GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Fetally-encoded GDF15 and maternal GDF15 sensitivity are major determinants of nausea and vomiting in human pregnancy.

Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternal GDF15 gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant in GDF15 which strongly predisposes mothers to HG, particularly when the fetus is wild-type, was found to markedly impair cellular secretion of GDF15 and associate with low circulating levels of GDF15 in the non-pregnant state. Consistent with this, two common GDF15 haplotypes which predispose to HG were associated with lower circulating levels outside pregnancy. The administration of a long-acting form of GDF15 to wild-type mice markedly reduced subsequent responses to an acute dose, establishing that desensitisation is a feature of this system. GDF15 levels are known to be highly and chronically elevated in patients with beta thalassemia. In women with this disorder, reports of symptoms of nausea or vomiting in pregnancy were strikingly diminished. Our findings support a causal role for fetal derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to GDF15, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Interaction of malaria with a common form of severe thalassemia in an Asian population.

In many Asian populations, the commonest form of severe thalassemia results from the coinheritance of HbE and beta thalassemia. The management of this disease is particularly difficult because of its extreme clinical diversity; although some genetic and adaptive factors have been identified as phenotypic modifiers, the reasons remain unclear. Because the role of the environment in the course of severe thalassemia has been neglected completely and because malaria due to both Plasmodium falciparum and Plasmodium vivax has been prevalent in Sri Lanka, we carried out a pilot study of patients with HbE beta thalassemia that showed high frequencies of antibodies to both parasite species and that 28.6% of the children had DNA-based evidence of current infection with P. vivax. Malarial antibodies then were assessed in patients with HbE beta thalassemia compared with those in age-matched controls. There was a significant increase in the frequency of antibodies in the thalassemic patients, particularly against P. vivax and in young children. There was also a higher frequency in those who had been splenectomized compared with those with intact spleens, although in the latter it was still higher than that in the controls. The thalassemic patients showed significant correlations between malaria antibody status and phenotype. Patients with HbE beta thalassemia may be more prone to malaria, particularly P. vivax, which is reflected in their clinical severity. Because P. vivax malaria is widespread in Asia, further studies of its interaction with HbE beta thalassemia and related diseases are required urgently as a part of ongoing thalassemia control programs.

Is the beta thalassaemia trait of clinical importance?

Although the beta thalassaemia trait affects millions of people worldwide, there have been no controlled studies to determine whether it is associated with any clinical disability or abnormal physical signs. To address this question, 402 individuals were studied: 217 with beta thalassaemia trait, of whom 154 were aware of the diagnosis and 63 were unaware until after the completion of the study; 89 normal controls; and 96 controls with mild hypochromic anaemia. There was a significant increase in symptoms ascribable to anaemia and episodes of pyrexia in those with the beta thalassaemia trait that were not influenced by prior knowledge that they had this condition. There was no difference in physical findings, notably splenomegaly, between those with beta thalassaemia trait and either control group.

Age-related changes in adaptation to severe anemia in childhood in developing countries.

Severe forms of anemia in children in the developing countries may be characterized by different clinical manifestations at particular stages of development. Whether this reflects developmental changes in adaptation to anemia or other mechanisms is not clear. The pattern of adaptation to anemia has been assessed in 110 individuals with hemoglobin (Hb) E beta-thalassemia, one of the commonest forms of inherited anemia in Asia. It has been found that age and Hb levels are independent variables with respect to erythropoietin response and that there is a decline in the latter at a similar degree of anemia during development. To determine whether this finding is applicable to anemia due to other causes, a similar study has been carried out on 279 children with severe anemia due to Plasmodium falciparum malaria; the results were similar to those in the patients with thalassemia. These observations may have important implications both for the better understanding of the pathophysiology of profound anemia in early life and for its more logical and cost-effective management.

Haemoglobin E beta thalassaemia in Sri Lanka.

Haemoglobin E beta thalassaemia is the commonest form of severe thalassaemia in many Asian countries, but little is known about its natural history, the reasons for clinical diversity, or its management. We studied 109 Sri Lankan patients with the disorder over 5 years. 25 patients were not receiving transfusion; transfusion was stopped with no deleterious effect in a further 37. We identified several genetic and environmental factors that might contribute to the phenotypic diversity of the disorder, including modifiers of haemoglobin F production, malaria, and age-related changes in adaptive function. Our findings suggest that haemoglobin E beta thalassaemia can be managed without transfusion in many patients, even with low haemoglobin levels. Age-related changes in the pattern of adaptation to anaemia suggest that different and more cost-effective approaches to management should be explored.

The global distribution of length polymorphisms of the promoters of the glucuronosyltransferase 1 gene (UGT1A1): hematologic and evolutionary implications.

The promoter region of the UDP glucuronosyltransferase 1 gene (UGT1A1) contains a run of thymine-adenine (TA) repeats, usually six (TA)(6). As well as its relationship to Gilbert's syndrome, homozygosity for the extended sequence, (TA)(7) (TA)(7), has been found to be an important risk factor for hyperbilirubinemia and gallstones in patients with hemoglobin E-beta-thalassemia and other intermediate forms of beta thalassemia. To assess the importance of this polymorphism in these common disorders a wide-scale population study of the relative frequency of the size alleles of the UGT1A1 promoter has been carried out. Homozygosity for the (TA)(7) allele occurs in 10-25% of the populations of Africa and the Indian subcontinent, with a variable frequency in Europe. It occurs at a much lower frequency in Southeast Asia, Melanesia, and the Pacific Islands, ranging from 0 to 5%. African populations show a much greater diversity of length alleles than other populations. These findings define those populations with a high frequency of hemoglobin E-beta-thalassemia and related disorders that are at increased risk for hyperbilirubinemia and gall bladder disease and provide evolutionary insights into how these polymorphisms have arisen and are so unequally distributed among human populations.

Genetic determinants of jaundice and gallstones in haemoglobin E beta thalassaemia.

Chronic hyperbilirubinaemia, gallstone formation, and gall bladder disease are unusually common in people with haemoglobin E beta thalassaemia in Sri Lanka. To determine whether this has a genetic basis we compared the bilirubin levels and frequency of gallstones in patients with different alleles of the UGT*1 gene. There was a significantly higher bilirubin level in those with the 7/7 genotypes compared with 6/6 and 6/7 genotype (p=0.032 and 0.0015 respectively), who also appeared more prone to gallstone formation. These results suggest that the UGT*1 genotpe is of importance in the genesis of gallstones in this population of patients.

Thalassaemia in Sri Lanka: implications for the future health burden of Asian populations. Sri Lanka Thalassaemia Study Group.

BACKGROUND: Thalassaemias pose an increasing problem for the Indian subcontinent and many Asian countries. We analysed the different types of thalassaemia in the Sri Lankan population, surveyed gene frequencies in schoolchildren, and estimated the burden of disease and requirements for its control. METHODS: We analysed blood samples from patients attending clinics in nine hospitals and defined the different types of beta thalassaemia by high-performance liquid chromatography (HPLC) and DNA analysis. The range of mutations was obtained by analysis of beta-globin genes. Capillary blood was obtained from schoolchildren from different parts of the island and analysed by HPLC to provide an approximate assessment of the carrier frequency of beta thalassaemia and haemoglobin E (HbE). To estimate the frequency of alpha thalassaemia the alpha-globin genotypes were also analysed when it was possible. FINDINGS: Blood samples were obtained from 703 patients with beta thalassaemia and from 1600 schoolchildren. The thalassaemia mutations were unevenly spread. Although 23 different beta-thalassaemia mutations were found, three accounted for the thalassaemia phenotype in about 70% of the patients, most whom are homozygotes or compound heterozygotes for IVS1-5 (G-->C) or IVS1-1 (G-->A). The third common mutation, codon 26 (G-->A), which produces HbE, interacts with one or other of these mutations to produce HbE/beta thalassaemia; this comprises 13.0-30.9% of cases in the main centres. Samples from 472 patients were analysed to determine the alpha-globin genotype. Overall, 15.5% patients were carriers for deletion forms of alpha+ thalassaemia. Average gene frequencies showed that there will be more than 2000 patients requiring treatment at any one time, in the future, of whom those with HbE/beta thalassaemia will account for about 40%. INTERPRETATION: In Sri Lanka, interactions of the two common beta-thalassaemia alleles will nearly always result in a transfusion-dependent disorder. However, about 40% of patients will have HbE/beta thalassaemia, which has a variable course. The management of these disorders could require about 5% of the total health budget. We need to learn more about the natural history and appropriate management of HbE/beta thalassaemia if resources are to be used effectively.

Low dose subcutaneous adrenaline to prevent acute adverse reactions to antivenom serum in people bitten by snakes: randomised, placebo controlled trial.

OBJECTIVE: To assess the efficacy and safety of low dose adrenaline injected subcutaneously to prevent acute adverse reactions to polyspecific antivenom serum in patients admitted to hospital after snake bite. DESIGN: Prospective, double blind, randomised, placebo controlled trial. SETTING: District general hospital in Sri Lanka. SUBJECTS: 105 patients with signs of envenomation after snake bite, randomised to receive either adrenaline (cases) or placebo (controls) immediately before infusion of antivenom serum. INTERVENTIONS: Adrenaline 0.25 ml (1:1000). MAIN OUTCOME MEASURES: Development of acute adverse reactions to serum and side effects attributable to adrenaline. RESULTS: 56 patients (cases) received adrenaline and 49 (controls) received placebo as pretreatment. Six (11%) adrenaline patients and 21 (43%) control patients developed acute adverse reactions to antivenom serum (P=0.0002). Significant reductions in acute adverse reactions to serum were also seen in the adrenaline patients for each category of mild, moderate, and severe reactions. There were no significant adverse effects attributable to adrenaline. CONCLUSIONS: Use of 0.25 ml of 1:1000 adrenaline given subcutaneously immediately before administration of antivenom serum to patients with envenomation after snake bite reduces the incidence of acute adverse reactions to serum.

Hepatitis B and C virus markers among new entrant medical students.

AIM: To investigate the presence of hepatitis B and C virus markers in new entrant medical students at the Faculty of Medicine, University of Kelaniya. METHOD: 456 students (mean age 24 years, SD 3.5, 257 men) were investigated before they were exposed to clinical work, using a questionnaire to assess sociodemographic factors and possible risk factors for contracting hepatitis B or C. Blood samples were tested for HBs Ag and anti HBs (n = 456), and anti-HCV (n = 162 randomly selected samples) with a third generation sandwich radioimmunoassay technique. RESULTS: The students were from 20 of the 25 districts in the country, although their distribution was not inform. A past history of hepatitis or jaundice was obtained from 24 (5.3%) and 6 (1.3%) students respectively. None of them had been vaccinated against hepatitis B. At least one risk factor for hepatitis B or C was present in 32 (7%) of them. None of the samples were positive for HBsAg or anti-HCV, and only two (0.44%) were positive for anti-HBs. CONCLUSION: Our results support the view that exposure to hepatitis B and C seems to be uncommon in this country, at least up to young adulthood. As most new entrant medical students are not immune to these infections there is a strong case to vaccinate them against hepatitis B before they are exposed to clinical work.