicl s u b j e c l ~ .'Treatlnent w i t t i T r atrikingly reduced
residence
times
o f ' chylomic~~ot~-'l'(;
a s it
lowet-ed total fasting TG. O n the other hand, the ap~o~~-~I~~~
parently abnormal risein n o n c t ~ y l o ~ n i c ~ persisted after therapy i n most o f ' the patients.
Table 9 presentsrcsults
for thehyperthyl-oid
gIoup. T h e residence time of'chylornic~1-on-'I'(~
was i n

TABLE 5.

Plasma and VLDL triglycerides and lipases (obese hypothyroid patients)

mgid

ptnol F.4ihriml

tngidl

(?I)"

11

11I

409 f 125
403 f 88

328
323

13.4
20.4

9.3
9.4

12

I1I

260 (1)
40 (1)

195

10.3
18.5

IO. 1

174 f 29
195 f 24

102
118

18.7
28.7

17.2
20.5

122
114

14.8

19.2

190 (1)

11.9

19.1

I1I

13

I1I

14

15

200 (1)

13.4

I1I

179 f 30(9)
167 4 31(21)

125
I15

17.5
iO.8

4.8
6.0

16

I11

557
294

243
50

4.59
227

23.0
27.6

20.3
16.0

f 13
108 f 21

88
63

13.1
15.0

- <
.J
5.0

136 2 32 (5)
105 ( I )

88
.5 1

17.9
28.8

11.6
11.1

1559

11.2

21.9
14.4

I1I

18

I 1I

19

I1I

20

I11

21

11I

22

I 1I
I1I

23

137

1806 ? 372
l l 7 7 f 611

1005

292 2 48
179 f 34

225
I25

20.0
60.8

8.I

870
381

734
303

19.2
50.4

18.8
17.1

29

12.3
20. I

10.8

15

487 2 118
3 3 6 f 80

397
264

12.2
-

10.0

f 298
f 71

60 ( I )
40 (1)

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1.5

17

Mean

SD

7.0

15..i
-

24

I1I

178 f 37
158 It 27

14.1 125
17.1 107

4.5
11.7

25

I1I

224 f 4
214 f 27

141
133

16.3
21.1

12.1
10.6

26

I 1I

1 7 9 f 36
111 f 49

106

12.9
16.6

11.1

14.8 t 1.1
24.2 t :3.gC

12.9 f 1 . J
12.9 ? 1.2''

SEM

11
~

384
226
~~

108

71'

52
302
I99
~

f 95
2 63'

9 . 3

See footnotes in Table 2 as to whether patients were studied for brief or pt-olongeci periocls as
inpatients.
See footnote b of 'I'ahle 4.
r [I'~fferences
..
between Periods I (hypothyroid) and 11 (euthyroid) were significant a t P < 0 . 0 2
hy paired analysis.
" Differences not significant at P < 0 . 0 5 .
"

son, data also are given for 2 f subjects with normal

VLDL-TG and normal weight (Table 10) and for 10
euthyroid, obese patients (Table
1 1 ) . Eightpatients
with hypothyroidism were nonobese (Table 10). Their
VLDL-TG transport
values for concentrations, transport rates, and
FCR
Data for transport of VLDL-TG are shown for the
of VLDL-TG were very similar to non-obese, euthythree groups i n Tables 10, 11, a n d 12. Forcompari-roidpatients.Thus,despitetheirhypothyroidism,

the normal range during the hyperthyroid period,

and no differences were noted after return to the
euthyroid state.

Abrams, Grundy, and Ginsherg

Triglyceride metabolism in hypo- and hyperthyroidism

313

T A B L E 6.

Plasma and VLDL triglycerides and lipases (hyperthyroid patients)

I'osthepal~n l.ipol!tic Activit\

P;uienlo

I'&d

ll1gldl 2

27

I
II

SD

tl.1 G I .

\ ' l J ~ I .I ' G

P l ~ l \ l l l ~'1.G
l

iI1 I

prrrol F z 4 1 l ~ ~ ~ n r I

lll,~Ill/

24
23

64 t 14
62 c 18

LPI.

9.2
11.4

5.6
5.2

116 t 22 (4)
104 f 20 (4)

70

II

59

10.2
17.1

7.3

29

1
11

108 2 31 (4)
1 0 1 t 24 (4)

62
57

32.0
11.7

10.7
6.0

30

I
I1

55 ( I )
98 i 20 (4)

26
36

28.4
40.8

10.7

II

103 t 62
x3 t 28 (2)

59
46

63.5
42.1

1.5.8
35.2

I
I1

I S 1 c 21 ( 3 )
171 t- 9 ( 3 )

83
I18

66.8
22.6

10.1
17.6

76
71

30.0

12.1

/ I12.4
82

20.4
20.8

15.9

28

31

32
33

I1

35

I
II
I
II

I23 t 2 3
1 I 7 t 31

28.0

c 26
I30 f 22

124

"

17.1

9.0

186 t 18

132

231

171

12.2
10.2

5.6
.5.7

28

36

I
II

66 ( I )
72 ( 1 )

25
29

3 1.9
19.6

17.0
17.1

37

I
II

50
89

5 (4)
23 (6)

37
50

5.8
4.6

.5.4
10.6

118 t- I O (6)
1 3 0 ( I26.5
)

72
82

32.4

14.1

65
107

16.3
11.7

8.~5
17.6

622 8
7 3 f 11"

27.5 t- 5 . 3
20.7 f 3.2"

38

I14.3
I
39

I
11

Mean t SEkl

I
II

f
f

1I

O 2 30
158 t 27

106

IO

119 t 13"

11.6 t 1.6
14.0 5 2.2'

' See footnotes in Table 3 a s t o \\hethe). patients wett studied for hr-id0 1 . prolonged periods
as inpatients.
See footnote b of 'I'ahle 4.
' DifferencebetweenPeriods
1 (hypoth\roid) a n d I I (euthyroid) were n o t statistically
significant at P < 0.05 1)) paired analy4s.

'

these patients demonstrated no evidenceo f a r e m o v d

defect for VLDL-TG.
Eight other hypothyroid patients were obese
(> 120%
IW) (Table 1 l ) , and their results are compared
to
thoseoftenobese,euthyroidsubjects
with normal
plasma TG. Both concentrations and transport rates
of-VLDL-TG were much greater than those
o f normal
subjects and non-obese, hypothyroid patients. On the
other hand, the transport ratesin obese, hypothyroid
patients were only slightly greater than in the obese,
euthyroid subjects.However,themean
FCK in the
former group was about half that of the latter, and
consequently,theaverageVLDL-TGconcentration
of the hypothyroid group was much greater thanth;lt

314

Journal of Lipid Research Volume 2 2 , 3981

of euthyroid patients. I n other words, obese, hypothyroidpatientsfailedtoenhancetheirclearance

capacity, as did euthyroid patients, and thus they were
unable t o maintaintheirVLDL-TG
levels in the
normal range.
'I'able I 2 showsresultsfor
ten hyperthyroidpatients.Only two o f thesepatientswereobese,and
theirdata w i l l beconsidered with the others. The
mean VLDL-TG concentration was relatively l o w (74
t 11 mg/dl), and yet transport was frequently on the
highside of normal(mean = 12.8 t 1.8mg/hr/kg
I W). T h e low levels of VLDL-I'G thus were the result
of- an unusually high FCK (0.441 t 0.010 hr-).
T h e effects of- treatment on VLDL-TG transport

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34

(3)

26.1

TABLE: 7. Chylomicron clearance" (normotriglyceridenlic,hypothyroidpatients)

Lipid5
Fasting

LP-7'G

Residence
Time
C M-TG

vqM1

mi,,

Far
Lipids
Infusion

A
I'~tie111

\\'t

Pel-iod

x;

Chol

(:hol

LP-TG

CM-TG

rngldl

lllg/ll/

H ) poth! wid
1

\'OR

I
I1

390
162

177
191

427
173

287
104

30
15

I10
-87

4. I
2.0

NOR

I
II

230
200

118
119

217
226

172
169

37
118

54
50

4.9
15.8

I
I1

135

146

36
123

163
170

164
222

37
20

128
99

4.8
2.6

I
11

274
237

63
74

307
2.55

1 I8
147

32
48

55
73

4.1
6.1

NOR

NOR

NOR

I
I1

250
203

104
140

275
22 1

167
164

21
22

59
24

2.6
2.8

NOR

240

156

256

253

16

97

2.0

NOR

232

202

25 1

254

35

52

4.3

NOR

1
11

229
22 1

204
123

257
255

226
200

39
29

22
77

4.2
3.5

IO

NOR

235

113

250

193

I6

80

1.9

24

OB

277

179

293

220

11

41

1.0

20
34
19.3 t 14

139 2 18
117 f 26
128 ? 15

270 t 22
274 ? 37
217 f I5

205 t 16
189 ? 24
168 ? I7

27 t- 3
32 ? 2
25 f 5

70
71
39

176

1142 9

178

133 t 12

49 t 6

20

Mean ? SEM
10 patients
6 patients
6 patients
Euthyroid
21 subjects
"

I
I
I1

249
251

?
2

I1

10
16
27

3.4 2 0.4
4.1 rt 0.3
5.5 ? 2.1

10

6.5 ? 0.9

.-2hhre\iations: Chol. cholesterol; 'TG, triglyceride; LP-TG. lipoprotein-TC; CM-I'G, chylomicron-TG; NOR, normal; OB, obese.

in hypo- and hyperthyroid patientsalso are presented

in Tables10, 11, and 12.In five non-obese,hypothyroid patients, who were studied
in both periods,
VL,DL-TG levels increased after treatment by 26%
( P < 0.05) (Table IO). This increment was d u e to a
significant increase in VLDL-TG synthesis; the FCR
was notaltered by treatment. Sevenobese patients
with hypothyroidism also werestudied in the two
periods. In contrast to the non-obese patients,
T, treatment in obese subjects caused a significant reduction
in VLDL-TG. In these obese patients, the reduction
of VLDL-TG was duetoa
significantly decreased
transport and not t o a greater FCR. These data thus
presenttheparadoxthatnon-obese,hypothyroid
patients accelerated their synthesis of VLDL-TGwith
T 4 treatment while the reverse occurred in the obese
patients.
For eight hyperthyroid patients, VLDL-TG
levels
were increased only slightly after treatment (Table
12). Transport rates remained essentially the same as
did the FCR. Thus, despite a return to the euthyroid
state, the hyperthyroid patients maintained a rapid
clearance for VLDL-TC.

VLDL particle sizes

T h e particle-size distributions of VLDL for hypothyroid and hyperthyroid patients are presented in
Table 13. These results are compared to those of ten
normal,euthyroidsubjectsandtenhyperlipidemic
patients also studied in our laboratory (21). Patients
with hypothyroidism were found to have a relatively
large percentage of theirVLDL particles in the small
diameterranges(i.e.,100-250
A). Although it has
been shown previously from this laboratory that the
VLDL fraction can have significant proportions of its
particles in this range(21),patients with hypothyroidism appeared to have a disproportionately high
fraction of small VLDL. Those with hyperthyroidism,
in contrast, generally had a typical distribution.
DISCUSSION
T h e most striking action of thyroid hormones on
plasma lipids is to lower plasma cholesterol. T h e influence of these hormones on triglycerides has been
defined less well, and the present study was under-

Ahrams, Grundy, and G i r d e r g Triglyceride metabolism in hypo- and hyperthyroidism

315

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ti

T A B L E 8. Chylomicron clearance (hypertriglyceridemic,hypothyroidpatients)

P A n g Lipids Ke\idenre
Pallent

bt

Period

TG

(:h(Jl

Lipid? Fat Inlu>io~l

LP1.G

(:I101

16

OB
0B

540
377
I347

272
186

123.5

179
205

605
970

21
24

495
I
I1

273
260

28i
278

663
279
,508

82
16

168

229

29 I
79

34 214

248

163

100

>

21

29 I O
1320

.5 3 x
3 72

2.540
I676

IO72
279

-370

336

226
30

I064
255

614
1.50

635

66
16

1540
606

408
38

~59 0
229

2 14
158

196

0B

I
I1

($70
350

20

OB

I
I1

29 1
124 126

429
197

3I3

I
II

428
I X8

950

455
207

I
I1

356 f 69
207 f 34

936 f 405
430 -c 184

239

3i.5 2

H\.~)eIt~.iglyc.er.itletllia
(euth) ~micl)
3 1 patient\
I

377

37

347
222

_t 323
749 i 256

398 f 161
119 f 45

240 2 8

4 I 4 ?270
34

50

1215

4
0.5

58

i 36

2
-43

41

279 -t 176
319 t- 140

61
13

-t
-t

34
5

I5

34

33

Ahl~t-e\iations:Chol, c.hole,tet-ol; IG, triglycetitle; L P - T C ; , l i p o l ~ ~ ( J ~ ~ i(:\l-.l-G,

t~-t(~
c h~~ I o 1 t I i c r o n LC;;
&OR,
Values Iron> patient 19 n o t indutletl i n calculation 01 the tnealls.

39

O B , obese.

11or111;1l:

o f the f~lt-inducedo r exogenous type; t h a t is, most

taken to discover whether thyroid
hortnones significantly alter TG metabolism.
c h y l o n 1 i c r o t l e ~ ~Fur~i~~.
patients do nothavefasting
thel-more, in quantitative 111easurements o f chyloElevations of plasm;^ T(; have been reported fl-et n i c ~ ~t)unr n o \ w , hypothyroid patients without fasting
quently in tlypothyr.oinisn1. Hotvcver, ;I review of the
literature re\,eals that s o m e patients with hypothyhypet~tt~iglyceridetr~ia
were f 0 u n d to clear chyloroidism have normal IG ( I O , 22); others have tniltl
tnicronsas
well as did n o l m a l sut?jects. I n some
patients w i t h hypel-triglycel-idemia, a delayed clearto moderate elc\.ations (1, 3, 7, 2 2 ) , and ;I few h a v e
marked hypertriglycel-idemia (6, 10, 22). O u t data are
ance o f chylomicrons was noted; howevcr, this same
W;IS ohsel.vedpreviously
i n euthyroid
i n accord. Not everypatient
with h y ~ ) o t h y r o i d i s ~ ~phenomenon
~
had hy~)~rt~-iglycel-iclelnia;
howe\.er, a significant
patients w i t h fastinghypertriglycel-ideInia (15), and
t h u s it is n o t uniquefor hypothyl-oidisrr1. I n h y p o It-action of them did. In 7 o f 26 Imtients, 1-G le\.els
were greater than 250 Ingidl. Although a return to the
thyroid patients with hypertl-iglycet-idemia, treatnletlt
tvith -I.4 appeared to impro\e chylomic~-onclearance,
euthyroidstate
rarely reduced ~l.(;b y astriking
but this may have been due simply to a red1tctiou i t 1
degree, me;m 1 . G levcls i n most patients were lo\ver
VI,DL, a n c l decreased cotnpetition for t-etno\-alsi(cs.
after therapy-,indicatingthathy~~othyroidistr~ m u s t
Ihereli)re, the weight o f o u t - data indicate that ~ n o \ t
ha\,e some I~(;-ele\.ating effect. lut-thermore, hyperhypothyroid patientsdo not p o s s e s s a clearance defect
thyroid patients generally had lower ~ 1 - Glevels than
fix chylomicrons.
those with llyl~otl~yt.oiclisrn.
l h r ~ sive might exatnine
possible mechat~isn~s
whereby thyroid Ilomlone lowers
lhese observations were sur-prising because several
workers
have
reported
that
patients
.I(; o r a deficiency o f this h o r m o n e raises them.
with h y p o 011e r a y i n which thyroid hormone tnighL lower
tllyr-oidism m a y have a deficiency of lipoprotein
-I.(; \ v o u l d be t o p~.omote theirclearance f-rorn plasma.
lipase a s measured by post-heparin lipolytic activity
11 s o , patients with hy1~oth?,1.oidistll
theoretically
(PHI..?\) ( 3 , 4, 9 ) . Inthepresent
s t u d y , we reshould have reduced clearance o f either exogenous
examined this possiblity by fractionating PHLA into
o r endogenotts .lG. Ho\vcver, ;IS noted b y Nikkila
two enzymes: I.PL and HTGL. I n our hypothyroid
and K e k k i (4) and conlirmetl i n this s t u d y , hyperLPL was i n he normal
patients, I~e~~;~rin-releasaI,le
triglyceritlemia i n hypothyr~oitl patientsusttally is n o t
range and \vas n o t altered by treatment. Ihcrefol-e,

316

Journal of Lipid Research

Volumc 22, 1981

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I
I1

Mean f SEM

rnzn

lll,lg(ll

262
I 60

OB

OB

CWI.(;

I1

18

21

Time

LP- IC;

rngldi

lrI!&i

Hypothyroid
I1

CM-~IC

mains that thyroid hormone could influence catabolism of VLDL, the other TG-rich particle of plasma.
Indeed,when
plasma T G is elevated in hypothyroidism, the increase occurs mainly in VLDL. Mechanisms for endogenous hypertriglyceridemia in hypothyroidsubjectshavebeenexaminedpreviously
by
Nikkila and Kekki (4); they
estimated
turnover
rates o f plasma T G using single-exponential analysis
of VI,DI,-TG specific-activity curves following injectionof[3H]glycerol.Althoughthe
validity of their
method can be questioned (16, 20), their conclusions
are of interest nevertheless. They suggest that synthesis of plasma TC in hypothyroidism is normal, but
the fractional clearance (FCR) is markedly reduced.
In our patients with hypothyroidism, the tnajority
had normal concentrationsof VLDL-TG. Thiswas almost
invariably
true
for
nonobese
patients,
but
several of theobesealsohavenormal
T G . Among
those without increased TG, fractional clearance rates
of VLDL-TG were
in the same range
as thoseof euthyroid, normotriglyceridernic subjects. These observa-

TABLE 9. Chylomicronclearance(hyperthyroidpatients)"

rrrgMl

53

27
75
28

125

67

I1

154

97
47 211

I1

2.9
29

95

109
174

I1
30 84
148

10.4

I
11

125 31
186

117
77

175

103

I
11

196
219 20 1

229 I 1

229

I
11

92
173

166

113

33

61

209
26

34

142
182

53

175

38

101

170 3 9

I1

Mean f SEM
11 patients
9 patients
9 patients

I
I
II

2.9

190
170

32
52

228

245
75

121 95
7.0
167
54

22
31

85

4.1

53

90

6.4

121
10 1

5.7

0.3
2.7

99

5.6

66
79

2.8

f5

64 -+ 1 1

3 . 6 c 0.6

5
f7

66 f 12
8 6 - t 17

3.5
5.3

118
32

330

203
237

273

191

125

48
3.8
3

139
176 162

129 f 12
128 2 14
181 97
f 9

2.9

165

1
57

22
21

58

146

99

154

37
68

2.0
3.1

170

35
92

19
-1

74

30
207 59

rnm

15

23 161

4.3

101
153

1
I1

72

Ilfgldl

1ng/dI

78

81

-t

12

81

?
f

14
18

7.3

142 13
141 ? 15
192 f 10

14829
f 22
150
28 2 23
180 f42
25

27
71

0.6
0.9

" Abbreviations: Chol, cholesterol; TG, triglyceride, LP-TG, lipoprotein-TG; CM-TG, chylomicron-TG.

Abrams, Grundy, and Ginsberg

Triglyceride metabolism in hypo- and hyperthyroidism

317

Downloaded from www.jlr.org by guest, on January 27, 2015

we have not confirmed that hypothyroid patients have

a deficiency of LPL; thisis consistent with the finding
that they have a normal clearance of chylomicrons.
In contrast to LPL, postheparin HTGL was low in
the hypothyroid state. This decrease
in HTGL was
observed in both nonobese and obese patients
with
hypothyroidism.Furthermore,
activities ofHTGL
returnedtonormal
in bothgroups
following T,
therapy. Apparently, however, this enzyme does not
play asignificantroleinlipolysisofchylomicrons,
at least to the extent that a reduction in HTGL can
affectchylomicronclearance
in anadverse
way.
T h e r e is the possibility that low HTGL might have
been responsible in part tor the unusually high
rise
in nonchylomicron-'IG during duodenal infusion of
fat. Whether this increase in nonchylomicron-TG reflects adelayedretno\dofchylomicronremnants
ormoreVLDIAzed,
smallchylomicrons
was not
determined.
Althoughchylomicronclearance
in mosthypothyroidsubjects is notimpaired,the
possibility re-

TABLE 10. VLDL-TG transport data (nonobese hypothyroid group)

Period

Patient

17.3

18.1

2 5.8

0.173

11

I
I1

4
5

7
23.3

10.8
2039

16.4
10

"

I'

mglhdkg

,ngih,lkg IN'

112
1 I4

676
976

12.5

12.0

0.230
0.326

72

362
1004

16.I

0.300

115
15.9

6i

6.1

i.4

0.456
0.262

709

1O.Y

11.7

0.367

209

138
13.Y200

777
1215

8.9

132
I36

680

9.9
I .5 . 5

99 2 25
98 t 20
123 5 24"

755 f 204
508 ? 136
929 5 142h

136 2 7

872 11.4
2 71

I
11

0.219

756
26.1

0.26.5

10.5

0.153
0.165

11.7

0.254

11.0f 2.4
8.8 5 1.2
13.9f 2.1"

0.7

0.

167

18.3

12.0t 2.2
9.5 f 1.2
14.8 t 2.2"

12.1 0.207
2 0.8

0.254 t 0.038
0.235 t 0.056
0.261 t 0.027''

r 0.016

The difference between Periods I and I1 was not statistically significant at P < 0.05 for the live patient5 studied i n I~oth period\.
Difference between Periods I and I I significant at P < 0.05 by paired analysis.

tionsinhypothyroidpatientswithouthypertriglyceridemia plainlyindicatethatmanypatients
with
hyperthyroidism do not havea clinically significant
defect in removal of VLDL-'TG.
Following treatment of our nonobese patients with
T4,their plasma concentrations o f VI,DL-'IG actually
showed a slight increase. This
rise was the result o f '
enhanced synthesis of VLDL-TG, and it is contrary
to what might have been expected
f'rom the recent
report of Keyes and Heimberg (23). 'l'hese workers
showed in isolated, perfused rat livers that the hypothyroid state caused a reduction in oxidation of fatty
acids andagreaterproduction
of VI,DL-I'G. Although these observations undoubtedly are true, the
in vivo situation may be different. Previousinvestigators (24-31) havefoundthat
in hypothyroidism
the circulating levels of free fatty acids (FFA) are reduced that might curtail availability o f FFA as a precursor for synthesis of VLlIL-'I'<;. With T,treatment,
FFA flux should be increased which may account for
the rise in synthetic rates of VLDL-I'G in nonobese,
hypothyroid patients.
In contrast to nonobese patients, those
with both
hypothyroidism and obesity commonly had elevated
concentrations of VLDL-TG.Withoutdoubt,their

318

7.1
5.9

9.8
I03

Ill

43
384

'

Nlglh I

34
49

I1

FCR

Journal of Lipid Research Volume 22, 1981

hypertriglyceridernia was d u e partly t o overproduction of VLDL-TG and to increasing the load on the
' f G removalsystem. Thedatashowedthatobese,
hypothyroid patients, like obese, euthyroid patients
previouslystudied in ourlaboratory (20), havean
excessive production of VLDL-TG. Ineuthyroid
patients withobesity,elevatedsynthesis
of VLDL
presumably is due to enhancedfasting
FFA and
augmentedintake
o f totalcalories;bothshould
provide increased fatty acids and glucose for VLDLT G synthesis.Increasedcaloricintake
a l s o maybe
a major factor in the elevated transport of VLDL-TG
in ourobese,hypothyroidpatients.Despitetheir
hypothyroidism,most
o f theobese
subjectswere
foundtorequireincreasedcaloricintaketotnaintainconstantbodyweight.Nonetheless,theirsynthesis of VLDL-TG may have been further accentuated by hypothyroidism.Onen~echanisrncouldbe
that shown by Keyes and Heirnberg(23), i.e., curtailed
hepatic oxidation o f FFA and diversion to T G synthesis. Also, if' peripheralutilization
o f ' F F 4a n d
glucose is lessened by l o w thyroid hormone, as it nnquestionably is, any unused calories of either type
may be shunted t o the liver for synthesis of VLDL-TG.
Bothmechanisms are compatible with the data ob-

Downloaded from www.jlr.org by guest, on January 27, 2015

Euthyroid, nonobese
(111ean t SEM)
27 patients

5.8

rra~npo~t

mgld

II

11I065

Hypothyroid
(mean 2 SEM)
8 patients
5 patients
5 patients

\'I.DI.-TC

\.'LDL-'I'G

T A B L E 11. VLD1.-TG transportdata (ohese hypothyroid)

Ingid

wgih 1-

mglhrikg

mgihrlkg I I+'

I1

26 1
200

1977
1345

23.8
16.2

28.4
19.3

0.214
0.190

16

1
11

415
289

2376
2191

24.7
22.8

26.5
24.4

0.145
0.192

17

I
11

103
76

1084
612

11.4
6.4

15.8
8.9

0.272
0.209

19

450

I827

20.3

27.0

0.108

21

513
304

2756
1984

28.4
20.3

41.8
30.1

0.135
0.163

82
80

1483
669

13.6
6.1

21.4
9.6

0.4 15
0.192

307
249

1326
1675

14.4
18.2

25.4
32.0

0.113
0.176

74
52

695
410

5.5
3.3

13.9
8.2

0.192
0.161

276 t 62
251 t 66
179 t 41"

1691 t 241
1671 t 277
1269 t 270"

17.8 t 2.8
17.4 t 3.1
13.4 t 3.0"

25.0 t 3.1
24.7 t 3.5
18.9 t 3.9"

0.199 t 0.039
0.212 t 0.094
0.183 t 0.006b

127 t 15

1414 t 248

12.3 t 2.1

19.9 t 3.4

0.3 15 t 0.049

I1

I1
24

I1

2.5

I
11

26

I1
Hplmthyroid
(mean t SEbI)
8 patients
7 patients
7 patients
Euthyroid (ohese)
( ~ n e a nt S E M )
I O patients

I
11

(' Period 11 significantly different from Period I by paired t

"

test

117"

( P < 0.05).

Period 11 not significantly different from Period I.

146rttms, Grundy, and Ginsberg

Triglyceride metabolism in hypo- and hyperthyroidism

319

Downloaded from www.jlr.org by guest, on January 27, 2015

evident only during the challenge of excess productainedaftertreatmentofhypothyroidism

in these
tion of VLDL-TG andis not apparent when synthetic
patients. During treatment with T,, caloric intake had
rates are in the normal range. Nevertheless, in most
toberaisedsomewhat
to maintainconstantbody
nonobese patients with hypothyroidism, the FCR inweight, but in spite of the greater ingestion of calories,
secretionofVLDL-TGwaned.Thus,augmented
creased with T, therapydespitearise
in synthetic
oxidation of FFA and glucose in both the periphery
rate(Table 10); thiscertainlysuggeststhat
T, inand liver may have diminished substrate
availability
creases the clearanceof- VLDL-TG. The concept that
for synthesis of VLDL-TG.
T, promotes VLDL-TG removal is supported by the
Although overproduction of VLDL-TG
was a major results in hyperthyroidpatients. I n thesepatients,
factor in hypertriglyceridemiainourobese,hypothe FCR ofVLDL-TG was twice thatofnormal.
thyroid patients, it should be noted that these patients Despite the fact thatmanyofthesepatientshad
did not synthesize more VLDL-TG than most obese,
synthetic rates of VLDL-TG
in the high-normal range,
euthyroid patients without hypertriglyceridemia who
which coulcl have been due to heightened mobilizawere studied earlier in our laboratory (20).The latter
tion of FFA from adipose tissue, their concentrations
patients seemingly had the capacity
to amplify removal
usuallywere verylow. This was due to their rapid
of VLDL-TG to compensate for their overproduction clearance of VLDL-TG.
andthustoavoiddevelopmentofhypertriglyceriOf interest, abnormalitiesin VLDL-TG metabolism
demia.
The
obese
patients
with hypothyroidism
in hyperthyroid and obese, hypothyroid patients did
evidently did not have the same facility to accelerate
not revertentirelytonormalfollowingtherapy.
clearance in responsetooverproduction,andconSeveralobesepatientsmaintainedvaryingdegrees
sequentlytheydevelopedelevatedTG.Thus,they
of hypertriglyceridemia after T, therapy. This may
canbesaid
to havearelativedefect
in clearance
have been due toslow return of catabolic mechanisms
of VLDL-TG. From a clinical viewpoint, the catabolic
to normal, to persistent obesity, o r possibly in some
defectforVLDL-TG
in hypothyroidismbecomes
cases, to an underlying primary hypertriglyceridemia.

T A B L E 12. VLDL-TG transportdata(hyperthyroidgroup)

Period

Patient

VLDL-TG Transport

VLDL: I'G
mglhr

lflgld/

FCR

mglhrlkg

mglhrlkg IW

344
970

6.7
19.0

5.7
16.2

0.502
0.750

hr"

1
11

27
51

28

85

811

14.0

12.2

0.347

29

I
I1

81
97

1401
1045

20.9
15.6

19.9
14.8

0.569
0.355

22
61

428
1125

.5.8
15.3

5.8
15.3

0.601
0.569

I1

116
95

11 14
1032

15.3
14.1

15.7
14.5

0.298
0.337

33

107

1500

18.6

21.0

0.404

34

I
I1

80
115

47
987

6.4
13.2

7.3
15.1

0.175
0.260

35

I
I1

120
154

442
773

6.5
11.4

7.6
13.3

0.120
0.163

II

37
39

1047
310

16.6
8.1

16.6
8.1

0.873
0.404

I
11

60
80

1094
669

10.0
6.1

15.8
9.6

0.542
0.405

7 4 * 11
6 8 + 13
87 t 13"

822 i 154
738 t 170
889 f 76"

12.1 2 1.8
10.6 i 2.0
13.2 f 1.3'

12.8 f 1.7
11.8 i 1.8
13.4 i 0.9"

0.397 + 0.1 19
0.460 f 0.088
0.405 + 0.085"

30

11

31

37
39

Mean i SEM
10 patients
8 patients
8 patients
"

1
I1

Period 11 not significantly different

Downloaded from www.jlr.org by guest, on January 27, 2015

27

from Period I by paired analysis.

T A B L E 13. VLDL particlesizedistribution(bydiameter)

VLDL Particle Frequency ( Q )
Subject\

<lo0

Hypothyroid
8 7
9
10
I1
21 4
26

27

24
27

H) perthyroid
28 42
29
3 0 19
32
34
39

15
19

f SEM

Euthyroid subjects ( n
Mean f SEM

0
0
0
0
0
2

100-170

34
38
0
46
42
4

12
50

.i

170-250 .&

27
26
10

27 t 9

24 ?203

2
0
28

32

35

0
0

250-300

235
230
286
228
8
245
41
287
?

12

0 t0

51-5

2 4
16 34

0 2 0

10 f
154

t
244

3*2

5 2 2

17 + 4

<300

.k

Mean

28
22
24
26
29
28
9

302
11

.k

2
26 i-252

41
33
34
51
58
50

332
37
325
34
318
35
f3

SD

109
102
48
148
124
76
f

12

Chol

mgldl

mgldl

24 1
213
171
36 1
56 1
93

244
253
167
193
293
233

273

63
64
108
78
70
75

284
26 1

-rG

f 230
74

104
118
51
179
150
90

45 f
304
5

i 115
12

f110
20

503086

15

81 f
192
16

50 f
310
4

f 10

20

104
93
96
131
186
48
i 21

10)

Euthyroid hyperlipidemia
(11 = 10)
Mran -t SEM

320

4
2
0
10
0
0
3 2 2

Mean i SEM

Mean

,k

Journal of Lipid Research Volume 22, 1981

25

*3

347

f 232
40

13

'l'his work was supported in part by the Veterans Administration; D r . Jeffrey J. Ahrams was an Associate InvestiM. Grundy is a Medical Investigator
gatorandDr.Scott
o f the Veterans Administration. T h e investigation was also
supported by Grant AM-I6667 from the National Institute
o f Arthritis,Metaholism,and DigestiveDiseases and No.
HI*-14 197 awarded by the National, Heart, Lung, and
Blood
Institute, HDSIDHHS. .I'he authors wish to express their
appreciation t o Marjorie
Whelan,
Joan
Rupp,
Lianne
o f . the Nursing and Dietetic Services
k i p p e r , ; ~ n others
d
o f the Veterans Administration Medical Center, San Diego.
Excellent technicalhelp
was also provided by Robert
Atn-ams, Grundy,and Ginsberg

Analytical Chemistry.MediadInc.,
New York. 341344.
14. Baginsky, M. La., and W. V. Brown.1979.
A new
of lipoprotein lipase
methodforthemeasurement
in postheparin plasma usingsodiumdodecylsulfate
fortheinactivationofhepatictriglyceridelipase.
J . Lipid Res. 20: 548-556.
15. Grundy, S. M., and H. Y. I. Mok. 1976. Chylomicron
clearance in normal and hyperlipidemic man.
Mrtabolbm. 25: 1225-1239.
16. Zech, I,. A . , S. M. Grundy, D. Steinberg,and
M.
Berman.1979.A
kinetic modelforproductionand
triglycmetabolism of very low densitylipoprotein
erides:evidencefora
slow productionpathwayand

Triglyceride metabolism in hypo- and hyperthyroidism

32 1

Downloaded from www.jlr.org by guest, on January 27, 2015

Ronimus, Janna Naylor, James Hobza, Lynne Lesh, Susan

Likewise, even after treatment of hyperthyroid paButler, Richard Earl, and Leanna Johansen.
tients and return to the euthyroid state, many of these
Manuscript
received 29 January 1980 and in revised form 12
patients still had anincreased FCR of VLDL-TG. This
September 1980.
phenomenon has been noted before by Nikkila and
Kekki (4),and it presumablymirroredthecontinued activation of clearance pathways after removal
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