Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis

Findings consistent with the hypothesis that increased central opioidergic tone contributes to the pruritus of cholestasis provide a rationale for treating this form of pruritus with opiate antagonists. However, initiation of therapy with an opiate antagonist in a cholestatic patient may precipitate a transient opioid withdrawal-like reaction. A woman with chronic cholestasis and disabling pruritus experienced severe transient opioid withdrawal-like reactions after oral administration of 12.5 and 2 mg naltrexone. Subsequently, naloxone was administered by intravenous infusion. Initially, the infusion rate was low and subtherapeutic. It was gradually increased to a rate known to be effective in inducing opioid antagonism. Oral naltrexone was then reintroduced without any reaction occurring. During the ensuing 12 months, while taking naltrexone, 25 mg daily, the patient has been completely free from pruritus. These observations strongly support the hypothesis that increased central opioidergic tone is a component of the pathophysiology of cholestasis.     

Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis,a crossover,double blind,placebo-controlled study

BACKGROUND/AIMS: To assess the efficacy and safety of naltrexone for the short and long term treatment of pruritus of cholestasis. METHODS: Twenty patients with pruritus and cholestasis were included. A baseline pruritus score was obtained over 1 week. Patients were then randomized to receive 50 mg/day of naltrexone or placebo for 2 weeks. Subsequently, a 1-week washout period ensued and patients were crossed over to the other therapy for 2 additional weeks. Pruritus was assessed daily with a visual analogue scale (VAS) from 0 to 10. Patients whose pruritus decreased >50% of basal with naltrexone received naltrexone 50 mg/day for 2 additional months. RESULTS: Mean basal VAS was similar in both groups. VAS showed greater and more significant changes with naltrexone than with placebo (P<0.0003). In nine out of 20 patients (45%) receiving naltrexone, pruritus decreased >50% compared to basal value, including five whose pruritus disappeared completely. No significant changes were observed in serum biochemistry. Most of the adverse events that occurred during the first 48 h of naltrexone therapy were consistent with opioid withdrawal-like phenomena and spontaneously disappeared 2 days after starting treatment. CONCLUSIONS: Naltrexone can be considered as an alternative option to treat pruritus of cholestasis. In the current study, side effects were transient and did not require specific medication.     

Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease

Pruritus due to cholestatic liver disease can be particularly difficult to manage and frequently is intractable to a variety of medical therapies. The aim of our study is to evaluate the efficacy of delta-9-tetrahydrocannabinol (delta-9-THC) for intractable cholestatic related pruritus (ICRP) that has failed conventional (and unconventional) remedies. Three patients were evaluated for plasmapheresis because of ICRP. All 3 patients had previously been extensively treated with standard therapies for ICRP including: diphenhydramine, chlorpheniramine, cholestyramine, rifampicin, phenobarbital, doxepin, naltrexone, UV therapy, and topical lotions. Even multiple courses of plasmapheresis were performed without any benefit for the intractable pruritus. All patients reported significant decreases in their quality of life, including lack of sleep, depression, inability to work, and suicidal ideations. All patients were started on 5 mg of delta-9-THC (Marinol) at bedtime. All 3 patients reported a decrease in pruritus, marked improvement in sleep, and eventually were able to return to work. Resolution of depression occurred in two of three. Side effects related to the drug include one patient experiencing a disturbance in coordination. Marinol dosage was decreased to 2.5 mg in this patient with resolution of symptoms. The duration of antipruritic effect is approximately 4-6 hrs in all three patients suggesting the need for more frequent dosing. Delta-9-tetrahydrocannabinol may be an effective alternative in patients with intractable cholestatic pruritus.     

Effect of oral naltrexone on pruritus in cholestatic patients

AIM:To determine the efficacy and potential complica-tions of oral naltrexone used in the treatment of pruritusin cholestatic patients and to compare them with otherstudies.METHODS:Thirty-four enrolled cholestatic patientscomplaining of pruritus were studied.In the initial phase,pruritus scores during day and night were evaluated.Sub-sequently,patients were given a placebo for one weekfollowed by naltrexone for one week.In each therapeuticcourse(placebo or naltrexone)day and night pruritusscores were distinguished by a visual analogue scale(VAS)system and recorded in patients'questionnaires.RESULTS:Both naltrexone and placebo decreased VASscores significantly.Naltrexone was more effective thanplacebo in decreasing VAS scores.Both day and nightscores of pruritus decreased by half of the value priorto therapy in thirteen patients(38%).Daytime pruritusimproved completely in two patients(5.9%),but no im-provement in the nighttime values was observed in anypatient.Sixteen patients(47%)suffered from naltrexonecomplications,eleven(32%)of them were related to itswithdrawal.Complications were often mild.In the caseof withdrawal,the complication was transient(withinthe first 24-28 h of therapy)and self-limited.We had tocease the drug in two cases(5.9%)because of severewithdrawal symptoms. CONCLUSION:Naltrexone can be used in the treatmentof pruritus in cholestatic patients and is a safe drugshowing few,mild and self-limited complications.     

The role of liver transplantation in the management of portal hypertension

Liver transplantation is the treatment of choice for end stage liver disease and not a treatment specifically for portal hypertension. A patient with complications of portal hypertension must be evaluated for the presence, etiology, and severity of liver disease to determine the most appropriate therapy. In a Child's Class A patient, who would not be a liver transplant candidate for two to three years, surgical shunts may be indicated. Shunt surgery, however, does not address the underlying liver disease. Liver transplantation is reserved for the patient with complications of cirrhosis (such as ascites, encephalopathy, malnutrition, intractable pruritus, and variceal hemorrhage) for whom no other form of therapy exists.     

Partial external biliary diversion for intractable pruritus and xanthomas in Alagille syndrome

Alagille syndrome (AGS) causes intractable pruritus and disfiguring xanthomas because of retained bile acids and cholesterol. This study was performed to determine whether partial external biliary diversion (PEBD) is effective for relief of pruritus and xanthomas in AGS patients who fail conventional medical therapy. Between the years 1985 and 2001, 9 AGS patients underwent PEBD. Complete follow-up data were available for all patients. The average age at PEBD was 4.8 (range 1.4-10) years. The average duration of follow-up was 7.5 (range 0.5-16.0) years. All 9 patients had severe, mutilating pruritus (grade 4) prior to diversion. At 1 year post-PEBD, the average pruritus score was 1.1; 8 patients had only mild scratching when undistracted. Three patients with extensive xanthomas prior to PEBD had complete resolution within 1 year. Mean serum bile salt levels (n = 5) decreased from 136.5 to 37.1 micromol/L and mean cholesterol (n = 7) from 724 to 367 mg/dL 1 year after PEBD. A single 21-year-old patient with PEBD for 14 years experienced an increase in pruritus from grade 1 to grade 4 within 2 months of elective reversal of PEBD. In conclusion, PEBD is effective for treating severe pruritus and hypercholesterolemia in AGS patients without cirrhosis who did not respond to medical therapy. PEBD should be considered as a therapeutic option for these patients before referral for liver transplantation because of morbid complications.     

The molecular adsorbent recirculating system as a liver support system. Summary of Mexican experience

Aim. The aim of this study was to assess the effects of the molecular absorbent recirculating system (MARS) on patients with acute liver failure (ALF) and liver failure with cirrhosis (AoCLF) as well as in cholestatic patients with intractable pruritus in a Mexican population.Material and methods. From August 2003 to December 2011, MARS was used in 38 patients with ALF, 15 patients with AoCLF, and 17 cholestatic patients with intractable pruritus. The patients were examined using a standard liver function test and for vital signs, presence of ascites and encephalopathy before and after each treatment. The therapeutic response, patient status, follow-up status, and need for liver transplantation were determined.Results. Seventy-nine MARS procedures were performed. MARS was used for ALF in 54.3% of patients, AoCLF in 24.2%, and cholestatic disease in 21.5%. There were significant improvements in serum bilirubin (p = 0.000), aspartate aminotransferase (p = 0.000), alanine aminotransferase (p = 0.030), gamma-glytamyl transpeptidase (p = 0.044), alkaline phosphatase (p = 0.006), and encephalopathy grade (p = 0.000). Thirty-eight ALF patients were listed for emergency liver transplantation and treated with MARS; 20 of these patients died on a waiting list, 18 survived. only four underwent liver transplantation and 14 (37%) recovered without transplantation after the MARS procedure.Conclusion. MARS is a safe and effective procedure, especially for ALF patients. Our results suggest that MARS therapy can contribute to native liver recovery in ALF patients.     

Management of primary biliary cirrhosis

Opinion statement Primary biliary cirrhosis is a chronic, progressive disease for which there is no definitive treatment. Ursodeoxycholic acid, however, is of benefit for delaying progression to irreversible end-stage liver disease and prolonging survival free of transplantation. It is, therefore, the standard medical therapy for primary biliary cirrhosis. Orthotopic liver transplantation can be offered for patients with end-stage disease. Other important endpoints of treatment in this condition include management of the long-term complications of cholestasis such as pruritus, osteoporosis, and fat-soluble vitamin deficiencies. Pruritus is best treated with cholestyramine; rifampicin, antihistaminics, opioid-antagonists, and ondansetron can also be tried. Osteoporosis should be treated with calcium and vitamin D supplementation. Bisphosphonates or vitamin K2 may be of additional benefit to decrease the risk of fractures, but this is unproved as of yet. Deficiencies of vitamins A, D, E, and K should be treated with appropriate replacement. Finally, orthotopic liver transplant is indicated for cases of liver failure, intractable pruritus, or severe osteoporosis.     

Rifampin relieves pruritus in children with cholestatic liver disease

Chronic cholestatic liver disease in children frequently results in severe intractable pruritus. Current forms of therapy, including cholestyramine, are usually ineffective. Therefore, a 6-wk, double-blind, crossover study was designed to test the ability of rifampin to relieve pruritus in children with chronic cholestasis. Rifampin proved effective in alleviating pruritus in all five children tested compared with a placebo-treated group. After the 6-wk study period, rifampin was continued for 6 mo, and its effectiveness was maintained. No complications resulted from rifampin use. This study and a similar study in older patients with primary biliary cirrhosis suggest that a highly effective form of therapy is available for treatment of severe pruritus in patients with chronic cholestasis. These patients must be carefully selected and frequently monitored.     

Relief of intractable pruritus in polycythemia vera with recombinant interferon alfa

Following reports that recombinant interferon alfa (rIFNα), besides inducing clinical and hematologic remission in polycythemia Vera (PV), can also resolve intractable pruritus, we used rIFNα to treat 13 PV patients complaining of severe pruritus refractory to conventional treatment (venesection and/or cytostatics). rFNα was administered intramuscularly three times a week at a dosage of 3.0 × 10⁶ U. Eight patients (61.5%) reported a ± 50% reduction of pruritus, which occurred within 2–8 weeks from the start of rIFNα treatment, leading to a substantial improvement in their quality of life. Three patients had to stop rIFNα within the first month of therapy because of unacceptable side effects. Thus rIFNα seems to be capable of providing considerable relief of otherwise intractable pruritus in a good proportion of PV patients.     

Pruritus in chronic liver disease: Mechanisms and treatment

Pruritus is a complication of liver disease. It can have a marked negative impact on quality of life; when intractable, it is an indication for liver transplantation. The cause of this type of pruritus is unknown. There is, however, evidence to suggest that the pruritus associated with liver disease is mediated, at least in part, by endogenous opioids. A central mechanism has been proposed. Therapeutic interventions have concentrated on the removal of presumed and unknown pruritogens from the circulation, hepatic enzyme induction, and, over the past decade, opiate antagonists, the first specific treatment for the pruritus of cholestasis. Other pharmacologic interventions that change neurotransmission have recently been reported to decrease the pruritus in patients with liver disease, as has a newly developed system that applies albumin-based dialysis. These interventions are promising, but they must be tested in properly controlled behavioral trials.     

Plasma separation and anion adsorption transiently relieve intractable pruritus in primary biliary cirrhosis

BACKGROUND/AIMS: Pruritus can be a severely disabling symptom in patients with primary biliary cirrhosis who do not respond to treatment with ursodeoxycholic acid, anion exchangers, enzyme inducers, or opiate antagonists. The aim of this study was to assess the clinical efficacy of plasma separation and anion adsorption in the treatment of intractable pruritus of cholestasis. METHODS: Three patients with primary biliary cirrhosis and intractable pruritus defined by severity of pruritus 7 on a rating scale between 0 (no pruritus) and 10 (maximal pruritus) on at least 4 of 7 days despite medical treatment were treated with plasma separation and anion adsorption on three consecutive days. Fatigue was assessed using the Fisk Fatigue Severity Score and quality of life was assessed by the PBC-40, a disease specific health related quality of life measure. RESULTS: Improvement in pruritus, fatigue, and quality of life was transiently observed in all patients. Serum bile acid levels showed no association with intensity of pruritus, and the bile acid pattern was not altered. The treatment was well tolerated by all patients. CONCLUSIONS: Plasma separation and anion adsorption seem to be a safe and effective therapeutic option for patients with primary biliary cirrhosis suffering from intractable pruritus.     

Partial Internal Biliary Diversion: A Solution for Intractable Pruritus in Progressive Familial Intrahepatic Cholestasis Type 1

Biliary diversion offers a potential option for intractable pruritus in children with chronic cholestatic disorders. Progressive familial intrahepatic cholestasis (PFIC) is an inherited disorder of impaired bile acid transport and excretion, which presents with jaundice and pruritus in the first few months of life and progresses to cirrhosis by infancy or adolescence. We report a child with PFIC type 1 who underwent internal biliary diversion for intractable pruritus and was relieved of his symptoms.     

Liver transplantation in an adult with sclerosing cholangitis due to Langerhans cell histiocytosis

Sclerosing cholangitis due to Langerhans cell histiocytosis (LCH) is a rare cause of end-stage liver disease, seen mainly in children. Only a few adult cases have been reported worldwide. Liver transplantation may be a viable treatment option for what is otherwise an irreversible condition. We describe a 65-year-old female with LCH who developed severe sclerosing cholangitis with jaundice, intractable pruritus and peritoneal disease. She underwent orthotopic liver transplantation with complete amelioration of symptoms and remained well 14 months following her operation. Explant histology confirmed LCH involvement with an associated extensive sclerosing cholangitis. Symptomatic LCH cholangiopathy is an emerging indication for liver transplantation in adults.     

Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: Outcome and therapeutic strategies

Recent evidence points towards the role of genotype to understand the phenotype, predict the natural course and long term outcome of patients with progressive familial intrahepatic cholestasis (PFIC). Expanded role of the heterozygous transporter defects presenting late needs to be suspected and identified. Treatment of pruritus, nutritional rehabilitation, prevention of fibrosis progression and liver transplantation (LT) in those with end stage liver disease form the crux of the treatment. LT in PFIC has its own unique issues like high rates of intractable diarrhoea, growth failure; steatohepatitis and graft failure in PFIC1 and antibody-mediated bile salt export pump deficiency in PFIC2. Drugs inhibiting apical sodium-dependent bile transporter and adenovirus-associated vector mediated gene therapy hold promise for future.     

Liver transplantation for cholestatic liver disease

Opinion statement Liver transplantation is an effective form of therapy for patients with end-stage cholestatic disease that improves both survival and quality of life. Liver transplantation is very effective for the treatment of intractable pruritus but less effective for the treatment of lethargy. Survival rates are good (more than 70% at 5 years); these patients are at greater risk of developing acute and chronic rejection and are more likely to require long-term immunosuppression. Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) recur in the graft. Recurrent PSC may be difficult to differentiate from secondary sclerosing cholangitis, but it recurs in up to 60% of patients at 5 years and may reduce graft survival. PBC recurrence, noted in up to 40% of patients at 10 years, has little effect on graft survival with respect to cancers. Patients with PSC are at greater risk of both colonic cancer (which may be reduced by ursodeoxycholic acid) and cholangiocarcinoma. Diagnosis of cholangiocarcinoma before transplantation usually contraindicates transplantation. The main challenges facing liver transplantation are the need to expand the donor pool and the need to find immunosuppressive regimens with fewer long-term toxicities.     

Treatment of severe refractory pruritus with fractionated plasma separation and adsorption (Prometheus)

OBJECTIVE: Severe pruritus is a serious complication of cholestatic liver disease. Prometheus is a recently introduced extracorporeal liver support system with direct toxin adsorption of the patient's albumin fraction (FPSA; fractionated plasma separation and adsorption). Here we report on the effect of Prometheus therapy in patients with intractable cholestatic pruritus. MATERIAL AND METHODS: Seven patients with different liver diseases and severe pruritus refractory to all medical treatment efforts for more than 4 weeks were treated with Prometheus (3-5 times, 18+/-3 h total). Pruritus intensity was assessed using the visual analogue scale (VAS; from 0 = no pruritus to 10 = unbearable pruritus), and VAS, serum bile acids and total bilirubin were evaluated directly before and after Prometheus treatment, as well as 4 weeks later. RESULTS: After Prometheus therapy, VAS values had dropped significantly from 9+/-1 to 3+/-3 (p<0.001). Likewise, serum bile acids decreased (from 248+/-192 to 101+/-85 micromol/l; p<0.03). All patients, with the exception of one with no initial bile acid elevation, reported a pronounced improvement in pruritus with Prometheus therapy, although in two anicteric patients the amelioration lasted only a few days. In the other four patients a distinct benefit was still observed 4 weeks after the treatment. CONCLUSIONS: Prometheus therapy significantly improved refractory pruritus in all patients with elevated bile acid levels, but in some patients the clinical benefit was of short duration. The clinical findings suggest that we have to better characterize those patients who might derive a long-lasting benefit from this invasive and expensive treatment.     

Propofol and Cholestatic Pruritus

Hepatic cholestatis is frequently associated with pruritus. This pruritus is often intractable and resistant to conventional treatment. We treated three patients with intractable cholestatic pruritus with subhypnotic doses of propofol, a new intravenous anesthetic induction agent. All patients rapidly became itch- and scratch-free for a period of 60-90 min. No sedation occurred; no other side effects were observed.     

Treatment of pruritus with Prometheus dialysis and absorption system in a patient with benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disorder characterized by recurrent episodes of jaundice and itching. Episodes of cholestasis last variously from 1 week to several months, may start at any age and usually resolve spontaneously. No effective treatment has been found as yet. We report a case of genetically proven BRIC in a male patient who developed three episodes of pruritus and jaundice at the age of 14, 16 and 19 years. During the third episode, he did not respond to pharmacological medical therapy, and fractionated plasma separation and absorption (FPSA, Prometheus) was performed to manage intractable pruritus. The treatment immediately alleviated pruritus, lowered serum bilirubin concentration and induced sustained remission in the 5‐year follow up. FPSA seems to be a safe and effective way of treatment for BRIC in patients with severe pruritus and prolonged jaundice.     

Fosinopril-induced prolonged cholestatic jaundice and pruritus: first case report

We report a case of fosinopril-induced prolonged cholestatic jaundice and pruritus in a 61-year-old man, with no previous hepatobiliary disease, who presented with asthenia, jaundice and itching 3 weeks after starting fosinopril therapy. Other drugs taken by the patient were not considered probable causes. The diagnostic evaluation showed no biliary obstruction and other possible causes of intra-hepatic cholestasis were excluded. Liver biopsy showed cholestasis without bile duct damage. The disease ran a severe course during the 2 months of hospitalization, with prolonged itching for 6 months, eventually controlled with oral naltrexone. Jaundice subsided after 4 months, with anicteric cholestasis persisting for more than 18 months. Similar occurrences have been reported with other inhibitors of angiotensin-converting enzyme (mostly captopril), but this is the first case of an important adverse reaction to fosinopril.