Cholestatic Pruritus in Children: History
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Pruritus in the setting of cholestatic liver disease is difficult to treat and occurs in patients ranging in age from infancy to adulthood. Likely multifactorial in etiology, this symptom often involves multimodal therapy targeting several pathways and mechanisms proposed in the underlying etiology of cholestatic pruritus. Conventional therapies for the treatment of cholestatic pruritus in children include ursodeoxycholic acid, cholestyramine, hydroxyzine, and rifampin. Therapies used in the adult population with limited data in pediatric patients include opioid antagonists and selective serotonin reuptake inhibitors. Ileal bile acid transport inhibitors have been shown to alleviate pruritus in many children with Alagille syndrome and progressive familial intrahepatic cholestasis and it is an additional therapy available for consideration for these patients. Ultimately, surgical management and liver transplantation are considered in select refractory cases.

  • pediatrics
  • pruritus
  • cholestasis
  • liver disease

1. Introduction

Defined as the impaired secretion of bile, cholestasis commonly presents in the setting of hepatobiliary disease. This can occur due to anatomic obstruction, abnormal structures of the biliary system, infection, inflammation, or having a defective protein involved in the metabolism, transport, or excretion of the bile components. Within the pediatric population, various liver diseases may present with cholestasis with distinct characteristics of each disease as well as certain overlapping symptoms. Classic signs and symptoms associated with cholestasis include jaundice, scleral icterus, pruritus, xanthomas, steatorrhea, and failure to thrive. Cholestatic pruritus itself can be a frustrating and debilitating symptom for children with liver disease as it may be severe, unrelenting, and difficult to manage medically. Regardless of age, a notable number of patients with cholestatic liver disease experience refractory symptoms despite maximal medical management [1,2]. Within the pediatric populations, therapeutic options are even more limited due to insufficient data regarding safety and efficacy of various therapies in infants and children [3]. In children, severe pruritus is associated with functional impacts such as interference with sleep and mood disturbances [4]. Additionally, caregivers bear a notable burden of their child’s symptoms, with the severity of the child’s pruritus demonstrating strong correlation with impaired parental quality of life [5]. In certain patients with severe pruritus unable to be controlled with medications, procedural interventions such as nasobiliary and transcutaneous drainage, biliary diversion, or liver transplantation are considered to address the unrelenting itching [1,6].
Cholestatic disorders may involve intrahepatic cholestasis, which occurs due to impaired excretion of bile within the liver itself, or extrahepatic cholestasis, caused by obstruction to bile flow outside of the liver. Examples of intrahepatic cholestasis include Alagille syndrome, where patients demonstrate a paucity of bile ducts, and progressive familial intrahepatic cholestasis, caused by impairment of an enzyme crucial to bile excretion [7,8]. Extrahepatic cholestasis may be seen in anatomic anomalies such as choledochal cysts [9]. Both biliary atresia, a disease characterized by progressive obliteration of the biliary system, and primary sclerosing cholangitis (PSC), a disease involving stricturing of the biliary system within and outside of the liver, may result in both intrahepatic and extrahepatic cholestasis [10,11]. Many patients with these diagnoses experience pruritus, with 20–84% of patients with PSC reporting pruritus, and 76–80% of patients with progressive familial intrahepatic cholestasis (PFIC) experiencing pruritus [7,10]. Pruritus tends to present earlier, such as in infancy, in patients with PFIC1 and PFIC 2, whereas patients with PFIC 3 more often developed pruritus in later years [7]. In Alagille syndrome, pruritus occurs in an estimated 59–88% of patients, of which 45% are estimated to have severe pruritus [8]. The underlying cause of pruritus in cholestatic liver disease remains unknown with differing characteristics present amongst patients that experience severe itching [12]. Interestingly, patients may experience significant pruritus early on in their disease course which then subsides despite stable or even worsening cholestasis. Furthermore, even with significant cholestasis, some patients with these diseases never experience pruritus associated with liver disease [1].

2. Management of Cholestatic Pruritus in Children

2.1. Ursodeoxycholic Acid

In pediatric practice, many patients are started on ursodeoxycholic acid, a synthetic bile acid, early in their disease course to improve the bile flow. While physicians may initiate this medication to alleviate cholestasis regardless of whether pruritus is present, it may also be considered as an off-label option in management of pruritus [1]. Even though this medication is technically a bile acid itself, it works to help improve hepatobiliary secretion and decrease bile toxicity [33,34,35]. 

2.2. Bile Acid Binding Resins

Clinicians may also attempt to reduce serum bile acid concentrations with bile acid binding resin cholestyramine, which sequesters bile acids in a resin complex for excretion to decrease bile acid reuptake in the distal small bowel. This medication is the only one approved specifically for use of cholestatic pruritus in adults and it is often considered first line for pruritus management in the adult population [33]. As a result of decreased uptake of bile acids in the distal small bowel, this medication promotes a decreased accumulation of bile acids, thus alleviating the itch sensation in some patients. However, it rarely completely treats or controls cholestatic pruritus [1]. In conditions involving impaired secretion of bile acids into the intestines, such as biliary atresia, Alagille syndrome, or PFIC, the role of bile acid binding resins have low utility given the lack of available bile acids to bind. Furthermore, malabsorption of fats and fat-soluble vitamins may occur with this medication. Children with cholestatic liver disease are already at increased risk for fat soluble vitamin deficiency and poor weight gain due to their underlying disease [33]. Subsequently, this side effect may limit the use of this medication in the pediatric population.

2.3. Antihistamines

The conventional initial therapy for the symptom of pruritus in pediatric cholestatic liver disease is the use of antihistamines. Even though antihistamines such as hydroxyzine are often trialed early as pruritus therapy, the origins of cholestatic pruritus appear distinct from those seen with histaminergic itch [2,35]. Histamine is often involved in several common causes of itch, such as allergic response, urticaria, and atopic dermatitis and dosing of antihistamines is commonly based on indications for these alternative causes of itching [36]. As discussed, previous studies demonstrate alternative underlying mechanisms for cholestatic pruritus, one specific example being the family of mas-related G-protein coupled receptors, including MRGPRX1 and MRGPRX4 as itch receptors expressed in dorsal root ganglions of humans mediating non-histaminergic itch [6,37]. Even so, histamines are often trialed with limited effectiveness and the commonly experienced side effect of drowsiness [33,34].

2.4. Rifampin

Rifampin is often a second line therapy for treatment of cholestatic pruritus in children and produces notable improvement in pruritus in many patients. However, rifampin’s mechanism of action in the treatment of cholestatic pruritus has not been definitively determined. Some proposed mechanisms of action of this therapy include inhibiting transcription of autotaxin, thus mediating the LPA/ATX pathway [31,33]. Additionally, rifampin may play a role in the activation of the nuclear pregnane X receptor which enhances enzymatic reactions that make bile acids more hydrophilic and less toxic. This is thought to allow for increased elimination of bile and bilirubin [1,38]. 
Rifampin has been noted in the literature to have potential therapeutic use specifically in cases of extrahepatic cholestasis. Alternative agents, such as opioid antagonists, have been shown in some studies to have little to no effect at treating pruritus in the setting of extrahepatic cholestasis, whereas rifampin was effective in these cases [39]. Other sources have noted the utility of rifampin in treating cholestatic itch in cases of primary biliary cholangitis (PBC) and intrahepatic cholestasis of pregnancy [40,41]. While these conditions are more commonly seen in the adult population, the effective use of rifampin in these disorders demonstrates the potential of this medication for a spectrum of conditions demonstrating cholestatic itch.

2.5. Opioid Antagonists

Many patients with cholestatic pruritus have been known to respond to opioid antagonists such as naltrexone with relief of their pruritus [42]. Additionally, patients with cholestatic pruritus have even demonstrated symptoms of opioid withdrawal such as tachycardia, hypertension, abdominal pain, and piloerection when initiating opioid antagonist therapy, suggesting increased opioidergic tone at baseline in these patients [6,42]. The mechanisms for this heightened opioid pathway are unknown, but with consideration of endogenous opioids being produced in the liver in the setting of cholestasis [42]. Opioid antagonists can be administered either by IV (intravenous injection) or PO (per os) for treatment of cholestatic pruritus. However, one concern with this therapy is the development of tolerance to this medication due to continued exposure to opioid antagonists, causing decreasing efficacy of opioid antagonist therapy [6]. Sparse data regarding the use of opioid antagonists in the management of cholestatic pruritus in children is currently available in the literature and this medication has not been approved by the United States Food and Drug Administration (FDA) in patients under 18 years of age [34,35]. However, naltrexone has been used to treat cholestatic pruritus in patients aged as young as 17 months, per case report [43]. 
While some consider opioid antagonists to have little utility in treating pruritus in cases of extrahepatic cholestasis, with a potential for better therapeutic effect in cases of intrahepatic cholestasis, the multifactorial nature of pruritus, with variation even between individuals with the same disease, suggests a benefit to following a step-wise approach with consideration of opioid antagonists in those that do not fully respond to rifampin, regardless of the extrahepatic or intrahepatic nature of the cholestasis [39,44].

2.6. Selective Serotonin Reuptake Inhibitors

While levels of serotonin are not consistently correlated with presence or severity of cholestatic pruritus, the use of selective serotonin reuptake inhibitors has been seen to alleviate pruritus in cases refractory to other treatment regimens and is used as a fourth line in treatment of cholestatic pruritus in adult patients [6,34]. One study investigated the use of sertraline for treatment of pruritus in pediatric patients with Alagille syndrome or PFIC, with improved pruritus noted in 14 of the 20 patients treated with the medication. In this study, 10 of the 20 patients were classified as responders based on criteria determined prior to commencement of the study, including outcomes of improved pruritus with the additional endpoints of either improved skin scratching score or improved sleep score. Three patients experienced adverse events leading to discontinuation of the medication, including agitation, skin reaction, and vomiting. In this study, the youngest patient was 1.8 years old. While the study does not note which patients required discontinuation of the medication, it does note that adverse events were reversible [3]. 

2.7. Ileal Bile Acid Transport (IBAT) Inhibitors

New pharmacologic interventions targeting enterohepatic bile acid circulation have been developed and are currently used in the management of Alagille syndrome and PFIC specifically. Maralixibat has recently been approved by the United States FDA as an IBAT inhibitor used in Alagille syndrome, aimed to decrease enterohepatic bile acid circulation, thus decreasing bile acid stores and alleviating burdens of cholestasis including a potential therapeutic role for cholestatic pruritus. Similarly, odevixibat has been FDA approved for management of PFIC [34,45]. Maralixibat was found to demonstrate improved serum bile acid levels and statistically significant reduction in pruritus in patients with Alagille syndrome [46]. Furthermore, clinical trials have shown improved growth for patients with Alagille syndrome and PFIC on maralixibat [46,47]. In clinical trials, odevixibat has been shown to decrease bile acid levels and pruritus severity, in addition to improving sleep quality in patients with Alagille syndrome, PFIC, and biliary atresia. While IBAT inhibitors may have a broader role in the management of Alagille syndrome and PFIC, trials have demonstrated benefits specifically regarding improved pruritus in these populations [34,45,46,47].

2.8. Surgical Management

Patients with certain pediatric cholestatic liver diseases, specifically including PFIC and Alagille syndrome, who are refractory to medical management of pruritus may benefit from surgical intervention to treat their itching. Biliary diversion functions to reduce enterohepatic circulation, thus decreasing retention of certain substances including bile acids and bile salts which may contribute to pruritus [1,48]. Prior to surgery, some patients first trial nasobiliary drainage to gauge the degree of improvement that surgical intervention may provide. Nasobiliary drainage involves endoscopic placement of a nasobiliary tube which then drains substances from the biliary system, decreasing the amount of potential pruritogens in the body. Partial external biliary diversion involves the creation of a conduit allowing for a notable portion of the volume of bile flowing from the liver to be redirected externally, thus minimizing enterohepatic circulation of pruritogens. Partial internal biliary diversion serves as an alternative surgical option and classically involves use of an isolated portion of jejunum as an internal conduit between the gallbladder and colon, thus avoiding the distal small bowel where reuptake of bile acids occurs [48].
Surgical interventions clearly involve risks, complications, and limitations. Partial external biliary diversion involves the creation of an external stoma which requires care and attention. Stoma output may at times be high in volume and result in electrolyte abnormalities and dehydration. Other complications may involve para stomal hernia, cholangitis, and small bowel obstruction. Partial internal diversion has been trialed as a surgical technique relatively recently compared to external diversion, resulting in less known data regarding risks and potential complications. However, similar to partial external diversion, one known risk of partial internal diversion includes that of adhesive small bowel obstruction. More commonly, patients experience choleretic diarrhea due to the high load of bile salts diverted to the colon. Theoretical risks of increased colon cancer due to significant colonic exposure to bile acids as well as the hypothesized increased risk of cholangitis have not yet been demonstrated in the literature [48].
Ultimately, liver transplantation is considered in some pediatric patients with cholestatic liver disease who suffer from pruritus. Transplantation may ultimately be indicated regardless of pruritus severity when liver disease progresses to cirrhosis. In certain cases where significant progression of liver disease is predicted, transplant in the setting of severe pruritus may be considered to definitively treat the pruritus without first performing other surgical interventions such as biliary diversion [6,48].

This entry is adapted from the peer-reviewed paper 10.3390/biology12050756

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