207

Failure of the lymphatic system to transport lymph from the

interstitial space back to the bloodstream results in lymphatic
stasis. If the collateral lymphatic circulation is insufcient and
all compensatory mechanisms are exhausted, the protein-rich
interstitial uid accumulates and lymphedema develops. In
lymphedema, caused by either congenital or acquired dys-
function of the lymphatic system, the microcirculation in the
affected area of the body is disrupted. The transport of the
excess tissue uid containing lymphocytes, different plasma
proteins, immunoglobulins, and cytokines is impaired
and chronic inammatory changes in the subcutaneous tis-
sue and skin develop. Progress in ultrastructural, cytochemi-
cal, and imaging studies and improvement in conservative
and surgical treatment of lymphedema have stimulated
substantial interest in lymphatic disease.
Historical background
Lymph vessels were mentioned more than 2000 years ago by
Aristotle, who described nerves which contain colorless
liquids and later by members of the Alexandrian School of
Medicine, who recognized arteries in the mesentery full of
milk. This knowledge, however, was lost during the Middle
Ages, and it was only in the Renaissance that attention was fo-
cused again on the lymphatic system. The thoracic duct was
observed in 1563 by Eustachius, who called it vena alba
thoracis. He failed, however, to recognize the function of the
thoracic duct and its relation to the lymphatic system. The
discovery of the lymphatics is attributed to the Italian
anatomist Gasparo Aselli, who in 1622 observed the mesen-
teric lymphatics in a well-fed dog. He also recognized the
function of the lacteals, although he suggested mistakenly that
the chyle absorbed from the intestine by the mesenteric lym-
phatics was transported to the liver. In 1651, Pecquet described
the thoracic duct and recognized the correct route of lym-
phatic transport from the mesenteric lymphatics through the
receptaculum chyli and the thoracic duct to the subclavian
vein. Further details on the anatomy of the lymphatic system
were published in the 17th century by Bartholin and Rudbeck,
and by the great anatomists of the 18th century, Mascagni and
Cruikshank. It was most likely William Hunter who recog-
nized the lymphatics as a separate system responsible for
absorption.
Although Hunter suggested that the lymphatics were
closed tubes, one of his students, Hewson, recognized that
they had physiologic orices, which, like capillary tubes
sucked up tissue uid. It was not until the turn of the 20th
century, however, that Starling conrmed the relationship
between the oncotic pressure of the plasma proteins and the
hydrostatic pressure in the capillaries.
1,2
Starling suggested
that lymph formed by ltration of the blood through the capil-
lary walls. Drinker,
3
and later Rusznyk and colleagues,
4
de-
serve the credit for clarifying the details of protein absorption
from the intercellular space via the lymphatic system. Interest
in lymphatic diseases was greatly enhanced by Kinmonth,
who described a clinically usable technique of direct contrast
lymphangiography in 1952.
5
Improvement in other imaging
techniques, such as lymphoscintigraphy,
6,7
indirect lymphan-
giography,
8,9
and magnetic resonance imaging,
1012
furthered
the understanding of the structure and function of the lym-
phatic system in different lymphatic disorders. Progress in
conservative management
13,14
and development of micro-
surgical operations on the lymph vessels
1517
also have stimu-
lated experimental and clinical research in lymphatic diseases.
Development of the lymphatic system
The lymphatic system is rst apparent in the human fetus at 6
weeks of gestation, and it consists of paired jugular, iliac, and
retroperitoneal lymph sacs (Fig. 18.1).
18
The origin of the lym-
phatic system is controversial, but it is most likely a derivative
from the venous system. Another possible theory is that it
develops independently of the veins from the mesenchymal
tissue. The lymph vessels grow from the paired primitive
lymphatic sacs and coalesce along the major veins to form the
afferent vessels, nodes, and efferent lymphatic ducts. The
Physiologic changes in lymphatic
dysfunction
Peter Gloviczki
18
Vascular Surgery: Basic Science and Clinical Correlations, Second Edition
Edited by Rodney A. White, Larry H. Hollier
Copyright 2005 Blackwell Publishing
cisterna chyli develops from one of the large retroperitoneal
lymph sacs, whereas the other forms the mesenteric lymphat-
ic system. There are paired thoracic ducts in the embryo, and
the mature thoracic duct develops from fusion of the upper
portion of the left and the lower portion of the right thoracic
duct. The right cervical lymphatic duct is formed by the right
jugular lymphatic sac. This receives lymph from the right face,
neck, and the right upper extremity, and from the upper part of
the right thorax and mediastinum. Abnormalities in the devel-
opment of the lymphatic system include agenesis, hypoplasia,
or hyperplasia of the lymphatics with valvular incompetence.
They may result in lymphedema or in abnormalities in the
circulation of the chyle, such as chylous ascites, chylothorax,
reux of chyle to the pelvis or lower extremities, or protein-
losing enteropathy. Persistence of some of the embryonic
sacs may cause the development of lymphatic cysts, which
may or may not communicate with the lymphatic system.
Anatomy of the lymphatic system
The adult lymphatic system consists of peripheral lymph ves-
sel, lymph nodes, and major lymphatic trunks. The peripheral
lymph vessels collect lymph from the lymphatic capillaries,
which absorb a portion of the interstitial uid from the inter-
stitial space. Afferent lymph channels transport lymph to the
lymph-conducting elements of the lymph nodes, which lter
and further conduct the lymph uid to efferent lymphatic
channels. Signicant communications between the lymphatic
and venous system in lymph nodes normally do not exist.
Eighty percent of the lower extremity lymph is carried by
the supercial lymphatic system. Although there is a lateral
supercial bundle located around the lesser saphenous vein,
most of the lower extremity lymph is transported by lymph
channels of the supercial medial bundle (Fig. 18.2). There is a
deep lymphatic network that runs in close proximity to the
tibial and peroneal vessels and transports lymph through
the popliteal lymph nodes into the deep femoral lymphatics.
The supercial and the deep lymphatics join in the inguinal
lymph nodes and drain lymph toward the aortoiliac lym-
phatic system. The cisterna chyli is located between the aorta
and the inferior vena cava, usually at the level of L1 to L2.
Mesenteric lymphatics join the lower extremity and pelvic
lymphatics at this level and drain through the thoracic duct to
the left subclavian vein (Fig. 18.3). A very small amount of
mesenteric lymph is drained toward the liver around the he-
patic vein and the diaphragm to the mediastinal lymphatics.
The upper extremity lymphatics run along the major veins
of the arm. Although the medial arm bundle is the most signif-
icant route of lymph drainage in normal patients, after axillary
node dissection lymph is drained primarily through the
lateral lymphatic bundle to the deltoideopectoral and supra-
clavicular nodes (Fig. 18.4).
Asingle layer of endothelial cells forms the inner layer of the
lymphatic capillaries. Basal membranes similar to blood capil-
laries are not present. The lymphatic capillaries contain
bicuspid lymphatic valves, which play a crucial role in the
initial lymphatic transport and are responsible for the unidi-
rectional lymphatic ow. The capillaries are anchored by small
microbrils that expand the endothelial cells and increase the
lumen of the capillaries if the tissue pressure is elevated.
19,20
Although smaller molecules may traverse the lymphatic
PART I Vascular pathology and physiology
208
A
B C
Figure 18.1 Development of the lymphatic system. (A) Seven-week embryo
with paired iliac, retroperitoneal, and jugular lymph sacs. (B) At 9 weeks of
gestation, paired thoracic ducts are present with numerous connections
across the midline. (C) Portions of both primitive thoracic ducts persist to
form the thoracic duct in the adult. The right lymphatic duct is formed from
the primitive right jugular lymphatic sac. (From Cambria RA, Gloviczki P.
Lymphedema: pathophysiology and management. In: Callow AD, ed.
Vascular Surgery. Norwalk, CT: Appleton & Lange, 1995:1593.)
CHAPTER 18 Physiologic changes in lymphatic dysfunction
209
endothelial cells with active phagocytosis, large molecules
enter through the gaps between the endothelial cells of the
lymphatic capillary.
Lymphatic physiology
According to Starlings law, hydrostatic and osmotic pressures
in the capillaries and in the interstitial space determine the
amount of interstitial uid that is ultraltered from the blood
plasma. Additional factors responsible for interstitial uid
exchange include capillary permeability, the number of active
capillaries, the ratio of precapillary arteriolar to postcapillary
venular resistance, and the total extracellular uid volume.
The amount of uid that moves across the capillary wall is
tremendous, considering that the cardiac output is about
8000 l during a 24-h period. It is likely that an amount equal to
the total plasma volume enters the interstitial place and leaves
through the venous end of the capillaries and the lymphatics
every minute.
21
The lymphatic system is responsible for the
transport of 24 l of interstitial uid daily. During the same
time, approximately 100g of plasma protein is carried back to
the circulation by the lymphatics.
22
The protein content of the
lymph is somewhat less than that of the plasma, and lymph
vessels from various parts of the body contain different
amounts of protein (Table 18.1). The lymphatic capillaries are
able to transport large molecules, even those with a molecular
weight over 1kDa.
23
Figure 18.2 Anatomy of major lymph vessels and lymph nodes of the lower
extremity. (From Gloviczki P. Microsurgical treatment for chronic
lymphedema: an unfullled promise? In: Bergan JJ, Yao JST, eds.
Venous Disorders. Philadelphia: WB Saunders, 1990:344.)
Figure 18.3 Anatomy of the thoracic duct.
(From Gloviczki P, Noel AA. Lymphatic
reconstructions. In: Rutherford RB, ed. Vascular
Surgery, 5th edn. Philadelphia: WB Saunders,
2000:2159, with permission from Elsevier.)
The single most important determinant of lymph ow
through the lymphatic capillaries and the collecting lymph
vessels is the intrinsic contractility of the lymph vessels. In
addition, lymph ow in inuenced by increased interstitial
pressure, muscular activity, arterial pulsation, respiratory
pressure, and gravity. Increase in interstitial volume and inter-
stitial pressure results in opening of the gaps between the
endothelial cells of the terminal lymphatics and an increase in
lymphatic transport. Because the endothelial cells contain
actin and are able to contract actively, contraction of terminal
lymphatics with the help of competent valves enables rapid
lymphatic transport. Intrinsic contractility of the smooth
muscle in larger collecting vessels allows further propulsion of
the lymph. Strength and frequency of the contractions are
greatly inuenced by changes in intraluminal pressure.
24
Adrenergic stimulation
25
and endothelin
26
also have been
shown to result in contraction of the lymph vessels. Patent
blue dye injected into the subcutaneous tissue is transported
centrally in the lymph vessels at the rate of 45mm/s, even
without any muscular exercise. Intrinsic contractions of the
lymph vessel wall with competent valves are able to propel
lymph intermittently against a pressure as high as 50mmHg.
The major difference that distinguishes the lymphatic sys-
tem from the venous system is that the veins are lled with a
continuous liquid column. The lymphatic system, however, is
not fully primed, and only if there is longstanding stasis
does the lymph column ll the lymphatic channels complete-
ly.
23
It is only in these conditions that muscular contraction or
external massage play an important role in forward propul-
sion of the lymph and facilitate lymphatic transport.
Pathophysiology of lymphedema
Lymphedema develops when the lymphatic load exceeds the
transport capacity of the lymphatic system. In patients with
lymphatic obstruction, numerous compensatory mechanisms
develop. These include collateral lymphatic circulation, de-
velopment of spontaneous lymphovenous anastomoses, and
increased activity of tissue macrophages to split macro-
molecules in the interstitial space, enabling them to be reab-
sorbed through the venous end of the capillaries (Fig. 18.5).
If the lymphatic transport is impaired due to injury or ob-
struction to the lymph vessels and lymph nodes, the different
compensatory mechanisms can function effectively for a
period of time. This explains why chronic lymphedema of the
limbs may develop several months or even years after an
edema-free state after inguinal or axillary node dissection or
irradiation.
Lymphedema is a high-protein edema that, except very
early in the course of the disease, is nonpitting in nature (Fig.
18.6). Without treatment, the high-protein edema uid in the
subcutaneous tissue will be replaced by brous material, in-
ammatory cells accumulate, and progressive brosis of the
subcutaneous tissue and skin develops. Fibrosis of the lymph
vessels leads to loss of permeability and loss of intrinsic con-
tractility. Dilation of the lymph vessels causes valvular incom-
petence, and the inammatory and brotic changes destroy
the valve leaets, further decreasing the transport capacity of
the lymphatic system. Microsurgical reconstruction in this
late stage of lymphedema, using brotic and incompetent
lymphatics, cannot restore normal lymphatic transport.
Progression of lymphedema results in brotic obstruction of
PART I Vascular pathology and physiology
210
Table 18.1 Approxiamte protein content of lymph in humans*
Lymph origin Protein content (g/dl)
Ankle 0.5
Limbs 2
Intestine 4
Liver 6
Thoracic duct 4
*Data based on various studies in humans and animals.
(From Ganong WF. Review of Medical Physiology, 10th edn. Los
Altos, CA: Lange Medical Publications, 1981: 452.)
Figure 18.4 Anatomy of major lymph vessels and lymph nodes of the upper
extremity. (From Gloviczki P. Microsurgical treatment for chronic
lymphedema: an unfullled promise? In: Bergan JJ, Yao JST, eds.
Venous Disorders. Philadelphia: WB Saunders, 1990:344.)
Figure 18.5 Stages in development of
postsurgical lymphedema. (Modied from
Gloviczki P, Schirger A. Lymphedema. In: Spittell
JA, ed. Clinical Medicine. Philadelphia: Harper &
Row, 1985:1.)
Figure 18.6 Chronic secondary lymphedema of the left lower extremity in a 47-year-old
man after iliac node dissection, followed by irradiation.
the lymph nodes and the major lymph vessels. Even the larger
lymphatic collaterals, which functioned effectively in the ini-
tial period after lymphatic obstruction, may occlude with
time. In this stage, dilated dermal lymphatics provide the only
lymphatic drainage of the extremity. Using noninvasive func-
tional tests, such as radionuclide lymphoscintigraphy per-
formed with technetium-labeled antimony sulfur colloid, it is
possible to repeat the studies in the same patient and docu-
ment progression of the disease (Fig. 18.7).
Lymphatic stasis also results in deciency of important im-
munoglobulins, cytokines, and plasma proteins. Because of
chronic inammatory changes in the subcutaneous tissue and
the skin, there frequently is increased vascularity in the lym-
phedematous limb, and inammatory cells accumulate. The
affected limb has an increased sensitivity to fungal and bacter-
ial infections. Obstructive lymphangitis further destroys the
lymphatic system and results in progression of the lymphede-
ma. In long-standing, neglected lymphedema, irreversible
sclerosis of the subcutaneous tissue and skin develops. Lym-
phangiosarcoma, which is a severe late complication of
secondary lymphedema, fortunately is rare.
Pathophysiology of chylous disorders
Disorders in the circulation of chyle usually are caused by lym-
phangiectasia or megalymphatics, with or without obstruc-
tion of the thoracic duct (Fig. 18.8).
27,28
Because of valvular
incompetence, chyle in these patients may reux to the pelvis
or lower extremities, causing chylorrhea from small vesicles in
the skin of the limb, scrotum, or labia (Fig. 18.9). Reux to the
kidney may lead to chyluria, whereas transudation through or
rupture of abdominal lymphatics results in chylous ascites.
Rupture of the lymphatics into the lumen of the gut causes
protein-losing enteropathy, and chylothorax develops if the
PART I Vascular pathology and physiology
212
A
B
Figure 18.7 Lymphoscintigram in a 44-year-old woman with secondary
lymphedema of the right lower extremity. (A) Note absence of right iliac
nodes and the presence of right inguinal nodes and collaterals. (B) Note
deterioration of lymphatic drainage 10 months later. There is no lling of the
right inguinal nodes or collaterals. The patient had a recent episode of
lymphangitis.
Figure 18.8 Contrast lymphangiogram in an 18-year-old man with
lymphangiectasia, protein-losing enteropathy, and chylous ascites
demonstrates dilated and tortuous thoracic duct.
thoracic duct or mediastinal, intercostal, or diaphragmatic
lymphatics rupture.
Secondary chyloperitoneum or chylothorax is caused most
frequently by malignant tumors, primarily lymphoma, or by
injury to the thoracic duct. The latter usually is iatrogenic, oc-
curring during operations on the thoracoabdominal aorta
2931
or, rarely, after a high translumbar aortography.
32
Chyle is a sterile alkaline uid, odorless, and milky in ap-
pearance. Its protein content is around 4g/dl and the fat con-
tent ranges from 0.4 to 4g/dl. The fat stains with Sudan stain
and this test conrms the diagnosis of chyle in the peritoneal or
thoracic aspirate. The specic gravity of chylous uid is
greater than 1012g/dl.
Loss of chyle into the body cavities or through chylocuta-
neous stulas has important physiologic consequences. If not
treated, it leads to malnutrition, hypoproteinemia, hypo-
cholesterolemia, hypocalcemia, immunodeciency, and se-
vere metabolic disturbances.
27,28
Lymphopenia and anemia
contribute to the poor immune function in these patients.
Chylous effusion in a patient with malignancy usually
CHAPTER 18 Physiologic changes in lymphatic dysfunction
213
A
B
Figure 18.9 (A) Chyle draining through small
vesicles of the skin at the left groin of a 16-year-
old girl with lymphangiectasia and severe reux
of the chyle. (B) Intraoperative photograph of
dilated, incompetent iliac lymphatics
containing chyle.
carries an ominous prognosis. The outcome of patients with
primary chylous disorders and reux of the chyle depends on
the effectiveness of medical treatment. To compensate for the
physiologic changes caused by the loss of chyle, treatment is
directed at decreasing production of the chyle with a medium-
chain triglyceride diet, or by parenteral nutrition. In addition
to adequate calorie and protein replacement, calcium, lost in
chyle, also should be replaced. Reux can be controlled effec-
tively with radical excision and ligation of the retroperitoneal
lymphatics in most cases. In patients with chylous effusion,
the site of lymphatic rupture should be oversewn if medical
treatment, paracentesis, or thoracentesis are ineffective. In
some patients with protein-losing enteropathy, the most dis-
eased segment of the small bowel may have to be resected to
decrease loss of chyle into the gastrointestinal tract.
27,28
Trans-
plantation of small bowel for severe mesenteric lymphangiec-
tasia remains a task of the future, and it requires, as do many
other aspects of lymphatic disorders, further clinical research.
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