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AP values &#8203;&#8203;greater than 1&#46;5 times the upper limit of normal &#40;ULN&#41; and GGT levels three times the ULN&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Clinically&#44; the impaired bile flow can present as fatigue&#44; osteoporosis&#44; fat malabsorption&#44; clotting disorders&#44; jaundice&#44; and pruritus&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Pruritus is a frequent symptom that accompanies several liver diseases&#44; particularly cholestatic ones&#46; It can be mild and tolerable&#44; but it can also dramatically reduce the quality of life&#44; cause considerable sleep deprivation&#44; depressive symptoms&#44; and induce suicidal ideation in the most severely affected patients&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Because it is a subjective sensation whose intensity is difficult to estimate&#44; cholestatic pruritus still receives little attention from some patients and&#44; unfortunately&#44; from many physicians&#46; This happens because&#44; very often&#44; it is mistakenly considered a condition that is not worth&#44; in fact&#44; assessing or treating&#46; Nevertheless&#44; evidence suggests that it is a symptom with a substantial impact on the quality of life of patients with cholestatic liver disease&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Associated diseases and epidemiology</span><p id="par0030" class="elsevierStylePara elsevierViewall">Pruritus can develop in patients with cholestasis related to any etiology&#46; Cholestasis is classified according to its origin at different levels of the biliary system&#46; The main affected sites and their respective examples are hepatocellular secretory failure &#40;intrahepatic cholestasis of pregnancy&#44; progressive familial intrahepatic cholestasis&#44; benign recurrent intrahepatic cholestasis&#44; drug-induced cholestasis&#41;&#59; intrahepatic bile duct abnormalities &#40;primary biliary cholangitis&#44; primary sclerosing cholangitis&#44; Alagille syndrome&#41;&#44; and extra-hepatic obstructive cholestasis &#40;cholelithiasis&#44; primary and secondary sclerosing cholangitis&#44; cholangiocarcinoma&#44; pancreaticobiliary ductal junction carcinoma&#44; hilar lymph node metastasis&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> All these conditions&#44; therefore&#44; represent potential diseases associated with cholestatic pruritus&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">It should be noted that the prevalence of pruritus in different cholestatic liver diseases varies considerably&#46; It is&#44; for instance&#44; the main symptom of intrahepatic cholestasis of pregnancy &#40;IHCP&#41;&#46; It occurs in 70&#37; to 80&#37; of patients with primary biliary cholangitis &#40;PBC&#41; and primary sclerosing cholangitis &#40;PSC&#41;&#44; and its frequency decreases with disease progression&#46; This symptom is also present in 16&#37; to 45&#37; of obstructive cholestasis from calculus or tumor &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Overall&#44; pruritus secondary to liver disease is more frequently seen in intrahepatic than extra-hepatic cholestatic diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Pathophysiology</span><p id="par0040" class="elsevierStylePara elsevierViewall">The pathophysiological mechanism of cholestatic pruritus is still not well defined&#46; Several hypotheses have been raised in the past&#46; The most important one included the participation of bile acids and endogenous opioids&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Bile acids</span><p id="par0045" class="elsevierStylePara elsevierViewall">Bile acids have been implicated in the pathogenesis of cholestasis pruritus&#46; They accumulate in the tissues of patients with liver disease and &#8211; under experimental conditions that included intracutaneous injections in normal volunteers &#8211; bile acids have been reported to produce local &#8220;itching&#8221;&#46; The injection of substances into the skin&#44; however&#44; is not a model for studying the pruritus caused by cholestasis&#46; The idea that bile acids cause pruritus in cholestasis was further perpetuated by a report of four patients with PBC who experienced pruritus after ingestion of synthetic bile acid&#46; Three observations&#44; however&#44; do not tend to support the fact that these substances cause pruritus in cholestasis&#46; First&#44; as patients with liver disease progress to failure&#44; bile acid levels become extremely high&#44; and the pruritus tends to cease&#46; Second&#44; despite showing marked elevations in serum bile acid levels&#44; not all patients with cholestasis report pruritus&#46; Third&#44; this symptom fluctuates regardless of serum bile acid levels&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Endogenous opioids</span><p id="par0050" class="elsevierStylePara elsevierViewall">The pruritic effects of opioids&#44; on the other hand&#44; vary depending on the activity of their receptor subtypes&#46; Endogenous opioids can activate &#956;-opioid receptors &#40;MOR&#41; to induce pruritus&#44; while incitement of &#954;-opioid receptors &#40;KOR&#41; inhibits it&#46; An imbalance between MOR &#40;increased&#41; and KOR &#40;decreased&#41; has been suggested in conditions associated with pruritus&#44; such as end-stage renal disease and cholestasis&#46; As the liver disease progresses&#44; liver clearance of endogenous opioids decreases&#44; with a consequent increase in their serum levels&#46; However&#44; pruritus severity does not correlate with endogenous opioid levels&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Lysophosphatidic acid &#40;LPA&#41; and autotaxin &#40;ATX&#41;</span><p id="par0055" class="elsevierStylePara elsevierViewall">Findings indicate that LPA&#44; a potent neuronal activator&#44; as well as ATX&#44; the enzyme that produces LPA&#44; are key elements in the pathophysiology of pruritus in cholestasis&#46; Serum ATX activity correlates with pruritus intensity and response to treatment in patients with cholestatic pruritus&#44; but not with this symptom when it is associated with other etiologies&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;12&#8211;17</span></a> Carrion et al&#46; &#40;2018&#41; found in patients with cholestasis and pruritus that ATX activity is significantly higher than in those with cholestasis without pruritus&#44; and ATX levels correlate with the severity of this symptom&#46; Additionally&#44; the response to therapeutic interventions &#40;bile acid-binding resins or rifampicin&#41; is associated with decreased serum autotaxin activity&#44; further supporting the role of autotaxin-LPA in the pathogenesis of pruritus in cholestasis&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Given all these hypotheses&#44; it is worth noting that there has been great progress in recent decades regarding the understanding of cholestatic pruritus mechanisms&#46; Although the exact pathophysiology of this type of pruritus remains unclear&#44; current evidence supports a mixed origin &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> At the tissue level&#44; as already mentioned&#44; local deposition of excess bile salts was the first suggested mechanism for pruritus in cholestatic disease&#46; To date&#44; the proposed modulators of the pruritic mechanism of cholestasis include bile salts&#44; opioids&#44; histamine and lysophosphatidic acid-LPA &#40;through autotaxin-ATX&#41;&#44; progesterone&#44; estrogens&#44; and serotonin&#46; The best current evidence suggests a complex interaction of these substances&#44; and so there are therapeutic agents for multiple targets&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Clinical manifestations</span><p id="par0065" class="elsevierStylePara elsevierViewall">Cholestatic pruritus can occur at any stage of liver disease&#46; Its intensity is often exacerbated by psychological stress&#44; heat&#44; and contact with wool&#46; Cold temperatures often produce symptom relief&#46; Moreover&#44; pruritus is more common in women&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Pruritus associated with cholestasis often exhibits a circadian rhythm&#44; with patients reporting greater intensity in the early hours of the night&#46; This type of pruritus is usually reported to be most pronounced on the palms of the hands and soles of the feet&#44; but it can be generalized and range from mild to severe&#46; In contrast to the pruritus seen in dermatological disorders&#44; primary skin lesions are not detectable in these patients&#46; However&#44; intense scratching can cause secondary alterations&#44; such as excoriations&#44; folliculitis&#44; lichenification&#44; and prurigo nodularis&#44; which occasionally lead to a misinterpretation of its etiology as a primary skin condition&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Determining the intensity of pruritus as objectively as possible is extremely relevant&#44; not only for research purposes but also in clinical practice&#44; for adequate therapeutic follow-up&#46; However&#44; there is no &#8216;one-size-fits-all&#8217; scoring system&#46; Currently&#44; there are several assessment methods for estimating the severity of pruritus&#58; the measurement of the sensory threshold or the act of excoriating and the one-dimensional pruritus severity scales&#44; for instance&#44; the Visual Analog Scale &#40;VAS&#41;&#44; the Numerical Scale &#40;NS&#41;&#44; and the Verbal Assessment Scale&#44; in addition to multidimensional questionnaires such as the 5-D Itch Scale &#40;5D-IS&#41;&#44; the Pruritus Severity Scale&#44; and the Eppendorf Pruritus Questionnaire&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Based on recently published consensuses&#44; the use of VAS in daily clinical practice and of at least two independent methods in research studies or clinical trials is recommended&#46; However&#44; no widely accepted&#44; standardized&#44; and validated questionnaire for objective measurement of pruritus is available&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">A more accurate method of objectively assessing pruritus is to use the excoriating activity monitoring system&#44; which involves applying piezoelectric film technology to generate a scratch transducer that is attached to a fingernail&#44; allowing the recording of the act of scratching&#46; Irrespective of limb movement during long periods&#44; for instance&#44; 24&#8239;hours&#46; These instruments were designed and validated&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Diagnosis</span><p id="par0090" class="elsevierStylePara elsevierViewall">A presumptive diagnosis of cholestatic pruritus can be made in patients with cholestasis who complain of itching&#46; However&#44; when there is no known cause of cholestasis&#44; it should be considered that approximately one in five patients with generalized pruritus has a systemic disease&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In this context&#44; there is a long list of differential diagnoses for the causes of pruritus&#44; such as skin diseases&#44; systemic diseases &#40;lymphoma and other neoplasms&#44; uremia and chronic renal failure&#44; hypothyroidism&#44; diabetes&#44; iron deficiency anemia&#41;&#44; psychogenic&#44; neurological&#44; and iatrogenic pruritus&#44; for instance&#44; caused by drugs&#46; At least a detailed skin examination should be performed to look for primary skin changes related to dermatological disorders&#44; in addition to adequate patient history&#44; physical examination&#44; and a comprehensive laboratory evaluation&#44; which may include imaging tests&#44; to rule out&#44; among other conditions&#44; myeloproliferative diseases or uremic pruritus in end-stage renal disease&#44; considering that hepatobiliary disorders&#44; chronic kidney disease&#44; and hematological disorders are the three most common systemic conditions associated with chronic pruritus&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;19</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The initial evaluation should include complete blood count &#40;CBC&#41;&#44; thyroid hormone&#44; urea&#44; and creatinine levels&#44; chest X-ray&#44; and markers of cholestasis and liver disease&#44; including alkaline phosphatase&#44; gamma-GT&#44; as well as bilirubin and aminotransferase levels&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">It is important to consider that clinical signs suggestive of chronic liver diseases&#44; such as jaundice&#44; palmar erythema&#44; and telangiectasias&#44; are only seen in a minority of patients&#44; as pruritus often occurs in the early stages of liver disease&#46; Therefore&#44; attention should be paid to the possibility of cholestatic pruritus when a patient presents with chronic pruritus without specific dermatological signs&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Treatment</span><p id="par0110" class="elsevierStylePara elsevierViewall">Assuming that the unknown pathogenesis of cholestatic pruritus is one of the factors preventing the development of effective therapy&#44; it is understood why treatment options are limited and still do not provide relief for all patients&#46; A practical recommendation for the step-by-step management of this symptom is based on the guidelines of the European Association for the Study of the Liver &#40;EASL&#41; and the American Association for the Study of Liver Diseases &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29</span></a> The proposal&#44; as the first step in the treatment of patients with cholestatic pruritus&#44; is to treat the underlying hepatobiliary disease and ruling out bile duct obstruction&#46; In cases of bile duct obstruction&#44; endoscopic&#44; radiological&#44; or surgical correction should be performed&#46; In drug-induced cholestasis&#44; discontinuation of the implicated agents is the treatment of choice&#46; In intrahepatic cholestasis of pregnancy and primary biliary cholangitis&#44; ursodeoxycholic acid &#40;UDCA&#41; is the first treatment option&#46; UDCA is a disease-modifying therapy&#44; but there is no evidence that it has any effect on pruritus&#44; except in intrahepatic cholestasis of pregnancy&#46; In PBC patients who do not respond to UDCA alone&#44; bezafibrate can be used&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;19</span></a> Currently&#44; peroxisome proliferator-activated receptor agonists &#40;PPARs&#41; such as bezafibrate have also been considered as an experimental treatment option for refractory cholestatic pruritus&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">If the underlying hepatobiliary disease cannot be corrected&#44; systematic treatment should be initiated&#44; aiming at controlling pruritus in a gradual approach&#44; as suggested in the aforementioned guideline recommendations for the management of pruritus in cholestatic patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29</span></a> There are four objectives in cholestatic pruritus therapy&#46; The first one is to remove substances associated with pruritus from the enterohepatic cycle through bile acid sequestrants &#40;cholestyramine&#41;&#46; The second objective is to control the metabolism of some factors associated with pruritus by the pregnane X receptor &#40;PXR&#41;&#44; such as rifampicin&#44; an enzyme inducer&#46; The third and fourth objectives are related to the perception of pruritus&#46; This is the case of &#181;-opioid antagonists and selective serotonin reuptake inhibitors &#40;SSRIs&#41;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The suggested doses of these medications are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; It is important to note that all the aforementioned drugs&#44; except for cholestyramine&#44; are considered &#8220;off-label&#8221; in the management of cholestatic pruritus&#46; Although frequently prescribed in clinical practice&#44; antihistamines are generally ineffective in hepatic pruritus&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;31</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">In the management of treatment-refractory pruritus&#44; removal of possible factors associated with the symptom from the systemic circulation using the molecular adsorbent recirculating system &#40;MARS&#41; or plasmapheresis may be attempted&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Newer agents under consideration for the treatment of cholestatic pruritus include ileal bile acid transporter &#40;IBAT&#41; and autotaxin inhibitors&#46; IBAT represents an interesting therapeutic target for the interruption of the enterohepatic cycle&#44; thus increasing the secretion of bile salts by the intestinal tract&#46; Examples of IBAT inhibitors are linerixibat&#44; maralixibat&#44; and odevixibat&#46; Another medication for pruritus control is the &#954;-opioid receptor agonist&#44; nalfurafine&#44; which has been approved in Japan for the treatment of cholestatic pruritus since 2015&#46; Physical approaches such as nasobiliary drainage and ultraviolet B &#40;UVB&#41; radiation phototherapy constitute experimental treatments&#44; with case reports showing benefits&#44; but without randomized controlled trials yet&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29&#44;32</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">In addition to systemic treatment&#44; general skincare guidelines should be given to patients&#46; These include using emollients and topical moisturizing and cooling agents &#40;e&#46;g&#46; emollients containing 1&#37;&#8211;2&#37; menthol&#41;&#44; shortening of fingernails&#44; encouraging the use of light clothing made of natural fibers such as cotton&#44; avoiding woolen and clothing that is too tight&#46; Cold water baths in situations where the pruritus is aggravated by heat and psychological interventions can also be useful&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;32</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusion</span><p id="par0130" class="elsevierStylePara elsevierViewall">Pruritus is a common symptom in many dermatological conditions&#44; and therefore&#44; dermatologists are usually the first physicians to evaluate patients with this symptom&#46; In this context&#44; it is extremely important for these professionals to have knowledge about the systemic conditions related to it&#44; particularly the one addressed in the present article&#44; cholestasis&#46; Therefore&#44; chronic pruritus in the absence of specific skin alterations should always encourage the request for laboratory markers of cholestasis&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">It should be noted that the greater the understanding on this subject&#44; the greater the chances of developing effective therapies for cholestatic pruritus and&#44; consequently&#44; improving the quality of life of these patients&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Financial support</span><p id="par0140" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Authors&#8217; contributions</span><p id="par0145" class="elsevierStylePara elsevierViewall">Thais Reginatto Nietsche&#58; Design and planning of the study&#59; data collection&#44; or analysis and interpretation of data&#59; drafting the article or critical review of important intellectual content&#59; collection&#44; analysis and interpretation of data&#59; critical review of the literature&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Gabriel Dotta&#58; Drafting of the manuscript or critical review of important intellectual content&#59; collection&#44; analysis&#44; and interpretation of data&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Carlos Baptista Barcaui&#58; Design and planning of the study&#59; approval of the final version of the manuscript&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Maria L&#250;cia Cardoso Gomes Ferraz&#58; Design and planning of the study&#59; effective participation in research orientation&#59; approval of the final version of the manuscript&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflicts of interest</span><p id="par0165" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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              "titulo" => "Lysophosphatidic acid &#40;LPA&#41; and autotaxin &#40;ATX&#41;"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">This review is focused on updating knowledge about cholestatic pruritus&#46; It summarizes clinical-epidemiological characteristics&#44; pathophysiology&#44; diagnostic approach&#44; and evidence-based therapeutic recommendations regarding this form of pruritus&#46; Pruritus is a frequent symptom that accompanies several liver diseases&#44; particularly cholestatic ones&#46; The symptom may be mild and tolerable&#44; but it can also dramatically reduce the quality of life&#46; Although the exact pathophysiology of this form of pruritus remains unclear&#44; current evidence supports a mixed origin&#46; It is extremely important for dermatologists to have knowledge about cholestatic pruritus since they are usually the first physicians to be sought by the patient when they experience the symptom&#46; In the absence of specific dermatological alterations&#44; cholestasis must always be considered as a possible cause of pruritus&#46; In addition to allowing an adequate diagnosis&#44; a better pathophysiological understanding of hepatic pruritus provides the identification of new therapeutic targets and&#44; consequently&#44; optimization of the approach in patients with this condition&#46;</p></span>"
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Review
Cholestatic pruritus: a knowledge update
Thaís Reginatto Nietschea,
Autor para correspondência
, Gabriel Dottaa, Carlos Baptista Barcauib, Maria Lúcia Cardoso Gomes Ferraza
a Hospital São Paulo, Universidade Federal de São Paulo, São Paulo, SP, Brazil
b Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, RJ, Brazil
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Classification of cholestasis according to its origin in the biliary system and corresponding examples&#46; PBC&#44; Primary Biliary Cholangitis&#59; PSC&#44; Primary Sclerosing Cholangitis&#59; SSC&#44; Secondary Sclerosing Cholangitis&#44; IHCP&#44; Intrahepatic Cholestasis of Pregnancy&#59; PFIC&#44; Progressive Familial Intrahepatic Cholestasis&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Cholestasis is defined as a decrease in biliary flow secondary to impaired secretion by hepatocytes or the obstruction of this flow in the intra- or extra-hepatic bile ducts&#46; On the other hand&#44; the clinical description of cholestasis is any condition in which substances normally excreted in the bile are retained&#46; Serum levels of conjugated bilirubin and bile salts are the most commonly measured ones&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The cutoff levels of serum alkaline phosphatase &#40;AP&#41; and gamma-glutamyl transferase &#40;GGT&#41; that characterize cholestasis and require diagnostic investigation are debated&#58; AP values &#8203;&#8203;greater than 1&#46;5 times the upper limit of normal &#40;ULN&#41; and GGT levels three times the ULN&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Clinically&#44; the impaired bile flow can present as fatigue&#44; osteoporosis&#44; fat malabsorption&#44; clotting disorders&#44; jaundice&#44; and pruritus&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Pruritus is a frequent symptom that accompanies several liver diseases&#44; particularly cholestatic ones&#46; It can be mild and tolerable&#44; but it can also dramatically reduce the quality of life&#44; cause considerable sleep deprivation&#44; depressive symptoms&#44; and induce suicidal ideation in the most severely affected patients&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Because it is a subjective sensation whose intensity is difficult to estimate&#44; cholestatic pruritus still receives little attention from some patients and&#44; unfortunately&#44; from many physicians&#46; This happens because&#44; very often&#44; it is mistakenly considered a condition that is not worth&#44; in fact&#44; assessing or treating&#46; Nevertheless&#44; evidence suggests that it is a symptom with a substantial impact on the quality of life of patients with cholestatic liver disease&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Associated diseases and epidemiology</span><p id="par0030" class="elsevierStylePara elsevierViewall">Pruritus can develop in patients with cholestasis related to any etiology&#46; Cholestasis is classified according to its origin at different levels of the biliary system&#46; The main affected sites and their respective examples are hepatocellular secretory failure &#40;intrahepatic cholestasis of pregnancy&#44; progressive familial intrahepatic cholestasis&#44; benign recurrent intrahepatic cholestasis&#44; drug-induced cholestasis&#41;&#59; intrahepatic bile duct abnormalities &#40;primary biliary cholangitis&#44; primary sclerosing cholangitis&#44; Alagille syndrome&#41;&#44; and extra-hepatic obstructive cholestasis &#40;cholelithiasis&#44; primary and secondary sclerosing cholangitis&#44; cholangiocarcinoma&#44; pancreaticobiliary ductal junction carcinoma&#44; hilar lymph node metastasis&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> All these conditions&#44; therefore&#44; represent potential diseases associated with cholestatic pruritus&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">It should be noted that the prevalence of pruritus in different cholestatic liver diseases varies considerably&#46; It is&#44; for instance&#44; the main symptom of intrahepatic cholestasis of pregnancy &#40;IHCP&#41;&#46; It occurs in 70&#37; to 80&#37; of patients with primary biliary cholangitis &#40;PBC&#41; and primary sclerosing cholangitis &#40;PSC&#41;&#44; and its frequency decreases with disease progression&#46; This symptom is also present in 16&#37; to 45&#37; of obstructive cholestasis from calculus or tumor &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Overall&#44; pruritus secondary to liver disease is more frequently seen in intrahepatic than extra-hepatic cholestatic diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Pathophysiology</span><p id="par0040" class="elsevierStylePara elsevierViewall">The pathophysiological mechanism of cholestatic pruritus is still not well defined&#46; Several hypotheses have been raised in the past&#46; The most important one included the participation of bile acids and endogenous opioids&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a></p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Bile acids</span><p id="par0045" class="elsevierStylePara elsevierViewall">Bile acids have been implicated in the pathogenesis of cholestasis pruritus&#46; They accumulate in the tissues of patients with liver disease and &#8211; under experimental conditions that included intracutaneous injections in normal volunteers &#8211; bile acids have been reported to produce local &#8220;itching&#8221;&#46; The injection of substances into the skin&#44; however&#44; is not a model for studying the pruritus caused by cholestasis&#46; The idea that bile acids cause pruritus in cholestasis was further perpetuated by a report of four patients with PBC who experienced pruritus after ingestion of synthetic bile acid&#46; Three observations&#44; however&#44; do not tend to support the fact that these substances cause pruritus in cholestasis&#46; First&#44; as patients with liver disease progress to failure&#44; bile acid levels become extremely high&#44; and the pruritus tends to cease&#46; Second&#44; despite showing marked elevations in serum bile acid levels&#44; not all patients with cholestasis report pruritus&#46; Third&#44; this symptom fluctuates regardless of serum bile acid levels&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Endogenous opioids</span><p id="par0050" class="elsevierStylePara elsevierViewall">The pruritic effects of opioids&#44; on the other hand&#44; vary depending on the activity of their receptor subtypes&#46; Endogenous opioids can activate &#956;-opioid receptors &#40;MOR&#41; to induce pruritus&#44; while incitement of &#954;-opioid receptors &#40;KOR&#41; inhibits it&#46; An imbalance between MOR &#40;increased&#41; and KOR &#40;decreased&#41; has been suggested in conditions associated with pruritus&#44; such as end-stage renal disease and cholestasis&#46; As the liver disease progresses&#44; liver clearance of endogenous opioids decreases&#44; with a consequent increase in their serum levels&#46; However&#44; pruritus severity does not correlate with endogenous opioid levels&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Lysophosphatidic acid &#40;LPA&#41; and autotaxin &#40;ATX&#41;</span><p id="par0055" class="elsevierStylePara elsevierViewall">Findings indicate that LPA&#44; a potent neuronal activator&#44; as well as ATX&#44; the enzyme that produces LPA&#44; are key elements in the pathophysiology of pruritus in cholestasis&#46; Serum ATX activity correlates with pruritus intensity and response to treatment in patients with cholestatic pruritus&#44; but not with this symptom when it is associated with other etiologies&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;12&#8211;17</span></a> Carrion et al&#46; &#40;2018&#41; found in patients with cholestasis and pruritus that ATX activity is significantly higher than in those with cholestasis without pruritus&#44; and ATX levels correlate with the severity of this symptom&#46; Additionally&#44; the response to therapeutic interventions &#40;bile acid-binding resins or rifampicin&#41; is associated with decreased serum autotaxin activity&#44; further supporting the role of autotaxin-LPA in the pathogenesis of pruritus in cholestasis&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Given all these hypotheses&#44; it is worth noting that there has been great progress in recent decades regarding the understanding of cholestatic pruritus mechanisms&#46; Although the exact pathophysiology of this type of pruritus remains unclear&#44; current evidence supports a mixed origin &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> At the tissue level&#44; as already mentioned&#44; local deposition of excess bile salts was the first suggested mechanism for pruritus in cholestatic disease&#46; To date&#44; the proposed modulators of the pruritic mechanism of cholestasis include bile salts&#44; opioids&#44; histamine and lysophosphatidic acid-LPA &#40;through autotaxin-ATX&#41;&#44; progesterone&#44; estrogens&#44; and serotonin&#46; The best current evidence suggests a complex interaction of these substances&#44; and so there are therapeutic agents for multiple targets&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Clinical manifestations</span><p id="par0065" class="elsevierStylePara elsevierViewall">Cholestatic pruritus can occur at any stage of liver disease&#46; Its intensity is often exacerbated by psychological stress&#44; heat&#44; and contact with wool&#46; Cold temperatures often produce symptom relief&#46; Moreover&#44; pruritus is more common in women&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Pruritus associated with cholestasis often exhibits a circadian rhythm&#44; with patients reporting greater intensity in the early hours of the night&#46; This type of pruritus is usually reported to be most pronounced on the palms of the hands and soles of the feet&#44; but it can be generalized and range from mild to severe&#46; In contrast to the pruritus seen in dermatological disorders&#44; primary skin lesions are not detectable in these patients&#46; However&#44; intense scratching can cause secondary alterations&#44; such as excoriations&#44; folliculitis&#44; lichenification&#44; and prurigo nodularis&#44; which occasionally lead to a misinterpretation of its etiology as a primary skin condition&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Determining the intensity of pruritus as objectively as possible is extremely relevant&#44; not only for research purposes but also in clinical practice&#44; for adequate therapeutic follow-up&#46; However&#44; there is no &#8216;one-size-fits-all&#8217; scoring system&#46; Currently&#44; there are several assessment methods for estimating the severity of pruritus&#58; the measurement of the sensory threshold or the act of excoriating and the one-dimensional pruritus severity scales&#44; for instance&#44; the Visual Analog Scale &#40;VAS&#41;&#44; the Numerical Scale &#40;NS&#41;&#44; and the Verbal Assessment Scale&#44; in addition to multidimensional questionnaires such as the 5-D Itch Scale &#40;5D-IS&#41;&#44; the Pruritus Severity Scale&#44; and the Eppendorf Pruritus Questionnaire&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Based on recently published consensuses&#44; the use of VAS in daily clinical practice and of at least two independent methods in research studies or clinical trials is recommended&#46; However&#44; no widely accepted&#44; standardized&#44; and validated questionnaire for objective measurement of pruritus is available&#46;<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">23&#44;24</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">A more accurate method of objectively assessing pruritus is to use the excoriating activity monitoring system&#44; which involves applying piezoelectric film technology to generate a scratch transducer that is attached to a fingernail&#44; allowing the recording of the act of scratching&#46; Irrespective of limb movement during long periods&#44; for instance&#44; 24&#8239;hours&#46; These instruments were designed and validated&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Diagnosis</span><p id="par0090" class="elsevierStylePara elsevierViewall">A presumptive diagnosis of cholestatic pruritus can be made in patients with cholestasis who complain of itching&#46; However&#44; when there is no known cause of cholestasis&#44; it should be considered that approximately one in five patients with generalized pruritus has a systemic disease&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">In this context&#44; there is a long list of differential diagnoses for the causes of pruritus&#44; such as skin diseases&#44; systemic diseases &#40;lymphoma and other neoplasms&#44; uremia and chronic renal failure&#44; hypothyroidism&#44; diabetes&#44; iron deficiency anemia&#41;&#44; psychogenic&#44; neurological&#44; and iatrogenic pruritus&#44; for instance&#44; caused by drugs&#46; At least a detailed skin examination should be performed to look for primary skin changes related to dermatological disorders&#44; in addition to adequate patient history&#44; physical examination&#44; and a comprehensive laboratory evaluation&#44; which may include imaging tests&#44; to rule out&#44; among other conditions&#44; myeloproliferative diseases or uremic pruritus in end-stage renal disease&#44; considering that hepatobiliary disorders&#44; chronic kidney disease&#44; and hematological disorders are the three most common systemic conditions associated with chronic pruritus&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;19</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">The initial evaluation should include complete blood count &#40;CBC&#41;&#44; thyroid hormone&#44; urea&#44; and creatinine levels&#44; chest X-ray&#44; and markers of cholestasis and liver disease&#44; including alkaline phosphatase&#44; gamma-GT&#44; as well as bilirubin and aminotransferase levels&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">It is important to consider that clinical signs suggestive of chronic liver diseases&#44; such as jaundice&#44; palmar erythema&#44; and telangiectasias&#44; are only seen in a minority of patients&#44; as pruritus often occurs in the early stages of liver disease&#46; Therefore&#44; attention should be paid to the possibility of cholestatic pruritus when a patient presents with chronic pruritus without specific dermatological signs&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Treatment</span><p id="par0110" class="elsevierStylePara elsevierViewall">Assuming that the unknown pathogenesis of cholestatic pruritus is one of the factors preventing the development of effective therapy&#44; it is understood why treatment options are limited and still do not provide relief for all patients&#46; A practical recommendation for the step-by-step management of this symptom is based on the guidelines of the European Association for the Study of the Liver &#40;EASL&#41; and the American Association for the Study of Liver Diseases &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29</span></a> The proposal&#44; as the first step in the treatment of patients with cholestatic pruritus&#44; is to treat the underlying hepatobiliary disease and ruling out bile duct obstruction&#46; In cases of bile duct obstruction&#44; endoscopic&#44; radiological&#44; or surgical correction should be performed&#46; In drug-induced cholestasis&#44; discontinuation of the implicated agents is the treatment of choice&#46; In intrahepatic cholestasis of pregnancy and primary biliary cholangitis&#44; ursodeoxycholic acid &#40;UDCA&#41; is the first treatment option&#46; UDCA is a disease-modifying therapy&#44; but there is no evidence that it has any effect on pruritus&#44; except in intrahepatic cholestasis of pregnancy&#46; In PBC patients who do not respond to UDCA alone&#44; bezafibrate can be used&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;19</span></a> Currently&#44; peroxisome proliferator-activated receptor agonists &#40;PPARs&#41; such as bezafibrate have also been considered as an experimental treatment option for refractory cholestatic pruritus&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0115" class="elsevierStylePara elsevierViewall">If the underlying hepatobiliary disease cannot be corrected&#44; systematic treatment should be initiated&#44; aiming at controlling pruritus in a gradual approach&#44; as suggested in the aforementioned guideline recommendations for the management of pruritus in cholestatic patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29</span></a> There are four objectives in cholestatic pruritus therapy&#46; The first one is to remove substances associated with pruritus from the enterohepatic cycle through bile acid sequestrants &#40;cholestyramine&#41;&#46; The second objective is to control the metabolism of some factors associated with pruritus by the pregnane X receptor &#40;PXR&#41;&#44; such as rifampicin&#44; an enzyme inducer&#46; The third and fourth objectives are related to the perception of pruritus&#46; This is the case of &#181;-opioid antagonists and selective serotonin reuptake inhibitors &#40;SSRIs&#41;&#44; respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The suggested doses of these medications are shown in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46; It is important to note that all the aforementioned drugs&#44; except for cholestyramine&#44; are considered &#8220;off-label&#8221; in the management of cholestatic pruritus&#46; Although frequently prescribed in clinical practice&#44; antihistamines are generally ineffective in hepatic pruritus&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;31</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0120" class="elsevierStylePara elsevierViewall">In the management of treatment-refractory pruritus&#44; removal of possible factors associated with the symptom from the systemic circulation using the molecular adsorbent recirculating system &#40;MARS&#41; or plasmapheresis may be attempted&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Newer agents under consideration for the treatment of cholestatic pruritus include ileal bile acid transporter &#40;IBAT&#41; and autotaxin inhibitors&#46; IBAT represents an interesting therapeutic target for the interruption of the enterohepatic cycle&#44; thus increasing the secretion of bile salts by the intestinal tract&#46; Examples of IBAT inhibitors are linerixibat&#44; maralixibat&#44; and odevixibat&#46; Another medication for pruritus control is the &#954;-opioid receptor agonist&#44; nalfurafine&#44; which has been approved in Japan for the treatment of cholestatic pruritus since 2015&#46; Physical approaches such as nasobiliary drainage and ultraviolet B &#40;UVB&#41; radiation phototherapy constitute experimental treatments&#44; with case reports showing benefits&#44; but without randomized controlled trials yet&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;29&#44;32</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">In addition to systemic treatment&#44; general skincare guidelines should be given to patients&#46; These include using emollients and topical moisturizing and cooling agents &#40;e&#46;g&#46; emollients containing 1&#37;&#8211;2&#37; menthol&#41;&#44; shortening of fingernails&#44; encouraging the use of light clothing made of natural fibers such as cotton&#44; avoiding woolen and clothing that is too tight&#46; Cold water baths in situations where the pruritus is aggravated by heat and psychological interventions can also be useful&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">28&#44;32</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Conclusion</span><p id="par0130" class="elsevierStylePara elsevierViewall">Pruritus is a common symptom in many dermatological conditions&#44; and therefore&#44; dermatologists are usually the first physicians to evaluate patients with this symptom&#46; In this context&#44; it is extremely important for these professionals to have knowledge about the systemic conditions related to it&#44; particularly the one addressed in the present article&#44; cholestasis&#46; Therefore&#44; chronic pruritus in the absence of specific skin alterations should always encourage the request for laboratory markers of cholestasis&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">It should be noted that the greater the understanding on this subject&#44; the greater the chances of developing effective therapies for cholestatic pruritus and&#44; consequently&#44; improving the quality of life of these patients&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Financial support</span><p id="par0140" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Authors&#8217; contributions</span><p id="par0145" class="elsevierStylePara elsevierViewall">Thais Reginatto Nietsche&#58; Design and planning of the study&#59; data collection&#44; or analysis and interpretation of data&#59; drafting the article or critical review of important intellectual content&#59; collection&#44; analysis and interpretation of data&#59; critical review of the literature&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">Gabriel Dotta&#58; Drafting of the manuscript or critical review of important intellectual content&#59; collection&#44; analysis&#44; and interpretation of data&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">Carlos Baptista Barcaui&#58; Design and planning of the study&#59; approval of the final version of the manuscript&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Maria L&#250;cia Cardoso Gomes Ferraz&#58; Design and planning of the study&#59; effective participation in research orientation&#59; approval of the final version of the manuscript&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflicts of interest</span><p id="par0165" class="elsevierStylePara elsevierViewall">None declared&#46;</p></span></span>"
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              "titulo" => "Lysophosphatidic acid &#40;LPA&#41; and autotaxin &#40;ATX&#41;"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">This review is focused on updating knowledge about cholestatic pruritus&#46; It summarizes clinical-epidemiological characteristics&#44; pathophysiology&#44; diagnostic approach&#44; and evidence-based therapeutic recommendations regarding this form of pruritus&#46; Pruritus is a frequent symptom that accompanies several liver diseases&#44; particularly cholestatic ones&#46; The symptom may be mild and tolerable&#44; but it can also dramatically reduce the quality of life&#46; Although the exact pathophysiology of this form of pruritus remains unclear&#44; current evidence supports a mixed origin&#46; It is extremely important for dermatologists to have knowledge about cholestatic pruritus since they are usually the first physicians to be sought by the patient when they experience the symptom&#46; In the absence of specific dermatological alterations&#44; cholestasis must always be considered as a possible cause of pruritus&#46; In addition to allowing an adequate diagnosis&#44; a better pathophysiological understanding of hepatic pruritus provides the identification of new therapeutic targets and&#44; consequently&#44; optimization of the approach in patients with this condition&#46;</p></span>"
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