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IS IT ALL IN THE GENES?
▸ Nicastro E, Loudianos G, Zancan L, . Genotype–phenotype correlation in Italian children with Wilson’s disease. J Hepatol 2009;50:555–61.
Wilson disease is an autosomal recessive condition with >400 mutations described in the gene that encodes a transmembrane copper-transporting P-type ATPase. The disease presents with a broad range of manifestations, and age of onset ranges from 2 to 71 years. However, the variability in the clinical and laboratory features has not been explained.
Nicastro et al retrospectively studied 58 children (34 male, median age at diagnosis 7.4 years) from 47 unrelated families using a two-step approach (using single-strand conformation polymorphism (SSCP) and sequencing). This revealed 34 different mutations accounting for 91% of the studied alleles. Mutations were grouped as homozygotes and compound heterozygotes for missense mutation versus homozygotes for nonsense and frameshift mutations. Serum ceruloplasmin and copper were lower among subjects homozygous for nonsense and frameshift mutations than for those with missense mutations. After therapy, serum alanine aminotransferase did not normalise in 23.6% of patients with missense mutations vs 45.5% of patients with nonsense/frameshift mutations. This differentiation may relate to residual functional activity of ATPase 7B in patients carrying missense mutations in contrast to those with nonsense/frameshift mutations with no functional activity. Hence, the type of mutation explains at least a part of Wilson disease phenotype.
Although the authors argue with enthusiasm that mutation analysis should be considered as an integrative tool for such a challenging diagnosis, the study also found a direct linear correlation between age at diagnosis and urinary copper excretion at diagnosis. This gives a perspective to the genotype–phenotype correlation described in the study.
ULCERATIVE COLITIS IS ON THE RISE IN ASIA
▸ Chow DKL, Leong RWL, Tsoi KKF, . Long-term follow-up of ulcerative colitis in the Chinese population. Am J Gastroenterol 2009;104:647–54.
The incidence and prevalence of inflammatory bowel disease (IBD) in the Western world increased markedly in the mid 20th century with the advent of industrialisation and urbanisation. A similarly rapid increase in the prevalence of IBD now appears to be occurring in Asia. Chow et al have characterised a population-based cohort of patients with ulcerative colitis (UC) in China. All patients with UC diagnosed in the Shatin district of Hong Kong between 1985 and 2006 were identified by review of medical records from the Prince of Wales Hospital and studied prospectively beginning in 2001. The age-standardised estimates of incidence and prevalence for UC in 2006 were 2.1 (95% CI 1.1 to 3.7) and 26.5 (95% CI 22.6 to 30.9) per 100 000 population. These figures are similar to published estimates from other parts of East Asia, but still lower than estimates from India. Of note, the incidence of UC in Hong Kong appears to have increased approximately sixfold since 1986 and is continuing to rise. Among 172 patients followed for 1393 patient-years, only one developed colorectal cancer. The cumulative colectomy rate per 10 years of follow-up was 7.6%, which is lower than that reported in Western cohorts. Overall, these data provide strong evidence for a potent environmental influence on the pathogenesis and epidemiology of UC. Whether this reflects adoption of Western lifestyles, improvements in hygiene or other consequences of urbanisation remains to be determined. Until then, Asian epidemiologists have been presented with an invaluable opportunity to provide insight.
GLUCOSE AND GASTRIC CANCER
▸ Ikeda F, Doi Y, Yonemoto K, . Hyperglycemia increases risk of gastric cancer posed by Helicobacter pylori infection: a population-based cohort study. Gastroenterology 2009;136:1234–41.
There have been reports of increased risk of malignancy in subjects with diabetes. However, there has been little good quality prospective evidence published examining this issue in the field of gastric cancer. Ikeda et al address this by reporting data from a Japanese cohort of >2500 individuals followed-up over a 14-year period. At baseline, glycosylated haemoglobin (HbA1c) levels were measured, data concerning demographics, lifestyle and dietary habits were collected, and Helicobacter pylori status was determined (via serology).
Incidence data for gastric cancer were collected prospectively by scheduled interviews with participants, via local hospital records and by performing postmortem examinations in the deceased during follow-up. Individuals were divided into four groups according to level of HbA1c: ⩽4.9%, 5.0–5.9%, 6.0–6.9% and >7%. Hazard ratios (HRs) for gastric cancer were calculated, using the group with the lowest incidence of gastric cancer as the reference, adjusted for all other baseline data. A subgroup analysis was performed according to H pylori status and level of HbA1c.
Only one participant was lost to follow-up at study completion in 2002, and >75% of those who died underwent a postmortem examination. There were a total of 97 gastric cancers diagnosed in this population. The results of this study are compelling, with adjusted HRs between 2 and 2.5 for the development of gastric cancer in the 6.0–6.9% and >7% groups. When HRs were calculated according to level of HbA1c and H pylori status, the highest occurred in H pylori-positive individuals with an HbA1c ⩾6.0% (fig 1).
This study provides evidence that HbA1c levels have an independent association with subsequent development of gastric cancer, but that there is a synergistic effect with H pylori infection. What drives this association is unclear presently, and further studies replicating these data are required.
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