Sammy Pak Lam Chen

Case series on a diversity of illicit weight-reducing agents: from the well known to the unexpected

AIMS To provide an overview of illicit weight-reducing agents found in over-the-counter slimming products ingested by poisoned patients. METHODS The clinical details and analytical findings of slimming products involved in poisoning cases between 2004 and 2009 were reviewed. RESULTS Sixty-six (including one fatal) poisoning cases were encountered. Eighty-one products were analysed and found to contain undeclared prescription weight-loss drugs, drug analogues, banned drugs, drugs used for an inappropriate indication or animal thyroid tissue, with up to six illicit agents within the same product. Many products were readily available from shops or the Internet. CONCLUSIONS A rich diversity of illicit, potentially harmful weight-reducing agents was found in over-the-counter slimming products.

Aconite poisoning over 5 years: a case series in Hong Kong and lessons towards herbal safety.

AbstractBackground: Aconite poisoning is a severe, life-threatening poisoning related to the use of traditional Chinese medicine (TCM). Despite current legislation, repeated poisoning cases are steadily encountered. Objective: The aim of the study was to summarize the clinical features and to elucidate the causative and contributory factors leading to aconite poisoning. Methods: This study was conducted within the Hospital Authority Toxicology Reference Laboratory, which is the sole tertiary referral clinical toxicology laboratory in Hong Kong. This retrospective study reviewed all confirmed aconite poisoning cases handled by a clinical toxicology laboratory between April 2004 and July 2009. The diagnosis in all cases was confirmed biochemically by detecting aconitum alkaloids in urine specimens. Additionally, herbal specimens were morphologically identified and herbal formulae were studied and transcribed. The cause of poisoning for each case was determined whenever possible. Results: Fifty-two cases were examined in this aconite poisoning case series. Neurological, cardiovascular and gastrointestinal toxicities were encountered in 49 (94.2%), 46 (88.5%) and 31 (59.6%) patients, respectively. The poisoning was severe in 6 (11.5%) patients, moderate in 17 (32.7%) patients and mild in 29 (55.8%) patients. Amongst 44 patients (84.6%) in whom the underlying reasons of poisoning could be determined, four major causes were found. These included overdose- prescription of a higher than recommended dosage of aconite herbs in 17 (32.7%) cases; ‘hidden’ poisoning (the aconite herb was not prescribed but dispensed inadvertently) in 17 (32.7%) cases; usage of inadequately processed herbs in 7 (13.5%) cases; and dispensary error in 2 (3.9%) cases. No case fatality was recorded. Conclusion: In the majority of cases in this series, the causes of poisoning can be traced to poor-quality herbs, poor quality of prescription practice, or dispensary errors. The quality issues of TCM practice should be critically addressed to minimize this poisoning threat.

Biochemical and molecular characterization of tyrosine hydroxylase deficiency in Hong Kong Chinese

Tyrosine hydroxylase deficiency is a rare neurotransmitter disorder affecting the rate-limiting step in catecholamine biosynthesis. There are about 40 cases reported worldwide. Here, we report the biochemical and molecular findings of eight unrelated Chinese patients with tyrosine hydroxylase deficiency. We have identified eight novel mutations with 5 missense, 2 nonsense and 1 splicing mutations in the TH gene, namely p.R153X, p.R169X, p.G294R, p.G315S, p.A385V, p.I394T, p.G408R, and c.1163+5G>C. The mutations of the TH gene in Chinese are heterogeneous.

Measurement of yunaconitine and crassicauline A in small-volume blood serum samples by LC–MS/MS: Tracing of aconite poisoning in clinical diagnosis

Aconite poisoning is one of the most serious types of herb-related medical emergencies. In Hong Kong, many if not most of these poisoning cases are due to confusion in herbal species; that is, the wrong herbs are used in prescriptions. Such human errors, while inevitable perhaps, can be serious, and sometimes fatal. The chemical components responsible for aconite poisoning are yunaconitine and crassicauline A. In the present study, a rapid and sensitive method for the screening and quantification of yunaconitine and crassicauline A in human serum, using LC-MS/MS, was developed and validated. Methyllycaconitine was chosen as the internal standard. The limit of detection (LOD) of yunaconitine and crassicauline A were found to be 0.022 and 0.021 ng/mL, respectively. The limit of quantification (LOQ) was 0.1 ng/mL for both yunaconitine and crassicauline A. The recovery of yunaconitine and crassicauline A ranged from 78.6% to 84.9% and 78.3% to 87.2%, respectively. The matrix effect of yunaconitine and crassicauline A ranged from 110.0% to 130.4% and 121.2 to 130.0%, respectively. Both yunaconitine and crassicauline A were stable in serum for at least 3 months at -20 °C, and the extracts were stable for at least 7 days. For clinical applications, serum samples of two patients confirmed to have had aconite herbs poisoning in 2008 were quantified using the developed method. The result showed that this method can be utilized in clinical routine applications. This screening method expedites the diagnosis in cases of suspected aconite poisoning, thus enabling doctors to treat the condition more quickly and effectively.

Adulteration of proprietary Chinese medicines and health products with undeclared drugs: experience of a tertiary toxicology laboratory in Hong Kong

AIMS Proprietary Chinese medicines (pCMs) and health products, generally believed to be natural and safe, are gaining popularity worldwide. However, the safety of pCMs and health products has been severely compromised by the practice of adulteration. The current study aimed to examine the problem of adulteration of pCMs and health products in Hong Kong. METHODS The present study was conducted in a tertiary referral clinical toxicology laboratory in Hong Kong. All cases involving the use of pCMs or health products, which were subsequently confirmed to contain undeclared adulterants, from 2005 to 2015 were reviewed retrospectively. RESULTS A total of 404 cases involving the use of 487 adulterated pCMs or health products with a total of 1234 adulterants were identified. The adulterants consisted of approved drugs, banned drugs, drug analogues and animal thyroid tissue. The six most common categories of adulterants detected were nonsteroidal anti-inflammatory drugs (17.7%), anorectics (15.3%), corticosteroids (13.8%), diuretics and laxatives (11.4%), oral antidiabetic agents (10.0%) and erectile dysfunction drugs (6.0%). Sibutramine was the most common adulterant (n = 155). The reported sources of these illicit products included over-the-counter drug stores, the internet and Chinese medicine practitioners. A significant proportion of patients (65.1%) had adverse effects attributable to these illicit products, including 14 severe and two fatal cases. Psychosis, iatrogenic Cushing syndrome and hypoglycaemia were the three most frequently encountered adverse effects. CONCLUSIONS Adulteration of pCMs and health products with undeclared drugs poses severe health hazards. Public education and effective regulatory measures are essential to address the problem.

Application of pharmacogenetics: UGT1A1*28 and nilotinib-induced unconjugated hyperbilirubinaemia in a patient with chronic myeloid leukaemia

Sir, With the completion of Human Genome Project and the advent of more user-friendly molecular technologies, diagnostic genetic testings have been rendered more accessible to routine patient care. Pharmacogenetics has paved the way to personalised medicine. Zimmern emphasised in his editorial the application of translational research in clinical medicine. Genetic variations in individuals depict the differences in both pharmacokinetics and pharmacodynamics. UGT1A1 is one of the nine isoenzymes encoded by the UGT1A locus, a superfamily of phase II drug metabolising enzymes that catalyse the glucuronidation reaction, converting xenobiotic and endogenous compounds to water soluble molecules that can be readily excreted by the kidney. It is the sole enzyme responsible for bilirubin metabolism. Mutations in UGT1A1 gene result in unconjugated hyperbilirubinaemia of varying severity. The most severe is Crigler-Najjar syndrome (type 1, MIM#218800; type II, MIM#606785) in which the enzyme activity is null or very low. Other conditions which are more benign include Gilbert’s syndrome (MIM#143500) and transient familial neonatal hyperbilirubinaemia (MIM#237900) that includes breastfeeding jaundice. Gilbert’s syndrome is characterised by mild unconjugated non-haemolytic hyperbilirubinaemia in the absence of liver disease. Traditionally, Gilbert’s syndrome is diagnosed by exclusion. Nowadays it can be readily diagnosed by genetic analysis of the UGT1A1 gene. In particular, the dinucleotide repeat polymorphism in the TATA element of the promoter region accounts for about one-third of Gilbert’s syndrome in Chinese patients. Normal people have six TA repeats (A(TA)6TAA) whereas the presence of an extra TA repeat (A(TA)7TAA) lowers the gene expression and thus reduces enzyme activity. This mutation is termed UGT1A1*28. Its presence is necessary for Gilbert’s syndrome but the manifestation of hyperbilirubinaemia requires other precipitating factors such as fasting, illness, or drug administration. Nilotinib (AMN107; Tasigna) is a newer generation tyrosine kinase inhibitor for the treatment of imatinib-resistant chronic myeloid leukaemia (CML). We report a case that developed unconjugated hyperbilirubinaemia after being treated with nilotinib for CML. Genetic analysis revealed homozygosity for the UGT1A1*28 variant. While nilotinib is not metabolised by UGT1A1, the drug inhibits UGT1A1 activity. The combined impact of nilotinib inhibition and UGT1A1*28 variant explains the hyperbilirubinaemia. The patient was a 73-year-old Chinese man diagnosed to have CML since late 1998. He had been taking hydroxyurea since then. Imatinib, a tyrosine kinase inhibitor, was added from July 2001 to November 2005. However, the latter treatment was terminated because of pleural effusion. Repeated blood tests and bone marrow trephine biopsy in April 2006 showed blastic transformation change. The patient sub-

NMR-based urinalysis for rapid diagnosis of β-ureidopropionase deficiency in a patient with Dravet syndrome.

BACKGROUND Beta-ureidopropionase deficiency is a rare inborn error of metabolism (IEM) affecting pyrimidine metabolism. To-date, about 30 genetically confirmed cases had been reported. The clinical phenotypes of this condition are variable; some patients were asymptomatic while some may present with developmental delay or autistic features. In severe cases, patients may present with profound neurological deficit including hypotonia, seizures and mental retardation. Using NMR-based urinalysis, this condition can be rapidly diagnosed within 15 min. CASE An 11-month-old Chinese boy had dual molecular diagnoses, β-ureidopropionase deficiency and Dravet syndrome. He presented with intractable and recurrent convulsions, global developmental delay and microcephaly. Urine organic acid analysis using GC-MS and NMR-based urinalysis showed excessive amount of β-ureidopropionic acid and β-ureidoisobutyric acid, the two disease-specific markers for β-ureidopropionase deficiency. Genetic analysis confirmed homozygous known disease-causing mutation UPB1 NM_016327.2: c.977G>A; NP_057411.1:p.R326Q. In addition, genetic analysis for Dravet syndrome showed the presence of heterozygous disease-causing mutation SCN1A NM_001165963.1:c.4494delC; NP_001159435.1:p.F1499Lfs*2. CONCLUSIONS The differentiation between Dravet syndrome and β-ureidopropionase deficiency is clinically challenging since both conditions share overlapping clinical features. The detection of urine β-ureidoisobutyric and β-ureidopropionic acids using NMR or GC-MS is helpful in laboratory diagnosis of β-ureidopropionase deficiency. The disease-causing mutation, c.977G>A of β-ureidopropionase deficiency, is highly prevalent in Chinese population (allele frequency=1.7%); β-ureidopropionase deficiency screening test should be performed for any patients with unexplained neurological deficit, developmental delay or autism.

Improvement of bone mineral density after enzyme replacement therapy in Chinese late-onset Pompe disease patients

ObjectiveLate-onset Pompe disease (LOPD) is a lysosomal storage disease resulted from deficiency of the enzyme acid α-glucosidase. Patients usually develop a limb-girdle pattern of myopathy and respiratory impairment, and enzyme replacement therapy (ERT) is the only specific treatment available. Recently, LOPD has been associated with low bone mineral density (BMD), but the effect of ERT on BMD is inconclusive. In this report we described our early observations on the change of BMD after ERT in Chinese LOPD patients.ResultsWe studied four Chinese LOPD patients with different severities of myopathy. All were underweight, and three had osteoporosis at baseline. We found significant weight gain in three patients after ERT and all four patients showed improvement in BMD. The biggest improvement, 84.4% increase in BMD, was seen in a lady with the most prominent weight recovery. Our results suggest that ERT improves BMD in Chinese LOPD and weight gain could be a major contributor to this effect.

Electronic chemical pathology consultation service and dried blood spot metabolic screening in hospital patients

Aim Inborn errors of metabolism (IEM) are an unpopular and difficult subject and most clinicians are unfamiliar with them. Although chemical pathologists have a long-standing practice in advising test strategy and result interpretation especially from primary care, such consultations are usually informal, unstructured and those related to IEM are infrequently requested. This study aims to provide a formal electronic consultation service and to apply tandem mass spectrometry-based dried blood spot metabolic screening (DBSM) as a rapid first-line test for patients suspected of IEM. Methods DBSM and a chemical pathology consultation were ordered through the hospital computer terminals. DBSM detected 29 metabolic disorders. The clinical data and metabolic results for the 12-month period were reviewed. Results There were 279 consultations of which 209 were initiated by paediatricians and 70 by adult physicians. The main reasons for consultation were developmental delay, neurological abnormalities, unexplained biochemical abnormalities and monitoring of patients with IEM. There were 158 DBSM requests. One positive case of isovaleric acidaemia was detected. Conclusions All high-risk paediatric patients should have a DBSM and a timely electronic chemical pathology consultation as a rapid and cost-effective first-line screening. Provision of a visible, accessible and helpful consultation service enables professional reimbursement.