Cholestatic pruritus : an update.

Pruritus is a common, troublesome symptom in patients with cholestatic liver diseases, especially frequent in intrahepatic cholestasis of pregnancy (ICP) and in primary biliary cholangitis (PBC). Cholestatic associated pruritus can have profound effects on the quality of life. The underlying mechanism is still poorly understood. Severe potential pruritogens have been discussed, such as bile salts, opioids, steroid and lysophosphatidic acid (LPA), but none of these are considered as key mediators. Because of this unraveling pathophysiology the treatment of hepatogenic pruritus often represents a clinical challenge. The EASL guidelines have suggested a step-wise approach, starting with elimination of pruritogens by bile acid sequestrants (cholestyramine), in second line managing the metabolism of pruritogens (rifampicin) and in third-line and fourth- line by modifying the itch perception with µ-opioid antagonist or selective serotonin reuptake inhibitors (SSRI). In treatment-refractory pruritus interruption of the enterohepatic cycle by molecular absorbent recirculating system (MARS), nasobiliairy drainage or experimental therapy such as Ultraviolet B light therapy can be considered. Liver transplantation may be reserved for intractable pruritus. Clinical trials with novel agents are ongoing, potentially providing efficacious options in the future.

Gulf war illness-related chemicals increase CD11b/c+ monocyte infiltration into the liver and aggravate hepatic cholestasis in a rodent model.

Gulf War Illness (GWI) is a chronic multisymptom disorder affecting veterans of the 1990-91 Gulf war. GWI was linked with exposure to chemicals including the nerve gas prophylactic drug pyridostigmine-bromide (PB) and pesticides (DEET, permethrin). Veterans with GWI exhibit prolonged, low-level systemic inflammation, though whether this impacts the liver is unknown. While no evidence exists that GWI-related chemicals are hepatotoxic, the prolonged inflammation may alter the liver's response to insults such as cholestatic injury. We assessed the effects of GWI-related chemicals on macrophage infiltration and its subsequent influence on hepatic cholestasis. Sprague Dawley rats were treated daily with PB, DEET and permethrin followed by 15 minutes of restraint stress for 28 days. Ten weeks afterward, GWI rats or naïve age-matched controls underwent bile duct ligation (BDL) or sham surgeries. Exposure to GWI-related chemicals alone increased IL-6, and CD11b+F4/80- macrophages in the liver, with no effect on biliary mass or hepatic fibrosis. However, pre-exposure to GWI-related chemicals enhanced biliary hyperplasia and fibrogenesis caused by BDL, compared to naïve rats undergoing the same surgery. These data suggest that GWI patients could be predisposed to developing worse liver pathology due to sustained low-level inflammation of the liver when compared to patients without GWI.

Quality of life in adults with lymphedema cholestasis syndrome 1.

BACKGROUND: LCS1 (Lymphedema Cholestasis Syndrome 1/Aagenaes syndrome) is a rare, hereditary disorder, where the highest known prevalence is in Norway. The disorder is characterized by lymphedema and periodic cholestasis from birth or the neonatal period. This study aimed to examine internal reliability of the SF-36, in addition to the group's overall- and health related quality of life (OQoL and HRQoL) and psychosocial well-being. METHODS: Twenty adults (aged 18-65) in Norway have been diagnosed with LSC1. Eighteen of these patients were included in the study and completed four questionnaires on overall and health related quality of life and psychosocial well-being: Cantril's Ladder (CL), The Kaasa Test, the SF-36, and a lymphedema anamnesis questionnaire. Demographic data were registered, and 15 of the patients underwent a physical examination of the lymphedema. SF-36 scores were compared with those of 360 age and gender matched controls drawn from an earlier survey of the Norwegian general population. The Mann-Whitney U test and Chi-square (χ2) test were used to test internal differences in the patient group. RESULTS: Health-related quality of life (HRQOL) was significantly reduced in patients with LSC1 compared to controls, in three out of eight areas, role physical, general health and mental health. Females scored significantly better than males in the patient group in two areas of SF-36, in CL, and in one of three scales of The Kaasa Test. Severe lymphedema was found to be significantly correlated to bodily pain and reduced mental health. The level of education was positively correlated to mental health. CONCLUSION: Overall quality of life (OQoL), health related quality of life (HRQoL) and psycho-social well-being were good in the patient group, but some dimensions of HRQoL were reduced. More severe extent of lymphedema was associated with poorer HRQoL.

Interactions Between Platelets and Inflammatory Monocytes Affect Sickness Behavior in Mice With Liver Inflammation.

BACKGROUND & AIMS: Patients with inflammatory liver disease commonly develop debilitating symptoms, called sickness behaviors, which arise via changes in brain function. Monocytes that produce tumor necrosis factor interact with cerebral endothelial cells to activate microglial cells and promote sickness behavior. Platelets regulate inflammation, and aggregates of monocytes and platelets are increased in the circulation of patients with liver disease. We investigated the role of platelets in inducing inflammatory features of circulating monocytes and promoting sickness behaviors in mice with cholestatic liver injury. METHODS: We performed bile-duct ligations or sham surgeries on C57BL/6 or toll-like receptor 4 (TLR4)-knockout mice to induce liver inflammation. Liver inflammation was also induced in a separate group of mice by administration of concanavalin A. Circulating platelets, aggregates of monocytes and platelets, and activation of microglial cells were measured by flow cytometry. To deplete platelets, mice were given anti-thrombocyte serum or normal rabbit serum (control) 4 days after surgery. Interactions between monocytes and cerebral endothelial cells were analyzed by intravital microscopy. Sickness behaviors were quantified based on time spent by adult mice engaging in social behaviors toward a juvenile mouse, compared with time spent in nonsocial behavior or remaining immobile. RESULTS: Aggregates of monocytes and platelets in circulation of mice increased significantly following bile-duct ligation. Platelet-monocyte interactions were required for activation of inflammatory monocytes and production of tumor necrosis factor. Platelet depletion greatly reduced adhesive interactions between inflammatory monocytes and adhesive interactions with cerebral endothelial cells and activation of the microglia, as well as development of sickness behavior. Furthermore, TLR4 signaling was important for aggregation of monocytes and platelets, and development of sickness behavior following bile-duct ligation. These findings were confirmed in mice with concanavalin A-induced liver injury. CONCLUSIONS: In mice with liver inflammation, we found TLR4 and aggregates of monocytes and platelets to regulate microglial activation and development of sickness behavior. These findings might lead to new therapeutic strategies for liver disease-associated symptoms.

Assessment of School Readiness in Chronic Cholestatic Liver Disease: A Pilot Study Examining Children with and without Liver Transplantation.

Background. Assessment of school readiness evaluates physical, social-emotional, and neuropsychological domains essential for educational success. Cognitive testing of preschool aged children with chronic liver disease may guide more timely interventions and focused efforts by health care providers. Patients and Methods. Children with chronic cholestatic liver disease diagnosed as an infant and still with their native liver (NL) and children who received a liver transplant (LT) before age of 2 years underwent testing with a battery of well-validated pediatric psychometric measures. Results. Eighteen (13 LT, 5 NL) patients (median age of 4.45 and 4.05 years, resp.) were tested. Median Full-Scale IQ was 98 (range 102-116) for LT and 116 [(range 90-106), p = 0.35, NS] for NL subjects. LT recipients had significantly greater visual based difficulties, poorer caregiver rated daily living skills (p = 0.04), and higher levels of executive function based difficulties (e.g., inattention, inhibition). Conclusion. This pilot study highlights the risk of neuropsychological difficulties in early school age children who were under 2 years of age at time of LT. Comprehensive early school age assessment should integrate psychometric measures to identify children at greatest risk, thus allowing for proactive educational intervention.

Can familial factors account for the association of body mass index with poor mental health in men or women?

OBJECTIVE: This study examined if associations between body mass index (BMI) and mental and physical health were independent of genetic and familial factors. METHOD: Data from 2831 twins (66% female) were used in an epidemiological co-twin control design with measures of BMI and mental and physical health outcomes. Generalized estimating equation regressions assessed relationships between BMI and health outcomes controlling for interdependency among twins and demographics. Within-pair regression analyses examined the association of BMI with health outcomes controlling for genetic and familial influences. RESULTS: Adjusted analyses with individual twins found associations in women between BMI and perceived stress (P=.01) and depression (P=.002), and the link between BMI and depression (P=.03) was significant in men. All physical health outcomes were significantly related to BMI. Once genetic and familial factors were taken into account, mental health outcomes were no longer significantly associated with BMI. BMI in women remained related to ratings of physical health (P=.01) and body pain (P=.004), independent of genetic and familial influences. CONCLUSION: These findings suggest that genetic and familial factors may account for the relationship between increased weight and poor mental health.

Involvement of opioidergic and nitrergic systems in memory acquisition and exploratory behaviors in cholestatic mice.

Bile duct ligation (BDL) is an animal model used in cholestatic disease research. Both opioidergic and nitrergic systems are known to be involved in cholestasis. The aim of this study was to investigate the possible interaction between these two systems in BDL-induced memory formation and exploratory behaviors in mice. Male mice weighing 25-30 g were divided into nonoperated controls, sham-operated, and BDL groups. One-trial step-down and hole-board paradigms were used to assess memory acquisition and exploratory behaviors, respectively. Cholestasis did not alter memory acquisition while increasing exploratory behaviors 7 days after BDL. A pretraining intraperitoneal injection of L-arginine (50, 100, and 200 mg/kg), L-NG-nitroarginine methyl ester (L-NAME) (5, 10, 20, and 40 mg/kg), or naloxone (0.125, 0.25, and 0.5 mg/kg) did not alter memory acquisition or exploratory behaviors, whereas morphine (5 and 7.5 mg/kg) decreased memory acquisition in sham-operated animals. Moreover, although injection of L-NAME and naloxone exerted no effect on memory acquisition in the 7 days post-BDL mice, L-arginine (100 and 200 mg/kg) and morphine (2.5, 5, and 7.5 mg/kg) injection reduced it. In contrast, L-NAME and naloxone, but not morphine or L-arginine, reduced the BDL-induced exploratory behaviors. Coadministration of subthreshold doses of morphine (1.25 mg/kg) and L-arginine (50 mg/kg) caused a memory deficit in 7 days post-BDL mice. However, the memory deficit induced by the effective doses of morphine (2.5 mg/kg) or L-arginine (200 mg/kg) in these mice was restored by the administration of either naloxone (0.5 mg/kg) or L-NAME (40 mg/kg). In addition, naloxone and L-NAME reduced the exploratory behaviors in L-arginine-pretreated mice but not in morphine-pretreated mice. We conclude that there appears to be a synergistic effect between opioidergic and nitrergic systems on memory acquisition and exploratory behaviors in cholestatic mice.

Characteristics related to sexual experience and condom use among Jamaican female adolescents.

Young women in Jamaica face significant risk for HIV and other STIs. A clearer understanding of the factors associated with sexual experience and unprotected intercourse is needed. Data were collected from 330 adolescent females aged 13 to 17 recruited through community based organizations in Kingston, Jamaica, from 2009-2011. Nearly one-third of sexually experienced participants reported not using a condom the last time they had sex. Characteristics associated with sexual experience included older age, marijuana use, and less comfort talking to mother about sexual topics. Characteristics associated with condom use included perceived importance of religion, positive attitudes toward condoms, and not-having multiple sexual partners. Sexually experienced Jamaican female adolescents were engaging in behaviors that made them vulnerable to HIV and other STIs. Interventions with young adolescent girls and their mothers are recommended to postpone sexual debut and promote safer sexual behaviors in those who do engage in sex.

Reflection on a pregnancy complicated by obstetric cholestasis.

Gemma Steele, a midwife, shares her personal reflection on her first pregnancy which was complicated by obstetric cholestasis. Gemma gives insight as to how debilitating it can be suffering from this condition and highlights that a woman can be diagnosed as early as six-eight weeks gestation. For this reflection, Gemma used Gibbs' reflective cycle (Gibbs 1988) to help explore the experience and guide the reflective process (Bulman 2008).

Síndrome de Alagille experiencia clínica de catorce casos en Medellín, Colombia / Alagille syndrome, clinical experience of fourteen cases in Medellin, Colombia

Introducción: El Síndrome de Alagille corresponde a una alteración autosómica dominante con expresión variable. Se caracteriza por colestasis crónica con escasez de los conductos biliares interlobulares asociada a alteraciones cardiovasculares, oftálmicas, sistema esquelético, riñones y facies característica. Su distribución es mundial con frecuencia de 1 por cada 100000 nacidos vivos. Objetivo: Describir las características clínicas, la evolución y la sobrevida de catorce pacientes, con diagnóstico de Síndrome de Alagille atendidos en un período de 16 años en Medellín, Colombia. Materiales y métodos: Es un trabajo observacional descriptivo de reporte de casos de los hallazgos morfológicos y la evolución de los pacientes con diagnóstico de Síndrome de Alagille. Resultados: Grupo compuesto por ocho niños y seis niñas, con edades entre los dos meses y los diez años al momento de diagnóstico. El síndrome completo se presentó en 28%. Los hallazgos más frecuentes, estenosis valvular de la arteria pulmonar y la alteración vertebral se presentaron en el 79%. Tres pacientes 21%, fallecieron, uno de ellos después de recibir trasplante hepático. De los once sobrevivientes dos niñas fueron sometidas a trasplante y se encuentran en buenas condiciones. Los nueve restantes padecen hepatopatía colestásica crónica y reciben tratamiento médico. Conclusión: El Síndrome de Alagille se debe tener en cuenta en el diagnóstico de colestasis crónica infantil. Para establecer la distribución y frecuencia de esta enfermedad en nuestro país es necesario desarrollar investigaciones que idealmente incluyan el estudio de la mutación genética en los pacientes y su familia cercana.

Introduction: The Alagille Syndrome is an autosomic dominant disorder with variable expression. Chronic cholestasis, characteristic facial appearance and abnormalities heart, skeleton, eye, kydnes with hypoplasia of the biliary ducts. Initial description in France, with mundial distribution her frecuence is 1/100000. Objective: To describe the clinical characteristic and evolutions of fourteen patients with diagnosis Alagille Syndrome in Medellín Colombia. Materials and methods: Descriptive retrospective study with variables obtained from clinical records of patients with diagnosis Alagille Syndrome. Results: Eight boys and six girls. The age at diagnosis varied two months at nine years. Complete syndrome was present in 28%. The most frecuent alterations were valvular stenosis pulmonary artery and failure of anterior vertebral arch fusion (butterfly vertebrae) 79%. The clinical evolution was variable, death occurred in three patients 21%, one girl post liver transplantation. Nine children had chronic hepatopathy controlled with medical treatment and two girls had liver transplantation with satisfactory evolution. Conclusions: In Colombia, the poblational incidence is not defined it is necessary to know the distribution of syndrome at future study.

Quality of life following liver transplantation: a comparative study between Familial Amyloid Neuropathy and liver disease patients.

BACKGROUND: It has been demonstrated in many studies that quality of life can be improved after liver transplantation in patients with liver disease. Nevertheless, quality of life improvement in specific groups of transplanted patients such as those with Familial Amyloid Polyneuropathy has not yet been explored. The present study aimed to compare the change in quality of life following liver transplantation between patients with Familial Amyloid Polyneuropathy (FAP) and patients with liver disease. RESULTS: Patient's mental quality of life showed an improvement in all liver disease patients, and a worsening in FAP patients, resulting in a significant difference between the two groups. Regarding physical quality of life, although a similar improvement was seen in both groups, FAP patients had significantly less improvement than the sub-group of decompensated liver disease (Child-Pugh B and C). CONCLUSION: It is concluded that liver transplantation has a less beneficial impact in FAP patient's physical quality of life, probably because they are not so much disabled by their disease at the moment of liver transplantation. The lesser improvement in mental quality of life of FAP patients may be due to their particular psychological profile and greater expectations towards transplantation.

Downregulated hypothalamic 5-HT3 receptor expression and enhanced 5-HT3 receptor antagonist-mediated improvement in fatigue-like behaviour in cholestatic rats.

The serotonin neurotransmitter system, including the 5-HT(3) receptor, has been implicated in the genesis of fatigue in patients with liver disease. Therefore, we examined the possible role of 5-HT(3) receptors in cholestasis-associated fatigue. Rats were either bile duct resected (BDR) or sham resected and studied 10 days postsurgery. A significant decrease in hypothalamic 5-HT(3) receptor expression was detected by immunohistochemistry and Western blot in BDR vs sham rats, coupled with increased hypothalamic serotonin turnover identified by an elevated 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT ratio in BDR vs sham rats. To examine fatigue-like behaviour, an activity meter was used. BDR rats exhibited significantly lower locomotor activity than did sham animals. Subcutaneous injection of the 5-HT(3) receptor antagonist tropisetron (0.1 mg kg(-1)) resulted in significantly increased locomotor activity in BDR rats compared to the activity in saline-treated controls, but was without effect in sham rats. However, a 10-fold higher dose of tropisetron significantly increased locomotor activity in both BDR and sham rats compared to saline-injected controls. These findings indicate that cholestasis in the rat is associated with increased hypothalamic serotonin turnover, decreased hypothalamic 5-HT(3) receptor expression, and enhanced sensitivity to locomotor activation induced by 5-HT(3) receptor antagonism, thereby implicating the 5-HT(3) receptor system in cholestasis associated fatigue.

Palliative percutaneous drainage in malignant biliary obstruction. Part 1: indications and preprocedure evaluation.

A diagnosis of liver metastasis, periportal adenopathy, or hepatobiliary cancer often is accompanied by findings of biliary obstruction. Malignant biliary obstruction frequently is associated with pruritus, anorexia, cholangitis, or hyperbilirubinemia, which that precludes treatment with chemotherapeutic agents that are excreted or metabolized hepatically. In patients with low biliary obstruction, endoscopic stent placement may accomplish drainage of the entire biliary tree without the need for an external device. Patients with high bile duct obstruction, on the other hand, may need a percutaneous approach to drain the target ducts and avoid draining an atrophic segment or lobe. This first of a series of two articles concerning palliative percutaneous biliary intervention will review the indications for biliary drainage and the preprocedure evaluation of this complicated patient population.

Role of nitric oxide in hypodipsia of rats with obstructive cholestasis.

Cholestasis is associated with the overproduction of nitric oxide (NO), and NO acts as an inhibitory mechanism when thirst is stimulated by water deprivation or by angiotensin II. Due to the presence of hypodipsia in the cholestatic condition, we have compared the rate of water intake between bile duct-ligated (cholestatic) and sham-operated rats. We have evaluated the effect of NO synthesis inhibition by N(G)-nitro-L-arginine (L-NNA, 10 mg kg(-1)/day) on the rate of water intake in cholestatic rats. The results showed that plasma alkaline phosphatase activity (a marker of liver damage) increased after bile-duct ligation, and that its elevation was partially (but significantly) prevented by treatment with L-arginine. A two-week bile-duct obstruction induced a significant decrease in the rate of water intake compared with sham-operated animals (35.87 +/- 1.45 vs 42.37 +/- 1.99 mL/day, P < 0.05). This effect was corrected by the daily administration of L-NNA. Surprisingly, L-arginine (200 mg kg(-1)/day) showed similar activity as L-NNA in cholestatic rats and increased water intake, but not in control animals. Systemic NO synthesis inhibition corrected the decrease in water intake observed in cholestatic rats. This suggests an important role for NO in the pathophysiology of hypodipsia in cholestatic subjects. The effect of chronic L-arginine administration observed in cholestatic rats but not seen in the control rats could be explained theoretically by the amelioration of cholestasis-induced liver damage by chronic L-arginine administration in bile duct-ligated rats.

Endogenous nitric oxide modulates naloxone-precipitated withdrawal signs in a mouse model with acute cholestasis.

Cholestasis liver disease is associated with clinical and experimental findings consistent with increased opioidergic neuromodulation, increased plasma total activity, and elevated plasma enkephalin concentrations. The effect of the nitric oxide (NO) synthase inhibitor, L-nitro-arginine (L-NA, 0.03, 0.1, 0.3, 1 mg/kg), and the nitric oxide precursor, L-Arg (30 mg/kg), on antinociception induced by bile duct resection or sham operation, as well as on opioid dependence, was examined in male albino Swiss mice. Repeated (5 days) administration of L-NA attenuated signs of dependence, as assessed by naloxone (5 mg/kg)-precipitated withdrawal, and decreased the antinociception; however, L-Arg potentiated withdrawal signs and increased the antinociception. The results of this study support the involvement of the L-arginine/nitric oxide pathway in the opioidergic-dependent manifestation of cholestasis in an animal model.

Augmented interleukin-1beta-induced depression of locomotor activity in cholestatic rats.

"Sickness behaviors" such as lethargy, fatigue, and malaise occur commonly in patients with cholestatic liver diseases and contribute significantly to the morbidity associated with these diseases. However, the cause of these symptoms is unknown. Interleukin-1beta (IL-1beta) released within the brain has been implicated in the genesis of a number of "sickness behaviors," including malaise and lethargy. Therefore, we investigated whether experimental cholestatic liver disease caused by bile duct resection (BDR) in rats is associated with enhanced central sensitivity to IL-1beta-induced "sickness behaviors." The central infusion of IL-1beta at a dose that produced an insignificant decrease in locomotor activity in control rats produced a striking reduction in locomotor activity in cholestatic rats. The anorectic response to central IL-1beta infusion was similar in cholestatic and noncholestatic animals and did not parallel our locomotor activity findings. Therefore, cholestatic liver injury is characterized by augmented central responsiveness to IL-1beta with respect to a decrease in locomotor activity. These findings may explain, at least in part, the high incidence of symptoms such as fatigue, malaise, and lethargy that occur in cholestatic patients and may open novel future avenues for their treatment.

Chronic cholestasis in rats induces anhedonia and a loss of social interest.

Central fatigue commonly occurs in patients with primary biliary cirrhosis (PBC) and correlates closely with depression, and cholestatic rats exhibit central fatigue. Therefore, we undertook a series of experiments in both rats with cholestasis caused by bile duct resection (BDR) and sham-resected controls (15 days after surgery) to determine if experimental cholestasis is associated with symptoms of depression that can be modeled in rats, namely anhedonia (loss of pleasure) and the loss of social interest. BDR rats exhibited significant anhedonia compared with sham controls as indicated by a loss in their preference for consuming a saccharin solution, a highly desirable drink for rats. Furthermore, social interest was examined by determining the time BDR or sham rats spent investigating a juvenile rat in an open-field apparatus compared with the time spent on nonsocial behaviors. BDR rats exhibited significantly reduced time spent in social investigation and significantly more time in nonsocial behaviors than did sham rats. Major depression in humans is often associated with elevated circulating glucocorticoid levels and impaired glucocorticoid feedback. Therefore, we measured these parameters in BDR and sham rats and found a striking elevation in circulating glucocorticoid levels in BDR compared with sham animals. However, elevated circulating glucocorticoid levels in BDR rats suppressed normally in response to exogenous dexamethasone, indicating intact glucocorticoid feedback control at the pituitary level in BDR rats. In summary, we have identified behaviors in cholestatic rats that are consistent with those seen in depression.

Induced preference or conditioned aversion for sodium chloride in rats with chronic bile duct ligation.

We examined whether a learned aversion to saline could account for the reduction in saline intake produced by bile duct ligation (BDL) in rats and whether increased saline intake by BDL rats was associated with hypotension. In three experiments, rats were given continuous access to water in choice with saline after surgery. In Experiment 1, rats were deprived of food and fluid for 24 h and then given 2-h access to either 0.15 or 0.3 M saline. Rats received a BDL or sham-ligation immediately (paired) or 48 h after (nonpaired) the 2-h bout of saline ingestion. The results show that nonpaired BDL rats increased their daily saline intake relative to nonpaired sham-ligated or paired BDL rats approximately 1-4 weeks after surgery. In Experiment 2, when water and either cherry or grape Kool-Aid (0.05% w/v) dissolved in 0.15 M saline to distinguish the flavor of the solution was offered prior to surgery, BDL rats reduced their ingestion of grape-flavored saline after surgery regardless of whether they were exposed to grape- or cherry-flavored saline prior to surgery. In Experiment 3, when rats were offered water and 0.3 M saline 48 h after surgery, BDL rats ligated for 4 weeks increased their saline intake relative to sham-ligated controls and this elevation in saline intake by BDL rats was associated with hypotension. The results suggest that the symptoms associated with the BDL surgery can serve as effective unconditioned stimuli in the acquisition of learned flavor aversions, and that hypotension may play a role in the elevated intake of saline by BDL rats.

[Pruritus due to obstructive jaundice, with delusions of parasitosis].

A wide range of nonpsychiatric medical conditions can cause delusions. We present a 62-year-man with pruritus due to obstructive jaundice, who developed delusions of parasitosis, which he considered to be the reason for his pruritus++. The holistic approach to diagnosis and treatment of this combined disorder is important.