Effects of Hydroxyurea Treatment on Haemolysis in Patients with Sickle Cell Disease at Muhimbili National Hospital, Tanzania

Tanzania is one of the countries with a high burden of sickle cell disease (SCD). Haemolytic anaemia is a clinical feature of SCD, and has been linked to major complications leading to morbidity and mortality. Treatment with hydroxyurea (HU) has shown to induce foetal haemoglobin (HbF) which in turn decreases haemolysis in patients. This study aimed to investigate the effects of HU on haemolysis in SCD patients attending Muhimbili National Hospital, Tanzania by comparing their haemolytic parameters before and after therapy. Patients meeting the criteria were initiated on HU therapy for 3 months. Two haemolytic biomarkers: unconjugated plasma bilirubin levels and absolute reticulocyte counts were measured from patients’ blood samples at baseline and after 3 months of HU therapy and compared. Both absolute reticulocyte counts and indirect plasma bilirubin levels significantly declined after HU therapy. Median (IQR) plasma unconjugated bilirubin levels dropped significantly from 20.3 (12.7–34.4) μmol/L to 14.5 (9.6–24.1) μmol/L (p < 0.001) and mean (SD) absolute reticulocyte counts dropped significantly from 0.29 (0.1) x 109/L to 0.17 (0.1) x 109/L (p < 0.001) after therapy, thus, a decline in both haemolytic biomarkers after treatment was observed. This study found a potential for use of HU therapy in managing SCD patients in our settings evidenced by improvements in their haemolytic parameters. Clinical trials with a lager sample size conducted for a longer time period would be beneficial in guiding towards the inclusion of HU in treatment protocols for the Tanzanian population. Keywords: Sickle cell disease; hydroxyurea; haemolysis; foetal haemoglobin

Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia

Neonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT1*1 humanized mice and Ugt1a-deficient Gunn rats. Treatment of hUGT1*1 mice with UDCA or OCA at postnatal days 10–14 effectively decreased bilirubin in plasma (by 82% and 62%) and brain (by 72% and 69%), respectively. Mechanistically, our findings indicate that these effects are mediated through induction of protein levels of hUGT1A1 in the intestine, but not in liver. We further demonstrate that in Ugt1a-deficient Gunn rats, UDCA but not OCA significantly decreases plasma bilirubin, indicating that at least some of the hypobilirubinemic effects of UDCA are independent of UGT1A1. Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.

Bilirubin as a Metabolic Hormone: The Physiological Relevance of Low Levels

Recent research on bilirubin, a historically well-known waste product of heme catabolism, suggests an entirely new function as a metabolic hormone that drives gene transcription by nuclear receptors. Studies are now revealing that low plasma bilirubin levels, defined as 'hypobilirubinemia,' are a possible new pathology analogous to the other end of the spectrum of extreme hyperbilirubinemia seen in patients with jaundice and liver dysfunction. Hypobilirubinemia is most commonly presented in patients with metabolic dysfunction, which may lead to cardiovascular complications and possibly stroke. We address the clinical significance of low bilirubin levels. A better understanding of bilirubin's hormonal function may explain why hypobilirubinemia might be deleterious. We present mechanisms by which bilirubin may be protective at mildly elevated levels and research directions that could generate treatment possibilities for hypobilirubinemic patients, such as targeting of pathways that regulate its production or turnover or the newly designed bilirubin nanoparticles. Our review here calls for a shift in the perspective of an old molecule that could benefit millions of patients with hypobilirubinemia.

Rats Genetically Selected for High Aerobic Exercise Capacity Have Elevated Plasma Bilirubin by Upregulation of Hepatic Biliverdin Reductase-A (BVRA) and Suppression of UGT1A1

Exercise in humans and animals increases plasma bilirubin levels, but the mechanism by which this occurs is unknown. In the present study, we utilized rats genetically selected for high capacity running (HCR) and low capacity running (LCR) to determine pathways in the liver that aerobic exercise modifies to control plasma bilirubin. The HCR rats, compared to the LCR, exhibited significantly higher levels of plasma bilirubin and the hepatic enzyme that produces it, biliverdin reductase-A (BVRA). The HCR also had reduced expression of the glucuronyl hepatic enzyme UGT1A1, which lowers plasma bilirubin. Recently, bilirubin has been shown to activate the peroxisome proliferator-activated receptor-α (PPARα), a ligand-induced transcription factor, and the higher bilirubin HCR rats had significantly increased PPARα-target genes Fgf21, Abcd3, and Gys2. These are known to promote liver function and glycogen storage, which we found by Periodic acid–Schiff (PAS) staining that hepatic glycogen content was higher in the HCR versus the LCR. Our results demonstrate that exercise stimulates pathways that raise plasma bilirubin through alterations in hepatic enzymes involved in bilirubin synthesis and metabolism, improving liver function, and glycogen content. These mechanisms may explain the beneficial effects of exercise on plasma bilirubin levels and health in humans.

Morin attenuates dutasteride/tamsulosin-induced hepatic oxidative stress in rat

Dutasteride-Tamsulosin (DUT-TAM) is a combination drug for the treatment of symptoms of prostate enlargement (benign prostatic hyperplasia, BPH). Despite the efficacy, it is associated with some side effects, including hepatotoxicity. Therefore, this study investigated the attenuative effects of morin on DUT-TAMinduced organ toxicity. Twenty four male rats were divided into 4 groups (A-D) consisting of 6 animals each. Group A animals (control) were given olive oil, Group B animals were administered with DUT-TAM (5.4 mg/kg body weight of dutasteride + 3.4 mg/kg body weight of tamsulosin), Group C were given morin (100 mg/kg body weight) while group D animals were administered DUT-TAM and morin (5.4 mg/kg body weight dutasteride + 3.4 mg/kg body weight of Tamsulosin and 100 mg/kg body weight of morin). All the administrations were carried out orally for 14 days. DUT-TAM caused a significant increase in plasma bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) by 62%, 45% and 18% in the DUT-TAM treated group respectively, compared with the control (P˂0.05). However, treatment with morin significantly decreased the DUT-TAM-induced increase in plasma bilirubin concentration as well as AST and ALT activities. Furthermore, DUT-TAM administration decreased the activities of hepatic superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), as well as hepatic concentration of ascorbic acid and reduced glutathione (GSH) by 58%, 54%, 59%, 46% and 63% respectively, but increased malondialdehyde (MDA) level by 49% relative to the control (P˂0.05). However, treatment with morin significantly ameliorated the observed changes in these antioxidant parameters (P˂0.05). These data suggest that morin protects against hepatic toxicity, as well as oxidative stress induced by dutasteride-tamsulosin in rats. Keywords: Dutasteride, Tamsulosin, Prostate enlargement, Oxidative stress, Liver

Jaundice

Jaundice, also known as icterus, is the yellowish discolouration seen in skin, mucous membranes, and sclerae when the plasma bilirubin concentration is >40 μ‎mol/l. Jaundice may arise from increased production of bilirubin, for instance, in haemolysis; from reduced conjugation in the liver, as in Gilbert’s syndrome; or from reduced excretion via bile, as in intra-hepatic cholestasis. Jaundice also occurs when the flow of bile is obstructed, for instance, by gallstones or pancreatic cancer (extra-hepatic cholestasis). The clinical approach to the jaundiced patient is described in this topic.