J. Lipid Res.-1981-Abrams-323-38

8/16/2019 J. Lipid Res.-1981-Abrams-323-38

1/16

Cholesterol metabolism in hypothyroidism and

hyperthyroidism

in

man

Jeffrey J. Abrams and

Scott

M.

Grundy

Department of Medicine, Veterans Administration Medical Center and

University of California, San Diego, CA 92 16

Abstract Studies were carried out on cholesterol metabo-

lism in 11 nonobesepatientsand 16 obesepatients with

hypothyroidism a nd 13 with hyperthyroidism. T he patients

underwent everal investigations und er metabolic ward

conditions. Hypothyroid patients usually had an ncrease

in

low

density lipoprotein (LDL)-cholesterol. Several mech-

anisms may have combined to cause a high LDL. For instance,

the obese hypothyroid patients had an increase in cholesterol

synthesis. Absorption

of

cholesterol also was increased

frequently.However,othermechanismsnotexplored in

this study probably contributed

to

most

of

the fall in LDL-

cholesterol. Treatment of hypothyroid patients produced

the expected fall n LDL. On e possible mechanism could

be thathyroid ormones nhancehe conversion of

cholesterol into bile acids; hismechanism has been sug-

gested by otherworkers romanimalstudies.However,

no evidence was obtained in either hypothyroid or hy per-

thyroid patients that thyroid hormones alterynthesis of bile

acids. On heotherhand, hehormones ppeared to

increase the synthesis of cholesterol.Patients with hypo-

thyroidism frequently had supersaturated bile. T he cause

was mostly anenhancedsecretion

of

biliary cholesterol

associated with a tendency to obesity and increased ynthesis

of cholestero l. In contrast, he usually thin hyperthyroid

patients did not have supersatura ted bi1e.m Th e studies

show that thyroid hormones a influence LDL-cholesterol

by an action on he catabolism of LDL-independent of

alterations in synthesis,catabolism, absorption, or excre-

tion: b) stimulate synthesis

of

cholesterol;andc) affect

biliary lipid metabolism in large part by influencing energy

balance and choleste rol ynthesis.-Abrams, J J., and S .

M.

Grundy.

Cholesterol metabolism in hypothyroidismand

hyperthyroidism in man.j ipid Res. 1981.

22:

323-338.

Supplementary key words l o w

densityipoproteins . biliary

lipids . cholesterol balance

The hypercholesterolemia of hypothyroidism and

hypocholesterolemiaofhyperthyroidism are long-

recognized and well-accepted clinical findings (1

4).

The mechanismsofhypercholesterolemia in hypo-

thyroidism have been ascribed variously to decreased

clearance of cholesterol fro m plasma ( 5 - S ) , reduced

conversion of cholesterol to bile acids

in

the liver (9-

12),

and delayed removal of low density lipoprotein

from the plasma (13 ) . The reverse actions have been

suggested as being responsible for the ow cholesterol

concentrations in hyperthyroidism.

Because of these conflicting reports, we initiated

a series of studies to examine fu rthe r the actions of

thyroid hormones on the metabolism of cholesterol

and bile acids in man.These investigations were

carried out to ascertain whether lowering of plasma

cholesterol by thyroid hormones can be explained by

alterations in synthesis, excretion, or absorption of

sterols. A t the same time, these same processes were

examined fo r their relation to biliary lipids to deter-

minewhetherhyroid ysfunctionmight modify

saturation

of

bile with cholesterol.

METHODS

Patients

Studies

o n

metabolism of cholesterol and bile

acids were performed in most of the patients with

hypo- and hyperthyroidism escribed in the ac-

companying paper (14), and in this paper the same

numbersare used to designate each patient. The

patients were divided intohree groups , onobese and

obese hypothyroid patients,and hyperthyroid patients.

In he following text, henumbers of patients in

each study,along with theirparticularcharacter-

istics,

will

be delineated in more detail. These n-

vestigations were carried out on thepecial Diagnostic

and Treatment Unit, Veterans Administration Medical

Center, San Diego, CA. All patients gave informed

consent for their studies.

Th e results from the presentsubjects are compared

to those obtained n normal subjects who were studied

previously in our laboratory. Under each procedure

outlined below, the characteristicsof the ontrol

subjects are described.

Abbreviations:

TG,

triglyceride:VLDL. very

low

density ipo-

protein: LDL,

l o w

density lipoprotein;HDL, highdensity lipo-

protein: GLC, gas-liquid chromat ography:

I W,

ideal weight.

Journal

of

Lipid ResearchVolume22, 1981

323


2/16

Experimental design

A totalof 40 patien ts with thJ.roic1 disease was

studied. Some of the patients \\ere admitted to the

hospital for only shortperiods mostly or tudies

of riglyceridemetabolism)antl,except f'or meas-

urements of plasma lipoproteins, the) did o t

undergo

detailednvestigationfholesterolmetabolism.

In particular, several hypel-thyroid patients were too

symptomatic romheirdiseaseo complete

pro-

longed cholesterol balance. T h e status of eachpaLient

w i t h regard t o the period of hospitali~ ation is given

in Tables 1-3 of the companion paper ( 1 4 ) .

Long-term patients, after a brief period of'stahiliza-

tion in the hospital, were started

o n a n

isocaloric diet

and the intake

o f

calories vas adjusted s o that body

weights veremaintained onstant hroughout he

study. During the first month (Period I ) the patients

rvere maintained in their abnormal state (hypothyroid

or

hyperthyroid).

I n

addition to the tests do ne on tri-

glyceridemetabolismdescribed in the ornpan ion

paper

(14) ,

th e following ~ ~ ~ e a s ~ ~ ~ - c m e n t s\.ere made:

1 ) plasma ipids twice

~ v e e k l y ;

cholcstel-ol

i n

the

differen t ipoprot ein f'ractions

a t

the

end o f

each

period; c ) neut ral nd acidicteroidsromtool

samples collected daily;

d

lipid composition

o f

gall-

l>latlder bile (det ermi ned weekly); an d

P )

hepatic

secret ion of biliary lipids and pool sizes o f bile acids.

After appropriate treatment o f their disease state,

and eturn

t o euthyroidism, achpatient was re-

studied

for

anothermonth Period

11).

To keep

patients at their pretreatnnent \\eight, i t was

usual ly

necessary to alter the caloric intake a s compared t o

Period

I .

Otherwise, Period

I I

\ v a s

identical to Period

I , and the same measurements wel-e made.

Methodology

Plasma lipid ^

cmd lipoproteins. Totalplasma ho-

lesterol and T G weredeterminedonaTechnicon

Auto-AnalyzerModel

11,

Techniconnstruments

C:orp., Tarrytown,

NE

(15,16)). (:oncentrationsof

cholesterol i n very low den sity lipopro teins

( V L D L ) ,

l o w densityipoproteins LDL), ndhighdensity

lipoproteins (HDL) were estimateds described in the

Lipid Research Clinics Manu al of Laboratory Oper a-

tions ( 1 7 ) .

Cholesterolbalance tudies.

Patientswhounderwent

cholesterol balance studies were fed a diet of mixed

solid food and iquid formula containing40% of calories

as fat. This diet as very low in cholesterol to facilitate

measurements of sterol balance;t also contained a fat

content and composition similar to the normal

U.S.

diet. Each day the patientsweregiven hreemeals

of liquid formula and one with solid food. Formulas

were given at8:30

A M ,

4

P M ,

and

7 I'M:

they contained

15% o f calories as milk pro tein , 45% a s dextrose, and

40%

as fat, mostly in the form of lard. Formula s rvere

prepared by Hospital Diet ProductsChrp.,Buena

Park,

(:A.

One solid meal was given at 1 1

A M and

it

contained dry cereal (corn flakes), nonfat bread, skim

milk, added lard, and sugar for coffee. This diet pro-

\.itled for a

l o w

intake of choleste rol to f'acilitate esti-

mation

o f

cholesterol balance. Vitamin

ant l

minel-a1

supplements rvere givenaily. Each patient was

weigheddaily an d caloricntake

\ v a s ad,justed

to

maintain rveight at ;I constant lewl t h r o ~ ~ g h o u t

Estimations of'cholestel-ol balance ~v er e ma des de-

scribed

earlier

(

18-2 l ) . Stools were collected through-

o u t both dietary periods and usually

were

combined

into

4-clay

pool s . Fecal neutraland acidicsteroids

were isolated separately, and their masses were deter-

mined by gas-liquid chrornatograplly

(GL(;)

(18, 19).

G I 2 : analysis o f neutralsteroidsdistinguished be-

tlveen cholester-ol and pla nt sterols and their steroid

conversion products. .\nalyses were carried out entirely

h y chemicalprocedures. To cor rect or losses

o f

neutral steroids, beta-sitosterol was given a s capsules

(225

mg

twicedaily) ( L O) , andexcretions o f acidic

steroids were corrected for variations in fecal

f low

by

L I S ~

l chromic oxide (21).

For

control , 14 normal male subjects were studied

on the same dietary regimen andby the sa~nenalytic

techniques. Ages of controls ranged from 29 o 6 3

)ears (mean 51 years); their Iveights were

95-

115%'

of itteal.

The data on cholester ol balance are expressed in

three ways:

a

as bsolutevalues mg/day),

/ J

in

relation o otalbodyweight mg/dayper kg), and

c )

i n

relation o dealbodyweight (mg/:iday pe r kg

IN ).

We suggest that normalization of results to ideal

weight may in some cases provide a better cotnpa~-ison

between groups than absolute alues or those corrected

to otalbodyweight. Onead\:antage o f expressing

data in relation to ideal body weights tha t it is possible

to compare groups that differ inody size and deg ree

of'adiposity. For example , in obese patients, if'halance

data are based

on

actual ather han dealweight,

results

w i l l

bedistortedowardsnordinately low

values; in other words, dividing outputs by a arge

mass of adipose tissue

may

obscure real differences

in absolu te productio n rates. This issue wi l l be con-

sidered in m ote deta il in the Discussion section.

Lipid compositionof gallhladdu bile. Samples of fasting

gallbladder bile were obtained three times during each

of the two study periods. Samples were analyzed f o r

cholesterol, bile acids,andphospholipids.Samples

were aspirated from a single lumen tube positioned

by X-ray guidance in the econdportionofhe

the StLIdy.

324

Journal

of

Lipid Research Volume

2 2 , 19x1


3/16

duode num . Gallbladder contractionwas stimulated by

intraduodenal injection of an emulsion of safflower

oil, which \vas free of cholesterol and phospholipids .

Duodenal fluid rich in gallbladder bile was then col-

lected by s l o w suction over a period of 20 min. The

collected bile (30-50 ml) was thoroughly mixed and

a 10-ml sample was retained for analysis; the remainder

was returned to thepatient via the ube. Samples

were added immediately to 30 ml ofchloroform-

methanol 2: 1. Methods for separation of lipid com-

ponents were the same as usedbefore in ou r lab-

oratory (22).Cholesterol was measured on GLC as the

trimethylsilyl ether (19).Phospholipids were estimated

by the method of Rouser, Sidney, and Akira (23), and

bile acids were determined by a standard enzymatic

procedure 24,25) . Bile lipid composition was ex-

pressed a s molar % for each lipid component accord-

ing to Admirand and Small (25). Percent saturation

was calculated by the criteria of Carey and Small (26);

these workers found that aturation of bile is a function

of

total solids present.

For

calculation of percent

satura tion, we have assumed that gallbladderbile con-

tained 10% solids (25,26). For control, 14 subjects

used for cholesterol balance also were employed as

control for gallbladder bile composition. An average

of three samples was obtained from each patient.

Ou t p u t s o f biliary ipids. Hourly outputs of biliary

cholesterol, bile acids, and hospho lipids uring

constant feeding of a formula diet were determined

by themarker-dilution echniqueofGrundyand

Metzger (27). After an overnight fast, a three-lumen

tube was positioned in the duodenum with the two

most proximal outlets adjacent to the ampullaf Vater

and he hirdoutlet 10 cm distally. The tube was

placed in the correct position with X-ray guidance.

Th e same liquid formula as used throughout the tudy

was infusedontinuously through ne roxima l

lumen; P-sitosterol was also infused as adilution

marker. After allowing 4 hr for gallbladder contrac-

tion andfor stabilization of hepatic bile secretion,

hourly samples were obtainedor

6

hr from the second

proximal and distal outlets by slow and continuous

aspiration. Less than 5% of intestinal contents passing

these ports was aspira ted hrough he tubes. Since

the inputs of p-sitosterol and exogenous cholesterol

were known with precision, the rateof hepatic choles-

terol secretion could be estimated from the ratio of

cholesterol to p-sitosterol at t he d istal outlet . These

data combined with measurements of concentrations

of bile acids and phospholipids relative to cholesterol

at he proximal outlet permi tted calculation of the

hourly output of bile acids and phospholipids. Equa-

tions used in these calculations have been presented

previously along with correctionsorholesterol

contents of formula diets (27). In calculation of the

percent saturation of hepatic bile, we have assumed

that hepatic bile contains 3% solids (25, 26).

T h e pool size f bile acids was measured simultaneously

with hepatic secretion rates as described before (22) .

Briefly, 5 pCi of [24-''C]cholic acid (New England

Nuclear, Boston, M A ) was given intraduodenally at

thebeginning of theformula nfusion.After

4

hr

which allowed for equilibration, the ratio of isotope

to total bile acids ("specific activity") became constant

(22). A mean specific activitywas determinedon

hourly samples over the next

6

hr, and the otal pool

of bile acids was determined by dividing the dose of

radioactivity given by the mean specific activity.

For control, eight normal men were studied by the

same methods; their ages ranged from 29 to 60 years

(mean 47), and weights were 95- 115% of ideal.

Cholesterol absorption. Net absorption of cholesterol

was measured as recently described (28). The basic

equation for determining cholesterol absorption is as

follows:

Mass absorbed = (daily biliary secretion

+ exogenous intake - daily fecal excretion)

Daily secretion ates of cholesterol were estimated

by multiplyinghourly ecretion ates durin g con-

tinuous liquid formula nfusion by 24; this conver-

sion is based on our recent finding that hourly secre-

tion of biliary cholesterol

x

24 closely approximates

duodenal outputs through a 24-hr period measured

in patients given three equal meals at 8

A M ,

1

P M ,

and

6 PM (28).

When stimating holesterol bsorption by this

method, he value obtained is thenetabsorption

of cholesterol between the uppe r duod enum and the

anus.

I f

the intestine contributes cholesterol to the

lumen during the measurement, the net absorption

will

be reduced correspondingly. However, ase have

shown (28) ,values for percen tage cholesterol absorp-

tion are as high or higher than those obtained pre-

viously by other methods; his should not have oc-

curred

if

intestinal secretion of cholesterol had been

of consequence.

RESULTS

Plasma lipids and lipoprotein-cholesterol

Data for plasma lipids in nonobese,hypothyroid

patients efore andduring herapy with T4 are

presented in

Table 1.

Before treatment, total plasma

cholesterolaveraged289 18 mg/dl and, in most

patients, levels were reduced by

T4

therapy(mean

Abrums und Grundy Cholesterol metabolism in hypo- and hyperthyroidism 325


4/16

T A B L E 1. Plasma ipids(nonobesehypothyroidpatients)

~~

Total Total L D L H D L

Patienteriod"holesterolbriglycerides'holesterol"holesterol"

1

1

I 1

2

I

11

3 I

11

4

11

5 1

I 1

6

1

I 1

7 1

11

8

I

I 1

9 I

I1

10 I

I 1

40'

I

I 1

Mean SEM I

I1

mgldl -C

SD

332

t

44

197 33

226

2

184

2 5 5

5

24

152

t 13

148

5

159

20

1 3 4 ? 21

302 ? 12

273

2 5 0 t 16

2 1 6 2 24

242 38

291

2.51 -t 22

254

-t

4

303 -t 28

263 27

207 17

144 5

7

318 59

2 2 5 ? 24

2 8 9 t 18

221 t 1 T f

mgldl

234

139

1

I4

117

87

9 6

104

106

150

9 2

145

110

131

118

139

152

178

162

196

130

535

349

183 37

141 ? 22

mgldl

308

144

123

143

104

112

9 5

71

142

189

163

200

168

199

188

2

I O

177

123

8 9

I 5 9

109

171 t 20

136

5

13/

mgldl

59

5 5

64

8 2

40

38

3 6

41

4 7

5 6

5 5

3 8

8 4

5 6

40

24

2 6

49

3 5

42

30

4 6 t 4

49

6

Period

I ,

hypothyroid period;

11,

treated period (euthyroid).

Mean 5 S D for six determinations in last 3 weeks of each period; exceptions are Patients

Mean value for plasma

TG

o f each period; for variation, see Table 4, Ref

1 1 .

Value for

o n e

measurement at the end of

each

period.

Patient40 was n o t included n hecotnpanionstudy (14); he

w a s

5 9 yr old and weighe d

6 and 8 who had

only

one rneasuretnent in Period 11.

6 3 k g ( 1 0 0 ~ o f I W ) ; h i s a d m i s s i o n T S H w a s > 1 0 0 u n i t s a n d T , w a s ~ e r o ; t h e u r i c a c i d w a s 1 0 . 2 r n g / d l .

Difference between Period I and I 1

\vas

significantly different at

P

<

0.05 by paired I-test.

Difference between Period

I

a n d

11

not statistically significant.

=

22 1

?

17

mg/dl). Half of the patients had an initial

LDL-cholesterol of greater than

185

mg/dl and, in all

patientsexceptone

( N o . 3) ,

this raction was de-

creased fter eturn

to

the uthyroid tate.The

effects on HDL-cholestero l were variable. Some pa-

tients had an ncrease and others had a reduction,

with the net effect being no change in the mean.

Similaresultswere bservedor bese, ypo-

thyroidpatients

(Table

2).

Their degree

of

hyper-

cholesterolemia was about the same as for the non-

obesegroup.

All

patientsexceptonehada educ-

tion in total cholesterol with tr eatm ent and, in most

patients, LDL-cholesterol was decreased as

well.

H o w -

ever, in those with initial hypertriglyceridemia, treat-

ment with T4usually caused no change or an increase

in LDL-cholesterol imultaneous with a educt ion

in

T G .

In these obese patients, HDL-cholesterol was

relativelyow, ashasbeen eportedgenerally or

obese subjects (29). Tre atm ent with T4did not cause

a rise in HDL-cholesterol in this group.

As

expected, patients with hyperthyroidism usually

had a

low

plasma cholesterol

(Table 3).

Eleven of

13

had a concentration elow

200

mg/dl. LDL-cholesterol

concentrations likewise were

low,

and both total- an d

LDL-cholesterol increased with return to the euthyroid

state. Several hyperthyroid patients also had relatively

low HDL-cholesteroland,on hemean, this rac-

tion increased significantly af ter therapy.

Cholesterol balance

Cholesterol balance data for he hree groups of

patients are shown in Tables

4, 6,

and 8; based on

the assumption that these patients weren th e metabolic

steady state, their balance data were converted into

326 Journal of Lipid Research V o l u m e 22 , 1981


5/16

T A B L E 2. Plasma lipids obese hypothyroidpatients)

Total

Total LD LD L

Paricnr Period Cholesterol Triglycerides Cholesterol Cholesterol

I 1

12

13

14

15

16

17

18

19

20

2 1

22

23

24

25

26

Mean ? SEM

1

11

I

I1

1

11

I

11

1

I 1

1

11

1

I1

1

11

I

11

I

I 1

1

I 1

1

11

I

11

I

I 1

1

I1

I

I1

I

I 1

mgldl SD

221 ? 23

1862 21

297

215

370

4

39

370 17

256

218

296? 31

213

?

25

305

4

25

264f 29

261 t 26

1794 16

242 15

1394 30

541 103

455

?

55

292

-+

21

177

?

51

377 78

2 1 1 t 13

225

2 14

387 66

274? 27

329? 32

228? 18

263

t

22

239 10

256

t

23

187

4

42

3074 20

236? 20'

mgldl

409

403

260

40

174

195

200

190

179

167

557

294

137

108

136

105

1806

1177

292

179

870

38

1

60

40

487

336

178

158

224

214

179

111

384

?

108

256 67'

mgldl

104

68

199

140

257

208

158

125

174

I75

149

103

49

56

176

55

92

98

178

166

229

166

160

179

181

155

162

?

15

130 14'

nrgldl

28

23

46

67

56

50

60

55

32

39

61

41

19

18

23

21

34

31

35

40

34

34

46

32

48

35

40

?

4

37

t

4'

Period 1, hypothyroid period; 11, treated period (euthyroid).

*

Mean 5 SD for six determinations; exceptions are Patients 13, 15, and 23 who had only one

measurement in each period.

Mean value for plasma

T G of

each period; for variation, see Table

5,

Ref

14.

Value for one m easurement at the end of each period.

Difference significant at

P

< 0.025.

'Not significant.

values for synthesis of cholesterol and bile acids in state than in euthyroid controls (7.9 versus 9.6 mg/kg

Tables 5 , 7, and9. Also, values forproduction of perday;Table

5 ) .

Incontrast,production of bile

cholesterol and bile acids are presented for

14

normal acids was essentially normal before treatment. After

subjects in Table

5 .

therapy,our ofive patients hadn increase in outputs

Data

for

five nonobese, ypothyroid atients are of neutral steroids. While this increase was not

shown in

Tables 4

and

5 .

Before therapy, cholesterol statistically significant for the group, total synthesis

synthesis was somewhat lower in the hypothyroid of cholesterol was increased significantly following

Abrams and Grundy

Cholesterol metabolism in hypo- and hyperthyroidism

327


6/16

7 'ABI .E 3.

Plasma ipids (hypert hyroidpatients)

Total

Patients

rOral

Period

(:holestcrol rrigl ret-ide'

Ch(~le\~erol"

C h o l e s ~ c ~ ~ d

m,qldl ?

SD

lllgl~ll

l l l p l ~ l l

l l l , ~ l ~ l /

1.I)I. HIII .

27

1

114

t

19

6443

11

156 ? 12

6 29 61

28 1

151

t

25 116 8 66

I 1

207

t

21 104 152 46

29

1

117

t

21

1 0 89 21

I1 194 24

101

30

1

100

? 28 55 4

0

29

11

179 ? 21 98

119

4 8

31 I 183

t

70

10345

I I

177 -c 14 83 1 I f 5 6

3 2

I

I79 t 10

131

121 33

I I

2 5 5 5 3

171

2332

3 3 I 138 t 17

12327

I I

163 t

13 117

I l l 4 7

34 I

206 t 27 I24 156

0

I I

262 t 14 130941

3 5

1

201 t 22 186294

I I

309 t 25 23

1

210 .5

1

36

1

165 6 686

I I

24 1 7249 80

3 7

I

115

-c

290

I 1

209

-c

4 89

1

I77

3 8

I

117 -c 12 118 115 37

I 1

162

I3 0

1182

3 9 I 172

t

2 3

1

10

1183

I I 228 ? 18 1.58

Mean

t SE M I I55 10 106 ? 10

99

t I O 41 & 3

I I

211

-c

13

119 t

13' 149

t 15'

51

t

4'

Period I , hyperthyroid period; 11. treated period (euthyroid).

Mean SD for six determ inations ; excepti ons are Patient

41

who had only one measurement

in each period and Patient 38 who had one in Period

11.

Mean value for plasma TG

of

each perio d; for variation see Table 5, Ref

14.

Value

for one measurement at the end o f each period.

Differences between Periods

I

and

I I

not significant.

' ifferences significant at P

< 0.0

1

return o heeuth yroi d tate . Despite the rise in

cholesterol synthesis, production of bile acids was not

altered by T4 herapy.

Results for seven obese, hypothyroid patients are

presented in

Tables6

and

7.

When data were normal-

ized to total body weight, cholesterol synthesis per

kg

was only slightly increased; but when normalized

to

idealweight, which is abetter eflectionofactual

prod ucti on, synthesis rates for cholesterol were much

greater than normal even before treatment (Table).

Th e sa me was true for bile acids.Following reat-

men t with

T,,

fecal neutra l s tero ids were significantly

higher, as were total steroids and Cholesterol balance

(Table

6).

Bile acid excretion was unc han ged . Thu s,

as

with nonobese patient s, T, therapy caused a sig-

nificant rise in cholesterol synthesis, but bile acid syn-

thesis was not altered (Table

).

Th us , while treatment

with T4 caused a significant increase in synthesis of

cholesterol, these patients were overproducing choles-

terol and bile acids even before treatment.

When the data from aotal of 12 nonobese and bese

patients with hypothyroidism were combined, neutral

steroidexcretion was significantly ower by pair ed

analysisbefore reatment (4375

5 1

mg/day) han

after (621 * 58 mg/day) ( P < 0.05). Also, cholesterol

balance (synthesis) before treatment (848

2

117

mg/

day) was less than following therapy (IO7 5 153

mg/day) P

< 0.05).

On the other hand, combining

328 Journal

of Lipid

Research Volume 22 , 1981


7/16

T A B L E 4 .

Cholesterol balance data (nonobes e hypothyroid patients )

Fecal Steroid Excretions

Days:So.holesteroleutralcdic Total Cholesterol

Patient Stel-oid5 Stero idste~-oidsalanre

I 1

I 1

4

I

I 1

6 I

I 1

9 I

I 1

10 I

1 1

Mean

t

SEM I

I 1

34:5

34:6

3 4 : 5

51:6

29:5

34:6

40:5

32:6

24:6

24:4

m g l d q

92

92

148

118

135

135

105

105

99

9 9

116 1 1

110 t 8'

200

t 2 9

452

t

203

576 113

6 7 6 8 6

3 3 0 t 142

4 3 9 t 8

5.54 t 54

471 t 8 9

291 t 8 6

308 t 51

3 9 0 t 74

4 7 3

t

59

mgldn) ? SD

143 50

343

66

1 9 0 t 71 6 42

t

232

4 9 5 8 6 1071

?

180

519 t 134

1 1 9 5 6 6

206 t 72

536 194

393 81

852

t

78

275 c 16

8 2 0 t 36

236 23

708 t 88

279 128

570

t

193

389 148

696 t 183

335 81 668 t 126

3 4 5 t 59c

8 1 9

t

100'

251 6 6

551

t

232

923 140

1084 64

401

t

194

718

?

78

715 36

603 88

471

t

193

597 t 183

552 t 119

711

t

97

Period I, hypothyroid; Period 11, euthyroid.

Duration of balance period (days) and number

o f

successive stool pools analyzed; he ratio of the two figures gives the average

Difference between Periods

I

and

I 1

not statistically significant.

numbet-

of

days in each pool.

the bile acid data failed to produce a significant dif- and bile acids. In the one

of

these, who was not obese

ference between the two periods.

( N o .

33; 113%

I W ) ,

production rates

of

cholesterol

Data for hyperthyroidpatientsarepresented in and bile acids were 15.9 and 10.1 mg/kg IW/day,

Tables

8

and

9.

For he small number of patients respectively. In the other patient,who was obese (No.

who were able to complete the balance studies, he 39; 144% I W ) , synthesis rates were respectively 21.5

results were variable. Two patients

(Nos .

33 and 34) and6.5 mg/kg IW/day. Twootherhyperthyroid

had adistinct elevation in synthesis

of

both cholesterol

patients of normal weight had normal rates of syn-

TABLE

5 .

Steroid synthesis data (nonubese hypothyroid patients)

Patienc Period"holesterolynthesis Bile Acid Synthesis

1

4

6

9

10

Mean

t

SEM

Normal

(14 subjects)

Mean

S E M

I

I1

I

I 1

I

I 1

1

I 1

I

I 1

I

I1

mglkglda?

4.7

10.2

14.1

16 .6

5.2

9 .3

8.1

6 .9

7.2

9.2

7 .9 t 1.7

10.4

1.6b

9 .6 t 0 .6

I

I l i l d q

4 .5

9.8

14 .8

17 .4

5.7

10.3

9 .6

8 .1

7.4

9 .3

8.4

t

1.8

rnglkg-

11.0

t

1.6*

10.1

0.6

mglkglday

2 .7

3 . 5

7 .6

7 . 9

2.7

5.1

3 .1

2.7

4 .3

6.0

4.1 r 0 . 9

5 .0 t

0.9'

4 .9

t

0 .5

I Wldfly

mglkg-

2.5

3 .4

7 .9

8 .3

3 . 0

5 .6

3.7

3.2

4 .4

6 .1

4 .3

t 1.0

5 .3

t

0.9r

5 .1

t

0 .5

Period I, hypothyroid period;

11,

euthyroid period.

Difference between Periods I and

I 1

significant at

P

<

0 .05

by paired

t

tests

Difference not significant.

Abrums and Grundy Cholesterol metabolism in hypo- and hyperthyroidism

329


8/16

number of days in each pool.

Difference between Periods I and I 1 not statistically significant

Difference between Periods 1 and I 1 significant at

P

< 0 .025 .

thesis for both cholesterol and bile acids. Treatment

of three patients with hyperthyroidism produced no

change in the synthesis of either sterol.

Biliary lipid metabolism

Data for hourly output of biliary lipids and pool

sizes of bile acids are presented for the three groups

in Tables 10-12.

Table

10 compares data for four

nonobese, hypothyroid patients with eight nonobese,

euthyroid subjects. The results or the two groups

were very similar for all variables. Also, in the hypo-

thyroid patients, ipid composition and percent satura-

tion of stimulatedhepatic bile were unaltered by

therapy.On heotherhand, hepatic ecretionof

cholesterol was greaterafter herapy , which is in

accord with a corresponding increase in fecal neutral

steroids. The pool sizes of bile acids, which were in

thenormal ange in theuntreatedstate, were not

changed by treatment.

In heeigh t obese patients with hypothyroidism

(Table

ll), the saturation of hepatic bile was greater

than in nonobesepatients with and withouthypo-

thyroidism (Table 10) ; his was du e to a greater secre-

tion of cholesterol in the obese group. Trea tmentwith

T,

produced no consistent differences in either out-

putsof holesterol, bile acids, andphospholipids

or saturation of stimulated hepatic bile.

Complete s tudies of biliary lipid outpu ts were pos-

330 Journal

of

Lipid Research Volume 22 ,

198

1

T A B L E 6 .

Cholesterol balance data (obese hypothyroid patients)

Fecal

Steroid Excretions

Da).s:Ko. Cholestel-ol

Patlent

Neutral

Pel-io&'

Derernl.h 1nr;tkr

Srcroid5

Steroids

.Acidic

Tota l

Steroids

Cholesterol

Balance

m g / d q mgiday 2 SD

I 1 1 24:61 58 3 t 175

347 t 174

9 2 9 k 20114 ? 199

I 1 62:

1 2

135

5 4 5

t

26108 272 1 I 5 3

t 381

1018 380

17

I

23:6 147 389

t

5 3 904

t

310293

t

278

147

1146 277

534 t

116

850 t 483384 559237 559

109

8 1 3

t

180

6 8 6

t

19883

t

123169

t

296060

t

296

21 I 24:610 500 t

32

6 5 2 t 27152 t 33 1041 2r 31

114 938 19160 t 90598 t 184484 t 184

2 3

I 3 3 : 5

14562 368085 288947 t 498802 t 492

I1

35:6

160

9 5 6 -t 274644 t 364600 486440 486

24 I 34:66888

95

456 t 74044 14599 ? 145

11

35:64500

t

16193 8784

t

17649

t

176

26

1 31:6

11052 t 7768 ? 55

1120

t 5 8

1 1 29:6 110 827 t 5 40 0 ?0 1427 63 1317 t 6 3

1 0 1 o t 8

Mean

SEM I 143 155 5 5 94 6 t

99

1201

2r

134061 t 135

I 1 26:6

19 1

2 5 : 5

109

4 1 3

t

4 40 9

t

14922 180

I 1

34:6

11

3 7 : 6

I 1

131 t

8

727 t 68'' 734 t 165r474 203 1329 205

Period 1, hypothyroid; Period

11,

euthyroid.

Duration

of

balance period (days )

and

number o f successive stool pools analyzed; the ratio of the

t w o

figures gives the avera ge

sible in only two patients with hyperthyroidism

(Table

12). These patientshad a relatively low saturation

of stimulated hepatic bile, but otherwise their values

were unremarkable.Furthermore,reatmentpro-

duced no significant changes in any of the variables.

Finally, results for lipid composition of gallbladder

bile are presented in Tables 13- 1 5 . Th e gallbladder

bile of nonobese, hypothyroid patients was somewhat

higher han hatof omparable ontrol ubjects,

but treatment of the former did not cause a signif-

icant reduction in bile saturation

(Table

23). The

gallbladder bile was much more saturated in obese,

hypothyroid patients which is characteristic of obese

patients in general

(Table

14 . n these patients, the

molarpercentages of the hree biliary lipids were

essentially unaffected by T4 reatment, except thatwo

obese patients (N o s . 20 and 21) had a distinct in-

crease in bile saturation after return to the euthyroid

state.

By

way of contrast, in the only two patients with

hyperthyroidism in whom the studycould be com-

pleted, molar

%

cholesterol and satura tion were both

lower before treatment, but hey showed little change

in either after returno the euthyroid state

Table15).

Cholesterol

absorption

Values for cholesterol absorption in eight patients

with hypothyroidism are presented alongwith results

in ninenormal subjects in

Table

16.During heir


9/16

T A B L E 7.

Steroidsynthesis data (obese hypothyroid patients)

Patienteriod"holesterolynthesis Bilecidynthesis

11

17

19

21

23

24

26

Mean SEM

I

I1

I

I1

1

11

I

11

I

11

I

I 1

I

11

1

I 1

mglkglday

8.6

12.3

13.8

14.9

9.0

11.8

10.7

15.3

14.3

19.3

8.3

6.9

8.0

10.5

10.4 ? 1.0

13.0 1.5*

I Wlda):

mglkg-

10.2

14.6

18.1

19.5

12.0

15.7

15.8

22.5

22.5

30.5

13.2

11.0

20.2

26.3

16.0 1.7

20.0 f 2.6b

mglkglday

4.2

7.3

10.9

10.2

5.7

5.4

6.7

6.8

8.6

13.0

4.2

2.7

4.5

4.8

6.4 5 1.0

7.2 ? 1.3'

IWIday

mglkg-

5.0

8.7

14.3

13.4

7.5

7.1

9.9

10.0

13.6

20.6

6.7

4.3

11.4

12.0

9.8 1.3

10.9 2.0

I Period

I ,

hypothyroid period;

11,

euthyroid period.

Difference between Periods

I

and

I 1

significant at

P < 0.05

by paired t-test.

Difference not significant.

hypothyroidperiod hepatientsdidnothave e-

ducedabsorption

of

cholesterol (66 + 3%' versus

63 k 5% for normals). In fact, their percentage ab-

sorpt ion was lower after treatment with

T4.

Theoreti-

caIly, thiscouldhavebeen due either toagreater

flux of cholesterol into the intestiner to a more rapid

transit. Although biliary input was somewhat increased

by

T,, it

is likely that hehormone alsostimulates

intestinal transit.

In the one hyperthyroid patient ( N o . 34) who was

studied, he results are in accord. In he untreated

period, cholesterol nput was 852 mg/day; his fecal

neutral steroids averaged 318 mgiday leaving an ab-

sorption of 534 mg/day (63%). ollowing therapy, his

influx was greater, 1033 mg/day, but despite this his

fecal neutral steroids dropped o 255 mg/day. There-

fore, both absolute and percentage absorption (778

mg/day and 75%') weregreaterafterreturn o he

T A B L E 8. Cholesterolbalancedata hyperthyroidpatients)

33 1

34 I

I I

3 3 I

I 1

?I I

I I

Mean SEM 1

(4)

I (3)

I1 ( 3 )

mglrlq

28:605

33:708

33:6 97

35:64

2

i

5 85

3 3 : 5 145

3 5 : 6 14.5

113

I I

109

18'

116

15

5 1 8 ? I l l

318 5 1

155

f

66

473 134

380 f 139

I I83

? 386

600

161

623

?

192

6.58 266

378 128

m g l d q SD

724 ? 12.5

1242 ? 103

282 64

600

?

I09

235 f 84

490 ? I22

230 68 703 f

1 1 5

259 ?

95

639 224

440 f 43

1623 f 413

293 8794 f 176

419 111

1042

f

239

304 f

50

975 ? 325

262 18''

674

118

1137 f 103

492 109

393 ? 122

609 115

.554 f 224

1461 ? 413

749 ? 176

92.5 ? 227

854 305

565

103'

Period

I ,

I~yperthy~.oitl; Period

1,

euthyroid.

Duration

o f

b a l a n c e period

(da y s )

and number

of

successive

stool

pools analyred; he ratio o f the

t w o figures

gives the average

numbe~ - f days

n each pool.

Difterence between Periods

I

and

11

not statistirally signifirant.

Abrums and

Grundy Cholesterol metabolism in hypo- and hyperthyroidism 331


10/16

I 'ABLF. 9. Steroid ynthesis data (hyperth yroidpatients)

l',ltient Cholesterolynthesis Bile Acid S) nthesis

tr lg/k,y/dq mglkg-

u, .$kgl~loy

I

LVI/l//?

mgikg-

1 t //J

33 I 14. 15.9

9.0

10.1

34 I 6.6 7.5 3.8 4.3

11 5.2 6.0 3 . 3.6

3.5 1 9 0 10.5 3.4 4.0

I 1

8.2 9.5 3.8 4.5

I 1 7.6 11.0

3 0

4.3

6..i

9

I 14.9 21.5 4..i

Mean SE41

1

( 3 ) 10.2 2.5 13.2 i 4.3.9 -+ 0.3

I 1 ( 3 )

4.9 0.8

7.0 5

0.9"

8.8 -c 1.5" 3.3 t 0.3" 4.1 ? 0.3"

I Period

I ,

h~pertI1)ro id per iod;

11,

euthyroid period.

I

D i f f e ~ w ~ c eetween Periods I and

11

not significant.

euthyroid state. Again, it seems likely that the more sequences of' hypothyroidism andhyperthyroidism

rapid intestinal transit associated with hyperthyroidism

on themetabolism

of

cholesterol a nd bile acids an d to

had reduced cholesterol absorption.

determine whether abnormalities might be detected

thatcorrelate with variations nplasmacholesterol

concentrations. At the same time, possible modifica-

DISCUSSION

tions in biliary lipids, which might be secondaryo

alteredmetabolism of cholesterol and bile acids,

The hypocholesterolemicction

of

thyroid or- were explo red.

mones is well known,ndypothyroidatients

commonlyavelevatedlasmaholesterol while

lipoproteins

those with hyperthyro idism aveheeverse. TheThepr esen t work iscloses thathyroid ysfunc-

present tudy was designed oascertain hecon- ioncanaffectcholesterolconcentrations in each of

T A B L E 10. Hourly outputs o f biliary lipids and pool sizes of bile acids (nonobese, hypothyroid patients)

Lipid Com positio n Biliary Lipid Outp ut Bile

Saturationile .Acid

Patient Periodholestet-olilecidshospholipidshole~terolilecidshospholipids

( 3 %

olids) Pool Size

1

4

6

7

8

9

Mean

e

SEM

Normal

8 patients

m h r R

SD

4.1 0.7

78.0 2.0

6.2 0.8 76.7 ? 0.8

4.7 -t 1.4 76.5 7.5

4.1 0.7

78.1 c 2.3

4.9 0.6 75.5 ? 1 . 1

4.1 0.6 78.5

1.1

3.6 0.5

81.2 1.3

4.0 0.3

79.0 2.2

5.1 0.7

74.6

?

1.6

6.1

0.4

75.3 1.0

4.8 0.6 77.7 1.4

4.9 0.4* 76.6 0.8*

4.7 0.4 79.6 1.0

mglhr

-C SD

3 3 5 8

17.6 1.5 37 4 94 0f 204 32 6f 41

17. 2f 1.1 45 8 71 0f 116

249f 48

18.8 6.2 60 1 1

1382 482

484 100

17.7

-e

1.6 41 5

1029 f 159 361 43

19.6 0.8 51 5

1033 110 418 ? 49

17.3? 0.8

48 4 1213 249

415 75

1 5 . 0 t 0 . 8 3 8 ? 5

1131 c 215 32 4f 54

17.0 t 2.0 53 18 1365 c 548

450 175

20.2 t 1.4 53 7

986

c

176 416 52

18.5f 1.0

58 6 940 t 150 35 8f 48

17.5? 1 . 1 4 4 c 3

96 4f 90 338-e 35

18.5 ? 0.5* 56

2'

1180 e 113* 428 ? 27*

15.6 2.17 0.7 1139

?

180 340

c

46

R

g

1928

85.2 2370

129.3 2 142

92.9 2240

85.0

2

138

93.8 2099

86.4 4161

84.1 4789

85.5 546

1

95.3 1620

120.5 1796

98.4 10.6

2672 -t 716

98.2

c

7.7b

2899 859*

106.3 3.2 2921 ? 434

I T he data inc lude means SD for s ix hourly samples during the s teady s tate per iod of formula infusion.

Diffe renc e not statistically significant between Periods

I

and 11.

e Difference significant at P < 0.025.

332

Journal

of

Lipid Research Volume

22,

1981


11/16

TABLE 11 . Hour ly outputs of biliary lipids and pool sizes of bile acids (obese, hypothyroid patients)

Lipid Compo sition Biliary Lipid Ou tpu t Bile

Saturation Bile .\cid

Patienteriodholesterol Bile Acids Phospholipidsholesterol Bile Acids Phospholipids

(3% wlida)

Pool Size

15 I

I 1

16

I

I 1

17 I

I 1

19

I

I1

20 I

I 1

21 I

I1

23 I

I 1

26 I

I 1

Mean SEM

I

I 1

5.1 0.6

7.1 0.9

4.8

+

0.6

5.9 0.9

5.1 1.0

6.1 + 1.0

3.7 0.3

5.4 0.5

5.8

+

1.7

4.8

+

0.5

8.4 1.6

4.5 1.0

8.0 0.6

9.8 + 1.6

8.6 1.5

7.5

+

0.5

6.2

+

0.7

6.4 + 0.6'

molar

%

k

SD

77.5 1.5

70.7 2.5

81.1

+

4.7

70.5 t 4.9

78.9

+

1.5

73.8 + 3.5

72.9 + 1.8

73.1 + 1.9

78.1

+

3.3

77.4 + 1.5

73.6 + 3.3

74.9 + 1.6

74.0 + 1.4

72.9

+

3.1

72.1

+

1.5

74.1

+

0.9

76.0 1.2

73.4 0.8b

17.2 1.2

22.0 2.6

14.0

+

4.5

23.4 5.4

15.9 + 1.1

20.0

+

2.6

23.3 + 1.5

21.4

+

1.5

16.0

+

2.1

17.5 1.2

17.9 + 3.0

20.5 1.2

17.9

+

0.9

17.0 1.7

19.3 1.0

18.3 0.7

17.7 + 1.0

20.0

2

0.8*

52 11

78 ?

1 2

63

+

20

4 2 + 7

5 8 + 5

7 4 2 8

4 3 +

8

5 8 2 5

1 6 t 9

4 0 5 7

71 15

7 2 % 4

8 6 + 4

78 + 20

7 7 + 6

75

+

13

58 IT 8

65

+

6'

mgihr

*

SD"

976

+

213

1002

+

199

1992 707

663

+

135

1190 189

1238 + 188

1089 226

1017 188

320

+

169

815 + 112

844 + 254

1686 + 417

1030

+

113

775 274

862

146

971

t

223

1038 + 165

1021 114b

335 t 90

515 106

600

+

307

348 124

363 51

501 -+ 57

544 + 103

463 49

105f 65

2 9 0 t 4 5

315 85

716 + 170

384 + 25

297

-t

68

360 + 66

373

?

83

376 53

438 50"

R

107.0

123.0

116.7

99.0

113.3

113.9

63.2

96.6

127.6

99.6

167.0

83.6

159.5

199.7

161.7

147.8

127.0 12.4

122.1 + 13.gb

Nlg

3663

2.560

2959

2.569

4670

3755

4826

34.53

2073

1861

4329

3824

346 1

2064

2591

1413

3572 + 353

3085 + 446'

The data include means r SD for six hourly samples during the steady state period of formula infusion.

Difference significant at

P

<

0.025.

' iffe rence not statistically significant between Periods

1

and 11.

the different lipoprotein fractions. Th e major altera-

tion occurred in the LDL fraction. In both nonobese

and obeseatients with hypothyroidism, LDL-

cholesterol was relatively high and treatment with

T,

produceda

20%

reduction in both groups. Con-

versely, re turn to the uthyroid tate in patients

with hyperthyroidism evoked a mean rise in this frac-

tion of 51%.

The influence of thyroiddysfunction on HDL-

cholesterol seems more complex. Our hyperthyroid

patients had lower levels before treatment than after.

Th us , excess circulating thyroid hormone apparently

lowers HDL as

it

does LDL.

A

similar result has

been reported beforehand by Sachs, Wolfman, and

Murthy (30), and moreecently by Scottolini et al. (31).

Of interest, several of ou r hypothyroid patients also

had relatively low values of' HDL-cholesterol before

treatment.However,decreased values were mostly

present in the obese groupand several nonobese

patients actually had relatively high levels, as also was

reported by Scottolini et al. (31). Both Sachs et al.

(30)

and Scottolini et al. (31) reatedhypothyroid

patients with thyroid hormone and noted a depression

in HDL-cholesterol. This response was not reproduced

TABLE 12. Hour ly outputs of biliary lipids and pool sizes of bile acids (hypert hyroid patients)

Lipid Comp osition Biliary Lipid Ou tpu t Bile

Periodholesterol Bile Acids Phospholipidsholesterol Bile Acids Phospholipids (3% olids)

saturation Bile Acid

Patie nt Pool Size

molar % mglhr ?

SD

% mR

33

I

3.4

+

0.6 75.7

t

5.0 20.7 4.8

64

1 2

1804 270 774 -t 215 63.2

2832

I 1

5.0 0.6 73.5 2.3

21.4 1.8 51 11 966 207 435 84 89.7 55 16

34 I

3.6 0.6

79.1 ? 2.9

17.2 + 2.9

31 + 4 902 + 190

307 + 85 76.4

2

167

I 1

4.6

e

0.9

77.4 + 1.6 17.9 + 1.1

39 +

1 1

998 + 394 357 -c 140 94.2

2037

Mean +

SEM

I

3 . 5 e

0.1

77.4 t 1.7 19.Of

1.8

4 8 f

17

907 897 541 t 234 69 .8 + 6.6 25 00 c 333

I 1 4.8

. Z b

75.5 .gb 19.7 1.8b 45 6b 982 t 16' 396 + 3gb 92.0 2.2' 3777 1740b

The data include means t SD for six hourly samples during the steady state period of formula infusion.

Differenc e not statistically significant between Periods I and

11.

Abrums and Grundy Cholesterol metabolism in hypo- and hyperthyroidism 333


12/16

T A B L E 13. Lipid com posit ionof gallbladderbilea n dsaturation ndices

(uonobese hypothyroid patients)

Lipid Composition

%

Patient

Pel o d

Choh te r -o l

Bile i c i d s

Phospholipids

(I

% solid$)

Satur-ation

1

4

6

8

9

Mean

SEM

Normal-

14

subjects

Slean

SEM

I

I

I 1

1

11

I

I

11

1

( 3 )

I

3 )

11

( 3 )

7.6

12.3

9.5

7.7

6.9

10.4

8.2

11.2

9.2

t

0.4

10.1 0.8

9.2 0.7

7.7

t

0.4

nroir

R

71.4

71.0

69.0

71.8

3 . 3

74.3

72.2

66. I

72.1 t 0.3

71.7 0.2

70.1 1.6

74.8

t

0.9

21.0

16.7

22.0

20.4

1

. 6

19.6

19.6

22.5

19..5

0.3

18.9

?

0.6

20.7 0.3

18.6

t

0.6

a

109

198

131

112

1 1 1

1.57

122

150

139 8

144

16

1 3 1 t 7

1 2 0 t 4

I

Values represent

mean

o f th ree to fo u r d e termin a l io n s

i t1 each

p er io d .

I Differences between Periods I

and

I1 not statistically significant.

in out patients, perhaps because of their relatively

l o w le\~elsbefore herapy. ,4t least tw o factors may

havebeen esponsible or low HDL nourobese,

hypothyroid patients. First, obesity itself is accompanied

by reducedHDL

(20) ,

andsecond,manyof hese

patients had hypertriglyceridemia which is known to

be associated with a decreased HDL-cholesterol

( 3 2 ) .

Furthermore, with therapy, the HDL-lowering action

of T4 may ha\.e been offset to some extent h y a fall

in plasma TG.

Cholesterol balance

The decline of LDL-cholesterol induced by thyroid

hormones might he explained by modification

of

the

metabolism of cholesterol or bile acids.Two processes

havebeenproposed by otherworkers (9-12, 33) :

thyroid hormones may

a )

stimulate conversion

of

cho-

lesterol into bile acids or h ) accentuate outputs

of

neu-

tral steroids. Conceivably, as suggested by the cur rent

study, cholesterol absorption may also be depressed

' I 'AULE 14. Lipid comp osition otgallblatlder bileand satul-atiotl indices (obese h po th yr oi d patients)

Lipid Composition R

Patient Pet iod

( :ho lc t e r -o l

Bi le 4ctcls Phospholipids (101, solids)

Saturation

15 I

I 1

18

I

11

I9 I

I I

20

I

11

21

11

23

11

Mean

SEM I

11

11.7

1?.4

6.9

6.

1

7.7

9.2

7.8

12.6

x.

1

21.4

13.2

12.8

9.2 r 1.0

12.4 2.1

rNO IY

69.3

66.6

75.0

73.8

67.7

69.0

73.5

66.1

71.0

65.5

72.2

72.8

71.3 1 1

69.0

4 1.5

18.9

20.9

18.6

10.0

24.6

2 1.6

18.8

21.2

20.8

13.0

14.5

14.3

19.4

-+ 1.3

16.8

i

2.1

174

172

108

91

100

128

120

173

116

378

232

228

142 4 2 1

194

t

41

I Values represeut meau of thr ee t o

fout-

determ ination s in each prriod.

334 Journal of Lipid

Research

Volume 22,

198

1


13/16

TABLE 15. Lipid composition

of

gallbladder bile and saturation indices (hyperthyroid patients)

~~~~ ~ ~ ~~

Lipidomposition

%

Patient

Saturation

Periodholesterol Bile Acids Phospholipids (10 solids)

molp %

ro

33 I 3.4 75.7 20.7 50

I1 5.0 73.5 21.4 72

34

I

3.6 79.1 17.2 60

I1 4.6 77.4 17.9 75

Mean SEM I 3.5 0.1 77.4

?

1.7 19.0 1.8 55

?

5

11 4.8 ? 0.2 75.5 1.9 19.7 1.8 73 1

to some extent by the hormones. Th e results of our

research corroborate prior reports that thyroid hor-

mones ncrease outp uts

of

neutral steroids. In our

hypothyroid patients, these outputsere greater after

T4 herapy than before. Those with hyperthyroidism

had the reverse: their neutral steroid excretion was

higher before treatment than after. By way of con-

trast,outputs

of'

acidic steroidswerenotmodified

by treatment in either group. Thismplies that thyroid

hormones do not augment conversion of cholesterol

to bile acids in man.

Although the excretion of neutral steroids is seem-

ingly enhanced by the thyroid hormones, this action

need not be the cause of plasma cholesterol lowering.

Raised steroid utputsouldesultitherrom

mobilization

of

cholesterol from existing pools (as

plasma) or from promotion of cholesterol synthesis.

The for mer should cause a temporary rise in steroid

output s, the latter a sustained increment. Examina-

tion of individual data favored the latter, i.e., a sus-

tained elevation. Th ere for e, thyroid hormones p rob-

ably stimulate cholesterol synthesis, and it seems un-

likely that this action is related to their facility to

lower LDL.

Several preceding workers have reportedhat

cholesterol synthesis

is

suppressed in hypothyroidism

TABLE 16. Cholesterol absorption hypothyroidpatients)

~~ ~ ~~ ~~

Cholesterol

I npu t

Patienteriodietar) Biliary Outpu tholes terolbsorpt ion

Cholesterol

1

4

6

9

19

21

23

26

Mean

5

SEM

1

I 1

I

I

I

I1

I

11

I

I 1

I

I 1

I

I1

I

I1

I

I 1

mglday

92

92

148

118

135

135

105

105

109

109

110

114

145

160

110

110

119f 7

118 7

96

7

mglday

792

888

1080

1440

984

1224

1272

1392

1032

1392

1704

1728

2064

1872

1848

1800

1347 164

1473 118

1063 97

mglday

200

452

576

676

330

459

5 54

47 1

413

686

500

938

862

956

552

827

484 70

683 74

403 39

mglday

684

528

652

882

789

900

823

1026

728

815

1314

904

1347

1076

1406

1087

967 ? 116

902 64

757f 58

%

77

54

53

57

71

66

60

69

64

54

72

49

61

53

72

57

66 -+ 3

57 -c

3

65 5

~~~ ~

Abrams and

Grundy

Cholesterol metabolism in hypo-

and

hyperthyroidism 335


14/16

and ncreased nhyperthyroidism (5, 34-41).Our

data are in agreementwith these repor ts in a relative

but not in an absolute sense. The net effect of treat-

ment of hypothyroid patients with , was to augment

significantly the balance of cholesterol, and hence to

stimulate synthesis. From these findingswe must con-

clude that a lack of T, slackens production of choles-

terol. Nonetheless, obese, hypothyroid subjects regu-

larly had elevated synthetic rates. This phenomenon

probably was due n par t o an excessive intake of

calories required to maintain their obesity; the over-

productionofcholesterol in obesepatients is well-

recognized

(42) .

An additional factor that may have

contribu ted o excessive synthesisofcholesterol in

thesepati ents is adiminishedoxidationofcaloric

substrate. As Keyes and Heimberg (43) observed for

other lipids, the hypothyroid stateay divert 2-carbon

fragments away fromoxidation ocholesterolsyn-

thesis. Thus, in our obese patients, the mean produc-

tion of cholesterol n the hypothyroid state as greater

thannormal(16.0

k

1.7mg/day/kg

I W

versus10.1

mg/day/kg I W

for

normals). Nevertheless, i t was en-

hanced even more after treatment (to 20.0 2.6 mg/

day/kg

I W ) .

This findi ng again reveals that T 4 can

increase synthesis. Nonetheless, we conclude that the

caloricbalance, s eflected by obesity ornormal

weight, is more important for controlling the level of

cholesterol synthesis in hypothyroidism t han are con-

centrations of circulating T,. This conclusion also is

supported by the four balance studies donen hyper-

thyroid patients (Table 9).

To summarize, alterations in synthesis, catabolism,

absorption,orexcretion of cholesterolcannotex-

plain fully the changes in LDL-cholesterol found in

patients with thyroid dysfunction. They nevertheless

could play a supporting role.

For

example, in the un-

treated, hypothyroid state, many patients have an in-

crease in synthesis o f cholesterolandsecretion

of

VLDI,.Bothouldontribute

t o

elevated LDL-

cholesterol.Furthermore,absorptio n was relatively

high in hypothyroid subjects which should bolster an

elevated LDI,. However, these factors probably are not

crucial. More likely, LDL-cholesterol is influenced to

a greater extent by an independent action of thyroid

hormon es on the catabolism of LDL. For example,

Waltonet

al.

(13)have eported a diminished e-

moval

of

' I-labeled

LDL i n

hypothyroidpatients

andaccentuatedclear ance in those with hyperthy-

roidism. A stimulation of LDL catabolism by thyroid

hormones

also

is support ed by the preliminary report

of Chait, Albers, and Bierman (44) ;hey observed that

r4enhances both binding and degradation

of

LDL

in cultured human fibroblasts.

Biliary lipid metabolism

Th e influence of hypo-andhyperthyroidismon

biliary lipid metabolism also as explored in this study.

Preceding work in rats indicated that cholesterol con-

centrations in bile fall after these anima ls are made

hypothyroidand risewhen hey arehyperthyroid

(10,45,46). These findings were not confirmed in our

studies in man.Twohyperthyroidpatientsdidnot

have increased cholesterol secretion, and several pa-

tients with hypothyroidi sm did. An increased biliary

cholesterol in obese, hypothyroid patients s in accord

with our previous findings in obese, euthyroid sub-

jects (42). This high secretion

of

biliary cholesterol

in our hypothyroid patients evidentlyas the cause of

the supersaturation of gallbladder bile often found

in these patients. Furthermore, the failure to correct

this abnormality completely y treatment with T4 ub-

stantiates the concept that the state of nutrition (i.e.,

obesity or nonobesity) was thecrucialdeterminant

of bile saturation.Thus,he ffects fhyroid

hormon es on biliary lipids must be due in large part

to their influence on caloric balance.

Obesity and hypothyroidism

T h e division of our hypothyroid pat ients int o non-

obese and obese patients has been revealing. The non-

obese patients clearly had hypercholesterolemia that

could not be explained by overp roduc tion of choles-

terol or decr ease d ynthesis of bile acids.This strongly

suggests that other factors, such as decreased catab-

olism ofLDL,are mainly responsib le orelevated

LDL-cholesterol. On the other hand,majority of ou r

patients with hypothyroidism were obese, and weight

gain has been reported to be a presenting featuren 50

t o

75% ofpatients with hypothyroidi sm 47-49).

Presumably, the increase in weight is due to a reduc-

tion in oxidative utilization of calories. Once obesity

is es tablished and maintained, i t can become an in-

dep end ent f-actor regulating lipid metabolism. Thus,

despite their hypothyroidism, our obese patients ex-

hibited an abnormally high synthesis of cholesterol

that may have contributed in parto hypercholesterol-

emia. O n the oth er hand , by keepingbodyweight

constant in our obese subjects, we were able to show

that thyroid hormone, independent of body weight,

can stimulate the synthesis of cholestero1.a

Thi s w ork w as suppo r t e d in pa r t by the V e te ra ns A dmin i s -

t ra t ion: Dr . Je ffrey

J .

Abr ams was an Asso c ia te Invest iga tor

a nd D r . Sc o t t M. G r un dy is a Me d ic a l Inve s t iga to r o f he

Veterans Adm inist ra t ion . The nvest iga t ion was a lso sup-

po r t e d by G ra n t A M-I6667 f rom the N a t iona l In s t i t u t e

o f

Arthr i t i s , Metabol ism, and Digestive Diseases a nd No. HL-

14197

a w a r d e d

by

t he N a t iona l H e a r t ,

Lung,

a ndBlood

336

Journal

of

Lipid Research

V olume

22, 1981


15/16

Institute,HDS/DHHS. The uth ors wish to expressheir teins in hypo thyroidism nd thyrotoxicosis. Clin.ci.

appreciationoarjorieWhelan,oanupp,ianne 29: 217-238.

Leipper , and othe rs of the Nurs ing and Dietetic Services 14. Abrams, J. J., and

S .

M. Grundy . Metabolism o f plasma

of th e VeteransAdministration Medical Cente r, SanDiego.riglycerides in hypothyroidism nd yperthyroidism

Excellent technical help was also provided by Robert

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

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338 Journal of Lipid

Research

Volume 22, 1981

Documents

J. Lipid Res.-1981-Abrams-323-38