Pathophysiology and current management of pruritus in liver disease

Pruritus is frequently reported by patients with cholestatic hepatobiliary diseases such as primary biliary cirrhosis, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy and hereditary cholestatic syndromes, but may accompany almost any other liver disease. Increased concentrations of bile salts, histamine, progesterone metabolites or endogenous opioids have been controversially discussed as potential pruritogens in cholestasis in the past. Most recently, novel insights unravelled lysophosphatidic acid (LPA), a potent neuronal activator, as a potential pruritogen in pruritus of cholestasis. Nevertheless, the pathogenesis of pruritus in cholestasis is still not clearly defined and current antipruritic treatment strategies provide relief only in a part of the affected patients. Based on recent experimental and clinical findings, this review outlines the actual insight in pathogenesis of pruritus in cholestasis and summarizes evidence-based and experimental therapeutic interventions for cholestatic patients suffering from itch.     

Atypical causes of cholestasis

Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized in the pediatric population. In infants, the causes are usually congenital or inherited. Even though jaundice is a hallmark of cholestasis, it is not always seen in adult patients with chronic liver disease. Patients can have “silent” progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus. In this review, we will discuss some of the atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary atresia, total parenteral nutrition induced cholestasis and cholestasis secondary to drug induced liver injury.     

胆汁淤积性肝病并发皮肤瘙痒的发病机制及治疗进展

瘙痒是胆汁淤积性肝病如原发性胆汁性肝硬化、原发性硬化性胆管炎和妊娠期肝内胆汁淤积症的一个常见症状。既往研究的胆汁淤积性瘙痒的潜在致痒因子有胆盐、组胺、孕酮代谢产物、内源性阿片样物质和溶血性磷脂酸等。然而,胆汁淤积性瘙痒的确切发病机制尚不清楚,现有的止痒方法仅可使部分患者症状得到缓解,新的止痒方法已被提出和(或)正在研究中。在回顾近期关于胆汁淤积型肝病并发皮肤瘙痒的发病机制和治疗的实验和临床试验,以便提高对胆汁淤积性瘙痒的认识和治疗。     

Benign recurrent intrahepatic cholestasis: late initial diagnosis in adulthood

Benign recurrent intrahepatic cholestasis (BRIC) is a rare autosomal recessive or sporadic disorder, characterized by recurrent episodes of intense pruritus and jaundice that resolve spontaneously without leaving considerable liver damage. The attacks can start at any age, but the first attack is usually seen before the second decade of life. We report the case of a young adult male patient with BRIC who presented with recurrent cholestatic jaundice and pruritus with negative work up for all possible etiologies and a liver biopsy consistent with intrahepatic cholestasis. He improved on treatment with rifampicin and has not suffered another attack on follow up. Although in adulthood, BRIC diagnosis should be kept in mind in patients with recurrent cholestatic attacks with symptom free intervals after main bile duct obstruction and other congenital or acquired causes of intrahepatic cholestasis excluded.     

Pathogenesis and management of pruritus in cholestatic liver disease

Patients with cholestatic liver diseases such as primary biliary cirrhosis, primary sclerosing cholangitis and intrahepatic cholestasis of pregnancy commonly complain of pruritus. The underlying pathogenesis remains obscure with several mediators possibly playing an important role; these include lysophosphatidic acid, bile salts, opioids, histamine and progesterone metabolites. We describe in this review novel insights into the pathogenesis and management of pruritus in patients with cholestasis.     

Benign recurrent intrahepatic cholestasis (BRIC) in an adult

Benign recurrent intrahepatic cholestasis is a rare hereditary disorder characterised by recurrent episodes ofcholestasis. We report the case of a young male patient with benign recurrent intrahepatic cholestasis who presented to us with recurrent cholestatic jaundice and pruritus with negative work up for all possible aetiologies and a liver biopsy consistent with intrahepatic cholestasis. He improved on treatment with ursodeoxycholic acid and ondansterone and is doing well on follow up.     

Diagnostic and therapeutic approach to cholestatic liver disease.

When cholestatic liver disease is present, liver ultrasound should be performed to ascertain if cholestasis is extrahepatic or intrahepatic. If bile ducts appear dilated and the probability of interventional treatment is high, endoscopic retrograde cholagio-pancreatography (ERCP) or trans-hepatic cholangiography (THC) should be the next step. If the probability of interventional therapeutics is low, cholangio-MRI should be performed. Once bile duct dilation and space occupying lesions are excluded, a work up for intrahepatic cholestasis should be started. Some specific clinical situations may be helpful in the diagnostic strategy. If cholestasis occurs in the elderly, drug-induced cholestatic disease should be suspected, whereas if it occurs in young people with risk factors, cholestatic viral hepatitis is the most likely diagnosis. During the first trimester of pregnancy cholestasis may occur in hyperemesis gravidorum, and in the third trimester of gestation cholestasis of pregnancy should be suspected. A familial history of recurrent cholestasis points to benign recurrent intrahepatic cholestasis. The occurrence of intrahepatic cholestasis in a middle-aged woman is a frequent presentation of primary biliary cirrhosis, whereas primary sclerosing cholangitis should be suspected in young males with inflammatory bowel disease. The presence of vascular spider nevi, ascites, and a history of alcohol abuse should point to alcoholic hepatitis. Neonatal cholestasis syndromes include CMV, toxoplasma and rubinfections or metabolic defects such as cystic fibrosis, alpha1-antitrypsin deficiency, bile acid synthesis defects, or biliary atresia. The treatment of cholestasis should include a management of complications such as pruritus, osteopenia and correction of fat soluble vitamin deficiencies. When hepatocellular failure or portal hypertension-related complications occur, liver transplantation should be considered.     

A case report: nasobiliary drainage inducing remission in benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis is a rare hereditary disorder characterized by recurrent episodes of cholestasis and pruritus without anatomical obstruction. Generally, medical therapy is not effective in benign recurrent intrahepatic cholestasis. Here, we report the case of a young male patient with benign recurrent intrahepatic cholestasis who presented with cholestatic jaundice and pruritus, refractory to standard therapies. He improved on treatment with temporary endoscopic nasobiliary drainage. We propose that temporary endoscopic nasobiliary drainage should be considered in cholestatic benign recurrent intrahepatic cholestasis patients. A 36-year-old male patient admitted to our outpatient clinic with the complaint of pruritus. His anamnesis revealed that he experienced the same symptoms and signs in 2006. He was hospitalized in a hepatology clinic and was thoroughly examined. Liver biopsy was performed, and he was finally diagnosed as having benign recurrent intrahepatic cholestasis. Medical therapy options all proved to be ineffective and we were able to achieve remission in this patient only with the help of nasobiliary drainage. For this patient, we tried nasobiliary drainage in addition to the standard medical therapies. He improved on nasobiliary drainage. In conclusion, we propose that temporary endoscopic biliary drainage should be considered in cholestatic benign recurrent intrahepatic cholestasis patients. We hope that this case report contributes to the topic, since only a few nasobiliary drainage case experiences have been reported to date.     

Albumin liver dialysis as pregnancy-saving procedure in cholestatic liver disease and intractable pruritus

Progressive familial intrahepatic cholestasis type 3 （PFIC3） is a rare cholestatic liver disease. Such liver disease can get worse by female hormone disorder. Albumin dialysis or Molecular Adsorbent Recirculating System （MARS） has been reported to reverse severe cholestasis-linked pruritus. Here, we report the first use of MARS during a spontaneous pregnancy and its successful outcome in a patient with PFIC3 and intractable pruritus. Albumin dialysis could be considered as a pregnancy-saving procedure in pregnant women with severe cholestasis and refractory pruritus.     

Idiopathic adulthood ductopenia: case report and review of the literature

The clinical and pathological findings of idiopathic ductopenia were studied in a 30-year-old woman who initially manifested jaundice and pruritus. Serum biochemical tests of liver function indicated severe and progressive cholestasis. Viral hepatitis markers and circulating autoantibodies were absent. The patient had a normal cholangiogram and lacked evidence of inflammatory bowel disease. Histological examination of a liver specimen showed severe cholestasis and absence of interlobular bile ducts. Severe jaundice and intractable pruritus developed in the patient and served as the indications for liver transplantation 4 months after initial examination. Transplantation resulted in prompt and complete resolution of the jaundice and pruritus. Two types of idiopathic adulthood ductopenia associated with different prognoses are recognized. Patients with type 1 idiopathic adulthood ductopenia are asymptomatic or manifest symptoms of cholestatic liver disease. They tend to have less destruction of the intrahepatic bile ducts on liver biopsy specimens. Their clinical course ranges from spontaneous improvement to progression to biliary cirrhosis. In contrast, patients with type 2 idiopathic adulthood ductopenia generally manifest initial symptoms of decompensated biliary cirrhosis, have extensive destruction of the intrahepatic bile ducts on liver biopsy, and frequently require orthotopic liver transplantation.     

Congenital cholestatic syndromes: what happens when children grow up?

Although advances in the management of children with congenital cholestasis have enabled many to survive into adulthood with their native livers, even the most common of these conditions remains rare in adult hepatology practice. Among four congenital cholestatic syndromes (biliary atresia, Alagille syndrome, Caroli disease and congenital hepatic fibrosis, and progressive familial intrahepatic cholestasis), the published data on outcomes of the syndromes into adulthood suggest that a spectrum of severity of liver disease can be expected, from cirrhosis (almost universal in adults with biliary atresia who have not required liver transplantation) to mild and subclinical (eg, in the previously undiagnosed affected parent of an infant with Alagille syndrome). Complications associated with portal hypertension and nutritional deficiencies are common, and other associated features of the cholestatic syndrome may require appropriate attention, such as congenital heart disease in Alagille syndrome. Indications for liver transplantation include synthetic failure, progressive encephalopathy, intractable pruritus, recurrent biliary sepsis and recurrent complications of portal hypertension. Improved understanding of biliary physiology will hopefully translate into improved therapy for children and adults with cholestasis.     

Benign familial recurrent intrahepatic cholestasis

Three new cases of benign familial recurrent intrahepatic cholestasis in a brother, sister, and mother are reported. These cases emphasize the familial nature of the disorder and the characteristic clinical findings of recurrent attacks, cholestatic jaundice, pruritus with increases in the serum bilirubin, and increased alkaline phosphatase. A normal extrahepatic biliary tree was shown by dye studies, and liver biopsy showed central lobular cholestasis without any inflammation or necrosis. Liver function tests were normal between attacks. This condition must be differentiated from extrahepatic obstruction, parenchymal liver disease, drug-induced cholestatic disease, and other familial types of jaundice.     

Successful clinical application of extracorporal albumin dialysis in a patient with benign recurrent intrahepatic cholestasis (BRIC)

This is a case report of a 36 years old man who has been suffering for 20 years from benign recurrent intrahepatic cholestasis (BRIC). BRIC is a rare autosomal recessive disease characterised by prolonged episodes of intrahepatic cholestasis and pruritus alternating with periods of nearly normal liver function, and does not progress to cirrhosis. Since all former approaches to medical treatment of the patients severe pruritus were ineffective, the patient was treated by 3 sessions of albumin dialysis (MARS, Molecular Adsorbents Recirculating System). MARS dialysis decreased serum bilirubin levels by more than 60 % and effectively lowered serum bile acid levels by 45 %. The course of serum parameters was accompanied by a dramatic clinical improvement of the patients symptoms (pruritus, jaundice, fatigue etc.). MARS therapy appeared to shorten the duration of the cholestatic attack.     

Unexpected clinical remission of cholestasis after rifampicin therapy in patients with normal or slightly increased levels of γ-glutamyl transpeptidase

Objective: Rifampicin is an effective drug against pruritus in intrahepatic cholestasis. However, there is no specific hepatic disease in which its use could cause undoubtedly biochemical improvement. The aim of this study was to describe patients with complete remission of cholestatic symptoms after rifampicin therapy.
Methods: We reported three female patients with intrahepatic cholestasis with no evidence of viral, metabolic, or autoimmune liver diseases. Total bilirubin levels ranged from 13.2 to 27.2 mg/dl (before the first treatment with rifampicin), and in all of them γ-glutamyl transpeptidase values were within the normal range or slightly increased. Rifampicin therapy was administered orally, without any concomitant drug, with an effective dosage of 5–17 mg/kg/day.
Results: In all patients, pruritus ceased completely and bilirubin returned to normal values. The symptoms recurred after rifampicin withdrawal on, at least, three occasions in each patient, and these symptoms were always eliminated after its reintroduction. The patients had a total of 16 cholestatic episodes during a follow-up of 8 yr, with a complete clinical recovery in all of them. Undergoing therapy with a suitable dosage of rifampicin, none of the patients had a cholestatic crisis even during a period for as long as 12 months. The diagnosis of two patients was consistent with benign recurrent intrahepatic cholestasis, and it was not well defined in the remaining.
Conclusion: Rifampicin may induce clinical remission, and perhaps prevent clinical relapses of intrahepatic cholestasis with normal or slightly increased levels of γ-glutamyl transpeptidase.     

Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis

Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are rare, inherited cholestatic liver disorders that manifest in infants and children and are associated with impaired bile flow (ie cholestasis), pruritus and potentially fatal liver disease. There are no effective or approved pharmacologic treatments for these diseases (standard medical treatments are supportive only), and new, noninvasive options would be valuable. Typically, bile acids undergo biliary secretion and intestinal reabsorption (ie enterohepatic circulation). However, in these diseases, disrupted secretion of bile acids leads to their accumulation in the liver, which is thought to underlie pruritus and liver‐damaging inflammation. One approach to reducing pathologic bile acid accumulation in the body is surgical biliary diversion, which interrupts the enterohepatic circulation (eg by diverting bile acids to an external stoma). These procedures can normalize serum bile acids, reduce pruritus and liver injury and improve quality of life. A novel, nonsurgical approach to interrupting the enterohepatic circulation is inhibition of the ileal bile acid transporter (IBAT), a key molecule in the enterohepatic circulation that reabsorbs bile acids from the intestine. IBAT inhibition has been shown to reduce serum bile acids and pruritus in trials of paediatric cholestatic liver diseases. This review explores the rationale of inhibition of the IBAT as a therapeutic target, describes IBAT inhibitors in development and summarizes the current data on interrupting the enterohepatic circulation as treatment for cholestatic liver diseases including ALGS and PFIC.     

A woman with recent jaundice and pruritus

A middle-aged woman suffering from jaundice and pruritus that had begun a month previously was presented to a physician.At the first assessment, laboratory findings had revealed a cholestatic pattern and serologic tests for hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis A virus (HAV) were negative. Normal findings of abdominal computed tomography (CT) scan and endoscopic retrograde cholangiopancreatography (ERCP) ruled out extrahepatic causes of cholestasis. A liver biopsy was done and showed intrahepatic cholestasis without destruction of the bile ducts or granuloma.We assessed the intrahepatic causes of cholestasis. Finally the diagnosis was confirmed by means of a simple test.     

Nasobiliary drainage induces long-lasting remission in benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis (BRIC) is characterized by episodic cholestasis and pruritus without anatomical obstruction. Effective medical treatment is not available. We report complete and long-lasting disappearance of pruritus and normalization of serum bile salt concentrations in cholestatic BRIC patients within 24 hours after endoscopic nasobiliary drainage (NBD). Relative amounts of phospholipids and bile salts in bile collected during NBD appeared to be normal, but phospholipids other than phosphatidylcholine (especially sphingomyelin) were increased. In conclusion, we propose that temporary endoscopic nasobiliary drainage should be considered in cholestatic BRIC patients.     

Cholestatic liver diseases: slow progress in understanding and treating slowly progressive disorders

BACKGROUND: Cholestatic liver diseases are characterized by failure of normal amounts of physiological bile to reach the gastrointestinal tract. Any interference with normal bile flow from the canalicular membrane of the hepatocyte to the distal common bile duct may result in cholestasis. METHODS: Literature review. RESULTS: In primary biliary cirrhosis (PBC), the small intrahepatic bile ducts are destructed, resulting in obstruction of intrahepatic bile flow, whereas extrahepatic and/or intrahepatic biliary strictures block the passage of bile towards the intestine in primary sclerosing cholangitis (PSC). In contrast, the biliary tree is morphologically unaffected in less common cholestatic liver diseases as benign recurrent intrahepatic cholestasis (BRIC) and progressive familiar intrahepatic cholestasis (PFIC1-4). Genetic defects in hepatic canalicular transport mechanisms and bile salt synthesis deficiencies seem to underlie these types of cholestatic disorders. CONCLUSION: Recent advances in understanding and treatment of cholestatic liver diseases may help in better diagnosing and treating the various conditions characterized by cholestasis.     

Intrahepatic cholestasis of pregnancy and acute fatty liver of pregnancy. An unusual but favorable association?

During the 26th week of a first pregnancy, a 25-year-old woman presented with pruritus suggesting an intrahepatic cholestasis of pregnancy. The pruritus, however, persisted despite the premature delivery of a normal newborn at the 35th week. Moreover, aspartate aminotransferase activity increased, reaching a maximum of 38 times normal level on the 17th day after the delivery. Thus, an acute fatty liver of pregnancy was suspected and confirmed by liver biopsy. This patient appeared to have both intrahepatic cholestasis of pregnancy and acute fatty liver of pregnancy, an association not previously reported. It is suggested that intrahepatic cholestasis of pregnancy caused premature delivery, which in turn may have prevented the onset of severe maternal and fetal complications caused by acute fatty liver of pregnancy.