miRNA and miRNA target genes in intervention effect of Zhuyu pill on cholestatic rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: Zhuyu pill (ZYP), an effective prescription of traditional Chinese medicine, is composed of Coptis chinensis Franch. and Tetradium ruticarpum (A. Jussieu) T. G. Hartley and has shown potential anticholestatic effects. However, its mechanism of action in treating cholestasis remains unclear. Since post-transcriptional control of mRNA by micro-RNAs (miRNAs) represents an important mechanism of gene regulation, it is promising to explore this in relation to ZYP and cholestasis. AIM OF THE STUDY: To confirm the anticholestatic effect of ZYP and to explore its potential biological mechanism. MATERIALS AND METHODS: In this study, a cholestasis rat model was induced by α-naphthyl-isothiocyanate (ANIT, 50 mg/kg) and treated with ZYP (low dose: 0.6 g/kg, high dose: 1.2 g/kg). Serum biochemistry indices and liver histopathology were used to evaluate the model and efficacy, and miRNA sequencing was used to measure differences in miRNA expression in the liver between the control, model, low-dose ZYP, and high-dose ZYP groups. To verify the accuracy of sequencing results and explore the potential anti-cholestasis mechanism of ZYP, RT-PCR was used to identify differentially expressed miRNAs and their target genes. RESULTS: Both high- and low-dose ZYP exhibited significant anticholestatic effects, with the high-dose showing better effects than low-dose ZYP. Additionally, four differentially expressed miRNAs, rno-miR-147, rno-miR-20b-5p, rno-miR-29b-3p, and rno-miR-3586-3p, were found to be upregulated in cholestasis and downregulated after ZYP intervention. Eight target genes of the above miRNAs, including ABCG8, CLOCK, PLEC, SLC4A2, NEB, ADAMTS12, TTN and FAM174B were inhibited in cholestatic rats, exhibiting up-regulated expression tendencies after ZYP intervention, and the expression tendencies were significant negatively correlated with serum biochemical indices. CONCLUSIONS: ZYP can significantly reduce liver biochemical indices and improve liver tissue damage in cholestasis rats through the regulation of miRNA expression in the liver, producing a positive regulatory effect on bile excretion-related genes.

Protective effects of n-Butanol extract and iridoid glycosides of Veronica ciliata Fisch. Against ANIT-induced cholestatic liver injury in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Veronica ciliata Fisch. is a traditional medical herb that present in more than 100 types of Tibetan medicine prescriptions, most of which are used for liver disease therapy. Iridoid glycosides have been identified as the major active components of V.ciliata with a variety of biological activities. AIMS OF THE STUDY: The aim of this study is to explore the protective effect and potential mechanism of n-Butanol extract (BE) and iridoid glycosides (IG) from V.ciliata against ɑ-naphthyl isothiocyanate (ANIT)-induced hepatotoxicity and cholestasis in mice. MATERIALS AND METHODS: Mice were intragastrically (i.g.) given BE and IG at different dose or positive control ursodeoxycholic acid (UCDA) once a day for 14 consecutive days, and were treated with ANIT to cause liver injury on day 12th. Serum levels of hepatic injury markers and cholestasis indicators, liver index and liver histopathology were measured to evaluate the effect of BE and IG on liver injury caused by ANIT. The protein levels of tumor necrosis factor-α (TNF-α), nuclear factor kappa B(NF-κB), interleukin-6 (IL-6), Na+/taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), and the levels of oxidative stress indicators in liver tissue were investigated to reveal the underlying protective mechanisms of BE and IG against ANIT-induced hepatotoxicity and cholestasis. RESULTS: The n-Butanol extract (BE) and iridoid glycosides (IG) isolated from V.ciliata significantly decreased serum level of cholestatic liver injury markers aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), total bile acid (TBA), total bilirubin (TBIL), and direct bilirubin (DBIL) in ANIT-treated mice. Histopathology of the liver tissue showed that pathological damages were relieved upon BE and IG treatment. Meanwhile, the results indicated BE and IG notably restored relative liver weights, inhibited oxidative stress induced by ANIT through increasing hepatic level of superoxide dismutase (SOD), reduced glutathione (GSH), catalase (CAT) and decreasing hepatic content of malondialdehyde (MDA). Western blot revealed that BE and IG inhibited the expression of pro-inflammatory factors TGF-α, IL-6 and NF-κB. Furthermore, the decreased protein expression of bile acid transporters NTCP, BSEP, MRP2 were upregulated by BE and IG in a dose-dependent manner. CONCLUSION: The results have demonstrated that BE and IG exhibited a dose-dependently protective effect against ANIT-induced liver injury with acute intrahepatic cholestasis in mice, which might be related to the regulation of oxidative stress, inflammatory response and bile acid transport. In addition, these findings pointed out that iridoid glycosides as main active components of V.ciliata play a critical role in hepatoprotective effect of V.ciliata.

Picroside II protects against cholestatic liver injury possibly through activation of farnesoid X receptor.

BACKGROUD: Cholestasis, accompanied by the accumulation of bile acids in body, may ultimately cause liver failure and cirrhosis. There have been limited therapies for cholesteric disorders. Therefore, development of appropriate therapeutic drugs for cholestasis is required. Picroside II is a bioactive component isolated from Picrorhiza scrophulariiflora Pennell, its mechanistic contributions to the anti-cholestasis effect have not been fully elucidated, especially the role of picroside II on bile acid homeostasis via nuclear receptors remains unclear. PURPOSE: This study was designed to investigate the hepatoprotective effect of picroside II against alpha-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury and elucidate the mechanisms in vivo and in vitro. METHODS: The ANIT-induced cholestatic mouse model was used with or without picroside II treatment. Serum and bile biochemical indicators, as well as liver histopathological changes were examined. siRNA, Dual-luciferase reporter, quantitative real-time PCR and Western blot assay were used to demonstrate the farnesoid X receptor (FXR) pathway in the anti-cholestasis effects of picroside II in vivo and in vitro. RESULTS: Picroside II exerted hepatoprotective effect against ANIT-induced cholestasis by impaired hepatic function and tissue damage. Picroside II increased bile acid efflux transporter bile salt export pump (Bsep), uptake transporter sodium taurocholate cotransporting polypeptide (Ntcp), and bile acid metabolizing enzymes sulfate transferase 2a1 (Sult2a1) and UDP-glucuronosyltransferase 1a1 (Ugt1a1), whereas decreased the bile acid synthesis enzymes cholesterol 7α-hydroxylase (Cyp7a1) and oxysterol 12α-hydroxylase (Cyp8b1). In addition, expression of FXR and the target gene Bsep was increased, whereas aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), peroxisome proliferator-activated receptor alpha (PPARα) and their corresponding target genes were not significantly influenced by picroside II under cholestatic conditions. Furthermore, regulation of transporters and enzymes involved in bile acid homeostasis by picroside II were abrogated by FXR silencing in mouse primary cultured hepatocytes. Dual-luciferase reporter assay performed in HepG2 cells demonstrated FXR activation by picroside II. CONCLUSION: Our findings demonstrate that picroside II exerts protective effect on ANIT-induced cholestasis possibly through FXR activation that regulates the transporters and enzymes involved in bile acid homeostasis. Picroside II might be an effective approach for the prevention and treatment of cholestatic liver diseases.

Bone Health in Patients With Liver Diseases.

Osteoporosis is the most common bone disease in chronic liver disease (CLD) resulting in frequent fractures and leading to significant morbidity in this population. In addition to patients with cirrhosis and chronic cholestasis, patients with CLD from other etiologies may be affected in the absence of cirrhosis. The mechanism of osteoporosis in CLD varies according to etiology, but in cirrhosis and cholestatic liver disease it is driven primarily by decreased bone formation, which differs from the increased bone resorption seen in postmenopausal osteoporosis. Direct toxic effects from iron and alcohol play a role in hemochromatosis and alcoholic liver disease, respectively. Chronic inflammation also has been proposed to mediate bone disease in viral hepatitis and nonalcoholic fatty liver disease. Treatment trials specific to osteoporosis in CLD are small, confined to primary biliary cholangitis and post-transplant patients, and have not consistently demonstrated a benefit in this population. As it stands, prevention of osteoporosis in CLD relies on the mitigation of risk factors such as smoking and alcohol use, treatment of underlying hypogonadism, and encouraging a healthy diet and weight-bearing exercise. The primary medical intervention for the treatment of osteoporosis in CLD remains bisphosphonates though a benefit in terms of fracture reduction has never been shown. This review outlines what is known regarding the pathogenesis of bone disease in CLD and summarizes current and emerging therapies.

Cholestasis affects enteral tolerance and prospective weight gain in the NICU.

BACKGROUND: Intestinal Failure-Associated Liver Disease is characterized by cholestasis and hepatic dysfunction due to parenteral nutrition (PN) therapy. We described key features of cholestatic infants receiving PN to assess overall outcomes in this population at our institution. METHODS: This is a retrospective single center study of 163 neonates grouped into cholestatic (n = 63) and non-cholestatic (n = 100) as defined by peak conjugated bilirubin of ≥2.0 mg/dL or < 0.8 mg/dL, respectively. Univariate and multiple regression models were used to study associations between variables and outcomes of interest. RESULTS: Lower Apgar scores (4 ± 3 vs. 6 ± 3, p-value = <0.005 at 1 min; 6 ± 2 vs. 7 ± 2, p < 0.005 at 5 min) and lower birth weight (adj ß [SE] = 0.62 [0.27], p-value = 0.024) were risk factors for developing cholestasis. Cholestatic infants were more likely to have had gastrointestinal surgery (31 [49%] vs. 15 [15%], p-value <0.005), received PN for a longer duration (40 ± 39 days vs. 11 ± 7 days, p-value <0.005), and started enteral feeds later in life (86 ± 23 days vs. 79 ± 20 days, p-value <0.005) when compared to non-cholestatic infants. Weight percentiles in cholestatic infants were lower both at hospital discharge (14 ± 19 vs. 24 ± 22, p-value <0.005) and at 6 months of age (24 ± 28 vs. 36 ± 31, p-value = 0.05). CONCLUSIONS: Cholestasis in the NICU is a multifactorial process, but it has a long lasting effect on prospective weight gain in infants who receive PN in the NICU. This finding highlights the importance of follow-up for adequate growth and the potential benefit from aggressive nutritional support.

Fish oil-based lipid emulsion in the treatment of parenteral nutrition-associated cholestasis.

BACKGROUND: Parenteral nutrition-associated cholestasis (PNAC) is a serious complication in preterm infants receiving prolonged parenteral nutrition. Soybean lipid emulsion (SLE) seems to have a role in its pathogenesis, whereas fish oil-based emulsion (FOLE) seems to be able to reverse cholestasis. This study aimed to evaluate the effectiveness of a FOLE in reversing PNAC. METHODS: The effectiveness in reversing PNAC was evaluated in prospective cohort study of very preterm infants when compared to historical controls: twenty-six infants (27.0 ± 2.6 weeks GA; 724 ± 204 g) who developed cholestasis while receiving SLE were shifted to receive FOLE and were compared with 30 infants (27.3 ± 2.5 weeks GA¸ 838 ± 277 g) who continued to receive SLE at diagnosis of cholestasis. RESULTS: Time to reversal of cholestasis was the same in the two study groups (45 ± 21 vs 43 ± 32 days). CONCLUSIONS: FOLE does not seem to be superior to SLE in reversing cholestasis. Considering that definitive data on the actual efficacy of FOLE to reverse PNAC are lacking, larger randomized trials are required, mainly to asses if FOLE may have a role in PNAC prevention rather than PNAC treatment.

Mitochondria protection as a mechanism underlying the hepatoprotective effects of glycine in cholestatic mice.

Cholestasis is the stoppage of bile flow which could lead to serious clinical complications if not managed. Cytotoxic bile acids are involved in the pathogenesis of liver injury during cholestasis. There are no promising pharmacological interventions against cholestasis and its associated complications. This study examined the impact of glycine supplementation on liver mitochondria as a major target of bile acids-induced toxicity during cholestasis. Mice underwent BDL operation and received glycine (0.25% and 1% w:v in drinking water). Blood and liver samples were collected at scheduled time intervals (3, 7, and 14 days after BDL surgery). Plasma biomarkers of liver injury, along with markers of oxidative stress in the liver tissue were evaluated. Furthermore, liver mitochondria were isolated, and several mitochondrial indices were assessed. BDL-induced cholestasis was evident in mice as a significant elevation in plasma biomarkers of liver injury. Markers of oxidative stress were significantly increased in the liver of BDL animals. Liver injury was histopathologically evident by tissue necrosis, bile duct proliferation, hydropic changes, inflammation, and fibrosis. Furthermore, high level of reactive oxygen species, lipid peroxidation, depleted glutathione reservoirs, and impaired tissue antioxidant capacity were also detected in the liver of cholestatic mice. An assessment of liver mitochondrial function in BDL animals revealed an inhibition of mitochondrial dehydrogenases activity, collapse of mitochondrial membrane potential, mitochondrial swelling, and increase of reactive oxygen species (ROS), and lipid peroxidation (LPO). Furthermore, a significant decrease in mitochondrial ATP was detected in the liver mitochondria isolated from cholestatic animals. Glycine supplementation (0.25% and 1%) decreased mitochondrial swelling, ROS, and LPO. Moreover, glycine treatment improved mitochondrial membrane potential and restored liver mitochondrial ATP. On the other hand, it was found that glycine supplementation attenuated oxidative stress markers in the liver of BDL animals. Moreover, liver histopathological changes and collagen deposition were markedly mitigated by glycine treatment. The mechanisms for the beneficial effects of glycine administration in cholestatic animals might be linked to its ability for preserving cellular redox environment, preventing oxidative stress, and maintaining mitochondrial functionality.

Cholestatic hepatitis after diagnostic ajmaline challenge.

We report a cholestatic hepatitis in an elderly woman after ajmaline challenge during electrophysiological testing for Brugada syndrome. No other medication was reported in the previous 6 months of the onset of jaundice. Liver biopsy showed a cholestatic hepatitis with mild biliary damage. Liver enzymes normalized within 2 weeks as well as jaundice. To the best of our knowledge this is the second case of histologically proved cholestatic hepatitis induced by intravenous ajmaline testing.

Predictors of failure of fish-oil therapy for intestinal failure-associated liver disease in children.

BACKGROUND: Parenteral fish-oil (FO) therapy is a safe and effective treatment for intestinal failure-associated liver disease (IFALD). Patients whose cholestasis does not resolve with FO may progress to end-stage liver disease. OBJECTIVE: We sought to identify factors associated with the failure of FO therapy in treating IFALD to guide prognostication and referral guidelines. DESIGN: Prospectively collected data for patients treated with FO at Boston Children's Hospital from 2004 to 2014 were retrospectively reviewed. Resolution of cholestasis was defined as sustained direct bilirubin (DB) <2 mg/dL, and treatment failure as liver transplantation or death while DB was >2 mg/dL as of July 2015. Demographics, laboratory values, and medical history at FO therapy initiation were compared between patients who achieved resolution of cholestasis and those who failed therapy. RESULTS: Among 182 patients treated with FO, 86% achieved resolution of cholestasis and 14% failed therapy. Patients who failed therapy had median (IQR) lower birth weight [1020 g (737, 1776 g) compared with 1608 g (815, 2438 g); P = 0.03] and were older at FO initiation [20.4 wk (9.9, 38.6 wk) compared with 11.7 wk (7.3, 21.4 wk); P = 0.02] than patients whose cholestasis resolved. Patients who failed therapy had more advanced liver disease at therapy initiation than patients whose cholestasis resolved, as evidenced by lower median (IQR) γ-glutamyltransferase [54 U/L (41, 103 U/L) compared with 112 U/L (76, 168 U/L); P < 0.001], higher DB [10.4 mg/dL (7.5, 14.1 mg/dL) compared with 4.4 mg/dL (3.1, 6.6 mg/dL); P < 0.001], and a higher pediatric end-stage liver disease (PELD) score [22 (14, 25) compared with 12 (7, 15); P < 0.001]. A PELD score of ≥15, history of gastrointestinal bleeding, age at FO initiation ≥16 wk, presence of nongastrointestinal comorbidities, and mechanical ventilation at FO initiation were independent predictors of treatment failure. CONCLUSIONS: Most infants with IFALD responded to FO therapy with resolution of cholestasis, and liver transplantation was rarely required. Early FO initiation once biochemical cholestasis is detected in parenteral nutrition-dependent patients is recommended. This trial was registered at clinicaltrials.gov as NCT00910104.

Pathogenesis and Management of Pruritus in PBC and PSC.

Pruritus is a preeminent symptom in patients with chronic cholestatic liver disorders such as primary biliary cirrhosis and primary sclerosing cholangitis. More than two-thirds of these patients experience itching during the course of their disease. This symptom is also frequently observed in patients with other causes of cholestasis such as cholangiocarcinoma, inherited forms of cholestasis and intrahepatic cholestasis of pregnancy, but may accompany almost any other liver disease. The pathogenesis of pruritus of cholestasis remains largely elusive. Increased concentrations of bile salts, histamine, serotonin, progesterone metabolites and endogenous opioids have been controversially discussed as potential pruritogens. However, for these molecules, neither a correlation with itch intensity nor a causative link could be established. The G protein-coupled receptor for bile salts, TGR5, has been shown to be expressed in dorsal root ganglia and give rise to itch in rodents, albeit upon stimuli with suprapathological concentrations of bile salts. The potent neuronal activator lysophosphatidic acid (LPA) and its forming enzyme, autotaxin (ATX), could be identified in the serum of patients with cholestatic pruritus. ATX activity correlated with itch severity and effectiveness of several anti-pruritic therapeutic interventions in cholestatic patients. Thus, the ATX-LPA-axis may represent a key element in the pathogenesis of this agonizing symptom. Treatment options for pruritus of cholestasis remain limited to a few evidence-based and several experimental medical and interventional therapies. The current guideline-based recommendations include the anion exchange resins colestyramine, the pregnane X receptor-agonist and enzyme inducer rifampicin, the µ-opioid antagonist naltrexone, and the selective serotonin reuptake inhibitors sertraline. Still, a considerable part of patients is unresponsive to these drugs and requires experimental approaches including phototherapy, plasmapheresis, albumin dialysis or nasobiliary drainage. This review outlines the current knowledge on pathogenesis of cholestatic pruritus and summarizes evidence-based and experimental therapeutic interventions for cholestatic patients with itch.

The gut-liver axis.

PURPOSE OF REVIEW: The liver adaptively responds to extra-intestinal and intestinal inflammation. In recent years, the role of the autonomic nervous system, intestinal failure and gut microbiota has been investigated in the development of hepatic, intestinal and extra-intestinal disease. RECENT FINDINGS: The autonomic nervous system can be stimulated via enteral fat leading to cholecystokinin release, stimulating receptors in the gut and in the brain. This promotes bowel integrity, dampening the inflammatory response to food antigens. Consensus exists that intravenously administered long-chain fatty acids can cause liver damage but randomized-controlled trials are lacking. Disruption of the enterohepatic circulation of bile salts can give rise to cholestasis and nonalcoholic fatty liver disease, which may progress to fibrosis and cirrhosis. Reduced intestinal availability of bile salts reduces stimulation of the farnesoid X receptor. This may induce hepatic bile salt overload and associated hepatotoxicity through reduced action of intestinal fibroblast growth factor 19. Evidence is put forward to suggest that the intestinal microbiota is associated with liver abnormalities. SUMMARY: Enteral lipids reduce inflammation and liver damage during stress or systemic inflammation, whereas parenteral lipid is associated with liver damage. Maintaining the enterohepatic circulation of bile salts limits hepatic cholestasis through an farnesoid X receptor feedback pathway. Changes in gut microbiota composition may induce liver disease.

The effect of 5 intravenous lipid emulsions on plasma phytosterols in preterm infants receiving parenteral nutrition: a randomized clinical trial.

BACKGROUND: Elevated plasma phytosterol concentrations are an untoward effect of parenteral nutrition (PN) with vegetable oil-based lipid emulsions (LEs). Phytosterols are elevated in neonatal cholestasis, but the relation remains controversial. OBJECTIVE: The objective was to study the effect of 5 LEs on plasma phytosterols in preterm infants. DESIGN: One hundred forty-four consecutive admitted preterm infants (birth weight: 500-1249 g) were studied. Patients were randomly assigned to receive 1 of 5 different LEs: S [100% soybean oil (SO)], MS [50% medium-chain triglycerides (MCTs) and 50% SO], MSF (50% MCTs, 40% SO, and 10% fish oil (FO)], OS (80% olive oil and 20% SO), or MOSF (30% MCTs, 25% olive oil, 30% SO, and 15% FO). Phytosterols in the LEs and in plasma (on postnatal day 7 and day 14) were measured by gas chromatography-mass spectrometry. RESULTS: Patients in the S group had significantly higher total phytosterol intakes than did the other study groups. On PN days 7 and 14, plasma phytosterol concentrations were highest in the S group and lowest in the MOSF group. Despite similar ß-sitosterol intakes between the MS and MSF groups, plasma concentrations were significantly lower in the MSF than in the MS group. Only 3 patients (2.1%) developed cholestasis: 1 in the MS, 1 in the MSF, and 1 in the MOSF group. No cases of cholestasis were observed in the S and OS groups. CONCLUSIONS: In uncomplicated preterm infants receiving routine PN, we found a correlation between phytosterol intake and plasma phytosterol concentrations; however, cholestasis was rare and no difference in liver function at 6 wk was observed.

Avaliação e suporte nutricional na criança com colestase / Nutrition assessment and support of children with cholestasis

A colestase acomete 65% dos pacientes pediátricos com hepatopatia, sendo responsável por várias consequências clínicas, como: retenção hepática de substâncias excretadas pela bile, lesão hepática progressiva, má-absorção intestinal de gorduras e vitaminas lipossolúveis, anorexia e esteatorreia. Há risco subestimado de desnutrição nesses pacientes, que está associada a grande morbidade. Para classificar os pacientes quanto ao estado nutricional, usam-se os índices de avaliação do crescimento. Porém, considerando a condição clínica do paciente, que pode incluir visceromegalias e ascite, os índices que utilizam o peso na análise podem ser imprecisos. Nesses casos, o uso das medidas de pregas cutâneas e da circunferência braquial leva a avaliações mais fidedignas. O paciente com colestase exige suporte nutricional para compensar a má-absorção e possível desnutrição. Esse suporte inclui: aporte calórico elevado,ingestão proteica em níveis que não se induza hiperamonemia, oferta de ácidos graxos majoritariamente de cadeia média, suplementação de vitaminas lipossolúveis (A,D, E e K) e alguns minerais. Adequado suporte nutricional pode evitar a progressão rápida da doença hepática, facilitar o processo de cicatrização, aumentar a função imunológica, além de prevenir várias consequências da deficiência de uma variedade de micro ou macronutrientes que pode ocorrer na colestase...

Cholestasis affects 65% of pediatric patients with liver disease and it is responsible for several clinical consequences such as liver retention of substances excreted in bile, progressive liver damage, intestinal malabsorption of fats and fat-soluble vitamins, anorexia, and steatorrhea. There is an underestimated risk of malnutrition in these patients, whichis associated with high morbidity. Indexes of growth evaluation are used to classify patients according to their nutritional status. However, considering the clinical condition of the patient, which may include increase of some organs?s size and ascites, the indices that use weight in the analysis may be inaccurate. In these cases, the use of measures of skinfold thickness and arm circumference leads to more reliable evaluations. The patient with cholestasis requires nutritional support to compensate the malabsorption and possible malnutrition. This support includes: caloric intake higher than usual, protein intake at levels which do not induce hyperammonemia, an offer of fatty acids predominantly mediumchain (absorbed independently from the action of micellar bile acids), supplementation of fat-soluble vitamins (A, D, E and K) and some minerals. An adequate nutritional support can avoid the fast progression of liver disease, facilitate the healing process, and enhance immune function, besides of preventing many consequences from the deficiency of a variety of micro or macronutrients which may happens in cholestasis...

Management of copper deficiency in cholestatic infants: review of the literature and a case series.

Copper is an essential trace element, playing a critical role in multiple functions in the body. Despite the necessity of adequate copper provision and data supporting the safety of copper administration during cholestasis, it remains common practice to reduce or remove copper in parenteral nutrition (PN) solutions after the development of cholestasis due to historical recommendations supporting this practice. In neonates, specifically premature infants, less is known about required copper intakes to accumulate copper stores and meet increased demands during rapid growth. Pediatric surgical patients are at high risk for hepatic injury during long-term PN provision and a balance is needed between the potential for reduced biliary excretion of copper and adequate copper intakes to prevent deficiency. Copper deficiency has been documented in several pediatric patients with cholestasis when parenteral copper was reduced or removed. Few data guide the management of copper deficiency in the pediatric population. The following case series describes our experience with successfully managing copper deficiency in 3 cholestatic infants after copper had been reduced or removed from their PN. Classic signs of copper deficiency were present, including hypocupremia, anemia, neutropenia, thrombocytopenia, and osteopenia. Treatment included use of both parenteral and enteral copper supplementation. We suggest revision of current recommendations regarding decreasing copper in PN during cholestasis with a proposed algorithm for parenteral copper provision in the setting of cholestasis that is based on evaluation of measured serum copper concentrations.

Potential benefits of combined N-acetylcysteine and ciprofloxacin therapy in partial biliary obstruction.

This study investigates the potential benefits of antibiotics and N-acetylcysteine (NAC), a mucolytic agent, in patients who are candidates for endoscopic retrograde cholangiopancreatography (ERCP) due to partial bile duct obstruction. In total, 102 patients who had choledocholithiasis and choledochal dilatations by abdominal ultrasonography were included in the study. The patients were divided into placebo and NAC therapy groups. Physiological saline (equal volume with NAC solution) and ciprofloxacin (2 × 200 mg/d intravenously) were administered to the placebo group, and NAC (1800 mg/d intravenously) and ciprofloxacin (2 × 200 mg/d intravenously) were administered to the NAC group. In both groups, treatment protocols were administered for 7 days before ERCP. Total and direct bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), C-reactive protein (CRP), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), white blood cell (WBC) count, and neutrophil percent (NE%) levels were measured before the 7-day treatment protocol. The same measurements were also evaluated before ERCP. In the NAC group, the levels of ALP, GGT, WBC, CRP, and NE% decreased significantly (P < .001), whereas a significant decrease did not occur in the placebo group. The combined usage of NAC and ciprofloxacin can be an alternative therapeutic option until ERCP is performed in partial cholestatic patients.

Do patients with lymphoedema cholestasis syndrome 1/Aagenaes syndrome need dietary counselling outside cholestatic episodes?

BACKGROUND & AIMS: Patients with lymphoedema cholestasis syndrome 1/Aagenaes Syndrome need a fat reduced diet when cholestatic. We wanted to assess the need for dietary counselling outside cholestatic episodes, and hypothetized that no counselling was needed. METHODS: Fifteen patients above 10 years of age without symptoms of cholestasis were compared with a sex and age matched control group. Diet from a four-day weighed record and blood samples were compared between the two groups and with general Norwegian recommendations. RESULTS: The patients had a similar diet to the healthy controls, except for statistically significant lower intake of energy from total fat (p=0.04) and saturated fat (0.02), and fish (0.05). The patients met the dietary recommendations for macronutrients, except for saturated fat, monounsaturated fat, refined sugar and fibre. Supplements were needed to meet the micronutrient recommendations. Patients had a significantly lower serum level of alpha-tocopherol (0.01) compared with the control group, and the serum 25-OH D level was below reference ranges. CONCLUSIONS: The patients would benefit from counselling on fat quality, carbohydrates including fibre intake, and individual needs for vitamins D and E. To secure serum 25-OH D and alpha-tocopherol levels within reference ranges, regular examinations to determine the need for supplementary vitamins D and E are recommended.

Reversal of severe parenteral nutrition-associated liver disease in an infant with short bowel syndrome using parenteral fish oil (Omega-3 fatty acids).

Total parenteral nutrition is an important adjunct in the care of neonates with surgical disorders. Cholestasis is at present the most worrisome complication of this technique; it is difficult to treat and may progress to eventual cirrhosis and liver failure. This article reviews the pertinent clinical and nutritional data in a surgical patient with short bowel syndrome who developed parenteral nutrition-associated liver disease successfully treated with fish-oil based lipids.

Effects of low fat and babassu fat diets on nutritional status in obstructive cholestasis in young rats.

PURPOSE: To test the effects of a low fat diet compared with a babassu fat diet on nutritional status in obstructive cholestasis in young rats. METHODS: We submitted 40 rats in 4 groups of 10 animals each from P21 (21st postnatal day) to P49 to two of the following treatments: bile duct ligation or sham operation and low fat diet (corn oil supplying 4.5% of the total amount of energy) or babassu fat diet (this fat supplying 32.7% and corn oil supplying 1.7% of the total amount of energy). Weight gain from P25 to P49 every 4 days was measured. The Verhulst's growth function was fitted to these values of weight gain. Growth velocity and acceleration at each moment were estimated using the same equation. Total food and energy intake from P21 to P49, energy utilization rate (EUR) from P25 to P49 and fat absorption rate (FAR) and nitrogen balance (NB) from P42 to P49 were measured. Two Way ANOVA and the S.N.K. test for multiple paired comparisons were employed to study the effects of cholestasis and those of the diets and their interaction (p<0.05) on those variables. RESULTS: In cholestatic animals, a higher growth velocity at P45, a higher growth acceleration at P41 and P45, a greater EUR, a greater FAR and a greater NB, were found with the low fat diet as compared with the babassu fat diet. CONCLUSION: A low fat diet lessens the growth restriction brought about by cholestasis and allows for an improved dietary energy utilization and a better protein balance than the babassu fat diet.