Amelioration of Large Bile Duct Damage by Histamine-2 Receptor Vivo-Morpholino Treatment.

Histamine binds to one of the four G-protein-coupled receptors expressed by large cholangiocytes and increases large cholangiocyte proliferation via histamine-2 receptor (H2HR), which is increased in patients with primary sclerosing cholangitis (PSC). Ranitidine decreases liver damage in Mdr2-/- (ATP binding cassette subfamily B member 4 null) mice. We targeted hepatic H2HR in Mdr2-/- mice using vivo-morpholino. Wild-type and Mdr2-/- mice were treated with mismatch or H2HR vivo-morpholino by tail vein injection for 1 week. Liver damage, mast cell (MC) activation, biliary H2HR, and histamine serum levels were studied. MC markers were determined by quantitative real-time PCR for chymase and c-kit. Intrahepatic biliary mass was detected by cytokeratin-19 and F4/80 to evaluate inflammation. Biliary senescence was determined by immunofluorescence and senescence-associated ß-galactosidase staining. Hepatic fibrosis was evaluated by staining for desmin, Sirius Red/Fast Green, and vimentin. Immunofluorescence for transforming growth factor-ß1, vascular endothelial growth factor-A/C, and cAMP/ERK expression was performed. Transforming growth factor-ß1 and vascular endothelial growth factor-A secretion was measured in serum and/or cholangiocyte supernatant. Treatment with H2HR vivo-morpholino in Mdr2-/--mice decreased hepatic damage; H2HR protein expression and MC presence or activation; large intrahepatic bile duct mass, inflammation and senescence; and fibrosis, angiogenesis, and cAMP/phospho-ERK expression. Inhibition of H2HR signaling ameliorates large ductal PSC-induced damage. The H2HR axis may be targeted in treating PSC.

Biliary damage and liver fibrosis are ameliorated in a novel mouse model lacking l-histidine decarboxylase/histamine signaling.

Primary sclerosing cholangitis (PSC) is characterized by biliary damage and fibrosis. Multidrug resistance-2 gene knockout (Mdr2-/-) mice and PSC patients have increased histamine (HA) levels (synthesized by l-histidine decarboxylase, HDC) and HA receptor (HR) expression. Cholestatic HDC-/- mice display ameliorated biliary damage and hepatic fibrosis. The current study evaluated the effects of knockout of HDC-/- in Mdr2-/- mice (DKO) on biliary damage and hepatic fibrosis. WT, Mdr2-/- mice, and homozygous DKO mice were used. Selected DKO mice were treated with HA. We evaluated liver damage along with HDC expression and HA serum levels. Changes in ductular reaction were evaluated along with liver fibrosis, inflammation and bile acid signaling pathways. The expression of H1HR/PKC-α/TGF-ß1 and H2HR/pERK/VEGF-C was determined. In vitro, cholangiocyte lines were treated with HA with/without H1/H2 inhibitors before measuring: H1/H2HR, TGF-ß1, and VEGF-C expression. Knockout of HDC ameliorates hepatic damage, ductular reaction, fibrosis, inflammation, bile acid signaling and H1HR/PKC-α/TGF-ß1 and H2HR/pERK/VEGF-C signaling. Reactivation of the HDC/HA axis increased these parameters. In vitro, stimulation with HA increased HR expression and PKC-α, TGF-ß1, and VEGF-C expression, which was reduced with HR inhibitors. Our data demonstrate the key role for the HDC/HA axis in the management of PSC progression.

Direct Comparison of the Thioacetamide and Azoxymethane Models of Type A Hepatic Encephalopathy in Mice.

Acute liver failure is a devastating consequence of hepatotoxic liver injury that can lead to the development of hepatic encephalopathy. There is no consensus on the best model to represent these syndromes in mice, and therefore the aim of this study was to classify hepatic and neurological consequences of azoxymethane- and thioacetamide-induced liver injury. Azoxymethane-treated mice were euthanized at time points representing absence of minor and significant stages of neurological decline. Thioacetamide-treated mice had tissue collected at up to 3 days following daily injections. Liver histology, serum chemistry, bile acids, and cytokine levels were measured. Reflexes, grip strength measurement, and ataxia were calculated for all groups. Brain ammonia, bile acid levels, cerebral edema, and neuroinflammation were measured. Finally, in vitro and in vivo assessments of blood-brain barrier function were performed. Serum transaminases and liver histology demonstrate that both models generated hepatotoxic liver injury. Serum proinflammatory cytokine levels were significantly elevated in both models. Azoxymethane-treated mice had progressive neurological deficits, while thioacetamide-treated mice had inconsistent neurological deficits. Bile acids and cerebral edema were increased to a higher degree in azoxymethane-treated mice, while cerebral ammonia and neuroinflammation were greater in thioacetamide-treated mice. Blood-brain barrier permeability exists in both models but was likely not due to direct toxicity of azoxymethane or thioacetamide on brain endothelial cells. In conclusion, both models generate acute liver injury and hepatic encephalopathy, but the requirement of a single injection and the more consistent neurological decline make azoxymethane treatment a better model for acute liver failure with hepatic encephalopathy.

Gastrointestinal Bleeding Caused by Large Intestine Amyloidosis.

Background: Amyloidosis is a rare disorder caused by abnormal folding of proteins, leading to the dysfunction of normal tissues. Amyloid deposition can affect several organs, but deposition in the large intestine is rare. Case Presentation: A 79-year-old man presented with gastrointestinal bleeding and nonspecific symptoms of weight loss, dry heaves, dysphagia, and weakness. The patient underwent esophagogastroduodenoscopy and colonoscopy and a biopsy confirmed the diagnosis of intestinal amyloidosis. Conclusions: This case report highlights the importance of a strong differential when working up gastrointestinal bleeding that includes amyloidosis. Early identification and multidisciplinary involvement are crucial for management and tailored care to each patient's needs.

Prevalence of cannabinoid hyperemesis syndrome and its financial burden on the health care industry.

Cannabis is the most commonly consumed recreational drug in the world. As more states legalize cannabis use in some form, the incidence of cannabinoid hyperemesis syndrome (CHS) is expected to rise. CHS is a constellation of symptoms including severe cyclical nausea and vomiting and epigastric or periumbilical abdominal pain as a result of long-term cannabis use. Recognizing the diagnosis and educating patients on the benefits of cessation is essential, as these patients often undergo extensive and repeated evaluations in the clinic, emergency department, and inpatient setting that could be avoided with extensive history taking and early recognition of the syndrome. In this study, we compared costs incurred by patients in various settings to determine if there is a difference between patients with and without CHS. Although there were not statistically significant cost differences between groups for all cost categories, it is clear that patients with CHS consume considerably more health care dollars than patients who deny cannabis use, and obtaining a detailed social history is imperative to prevent unnecessary workups and increased financial burden on the health care industry.

The Direct Contribution of Astrocytes and Microglia to the Pathogenesis of Hepatic Encephalopathy.

Hepatic encephalopathy is a neurological complication resulting from loss of hepatic function and is associated with poor clinical outcomes. During acute liver failure over 20% of mortality can be associated with the development of hepatic encephalopathy. In patients with liver cirrhosis, 1-year survival for those that develop overt hepatic encephalopathy is under 50%. The pathogenesis of hepatic encephalopathy is complicated due to the multiple disruptions in homeostasis that occur following a reduction in liver function. Of these, elevations of ammonia and neuroinflammation have been shown to play a significant contributing role to the development of hepatic encephalopathy. Disruption of the urea cycle following liver dysfunction leads to elevations of circulating ammonia, which enter the brain and disrupt the functioning of astrocytes. This results in dysregulation of metabolic pathways in astrocytes, oxidative stress and cerebral edema. Besides ammonia, circulating chemokines and cytokines are increased following liver injury, leading to activation of microglia and a subsequent neuroinflammatory response. The combination of astrocyte dysfunction and microglia activation are significant contributing factors to the pathogenesis of hepatic encephalopathy.

Assessing adherence and cost-benefit of colorectal cancer screening for accountable providers.

The objective of this study was to assess adherence and costs-benefits of colorectal cancer (CRC) screenings from an accountable care organization/population health perspective. We performed a retrospective review of 94 patients (50-75 years of age) in an integrated safety net system for whom fecal CRC screening was abnormal for the period of June 1, 2014, to June 1, 2016. A cost-benefit model was constructed using Medicare payment rates and a sensitivity analysis. Most patients included in the study (64/94, 68%) received or were offered a colonoscopy. Of those receiving a colonoscopy, 24 of 45 (53%) had an abnormal finding. Total direct medical costs avoided by screening the patient panel was $32,926 but could have exceeded $63,237 had more patients received follow-up colonoscopies. A sensitivity analysis with 1000 patients demonstrated total monetary benefits between $2.2 million and $8.16 million when follow-up and colonoscopy rates were allowed to vary. Although the resulting rates of follow-up were within the range reported in the literature, there is room for improvement, especially considering the monetary benefit that could be used on other diseases. Health systems and payers should work cooperatively to structure payment models to better incentivize CRC screenings.

Metastatic calcinosis cutis in end-stage renal disease.

Alterations in calcium and phosphorus levels and joint pain are a common occurrence in end-stage renal disease patients. However, metastatic calcinosis cutis is a rare diagnosis that often combines these two findings, with extensive soft tissue calcification surrounding a large joint being the hallmark of this disease. The exact mechanism behind this clinical entity is unknown. The treatment and complications can be severe and disabling. Here, we discuss the case of a 26-year-old man presenting with unusually advanced skin and joint calcification of the shoulders, neck, hand, and penis.