perspectives

Triglycerides

in clinical

in nutrition

medicine

A review1 Manuel

Tzagournis,

M.D.2

ABSTRACT in

There

apply

they

to clinical of

a context

symptoms

and

increased

risk

both

lipids.

Disorders medicine.

from

also

in atherosclerosis

oflipid

and their

ease, the Impressive

insulin

to vascular

dis-

peoples. and

knowledge about lipids in the past two decades. Lipids are substances

that

an aqueous transporting

elaborate system of triglycerides, phos-

cells,

and free Apoproteins,

unite

with

recorded

are insoluble

fatty acids synthesized

cholesterol,

in

(FFA) has in certain

triglycerides,

and

phospholipids to form a complex called a lipoprotein. Several apoproteins have been identified: the Apo A group, Apo B, the Apo C series, Apo D, and Apo E (1). Most of the lipids are transported throughout the body in the form of lipoproteins. A specialized system involving chylomicrons is used for the transportation and disposition of exogenous (ingested) lipids. Free fatty acids are carried bound to plasma albumin. Physiological Adipose

calories The American

aspects tissue

and

is the

consists Journal

major

almost

ofClinical

reservoir

entirely

Nutrition

by diet

of

of tn-

31: AUGUST

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and/or

Am.

In

Nutr.

the

ofcaiories,

Several drugs

31:

factors

is quite

play

effective

a beneficial

absence

is

influences,

1437-1452,

mobility

is an

if this transports

genetic

Whether

J. Cli,a

There clear

that

weight,

ofhypertriglyceridemia.

effect

1978.

of

away

this

efficient

from

a source

of nutrition would be severely limited. One gram of adipose tissue yields almost 9 cal of energy. Fat exists in a virtually anhydrous

state. yield of the

media. An cholesterol,

pholipids, evolved.

been

Treatment

occurs.

lipoprotein

body

dramatic

neuromuscular

it is not

disorders.

diet,

with

and but

as

are reviewed

associated

common

underlying

including

bank

arises

be

complication

of the

glycenides.

become

metabolism

triglycerides,

by diverse

unknown.

in clinical

of civilized in technology

have

content

concentrations.

disorders

relationship

major disease advances

an atherosclerotic

manifestations

of triglycerides

knowledge

hepatosplenomegaly,

endogenous

cholesterol

is still

have

in lipid

until elevated

are affected

clinical

problems

interest

close

ofthe

metabolism

important

The

se, or the

and

many

in our

of triglyceride may

pain,

of hypertriglyceridemia

in relieving occurs

abdominal

with

triglycerides

advances concepts

Hypertriglyceridemia

as acute

pathogenesis

metabolism,

relevant

of the basic

be asymptomatic

per

Serum

many

Some

of atherosclerosis

in the

glucose

been

applicability. such

to triglycerides

a role

common

clinical signs

or it may

abnormalities, due

have

medicine.

In contrast, protein and carbohydrates only 1 to 2 cal per gram oftissue instead theoretical

4 cal.

male,

fat is estimated

body

weight.

of the fatty palmitic,

Oleic

acids. linoleic,

In an

acid

The

makes

stearic,

compounds instead

young

15% of total up about

remainder

half

consists

mynistic,

mitoleic acids. Triglycerides free diets contain primarily acids, linkage

average

to be about

and

produced saturated

of pal-

on fatfatty

with a single bond carbon of double or triple bonds (2).

In the United States, dietary fat constitutes 40 to 45% of the total caloric intake, and virtually

all of it is in the form

It is helpful ingested lipids.

to review the Triglycerides

of triglycerides.

disposition consisting

of of

‘From the Department of Medicine, Division of Endocrinology and Metabolism, The Ohio State University, College of Medicine, Columbus, Ohio 43210. 2Address reprint requests to: Manuel Tzagournis, M.D., The Ohio State University Hospitals, Columbus, Ohio 43210.

1978,

pp.

1437-1452.

Printed

in U.S.A.

1437

TZAGOURNIS

1438

long chain fatty acids enter the stomach and small intestine. Certain gastrointestinal hormones, the major one being gastric inhibitory polypeptide (GIP), retard the movement of gastric contents into the duodenum (3). In the duodenum as detergents,

fat mixes with bile salts producing aggregates

which known

act as

micelles. Bile salts also increase the efficiency of pancreatic lipase, an enzyme, which hydrolyzes triglycerides at the 1- and 3-glyceride positions. The resultant monoglyceride and fatty acids are absorbed in the duodenum and jejunum while the bile salts are reabsorbed

more

distally

in the

cellular fatty acids and adenotriphosphate a-glycerophosphate once 100

again.

ileum.

The

intra-

react with coenzyme A (ATP), and then with to form triglycerides

These

coalesce

into

particles

of

capillaries ( 1 1). Chylomicrons cleared by adipose tissue. Fatty ing

from

hydrolysis

albumin as FFA, into triglycerides tivity is released and

is possibly

may

become

enhanced

by

FFA. Insulin the absence

yet

by insulin

another

impedes of glucose

acid cycle, partially oxidized ketone bodies, or reconverted in the liver.

and blood (7).

venous

system

(Fig.

1). Medium

stream

The blood

as fatty

acids

bound

to albumin

by

most

can tissues

be removed except

brain (8). Lipopnotein lipases for hydrolysing the triglycerides chylomicrons process occurs

endothelial

possibly

from the

are responsible and clearing

cell or intracellularly. can

probably

pass

C

-

C

-

FA

C

-

FA

to

yield

and (17-21).

Endogenous the only

thyroFFA

with entry Krebs-citric

in the liver to triglycerides

triglycerides exogenous

source

triglycerides

of triglycerides

are

not

in the blood.

Endogenous triglycerides are transported very low density lipoproteins (VLDL). ing the elimination of exogenous fat

as Dunfrom

In the liver,

from

the

blood

(23).

About

one

third

of albumin

CELL

+

PANCREATK

LIPASE + BILE

enter

FIG. the

I. Triglyceride lymphatics.

absorption. Medium chain

to

through

iNTESTINAL

LUMEN

thy-

blood, fatty acids are taken up by the liver and incorporated into VLDL (22). FFA, released from adipose tissue, can be extracted

from the blood (9, 10). This at the border of the capillary

chylomicrons

lipase

may be metabolized by /3 oxidation of the carbon fragments in the

Obviously,

chylomicrons

and

insulin concentration is a potent stimulus for conversion of inactive adipose tissue lipase to an active form (18). Catecholamines, glucagon, corticotropin, thyroid, growth hormone,

tually

the

to

FFA release even in (17). A diminished

chorionic somatomammotropin, tropin also accelerate lipolysis

triglycerides, those fatty acids that have or 10 carbons, escape reesterification are transported directly in the portal

bound

not all studies show of insulin on lipopro16). in adipose cells are

to 1000 .t called chylomicrons (4, 5). Besides triglycerides, they consist of a protein surface, phospholipids and cholesterol (6). Chylomicrons enter the lymphatics and evenchain eight

avidly

result-

but most are reincorporated (12). Lipoprotein lipase acfrom tissue sites by heparin,

roid (13, 14). However, a stimulatory influence tein lipase activity (15, Stored triglycerides hydrolyzed

are

acids

Long chain fatty acids are incorporated fatty acids enter the portal vein directly.

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into

triglycerides

and

chylomicrons

TRIGLYCERIDES

IN

bound FFA is removed during one passage through the liver. Some are esterified and transported as VLDL. Also, fatty acids can be synthesized from any precursor which forms acetate or acetyl Co A (24, 25). Accordingly, endogenous triglycerides may be

derived

from

reassembled

exogenous

fatty

acids, FFA from adipose cells, or metabolic products of ingested glucose and protein.

VLDL

are

a large

group

of macromole-

cules synthesized and secreted mainly by liver and intestinal mucosal cells (22, 25). They contain large quantities of triglycerides assembled with small amounts of cholesterol, phopholipids, and apoprotein B as well as apolipoprotein C series. Fisher and Truit (26) have elegantly reviewed the process of Sequential delipidation of the VLDL in which triglycerides and the C apoproteins are removed in a stepwise fashion. The VLDL is made up of progressively smaller molecules with diminishing triglyceride and C apoprotein content as lipoprotein lipase acts upon them. The end product of VLDL metabolism is low density lipoprotein (LDL) with apoprotein B as the major protein unit. Many cells have the ability to bind LDL and utilize the cholesterol and phopholipid for membrane synthesis. Apoprotein B is critical in regulating cholesterol synthesis by influencing a key enzyme, hydroxymethyl glutarylCo A reductase (27). The C apoproteins are

transferred to high density lipoproteins (HDL) during metabolic degradation of VLDL. HDL with its major protein unit, apolipoprotein A, affects the activity thin-cholesterol acyltransferase (28), important lipid regulating enzyme.

proved

understanding

olism has triglyceride

of overall

resulted from disposition.

studies

lipid

of lecianother An im-

metab-

of endogenous

Classification Lip oproteins Various techniques have been used to separate lipoproteins. The relative proportions of lipid and protein in a lipoprotein complex result in different densities which can be sep-

arated teins They ical

by ultracentrifugation

(29).

Lipopro-

separate as VLDL, LDL, and HDL. can be further characterized by analytultnacentrifugation by adjusting the

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CLINICAL

MEDICINE

plasma density tion rates (Sf

related

1439

to 1.063 and values) which

to density

assigning flotaare inversely

(30). Chylomicrons and consist

values of 400 to 100,000 enous triglycerides and of protein, cholesterol,

have Sf of exog-

small amounts phospholipids. VLDL with Sf values of 20 to 200 contain endogenous triglycerides and more protein, cholesterol and phospholipids than chylomicrons. Analytical ultracentrifugation affords great accuracy and resolution of the lipopro-

tein patterns. Electrophoresis

very and

is another

technique

used

to separate lipoproteins. It is a simple, rapid, and effective technique (3 1). Serum proteins are separated by paper electrophoresis and then stained by a lipophilic dye. Chylomicrons remain at the origin while /9, pre-fl, and a lipoprotein bands migrate. The /1 lipoproteins correspond to the LDL, the pre-$ to the VLDL, and the a to the HDL. Agarose and polyacrylamide gel can be used instead of paper. These techniques give qualitative

rather Clinical

than

quantitative

information.

classflcation

Familial hyperlipidemia can be classified into five types based upon concentrations of the various lipoproteins (32). This same nomenciature is also useful in describing secondary hyperlipidemias. Type I hyperlipoproteinemia is a rare disorder characterized by the presence of chylomicrons in serum after an overnight fast of at least 12 hr. Lipoprotein lipase activity is

reduced ficient

or absent. while

Triglyceride

monoglyceride

lipase lipase

is de-

seems

to

be normal (33). The exogenous triglycerides appear as a creamy layer floating to the top of the plasma specimen after refrigeration overnight. Type II hyperlipidemia is characterized by an abnormal elevation of the fi lipoproteins (LDL). It is a relatively common disorder (34, 35). In Type Ila, /9 lipoproteins

are elevated while serum triglycerides (and pre-fl lipoproteins) are normal. In IIb, f and pre-$ lipoproteins are increased resulting in elevations of both cholesterol and endogenous triglyceride levels (36, 37). Type III hyperlipoproteinemia is a rare condition characterized by a broad f. band on electrophoresis and an abnormal lipoprotein on ul-

tracentrifugation

(38). Floating

fJ

lipoproteins

TZAGOURNIS

1440

are found which resemble VLDL. In addition, the conversion of VLDL to LDL is defective and subjects tend to have abnormalities in carbohydrate, insulin, and FFA metabolism (39). Serum triglycerides are elevated to about the same degree as the cholesterol level. Type IV hyperlipoproteinemia is characterized by increased pre-$ lipoprotein (VLDL) levels. Serum triglycerides are elevated to a greater extent than cholesterol. It is a common disorder, particularly in those with diabetes, obesity, and coronary disease (40-43). Endogenous triglycerides in plasma impart a milky turbidity which is uniform throughout the sample after overnight refrigeration. Type V hyperlipoproteinemia is characterized by elevated exogenous and endogenous triglycerides. Serum triglycerides are high and cholesterol levels are intermediate between those seen in types I and IV relative to the triglyceride levels. Types I, lIb, III, IV, and V hyperlipoproteinemias all share the property of increased serum triglycerides. Appropriate measurements and classification ofthe disorders characterized by hypertriglyceridemia have been possible for only the past two decades. This is in contrast to the many years of investigation dealing with clinical problems associated with hypercholesterolemia (44). Accordingly, the impact of serum triglycerides in clinical medicine has not been as great as that of cholesterol. New and pertinent information has appeared in the past several years and should continue to be of interest in the forseeable future. Clinical

aspects

Normal

values

of hypertriglyceridemia

Serum triglyceride concentrations vary greatly during the day. An increase in triglycerides is seen after a fatty meal (22), and either an increase or decrease can be found after ingestion of carbohydrates. Even fasting triglycerides show considerable variation in the same individual (45). Triglycerides must be measured after an overnight fast of at least 12 hr. It is preferable that the patient be on a regular diet and have maintained constant body weight for at least a few weeks. Normal serum concentrations tend to rise with age. A mean serum triglyceride of 65

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mg/l00 ml in subjects below the age of 20 years rises progressively to about 95 mg/lOO ml in the 6th decade (5, 46). Values above the 160 to 200 mg/lOO ml range are considered abnormal (5, 46, 47). The prevalence of hypertrigiyceridemia varies in reported studies. Diet, alcohol intake, age, sex, drug ingestion, and other conditions influence triglyceride concentration. Brown et al. (48) followed 1 85 1 middle aged men and reported that 42% of the healthy men and 55% of those with ischemic heart disease had hypertriglyceridemia. Elevated levels were based upon values exceeding the 95th percentile in healthy young adults. Lewis et al. (49) reported triglyceride levels exceeding 175 mg/lOO ml in 14% ofmen and 3% of women ages 20 to 69 years. On the other hand, Greenlandic Eskimos have extremely low plasma triglycerides (50). Interestingly, diabetes mellitus and coronary disease are virtually nonexistent in that population. First degree relatives of young survivors of myocardial infarctions have a high frequency of hyperlipidemia (5 1). In a study of 413 such relatives, 7% were found to have type IIb lipoprotein patterns and 9% were type IV. Many subjects with elevated triglycerides also have increased cholesterol levels (47-49, 51). The association of hypertriglyceridemia with diabetes mellitus and obesity is well recognized (52, 53). Insulin deficient diabetics, particularly when uncontrolled, have higher mean triglyceride levels than nondiabetics (54, 55). However, adult onset diabetics who tend to have excessive insulin responses to oral glucose (56), also have a high prevalence of hypertriglyceridemia (24, 47). Symptoms

and

signs

Mild hypertriglyceridemia is asymptomatic. It is detected when patients are screened for metabolic abnormalities. Patients with severe hypertriglyceridemia may give a history of episodic abdominal pain in childhood (57). Some of these episodes are diagnosed as pancreatitis, but pain can occur which is not due to pancreatitis. This pain characteristically disappears with effective treatment of the lipemia. Its genesis is unknown but might result from ischemia in tissues by chylomicron loaded capillaries.

TRIGLYCERIDES

IN

Eruptive xanthomas are characteristic skin lesions of severe hypertriglyceridemia. They are elevated lesions with a white-yellow centen on an erythematous base. They resemble pustules or crops of acne. Eruptive xanthomas reflect a severe lipemia, usually greater than 3000 mg/l00 ml, and chylomicrons are virtually always found. Lipemia retinalis, manifested by a white instead of red reflection from the arterioles, can be seen through the ophthalmoscope. Hepatosplenomegaly is due to fatty infiltration and phagocytosis by the reticuloendothelial cells. Foam cells may be seen in the bone marrow. Hypersplenism is rare, but mild elevation ofthe liver enzymes is not uncommon. Abnormal liver scans have been reported in 7 1% of patients with elevated triglyceride levels (58). Aarli (59) described a spastic-ataxic syndrome associated with hypertriglyceridemia which resolved with effective treatment. Lipid infiltration of the peripheral and central nervous system may result in polyneuropathy on myelopathy (59). Musculoskeletal symptoms, such as stiffness and polyarthritis have been described in adults with type IV hyperlipoproteinemia (60). Hyperuricemia accompanied by hypertriglyceridemia may decrease to normal with correction of the lipid disorder. Triglycerides

and

other

disorders

Hypertriglyceridemia found by routine screening tests sometimes signals the presence of another condition. Accurate identification of secondary hyperlipidemia is important because attention can be directed to the underlying disease. Diabetes mellitus represents the most fnequent underlying disease in a patient with hypertriglyceridemia (36, 52, 53). The lipid abnormalities represent a continuum of the deranged metabolic processes found in diabetes. An increase in exogenous and endogenous triglycerides in the diabetic can be due to insulin deficiency. Treatment with insulin results in a relatively rapid fall of triglycerides. However, familial hyperlipoproteinemia can coexist with diabetes despite excellent control of glucose metabolism. Increased endogenous triglycerides (type IV pattern) can be secondary to either insulin deficient diabetes or the mild adult onset form with ample insulin secretion.

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CLINICAL

MEDICINE

1441

Partial and total lipoatrophy is commonly associated with hypertriglyceridemia (61, 62). The type IV pattern is usually seen, but exogenous particles are also found in the insulin resistant form of lipoatrophic diabetes. Normal triglyceride storage in fat tissue is defective. The fat loss may be due to an intrinsic defect of the adipose cell or a normal cell may be influenced by a hormonal or neurogenic lipolytic stimulus. Another endocrine disorder that is associated with hypertriglyceridemia is hypothyroidism (63, 64). LDL are more consistently affected by deficiency of thyroid hormone than are those lipoproteins rich in triglycerides. The pattern of abnormal triglycerides most likely to exist resembles a type IV hyperlipoproteinemia. There is a decreased clearing of lipids in hypothyroidism while synthesis of triglycerides remains relatively normal (63). Synthesis of lipoprotein lipase or its effective activation seems to depend on adequate amounts of thyroid hormone. FFA are mildly depressed by hypothyroidism (65). Pancreatitis is known to occur in association with hypertriglyceridemia (66). Although the pathogenesis is poorly understood, hypertriglyceridemic patients may develop pancreatitis, and patients with acute pancreatitis develop hypertriglyceridemia. Cameron et al. (67) report that a type V lipoprotein electrophonetic pattern is most common with acute pancreatitis. Reduced lipoprotein lipase activity accounts for the impaired ability to clear circulating triglycerides (66). However, excessive alcoholic intake, the severe stress of illness, and associated diabetic consequences are certainly additional factors. It has been known for years that alcohol may produce hyperlipidemia (68, 69). Zieve’s syndrome is the dramatic clinical picture of alcoholic lipemia associated with jaundice and hemolytic anemia (69). Alcohol excess is a common secondary cause of hypertriglycenidemia (70). Enhanced hepatic and intestinal cell synthesis of VLDL following the ingestion of alcohol seems to account for the induction of hypertriglyceridemia (7 1, 72). Also, chylomicron clearance is delayed (73, 74). Renal disease is associated with hypertriglyceridemia. The nephrotic syndrome characteristically results in elevated cholesterol

1442

TZAGOURNIS

and LDL levels, however, increased VLDL with hypertriglyceridemia can be noted as well (75). The lipid elevations tend to be inversely related to the serum albumin (76, 77). Even in the absence of nephrotic syndrome, uremia elevates serum triglycerides (78). The associated glucose intolerance and increased insulin secretion probably enhance triglyceride synthesis. In addition, lipoprotein lipase activity is diminished resulting in delayed clearing of lipids (78). Dysglobulinemia, particularly multiple myeloma, has been reported with hypertriglyceridemia (79, 80). These proteins seem to bind serum lipids, however, abnormal plasma cells may synthesize lipoproteins in some cases (81). Some patients with autoimmune disorders bind heparin with concomitant diminution oflipase activity (82). These latter observations support the thesis that endogenous heparin plays a role in the normal clearing process after fat ingestion. Certain drugs may induce hypertriglyceridemia. The oral contraceptives produce elevations of the serum triglycerides (83, 84). The estrogen component of the drug is implicated. Endogenous triglycerides are thought to increase as a result of increased glucose and insulin levels. Lipoprotein metabolism may also be altered by estrogens. Hypertniglycendemia occurs as a complication of steroid therapy (85). Decreased post heparin lipolytic activity occurs, but increased synthesis of endogenous triglycerides is also a factor. Hypertriglyceridemia

and

atherosclerosis

Endogenous hypertriglyceridemia is commonly associated with premature atherosclerosis while exogenous hypertrigiyceridemia apparently is not. Since the etiology of atherosclerosis is unknown, no definite conclusions can be reached about triglycerides as an independent risk factor. Nevertheless, clinical experience strongly suggests that they play some role in atherogenesis. It is possible that elevated triglycerides have only a passive effect and are suspect only because hypertriglyceridemia frequently accompanies hypercholesterolemia. Lipid deposition in the arterial wall is a universal phenomenon in man. Progression of the lipid

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deposit to a plaque is not universal. All lipoproteins, with the possible exception of the chylomicrons, can physically diffuse into the arterial wall and accumulate there. Endothelial injury by a variety of means enhances lipid diffusion, and smooth muscle cells are stimulated to proliferate and migrate or undergo necrosis (86). Cholesterol, which is poorly metabolized by arterial tissue, is readily found in these lesions. Figure 2 points out that all of the lipoproteins carry some cholesterol. These lipoproteins are capable of depositing cholesterol and triglycerides, although HDL seems to have a protective effect on the arterial wall. Accordingly, it is not necessary to assign a primary role to either cholesterol or triglyceride in atherogenesis. It is, however, reasonable to consider the role of the lipoproteins as reflected by the triglyceride or cholesterol level. Most of the clinical evidence relating lipids to atherosclerosis arises from epidemiological studies. Relatively few prospective studies have been conducted to evaluate the importance of serum triglyceride levels in vascular disease. Carlson and Bottiger (87) reported that serum triglycerides are an independent additional risk for the development of coronary disease. In a 9-year follow-up of 3168 men, they found that the rate of coronary disease increases linearly with increasing triglycerides or cholesterol levels, and combined elevation of both lipids carry the highest risk. The increase in rate of coronary disease was 4.9/1000 for each quintile of increasing triglyceride level and 4. 1/1000 for each cholesterol quintile. In the Western Collaborative Study, subjects with serum triglycerides exceeding 176 mg/l00 ml had an annual incidence of cononary disease over three times that of subjects with levels under 100 mg/l00 ml (88). However, coronary disease was more highly conrelated with increased cholesterol levels than triglyceride levels in young subjects. In a Finnish population of 1600 men followed for 7 years, cardiovascular mortality increased 2fold in those with serum triglycerides in the highest quintile (89). It was difficult to assess the importance of elevated triglycerides as an independent factor in that study. Slack (90) analyzed the risk of ischemic heart disease in familial hyperlipoproteinemic states. The

TRIGLYCERIDES

FIG.

2. The

relative

content

IN

of cholesterol

greatest incidence of coronary disease occurred in patients with type II hyperlipidemia. However, those individuals with types III, IV, and V also showed an accelerated incidence of coronary heart disease in comparison to normal subjects or a similar population in the Fnamingham study. It should be mentioned that random rather than fasting specimens for lipid determinations were obtamed in the Framingham study. Thus, the role of triglycerides, in contrast to cholesterol as a risk factor, is undetermined in that study. Epstein et al. (91) in long term studies in Tecumseh, Michigan emphasized the importance of hypentriglyceridemia as well as hyperglycemia in increasing the incidence of coronary heart disease. Many retrospective studies demonstrate the association of hypertriglyceridemia and clinical manifestations of atherosclerosis (42, 47, 49, 53, 92-94). The greater prevalence of hypertriglyceridemia as compared to hypercholesterolemia in the general population is also reflected in atherosclerotic subjects. Hypertriglycendemia is common in conditions thought to predispose to atherosclerosis, such as diabetes and obesity. A spectrum of closely interrelated metabolic abnormalities is found in patients with established coronary heart disease and assessment of each variable as the important factor becomes difficult (52, 94). There is no unanimity of opinion concerning the importance of serum triglycerides in

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CLINICAL

and

triglyceride

MEDICINE

in each

1443

of the lipoproteins.

atherosclerosis. Many patients who have myocandial infarctions have normal serum triglyceride and cholesterol levels. Population studies have tended generally to incriminate cholesterol more strongly as the culprit in atherosclerosis than triglycerides (95, 96). Some reports virtually negate a correlation between triglycerides and atherosclerosis (97, 98). In the Albany study (97) patients with severe hypertriglyceridemia had a greater incidence of coronary disease, but there was no significant difference between mildly hypertriglyceridemic and normal individuals. In an extensive study of a family with type IV hyperlipidemia, no family member below the age of 70 suffered an atherosclerotic complication (98). Cohn et al. (99), in one of the few reports that deals with the importance of cholesterol compared with triglycerides, studied both lipids in patients with angiographically determined coronary disease. They concluded that coronary patients had significantly higher levels of both cholesterol and triglycerides than those without coronary disease. However, serum cholesterol was more significantly associated with coronary disease than was the triglyceride level, particularly in relation to multivessel disease. Most investigations favor the view that hypertriglyceridemia imparts some risk for developing atherosclerotic complications. Nevertheless, the available information does not establish whether triglycerides alone, or as-

TZAGOURNIS

1444

sociated genetic and ences are responsible (100, 101).

environmental influfor this phenomenon

Metabolic mechanisms hypertniglyceridemia

of

Hypertriglyceridemia results from increased synthesis of triglycerides, defective removal of lipids from the blood, or a combination of increased synthesis and decreased removal. It is easy to understand how a deficiency of enzymes, such as the lipoprotein lipases, could result in elevated triglycerides. However, the fundamental abnormality in patients with increased VLDL is complex. It is likely that many factors play contributory roles. Diet Serum triglycerides are influenced by a number of nutritional factors (101). The response depends on the amount of carbohydnate ingested (102), the type of carbohydrate ( 103), the number of calories ( 104), the proportions of saturated or unsaturated fat in the diet (105), the body weight (106), and the initial concentration of serum lipids (107). The duration of observation on a dietary regime, frequency of feedings, physical activity, and the use of formula feeding are other variables which make observations of triglyceride levels difficult to interpret. The most consistent and persistent data dealing with diet and hypertriglyceridemia concern sucrose and simple sugars. Some reports indicate that sucrose, glucose, and fructose, in contrast to starches (complex carbohydrates), are lipogenic in humans (103, 107-110). Others suggest that carbohydrates play a minor role in intensifying a fundamental abnormality in patients with hypertriglyceridemia (1 1 1-1 13). In most circumstances, simple sugar and sucrose ingestion causes a rise in serum triglycerides, acutely, and sugar restriction results in noticeable falls in triglyceride levels (1 14-1 16). It is not clear whether glucose or fructose is more important in stimulating a rise in triglycerides. The specific activity of both the glycerol and fatty acid moiety of the triglyceride molecule is increased to a greater extent after ingesting radioactive fructose than glu-

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cose (1 10). In primates, fructose is panticularly effective in increasing triglycerides (1 17). However, both simple sugars increase liver, serum, and adipose tissue triglycerides. Glucose stimulates insulin secretion while fructose does so to an insignificant degree. Both fructose and insulin separately stimulate production of VLDL in perfused livers of experimental animals (118). Diets high in glucose, fructose, and sucrose, in contrast to starch or high fat diets, enhance hepatic triglyceride synthesis under a variety of experimental conditions (1 19-121). This is not to deny that a defect in removal of triglycerides exists in some patients (121). However, hepatic lipogenesis appears to be the important process in most circumstances ( 1 16, 1 1 8- 120). The rapid rate of intestinal absorption of simple sugars and the amount of insulin secretion are probably important determinants of the lipogenic stimulus. Insulin The role of insulin on triglyceride metabolism is a fundamental one. Careful attention must be given to associated metabolic conditions when considering the effects of insulin on lipids. Insulin administered to an insulindeficient diabetic who is markedly hyperglycemic and also hyperlipemic, can dramatically reduce serum triglycerides. This is due to the potent antilipolytic action of insulin and, possibly, to activation of lipoprotein lipase (122, 123). On the other hand, insulin has important physiological effects on hepatic fatty acid and triglyceride synthesis. Figure 3 summarizes the major influences of insulin in the storage of calories from glucose and ingested fat. Specifically, insulin stimulates lipogenesis in liver, fat cells, and other tissues (124, 125). An over abundance of insulin, by an exaggeration of its physiologic effect, increases hepatic synthesis of triglycerides and results in hypertriglyceridemia (36, 47, 1 1 8, 124, 126-131). The close association of hyperinsulinism with obesity, glucose intolerance, and familial hyperlipidemia makes it difficult to conclusively implicate a single etiology. Hypertniglyceridemia, itself, may cause insulin resistance that could lead to compensatory hypeninsulinism ( 132). However, hyperlipidemic

TRIGLYCERIDES

IN

CLINICAL

,

\\

_

MEDICINE

-

__%

_

1445

_

PLASMA

FIG. 3. The influence steps. The sites of insulin triglyceride rich particles,

of insulin in directing fat and glucose action are indicated by the star. Fatty enter liver and fat cells where they can

subjects treated with clofibrate do not show a significant change in basal insulin levels despite impressive decreases in lipid levels (133). Several observations made in our laboratories support the concept that glucose intolerance associated with delayed but excessive insulin levels result in hypertriglyceridemia. A group of young nonobese patients with coronary disease were found to have a high frequency of glucose, insulin, and lipid abnormalities (47). A significant correlation existed between the degree of hyperinsulinemia and serum triglycerides. No similar relationship was demonstrable between insulin and cholesterol. Phenformin, a drug known to decrease glucose and insulin levels, produced concomitant decreases in endogenous triglyceride levels (36). Patients with hypercholesterolemia and normal triglycerides were not affected nor could the observations be related to weight changes. Some studies suggest that insulin has no major role in triglyceride regulation. Heimberg et al. (134) reported that hepatic output of triglyceride from perfused rat livers was similar in insulin treated animals and controls. In acute human experiments a negative correlation between insulin levels and serum triglycerides was observed in a diurnal pat-

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toward storage acids, resulting be reconstituted

calories is reflected in numerous from lipoprotein lipase action on into triglycerides.

tern after sucrose feeding (135). When one tries to reconcile the various observations, it appears that insulin affects several variables which ultimately determine a given triglyceride level. Acutely, insulin lowers FFA making less substrate available for incorporation into serum triglycerides. Insulin also enhances triglyceride removal under some cmcumstances. Both of these actions decrease serum triglycerides. More chronically, insulin enhances lipogenesis, particularly in the presence of ample glucose, resulting in increased serum triglycerides. Thus, the sensitive balance between synthesis and removal of triglycerides is a dynamic phenomenon which can be influenced by many comcomitant events. Diabetes Abnormal triglyceride metabolism is prominent in the diabetic state. Hypentniglycendemia may have a greater impact on vascular disease in diabetic than in nondiabetic patients (47, 53, 136). Santen et al. (136) have reported that diabetic patients with atherosclerosis could be distinguished from those without atherosclerosis more reliably by triglyceride levels than by cholesterol levels. The diabetic might have normal, decreased, or increased total levels of insulin.

1446

TZAGOURNIS

Accordingly, the severity of the diabetic state influences the pathogenesis of hypertrigiyceridemia. In the insulin deficient diabetic, lipolysis is increased thereby releasing FFA into the blood stream. The liver, whether or not diabetes is present, can extract FFA in relative proportion to the plasma concentration (137). The FFA is esterified, and hepatic triglyceride synthesis occurs. Why then does the uncontrolled diabetic not consistently show elevated triglycerides? Most likely, FFA are diverted to other uses under different circumstances. FFA can be oxidized by tissues and utilized in the Knebs citric acid cycle. Partial oxidation of FFA to ketone bodies by the liver, or FFA incorporation into other lipids such as phospholipids, are other diversions from triglyceride synthesis by controlling availability of glycerolphosphate, the skeleton to which the fatty acids attach to form a triglyceride molecule. Those triglycerides formed from fatty acids are transported as VLDL to adipose tissue where they can again be taken up, stored, or hydrolyzed to FFA (Fig. 3). In the insulindeficient diabetic, clearing of triglycerides may be impaired (14). Although a removal defect exists in some diabetics, the impairment of lipoprotein lipases in severe diabetes is not universal (122). In the mild diabetic with ample on excessive insulin secretion, different circumstances are operative. The liver is exposed to high glucose and high insulin levels. This is the case even though a nondiabetic might secret even greater amounts of insulin than the diabetic in response to the elevated glucose level. The combination of elevated glucose and insulin levels favors hepatic lipogenesis from the products of glucose metabolism (124-131). The triglycerides are secreted into the blood as VLDL. Several investigators have demonstrated that insulin facilitates the lipid synthesis even in arterial tissue (138, 139). Obesity The obese state is quite versatile in that almost all of the mechanisms discussed above can apply. There is insulin resistance in obesity resulting in elevated insulin levels when the pancreas is capable of responding. Diabetes is more frequent in obese persons than

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in lean ones. Dietary excesses of all types are common in obesity. These recognized catalysts are likely to be responsible for the increased prevalence of hypertriglyceridemia in obesity (140, 141). Excesses of carbohydrate, fat, or protein calories are ultimately convertible to triglycerides as a matter of energy economy. While an individual is in negative caloric balance, serum triglycerides tend to decrease. Under certain circumstances FFA are released at an abnormally rapid rate resulting in increased hepatic triglyceride output (142, 143). In obesity, there is greater FFA turnover (142). In addition, hypertrophied adipose cells remove triglycerides relatively slowly, possibly because of diminished insulin responsiveness (144). Treatment

of hypertriglyceridemia

As with other chronic disorders, it is proper to consider the goals that may be achieved by therapy of hypertriglyceridemia. The symptomatic person with abdominal pains, eruptive xanthomata, or neuromuscular manifestations should be relieved rapidly of severe hypertrigiyceridemia. On the other hand, the long term goal of preventing vascular disease is controversial. There is little proof that thenapy will be of benefit in preventing or reversing atherosclerosis in patients with abnormal triglyceride levels (145). The prompt treatment of severe hypertrigiyceridemia is best accomplished by a short fast. Although mildly hypertriglyceridemic subjects show little or no response to fasting for 1 to 2 days (146), severely hyperlipemic patients usually respond dramatically (147). Abdominal pain due to severe hypertriglyceridemia may mimic other acute medical or surgical crises. Chylomicrons are almost invariably increased in such patients. Restriction of dietary intake for 1 to 2 days, and hydration with half normal saline or 5% dextrose water result m impressive decreases in serum triglycerides and hepatosplenomegaly. Chronic treatment of hypertriglyceridemia must be prudent. Dietary or drug therapy might have to be continued for many years. The thesis, however, is reasonable that lowering lipoproteins which carry endogenous triglycerides and cholesterol reduces the risk of atherosclerosis. Likewise, the long-term

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therapy of syndromes associated with exogenous hypertriglyceridemia is likely to result in fewer episodes of abdominal pain, eruptive xanthomata, and enlargement of neticuloendothelial containing tissues. The lack of definitive proof concerning hyperlipidemia and vascular disease should not serve as an excuse for poor control when good control can be achieved. It should be emphasized that no investigation to date has shown that hypentriglyceridemia as opposed to normo-glyceridemia is beneficial to the individual. Diet Whether or not drug therapy is used, a dietary program should be prescribed for anyone with a primary hyperlipidemia. Caloric restriction to achieve ideal body weight is successful in a number of patients. Endogenous hypertriglyceridemia, which is common in middle aged people, is quite responsive to weight loss. In hypertriglyceridemia characterized by increased chylomicrons (types I and V) it is necessary to restrict fat in the diet (5, 8, 147). In the type I patient fat intake should be restricted to about 15% of the total calories. The reduction in exogenous fat permits the defective clearing mechanism to maintain serum triglycerides at levels low enough to avoid abdominal pain, pancreatitis, and eruptive xanthomata. If body weight or growth cannot be maintained on such a diet, a formula containing medium chain triglycerides may be added to the diet (7, 148). Patients with type V disorders can usually take a more liberal amount of fat. Attention must also be given to total calories, sugar intake, and underlying diseases. Since a variety of factors contributes to elevated endogenous triglycerides, the effects of diet are not uniform. Types lIb, III, IV, and V hyperlipidemias have been considered to be carbohydrate sensitive (43, 96, 107). But this concept is an over simplification. Weight reduction most consistently decreases endogenous triglycerides. Some patients respond very well to a reduction of carbohydrate intake to about 30% of total calories (42, 102). Some investigators report little on no differences in lipid responses whether starches on simple sugars were the major carbohydrate source (1 12, 1 13, 147). Simple sugan restric-

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tion may result in significant decreases in endogenous triglycerides even without weight loss (36). Dietary sucrose intake is alarmingly high in many individuals, and its elimination leads to gratifying results (106, 149, 150). There are relatively few studies that deal with the long term effects of carbohydrate restriction on serum lipids (96, 149). Ethanol intake may greatly increase endogenous triglycerides in susceptible individuals (70-74). Elimination of alcohol should be recommended to patients who are not responding adequately to diet. Exercise is helpful in combination with diet to reduce lipids (15 1). When the cholesterol is also elevated, additional dietary suggestions must be made. Reduction of dietary cholesterol to 200 or 300 mg per day, and a change in the ratio of polyunsaturated to saturated fatty acids from the usual 0.2 to 2.0 or more is recommended. The diet is quite acceptable and palatable to most people. Drug

therapy

A variety ofdrugs is available for treatment for hyperlipidemic disorders. Only a relatively few have been widely used because of shortcomings in efficacy, acceptability, and safety. Clofibrate (Atromid-S) is presently the most widely used and effective agent in the treatment of endogenous hypertriglyceridemia. Ifdietary and other nonpharmacological measures fail to satisfactorily control types III and IV hyperlipidemic patients, this drug is most likely to produce a fall in lipids (152-154). Cholesterol and triglyceride levels may decrease in patients with types lIb and V disorders also. Krasno and Kidera (155) studied over 3000 men for up to 39 months and showed a decrease in nonfatal myocardial infarctions in those treated with clofibrate compared to non-treated controls. The “protection” existed whether or not a hypolipidemic response was noted implicating a drug action on platelets or other factors (155). These fmdings have not been adequately confirmed by other investigators. The main mechanism of action of clofibrate is associated with its inhibition of VLDL release (147, 154). The drug is also accompanied by increased clearance of triglycerides, inhibition of FFA release by adi-

1448

TZAGOURNIS

pose tissue, and mild suppression of cholesterol synthesis ( 1 54- 1 56). Clofibrate causes side effects ofnausea, abdominal distress, and muscle pains, but generally it is well tolerated. It potentiates the effects of coumadin and can produce abnormal liven function tests. The recommended dose is 0.5 g three or four times daily. Androgenic and progestational steroids have been used to reduce serum triglycerides. Sacks and Woliman (157) reported that oxandrolone reduced VLDL in patients, possibly by inhibiting excess triglyceride synthesis. Norethindrone acetate, a synthetic progestagen, was shown to be effective, particularly in women with type V hyperlipoproteinemia (158). The reduction in triglycerides was associated with a rise in postheparin lipolytic activity and enhanced triglyceride clearing. These agents occasionally give a satisfactory response but are generally weak and unpredictable hypolipidemic agents. Phenformin, an oral hypoglycemic agent, has mild hypolipidemic properties (36, 47, 159). Its major acti’n appears to be in decreasing glucose and insulin levels thereby reducing hepatic lipogenesis. Phenformin decreases endogenous triglycerides. It is associated with reduced lipolytic rates. The drug is no longer available in the United States and is of interest only from the point of view of the pathogenesis of some hypertriglyceridemias. Nicotinic acid lowers LDL and VLDL (5, 160). It reduces FFA by inhibiting lipolysis. Nicotinic acid decreases both cholesterol and triglyceride concentrations by limiting FFA substnate for triglycerides and reducing conversion of VLDL to LDL. The major disadvantage of this drug is the side effects associated with the 3 to 8 g per day dose. Flushing, headaches, peptic distress, liver toxicity, and decreased glucose tolerance are troublesome enough to discourage its use in hypertriglyceridemia. Pharmacological treatment of hyperlipidemia is usually chronic and, therefore, expensive. Side effects and drug interactions must be appreciated by the physician and the patient. Intermittent attempts to decrease or eliminate a drug is worthwhile. It emphasizes to the patient the physician’s belief that diet is the best long-term treatment for hyperlip-

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idemia. The prudent use of dietary and pharmacological treatments should be effective in relieving many of the clinical manifestations of hypertriglyceridemia. It is still unknown whether a beneficial effect also occurs in prevention of atherosclerosis. El References 1. SCHONFELD, G., S. W. WEIDMAN, J. L. WITZTUM AND R. M. BOwEN. Alterations in levels and interrelationships of plasma apolipoproteins induced by diet. Metabolism 25: 261, 1976. 2. REISER, R. Saturated fat in the diet and serum cholesterol concentration: a critical examination of the literature. Am. J. Chin. Nutr. 26: 524, 1973. 3. BRowN, J. C., AND J. R. DRYBURG. A gastric inhibitory polypeptide. II. The complete amino acid sequence. Canad. J. Biochem. 49: 867, 1971. 4. ISSELBACHER, K. J. Mechanisms of absorption of long and medium chain triglycerides. In: Medium Chain Triglycerides, edited by J. R. Senior. Philadelphia: University of Pennsylvania Press, 1968, chapt. 3, pp. 2 1-34. 5. FREDERICK5ON, D. S., AND R. L. LEVY. Familial hyperlipoproteinemia. In: The Metabolic Basis of Inherited Disease, (3rd. ed). edited by J. B. Stanbury, J. B. Wyngaarden and D. S. Frederickson. New York: McGraw-Hill Book Co., 1972, chapt. 28, pp. 545-5 12. 6. ZILVERSMIT, D. B. The surface coat of chylomicrons: lipid chemistry. J. Lipid Res. 9: 180, 1968. 7. GREENBERGER, N. J., AND T. G. SKILLMAN. Medium chain triglycerides. New Engl. J. Med. 280: 1045, 1969. 8. Scow, R. 0. Transport of triglyceride; its removal from blood circulation and uptake by tissues. In: Parental Nutrition, edited by H. C. Meng and D. H. Law. Springfield: Charles C Thomas, 1970, chapt. 24, pp. 294-339. 9. STEINER, G. Lipoprotein lipase in fat-induced hyperlipemia. New Engl. J. Med. 279: 70, 1968. 10. ROBINSON, D. S. The clearing factor lipase and its action in the transport of fatty acids between the blood and the tissues. Advan. Lipid Res. 1: 133, 1963. 1 1. MAJNO G. Ultrastructure of the vascular membrane. In: Handbook of Physiology; Circulation Section, edited by W. F. Hamilton, and P. Dow. Physiological Soc., Washington, 1965, chap. 64, vol. 3, 2293-2375. 12. LEVINE, R., AND D. E. Hotr. Carbohydrate homeostasis. New Engl. J. Med. 283: 237, 1970. 13. KORN, E. D. Clearing factor, heparin-activated lipoprotein lipase. I . Isolation and characterization of the enzyme from normal rat heart. J. Biol. Chem. 215: 1, 1955. 14. SCHNATZ, J. D., AND T. P. O’CONNOR. Studies on lipemia of diabetic acidosis. Diabetes 16: 534, 1967. 15. JONES, D. P., G. R. PLOTKIN AND R. A. ARKY. Lipoprotein lipase activity in patients with diabetes, with and without hyperlipemia. Diabetes 15: 565, 1966 16. PERRY, W. F. Heparin-activated lipase in diabetic,

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