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Cholestasis-induced pruritus treated with ultraviolet B phototherapy: An observational case series study
Research Article
Cholestasis-induced pruritus treated with ultraviolet B phototherapy: An observational case series study Sofie Decock1, Rik Roelandts2, Werner Van Steenbergen1, Wim Laleman1, David Cassiman1, Chris Verslype1, Johan Fevery1, Jos Van Pelt1, Frederik Nevens1,⇑ 1
Department of Hepatology, University Hospital Gasthuisberg, K.U. Leuven, Belgium; 2Department of Dermatology, University Hospital Gasthuisberg, K.U. Leuven, Belgium
Background & Aims: Pruritus is a disabling complication of cholestatic liver disorders. Its management remains challenging. Ultraviolet B (UVB) phototherapy has been successfully used to treat pruritus in other indications. Methods: This is an observational case series. The study population consists of 13 patients (10 females, mean age 52 years) with pruritus due to different cholestatic liver disorders: PBC (n = 4), PSC (n = 2), drug-induced (n = 3) and persistent cholestasis after liver transplantation (LT) (n = 4). Serum alkaline phosphatase levels were: 686 ± 363 l/L and serum bile acids levels: 147 ± 15 lmol/L. In all patients, conventional medical treatment had failed to control pruritus. Perception of pruritus was recorded by the visual analogue scale (VAS). Results: The mean follow-up was 3 years. Ten patients (77%) had more than 60% reduction in perceived pruritus of which 4 had more than an 80% reduction. Median [25–75% percentiles] VAS score before and after treatment decreased from 8.0 [8.0–10] to 2.0 [1.5–2.1] (p <0.001). The mean number of irradiations required to obtain this effect was 26 ± 17 (average duration of phototherapy: 8 weeks). No significant changes in cholestatic serum markers were observed. Four patients (30%) needed an additional phototherapy course because of recurrent pruritus and in all of them again a marked improvement of pruritus was observed. The therapy was well tolerated, except in two patients who developed, during retreatment, pronounced erythema in one case and paresthesia in the other case. Conclusions: UVB phototherapy appears to be a promising and well tolerated treatment also for cholestasis-associated pruritus. Ó 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Introduction Twenty-five to eighty percent of the patients with cholestatic liver disease such as primary biliary cirrhosis (PBC) and primary
Keywords: Pruritus; Cholestasis; UVB; Phototherapy; Autotoxin. Received 13 October 2011; received in revised form 4 April 2012; accepted 4 April 2012; available online 18 May 2012 ⇑ Corresponding author. Address: Department of Hepatology, University Hospital Gasthuisberg, K.U. Leuven, Herestraat 49, B-3000 Leuven, Belgium. Tel.: +32 16 344299; fax: +32 16 344387. E-mail address: [email protected] (F. Nevens).
sclerosing cholangitis (PSC) complain of pruritus [1–3]. Hepatogenic pruritus can become so invalidating that it leads to sleep deprivation, depression, and suicidal attempts and might for these reasons warrant liver transplantation. On the other hand, after LT, ischemic biliary strictures are also a common cause of refractory pruritus [4]. The pathogenesis of cholestatis-induced pruritus remains unclear. Increased serum and tissue concentrations of bile salts, steroid hormones, endogenous opioids, histamine, and serotonine are found but none of these substances is directly responsible for pruritus [5]. Recently serum levels of the lysophosphatidic acid-forming enzyme autotaxin were markedly higher in cholestatic patients with pruritus and the autotaxin activity in these patients correlated with itch intensity [6]. Since the exact molecular mechanisms of pruritus are still unknown, the management of cholestasis-induced pruritus remains challenging. The European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) guidelines recommend first line therapy with cholestyramine, second line therapy with rifampicin and third line therapy with opiate antagonists [1,7]. Ultraviolet B (UVB) phototherapy is successfully used to treat pruritus in patients without liver disease [8]. The aim of the present study was to explore the safety and efficacy of ultraviolet phototherapy in patients with pruritus due to cholestatic liver diseases.
Materials and methods Study population All patients with a stable cholestatic liver disease and therapy-refractory pruritus treated with UVB phototherapy at the University Hospitals Leuven from 2006 to 2010 were included in the study. Therapy-refractory pruritus was defined as pruritus for which medical treatment had failed. This treatment included cholestyramine, rifampicin, naltrexone and, in two patients, also Molecular Adsorbent Recirculating System (MARS, Gambro AB, Lund, Sweden), which only offered some temporally relief. In three patients with ischemic bile duct strictures after LT, several endoscopic attempts were performed with balloon dilatations and stents. UVB phototherapy All patients were treated with broadband UVB phototherapy using a total body irradiation cabinet (Winora, Munich, Germany). The irradiation cabinet contains 50 broadband UVB tubes (Philips TL12, Eindhoven, The Netherlands). The UVB
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Research Article irradiation was measured with an International Light ILT 1400-A UVB meter (International Light Technologies Inc., Peabody, USA). Prior to the start of irradiation, the minimal erythema dose (MED) was determined. This was done with fixed increasing doses of broadband UVB light on five 1 cm2 areas on the back of the – otherwise covered- patient. Readings were done immediately and 24 h after exposure. The MED was the minimum UVB dose that produced erythema 24 h after exposure. The UVB starting dose was 50% of the MED. The irradiations were given three times a week (on Monday, Wednesday, and Friday). Each time, the UVB dose was increased by 10–20% of the initial MED, according to the tolerance of the patient. UVB phototherapy was discontinued if no improvement of pruritus occurred after 13 sessions. If improvement of VAS was noted, treatment was continued untill VAS score did not improve further or until an 80% improvement of pruritus was obtained. UVB phototherapy could be continued up to a maximum of 60 sessions. Retreatment was possible in case of recurrence of pruritus. Pruritus scoring Perception of pruritus was recorded before each session with the aid of a visual analogue scale (VAS) on which the patients drew a line where 0 represents no pruritus and 10 the worst imaginable pruritus. Autotaxin Autotaxin enzymatic activity in serum was determined on stored serum at baseline with an assay from Echelon Biosciences (Salt Lake City, USA) using the fluorogenic substrate FS-3. The increase in fluorescence over time was measured in an Fluoroskan Ascent FL fluoro/luminometer (Thermolab systems, Helsinki, Finland). The assay was performed according to the manufactures instruction with each sample determined in duplicate. The results are expressed as ATX units, defined as pM FS-3 substrate (Iysophosphatidylcholine analogue) hydrolyzed/minute in assay buffer. The autotaxin enzymatic activity in serum was also measured in 9 normal volunteers and was 253 ± 53 ATX units (range 150–335). Patients were informed about the nature of the study treatment and all gave their consent. Statistical analysis Statistical analysis was performed using SigmaSTAT 3.5 (Jandel, USA). Wilcoxon Signed Rank Test or Mann–Whitney Rank Sum Test were used when appropriate. Data are given as mean ± SD or median (25–75% percentiles) if indicated. p 60.05 was considered statistically significant.
Results Patient characteristics Thirteen patients (10 females, mean age 52.5 ± 13.2 years, range 28–73) with a cholestatic liver disease fulfilled the inclusion criteria and were treated with UVB phototherapy from 2006 to 2010. In all these patients medical treatment (including cholestyramine, rifampicin, naltrexone, and two patients with MARS) had failed to control pruritus. Six patients had a primary chronic cholestatic liver disease (4 PBC, 2 PSC), four patients had persistant severe cholestasis after LT (three ischemic bile duct strictures and one vanishing bile duct syndrome due to ductopenic rejection) and three patients had a drug-induced cholestatic hepatitis. The mean level of alkaline phosphatase (AP) was 686 ± 363 U/L (range 283–1437 U/L, normal value: 6240 U/L). The mean level of total bilirubin was 3.01 ± 4.02 mg/dl (range 0.57–14.11 mg/dl, normal value: 61 mg/dl). The mean serum level of bile acids was 147 ± 15 lmol/L (range 51–405, normal value: 68 lmol/L). The other characteristics are given in Table 1. Autotaxin levels The autotaxin enzymatic activity of the patients significantly differed from the control patients and this was also the case for both subgroups of patients (without or with LT) vs. the controls: respectively p = 0.002 and p = 0.007. Effect, duration and tolerability of UVB-treatment The patients had a mean follow-up of 40 ± 34 months (range 7– 132). No significant changes were observed in the parameters of cholestasis during treatment (Table 2). No improvement of pruritus occurred after 13 sessions of UVB phototherapy in one patient and treatment was stopped (patient 1). In the other patients, improvement was observed and UVB
Table 1. Baseline characteristics of the patients with pruritus treated with UVB phototherapy.
Pruritus VAS
Overall n = 13 (mean ± SD) 8.7 ± 1.1
8.7 ± 1.0
Graft dysfunction n=4 (mean ± SD) 8.9 ± 1.3
Age (yr)
52.5 ± 13.2
53.9 ± 12.6
49.5 ± 12.5
Female/Total
10/13
7/9
3/4
AP (U/L)
686 ± 377
540 ± 322
1013 ± 296
γGT (U/L)
253 ± 192
174 ± 89
431 ± 246
Bilirubin (mg/dl)
3.01 ± 4.02
3.63 ± 4.75
1.59 ± 0.70
Autotaxin (U)
686 ± 332
833 ± 356
466 ± 103
Bile acids (µmol/L)
147 ± 15
236 ± 138
58 ± 7
ALT (U/L)
159 ± 23
176 ± 26
95 ± 43
Albumin (g/L)
39.1 ± 6.0
39 ± 5.1
39.2 ± 6.0
Prothrombin (%)
106.6 ± 23.0
102.1 ± 21.5
115.5 ± 20.7
Hemoglobin (g/dl)
12.1 ± 1.7
12.4 ± 1.8
11.6 ± 0.9
Leukocyte (cell/109)
5.4 ± 1.6
5.8 ± 1.3
4.6 ± 1.8
229 ± 138
275 ± 138
137 ± 37
9
Platelets (cell/10 )
638
Chronic cholestasis n=9 (mean ± SD)
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JOURNAL OF HEPATOLOGY Table 2. Evolution of the degree of pruritus assessed by VAS and biochemical parameters of cholestasis during the first phototherapy course.
Pt
Underlying liver disease
Number of irradiations
VAS
End
Alkaline phosphatase (U/L) Start End
Start 1
PBC
13
8
Start
End
Start
End
8
283
0.68
0.42
171
212
2
PBC
15
3
PBC
52
8
2
1309
1618
0.57
0.63
358
544
8
2.5
352
526
0.94
0.69
292
577
4
PBC
60
8
2
333
316
1.35
1.72
149
144
5 6
PSC
60
10
5
616
798
3.18
1.37
185
716
PSC
18
10
2
583
672
14.11
19.9
60
31
7
Ischemic bile duct strictures post LT (NASH)
20
10
0
845
724
1.61
1.16
83
61
8
Ischemic bile duct strictures post LT (drug-induced)
20
7.5
1.5
1437
1581
2.54
1.31
551
1054
9
Ischemic bile duct strictures post LT (ADPKD)
15
8
1.5
992
882
0.89
0.99
441
444
10
Vanishing bile duct syndrome post LT (HCV)
17
10
2
779
670
1.34
0.77
648
612
11
Drug-induced
18
8
1.5
367
252
1.30
2.63
76
22
12
Drug-induced
16
8
1.5
674
399
1.46
5.73
85
n.a.
13
Drug-induced
20
10
0.5
345
349
9.09
0.9
191
995
311
Total bilirubin (mg/dl)
γGT (U/L)
Alkaline phosphatase, normal value: 6240 U/L; total bilirubin, normal value: 61 mg/dl; gGT, normal value: 635 U/L. VAS, visual analogue scale; NASH, non-alcoholic steatohepatitis; ADPKD, autosomal dominant polycystic kidney disease; HCV, hepatitis C; Pt, patient.
8
VAS score
10
8
VAS score
10 6 4 2
p <0.001
0 Before After First phototherapy course Fig. 1. VAS of the perception of pruritus before and after the first phototherapy course.
phototherapy was continued (12/13 patients) until pruritus stabilized/did not improve further (8/12 patients) or until a 80% improvement of VAS was obtained (4/12 patients). In general, 10 patients (77%) had a more than 60% reduction in perceived pruritus of which four had more than an 80% reduction. Median [25–75% percentiles] VAS score before and at the end of the first phototherapy course decreased from 8.0 [8.0–10] to 2.0 [1.5–2.1] (p <0.001) (Fig. 1). The number of irradiations required varied between 12 and 60 with a mean of 26 ± 17 (approximately 8 weeks of treatment). Four patients (30%) needed a second phototherapy course because of recurrence of pruritus after a mean of 11 months (range 4–30) (Fig. 2). Patient number three received a second phototherapy and she again reported a reduction in pruritus but the effect was perceived as less pronounced (VAS score from 8 to 5 vs. 8 to 2 previously). The second course was complicated by pronounced erythema. Patient number 7 was retreated with three additional courses of UVB therapy (each time 12 irradiations), each course leading to complete resolution of pruritus. In patient number 8 the second UVB phototherapy course was as efficacious as the first. Finally, patient number 9 responded well to the first phototherapy course (VAS score from 8 to 2)
6 4 2 0
Before After
Before After
First phototherapy Second phototherapy course course Fig. 2. VAS before and at the end of first and second phototherapy course of the four patients retreated with UVB. Time interval between the first and the second phototherapy course ranged from 4 to 30 months with a mean of 11 months.
and the second course was as efficacious as the first, but treatment needed to be interrupted because of generalized paraesthesia. As mentioned earlier, four patients developed intractable pruritus after LT. In three patients (patients 7, 8, and 9) pruritus was caused by ischemic bile duct strictures and occurred 16 months, 6 months, and 5 years after LT, respectively. In patient number 10, pruritus was due to vanishing bile duct syndrome (occurring 10 years after LT). Currently, this patient controls pruritus further, by regular holidays to sunny destinations. Interestingly, the two patients, both suffering from ischemic bile duct strictures post liver transplantation, who were non-responders to MARS, responded very well to UVB phototherapy. Their bile acid level prior to MARS treatment was 99 and 65 lmol/L, respectively. After a mean follow-up of 32 ± 3 months (range 29–34) four patients (patients 2, 4, 5, and 6) underwent LT. One of these patients died (patient 5). The other nine patients are still alive. None of the patients who developed pruritus post-LT (patients 7, 8, 9, and 10) have been re-transplanted yet. In none of the
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Research Article patients who were treated with UVB phototherapy (even the patients under immunosuppression after LT) malignancies of the skin were observed after a mean follow-up of 32 ± 3 months (range 29–34). In general, broadband UVB phototherapy was well tolerated. Side effects in our study were erythema (one patient) and paraesthesia (one patient).
Discussion We observed a beneficial effect of UVB phototherapy in our patients with a cholestatic liver disease and therapy-refractory pruritus. The present study was not a randomized trial and spontaneous relief of the pruritus is possible. However, during treatment, there was no change in the degree of cholestasis and 30% of the patients reported again relieve of pruritus after additional courses during a mean observation time of 3 years. Broadband UVB phototherapy refers to a treatment using ultraviolet lamps that emit light in a broad range over the UVB spectrum (wavelengths 290–320 nm). UVB phototherapy is widely accepted as an efficient treatment for pruritus in patients with chronic renal failure, atopic dermatitis, aquagenic pruritus, systemic mastocytosis, and cutaneous T cell lymphoma [8–13]. Until now, only three papers have described the effect of UVB phototherapy for cholestasis-associated pruritus. The first paper was published in 1980 and showed a remarkable improvement of pruritus in five of six PBC patients treated with UVB phototherapy [14]. The second paper was published in 1987 and reported on successful UVB treatment of pruritus in one patient with PBC [15]. The third paper was published in 1994 also as a case report and described the beneficial effect of phototherapy on cholestasis-associated pruritus in a 7-year-old child [16]. At present, EASL and AASLD guidelines do not mention UVB phototherapy as a treatment option for pruritus in the context of cholestatic liver disorders [1,7]. This is definitely due to a paucity of supporting evidence in medical literature but probably more likely due to unawareness about UVB phototherapy as a possible treatment option for hepatogenic pruritus. Considering the fact that the medical armamentarium for pruritus is limited and that invasive and expensive treatments, such as MARS, have been reported to be acceptable, UVB-phototherapy might be considered a ‘‘between’’ option to the earlier mentioned options [17,18]. The pathophysiology of cholestasis-associated pruritus remains obscure. Several hypotheses such as enhanced serum levels of bile salts and opioids have been implicated but a correlation between itch intensity and bile salt or opioid level has never been documented. A recent work by Kremer et al. has shown that patients with cholestatic pruritus had significantly elevated serum levels of the autotaxin enzyme and its end-product lysophosphatidic acid (LPA) and that autotaxin activity correlated significantly with itch intensity [6]. Intradermally injected LPA induced pruritus in mice in a dose-dependent manner [19]. Our patient series with refractory pruritus confirms increased autotaxin levels compared to healthy controls. Since these are recent insights, it was not possible in the present study to correlate the improvement in pruritus with changes in levels of autotaxin. Therapeutic approaches to relief pruritus aim at removing pruritogens from the enterohepatic circulation (cholestyramine), at stimulating biotransformation of pruritogens in liver and/or gut by enzyme inducers (rifampicin), at modifying central itch 640
signaling by opioid antagonists and selective serotonin re-uptake inhibitors (naltrexone, sertraline) or at removing pruritogens from the systemic circulation by MARS [20]. The precise mode of action of UVB phototherapy on cholestasis-associated pruritus is not yet clarified. As already mentioned, broadband UVB phototherapy uses a very specific range of wavelengths between 290 to 320 nm. These wavelengths are well known to enter the epidermis at the level of the dermo-epidermal junction. The epidermis consists of keratinocytes and itch-specific nerve endings and is now looked upon as the itch receptor of the body [9]. We hypothesize that UVB phototherapy decreases itch perception by influencing the itch-specific nerve endings or induces chemical modification of the pruritogen in the skin. In our study, UVB phototherapy did not influence serum parameters of cholestasis. This does not exclude however, the possibility of increased urinary excretion of bile acids, as previously reported [16]. A recent review showed that the risk of skin cancer in patients with psoriasis treated with UVB phototherapy is not significantly increased [21]. However, caution should be taken in patients with a history of melanoma or non-melanoma skin cancers. Transplant recipients are at risk of skin cancer. At least in our study in none of our LT patients skin cancer was observed after a mean followup of 32 months. In all patients who are treated with UVB phototherapy the use of goggles is required to decrease the risk of UVkeratitis and eventually cataract formation and the use of genital shields in male patients is recommended and this was done in all our patients [22]. Sun exposure needs to be avoided during UVB phototherapy and preventive application of sunblock is recommended after each irradiation. Use of photosensitizing medication (such as quinolones, tetracyclines, non-steroidal antiinflammatory drugs, thiazides, fibrates) is contra-indicated during UVB phototherapy given the risk of erythema. UVB treatment is contraindicated in patients with a known history of lupus erythematosus and xeroderma pigmentosum. Finally, pregnancy is not considered a contraindication for UVB phototherapy. In summary: UVB phototherapy appears to be a promising and well tolerated treatment for cholestasis-associated pruritus. Given these results, prospective randomized controlled trials are warranted.
Financial support W. Laleman, D. Cassiman, and F. Nevens are senior clinical investigators for the Fund for Scientific Research – Flanders (Fundamenteel klinisch mandaat – FWO Vlaanderen).
Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References [1] Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ. Primary biliary cirrhosis. Hepatology 2009;50:291–308. [2] Chapman R, Fevery J, Kalloo A, Nagoorney DM, Boberg KM, Schneider B, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51:660–678. [3] Bergasa NV. The pruritus of cholestatis. J Hepatol 2005;43:8.
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JOURNAL OF HEPATOLOGY [4] Pirenne J, Monbaliu D, Aerts R, Desschans B, Liu Q, Cassiman D, et al. Biliary strictures after liver transplantation: risk factors and prevention by donor treatment with epoprostenol. Transplant Proc 2009;41:3399–3402. [5] Kremer AE, Beuers U, Oude-Elferinck R, Pusl T. Pathogenesis and treatment of pruritus in cholestasis. Drugs 2008;68:2163–2182. [6] Kremer AE, Martens JJ, Kulik W, Ruëff F, Kuiper EM, van Buuren HR, et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 2010;139:1008–1018. [7] European Association for the Study of the Liver. EASL clinical practice guidelines: management of cholestatic liver diseases. J Hepatol 2009;51:237–267. [8] Greaves MW. Itch in systemic disease: therapeutic options. Dermatol Ther 2005;18:323–327. [9] Rivard J, Lim HW. Ultraviolet phototherapy for pruritus. Dermatol Ther 2005;18:344–354. [10] Greaves MW. Recent advances in pathophysiology and current management of itch. Ann Acad Med Singapore 2007;36:788–792. [11] Meduri NB, Vandergriff T, Rasmussen H, Jacobe H. Phototherapy in the management of atopic dermatitis: a systematic review. Photodermatol Photoimmunol Photomed 2007;23:106–112. [12] Darsow U, Wollenberg A, Simon D, Taïeb A, Werfel T, Oranje A, et al. ETFAD/ EADV eczema task force 2009 position paper on diagnosis and treatment of atopic dermatitis. J Eur Acad Dermatol Venereol 2010;24:317–328. [13] Pugashetti R, Lim HW, Koo J. Broadband UVB revisited: is the narrowband UVB fad limiting our therapeutic options ? J Dermatolog Treat 2010;21:326–330.
[14] Hanid MA, Levi AJ. Phototherapy for pruritus in primary biliary cirrhosis. Lancet 1980;2:530. [15] Cerio R, Murphy GM, Salden GE. A combination of phototherapy and cholestyramine for the relief of pruritus in primary biliary cirrhosis. Br J Dermatol 1987;116:265–267. [16] Rosenthal E, Diamond E, Benderly A, Etzioni A. Cholestatic pruritus: effect of phototherapy on pruritus and excretion of bile acids in urine. Acta Paediatr 1994;83:888–891. [17] Laleman W, Wilmer A, Evenepoel P, Verslype C, Fevery J, Nevens F. Review article: non-biological liver support in liver failure. Aliment Pharmacol Ther 2006;23:351–363. [18] Parés A, Herrera M, Avilés J, Sanz M, Mas A. Treatment of resistant pruritus from cholestasis with albumin dialysis: combined analysis of patients from three centers. J Hepatol 2010;53:307–312. [19] Hashimoto T, Ohata H, Momose K. Itch-scratch responses induced by lysophosphatidic acid in mice. Pharmacology 2004;72:51–56. [20] Kremer AE, Oude Elferink RPJ, Beuers U. Pathophysiology and current management of pruritus in liver disease. Gastroenterol Clin Biol 2011;35:89–97. [21] Lee E, Koo J, Berger T. UVB phototherapy and skin cancer risk: a review of the literature. Int J Dermatol 2005;44:355–360. [22] Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et al. Guidelines of care for treatment of psoriasis with phototherapy and photochemotherapy. J Am Acad Dermatol 2010;62:114–135.
Journal of Hepatology 2012 vol. 57 j 637–641
641
Cholestasis-induced pruritus treated with ultraviolet B phototherapy: An observational case series study Sofie Decock1, Rik Roelandts2, Werner Van Steenbergen1, Wim Laleman1, David Cassiman1, Chris Verslype1, Johan Fevery1, Jos Van Pelt1, Frederik Nevens1,⇑ 1
Department of Hepatology, University Hospital Gasthuisberg, K.U. Leuven, Belgium; 2Department of Dermatology, University Hospital Gasthuisberg, K.U. Leuven, Belgium
Background & Aims: Pruritus is a disabling complication of cholestatic liver disorders. Its management remains challenging. Ultraviolet B (UVB) phototherapy has been successfully used to treat pruritus in other indications. Methods: This is an observational case series. The study population consists of 13 patients (10 females, mean age 52 years) with pruritus due to different cholestatic liver disorders: PBC (n = 4), PSC (n = 2), drug-induced (n = 3) and persistent cholestasis after liver transplantation (LT) (n = 4). Serum alkaline phosphatase levels were: 686 ± 363 l/L and serum bile acids levels: 147 ± 15 lmol/L. In all patients, conventional medical treatment had failed to control pruritus. Perception of pruritus was recorded by the visual analogue scale (VAS). Results: The mean follow-up was 3 years. Ten patients (77%) had more than 60% reduction in perceived pruritus of which 4 had more than an 80% reduction. Median [25–75% percentiles] VAS score before and after treatment decreased from 8.0 [8.0–10] to 2.0 [1.5–2.1] (p <0.001). The mean number of irradiations required to obtain this effect was 26 ± 17 (average duration of phototherapy: 8 weeks). No significant changes in cholestatic serum markers were observed. Four patients (30%) needed an additional phototherapy course because of recurrent pruritus and in all of them again a marked improvement of pruritus was observed. The therapy was well tolerated, except in two patients who developed, during retreatment, pronounced erythema in one case and paresthesia in the other case. Conclusions: UVB phototherapy appears to be a promising and well tolerated treatment also for cholestasis-associated pruritus. Ó 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
Introduction Twenty-five to eighty percent of the patients with cholestatic liver disease such as primary biliary cirrhosis (PBC) and primary
Keywords: Pruritus; Cholestasis; UVB; Phototherapy; Autotoxin. Received 13 October 2011; received in revised form 4 April 2012; accepted 4 April 2012; available online 18 May 2012 ⇑ Corresponding author. Address: Department of Hepatology, University Hospital Gasthuisberg, K.U. Leuven, Herestraat 49, B-3000 Leuven, Belgium. Tel.: +32 16 344299; fax: +32 16 344387. E-mail address: [email protected] (F. Nevens).
sclerosing cholangitis (PSC) complain of pruritus [1–3]. Hepatogenic pruritus can become so invalidating that it leads to sleep deprivation, depression, and suicidal attempts and might for these reasons warrant liver transplantation. On the other hand, after LT, ischemic biliary strictures are also a common cause of refractory pruritus [4]. The pathogenesis of cholestatis-induced pruritus remains unclear. Increased serum and tissue concentrations of bile salts, steroid hormones, endogenous opioids, histamine, and serotonine are found but none of these substances is directly responsible for pruritus [5]. Recently serum levels of the lysophosphatidic acid-forming enzyme autotaxin were markedly higher in cholestatic patients with pruritus and the autotaxin activity in these patients correlated with itch intensity [6]. Since the exact molecular mechanisms of pruritus are still unknown, the management of cholestasis-induced pruritus remains challenging. The European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) guidelines recommend first line therapy with cholestyramine, second line therapy with rifampicin and third line therapy with opiate antagonists [1,7]. Ultraviolet B (UVB) phototherapy is successfully used to treat pruritus in patients without liver disease [8]. The aim of the present study was to explore the safety and efficacy of ultraviolet phototherapy in patients with pruritus due to cholestatic liver diseases.
Materials and methods Study population All patients with a stable cholestatic liver disease and therapy-refractory pruritus treated with UVB phototherapy at the University Hospitals Leuven from 2006 to 2010 were included in the study. Therapy-refractory pruritus was defined as pruritus for which medical treatment had failed. This treatment included cholestyramine, rifampicin, naltrexone and, in two patients, also Molecular Adsorbent Recirculating System (MARS, Gambro AB, Lund, Sweden), which only offered some temporally relief. In three patients with ischemic bile duct strictures after LT, several endoscopic attempts were performed with balloon dilatations and stents. UVB phototherapy All patients were treated with broadband UVB phototherapy using a total body irradiation cabinet (Winora, Munich, Germany). The irradiation cabinet contains 50 broadband UVB tubes (Philips TL12, Eindhoven, The Netherlands). The UVB
Journal of Hepatology 2012 vol. 57 j 637–641
Research Article irradiation was measured with an International Light ILT 1400-A UVB meter (International Light Technologies Inc., Peabody, USA). Prior to the start of irradiation, the minimal erythema dose (MED) was determined. This was done with fixed increasing doses of broadband UVB light on five 1 cm2 areas on the back of the – otherwise covered- patient. Readings were done immediately and 24 h after exposure. The MED was the minimum UVB dose that produced erythema 24 h after exposure. The UVB starting dose was 50% of the MED. The irradiations were given three times a week (on Monday, Wednesday, and Friday). Each time, the UVB dose was increased by 10–20% of the initial MED, according to the tolerance of the patient. UVB phototherapy was discontinued if no improvement of pruritus occurred after 13 sessions. If improvement of VAS was noted, treatment was continued untill VAS score did not improve further or until an 80% improvement of pruritus was obtained. UVB phototherapy could be continued up to a maximum of 60 sessions. Retreatment was possible in case of recurrence of pruritus. Pruritus scoring Perception of pruritus was recorded before each session with the aid of a visual analogue scale (VAS) on which the patients drew a line where 0 represents no pruritus and 10 the worst imaginable pruritus. Autotaxin Autotaxin enzymatic activity in serum was determined on stored serum at baseline with an assay from Echelon Biosciences (Salt Lake City, USA) using the fluorogenic substrate FS-3. The increase in fluorescence over time was measured in an Fluoroskan Ascent FL fluoro/luminometer (Thermolab systems, Helsinki, Finland). The assay was performed according to the manufactures instruction with each sample determined in duplicate. The results are expressed as ATX units, defined as pM FS-3 substrate (Iysophosphatidylcholine analogue) hydrolyzed/minute in assay buffer. The autotaxin enzymatic activity in serum was also measured in 9 normal volunteers and was 253 ± 53 ATX units (range 150–335). Patients were informed about the nature of the study treatment and all gave their consent. Statistical analysis Statistical analysis was performed using SigmaSTAT 3.5 (Jandel, USA). Wilcoxon Signed Rank Test or Mann–Whitney Rank Sum Test were used when appropriate. Data are given as mean ± SD or median (25–75% percentiles) if indicated. p 60.05 was considered statistically significant.
Results Patient characteristics Thirteen patients (10 females, mean age 52.5 ± 13.2 years, range 28–73) with a cholestatic liver disease fulfilled the inclusion criteria and were treated with UVB phototherapy from 2006 to 2010. In all these patients medical treatment (including cholestyramine, rifampicin, naltrexone, and two patients with MARS) had failed to control pruritus. Six patients had a primary chronic cholestatic liver disease (4 PBC, 2 PSC), four patients had persistant severe cholestasis after LT (three ischemic bile duct strictures and one vanishing bile duct syndrome due to ductopenic rejection) and three patients had a drug-induced cholestatic hepatitis. The mean level of alkaline phosphatase (AP) was 686 ± 363 U/L (range 283–1437 U/L, normal value: 6240 U/L). The mean level of total bilirubin was 3.01 ± 4.02 mg/dl (range 0.57–14.11 mg/dl, normal value: 61 mg/dl). The mean serum level of bile acids was 147 ± 15 lmol/L (range 51–405, normal value: 68 lmol/L). The other characteristics are given in Table 1. Autotaxin levels The autotaxin enzymatic activity of the patients significantly differed from the control patients and this was also the case for both subgroups of patients (without or with LT) vs. the controls: respectively p = 0.002 and p = 0.007. Effect, duration and tolerability of UVB-treatment The patients had a mean follow-up of 40 ± 34 months (range 7– 132). No significant changes were observed in the parameters of cholestasis during treatment (Table 2). No improvement of pruritus occurred after 13 sessions of UVB phototherapy in one patient and treatment was stopped (patient 1). In the other patients, improvement was observed and UVB
Table 1. Baseline characteristics of the patients with pruritus treated with UVB phototherapy.
Pruritus VAS
Overall n = 13 (mean ± SD) 8.7 ± 1.1
8.7 ± 1.0
Graft dysfunction n=4 (mean ± SD) 8.9 ± 1.3
Age (yr)
52.5 ± 13.2
53.9 ± 12.6
49.5 ± 12.5
Female/Total
10/13
7/9
3/4
AP (U/L)
686 ± 377
540 ± 322
1013 ± 296
γGT (U/L)
253 ± 192
174 ± 89
431 ± 246
Bilirubin (mg/dl)
3.01 ± 4.02
3.63 ± 4.75
1.59 ± 0.70
Autotaxin (U)
686 ± 332
833 ± 356
466 ± 103
Bile acids (µmol/L)
147 ± 15
236 ± 138
58 ± 7
ALT (U/L)
159 ± 23
176 ± 26
95 ± 43
Albumin (g/L)
39.1 ± 6.0
39 ± 5.1
39.2 ± 6.0
Prothrombin (%)
106.6 ± 23.0
102.1 ± 21.5
115.5 ± 20.7
Hemoglobin (g/dl)
12.1 ± 1.7
12.4 ± 1.8
11.6 ± 0.9
Leukocyte (cell/109)
5.4 ± 1.6
5.8 ± 1.3
4.6 ± 1.8
229 ± 138
275 ± 138
137 ± 37
9
Platelets (cell/10 )
638
Chronic cholestasis n=9 (mean ± SD)
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JOURNAL OF HEPATOLOGY Table 2. Evolution of the degree of pruritus assessed by VAS and biochemical parameters of cholestasis during the first phototherapy course.
Pt
Underlying liver disease
Number of irradiations
VAS
End
Alkaline phosphatase (U/L) Start End
Start 1
PBC
13
8
Start
End
Start
End
8
283
0.68
0.42
171
212
2
PBC
15
3
PBC
52
8
2
1309
1618
0.57
0.63
358
544
8
2.5
352
526
0.94
0.69
292
577
4
PBC
60
8
2
333
316
1.35
1.72
149
144
5 6
PSC
60
10
5
616
798
3.18
1.37
185
716
PSC
18
10
2
583
672
14.11
19.9
60
31
7
Ischemic bile duct strictures post LT (NASH)
20
10
0
845
724
1.61
1.16
83
61
8
Ischemic bile duct strictures post LT (drug-induced)
20
7.5
1.5
1437
1581
2.54
1.31
551
1054
9
Ischemic bile duct strictures post LT (ADPKD)
15
8
1.5
992
882
0.89
0.99
441
444
10
Vanishing bile duct syndrome post LT (HCV)
17
10
2
779
670
1.34
0.77
648
612
11
Drug-induced
18
8
1.5
367
252
1.30
2.63
76
22
12
Drug-induced
16
8
1.5
674
399
1.46
5.73
85
n.a.
13
Drug-induced
20
10
0.5
345
349
9.09
0.9
191
995
311
Total bilirubin (mg/dl)
γGT (U/L)
Alkaline phosphatase, normal value: 6240 U/L; total bilirubin, normal value: 61 mg/dl; gGT, normal value: 635 U/L. VAS, visual analogue scale; NASH, non-alcoholic steatohepatitis; ADPKD, autosomal dominant polycystic kidney disease; HCV, hepatitis C; Pt, patient.
8
VAS score
10
8
VAS score
10 6 4 2
p <0.001
0 Before After First phototherapy course Fig. 1. VAS of the perception of pruritus before and after the first phototherapy course.
phototherapy was continued (12/13 patients) until pruritus stabilized/did not improve further (8/12 patients) or until a 80% improvement of VAS was obtained (4/12 patients). In general, 10 patients (77%) had a more than 60% reduction in perceived pruritus of which four had more than an 80% reduction. Median [25–75% percentiles] VAS score before and at the end of the first phototherapy course decreased from 8.0 [8.0–10] to 2.0 [1.5–2.1] (p <0.001) (Fig. 1). The number of irradiations required varied between 12 and 60 with a mean of 26 ± 17 (approximately 8 weeks of treatment). Four patients (30%) needed a second phototherapy course because of recurrence of pruritus after a mean of 11 months (range 4–30) (Fig. 2). Patient number three received a second phototherapy and she again reported a reduction in pruritus but the effect was perceived as less pronounced (VAS score from 8 to 5 vs. 8 to 2 previously). The second course was complicated by pronounced erythema. Patient number 7 was retreated with three additional courses of UVB therapy (each time 12 irradiations), each course leading to complete resolution of pruritus. In patient number 8 the second UVB phototherapy course was as efficacious as the first. Finally, patient number 9 responded well to the first phototherapy course (VAS score from 8 to 2)
6 4 2 0
Before After
Before After
First phototherapy Second phototherapy course course Fig. 2. VAS before and at the end of first and second phototherapy course of the four patients retreated with UVB. Time interval between the first and the second phototherapy course ranged from 4 to 30 months with a mean of 11 months.
and the second course was as efficacious as the first, but treatment needed to be interrupted because of generalized paraesthesia. As mentioned earlier, four patients developed intractable pruritus after LT. In three patients (patients 7, 8, and 9) pruritus was caused by ischemic bile duct strictures and occurred 16 months, 6 months, and 5 years after LT, respectively. In patient number 10, pruritus was due to vanishing bile duct syndrome (occurring 10 years after LT). Currently, this patient controls pruritus further, by regular holidays to sunny destinations. Interestingly, the two patients, both suffering from ischemic bile duct strictures post liver transplantation, who were non-responders to MARS, responded very well to UVB phototherapy. Their bile acid level prior to MARS treatment was 99 and 65 lmol/L, respectively. After a mean follow-up of 32 ± 3 months (range 29–34) four patients (patients 2, 4, 5, and 6) underwent LT. One of these patients died (patient 5). The other nine patients are still alive. None of the patients who developed pruritus post-LT (patients 7, 8, 9, and 10) have been re-transplanted yet. In none of the
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Research Article patients who were treated with UVB phototherapy (even the patients under immunosuppression after LT) malignancies of the skin were observed after a mean follow-up of 32 ± 3 months (range 29–34). In general, broadband UVB phototherapy was well tolerated. Side effects in our study were erythema (one patient) and paraesthesia (one patient).
Discussion We observed a beneficial effect of UVB phototherapy in our patients with a cholestatic liver disease and therapy-refractory pruritus. The present study was not a randomized trial and spontaneous relief of the pruritus is possible. However, during treatment, there was no change in the degree of cholestasis and 30% of the patients reported again relieve of pruritus after additional courses during a mean observation time of 3 years. Broadband UVB phototherapy refers to a treatment using ultraviolet lamps that emit light in a broad range over the UVB spectrum (wavelengths 290–320 nm). UVB phototherapy is widely accepted as an efficient treatment for pruritus in patients with chronic renal failure, atopic dermatitis, aquagenic pruritus, systemic mastocytosis, and cutaneous T cell lymphoma [8–13]. Until now, only three papers have described the effect of UVB phototherapy for cholestasis-associated pruritus. The first paper was published in 1980 and showed a remarkable improvement of pruritus in five of six PBC patients treated with UVB phototherapy [14]. The second paper was published in 1987 and reported on successful UVB treatment of pruritus in one patient with PBC [15]. The third paper was published in 1994 also as a case report and described the beneficial effect of phototherapy on cholestasis-associated pruritus in a 7-year-old child [16]. At present, EASL and AASLD guidelines do not mention UVB phototherapy as a treatment option for pruritus in the context of cholestatic liver disorders [1,7]. This is definitely due to a paucity of supporting evidence in medical literature but probably more likely due to unawareness about UVB phototherapy as a possible treatment option for hepatogenic pruritus. Considering the fact that the medical armamentarium for pruritus is limited and that invasive and expensive treatments, such as MARS, have been reported to be acceptable, UVB-phototherapy might be considered a ‘‘between’’ option to the earlier mentioned options [17,18]. The pathophysiology of cholestasis-associated pruritus remains obscure. Several hypotheses such as enhanced serum levels of bile salts and opioids have been implicated but a correlation between itch intensity and bile salt or opioid level has never been documented. A recent work by Kremer et al. has shown that patients with cholestatic pruritus had significantly elevated serum levels of the autotaxin enzyme and its end-product lysophosphatidic acid (LPA) and that autotaxin activity correlated significantly with itch intensity [6]. Intradermally injected LPA induced pruritus in mice in a dose-dependent manner [19]. Our patient series with refractory pruritus confirms increased autotaxin levels compared to healthy controls. Since these are recent insights, it was not possible in the present study to correlate the improvement in pruritus with changes in levels of autotaxin. Therapeutic approaches to relief pruritus aim at removing pruritogens from the enterohepatic circulation (cholestyramine), at stimulating biotransformation of pruritogens in liver and/or gut by enzyme inducers (rifampicin), at modifying central itch 640
signaling by opioid antagonists and selective serotonin re-uptake inhibitors (naltrexone, sertraline) or at removing pruritogens from the systemic circulation by MARS [20]. The precise mode of action of UVB phototherapy on cholestasis-associated pruritus is not yet clarified. As already mentioned, broadband UVB phototherapy uses a very specific range of wavelengths between 290 to 320 nm. These wavelengths are well known to enter the epidermis at the level of the dermo-epidermal junction. The epidermis consists of keratinocytes and itch-specific nerve endings and is now looked upon as the itch receptor of the body [9]. We hypothesize that UVB phototherapy decreases itch perception by influencing the itch-specific nerve endings or induces chemical modification of the pruritogen in the skin. In our study, UVB phototherapy did not influence serum parameters of cholestasis. This does not exclude however, the possibility of increased urinary excretion of bile acids, as previously reported [16]. A recent review showed that the risk of skin cancer in patients with psoriasis treated with UVB phototherapy is not significantly increased [21]. However, caution should be taken in patients with a history of melanoma or non-melanoma skin cancers. Transplant recipients are at risk of skin cancer. At least in our study in none of our LT patients skin cancer was observed after a mean followup of 32 months. In all patients who are treated with UVB phototherapy the use of goggles is required to decrease the risk of UVkeratitis and eventually cataract formation and the use of genital shields in male patients is recommended and this was done in all our patients [22]. Sun exposure needs to be avoided during UVB phototherapy and preventive application of sunblock is recommended after each irradiation. Use of photosensitizing medication (such as quinolones, tetracyclines, non-steroidal antiinflammatory drugs, thiazides, fibrates) is contra-indicated during UVB phototherapy given the risk of erythema. UVB treatment is contraindicated in patients with a known history of lupus erythematosus and xeroderma pigmentosum. Finally, pregnancy is not considered a contraindication for UVB phototherapy. In summary: UVB phototherapy appears to be a promising and well tolerated treatment for cholestasis-associated pruritus. Given these results, prospective randomized controlled trials are warranted.
Financial support W. Laleman, D. Cassiman, and F. Nevens are senior clinical investigators for the Fund for Scientific Research – Flanders (Fundamenteel klinisch mandaat – FWO Vlaanderen).
Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References [1] Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ. Primary biliary cirrhosis. Hepatology 2009;50:291–308. [2] Chapman R, Fevery J, Kalloo A, Nagoorney DM, Boberg KM, Schneider B, et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51:660–678. [3] Bergasa NV. The pruritus of cholestatis. J Hepatol 2005;43:8.
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[14] Hanid MA, Levi AJ. Phototherapy for pruritus in primary biliary cirrhosis. Lancet 1980;2:530. [15] Cerio R, Murphy GM, Salden GE. A combination of phototherapy and cholestyramine for the relief of pruritus in primary biliary cirrhosis. Br J Dermatol 1987;116:265–267. [16] Rosenthal E, Diamond E, Benderly A, Etzioni A. Cholestatic pruritus: effect of phototherapy on pruritus and excretion of bile acids in urine. Acta Paediatr 1994;83:888–891. [17] Laleman W, Wilmer A, Evenepoel P, Verslype C, Fevery J, Nevens F. Review article: non-biological liver support in liver failure. Aliment Pharmacol Ther 2006;23:351–363. [18] Parés A, Herrera M, Avilés J, Sanz M, Mas A. Treatment of resistant pruritus from cholestasis with albumin dialysis: combined analysis of patients from three centers. J Hepatol 2010;53:307–312. [19] Hashimoto T, Ohata H, Momose K. Itch-scratch responses induced by lysophosphatidic acid in mice. Pharmacology 2004;72:51–56. [20] Kremer AE, Oude Elferink RPJ, Beuers U. Pathophysiology and current management of pruritus in liver disease. Gastroenterol Clin Biol 2011;35:89–97. [21] Lee E, Koo J, Berger T. UVB phototherapy and skin cancer risk: a review of the literature. Int J Dermatol 2005;44:355–360. [22] Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et al. Guidelines of care for treatment of psoriasis with phototherapy and photochemotherapy. J Am Acad Dermatol 2010;62:114–135.
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