Gene-addition/editing therapy in sickle cell disease.

Gene therapy is an innovative strategy that offers potential cure for patients with sickle cell disease, and no appropriate donor for transplant consideration. While we await long term data from these clinical trials, we remain optimistic that gene therapy will become a standard of care for curative treatment in sickle cell disease. As gene therapy becomes a standard of treatment in sickle cell disease, we must also acknowledge the potential for financial burden to patients. We also must acknowledge the prevalence of sickle cell disease in low-resource settings. Hopefully, as we learn more about gene therapy, we can assess ways to overcome the financial toxicity that comes with this therapy.

An integrated therapeutic approach to sickle cell disease management beyond infancy.

Hydroxyurea, the first approved drug for sickle cell disease, decreases sickle hemoglobin polymerization by inducing fetal hemoglobin. Its effects in young children are excellent; responses in adults are variable and not curative. The goal of pharmacotherapy should not be disease "moderation" but reducing morbidity and mortality by diminishing both hemolytic anemia and vaso-occlusive events. This is best done by preventing sickle hemoglobin polymerization; if anti-polymerization treatment is insufficient, agents disrupting pathophysiologic pathways "downstream" of the sickle hemoglobin polymer should be added. We recommend that all patients should be started first on maximal doses of hydroxyurea. When the clinical and hematologic response to hydroxyurea is insufficient, as it is almost always in adults, we favor adding voxelotor, a hemoglobin-oxygen affinity-shifting agent that, likely in a pancellular distribution, decreases sickle hemoglobin polymerization. The P-selectin inhibitor crizanlizumab reduces sickle cell-endothelial interactions and can be used in patients with continued vaso-occlusive events. There is no physiologic reason that all three drugs could not be combined when the response to monotherapy or dual-drug therapy is poor. Drug therapy must be considered in the context of possibly "curative" cellular therapeutics and if needed, exchange transfusion programs.

Autoimmune Hepatitis in a Patient With Common Variable Immunodeficiency.

Common variable immunodeficiency (CVID), a condition characterized by impaired antibody production, is paradoxically associated with various autoimmune disorders. The most common causes of liver disease in patients with CVID are nodular regenerative hyperplasia, granulomatous infiltration of the liver, and chronic viral hepatitis. We present a case of autoimmune hepatitis in a patient with CVID.

Adult idiopathic cholestasis: a condition more common in the Canadian Inuit?

Despite extensive investigations, some patients have no identifiable cause for their cholestatic liver enzyme abnormalities. The aim of this study was to document the clinical, laboratory, radiologic and histologic features of adult patients with idiopathic cholestasis (AIC). A computerised database of referred patients to a tertiary care hospital outpatient department for assessment of hepatobiliary disorders between 2005 and 2015 was employed to identify and describe features associated with AIC. Of 6,560 patient referrals, sufficient documentation to warrant a diagnosis of AIC was present in 17 (0.26%) cases. Of the 17, a disproportionate number were Canadian Inuit (7/60, 12% Inuit referrals vs. 10/6,500, 0.16% non-Inuit referrals, p<0.0001). The median age of the 17 subjects was 57 years and nine (53%) were female. Clinical and/or laboratory evidence of autoimmune disorders was present in six (35%) cases. Clinical features of hepatic decompensation, radiologic findings in keeping with cirrhosis and histologic confirmation of cirrhosis were present in 47%, 31% and 42% of individuals, respectively. There were no significant improvements in cholestatic liver enzymes and function tests in those treated with ursodiol and/or immunomodulants (n=7) compared to those left untreated (n=10). In conclusion, AIC is a rare condition diagnosed by exclusion. It appears to be more common in the Canadian Inuit population and those with autoimmune disorders. Advanced liver disease is a frequent finding at presentation. Intervention with ursodiol and/or immunomodulants does not appear to be of therapeutic value.

Diagnostic considerations for cholestatic liver disease.

Cholestatic liver disease results from insufficient bile synthesis, secretion and/or flow through the biliary tract. Common presenting features include fatigue, pruritus, and cholestatic liver enzyme abnormalities wherein elevations of serum alkaline phosphatase and gamma-glutamyltransferases levels exceed those of alanine and aspartate aminotransferases. With prolonged cholestasis, fat soluble vitamin deficiencies, fibrosis, cirrhosis, and, on occasion, carcinoma of the biliary tract or liver can occur. Once mechanical obstruction to bile flow has been ruled out, the majority of causes can be classified as immune-mediated, infectious, or miscellaneous. Because specific therapeutic options are increasing for many causes of cholestasis, an accurate diagnosis is an important first step towards treatment. Thus, this review focuses on the diagnostic features of non-mechanical causes of cholestasis.

Efficacy of Ciji Hua'ai Baosheng formula on the expressions of vascular endothelial growth factor, kinase insert domain-containing receptor and basic fibroblast growth factor in mouse models of H(22) hepatocellular carcinoma.

OBJECTIVE: To investigate the efficacy of Ciji Hua'ai Baosheng formula (CHBF) on microvessel density (MVD) and vascular endothelial growth factor (VEGF), kinase insert domain-containing receptor (KDR) and basic fibroblast growth factor (bFGF) expression in serum and tumor tissue of mice receiving chemotherapy for the treatment of H(22) hepatocellular carcinoma. METHODS: Sixty Kunming mice were injected subcutaneously with H(22) hepatoma carcinoma cell suspensions into the right anterior armpit. Seven days later, all transplanted tumor were formed and the mice were intraperitoneally injected 200 mg/kg Cytoxan (CTX) to establish the models of tumor-bearing mouse chemotherapy, then they were randomly divided into model group, continuing CTX chemotherapy group (CTX group), and three CHBF (117, 58.5 and 29.25 g/kg) groups. After ten days of treatments, histology was observed, contents of VEGF, KDR and bFGF in serum and tumor tissue were measured by enzyme-linked immunosorbent assay (ELISA), VEGF and bFGF protein expression and MVD tagged by CD34 were detected by immunohistochemistry. RESULTS: MVD in CHBF (117, 58.5 g/kg) and CTX groups was significantly lower than that in model group (P < 0.01); expressions of VEGF, KDR and bFGF in serum and tumor tissue in CHBF (117 g/kg) group were less than those in model group (P < 0.05; P < 0.01); the expressions of MVD, VEGF and bFGF in tumor tissue of CHBF (117 g/kg) group were also less than those in CTX group (P < 0.05; P < 0.01). CONCLUSION: CHBF can effectively reduce the expression of VEGF, KDR and bFGF in serum and tumor tissue, and decrease MVD and delay tumor progression.