Diagnosis and management of Alagille and progressive familial intrahepatic cholestasis.

Alagille syndrome and progressive familial intrahepatic cholestasis are conditions that can affect multiple organs. Advancements in molecular testing have aided in the diagnosis of both. The impairment of normal bile flow and secretion leads to the various hepatic manifestations of these diseases. Medical management of Alagille syndrome and progressive familial intrahepatic cholestasis remains mostly targeted on supportive care focusing on quality of life, cholestasis, and fat-soluble vitamin deficiency. The most difficult therapeutic issue is typically related to pruritus, which can be managed by various medications such as ursodeoxycholic acid, rifampin, cholestyramine, and antihistamines. Surgical operations were previously used to disrupt enterohepatic recirculation, but recent medical advancements in the use of ileal bile acid transport inhibitors have shown great efficacy for the treatment of pruritus in both Alagille syndrome and progressive familial intrahepatic cholestasis.

Assessment of Pre-operative Vaginal Preparation for Laparoscopic Hysterectomy.

Objective: Determine the difference in microbial growth from the vagina and uterine manipulator among patients undergoing laparoscopic hysterectomy after randomization to one of three vaginal preparation solutions (10% Povidone-iodine, 2% Chlorhexidine, or 4% Chlorhexidine). Method: This was a prospective randomized controlled trial in an academic community hospital. Patients were ≥ 18 years old and scheduled for laparoscopic hysterectomy for benign and malignant indications. Results: Fifty patients were identified and randomized into each arm. Prior to surgery, the surgical team prepared the vaginal field using 10% Povidone-iodine, 2% Chlorhexidine, or 4% Chlorhexidine, according to group assignment. Cultures were collected from the vagina after initial preparation, prior to the colpotomy, and on surfaces of the uterine manipulator. Bacterial count from the baseline vaginal fornix/cervical canal cultures did not differ significantly among the three groups. There was a difference in bacterial count among the second cervical canal/vaginal fornix cultures (p < 0.01), with the Povidone-iodine arm demonstrating the highest level of growth of cultures (93.8%), followed by 2% Chlorhexidine (47.4%), and 4% Chlorhexidine (20%). There was no difference in growth on the uterine manipulator handle and no difference in vaginal itching or burning was found across the three arms postoperatively. Conclusion: Bacterial growth prior to colpotomy was the lowest with 4% Chlorhexidine followed by 2% Chlorhexidine, the Povidone-iodine group exhibited the highest bacterial growth. There was no difference in moderate to severe vaginal itching or burning. This showed that 4% Chlorhexidine is superior in reducing bacterial growth when used in laparoscopic hysterectomy.

Long-Term Outcomes of Patients With Progressive Familial Intrahepatic Cholestasis After Biliary Diversion.

OBJECTIVES: Progressive familial intrahepatic cholestasis is a heterogeneous group of genetic disorders characterized by disrupted bile homeostasis. Patients with this disease typically present with cholestasis and pruritus early in life and often progress to end-stage liver disease. The clinical symptoms that patients with progressive familial intrahepatic cholestasis encounter are usually refractory to medical treatment. Although the effects of biliary diversion surgery on native liver survival are not exactly known, this procedure may provide a positive impact on pruritus and laboratory parameters in these patients. MATERIALS AND METHODS: We retrospectively evaluated the clinical and laboratory characteristics of patients with progressive familial intrahepatic cholestasis who underwent partial external biliary diversion between 2002 and 2020 at our center. Diagnosis of progressive familial intrahepatic cholestasis was made by clinical, biochemical, and histopathological characteristics as well as genetic testing. RESULTS: Nine patients were included in the study. Five patients required liver transplant during follow-up, with 4 having liver transplant as a result of endstage liver disease (median interval of 5 years). In 1 patient, partial external biliary diversion was performed 1.5 years after liver transplant for severe diarrhea, metabolic acidosis, and hepatic steatosis. Four patients did not require liver transplant during follow-up (median follow-up time of 7.6 years). Pruritus responded well to partial external biliary diversion in all patients. Among laboratory values evaluated 6 months after biliary diversion, only albumin showed significant improvement. CONCLUSIONS: Partial external biliary diversion had favorable results on long-term follow-up. This procedure can provide the relief of pruritus and delay the requirement for liver transplant in patients with progressive familial intrahepatic cholestasis. In our view, partial external biliary diversion should be considered the first-line surgical management for patients with this disease.

Patient reported vaginal laxity, sexual function and stress incontinence improvement following vaginal rejuvenation with fractional carbon dioxide laser.

In this study, we have evaluated the efficiency of fractional carbon dioxide laser in the treatment of vaginal laxity and urinary incontinence. Thirty patients with vaginal laxity, sexual dysfunction and urinary incontinence complaints were treated with fractional carbon dioxide laser. Results were evaluated with patient questionnaires relating to comfort during the procedure and general satisfaction following the procedure. In the survey regarding comfort during the procedure, 90% (n:27) of the patients reported that they were comfortable during the procedure. The survey on the level of general satisfaction six months following the procedure revealed high-moderate level of satisfaction in 86% (n:26) of the patients. 66% (n:20) of the patients reported improved vaginal tightness and 63% (n:19) of the patients reported improvement in the quality of their sexual activity. Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire(PISQ-12) scores six months following the procedure were not significantly different when compared to the scores prior to the procedure. The average of Questionnaire for Urinary Incontinence Diagnosis(QUID) score prior to the procedure and six months following the procedure was 7.5 and 0.9 respectively (p < 0.05). Fractional carbon dioxide laser treatment results in high level of satisfaction and improvement in vaginal laxity, sexual dysfunction and urinary incontinence symptoms in patients with genitourinary syndrome.

Partial Biliary Diversion May Promote Long-Term Relief of Pruritus and Native Liver Survival in Children with Cholestatic Liver Diseases.

INTRODUCTION: Rare cholestatic liver diseases may cause debilitating pruritus in children. Partial biliary diversion (PBD) may relieve pruritus and postpone liver transplantation which is the only other alternative when conservative treatment fails. The aim was to report long-term outcome after PBD in a population of 26 million people during a 25-year period. MATERIALS AND METHODS: This is an international, multicenter retrospective study reviewing medical journals. Complications were graded according to the Clavien-Dindo classification system. RESULTS: Thirty-three patients, 14 males, underwent PBD at a median of 1.5 (0.3-13) years at four Nordic pediatric surgical centers. Progressive familial intrahepatic cholestasis was the most common underlying condition. Initially, all patients got external diversion, either cholecystojejunostomy (25 patients) or button placed in the gallbladder or a jejunal conduit. Early complications occurred in 14 (42%) patients, of which 3 were Clavien-Dindo grade 3. Long-term stoma-related complications were common (55%). Twenty secondary surgeries were performed due to stoma problems such as prolapse, stricture, and bleeding, or conversion to another form of PBD. Thirteen children have undergone liver transplantation, and two are listed for transplantation due to inefficient effect of PBD on pruritus. Serum levels of bile acids in the first week after PBD construction were significantly lower in patients with good relief of pruritus than in those with poor effect (13 [2-192] vs. 148 [5-383] µmol/L; p = 0.02). CONCLUSION: PBD may ensure long-term satisfactory effect on intolerable pruritus and native liver survival in children with cholestatic liver disease. However, stoma-related problems and reoperations are common.

Ileal exclusion for pruritus treatment in children with progressive familial intrahepatic cholestasis and other cholestatic diseases.

BACKGROUND: Pruritus is a major health-related quality-of-life burden in progressive familial intrahepatic cholestasis (PFIC) and other childhood cholestatic liver diseases. Several nontransplant surgical techniques were developed in an attempt to ameliorate symptoms and slow disease progression. Very few case-series have been published on a particular intervention, ileal exclusion (IE), which has been considered to be inferior to the other approaches. METHODS: We conducted a single-center retrospective chart-review case-series of patients submitted to IE as the first-line surgical treatment at our institution from 1995 to 2018. The primary goal was pruritus relief, followed by survival with the native liver and improvement in biochemical parameters. RESULTS: Eleven patients were submitted to IE, with a mean follow-up of 60 months. Complete resolution or significant reduction of pruritus was obtained in 72.7% (n = 8) of patients. One patient (9.1%) had a major postoperative complication that required surgery. No other morbidities were reported. Two cases progressed to end-stage liver disease (ESLD) within the short-term and one year after surgery. CONCLUSIONS: This case series study shows that IE provided excellent results in pruritus control and permitted survival with the native liver. We believe IE is a safe procedure, with few associated morbidities, and should be considered more often as primary surgical treatment for PFIC and other cholestasis. LEVEL OF EVIDENCE: IV.

Long-term outcomes of six patients after partial internal biliary diversion for progressive familial intrahepatic cholestasis.

BACKGROUND: Partial internal biliary diversion (PIBD) is an alternative approach for the treatment of devastating pruritus in patients with progressive familial intrahepatic cholestasis (PFIC). In these patients quality of life can be improved and progression of liver disease can be delayed while waiting for liver transplantation. The aim of our study was to evaluate six patients with PFIC who have undergone PIBD in long-term follow-up. METHODS: Retrospective review of the records of six patients who underwent PIBD for PFIC between 2008 and 2010 was conducted to evaluate age, growth, clinical and laboratory studies for long-term outcome. RESULTS: Serum postoperative bile acid levels were reduced from a mean 340.1µmol/L (range 851-105) preoperatively to a mean of 96.3µmol/L at postoperative fifth year. The difference between pre- and postoperative bile acid levels was statistically significant (p=0.018). AST decreased from 79.1U/L (range 43-150U/L) to 64.6U/L (range 18-172U/L), ALT decreased from 102.8U/L (range 35-270U/L) to 84.6U/L and total bilirubin decreased from 2.9µmol/L (range 0.35-6.4µmol/L) to 1.53µmol/L (range 0.3-2.4). Again, the decrease in total bilirubin levels was significant (p=0.043). Pruritus was diminished from a mean of +4 (range 4-4) preoperatively to a mean of +2 (4-0). One patient who underwent liver transplantation owing to relapsing pruritus died from postoperative sepsis in the early postoperative period at the fifth year after PBID. Five symptom-free patients have not required liver transplantation at a mean period of 6.1±0.83years (5.1-7.0years) follow-up. CONCLUSION: PBID is an effective surgical procedure in the long-term and can delay the need for liver transplantation in children with PFIC by reducing jaundice and pruritus.

Clinical Variability After Partial External Biliary Diversion in Familial Intrahepatic Cholestasis 1 Deficiency.

OBJECTIVES: Familial intrahepatic cholestasis 1 (FIC1) deficiency is caused by a mutation in the ATP8B1 gene. Partial external biliary diversion (PEBD) is pursued to improve pruritus and arrest disease progression. Our aim is to describe clinical variability after PEBD in FIC1 disease. METHODS: We performed a single-center, retrospective review of genetically confirmed FIC1 deficient patients who received PEBD. Clinical outcomes after PEBD were cholestasis, pruritus, fat-soluble vitamin supplementation, growth, and markers of disease progression that included splenomegaly and aspartate aminotransferase-to-platelet ratio index. RESULTS: Eight patients with FIC1 disease and PEBD were included. Mean follow-up was 32 months (range 15-65 months). After PEBD, total bilirubin was <2 mg/dL in all patients at 8 months after surgery, but 7 of 8 subsequently experienced a total of 15 recurrent cholestatic events. Subjective assessments of pruritus demonstrated improvement, but itching exacerbation occurred during cholestatic episodes. High-dose fat-soluble vitamin supplementation persisted, with increases needed during cholestatic episodes. Weight z scores improved (-3.4 to -1.65, P < 0.01). Splenomegaly did not worsen or develop and 1 patient developed an aminotransferase-to-platelet ratio index score of >0.7 suggesting development of fibrosis 24 months after PEBD. CONCLUSIONS: Clinical variability is evident among genetically defined FIC1 deficient patients after PEBD, even among those with identical mutations. Recurrent, self-limited episodes of cholestasis and pruritus are reminiscent of the benign recurrent intrahepatic cholestasis phenotype. Despite diversion of bile from the intestinal lumen, weight gain improved while fat-soluble vitamin requirements persisted. Significant progression of liver disease was not evident during follow-up.

Different techniques for biliary diversion in progressive familial intrahepatic cholestasis.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a cholestatic liver disease of childhood. Pruritus resulting from increased bile salts in serum might not respond to medical treatment, and internal or external biliary drainage methods have been described. In this study, we aimed to evaluate different internal drainage techniques in patients with PFIC. PATIENTS AND METHODS: Between 2009 and 2014, seven children (4 male, 3 female, 3months-5years old), (median 2years of age) with PFIC were evaluated. The patients were reviewed according to age, gender, complaints, surgical technique, laboratory findings and outcome. In each two patients, cholecystoileocolonic anastomosis, cholecystojejunocolonic anastomosis and cholecystocolostomy were performed. Cholecysto-appendico-colonic anastomosis was the technique used in one patient. RESULTS: Jaundice and excessive pruritus were the main complaints. One of the patients with cholecystoileocolonic anastomosis died of comorbid pathologies (cirrhosis, adhesive obstruction and severe sepsis). Temporary rectal bleeding was observed in all the patients postoperatively. Regardless of the surgical technique, pruritus was dramatically decreased in all the patients in the postoperative period. CONCLUSION: Regardless of the technique, internal biliary diversion methods are beneficial for the relief of pruritus in PFIC patients. Selection of the surgical method might vary depending on the surgeon's preference and the surgical anatomy of the gastrointestinal system of the patient.

Total biliary diversion as a treatment option for patients with progressive familial intrahepatic cholestasis and Alagille syndrome.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) with low gamma-glutamyl transpeptidase (GGT) and Alagille syndrome are associated with persistent cholestasis and severe pruritus. Various types of biliary diversion have been used to reduce this pruritus and prevent liver dysfunction. We report our experience concerning the efficacy and safety of total biliary diversion (TBD) as an additional treatment option. METHODS: TBD was performed in four PFIC patients and one patient with Alagille syndrome, and was accomplished by anastomosing a jejunal segment to the choledochal duct terminating as an end stoma, or by disconnecting the choledochal duct after previous cholecystojejunocutaneostomy. RESULTS: TBD resulted in a marked improvement of symptoms and biochemical parameters in all PFIC patients. Despite relief of pruritus, cholestasis persisted in the Alagille patient. During 5-15years of follow-up, no clinical signs of fat malabsorption such as diarrhea or weight loss were encountered. However, to maintain adequate levels of fat-soluble vitamins, especially of vitamin K, substantial supplementation was necessary. CONCLUSIONS: Total biliary diversion can be a useful surgical treatment option for patients with low-GGT PFIC and possibly also Alagille syndrome, when partial biliary diversion is insufficient. It can be performed without inducing clinical signs of fat malabsorption although individualized supplementation of fat-soluble vitamins with careful monitoring is warranted.

Outcome of partial internal biliary diversion for intractable pruritus in children with cholestatic liver disease.

PURPOSE: Children with cholestatic disorders have undergone liver transplantation for intractable pruritus unresponsive to medical therapy even in the absence of liver failure. Biliary diversion procedures interrupt the entero-hepatic circulation of bile acids allowing them to be excreted in the feces thereby lowering the total bile acid pool. We evaluated the outcome of partial internal biliary diversion (PIBD) in children with intractable pruritus from inherited cholestatic disorders. METHODS: The records of children who underwent PIBD over a 4-year period were reviewed for etiology of liver disease, demographic data, preoperative and postoperative biochemical profile and improvement of pruritus. Standard statistical methods were used for analysis. RESULTS: Of the 12 children, 10 had progressive familial intrahepatic cholestasis (PFIC) and 2 had Alagille syndrome (AS). PIBD was done using an isolated jejunal loop as a conduit from gall bladder to mid ascending colon. Median period of follow up was 30 months. Pruritus resolved in nine children with significant reduction of serum bile acids (P < 0.02). CONCLUSION: To our knowledge, this is the largest reported series of children with PIBD. PIBD is a safe, well-tolerated and effective alternative to liver transplant in children with PFIC and AS who have intractable pruritus in the absence of synthetic liver failure.

Temporomandibular joint disorder and inner ear pruritus: resolution by eminectomy.

Recurrent dislocation of the temporomandibular joint (TMJ) disk is caused by many factors. Dislocation can result in an acute or chronic closed lock condition. Temporomandibular joint dysfunction is often presented with otalgia symptoms. Other aural symptoms such as deafness, tinnitus, pressure/blockage, and vertigo are also commonly presented together with TMJ dysfunction (Clin Otolaryngol Allied Sci. 1980;5:23-36). However, pruritus associated with TMJ dysfunction in the inner ear has never been reported in the literature. We report a case history of TMJ dysfunction and associated inner ear pruritus, which are both resolved by eminectomy.

Liver transplant in a case of arthrogryposis-renal tubular dysfunction-cholestasis syndrome with severe intractable pruritus.

Arthrogryposis-renal tubular dysfunction-cholestasis syndrome (MIM No. 208085) is a rare multisystem disorder involving the liver, kidney, skin, and central nervous and musculoskeletal systems. The syndrome is an autosomal-recessive trait, associated with germ-line mutations in the VPS33B gene. We report an Iranian boy of consanguineous cousin parents who had congenital deformities of the upper and lower extremities, severe ichthyosis, cholestasis, intractable pruritus, metabolic acidosis, and failure to thrive. Owing to cholestasis, severe intractable pruritus, and poor quality of life, he underwent a living-related liver transplant from his mother, and his ichthyosis and pruritus dramatically improved. To the best of our knowledge, this is a first case of someone with arthrogryposis-renal tubular dysfunction-cholestasis syndrome who underwent a liver transplant and is in good condition more than 5 years after surgery.

Early repeat endoscopic retrograde cholangiopancreatography: predictive factors and interventions required.

BACKGROUND/AIMS: Early repeat endoscopic retrograde cholangiopancreatography may be required due to various conditions in patients who underwent planned endoscopic retrograde cholangiopancreatography. We aimed to assess the factors leading to early repeat endoscopic retrograde cholangiopancreatography and to determine the patients who need closer follow-up. MATERIALS AND METHODS: A total of 691 patients with a mean age of 60.3±16.4 years who had naive papilla on endoscopic retrograde cholangiopancreatography were involved in the study. The patients who required repeat endoscopic retrograde cholangiopancreatography were identified. Presentations, predictive factors, treatment modalities, and outcomes of the patients were investigated. RESULTS: Early repeat endoscopic retrograde cholangiopancreatography was needed in 19 (2.7%) patients. The most common presentation was cholangitis in 10 (52.6%) and unresolved jaundice in 4 (21.1%). Multivariate analysis identified biliary stricture (p=0.024), stricture at the hilus (p=0.005) and unilateral drainage in the presence of hilar stricture (p=0.017) as the independent risk factors for early repeat endoscopic retrograde cholangiopancreatography. Stent migration or dysfunction was the most common underlying cause. Therapeutic interventions were nasobiliary drainage in 13, stent exchange in 4 and stone removal in 2. Additionally, percutaneous drainage in 4 patients, drainage of abscess in 2 patients and percutaneous drainage of gallbladder in 1 patient were performed. Three patients died due to their underlying illness. CONCLUSIONS: Unilateral stenting especially in hilar strictures is a predictive factor for early repeat endoscopic retrograde cholangiopancreatography with high mortality. These patients should be under close follow-up.

Long-term outcome after partial external biliary diversion for progressive familial intrahepatic cholestasis.

BACKGROUND: Though patients with progressive familial intrahepatic cholestasis (PFIC) typically require liver transplantation, initial surgical treatment includes partial biliary diversion (PBD) to relieve jaundice-associated pruritus. This study was undertaken to describe long-term PFIC outcome data, which are currently sparsely reported. METHODS: Retrospective review of 7 patients diagnosed with PFIC who underwent PBD between 2004 and 2008 was directed toward long-term postoperative outcome including resolution of jaundice/pruritus, stoma complications, interval to transplantation, and death. RESULTS: Six patients who underwent PBD experienced short-term resolution of jaundice and pruritus. Four patients experienced persistent stoma-related complications requiring a total of 14 revisions. Three symptom-free patients have not yet required liver transplantation post-PBD (average, 70 months; range, 59-78 months). Two patients underwent orthotopic liver transplantation (average, 44 +/- 18 months post-PBD). Two patients died at home because of gastroenteritis-associated dehydration before transplantation. CONCLUSION: Partial biliary diversion for PFIC is effective as a bridge to liver transplantation in improving jaundice and pruritus but may be associated with a high incidence of stoma-related complications. Persistent or recurrent pruritus after PFIC is associated with an increased risk of stoma prolapse or reflux. Insufficiently replaced stomal losses over time may increase the risk of dehydration-related complications in association with gastroenteritis.

Partial external biliary diversion in children with progressive familial intrahepatic cholestasis and Alagille disease.

BACKGROUND: Partial external biliary diversion (PEBD) is a promising treatment for children with progressive familial intrahepatic cholestasis (PFIC) and Alagille disease. Little is known about long-term outcomes. PATIENTS AND METHODS: A retrospective chart review of all patients undergoing PEBD in the University Medical Centre of Groningen (UMCG). RESULTS: Between 2000 and 2005, PEBD was performed on 14 children with severe pruritus (PFIC 11, mean age 5.3 +/- 4.4 years; Alagille 3, mean age 7.4 +/- 4.2 years). Stature was <-2 standard deviation score (SDS) in 50%. Median preoperative serum bile salt concentration was 318 micromol/L (range 23-527 micromol/L). Twenty-nine percent had severe liver fibrosis and 71% had mild or moderate fibrosis. Median follow-up was 3.1 years (range 2.0-5.7 years). One patient (7%) underwent a liver transplantation at 3.2 years post-PEBD. Two years postoperatively, 50% were without pruritus and 21% had mild pruritus. In 29%, pruritus had not diminished; 3 of them had severe fibrosis preoperatively. In patients with mild or moderate fibrosis, PEBD decreased serum bile salts (105 micromol/L [range 8-269 micromol/L] 2 years postoperatively). Bile salts did not decrease in the patients with severe fibrosis. Two years after PEBD, 27% had a stature below -2 SDS. CONCLUSIONS: At median follow-up of 3.1 years after PEBD, pruritus has been relieved in 75%. Bile salts level and growth are improved in most patients. Longer follow-up is needed to determine whether PEBD can postpone or avoid the demand for liver transplantation.