Download Skin Manifestations in Primary Biliary Cirrhosis: with Emphasis on

ࣧ൴ّᓙϗ៭᎕ّքർ̼̝ϩቲܑᇈ ;
඾ࢦ‫ٺ‬เҒሳܑ̝ன
ę 21 ּঽּࡁտ ę
໅Ԡฯ Ѧछ༉ *
ਆ௽ᗁੰϩቲࡊ
઼ϲέ៉̂ጯ‫ܢ‬నᗁੰϩቲొ *
Skin Manifestations in Primary Biliary Cirrhosis:
with Emphasis on Xanthomas
— A Study of 21 Cases —
Chih-Hsiung Yang
Chia-Yu Chu*
We herein retrospectively analyze the cutaneous manifestations of 21 cases with primary biliary
cirrhosis (PBC) during the past 12 years in our hospital. Among them, the most common skin manifestations of PBC is pruritus ( 61.9 % ), followed by jaundice ( 52.4 % ), xanthomas and xanthelasmas
(33.3%), hyperpigmentation (14.3%), and lichen planus (4.8%). We also described three cases presenting as several types of xanthomas due to secondary hypercholesterolemia and hyperlipidemia in
PBC. The relationship between lipoprotein disturbances and different types of xanthomas was identified. Types of xanthomas are valuable diagnostic markers of the underlying lipid and lipoprotein disturbances. In these patients, despite conventional dietary, drug, and plasmapheresis therapies, there
was no improvement in the size and number of the xanthomas. Liver transplantation for decompensated chronic liver disease resulted in complete resolution of xanthomas in all our cases. It is a drastic but
successful remedy for complications of abnormal lipid metabolism associated with primary biliary cirrhosis.(Dermatol Sinica 21 : 304-316, 2003)
Key words: Xanthoma, Primary biliary cirrhosis, Liver transplantation
ԧࣇдѩаᜪ࿅Ν 12 ѐֽώੰ෧ᕝࠎࣧ൴ّᓙϗ៭᎕ّքർ̼۞ 21 ּঽּ̝ϩቲܑ
னĂ‫ͽ̚׎‬ສᚧ ( 61.9 % ) ౵૱֍Ă‫׎‬Ѩ̶Ҿߏเ৅ ( 52.4 % )ăเҒሳᄃீᖁเ೹ሳ
( 33.3 % )ăҒ৵࿅‫ޘ‬Օ඾া ( 14.3 % )ă޴πࡾᜌ ( 4.8 % )ĄТॡ˵дѩಡӘˬ࣎ࣧ൴ّᓙϗ៭
᎕ّքർ̼‫׀‬кᇹّเҒሳ۞ܑனĂᖣѩᗃ୻ѩᙷঽˠ਌కϨ΃ᔁள૱ᄃЧ‫ݭ‬เҒሳ۞ᙯ
From the Department of Dermatology, Cardinal Tien Hospital and National Taiwan University Hospital*
Accepted for publication: March 12, 2003
Reprint requests: Chia- Yu Chu, M. D., Department of Dermatology, National Taiwan University Hospital, No 7, Chung-Shan South
Road, Taipei, Taiwan, R.O.C.
TEL: 886-2-23562141 FAX: 886-2-23934177
304
ࣧ൴ّᓙϗ៭᎕ّքർ̼̝ϩቲܑᇈ;඾ࢦ‫ٺ‬เҒሳܑ̝ன
ܼćซֹ҃เҒሳјࠎ෧ᕝѩᙷঽଈ਌ኳள૱۞ӀጡĄϡ฼ࢴଠ‫ט‬ăᘽ‫̈́ۏ‬ҕ୵౅‫ژ‬Ă࠰̙
ਕԼච‫̈́̈̂׎‬ᇴϫć઱ѣք᝙ொങߏၔ‫غ‬ͷјΑ۞‫ڼ‬ᒚ͞‫ڱ‬Ą( ̚රϩᄫ 21 : 304 - 316,
2003 )
INTRODUCTION
Primary biliary cirrhosis (PBC) is a chronic, idiopathic, progressive, cholestatic liver disease that usually affects middle - aged women
and eventually leads to liver failure. 1, 2 The
course of the disease usually extends over a
period of 10 years or more. The early stage of
PBC is typically insidious and marked by pruritus and fatigue. Subsequently, increasing pigmentation of the skin, jaundice, and steatorrhea
are seen. Protraction of the cholestasis leads to
decompensated hepatocellular disease and is
manifested by hemorrhage, pathologic fractures
due to osteoporosis, ascites, hepatic encephalopathy, and the formation of cutaneous xanthomas. Patients with PBC can develop xanthomas due to secondary hypercholesterolemia
and hyperlipidemia.1, 2 Here we reviewed the
skin manifestations of 21 patients with PBC
diagnosed in recent 12 years and described 3
cases who had marked hyperlipidemia and several types of extensive xanthomatosis. The relationship between lipoprotein disturbances and
different types of xanthomas was found.
Despite multiple aggressive management, only
liver transplantation could result in maintaining
a sustained lipid lowering effect and resolution
of xanthomatosis.
extrahepatic bile ducts by endoscopic retrograde cholangiography or operative cholangiography.2-4 Pathological staging was performed
according to Scheuer’s classification.5 None of
the patients had clinical evidence of coronary
artery disease. The clinical courses and laboratory data of the three patients (case 1, 2, and 3)
were regularly followed at our Dermatological
Clinic. For the other cases, we reviewed and
analyzed their medical records, and then telephoned them for checking the clinically relevant events.
MATERIALS AND METHODS
We retrospectively reviewed the medical
records of all patients diagnosed as PBC in the
National Taiwan University Hospital between
January 1991 and December 2002. Totally, 21
patients were diagnosed as PBC under the following criteria: a Alkaline phosphatase ( ALP )
more than 1.5 times the upper limit of normal,
b the presence of anti-mitochondrial antibody
in the serum, c a compatible histologic appearance of a liver biopsy specimen, and d normal
RESULTS
The study group consisted of 21 patients
( 5 males and 16 females, 23.8 % and 76.2 %
respectively ) with varying severity of PBC
recruited from the gastroenterological clinics of
our hospital. The age ranged from 37 to 78
years old and the mean is 51.6. The clinical
course had been variable. The brief clinical
manifestations, lipid profiles and physical findings were summarized in Table I. The most
common skin manifestations of PBC is pruritus
Dermatol Sinica, December 2003
STATISTICAL ANALYSIS AND RESULTS
The 21 patients were divided into two
groups to study the relationship between the
presentation of xanthomas and the clinical
backgrounds. Group 1 was patients with clinical
evident xanthomas ( xanthelasma alone was
excluded), while the group 2 was patients without xanthomas. The clinical backgrounds
including sex ratio, age, serum immunoglobulin
M ( IgM) level, pathological staging of the liver
biopsy and the plasma cholesterol level were
recorded. All the variables were compared with
the use of Fisher’s exact test or Wilcoxon rank
sums test ( SAS software, SAS Institute, Cary,
N.C.).
305
໅Ԡฯ
Table I. Summary of the clinical backgrounds of the 21 cases of PBC
No. Sex Age Follow-up
Xnthomas
period since
diagnosis
1# F
49 5y
+
2#
3#
F
F
43
37
3y8m
3y2m
+
+
4
F
5ŕ F
43
55
1y
16ys
+
+
6
F
73
2y9m
-
7
8
9
10
M
F
F
F
48
36
47
57
4m
2y1m
1y9m
9y
-
11
12
M
M
38
56
2y3m
3y1m
-
13
14
F
M
51
42
6y7m
4y10m
-
15
M
40
4y6m
-
16# F
78
11y4m
-
17
F
68
3y6m
-
18
F
48
5y7m
-
19 F
20# F
52
62
7y
10y
-
21ŕ F
61
9y5m
-
Xanthelasma IgM ANA Liver CHO
TG
Clinical
biopsy level
level
manifestations
stage
+
+
III
316-1503 240-812 P*, J, LP, F, BWL,
Poor appetite,
Steatorrhea
+
+
III
515-1100 215-538 J*, P, RUQ pain, F
+
+
+
III
610-1088 164-291 F*, J, P, BWL,
Poor appetite,
Dry eye
+
+
II
536-1040 211-406 J*,, P, F
+
+
III
432-745 148-232 P*,J, RUQ pain,
Poor appetite,
BWL
+
I
237-325 72-146 F*, BWL, Poor
appetite
II
399-438 208-297 P*, J
+
I
191-440 74-223 F*
+
+
I
216-231
F*, Pale stools
+
II
130-255 65-103 F*, Poor appetite,
BWL
II
190-262 124-166 Steatorrhea*, F
+
II
295-427, 122-161 P*, F
474
+
+
II
227-397 105-234 P*, F
+
II
217-422, 72-282, P*, F
458
314
+
II
249-417 147-378 P*, J, F,
Hyperpigmentation
+
III
140-273 63-106 P*, J, F, Poor
appetite, Dry eye,
BWL, EV
+
+
IV
172-211 92-114 BWL, F, Poor
appetite, Dry eye,
EV
+
+
+
IV
265-297 153-271 P*, J, F,
Hyperpigmentation,
Dry eye, EV
I
183-210 68-126 Hyperpigmentation
+
+
IV
196-257 41-190 P*, J, BWL, Poor
appetite
+
+
IV
152-352 69-181 J*, BWL, F, EV,
Hepatic
encephalopathy
# Patient had received liver transplantation
ŕ Current status: Dead
* = First symptom
Antibodies and IgM at the time of diagnosis (ANA: antinuclear antibodies)
Liver biopsy stage:
I: chronic non-suppurative destructive cholangitis;
II: portal inflammation with ductular proliferation;
III: fibrosis
IV: cirrhosis
CHO: cholesterol, TG: triglycerides
P:pruritus, J: jaundice, LP: lichen planus
BWL: body weight loss, F: fatigue, RUQ: right upper quadrant EV: esophageal varices
306
Dermatol Sinica, December 2003
ࣧ൴ّᓙϗ៭᎕ّքർ̼̝ϩቲܑᇈ;඾ࢦ‫ٺ‬เҒሳܑ̝ன
Table II Summary of the statistical results of 21 cases
Variables
Sex ratio-M : F
Age
Mean
Range
IgM
CHO (>450 mg/dL
for more than 3
months)
Early PBC
(I,II)
Advanced PBC
(III/IV)
NS = Not significant
Group 1(case 1-5)
(N = 5)
0:5
Group 2 (case 6-21)
(N = 16)
5:11
45.4 ± 6.8
37-55
5
5
53.6 ± 12.4
36-78
9
0
0.098 (NS)
0.000491
1
11
0.08
4
5
( 13 cases, 61.9 % ), followed by jaundice ( 11
cases, 52.4 % ), xanthomas or xanthelasmas ( 7
cases, 33.3 % ), hyperpigmentation ( 3 cases,
14.3 % ), and lichen planus ( 1 case, 4.8 % ). In
10 patients, generalized pruritus is the first
symptoms (47.6%) and jaundice in 3 (14.3%).
These two cardinal symptoms coexist in 10
patients (47.6%). In 7 cases with xanthomas or
xatholasmas, three cases developed both xanthomas and xantholasmas, two cases only had
xanthomas, and two cases had xanthelasmas
alone. As compared with the group 2 (16 cases)
with no xanthomas, the group 1 (5 cases) with
xanthomas had a statistically significant relationship with the total cholesterol level exceeding 450 mg / dL for more than 3 months (0% vs
100 %, p = 0.000491 ). Comparing the group 1
and group 2 patients including the sex ratio, age
distribution, IgM level, and pathological staging
of the liver biopsy, patients with more advanced
PBC ( III, IV ) had a higher risk in developing
xanthomas. ( Odds ratio = 8.8 [ 95 % confidence
interval 0.77 ~ 100.26 ] ) ( Table II ). The plasma
cholesterol levels were elevated in patients with
all stages of PBC, except 2 patients ( case 17
and 19 ). The positive antinuclear antibody
(ANA) and elevated IgM levels were noted in
57% and 67% of the patients respectively, but
there was no evidence that patients with elevated serum levels of these antibodies had a higher
Dermatol Sinica, December 2003
P value
0.215 (NS)
0.2309 (NS)
frequency of histological or biochemical features suggestive of chronic active hepatitis. The
clinical xanthoma type, clinical presentation,
the lipoprotein disturbances and histories of the
five cases are described and summarized in
Table III. Patients 1-3 developed widespread
xanthomas 7 months to 12 months after the initial presentation symptoms or signs of PBC.
Xanthomas and xanthelasmas, if concurrently
developed, appeared at about the same time.
The appearance and disappearance of the various xanthomata in the presenting patients were
closely correlated with the level of lipid profile
( Table III ). Five of our patients underwent
orthotopic liver transplantation for advanced
PBC.
CASE REPORT
Case 1
A 49-year-old woman admitted in
December 1997 had had generalized pruritus,
jaundice, fatigue and body weight loss for 10
months. At that time, liver function tests
revealed total bilirubin 19.4 mg / dL ( normal
0.2 - 1.2 ), direct bilirubin 15.0 mg / dL ( normal
0 - 0.4 ), AST 96 U / L ( normal 5 - 31 ), ALT 64
U / L (normal 0-31), and ALP 1088 U / L (normal 64-238). Serology tests to hepatitis viruses
B, C and D were all negative. The ANA was
positive with a titer of 1 : 1280 ( speckled type)
307
໅Ԡฯ
Table III. Summary of the clinical xanthoma types, the clinical presentations and the lipoprotein disturbances in our cases.
Sex/Age
Stage at
diagnosis
Xanthoms
Case 1
F/49
III
Onset from the 7 months
time of PBC s/s
(Pre-xanthomatous stage)
Location
Trunk, limbs,
palms
Case 2
F/43
III
Case 3
F/37
III
Case 4
F/43
II
Case 5
F/55
III
8 months
12 months
6 months
10 months
Face, palms,
Finger creases,
plantar, forearms, palms elbows,
elbows,
soles, ears,
buttocks
Face, palms
Palms,soles
IIa ,IIb
V
V
IIa
Represented
phenotype
V, IIb
Clinical types
of xanthomas
Eruptive,
Tuberous
Tuberous,
Tendinous
Tuberoeruptive (
LDL)
Planar, Tendinous Xanthelasma
Tuberous
Planar
Xanthelasma
Tuberoeruptive
Planar
Xanthelasma
Tuberous
Symptoms
itching
itching
Pain interfering
sleep,
affecting fine
motor activity
itching
itching
+/+/+
+/+/-
+/+/-
+/+/-
-/-/-/-/-
+/+
-/-
+/+
-/-
+/+
+/+
+
+
+
-
-
12 months
3 months
2 months
(Except xanthelasma)
Medical treatments
Diet/ drugs/
+/+/+
plamapheresis
Response
to the treatments
Lipid profiles -/-/Xanthomas
-/-/Liver
transplantation
Duration of
complete
regression
after
transplantation
and the antimitochondrial antibody was also
positive (1 : 20). The serum IgM level was 405
mg / dL (normal 160.57±72.21). The liver biopsy showed the findings consistent with PBC. On
308
the basis of the above findings, PBC was diagnosed.
In January 1998, numerous pinhead - to
ricegrain - sized yellowish papules with some-
Dermatol Sinica, December 2003
ࣧ൴ّᓙϗ៭᎕ّքർ̼̝ϩቲܑᇈ;඾ࢦ‫ٺ‬เҒሳܑ̝ன
1A
1B
Fig. 1A
Tuberoeruptive xanthomas on the calf of case 1.
Fig. 1B
Planar xanthomas of case 1, shown here on the palms. Unlike palmar crease xanthomas, they are well-demarcated plaques that extend beyond the palmar creases.
what reddish hue were noted on the whole body.
At that time, the cholesterol and triglycerides
( TG ) levels were 317 mg / dL ( normal 130 220 ) and 812 mg / dL ( normal 130 - 220 ),
respectively. Eruptive xanthomas were diagnosed. The skin lesions resolved gradually in
the following 2 months with change of the lipid
profile to cholsterol 562 mg / dL and TG 359
mg / dL. In July 1998, she developed several
pea - to bean - sized, itching, violaceous polygonal patches and plaques scattered over the trunk
and limbs without affecting the oral and genital
mucosae. A skin biopsy from a lesion on the
left thigh showed a diagnosis of lichen planus
Dermatol Sinica, December 2003
( LP ) with xanthomatous changes. 6 About 1
month later, a gradual onset of generalized
tuberoeruptive xanthomas on the patient’s trunk
and extremities (Fig. 1A) as well as planar xanthomas mimicking palmar crease xanthomas
( Fig. 1B ) over the palms were noted. Most of
the earliest xanthoma lesionsdeveloped on the
preceding LP lesion sites. At that time, the lipid
profile of the patient was total cholesterol 648
mg / dL, high - density lipoprotein ( HDL ) 26
mg / dL ( normal > 35 ), low - density lipoprotein
( LDL ) 369 mg / dL ( normal < 150 ), very - low density lipoprotein ( VLDL ) 253 mg / dL ( normal < 40 ) and TG 538 mg / dL. A low - fat diet
309
໅Ԡฯ
Fig. 1C
Resolution of xanthomas of case 1, 1 year after liver transplantation.
and simvastatin were administered in addition
to cholestyramine and ursodiol to treat her PBC
with secondary hyperlipidemia and xanthomas.
Her cholesterol level still progressively
increased with persistent development of new
xanthoma lesions in the following 6 months.
There were various types of xanthomas including tuberoeruptive, tuberous, planar xanthomas
mimicking palmar crease xanthomas and tendinous xanthomas. She underwent plasmapheresis
for three times during January 1999 and there
was no improvement in either the cholesterol,
LDL and TG levels or in the size and number of
the xanthomas. She received an orthotopic liver
transplantation in March 1999 and the postoperative course was relatively uneventful.
Seven months after the transplantation, her
serum bilirubin was 0.4 mg / dL, AST 15 U / L ,
ALT 10 U / L, cholesterol 222 mg / dL, TG 284
mg / dL. The lipoprotein levels were also nearly
normal. The xanthomas improved quickly after
the transplantation and was completely resolved
310
within 12 months (Fig. 1C).
Case 2
A 43-year-old woman had been well until
5 years previously when she had generalized
pruritus and fatigue followed by slight anorexia
and mild jaundice in January 1998. In conjunction with the clinical and serological evidences
including a positive antimitochondrial antibody
( 1 : 20 ), serum IgM 609.0 mg / dL and ALP
2350 U / L, a liver biopsy in April 1999 confirmed the diagnosis of PBC (Stage III).
In September 1998, multiple pea-to beansized, red - yellow papules and nodules developed on her face, palms, forearms, elbows, and
feet. Xanthelasmas and tuberous xanthomas
were diagnosed (Fig. 2A). A skin biopsy from a
lesion on the right palm revealed a circumscribed tumor in the dermis composed of nests
of foamy histiocytes. The lipid profile indicated
the total cholesterol 752 mg / dL, TG 215
mg / dL, HDL 22 mg / dL, and LDL 687 mg / dL.
Dermatol Sinica, December 2003
ࣧ൴ّᓙϗ៭᎕ّքർ̼̝ϩቲܑᇈ;඾ࢦ‫ٺ‬เҒሳܑ̝ன
2A
2B
Fig. 2A
Tuberous xanthomas (case 2) may develop de novo or result from aggregation of several tuberoeruptive xanthomas.
Fig. 2B
Tendinous xanthomas of case 2 are shown here that affect her Achilles tendons.
About 6 months later, a gradual onset of tendinous xanthomas affecting her Achilles tendons
was noted (Fig. 2B). At that time,the lipid profile of the patient was total cholesterol 946
mg / dL, TG 405 mg / dL, HDL 25 mg / dL, LDL
840 mg / dL. There was no objective improvement in either the levels of cholesterol and TG
or in the size of the xanthomas, though ursodiol
and cholestyramine were administered. She had
ever undergone plasmapheresis for three times
in July 2000, but the xanthomas persisted. She
received an orthotopic liver transplantation in
August 2000, and recovered rapidly. After the
surgery, the liver function tests normalized, and
Dermatol Sinica, December 2003
the lipid profile checked 3 months after transplantation showed the cholesterol 215 mg / dL,
TG 165 mg / dL. The lipoprotein levels were
also nearly normal. The number and size of
xanthomas decreased quickly after the transplantation and all the xanthomas completely
resolved within 3 months after the surgery.
Case 3
A 37-year-old woman with established
PBC (stage III) of 3 years' duration had presented initially generalized malaise, jaundice and
tea - colored urine in December 1998. Multiple
pea - to bean - sized, itching, painful, yellowish
311
໅Ԡฯ
A
B
Fig. 3
The infiltrate of upper dermis consisted mainly of foamy histiocytes and a few inflammatory cells,left thumb.
(A) (H & E, X 100), (B) (H & E,X 400).
nodules were noted initially on the bilateral finger creases in January 2000. The painful and
itching lesions spread to the palms, soles, ears,
elbows and buttocks as well as progressed in
size over the ensuing 6 months. Fine motor
activity of her hands was affected and the plantar nodules were painful even without pressure
leading to interference of sleep. A skin biopsy
from a lesion on the left thumb revealed a bandlike foamy histiocyte aggregation mixed with
lymphocytes in the upper dermis ( Fig. 3 ). Oil
red and Sudan III stains both showed positive
staining. Planar xanthomas mimicking palmar
crease xanthomas and tuberoeruptive xanthomas were diagnosed. At that time, the lipid
profile of the patient indicated the total cholesterol 1088 mg / dL, HDL 43 mg / dL, LDL 610
mg / dL, and TG 404 mg / dL. She also had
bilateral xanthelasmas ( Fig. 4 ). She received a
low-cholesterol, low-fat diet as well as ursodiol and cholestyramine.
After 2 years of therapy, the plasma cholesterol level decreased from 1088 to 404
mg / dL, and the plasma TG level from 178 to
112 mg / dL. She had some symptomatic
improvement in the discomfort of her hands and
feet. There was no objective decrease in the size
of the xanthomas. She underwent an orthotopic
liver transplantation in August 2002. Two
months after the transplantation, her serum
312
Fig. 4
Xanthelasmas on the periorbital areas of case 3.
Dermatol Sinica, December 2003
ࣧ൴ّᓙϗ៭᎕ّքർ̼̝ϩቲܑᇈ;඾ࢦ‫ٺ‬เҒሳܑ̝ன
bilirubin was 0.9 mg / dL, AST 26 U / L , ALT
17 U / L, cholesterol 192 mg / dL, TG 122
mg / dL.The lipoprotein levels were also nearly
normal.The xanthomas improved quickly after
the transplantation and completely resolved
within 2 months except the xanthelasma
lesions.
DISCUSSION
The onset of PBC typically occurs
between the age of 30 and 65, and 90% of the
patients were women. 1 In our series of 21
patients, the average age is 51.6 years old. 76%
of our patients were women. Gradual onset of
pruritus followed by jaundice is by far the most
frequent presentation. Reviewing the literature,
the common cutaneous manifestations of PBC
in the order of frequency are pruritus, jaundice,
hyperpigmentation, xanthomas, and rarely
lichen planus.2 Our study of 21 patients also
showed a similar clinical skin presentations
except hyperpigmentation and xanthomas,
which showed more cases of developing xanthomas than those of developing hyperpigmentation in our series. Fatigue is noted in up to 78
% of patients.7 Seventeen of our patients presented with fatigue (81%).
PBC is a chronic, cholestatic liver disease,
hallmarked by progressive, inflammatory
destruction of the intrahepatic bile ducts.
Current evidences suggests that the tissue injury
observed may be related to an autoimmune
pathogenesis.1, 2, 8 Plasma levels of cholesterol,
TG, and phospholipids are often elevated in
patients with PBC.4 Therefore, patients with
PBC can develop several types of xanthomas
due to secondary hypercholesterolemia and
hyperlipidemia. The liver is the major site of
lipoprotein synthesis, and the hepatic LDL
receptors removes 70 % of the LDL from the
plasma. 9, 10 The serum free - cholesterol also
increases due to a decreased hepatic synthesis
of lecithin:cholesterol acyltransferase, which is
the major intravascular cholesterol esterifying
factor in plasma.4 The cholesterol elevations are
often accompanied by increases in LDL and
decreases in HDL concentrations.9, 10
Dermatol Sinica, December 2003
The plasma cholesterol levels are elevated
in at least half of the PBC patients and may
exceed 1000 mg / dL in PBC patients with xanthomas.1, 7 Four of our patients with xanthomas
had the cholesterol levels exceeding 1000
mg / dL. A standardized assessment on 85
patients with PBC within 1 year of developing
symptoms revealed 22 % of the patients had
cutaneous xanthomas.11 In our series, 23.8% of
the patients developed xanthomas within one
year after diagnosing PBC.
Many types of xanthomas appear in longstanding hypercholesterolemia: if the plasma
cholesterol levels are greater than 450 mg / dL
for more than 3 months, such lesions invariably
ensued.12 Patients 12 and 14 have had the total
cholesterol level as high as 450-480 mg / dL for
two months. It seems that the period of time
during which they had cholesterol exceeding
450 mg / dL was short, which may explain the
failure of developing xanthomas. Spontaneous
regression of generalized tuberous xanthomas,
coincident with a sustained decrease of the plasma cholesterol levels below 450 mg / dL with a
good response to the diet and drug therapies
was observed in patient 5. Under these conditions, almost complete resolution of the xanthomas occurred within 2 years in patient 5.
The duration of elevation of the serum lipids is
an important factor. Xanthomas are composed
almost exclusively of foam cells, which are
believed to represent the tissue macrophages
that have phagocytosed the lipid components of
lipoproteins deposited in tissues. Xanthomas are
now considered to be reactive lesions to altered
lipid metabolism. Recent evidence has demonstrated transport of serum lipoproteins through
endothelial membranes and then phagocytosed
by the foam cells. These lipoproteins are then
degraded to lipids and stored in vacuoles. 13
Capillary microleakage of lipoproteins
enhanced by tissue trauma and subsequent
phagocytosis by the dermal histiocytes could
lead to the formation of xanthomas in patients
with hyperlipidemia.14 Thus areas subjected to
stress, friction or injury, particularly the extensor surfaces, buttocks, tendons, and skin creases
313
໅Ԡฯ
have a predilection for xanthoma formation.14
Xanthoma has been classified into eruptive,
tuberoeruptive, tuberous, tendinous, or planar
xanthomas on the basis of clinical morphology,
anatomic distribution, and the mode of development.14 The development of xanthomas in areas
previously affected by erythroderma15 or chronic inflammatory skin diseases16 further supports
that local tissue factors might play a role in the
formation of xanthomas. In case 1, Chu et al.
also hypothesize that the damage to basal keratinocytes in LP lesions accompanied by systemic hypercholesterolemia could lead to the
development of xanthomas in LP lesions.6
The correlations of clinical xanthoma
types and the lipid profile are discussed and the
lipoprotein component that accumulates in tissues is the critical determinants of the types of
xanthomas.14 It will provide a causal explanation for the specific relationship between
lipoprotein disturbances, lipid profile and types
of xanthomas. Types of xanthomas are valuable
diagnostic markers of the underlying lipid and
lipoprotein disturbances for dermatologists.14, 17
Eruptive xanthomas are a sign of chylomicronemia and elevated plasma level of VLDL.
Tendinous xanthomas are seen almost always
exclusively in disorders characterized by elevated plasma levels of LDL or altered forms of
LDL. Tuberoeruptive xanthomas develop as a
result of deposition of chylomicron remnants,
VLDL, VLDL remnants, or components of
these lipoproteins in tissues ( thus elevated TG
and cholesterol ), whereas xanthomas at the
tuberous end of the spectrum are the result of
accumulation of LDL, VLDL remnants, or their
components. Planar xanthomas are also characteristic of disorders that cause hepatic cholestasis, such as PBC and biliary atresia.14 In these
conditions, free cholesterol cannot be excreted
properly into the bile and is instead regurgitated
into plasma, where free cholesterol binds with
albumin and phospholipid to form an abnormal
lipoprotein called lipoprotein X. Infiltration of
the lipoprotein X or its components into the dermis and subcutaneous tissue is probably responsible for the development of planar xan-
314
thomas.14 On the palms they can be differentiated from the palmar crease xanthomas by their
plaque appearance (rather than a diffuse macular discoloration), extension beyond the creases,
and evolution in a grayish or dusky hue.14
In our described 3 cases, all of them had
tuberoeruptive, tuberous, and planar xanthomas
that were related to the elevated plasma cholesterol level ( LDL ) or concurrent elevation of
cholesterol and TG ( LDL, VLDL ). However,
case 1 showed an episode of eruptive xanthomas during January to March 1998. At that
time, her lipid profile revealed TG 812 mg / dL
and cholesterol 317 mg / dL, which was compatible with the previous report that patients with
early histlogic stages of PBC presented with
mildly elevated VLDLs and LDLs, marked elevation of HDLs and TG.4 In contrast, patients
with advanced disease had marked elevation in
cholesterol and LDLs with the presence of
lipoprotein-X, and a significant decrease in
HDLs.4
Severe hypercholesterolemia associated
with chronic intractable cholestasis presents a
difficult management problems. 18 Recently,
ursodiol treatment ( 13 to 15 mg / kg ) has been
reported to achieve both a symptomatic
improvement and an " improvement " in serum
biochemical markers in patients with clinically
overt PBC. 7 Although the mechanism of the
protracted pruritus is not entirely clear,
cholestyramine, an oral bile salt - sequestering
resin, may be helpful in a dosage of 8 to 12 g / d
to improve both pruritus and the hypercholesterolemia.7 Cholesterol may also be lowered by
reducing dietary fat or increasing dietary
polyunsaturated fatty acid.7 Short-term plasmapheresis has been demonstrated to have a beneficial effect on hyperlipidemia and pruritus in
patients with PBC.7, 19-22 In patients with chronic
cholestasis who undergo successful liver transplantation, the cholestatic syndrome is no
longer present and the cholesterol and apoprotein synthesis could be normalized.7 In the presenting case 3, though diet and drug therapy
lowered the levels of cholesterol and TG, the
size of the xanthomas did not decrease.
Dermatol Sinica, December 2003
ࣧ൴ّᓙϗ៭᎕ّքർ̼̝ϩቲܑᇈ;඾ࢦ‫ٺ‬เҒሳܑ̝ன
Plasmapheresis has successfully decreased the
number and size of xanthomas in some but not
all patients with PBC.19-22 In the presenting cases
receiving plasmapheresis ( case 1 and case 2 ),
however, there was no decrease in the size of
xanthomas although large amounts of cholesterol were being removed temporarily during
the procedure.
The natural history of PBC is usually progressive over many years.1 The disease course
in the 3 discribed cases of our patients progressed inevitably and at the time of liver transplantation, they all had an end-staged liver disease associated with ascites and portal hypertension with variceal bleeding. They all tolerated liver transplantation well and their plasma
lipid levels normalized after the operation. The
most impressive thing was the speed with
which xanthomas resolved after liver transplantation: 2 months to 12 months later.
In a patient with PBC, if complications of
the xanthomas are making the quality of life
intolerable and cannot be ameliorated by conventional therapeutic approaches, liver transplantation would be the best treatment.7, 23 In
patients with advanced PBC who undergo liver
transplantation for other indications, it can be
expected that this procedure will normalize the
serum lipid abnormalities and lead to the resolution of xanthomas.
ACKNOWLEDGMENTS
The statistical analysis of the study was
performed by Miss Mei-Ping Tseng, MSc.
REFERENCES
1. Sherlock S, Sheuer PJ: The presentation and
diagnosis of 100 patients with primary biliary cirrhosis. N Engl J Med 289: 674-678,
1973.
2. Heathcote J: The clinical expression of primary biliary cirrhosis. Semin Liver Dis 17:
23-33, 1997.
3. Longo M, Crosignani A, Battezzati PM, et
al.: Hyperlipidemic state and cardiovascular
risk in primary biliary cirrhosis. Gut 51:
265-269, 2002.
Dermatol Sinica, December 2003
4. Jahn CE, Schaefer EJ, Taam LA, et al.:
Lipoprotein abnormalities in primary biliary
cirrhosis. Association with hepatic lipase
inhibition as well as altered cholesterol
esterification. Gastroenterology 89: 12661278, 1985.
5. Biliary disease and cholestasis. In: Scheuer
PJ. Liver biopsy interpretation. 3rd ed.
London : Bailliere Tindall, 36-59, 1980.
6. Chu CY, Yang CY, Huang SF, et al.: Lichen
planus with xanthomatous change in a
patient with primary biliary cirrhosis. Br J
Dermatol 142: 377-378, 2000.
7. Kaplan MM: Primary biliary cirrhosis. N
Engl J Med 335: 1570-1580, 1996.
8. Reed JR, De Luca N, McIntyre AS, et al.:
Localized morphea, xanthomatosis and primary biliary cirrhosis. Br J Dermatol 143:
652-653, 2000.
9. Brown MS, Anderson RGW, Goldstein JL:
Recycling receptors: the round-trip itinerary
of migrant membrane proteins. Cell 32:
663-667, 1983.
10. Brown MS, Goldstein JL: A receptor-mediated pathway for cholesterol hemostasis.
Science 232: 34-37, 1986.
11. Crowe J, Christensen E, Doniach D, et al.:
Early features of primary biliary cirrhosis:
analysis of 85 patients. Am J Gastroenterol
80: 466-468, 1985.
12. Sherlock S: Disease of live and biliary system. London: Lippincott Co, 214-250, 1975.
13. Walton KW, Thomas C, Dunkerley DJ: The
pathogenesis of xanthomata. J Am Acad
Dermatol 109: 271-289, 1973.
14. Cruz PD, East C, Bergstresser PR: Dermal,
subcutaneous, and tendon xanthomas: diagnostic markers for specific lipoprotein disorders. J Am Acad Dermatol 19: 95-111,
1988.
15. Walker AE, Sneddon IB: Skin xanthoma
following erythroderma . Br J Dermatol 80:
580-587, 1968
16. Cooper TW, Santa Cruz DJ, Bauer
EA:Verruciform xanthoma. J Am Acad
Dermatol 8: 463-467, 1983.
17. Parker F: Xanthomas and hyperlipidemias. J
315
໅Ԡฯ
Am Acad Dermatol 13: 1-30, 1985.
18. Bloom JR, Ghent CN: Management of the
intractable cholestasis of primary biliary cirrhosis. Semin Liver Dis 1: 345-353, 1981.
19. Turnberg LA, Mahoney MP, Gleeson MH,
et al.: Plasmaphoresis and plasma exchange
in the treatment of hyperlipidemia and xanthomatous neuropathy in patients with primary biliary cirrhosis. Gut 13: 976-981,
1972.
20. Keeling PWN, Bull J, Kingston P, et al.:
Plasma exchange in primary biliary cirrhosis. Postgrad Med J 57: 433-435, 1981.
316
21. Cohen LB, Ambinder EP, Wolke AM, et al.:
Role of plasmapheresis in primary biliary
cirrhosis. Gut 26: 291-294, 1985.
22. Ambinder EP, Cohen LB, Wolke AM, et al.:
The clinical effectiveness and safty of
chronic plasmapheresis in patients with primary biliary cirrhosis. J Clin Apheresis 2:
219-223, 1985.
23. Peters MG, Hoofnagle JH, McGarvey C, et
al.: Primary biliary cirrhosis: management
of unusual case with severe xanthomata by
liver transplantation. J Clin Gastroenterol
11: 694-697, 1989.
Dermatol Sinica, December 2003