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We herein retrospectively analyze the cutaneous manifestations of 21 cases with primary biliarycirrhosis (PBC) during the past 12 years in our hospital. Among them, the most common skin mani-festations 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 pre-senting as several types of xanthomas due to secondary hypercholesterolemia and hyperlipidemia inPBC. The relationship between lipoprotein disturbances and different types of xanthomas was identi-fied. Types of xanthomas are valuable diagnostic markers of the underlying lipid and lipoprotein dis-turbances. In these patients, despite conventional dietary, drug, and plasmapheresis therapies, therewas no improvement in the size and number of the xanthomas. Liver transplantation for decompensat-ed chronic liver disease resulted in complete resolution of xanthomas in all our cases. It is a drastic butsuccessful remedy for complications of abnormal lipid metabolism associated with primary biliary cir-rhosis.(Dermatol Sinica 21 : 304-316, 2003)

Key words: Xanthoma, Primary biliary cirrhosis, Liver transplantation

12 21

( 61.9 % ) ( 52.4 % )

(33.3%) (14.3%) (4.8%)

21

*

*

Skin Manifestations in Primary Biliary Cirrhosis:with Emphasis on Xanthomas

—A Study of 21 Cases—

Chih-Hsiung Yang Chia-Yu Chu*

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 SouthRoad, Taipei, Taiwan, R.O.C. TEL: 886-2-23562141 FAX: 886-2-23934177

Dermatol Sinica, December 2003 305

( 21 : 304 - 316,

2003)

INTRODUCTIONPrimary biliary cirrhosis (PBC) is a chron-

ic, idiopathic, progressive, cholestatic liver dis-ease that usually affects middle -aged womenand eventually leads to liver failure.1, 2 Thecourse of the disease usually extends over aperiod of 10 years or more. The early stage ofPBC is typically insidious and marked by pruri-tus and fatigue. Subsequently, increasing pig-mentation of the skin, jaundice, and steatorrheaare seen. Protraction of the cholestasis leads todecompensated hepatocellular disease and ismanifested by hemorrhage, pathologic fracturesdue to osteoporosis, ascites, hepatic encephalo-pathy, and the formation of cutaneous xan-thomas. Patients with PBC can develop xan-thomas due to secondary hypercholesterolemiaand hyperlipidemia.1, 2 Here we reviewed theskin manifestations of 21 patients with PBCdiagnosed in recent 12 years and described 3cases who had marked hyperlipidemia and sev-eral types of extensive xanthomatosis. The rela-tionship between lipoprotein disturbances anddifferent types of xanthomas was found.Despite multiple aggressive management, onlyliver transplantation could result in maintaininga sustained lipid lowering effect and resolutionof xanthomatosis.

MATERIALS AND METHODSWe retrospectively reviewed the medical

records of all patients diagnosed as PBC in theNational Taiwan University Hospital betweenJanuary 1991 and December 2002. Totally, 21patients were diagnosed as PBC under the fol-lowing criteria: aAlkaline phosphatase (ALP)more than 1.5 times the upper limit of normal,b the presence of anti-mitochondrial antibodyin the serum, c a compatible histologic appear-ance of a liver biopsy specimen, and dnormal

extrahepatic bile ducts by endoscopic retro-grade cholangiography or operative cholangiog-raphy.2-4 Pathological staging was performedaccording to Scheuer’s classification.5 None ofthe patients had clinical evidence of coronaryartery disease. The clinical courses and labora-tory data of the three patients (case 1, 2, and 3)were regularly followed at our DermatologicalClinic. For the other cases, we reviewed andanalyzed their medical records, and then tele-phoned them for checking the clinically rele-vant events.

STATISTICAL ANALYSIS AND RESULTS The 21 patients were divided into two

groups to study the relationship between thepresentation of xanthomas and the clinicalbackgrounds. Group 1 was patients with clinicalevident xanthomas ( xanthelasma alone wasexcluded), while the group 2 was patients with-out xanthomas. The clinical backgroundsincluding sex ratio, age, serum immunoglobulinM (IgM) level, pathological staging of the liverbiopsy and the plasma cholesterol level wererecorded. All the variables were compared withthe use of Fisher’s exact test or Wilcoxon ranksums test (SAS software, SAS Institute, Cary,N.C.).

RESULTS The study group consisted of 21 patients

( 5 males and 16 females, 23.8 % and 76.2 %respectively ) with varying severity of PBCrecruited from the gastroenterological clinics ofour hospital. The age ranged from 37 to 78years old and the mean is 51.6. The clinicalcourse had been variable. The brief clinicalmanifestations, lipid profiles and physical find-ings were summarized in Table I. The mostcommon skin manifestations of PBC is pruritus

306 Dermatol Sinica, December 2003

Table I. Summary of the clinical backgrounds of the 21 cases of PBCNo. Sex Age Follow-up Xnthomas Xanthelasma IgM ANA Liver CHO TG Clinical

period since biopsy level level manifestationsdiagnosis stage

1# F 49 5y + - + + III 316-1503 240-812 P*, J, LP, F, BWL,Poor appetite, Steatorrhea

2# F 43 3y8m + + + - III 515-1100 215-538 J*, P, RUQ pain, F3# F 37 3y2m + + + + III 610-1088 164-291 F*, J, P, BWL,

Poor appetite,Dry eye

4 F 43 1y + + + - II 536-1040 211-406 J*,, P, F5 F 55 16ys + - + + III 432-745 148-232 P*,J, RUQ pain,

Poor appetite, BWL

6 F 73 2y9m - - - + I 237-325 72-146 F*, BWL, Poor appetite

7 M 48 4m - - - - II 399-438 208-297 P*, J8 F 36 2y1m - - + - I 191-440 74-223 F*9 F 47 1y9m - - + + I 216-231 F*, Pale stools10 F 57 9y - - + - II 130-255 65-103 F*, Poor appetite,

BWL11 M 38 2y3m - - - - II 190-262 124-166 Steatorrhea*, F12 M 56 3y1m - - - + II 295-427, 122-161 P*, F

47413 F 51 6y7m - - + + II 227-397 105-234 P*, F14 M 42 4y10m - - + - II 217-422, 72-282, P*, F

458 31415 M 40 4y6m - + - - II 249-417 147-378 P*, J, F,

Hyperpigmentation16# F 78 11y4m - - - + III 140-273 63-106 P*, J, F, Poor

appetite, Dry eye,BWL, EV

17 F 68 3y6m - - + + IV 172-211 92-114 BWL, F, Poorappetite, Dry eye, EV

18 F 48 5y7m - + + + IV 265-297 153-271 P*, J, F,Hyperpigmentation,Dry eye, EV

19 F 52 7y - - - - I 183-210 68-126 Hyperpigmentation20# F 62 10y - - + + IV 196-257 41-190 P*, J, BWL, Poor

appetite21 F 61 9y5m - - + + IV 152-352 69-181 J*, BWL, F, EV,

Hepaticencephalopathy

# Patient had received liver transplantationCurrent status: Dead

* = First symptomAntibodies 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: fibrosisIV: cirrhosisCHO: cholesterol, TG: triglyceridesP:pruritus, J: jaundice, LP: lichen planusBWL: body weight loss, F: fatigue, RUQ: right upper quadrant EV: esophageal varices

Dermatol Sinica, December 2003 307

(13 cases, 61.9%), followed by jaundice (11cases, 52.4%), xanthomas or xanthelasmas (7cases, 33.3 % ), hyperpigmentation ( 3 cases,14.3%), and lichen planus (1 case, 4.8%). In10 patients, generalized pruritus is the firstsymptoms (47.6%) and jaundice in 3 (14.3%).These two cardinal symptoms coexist in 10patients (47.6%). In 7 cases with xanthomas orxatholasmas, three cases developed both xan-thomas and xantholasmas, two cases only hadxanthomas, and two cases had xanthelasmasalone. As compared with the group 2 (16 cases)with no xanthomas, the group 1 (5 cases) withxanthomas had a statistically significant rela-tionship with the total cholesterol level exceed-ing 450 mg / dL for more than 3 months (0% vs100%, p=0.000491). Comparing the group 1and group 2 patients including the sex ratio, agedistribution, IgM level, and pathological stagingof the liver biopsy, patients with more advancedPBC (III, IV) had a higher risk in developingxanthomas. (Odds ratio = 8.8 [95% confidenceinterval 0.77~ 100.26] ) (Table II ). The plasmacholesterol levels were elevated in patients withall stages of PBC, except 2 patients ( case 17and 19 ). The positive antinuclear antibody(ANA) and elevated IgM levels were noted in57% and 67% of the patients respectively, butthere was no evidence that patients with elevat-ed serum levels of these antibodies had a higher

frequency of histological or biochemical fea-tures suggestive of chronic active hepatitis. Theclinical xanthoma type, clinical presentation,the lipoprotein disturbances and histories of thefive cases are described and summarized inTable III. Patients 1-3 developed widespreadxanthomas 7 months to 12 months after the ini-tial presentation symptoms or signs of PBC.Xanthomas and xanthelasmas, if concurrentlydeveloped, appeared at about the same time.The appearance and disappearance of the vari-ous xanthomata in the presenting patients wereclosely correlated with the level of lipid profile( Table III ). Five of our patients underwentorthotopic liver transplantation for advancedPBC.

CASE REPORT Case 1

A 49-year-old woman admitted inDecember 1997 had had generalized pruritus,jaundice, fatigue and body weight loss for 10months. At that time, liver function testsrevealed total bilirubin 19.4 mg / dL ( normal0.2-1.2), direct bilirubin 15.0 mg / dL (normal0-0.4), AST 96 U / L (normal 5-31), ALT 64U / L (normal 0-31), and ALP 1088 U / L (nor-mal 64-238). Serology tests to hepatitis virusesB, C and D were all negative. The ANA waspositive with a titer of 1 : 1280 (speckled type)

Table II Summary of the statistical results of 21 casesVariables Group 1(case 1-5) Group 2 (case 6-21) P value

(N = 5) (N = 16)Sex ratio-M : F 0:5 5:11 0.215 (NS)Age

Mean 45.4 ± 6.8 53.6 ± 12.4 0.2309 (NS)Range 37-55 36-78

IgM 5 9 0.098 (NS)CHO (>450 mg/dL 5 0 0.000491for more than 3months)Early PBC 1 11 0.08(I,II)Advanced PBC 4 5(III/IV)

NS = Not significant

308 Dermatol Sinica, December 2003

and the antimitochondrial antibody was alsopositive (1 : 20). The serum IgM level was 405mg / dL (normal 160.57±72.21). The liver biop-sy showed the findings consistent with PBC. On

the basis of the above findings, PBC was diag-nosed.

In January 1998, numerous pinhead - toricegrain -sized yellowish papules with some-

Table III. Summary of the clinical xanthoma types, the clinical presentations and the lipoprotein dis-turbances in our cases.

Case 1 Case 2 Case 3 Case 4 Case 5Sex/Age F/49 F/43 F/37 F/43 F/55 Stage at III III III II IIIdiagnosisXanthoms

Onset from the 7 months 8 months 12 months 6 months 10 monthstime of PBC s/s (Pre-xanthomatous stage)Location Trunk, limbs, Face, palms, Finger creases, Face, palms Palms,soles

palms plantar, forearms, palms elbows, elbows, soles, ears,

buttocks

Represented V, IIb IIa ,IIb V V IIa phenotype

Clinical types Eruptive, Tuberous Tuberous Tuberoeruptive Tuberousof xanthomas Tuberous, Tendinous Planar Planar

Tuberoeruptive ( LDL) Xanthelasma Xanthelasma Planar, Tendinous Xanthelasma

Symptoms itching itching Pain interfering itching itchingsleep,affecting finemotor activity

Medical treatments Diet/ drugs/ +/+/+ +/+/+ +/+/- +/+/- +/+/- plamapheresis

Response to the treatments

Lipid profiles -/-/- -/-/- +/+ +/+ +/+ Xanthomas -/-/- -/-/- -/- -/- +/+

Liver + + + - -transplantation

Duration ofcomplete regression 12 months 3 months 2 months after (Except xanthelasma) transplantation

Dermatol Sinica, December 2003 309

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 diag-nosed. The skin lesions resolved gradually inthe following 2 months with change of the lipidprofile to cholsterol 562 mg / dL and TG 359mg / dL. In July 1998, she developed severalpea- to bean-sized, itching, violaceous polygo-nal patches and plaques scattered over the trunkand limbs without affecting the oral and genitalmucosae. A skin biopsy from a lesion on theleft thigh showed a diagnosis of lichen planus

( LP ) with xanthomatous changes.6 About 1month later, a gradual onset of generalizedtuberoeruptive xanthomas on the patient’s trunkand extremities (Fig. 1A) as well as planar xan-thomas mimicking palmar crease xanthomas(Fig. 1B) over the palms were noted. Most ofthe earliest xanthoma lesionsdeveloped on thepreceding LP lesion sites. At that time, the lipidprofile of the patient was total cholesterol 648mg / dL, high - density lipoprotein ( HDL ) 26mg / dL (normal > 35), low-density lipoprotein(LDL) 369 mg / dL (normal < 150), very- low-density lipoprotein (VLDL) 253 mg / dL (nor-mal < 40) and TG 538 mg / dL. A low-fat diet

Fig. 1ATuberoeruptive xanthomas on the calf of case 1. Fig. 1BPlanar xanthomas of case 1, shown here on the palms. Unlike palmar crease xanthomas, they are well-demar-cated plaques that extend beyond the palmar creases.

1A 1B

310 Dermatol Sinica, December 2003

and simvastatin were administered in additionto cholestyramine and ursodiol to treat her PBCwith secondary hyperlipidemia and xanthomas.Her cholesterol level still progressivelyincreased with persistent development of newxanthoma lesions in the following 6 months.There were various types of xanthomas includ-ing tuberoeruptive, tuberous, planar xanthomasmimicking palmar crease xanthomas and tendi-nous xanthomas. She underwent plasmapheresisfor three times during January 1999 and therewas no improvement in either the cholesterol,LDL and TG levels or in the size and number ofthe xanthomas. She received an orthotopic livertransplantation in March 1999 and the postoper-ative course was relatively uneventful.

Seven months after the transplantation, herserum bilirubin was 0.4 mg / dL, AST 15 U / L ,ALT 10 U / L, cholesterol 222 mg / dL, TG 284mg / dL. The lipoprotein levels were also nearlynormal. The xanthomas improved quickly afterthe transplantation and was completely resolved

within 12 months (Fig. 1C).

Case 2 A 43-year-old woman had been well until

5 years previously when she had generalizedpruritus and fatigue followed by slight anorexiaand mild jaundice in January 1998. In conjunc-tion with the clinical and serological evidencesincluding a positive antimitochondrial antibody( 1 : 20 ), serum IgM 609.0 mg / dL and ALP2350 U / L, a liver biopsy in April 1999 con-firmed the diagnosis of PBC (Stage III).

In September 1998, multiple pea- to bean-sized, red-yellow papules and nodules devel-oped on her face, palms, forearms, elbows, andfeet. Xanthelasmas and tuberous xanthomaswere diagnosed (Fig. 2A). A skin biopsy from alesion on the right palm revealed a circum-scribed tumor in the dermis composed of nestsof foamy histiocytes. The lipid profile indicatedthe total cholesterol 752 mg / dL, TG 215mg / dL, HDL 22 mg / dL, and LDL 687 mg / dL.

Fig. 1CResolution of xanthomas of case 1, 1 year after liver transplantation.

Dermatol Sinica, December 2003 311

About 6 months later, a gradual onset of tendi-nous xanthomas affecting her Achilles tendonswas noted (Fig. 2B). At that time,the lipid pro-file of the patient was total cholesterol 946mg / dL, TG 405 mg / dL, HDL 25 mg / dL, LDL840 mg / dL. There was no objective improve-ment in either the levels of cholesterol and TGor in the size of the xanthomas, though ursodioland cholestyramine were administered. She hadever undergone plasmapheresis for three timesin July 2000, but the xanthomas persisted. Shereceived an orthotopic liver transplantation inAugust 2000, and recovered rapidly. After thesurgery, the liver function tests normalized, and

the lipid profile checked 3 months after trans-plantation showed the cholesterol 215 mg / dL,TG 165 mg / dL. The lipoprotein levels werealso nearly normal. The number and size ofxanthomas decreased quickly after the trans-plantation and all the xanthomas completelyresolved within 3 months after the surgery.

Case 3A 37-year-old woman with established

PBC (stage III) of 3 years' duration had present-ed initially generalized malaise, jaundice andtea-colored urine in December 1998. Multiplepea- to bean-sized, itching, painful, yellowish

Fig. 2ATuberous xanthomas (case 2) may develop de novo or result from aggregation of several tuberoeruptive xan-thomas. Fig. 2BTendinous xanthomas of case 2 are shown here that affect her Achilles tendons.

2A 2B

312 Dermatol Sinica, December 2003

nodules were noted initially on the bilateral fin-ger creases in January 2000. The painful anditching lesions spread to the palms, soles, ears,elbows and buttocks as well as progressed insize over the ensuing 6 months. Fine motoractivity of her hands was affected and the plan-tar nodules were painful even without pressureleading to interference of sleep. A skin biopsyfrom a lesion on the left thumb revealed a band-like foamy histiocyte aggregation mixed withlymphocytes in the upper dermis (Fig. 3). Oilred and Sudan III stains both showed positivestaining. Planar xanthomas mimicking palmarcrease xanthomas and tuberoeruptive xan-thomas were diagnosed. At that time, the lipidprofile of the patient indicated the total choles-terol 1088 mg / dL, HDL 43 mg / dL, LDL 610mg / dL, and TG 404 mg / dL. She also hadbilateral xanthelasmas (Fig. 4). She received alow-cholesterol, low-fat diet as well as ursodi-ol and cholestyramine.

After 2 years of therapy, the plasma cho-lesterol level decreased from 1088 to 404mg / dL, and the plasma TG level from 178 to112 mg / dL. She had some symptomaticimprovement in the discomfort of her hands andfeet. There was no objective decrease in the sizeof the xanthomas. She underwent an orthotopicliver transplantation in August 2002. Twomonths after the transplantation, her serum

Fig. 3The 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).

A B

Fig. 4Xanthelasmas on the periorbital areas of case 3.

Dermatol Sinica, December 2003 313

bilirubin was 0.9 mg / dL, AST 26 U / L , ALT17 U / L, cholesterol 192 mg / dL, TG 122mg / dL.The lipoprotein levels were also nearlynormal.The xanthomas improved quickly afterthe transplantation and completely resolvedwithin 2 months except the xanthelasmalesions.

DISCUSSIONThe onset of PBC typically occurs

between the age of 30 and 65, and 90% of thepatients were women.1 In our series of 21patients, the average age is 51.6 years old. 76%of our patients were women. Gradual onset ofpruritus followed by jaundice is by far the mostfrequent presentation. Reviewing the literature,the common cutaneous manifestations of PBCin the order of frequency are pruritus, jaundice,hyperpigmentation, xanthomas, and rarelylichen planus.2 Our study of 21 patients alsoshowed a similar clinical skin presentationsexcept hyperpigmentation and xanthomas,which showed more cases of developing xan-thomas than those of developing hyperpigmen-tation in our series. Fatigue is noted in up to 78% of patients.7 Seventeen of our patients pre-sented with fatigue (81%).

PBC is a chronic, cholestatic liver disease,hallmarked by progressive, inflammatorydestruction of the intrahepatic bile ducts.Current evidences suggests that the tissue injuryobserved may be related to an autoimmunepathogenesis.1, 2, 8 Plasma levels of cholesterol,TG, and phospholipids are often elevated inpatients with PBC.4 Therefore, patients withPBC can develop several types of xanthomasdue to secondary hypercholesterolemia andhyperlipidemia. The liver is the major site oflipoprotein synthesis, and the hepatic LDLreceptors removes 70% of the LDL from theplasma.9, 10 The serum free - cholesterol alsoincreases due to a decreased hepatic synthesisof lecithin:cholesterol acyltransferase, which isthe major intravascular cholesterol esterifyingfactor in plasma.4 The cholesterol elevations areoften accompanied by increases in LDL anddecreases in HDL concentrations.9, 10

The plasma cholesterol levels are elevatedin at least half of the PBC patients and mayexceed 1000 mg / dL in PBC patients with xan-thomas.1, 7 Four of our patients with xanthomashad the cholesterol levels exceeding 1000mg / dL. A standardized assessment on 85patients with PBC within 1 year of developingsymptoms revealed 22 % of the patients hadcutaneous xanthomas.11 In our series, 23.8% ofthe patients developed xanthomas within oneyear after diagnosing PBC.

Many types of xanthomas appear in long-standing hypercholesterolemia: if the plasmacholesterol levels are greater than 450 mg / dLfor more than 3 months, such lesions invariablyensued.12 Patients 12 and 14 have had the totalcholesterol level as high as 450-480 mg / dL fortwo months. It seems that the period of timeduring which they had cholesterol exceeding450 mg / dL was short, which may explain thefailure of developing xanthomas. Spontaneousregression of generalized tuberous xanthomas,coincident with a sustained decrease of the plas-ma cholesterol levels below 450 mg / dL with agood response to the diet and drug therapieswas observed in patient 5. Under these condi-tions, almost complete resolution of the xan-thomas occurred within 2 years in patient 5.The duration of elevation of the serum lipids isan important factor. Xanthomas are composedalmost exclusively of foam cells, which arebelieved to represent the tissue macrophagesthat have phagocytosed the lipid components oflipoproteins deposited in tissues. Xanthomas arenow considered to be reactive lesions to alteredlipid metabolism. Recent evidence has demon-strated transport of serum lipoproteins throughendothelial membranes and then phagocytosedby the foam cells. These lipoproteins are thendegraded to lipids and stored in vacuoles.13

Capillary microleakage of lipoproteinsenhanced by tissue trauma and subsequentphagocytosis by the dermal histiocytes couldlead to the formation of xanthomas in patientswith hyperlipidemia.14 Thus areas subjected tostress, friction or injury, particularly the exten-sor surfaces, buttocks, tendons, and skin creases

314 Dermatol Sinica, December 2003

have a predilection for xanthoma formation.14

Xanthoma has been classified into eruptive,tuberoeruptive, tuberous, tendinous, or planarxanthomas on the basis of clinical morphology,anatomic distribution, and the mode of develop-ment.14 The development of xanthomas in areaspreviously affected by erythroderma15 or chron-ic inflammatory skin diseases16 further supportsthat local tissue factors might play a role in theformation of xanthomas. In case 1, Chu et al.also hypothesize that the damage to basal ker-atinocytes in LP lesions accompanied by sys-temic hypercholesterolemia could lead to thedevelopment of xanthomas in LP lesions.6

The correlations of clinical xanthomatypes and the lipid profile are discussed and thelipoprotein component that accumulates in tis-sues is the critical determinants of the types ofxanthomas.14 It will provide a causal explana-tion for the specific relationship betweenlipoprotein disturbances, lipid profile and typesof xanthomas. Types of xanthomas are valuablediagnostic markers of the underlying lipid andlipoprotein disturbances for dermatologists.14, 17

Eruptive xanthomas are a sign of chylomicrone-mia and elevated plasma level of VLDL.Tendinous xanthomas are seen almost alwaysexclusively in disorders characterized by elevat-ed plasma levels of LDL or altered forms ofLDL. Tuberoeruptive xanthomas develop as aresult of deposition of chylomicron remnants,VLDL, VLDL remnants, or components ofthese lipoproteins in tissues ( thus elevated TGand cholesterol ), whereas xanthomas at thetuberous end of the spectrum are the result ofaccumulation of LDL, VLDL remnants, or theircomponents. Planar xanthomas are also charac-teristic of disorders that cause hepatic cholesta-sis, such as PBC and biliary atresia.14 In theseconditions, free cholesterol cannot be excretedproperly into the bile and is instead regurgitatedinto plasma, where free cholesterol binds withalbumin and phospholipid to form an abnormallipoprotein called lipoprotein X. Infiltration ofthe lipoprotein X or its components into the der-mis and subcutaneous tissue is probably respon-sible for the development of planar xan-

thomas.14 On the palms they can be differentiat-ed from the palmar crease xanthomas by theirplaque appearance (rather than a diffuse macu-lar discoloration), extension beyond the creases,and evolution in a grayish or dusky hue.14

In our described 3 cases, all of them hadtuberoeruptive, tuberous, and planar xanthomasthat were related to the elevated plasma choles-terol level ( LDL ) or concurrent elevation ofcholesterol and TG (LDL, VLDL). However,case 1 showed an episode of eruptive xan-thomas during January to March 1998. At thattime, her lipid profile revealed TG 812 mg / dLand cholesterol 317 mg / dL, which was compat-ible with the previous report that patients withearly histlogic stages of PBC presented withmildly elevated VLDLs and LDLs, marked ele-vation of HDLs and TG.4 In contrast, patientswith advanced disease had marked elevation incholesterol and LDLs with the presence oflipoprotein-X, and a significant decrease inHDLs.4

Severe hypercholesterolemia associatedwith chronic intractable cholestasis presents adifficult management problems.18 Recently,ursodiol treatment (13 to 15 mg / kg) has beenreported to achieve both a symptomaticimprovement and an "improvement" in serumbiochemical markers in patients with clinicallyovert PBC.7 Although the mechanism of theprotracted pruritus is not entirely clear,cholestyramine, an oral bile salt - sequesteringresin, may be helpful in a dosage of 8 to 12 g / dto improve both pruritus and the hypercholes-terolemia.7 Cholesterol may also be lowered byreducing dietary fat or increasing dietarypolyunsaturated fatty acid.7 Short- term plasma-pheresis has been demonstrated to have a bene-ficial effect on hyperlipidemia and pruritus inpatients with PBC.7, 19-22 In patients with chroniccholestasis who undergo successful liver trans-plantation, the cholestatic syndrome is nolonger present and the cholesterol and apopro-tein synthesis could be normalized.7 In the pre-senting case 3, though diet and drug therapylowered the levels of cholesterol and TG, thesize of the xanthomas did not decrease.

Dermatol Sinica, December 2003 315

Plasmapheresis has successfully decreased thenumber and size of xanthomas in some but notall patients with PBC.19-22 In the presenting casesreceiving plasmapheresis (case 1 and case 2 ),however, there was no decrease in the size ofxanthomas although large amounts of choles-terol were being removed temporarily duringthe procedure.

The natural history of PBC is usually pro-gressive over many years.1 The disease coursein the 3 discribed cases of our patients pro-gressed inevitably and at the time of liver trans-plantation, they all had an end-staged liver dis-ease associated with ascites and portal hyper-tension with variceal bleeding. They all tolerat-ed liver transplantation well and their plasmalipid levels normalized after the operation. Themost impressive thing was the speed withwhich xanthomas resolved after liver transplan-tation: 2 months to 12 months later.

In a patient with PBC, if complications ofthe xanthomas are making the quality of lifeintolerable and cannot be ameliorated by con-ventional therapeutic approaches, liver trans-plantation would be the best treatment.7, 23 Inpatients with advanced PBC who undergo livertransplantation for other indications, it can beexpected that this procedure will normalize theserum lipid abnormalities and lead to the reso-lution of xanthomas.

ACKNOWLEDGMENTSThe statistical analysis of the study was

performed by Miss Mei-Ping Tseng, MSc.

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