Alagille syndrome and Wilson disease in siblings: a diagnostic conundrum.

The authors describe two siblings, each with a different, rare genetic condition that affects liver function. The index case, the 18-year-old asymptomatic brother of a young man recently diagnosed with Wilson disease, presented for Wilson disease screening and was also found to have abnormal liver function suggestive of cholestasis. However, ceruloplasmin level, 24 h urine copper concentration and liver synthetic function were normal. Further hepatic investigations and genetic mutation analysis were performed, ultimately leading to a diagnosis of Alagille syndrome. He was treated with ursodiol, which resulted in normalization of his liver function tests. Subsequently, he was found to be a carrier for a mutation in the Wilson disease gene, ATP7B. In the present report, the potential implications of being a heterozygote for Wilson disease in the context of Alagille syndrome are discussed. Also stressed is that care must be exercised by the clinician when diagnosing family members who may present with two different disorders closely mimicking one another.

Clinical characterization of patients with primary biliary cholangitis: A report from multiple Canadian centres.

Background: Primary biliary cholangitis (PBC) is a rare, chronic autoimmune, cholestatic liver disease affecting approximately 318 per million Canadians. There is limited information regarding the characterization of this patient population in Canada. Consequently, we aim to describe a cohort of PBC patients managed across liver centres serving this type of population. Methods: A cross-sectional examination of 1,125 PBC patient charts at 15 liver centres across Canada was conducted between January 2016 and September 2017. Results: Data from 1,125 eligible patients were collected from 7 Canadian provinces. The patient population was largely female (90.2%), had a median overall age of 61.3 years, and a median overall time since diagnosis of 6.4 years. Of the patients included in the study, 89% were on ursodeoxycholic acid (UDCA) therapy at a median dose of 14.0 mg/kg/day and 4.4% were previously treated with UDCA, whereas 6.6% were never treated with UDCA. Of the patients with available data (n = 1067), 289 (27.1%) presented with alkaline phosphatase (ALP) levels ≥200 IU/L and/or total bilirubin levels ≥21 µmol/L. Assessment of UDCA treatment response revealed that 26.6% and 38.3% of patients were inadequate responders according to the Toronto and Paris-II criteria, respectively. Mortality occurred in 1.2% (14) of patients, with liver-related adverse outcomes being more commonly observed in patients who discontinued UDCA compared to those who are currently on treatment (36.3% and 19.6%, respectively). Conclusion: This study showed that Canadian PBC patients present with demographics and features commonly reported in the literature for this disease. Over one third of PBC patients had inadequate response to UDCA treatment or were not currently being treated with UDCA. Consequently, there is a significant unmet therapeutic need in this Canadian PBC population.

Palbociclib-induced severe hepatitis: A case study and literature review.

Palbociclib is a selective and reversible CDK4/6 inhibitor approved for patients presenting with HR+ HER2- locally advanced or metastatic breast cancer. Its adverse effect (AE) is mainly reported on the occurrence of leukopenia and fatigue. Even though palbociclib has an extensive hepatic metabolism, there are rare reports about significant liver toxicity. We present the case of a 61-year-old female with metastatic breast cancer treated with palbociclib and an aromatase inhibitor (letrozole). The patient developed a rare AE of severe acute drug-induced hepatitis but improved dramatically after stopping the palbociclib and receiving treatment with N-acetylcysteine (NAC). The treatment with NAC may be a proof of concept for the mechanism of palbociclib liver injury.

Rituximab-induced autoimmune hepatitis: A case study and literature review.

Rituximab is a monoclonal antibody to CD20, often used to treat B-cell lymphomas and various autoimmune diseases. While there is extensive literature on rituximab-induced liver injury related to hepatitis B reactivation, there have been no reports to date of autoimmune-type idiopathic drug-induced liver injury from this drug. We present a case of necro-inflammatory hepatitis with autoimmune features in a 40-year-old female after receiving a second dose of rituximab for mucosa-associated lymphoid tissue (MALT) lymphoma, with a review of the literature.

Endoscopist-Directed Propofol as an Adjunct to Standard Sedation: A Canadian Experience.

BACKGROUND: Sedation practices vary widely by region. In Canada, endoscopist-directed administration of a combination of fentanyl and midazolam is standard practice. A minority of cases are performed with propofol. AIMS: To describe the safety of nonanaesthetist administered low-dose propofol as an adjunct to standard sedation. METHODS: This was a single-centre retrospective study of patients having undergone endoscopic procedures with propofol sedation between 2004 and 2012 in a teaching hospital in Montreal. Procedures were performed by gastroenterologists trained in Advanced Cardiovascular Life Support. Sedation was administered by intravenous bolus by a registered nurse, under the direction of the endoscopist. Outcomes of procedures were collected in the context of a retrospective chart review using the hospital's endoscopy database. RESULTS: Of patients undergoing endoscopies at our centre, 4930 patients received propofol as an adjunct to standard sedation with fentanyl and midazolam. Cecal intubation rate for colonoscopies (n = 2921) was 92.0%. Gastroscopies (n = 1614), flexible sigmoidoscopies (n = 28), endoscopic retrograde cholangiopancreatography (n = 331) and percutaneous endoscopic gastrostomy insertion (n = 36) had success rates, defined as successful completion of the procedure within anatomical limits, of 99.0, 96.4, 94.0 and 91.7%, respectively. The average dose of propofol used for each procedure was 34.5 ± 20.8 mg. Fentanyl was used in 67.4% of procedures at an average dose of 94.3 ± 17.5 mcg. Midazolam was used in 92.7% of cases at an average dose of 3.0 ± 0.7 mg. Reversal agents (naloxone or flumazenil) were used in 0.43% of the cases (n = 21). Patients who received propofol were discharged uneventfully within the usual postprocedure recovery time. One patient required sedation-related hospitalization. For patients having received propofol in addition to standard sedation agents, 99.6% experienced no adverse events. There were no mortalities. CONCLUSION: The use of low-dose propofol as an adjunct to fentanyl and midazolam, administered by a registered nurse under the direction of the endoscopist was safe and effective in patients at our centre.

Hemodynamic changes in visceral organs following closed head trauma in rats.

BACKGROUND: Gastrointestinal (GI) tract dysfunction is well documented following head injury. Our study sought to determine whether head injury causes an immediate impairment of the splanchnic circulation which may contribute to later GI sequelae. METHODS: Three groups of eight rats each received either no closed head trauma (CHT) (group 1) or CHT (groups 2 and 3) immediately following baseline measurements at time 0. The primary measures of interest - individual organ blood flows and cardiac output (radioactive microspheres), and individual organ and systemic vascular resistances - were determined in the control group, at 5 min after CHT in group 2, and at 15 min after CHT in group 3. RESULTS: CHT caused no significant change in portal venous inflow (flows were 2.40+/-0.36, 2.38+/-0.54, and 2.33+/-0.62 ml min(-1) 100g(-1)bw, mean+/-S.D., in groups 1, 2, and 3, respectively). Individual organ and total hepatic blood flow, cardiac index, splanchnic, portal, and total peripheral resistance, and mean arterial or portal venous pressure also did not differ significantly among groups. CONCLUSION: We found no significant changes in splanchnic circulation immediately after CHT in this rat model. Our results do not support the hypothesis that the splanchnic circulation is impaired immediately after head injury and that splanchnic blood flow impairment immediately after head injury may contribute to post-head injury GI dysfunction.

Comparison of a real-time polymerase chain reaction assay for lactase genetic polymorphism with standard indirect tests for lactose maldigestion.

BACKGROUND & AIMS: There is a discrepancy in outcome between the lactose tolerance and breath hydrogen tests for lactose maldigestion. The availability of a validated genetic test for lactase polymorphism allows a reevaluation of these tests. METHODS: Thirty healthy adults participated in a 50-g lactose challenge test at a university clinic. Blood was drawn for genetic and timed blood glucose testing (2 hours), and breath hydrogen was measured (4.5 hours). Lactase genetic polymorphism was assessed by a real-time polymerase chain reaction assay. Participants completed a diet questionnaire, and symptoms were recorded during the lactose challenge. Sensitivity and specificity were calculated for each indirect test. The 2-way kappa coefficient between these tests was evaluated. Student t test and Wilcoxon rank sum test were used to compare variables. RESULTS: The lactose tolerance test as a standard had an 87.5% sensitivity and 92.7% specificity for genetic status. Only a moderate agreement between lactose tolerance test and breath hydrogen test was observed (2-way kappa coefficient, .53; 95% confidence interval, .22-.83). When genetic status was used as standard, symptoms had a moderate sensitivity and specificity. Lactose tolerance test had very good sensitivity, and the breath test had excellent specificity. CONCLUSIONS: Both indirect tests independently have good to very good sensitivities and specificities for genetic lactase status. The noted disagreement likely reflects variables that affect the tests independently of intestinal lactase status. The value of these tests in the light of the availability of genetic testing is discussed.

Preoperative alpha-fetoprotein slope is predictive of hepatocellular carcinoma recurrence after liver transplantation.

BACKGROUND: Liver transplantation (LT) offers a possible cure for patients with hepatocellular carcinoma (HCC) and cirrhosis. However, tumour progression while on the waiting list and tumour recurrence after LT are common. The prognostic significance of various pre- and postoperative variables were investigated in regard to tumour recurrence, with an emphasis on the slope of preoperative serum alpha-fetoprotein (AFP) levels. patients and METHODS: Data from 48 patients who had HCC diagnosed preoperatively and underwent LT at the McGill University Health Centre (Montreal, Quebec) were reviewed retrospectively, and possible risk factors for tumour recurrence were examined. RESULTS: Univariate analysis revealed a positive correlation between the preoperative AFP slope and vascular invasion (P = 0.045), total tumour diameter at explant (P = 0.040), Cancer of the Liver Italian Program score (P = 0.017) and recurrence-free survival (P = 0.028). Of the preoperative variables examined, only the preoperative AFP slope was identified as an independent predictor of tumour recurrence by multivariate analysis. Receiver operating characteristic analysis showed that the best discriminant cut-off value, calculated as the value of the maximized likelihood ratio, was preoperative AFP slope greater than 50 microg/L per month. At this cut-off, sensitivity was 36%, and specificity was 97%. Patients with a preoperative AFP slope greater than 50 microg/L per month had a much worse one-year recurrence-free survival rate than those with a preoperative AFP slope 50 microg/L per month or less (40% versus 90%, P < 0.001). CONCLUSIONS: These results suggest that the preoperative AFP slope is an important predictor of HCC recurrence after LT and should be examined in future studies of patients receiving LT for HCC.

The effect of information level and coping style on pain and anxiety in needle liver biopsy.

Biopsy of the liver is an important diagnostic procedure. The procedure is invasive and may be painful for patients. Sedative drugs are not used because the associated drop in blood pressure mimics hemorrhage, a major complication of the procedure. Cognitive and behavioural techniques have been used to decrease stress in patients undergoing other medical procedures. In the present study, it is postulated that providing procedural and sensory information may reduce patient anxiety levels. Patient coping styles were evaluated and anxiety and pain levels were assessed by using a visual analogue scale. Subjects were randomly assigned to one of two groups. The control group received basic information about the procedure. The experimental group received the same basic information followed by more detailed educational information. Subjects also filled out the Krantz Health Opinion Survey, a short questionnaire used to classify coping styles as either information-seeking or information-avoiding. Seventy-five subjects (38 control and 37 experimental) with similar demographics were included in the present study. No significant differences were found in anxiety levels or pain levels 30 min and 6 h post-biopsy. There was also no significant difference between groups once coping style was added into the analysis. The study failed to show any advantage in providing additional information to subjects before liver biopsy, regardless of coping style.

Resected Hepatocellular Carcinoma in a Patient with Crohn's Disease on Azathioprine.

Hepatocellular carcinoma rarely occurs in patients without underlying cirrhosis or liver disease. While inflammatory bowel disease has been linked to certain forms of liver disease, hepatocellular carcinoma is exceedingly rare in these patients. We report the twelfth case of hepatocellular carcinoma in a patient with Crohn's disease. The patient is a 61-year-old with longstanding Crohn's disease who was treated with azathioprine and was found to have elevated liver enzymes and a new 3-cm liver mass on ultrasound. A complete workup for underlying liver disease was unremarkable and liver biopsy revealed hepatocellular carcinoma. The patient underwent a hepatic resection, and there is no evidence of recurrence at the 11-month follow-up. The resection specimen showed no evidence of cancer despite the initial biopsy revealing hepatocellular carcinoma. This case represents the third biopsy-proven complete spontaneous regression of hepatocellular carcinoma. Although large studies have failed to show a definite link between azathioprine and hepatocellular carcinoma, the relationship remains concerning given the multiple case reports suggesting a possible association. Clinicians should exercise a high degree of suspicion in patients with Crohn's disease who present with elevated liver enzymes, especially those on azathioprine therapy.

Prevalence and predictors of sleep disturbance among liver diseases in long-term transplant survivors.

BACKGROUND: Patients with cirrhosis are known to experience sleep disturbance, which negatively impacts health-related quality of life. OBJECTIVE: To assess the prevalence and predictors of sleep disturbance before and after liver transplantation (LT). METHODS: Both pre- and post-LT patients were administered the Basic Nordic Sleep Questionnaire. The primary outcome was overall sleep satisfaction; the secondary outcomes were sleep latency and sleep duration. RESULTS: Eighty-three patients participated pre-LT and 273 post-LT. Overall, participants having completed both pre- and post-LT questionnaires reported satisfactory sleep 61% of the time before LT and 65% of the time after LT. However, on review of all questionnaires, patients with alcoholic liver disease (ETOH) experienced dramatically less sleep disturbance (OR 0.13 [95% CI 0.03 to 0.60]) post-LT, whereas those with hepatitis C remained without improvement (OR 0.90 [95% CI [0.38 to 2.15]). On logistic regression, patients with ETOH had statistically less sleep satisfaction pre-LT (OR 5.8 [95% CI 1.0 to 40.5]) and significantly better sleep satisfaction post-LT (OR 0.50 [95% CI 0.20 to 1.00]) compared with those with hepatitis C. In addition, both ETOH and other conditions had significantly better sleep latency than hepatitis C patients. CONCLUSIONS: Sleep parameters for patients who undergo LT for hepatitis C do not improve following LT as much as they do in patients transplanted for ETOH. Following LT, patients transplanted for ETOH are significantly more satisfied with their sleep than those transplanted for hepatitis C. Physicians should address and manage sleep quality after LT, so as to ultimately improve quality of life.

Single-dose infliximab in hepatitis C genotype 1 treatment-naive patients with high serum tumour necrosis factor-alpha does not influence the efficacy of pegylated interferon alpha-2b/ribavirin therapy.

BACKGROUND: Serum tumour necrosis factor-alpha (TNF-α) levels correlate negatively with hepatitis C virus (HCV) antiviral response. OBJECTIVES: To test the hypothesis that a single infliximab induction dose would positively influence on-treatment virological response and sustained virological response (SVR). METHODS: The present study was a phase IIIB, randomized, prospective, open-label pilot trial conducted at eight Canadian sites. Treatment-naive HCV genotype 1-infected patients 18 to 65 years of age with high serum TNF-α values (>300 pg/mL) were randomly assigned to receive a single pretreatment induction infliximab infusion (5 mg/kg) seven days before antiviral therapy (arm A) or no pretreatment (arm B). All patients received pegylated interferon α2b (1.5 µg/kg/week) plus weight-based ribavirin (800 mg/day to 1400 mg/day) for up to 48 weeks. RESULTS: Eighty-five patients (arm A [n=41], arm B [n=44]; 70% male) received pegylated interferon α2b. The mean age (48.1 years), race (81% white) and METAVIR fibrosis stage (F0-2 = 79%, F3-4 = 21%) were similar between groups. Infliximab was well tolerated without attributable severe adverse events; 56.5% completed the study (arm A [n=21], arm B [n=27]). Most discontinuations were due to virological failure at weeks 12 (n=20 [23.5%]) and 24 (n=7 [8.2%]) and did not differ according to group. Numerically lower proportions of infliximab recipients achieved rapid virological response (19.5% versus 36.4%), complete early virological response (43.9% versus 59.1%) and SVR (34.1% versus 52.3%). However, between-group differences did not reach statistical significance. No differences in adverse event profile or laboratory measures were noted. CONCLUSION: A single infliximab dose before pegylated-interferon α2b and ribavirin therapy did not result in greater viral decline during the first 12 weeks of HCV therapy or improved SVR.

Mild Hypertransaminasemia in Primary Care.

The liver enzymes, alanine transaminase (ALT) or aspartate transaminase (AST), are commonly used in clinical practice as screening as well as diagnostic tests for liver diseases. ALT is more specific for liver injury than AST and has been shown to be a good predictor of liver related and all-cause mortality. Asymptomatic mild hypertransaminasemia (i.e., less than five times normal) is a common finding in primary care and this could be attributed to serious underlying condition or has transient and benign cause. Unfortunately, there are no good literatures available on the cost-effectiveness of evaluating patients with asymptomatic mild hypertransaminasemia. However, if the history and physical examination do not suggest a clear cause, a stepwise approach should be initiated based on pretest probability of the underlying liver disease. Nonalcoholic fatty liver disease is becoming the most common cause of mild hypertransaminasemia worldwide. Other causes include alcohol abuse, medications, and hepatitis B and C. Less common causes include hemochromatosis, α1-antitrypsin deficiency, autoimmune hepatitis, and Wilson's disease. Nonhepatic causes such as celiac disease, thyroid, and muscle disorders should be considered in the differential diagnosis. Referral to a specialist and a possible liver biopsy should be considered if persistent hypertransaminasemia for six months or more of unclear etiology.

Chylous ascites secondary to giant liver hemangioma.

Chylous ascites is rare in clinical practice. It is characterized by milky-appearing peritoneal fluid with a triglycerides concentration of >1.25 mmol/l (110 mg/dl). Its pathophysiology is related to a disruption in the normal lymphatic flow. It is more common after trauma (including post surgery), neoplasia or atypical infections such as tuberculosis or filariasis. Other rare medical causes have been reported. The treatment is supportive and focused on correction of the underlying pathology. We report here the first case of chylous ascites caused by giant liver hemangioma and discuss the management of this condition.

Clinical manifestations of portal hypertension.

The portal hypertension is responsible for many of the manifestations of liver cirrhosis. Some of these complications are the direct consequences of portal hypertension, such as gastrointestinal bleeding from ruptured gastroesophageal varices and from portal hypertensive gastropathy and colopathy, ascites and hepatorenal syndrome, and hypersplenism. In other complications, portal hypertension plays a key role, although it is not the only pathophysiological factor in their development. These include spontaneous bacterial peritonitis, hepatic encephalopathy, cirrhotic cardiomyopathy, hepatopulmonary syndrome, and portopulmonary hypertension.

Markers of inflammation and fibrosis in alcoholic hepatitis and viral hepatitis C.

High levels of profibrinogenic cytokine transforming factor beta (TGF-ß), metalloprotease (MMP2), and tissue inhibitor of matrix metalloprotease 1 (TIMP1) contribute to fibrogenesis in hepatitis C virus (HCV) infection and in alcohol-induced liver disease (ALD). The aim of our study was to correlate noninvasive serum markers in ALD and HCV patients with various degrees of inflammation and fibrosis in their biopsies. Methods. Serum cytokines levels in HCV-infected individuals in the presence or absence of ALD were measured. Student's-t-test with Bonferroni correction determined the significance between the groups. Results. Both tumor-necrosis-factor- (TNF)-α and TGF-ß levels increased significantly with the severity of inflammation and fibrosis. TGF-ß levels increased significantly in ALD patients versus the HCV patients. Proinflammatory cytokines' responses to viral and/or toxic injury differed with the severity of liver inflammation. A combination of these markers was useful in predicting and diagnosing the stages of inflammation and fibrosis in HCV and ALD. Conclusion. Therapeutic monitoring of TGF-ß and metalloproteases provides important insights into fibrosis.

Inflammation and repair in viral hepatitis C.

Hepatitis C viral infection (HCV) results in liver damage leading to inflammation and fibrosis of the liver and increasing rates of hepatic decompensation and hepatocellular carcinoma (HCC). However, the host's immune response and viral determinants of liver disease progression are poorly understood. This review will address the determinants of liver injury in chronic HCV infection and the risk factors leading to rapid disease progression. We aim to better understand the factors that distinguish a relatively benign course of HCV from one with progression to cirrhosis. We will accomplish this task by discussion of three topics: (1) the role of cytokines in the adaptive immune response against the HCV infection; (2) the progression of fibrosis; and (3) the risk factors of co-morbidity with alcohol and human immunodeficiency virus (HIV) in HCV-infected individuals. Despite recent improvements in treating HCV infection using pegylated interferon alpha (PEGIFN-alpha) and ribavirin, about half of individuals infected with some genotypes, for example genotypes 1 and 4, will not respond to treatment or cannot be treated because of contraindications. This review will also aim to describe the importance of IFN-alpha-based therapies in HCV infection, ways of monitoring them, and associated complications.

Use of sequence analysis of the NS5B region for routine genotyping of hepatitis C virus with reference to C/E1 and 5' untranslated region sequences.

Nucleotide sequence analysis of the NS5B region was performed to identify genotypes of 8,479 hepatitis C virus (HCV) RNA-positive patient samples collected in the Canadian province of Quebec. Genotypes could be determined for 97.3% of patients. Genotypes 1 to 6 were found in 59.4, 9.0, 25.7, 3.6, 0.6, and 1.8% of patients, respectively. Two isolates did not classify within the six genotypes. The subtype 1 distribution was 76.7% 1a, 22.6% 1b, and 0.7% others, while the subtype 2 distribution was 31.8% 2a, 47.6% 2b, 10.9% 2c, 4.1% 2i, and 5.6% others. Subtype 3a accounted for 99.1% of genotype 3 strains, while all genotype 5 samples were of subtype 5a. The subtype 4 distribution was 39.2% 4a, 15.4% 4k, 11.6% 4d, 10.2% 4r, and 23.6% others. The subtype 6 distribution was 40.4% 6e, 20.5% 6a, and 39.1% others. The 5' untranslated region (5'UTR) sequences of subtype 6e were indistinguishable from those of genotype 1. All samples that did not classify within the established subtypes were also sequenced in C/E1 and 5'UTR. C/E1 phylogenetic reconstructions were analogous to those of NS5B. The sequences identified in this study allowed the provisional assignments of subtypes 1j, 1k, 2m, 2r, 3i, 4q, 6q, 6r, and 6s. Sixty-four (0.8%) isolates classifying within genotypes 1 to 6 could not be assigned to one of the recognized subtypes. Our results show that genotyping of HCV by nucleotide sequence analysis of NS5B is efficient, allows the accurate discrimination of subtypes, and is an effective tool for studying the molecular epidemiology of HCV.