Clinical and biochemical impact of vitamin B6 deficiency in primary sclerosing cholangitis before and after liver transplantation.

BACKGROUND AND AIMS: We previously demonstrated that people with primary sclerosing cholangitis (PSC) had reduced gut microbial capacity to produce active vitamin B6 (pyridoxal 5'-phosphate [PLP]), which corresponded to lower circulating PLP levels and poor outcomes. Here, we define the extent and biochemical and clinical impact of vitamin B6 deficiency in people with PSC from several centers before and after liver transplantation (LT). METHODS: We used targeted liquid chromatography-tandem mass spectrometry to measure B6 vitamers and B6-related metabolic changes in blood from geographically distinct cross-sectional cohorts totaling 373 people with PSC and 100 healthy controls to expand on our earlier findings. Furthermore, we included a longitudinal PSC cohort (n = 158) sampled prior to and serially after LT, and cohorts of people with inflammatory bowel disease (IBD) without PSC (n = 51) or with primary biliary cholangitis (PBC) (n = 100), as disease controls. We used Cox regression to measure the added value of PLP to predict outcomes before and after LT. RESULTS: In different cohorts, 17-38% of people with PSC had PLP levels below the biochemical definition of a vitamin B6 deficiency. The deficiency was more pronounced in PSC than in IBD without PSC and PBC. Reduced PLP was associated with dysregulation of PLP-dependent pathways. The low B6 status largely persisted after LT. Low PLP independently predicted reduced LT-free survival in both non-transplanted people with PSC and in transplant recipients with recurrent disease. CONCLUSIONS: Low vitamin B6 status with associated metabolic dysregulation is a persistent feature of PSC. PLP was a strong prognostic biomarker for LT-free survival both in PSC and recurrent disease. Our findings suggest that vitamin B6 deficiency modifies the disease and provides a rationale for assessing B6 status and testing supplementation. IMPACT AND IMPLICATIONS: We previously found that people with PSC had reduced gut microbial potential to produce essential nutrients. Across several cohorts, we find that the majority of people with PSC are either vitamin B6 deficient or have a marginal deficiency, which remains prevalent even after liver transplantation. Low vitamin B6 levels strongly associate with reduced liver transplantation-free survival as well as deficits in biochemical pathways dependent on vitamin B6, suggesting that the deficiency has a clinical impact on the disease. The results provide a rationale for measuring vitamin B6 and to investigate whether vitamin B6 supplementation or modification of the gut microbial community can help improve outcomes for people with PSC.

Cholangiocarcinoma: Diagnosis and Management.

Cholangiocarcinoma is a highly lethal biliary epithelial tumor that is rare in the general population but has increased rates in patients with primary sclerosing cholangitis (PSC). It is heterogenous, and management varies by location. No effective prevention exists, and screening is likely only feasible in PSC. Patients often present in an advanced state with jaundice, weight loss, and cholestatic liver enzymes. Diagnosis requires imaging with magnetic resonance cholangiopancreatography, laboratory testing, and endoscopic retrograde cholangiopancreatography. Potentially curative options include resection and liver transplant with neoadjuvant or adjuvant chemoradiation. Chemotherapy, radiation, and locoregional therapy provide some survival benefit in unresectable disease.

Blocking H1/H2 histamine receptors inhibits damage/fibrosis in Mdr2-/- mice and human cholangiocarcinoma tumorigenesis.

Primary sclerosing cholangitis (PSC) patients are at risk of developing cholangiocarcinoma (CCA). We have shown that (1) histamine increases biliary hyperplasia through H1/H2 histamine receptors (HRs) and (2) histamine levels increase and mast cells (MCs) infiltrate during PSC and CCA. We examined the effects of chronic treatment with H1/H2HR antagonists on PSC and CCA. Wild-type and multidrug-resistant knockout (Mdr2-/- ) mice were treated by osmotic minipumps with saline, mepyramine, or ranitidine (10 mg/kg body weight/day) or a combination of mepyramine/ranitidine for 4 weeks. Liver damage was assessed by hematoxylin and eosin. We evaluated (1) H1/H2HR expression, (2) MC presence, (3) L-histidine decarboxylase/histamine axis, (4) cholangiocyte proliferation/bile duct mass, and (5) fibrosis/hepatic stellate cell activation. Nu/nu mice were implanted with Mz-ChA-1 cells into the hind flanks and treated with saline, mepyramine, or ranitidine. Tumor growth was measured, and (1) H1/H2HR expression, (2) proliferation, (3) MC activation, (4) angiogenesis, and (5) epithelial-mesenchymal transition (EMT) were evaluated. In vitro, human hepatic stellate cells were evaluated for H1HR and H2HR expression. Cultured cholangiocytes and CCA lines were treated with saline, mepyramine, or ranitidine (25 µM) before evaluating proliferation, angiogenesis, EMT, and potential signaling mechanisms. H1/H2HR and MC presence increased in human PSC and CCA. In H1/H2HR antagonist (alone or in combination)-treated Mdr2-/- mice, liver and biliary damage and fibrosis decreased compared to saline treatment. H1/H2HR antagonists decreased tumor growth, serum histamine, angiogenesis, and EMT. In vitro, H1/H2HR blockers reduced biliary proliferation, and CCA cells had decreased proliferation, angiogenesis, EMT, and migration. Conclusion: Inhibition of H1/H2HR reverses PSC-associated damage and decreases CCA growth, angiogenesis, and EMT; because PSC patients are at risk of developing CCA, using HR blockers may be therapeutic for these diseases. (Hepatology 2018).

[NISCH syndrome, a rare cause of neonatal cholestasis: A case report]. / Le syndrome NISCH, une cause rare de cholestase néonatale : à propos d'un cas.

NISCH syndrome is a rare autosomal recessive disease. It is characterized by scalp hypotrichosis, scarring alopecia, ichthyosis, and neonatal sclerosing cholangitis. It is caused by mutations in the CLDN1 gene encoding the claudin-1 protein, which is located at tight junctions. Fifteen cases have been reported to date and three different mutations have been identified. We report on the case of a 2-year-old boy from a consanguineous Moroccan family, presenting with NISCH syndrome and carrying the so-called Moroccan homozygous mutation (c.200-201delTT). The patient presented with the characteristic symptoms of the syndrome and a favorable progression with normalization of hepatic analyses under symptomatic treatment (vitamin supplementation and ursodeoxycholic acid). The currently limited availability of clinical and therapeutic data does not allow accurate prediction of the course of the disease and short- and long-term prognosis. Moreover, substantial interindividual variability has been reported. Description of new cases will provide new insights into the understanding and the overall management of this syndrome, the course of which remains elusive.

Coffee consumption protects against progression in liver cirrhosis and increases long-term survival after liver transplantation.

BACKGROUND: Therapeutic options to treat progression of end-stage liver disease (ESLD) or improve long-term survival after liver transplantation remain scarce. We investigated the impact of coffee consumption under these conditions. METHODS: We recorded coffee consumption habits of 379 patients with ESLD awaiting liver transplantation and 260 patients after liver transplantation. Survival was analyzed based on coffee intake. RESULTS: One hundred ninety-five patients with ESLD consumed coffee on a daily basis, while 184 patients did not. Actuarial survival was impaired (P = 0.041) in non-coffee drinkers (40.4 ± 4.3 months, 95% confidence interval [CI]: 32.0-48.9) compared with coffee drinkers (54.9 ± 5.5 months, 95% CI: 44.0-65.7). In subgroup analysis, the survival of patients with alcoholic liver disease (ALD; P = 0.020) and primary sclerosing cholangitis (PSC; P = 0.017) was increased with coffee intake while unaffected in patients with chronic viral hepatitis (P = 0.517) or other liver disease entities (P = 0.652). Multivariate analysis showed that coffee consumption of PSC and ALD patients retained as an independent risk factor (odds ratio [OR]: 1.94; 95% CI: 1.15-3.28; P = 0.013) along with MELD score (OR: 1.13; 95% CI: 1.09-1.17; P = 0.000). Following liver transplantation, long-term survival was longer in coffee drinkers (coffee: 61.8 ± 2.0 months, 95% CI: 57.9-65.8) than non-drinkers (52.3 ± 3.5 months, 95% CI: 45.4-59.3; P = 0.001). CONCLUSIONS: Coffee consumption delayed disease progression in ALD and PSC patients with ESLD and increased long-term survival after liver transplantation. We conclude that regular coffee intake might be recommended for these patients.

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.

Caspase 8 differentially controls hepatocytes and non-parenchymal liver cells during chronic cholestatic liver injury in mice.

BACKGROUND & AIMS: Receptor mediated cell death through the activation of caspases has been identified as an important mechanism to control life and death in various tissues and is thus crucial for the maintenance of liver tissue homeostasis. Here we investigated how caspase 8 (Casp8) differentially regulates immune-mediated liver injury and regeneration in distinct liver cell types during chronic liver injury. METHODS: Conditional knockout mice with hepatocellular (Casp8(Δhepa)) and ubiquitous deletion of Casp8 (Casp8(ΔMx)) were used in models of cholestatic hepatitis [(DDC (3,5-diethoxycarbonyl-1,4-dihydrocollidine) treatment, bile duct ligation (BDL) and choline deficient diet with ethionine supplementation (CDE)]. RESULTS: Mice with a hepatocellular deletion of Casp8 (Casp8(Δhepa)) were protected after DDC-treatment. Animals with a ubiquitous conditional Casp8 knockout (Casp8(ΔMx)) displayed a significantly enhanced liver injury in various models of cholestatic liver injury. This was associated with higher transaminases, bilirubin levels and finally more liver fibrosis. However, caspase 3 (Casp3) activity was reduced in both knockout strains, suggesting additionally mechanisms contributing to the phenotype. Casp8(ΔMx) mice displayed a stronger infiltration of mononuclear immune cells and more proliferation of liver-parenchymal cells in periportal areas. Further analysis confirmed that these infiltrating immune cells are resistant against extrinsic apoptosis. Bone-marrow-transplantation (BMT) experiments demonstrated that Casp8-deficient bone marrow derived cells are responsible for increased liver injury in DDC fed mice. CONCLUSIONS: Our results demonstrate that cell-type specific differences in apoptosis resistance mediated by Casp8 deletion are of significant relevance for the outcome of chronic liver injury.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis in a liver graft recipient: a case report.

BACKGROUND: Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy is a potentially curative approach for peritoneal carcinomatosis of colonic origin. So far experience concerning the use of this treatment option in transplant recipients is lacking. CASE REPORT: We herein present the case of a 31-year-old man who had previously been liver transplanted for primary sclerosing cholangitis. Approximately 10 years after transplantation colon carcinoma with co-existing peritoneal carcinomatosis was diagnosed. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy were conducted. Operative management under tacrolimus medication did not trigger infections, wound healing disorders or graft function impairment. At one year follow-up no tumor recurrence was detected. CONCLUSIONS: Recent literature suggests that proctocolectomy for colorectal cancer is considered feasible in liver graft recipients. Virtually all patients suffering from primary sclerosing cholangitis exhibit co-existing ulcerative colitis, rendering this subset of patient at risk for developing colonic malignancies. Furthermore chronic immunosuppression may facilitate malignant growth. The most feared complication in colorectal carcinomas is the occurence of peritoneal carcinomatosis, for which cytoreduction plus hyperthermic intraperitoneal chemotherapy may be a curative option. This, so far unique, case report suggests that even in this patient subset this treatment is feasible and for further cases this dual-approach for the management of PC in transplant recipients should be taken into account.

Neoadjuvant therapy protocol and liver transplantation in combination with pancreatoduodenectomy for the treatment of hilar cholangiocarcinoma occurring in a case of primary sclerosing cholangitis: case report with a more than 8-year disease-free survival.

Cholangiocarcinoma has historically represented a major contraindication to liver transplantation at many centers because of its high recurrence rate and low disease-free survival rate, even after radical surgery. Novel neoadjuvant therapy protocols combined with demolitive surgery and liver transplantation seem to achieve successful results in terms of overall and disease-free survivals. Surgery frequently seems to be unsatisfactory only for patients also suffering from chronic cirrhosis or end-stage liver disease. We have reported a case of hilar cholangiocarcinoma occurring in a case of primary sclerosing cholangitis treated with neoadjuvant radiochemotherapy and endoscopic brachytherapy, followed by liver transplantation combined with pancreatoduodenectomy, who has survived free of disease for >8 years.

Colorectal cancer in post-liver transplant recipients.

PURPOSE: Several malignancies have been reported to occur more often after liver transplantation. Whether this is also true for colorectal carcinoma is controversial. Our aims were 1) to compare the observed rate of colorectal carcinoma in a post-liver transplantation cohort with incidence data from the general Dutch population, and 2) to stratify for patients with and without primary sclerosing cholangitis, because primary sclerosing cholangitis is well established as a risk factor for colorectal carcinoma. METHODS: We searched the medical records of liver transplantation patients who had a liver transplantation in our center between 1986 and 2007 with a follow-up of at least 3 months. Incidence data from the general population were retrieved from the Dutch Comprehensive Cancer Registry. Outcome measures were defined as standardized incidence ratio and incidence rate per 100,000 person-years. RESULTS: Three hundred ninety-four patients (58% men; mean age at liver transplantation, 46.6 y) were included in the 1986 to 2007 period. Bowel investigation before liver transplantation had been performed in 73% of patients. Median follow-up was 5.1 years (range, 0.25-20 y). The mean age at the end of follow-up was 52 years (SD, 13 y). Colorectal carcinoma was diagnosed in four patients (1%) during follow-up. The overall standardized incidence ratio for colorectal carcinoma in post-liver transplant recipients was 2.16 (95% CI: 0.81-5.76) compared with the general population and 1.26 (95% CI: 0.31-5.03) for nonprimary sclerosing cholangitis post-liver transplant recipients. CONCLUSION: This study suggests that the incidence of colorectal carcinoma is not increased in non-primary sclerosing cholangitis post-liver transplantation compared with the general population. A more intense colorectal carcinoma surveillance program based on this result remains controversial in nonprimary sclerosing cholangitis post-liver transplant recipients.

The management of primary sclerosing cholangitis.

Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by a progressive, obliterating fibrosis of the intrahepatic and extrahepatic bile ducts. The pathogenesis of PSC is unknown, but it is thought to be an immune-mediated disease. Although the role of cupruretics, immunosuppressants (corticosteroids, azathioprine, tacrolimus, methotrexate), antifibrogenic agents, and ursodeoxycholic acid in the treatment of primary sclerosing cholangitis is reviewed, none of these agents has been shown to retard or reverse the rate of disease progression. Of these therapies, ursodeoxycholic acid at high doses looks the most promising, but large trials are needed to establish whether treatment with high-dose ursodeoxycholic acid influences the morbidity and mortality associated with primary sclerosing cholangitis.

Colonic cancer in a patient with primary sclerosing cholangitis and long-standing ulcerative colitis.

A 27-year-old woman with a 9-year history of ulcerative colitis involving the entire colon was admitted to our hospital in August 1992 because of bloody stools and left lower abdominal pain. She had been treated with sulfasalazine since 1983 and the colitis had been clinically quiescent or mild for 7 years. She had also been diagnosed as having primary sclerosing cholangitis (PSC) 4 years prior to this admission, based on the clinical, laboratory, and cholangiographic findings. A barium enema and colonoscopy showed an irregular mass obstructing the bowel lumen in the distal portion of the descending colon. Biopsy specimens taken from the mass revealed moderately differentiated adenocarcinoma, and a subtotal colectomy was performed. Histologic examination of the mass lesion showed moderately differentiated adenocarcinoma invading the pericolic adipose tissue. She is currently alive 3 years after surgery. PSC has recently been reported as a risk factor for colonic neoplasia in patients with long-standing ulcerative colitis. In Japan, however, colorectal cancer associated with PSC and ulcerative colitis has rarely been reported. The present case suggests that the risk of colonic cancer is higher in patients with ulcerative colitis and PSC than in patients with ulcerative colitis alone.

Assessment of nutritional status of patients with end-stage liver disease undergoing liver transplantation.

Nutritional assessment factors (including dietary history, anthropometric and biochemical measurements, and evaluation of immunocompetence) were retrospectively reviewed in 74 patients undergoing an initial liver transplantation procedure. The patients were subdivided into four categories on the basis of type of liver disease: chronic active hepatitis (N = 24), primary sclerosing cholangitis (N = 22), primary biliary cirrhosis (N = 20), and acute or subacute hepatitis (N = 8). Our nutritional assessment data indicated that malnutrition was present preoperatively in all liver transplantation groups but that each group had distinct characteristics. The group with primary biliary cirrhosis seemed to have the best hepatic synthetic function despite extreme wasting of muscle and fat. On the basis of all criteria, the group with acute hepatitis was the most malnourished of the various disease groups. Aggressive nutritional support, which includes adequate intake of nutrients and supplementation of vitamins and trace minerals, should be encouraged for all potential liver transplant patients.

An unusual presentation of inflammatory bowel disease.

A 32 year-old male presented to his general practitioner for a routine health check. Microscopic haematuria was noted in an otherwise asymptomatic and fit patient. Subsequent investigation was normal apart from abnormal liver function tests for which no cause was found. A cholecystectomy was performed for gallstones which were detected by ultrasound after the patient complained of upper right quadrant pain. Wedge biopsy of the liver at operation was suggestive of cholangitis. A barium enema was performed which revealed ulceration of the transverse colon suggestive of Crohn's disease. The association of cholangitis and inflammatory bowel disease is discussed.