Hereditary Hyperlipidemia in Malaysia: A historical Perspective of Six Decade of Research and Treatment.

No abstract available.

Identification and characterization of novel loss of function mutations in ATP-binding cassette transporter A1 in patients with low plasma high-density lipoprotein cholesterol.

OBJECTIVES: The current literature provides little information on the frequency of mutations in the ATP-binding cassette transporter A1 (ABCA1) in patients with low high-density lipoprotein cholesterol (HDL) levels that are referred to the clinic. In 78 patients with low plasma levels of HDL cholesterol that were referred to our clinic, we routinely screened for ABCA1 gene mutations and studied the functionality of newly identified ABCA1 missense mutations. METHODS: The coding regions and exon-intron boundaries of the ABCA1 gene were sequenced in 78 subjects with HDL cholesterol levels below the 10th percentile for age and gender. Novel mutations were studied by assessing cholesterol efflux capacity (using apolipoprotein A-I as acceptor) after transient expression of ABCA1 variants in BHK cells. RESULTS: Sixteen out of 78 patients (21%) were found to carry 19 different ABCA1 gene variants (1 frameshift, 2 splice-site, 4 nonsense and 12 missense variation) of which 14 variations were novel. Of three patients with homozygous mutations and three patients having compound heterozygous mutations only one patient presented with the clinical characteristics of Tangier Disease (TD) in the presence of nearly complete HDL deficiency. Seven out of eight newly identified ABCA1 missense mutations were found to exhibit a statistically significant loss of cholesterol efflux capacity. CONCLUSION: This study shows that one out of five patients who are referred to our hospital because of low HDL cholesterol levels have a functional ABCA1 gene mutation. It is furthermore demonstrated that in vitro studies are needed to assess functionality of ABCA1 missense mutations.

Silent exonic mutations in the low-density lipoprotein receptor gene that cause familial hypercholesterolemia by affecting mRNA splicing.

In a large group of patients with the clinical phenotype of familial hypercholesterolemia, such as elevated low-density lipoprotein (LDL) cholesterol and premature atherosclerosis, but without functional mutations in the genes coding for the LDL receptor and apolipoprotein B, we examined the effect of 128 seemingly neutral exonic and intronic DNA variants, discovered by routine sequencing of these genes. Two variants, G186G and R385R, were found to be associated with altered splicing. The nucleotide change leading to G186G resulted in the generation of new 3'-splice donor site in exon 4 and R385R was associated with a new 5'-splice acceptor site in exon 9 of the LDL receptor gene. Splicing of these alternate splice sites leads to an in-frame 75-base pair deletion in a stable mRNA of exon 4 in case of G186G and R385R resulted in a 31-base pair frame-shift deletion in exon 9 and non-sense-mediated mRNA decay.

Comparison of clinical with pathological nodal staging from systematic mediastinal lymph node dissection in early resectable non-small cell lung cancer.

INTRODUCTION: We compared the accuracy of clinical nodal (cN) status N0-1 with that of pathological nodal (pN) status obtained from systematic mediastinal lymph node dissection (SMLD) in primary non-small cell lung cancer. METHODS: Data from 22 consecutive patients, who underwent lung cancer resection and SMLD of at least three mediastinal lymph node stations, from November 2001 to May 2003, were ana1ysed retrospectively. Only patients with cN0-1 status on computed tomography (CT) referred for surgery, were included in this study. RESULTS: Mean age of patients was 66.6 +/- 8.1 years with a male to female ratio of 17:5. Mean number of lymph node stations dissected was 5.8 +/- 1.8. 41 percent had squamous cell carcinoma, 45.5 percent had adenocarcinoma, and 4.5 percent each had large cell carcinoma, bronchioalveolar carcinoma or a lymphoepithelial carcinoma. pN2 metastases were found in 27.3 percent of patients. The sensitivity of cN0-1 was only 12.5 percent, with a specificity of 92.9 percent and an area under the receiver operating characteristics curve of 0.53. The positive and negative predictive values of cN0-1 status were 50 percent and 65 percent, respectively, with an accuracy of 59 percent. 41 percent of patients were understaged with 27.3 percent in pathological stage III. Curative resections were achieved in 59 percent of patients. CONCLUSION: The sensitivity of cN0-1 status based on CT alone is extremely poor when compared with pN status from SMLD. Based on cN0-1 status alone without SMLD, 27.3 percent of patients in pN2 would have been understaged. We recommend that all patients with cN0-1 status should undergo SMLD of at least three appropriate mediastinal node stations, for more accurate staging.

Pulmonary hypereosinophilia.

INTRODUCTION: Eosinophilic lung diseases are a diverse group of pulmonary disorders linked by the common finding of increased eosinophilia in blood and/or tissue. They usually present to the clinician as pulmonary infiltrates with eosinophilia for which the differential diagnoses is fairly broad. CLINICAL PICTURE: Three patients presented with subacute cough, pulmonary infiltrates and a markedly elevated eosinophil count >1.5 x 109/L. Each case exemplifies its clinical peculiarities and pearls and illustrates the diversity in this group of disorders. TREATMENT: A common theme in the approach to its management is excluding infection before proceeding with therapy, often with steroids. OUTCOME: There is often a dramatic response to steroid therapy with resolution of symptoms and chest radiographic findings. CONCLUSION: The arbitrary label of "pulmonary hypereosinophilia" enables the differential diagnoses to be narrowed to the 4 main categories of infections with parasites or fungus, the Churg-Strauss syndrome, chronic eosinophilic pneumonia and the idiopathic hypereosinophilic syndrome.

Lipids and coronary heart disease in Asia.

In Western countries, it has been shown that coronary heart disease (CHD) is related to high serum total cholesterol (TC) levels. In less developed continents such as Asia and Africa, serum lipid levels are low and CHD incidence is much lower as compared with Western countries. With growing urbanization and industrialization in Asia, it has been shown that there is a concomitant rise in the level of serum TC and with it a rise in CHD. In all the Asian countries, serum TC levels are also higher in the urban compared with the rural population. Singapore, the only Asian country which is 100% urbanized since 1980, showed a rise of serum TC similar to that seen in the US and UK from the 1950s to the 1980s followed thereafter by a fall. This is reflected in the trend (rise followed by a fall) of CHD morbidity and mortality as well. In spite of a declining trend in serum TC level, CHD morbidity and mortality are still high in Singapore and comparable to the Western countries. The rest of the Asian countries show a different pattern from Singapore. In general, there is still a rising trend in serum TC level and in CHD mortality in most Asian countries. However, Japan is considered an exception in having a decreasing CHD mortality in spite of an increasing trend in serum TC. This may be attributed to a better control of other CHD risk factors such as hypertension and smoking. The rising trend in serum TC level remains a cause for concern, as this will emerge as a major problem for CHD morbidity and mortality in the future.

Low-density lipoprotein receptor gene mutations in a Southeast Asian population with familial hypercholesterolemia.

The aim of this study was to detect mutations in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in patients of Southeast Asian origin with clinically diagnosed familial hypercholesterolemia (FH) and to relate these findings with the observed lower incidence of coronary heart disease in this part of the world. A total of 86 unrelated patients with FH were selected on clinical grounds, and complete DNA analysis of the low-density lipoprotein (LDL)-receptor and apolipoprotein B (apoB) genes by DGGE and DNA-sequencing was performed. In the majority (73%) of the cohort studied, no mutations could be detected, even after extensive analysis of the LDL-receptor and apoB genes. However, the 22 patients with a mutation had significantly more xanthomas and a higher incidence of coronary heart disease and levels of low-density lipoproteins were also significantly different. There was no correlation between the type of the mutation and lipoprotein levels or clinical signs of atherosclerosis. The fact that the majority of the FH patients studied had no detectable mutation and that this group had a significant milder phenotype, suggests the presence of a third gene in the Southeast Asian population, predominantly leading to a disorder resembling a milder form of FH. A similar, but less frequent, trait has recently been described in a number of European families.

Endobronchial mass in a patient with Burkholderia pseudomallei infection.

INTRODUCTION: Burkholderia pseudomallei infection, the great mimicker of infectious diseases, has protean clinical manifestations. CLINICAL PICTURE: A 37-year-old man who presented with community-acquired pneumonia affecting the right upper lobe had unremitting fever. Bronchoscopy showed an endobronchial mass in the right upper lobe bronchus. TREATMENT: Intravenous ceftriaxone and oral erythromycin, with empiric antituberculous treatment added later. This was subsequently switched to intravenous ceftazidime and oral doxycycline after the diagnosis was made. OUTCOME: There was resolution of the endobronchial mass. CONCLUSION: This case illustrates a unique and unreported presentation of melioidosis.

Genetic causes of familial hypercholesterolaemia in a Malaysian population.

A total of 86 unrelated Malaysian patients with familial hypercholesterolaemia (FH) were studied for mutations in their low-density lipoprotein receptor (LDL-R) gene. Amongst them, 23 had a LDL-R gene mutation, while none having an Apolipoprotein B-3500 (Apo B-3500) mutation. Patients with the LDL-R gene defect appeared to have a higher level of low-density lipoprotein cholesterol (LDL-C), an increased incidence of xanthomas and coronary heart disease (CHD), but no relationships were found between the type of LDL-R gene mutations and their lipid levels or clinical signs of CHD. In contrast to Western data, our findings seemed to indicate a predominance of mutations in the ligand binding domain and an absence of Apo B-3500 gene mutation. The latter finding may offer a genetic basis as to why Asian patients with familial hypercholesterolaemia have lower LDL-C levels and less premature CHD than their Western counterparts.

Blood pressure, body mass index, heart rate and levels of blood cholesterol and glucose of volunteers during National Heart Weeks, 1995-1997.

The paper presents the results of a health screening programme conducted in 10 major centers in Malaysia--Kuala Lumpur, Penang, Ipoh, Johor Bahru, Alor Star, Kuala Terengganu, Malacca, Kota Bahru, Kuching and Kota Kinabalu during the National Heart Weeks, 1995-1997. There were 6,858 participants of both sexes aged between 6 years to 81 years old. The parameters involved in the screening programme were body mass index, blood pressure, heart rate, cholesterol and glucose. The following are the results of the study:- 1. The mean and standard deviation for the body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), total cholesterol (TC) and non fasting (random) blood glucose (GL) of the volunteers studied were 24.3 +/- 4.0 kg/m2, 128.3 +/- 21.1 mmHg, 79.6 +/- 11.9 mmHg, 77.2 +/- 12.1 bpm, 5.33 +/- 1.37 mmol/l and 5.11 +/- 1.97 mmol/l respectively. 2. There was a rising trend for BMI, SBP, DBP, TC and GL with age. The HR was higher in the younger age group of those below 20 years. Males tended to have higher mean values than females except for HR which was similar in both sexes. 3. The Malays, Chinese and Indians seemed to have closely similar mean values for SBP, DBP and HR but the Indians possessed the highest BMI (25.62 +/- 3.90 kg/m2), TC (5.61 +/- 1.48 mmol/l) and GL (5.41 +/- 2.43 mmol/l) among the three major ethnic groups. While the Ibans had highest TC (6.07 + 1.09 mmol/l), their GL level was the lowest (4.76 +/- 1.15 mmol/l). The Kadazans had the lowest TC level (4.94 +/- 1.39 mmol/l) among all the ethnic groups. 4. Among the participants screened, 31.9% were overweight (BMI > or = 25), 7.6% were obese (BMI > or = 30); 26.8% had raised SBP (> or = 140 mmHg) and 19.3% had raised DBP (> or = 90 mmHg); 13.6% of the participants had increased HR (> or = 90 bpm), 22% had raised TC (> or = 6.20 mmol/l) and 2% had raised GL (> or = 11.00 mmol/l). There was a higher prevalence for abnormal values with increasing age until between the ages of 60 or 70 years, when the values began to fall. 5. Age was positively correlated with SBP (r = 0.41***, df = 4351), DBP (r = 0.27***, df = 4351), TC (r = 0.22***, df = 3303) and GL (r = 0.16***, df = 2442) but negatively correlated with HR (r = -0.13***, df = 4351). The BMI was positively correlated with SBP (r = 0.29***, df = 2769), DBP (r = 0.31***, df = 2769), TC (r = 0.16***, df = 2137) and GL (r = 0.11**, df = 1637) but there was no correlation with HR (r = 0.03NS, df = 2771). The SBP and DBP were highly correlated with each other (r = 0.75***, df = 4351) and they also showed highly significant positive correlation (r = 0.08***-0.13***, df = 2441-3301) with TC and GL. TC was positively correlated with GL (r = 0.05* df = 2319) but only at the 5% probability level.

Familial hyperlipidaemia in Malaysian children.

This paper highlights two cases of paediatric familial hyperlipidaemia (hypercholesterolaemia and hypertriglyceridaemia). The first case was an 11 year old Chinese boy, a "homozygous" (Type II) hypercholesterolaemic patient. He had extremely high blood cholesterol level (19.4 mmol/l), severe multiple xanthoma and abnormal resting electrocardiogram. He had repeated heart attacks and died at the age of 15 in spite of early intervention, treatment and follow up. The second case was a 2 1/2 years old girl who had severe hypertriglyceridaemia. She had raised cholesterol (6.2 mmol/l) and extremely high triglycerides (14.8 mmol/l). The patient did not resemble Type I lipoproteinaemia which is classically seen in childhood. On the contrary, the patient exhibited clinical and biochemical manifestations of a Type V lipoproteinaemia which often occurs in adults. Apart from a Type V lipoprotein pattern, the patient had low post hepatic lipase activity (PHLA), Apo C II and Apo E2/E3 phenotype. In addition, the lipid profile of her family members (both the parents and brothers) had raised triglycerides and thus ruled out the Type I lipoprotein inheritance pattern, which is an autosomal recessive condition. The issue of paediatric hyperlipidaemia, their management and treatments are discussed.

Rapid mycobacterial tuberculosis detection in bronchoalveolar lavage samples by polymerase chain reaction in patients with upper lobe infiltrates and bronchiectasis.

In areas where tuberculosis is endemic, a positive sputum acid-fast bacilli (AFB) smear is frequently regarded as almost diagnostic of pulmonary tuberculosis (PTB). The main problem arises when the AFB smear is negative. The main aim of this study was to determine the clinical utility of rapid mycobacterial tuberculosis (MTB) detection in bronchoalveolar lavage (BAL) samples by polymerase chain reaction (PCR) in 52 patients who underwent diagnostic bronchoscopy for suspected PTB. These patients had either upper lobe infiltrates (n = 31) or bronchiectasis (n = 21). Mycobacterial culture is usually used as the gold standard of diagnosis. We chose to define active PTB based on positive mycobacterial cultures and/or histological evidence of caseous necrosis and AFB, and/or when there was clinical plus radiological improvement following therapy. We compared AFB smear, respiratory mycobacterial culture, BAL PCR for MTB and clinical active PTB. Four patients who were smear and culture negative had clinical and radiological clearance following anti-tuberculous therapy showing that using mycobacterial culture as a gold standard may have its limitations. When Kappa (a chance-corrected measure of agreement) was calculated for acid-fast bacilli smear and BAL PCR against our definition of active PTB, it was 0.28 (fair agreement) and 0.73 (substantial agreement), respectively. BAL PCR gave a sensitivity, specificity, positive and negative predictive values of 66.7%, 100%, 100% and 88%, respectively, for the group with upper lobe infiltrates. We also demonstrated that BAL for PCR has a good concordance with the final diagnosis of active tuberculosis.

Ethnicity, obstructive sleep apnoea and ischaemic heart disease.

We studied the relationship between different ethnic groups, obstructive sleep apnoea (OSA) and ischaemic heart disease. Four hundred and thirty-two inpatients from the medical wards were interviewed. Limited overnight sleep studies were done in 129 of those who had habitual snoring, daytime sleepiness based on an Epworth sleepiness scale of 8 or more, or a large neck size of 40 cm or more. There were 315 Chinese (72.9%), 67 Malays (15.5%), 43 Indians (10%) and 3 from other races (1.4%). The prevalence of OSA was 19.7%, 30% and 12% among the Chinese, Malays and Indians, respectively. The prevalence ratio for OSA was 1.52 in Malays using Chinese patients as the baseline (P = 0.07). The median neck circumference was 37 cm in both racial groups. The median body mass index was 22.7 kg/m2 in Chinese compared to 23.6 kg/m2 in Malays. The median apnoea-hypopnoea index was 22.7, 19.0 and 26.9 events/hour among the Chinese, Malays and Indians, respectively. OSA was independently associated with the prevalence of IHD (adjusted prevalence ratio 1.68; 95% CI: 1.15, 2.46; P = 0.009). The prevalence of ischaemic heart disease (IHD) was 31%, 24% and 28% in Chinese, Malays and Indians, respectively. The prevalence ratio for IHD in Malays compared to Chinese was 0.77. After adjusting for OSA, there was an even greater reduction in the risk of IHD (adjusted prevalence ratio 0.70). This suggests that OSA is a confounder in the relationship between race and ischaemic heart disease.

Patients' knowledge and attitude towards treatment and control of hypertension: a nation-wide telephone survey conducted in Malaysia.

The telephone survey of 2,526 hypertensive subjects showed 94% of the respondents were aware of the importance in controlling hypertension. Among these 504 were not on anti-hypertensive medication while the majority of 2,022 were currently on anti-hypertensive medication. Of those who were not on medication, 80% (n = 403) were found non-hypertensive on follow-up. The remaining 20% (n = 101) were confirmed hypertensive and were offered medication. However, 38 subjects refused to take medication and 63 subjects complied with medication but subsequently gave up. The main reasons for giving up medication included lack of motivation (38%), doctors' advice (20%), side effects (19%) and concern of side effects (10%). Of 2,022 hypertensive respondents who were currently on medication, almost half (44%, n = 890) required a change of medication due to side effects (40%, n = 356) or the blood pressure not controlled with the previous medication (33%, n = 294). Despite the change in medication, 42% (n = 150) still continued to suffer from some form of side effects. The information obtained from this survey suggested it is important to recommend some strategies to improve patient compliance. These strategies comprise of motivating the patient, improving medication with less side effects, improving potency and efficiency of medication, and reduction of cost in medication. In addition, convenient blood pressure monitoring such as home blood pressure monitoring is also encouraged.

Malaria requiring intensive care.

We studied 24 consecutive adult patients with malaria who required intensive care between 1 January 1994 and 31 December 1997. This was out of a total of 256 patients hospitalised at the Singapore General Hospital with malaria during these 4 years. Our aim was to characterise the type and severity, clinical features, complications, treatment and outcome of adult patients with malaria who required intensive care. In addition, we compared the actual and predicted mortality based on the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. The travel history, prophylaxis, duration of fever before receiving treatment, type of malaria and severity, clinical data, complications, APACHE II score, treatment and outcome were analysed. Most cases were imported by locals travelling overseas or foreigners infected with the parasite elsewhere. Four patients had vivax malaria and 20 patients had severe falciparum malaria. All but 1 patient received transfusion with blood products and 6 patients with severe falciparum malaria had exchange transfusions. Complications were restricted to infection with P. falciparum: 9 patients required acute dialysis and 8 required mechanical ventilation. Three patients died giving a mortality of 15% for severe falciparum malaria. The overall mortality of patients with malaria was 1.2%. The mortality of patients with malaria requiring intensive care was 12.5% as compared with a predicted mortality of 18.7% based on the APACHE II prognostication system.

Aetiology and outcome of severe community-acquired pneumonia in Singapore.

The aim of this study was to determine the aetiology and outcome of severe community-acquired pneumonia, and to assess whether the existing guidelines for initial antimicrobial therapy are being applied. The records of 57 consecutive nonimmunocompromised patients admitted to the medical intensive care unit (ICU) between January 1989 and May 1993 with this diagnosis were reviewed. The microbiological data, chest radiographic changes and outcome were analysed. Nine (16%) of the 57 patients had pulmonary tuberculosis. When these patients were excluded from further analysis, a microbiological diagnosis was made in 41 (72%) cases. The most commonest pathogens were Burkholderia pseudomallei (n=10), Klebsiella spp. (n=5) and Staphylococcus aureus (n=5), Mycoplasma pneumoniae (n=4) and Streptococcus pneumoniae (n=2) were less common. This microbiological spectrum was quite different from that in the West, where the incidence of S. pneumoniae was higher. Also, when pulmonary tuberculosis was excluded, the mortality (67%) was much higher than that in other series. This was attributed to the high incidence of unrecognized B. pseudomallei infection, which is associated with a very high mortality in the region under study. In addition to applying published guidelines on severe community-acquired pneumonia, the endemicity of certain organisms such as Mycobacterium tuberculosis and Burkholderia pseudomallei in different geographical regions needs to be considered when choosing initial empirical antimicrobial therapy.

Denaturing gradient-gel electrophoresis screening of familial defective apolipoprotein B-100 in a mixed Asian cohort: two cases of arginine3500-->tryptophan mutation associated with a unique haplotype.

The Arg-to-Trp substitution at codon 3500 in the apolipoprotein (apo) B-100 gene is established as a cause of familial defective apo B-100 (FDB), a functional mutation, resulting in reduced LDL receptor binding and manifest hypercholesterolemia. In a search for similar mutations in 163 Malaysians, we screened the putative receptor-binding region (codons 3456-3553) of the apo B-100 gene by PCR amplification and denaturing gradient-gel electrophoresis. Four single-base mutations were detected and confirmed by DNA sequencing. Two females, a Chinese and a Malay, had the same CGG3500-->TGG mutation, resulting in an Arg3500-to-Trp substitution. This is the second published report of such an independent mutation involving the same codon as the established Arg3500-to-Gln mutation. The two other mutations detected, CTT3517-->CTG and GCC3527-->GCT, resulted in degenerate codons with no amino acid substitutions. All four mutations were associated with a unique apo B haplotype, different from those found in Caucasian FDB patients but concurring with that previously reported for two other Asians with FDB.

Serum lipids and their relationship with other coronary risk factors in healthy subjects in a city clinic.

Over a thousand subjects who visited a city private medical clinic for health screening and advice were examined for their lipid profile and other cardiovascular risk factors. The mean TC, TG, LDL-C and HDL-C were 5.43, 1.45, 3.61 and 1.15 mmol/l. Their derived ratios viz, TC:HDL-C and LDL:HDL-C were 5.11 and 3.43 respectively. The prevalence of hyperlipidaemia was moderately high. Of the subjects studied 58.5% had elevated serum cholesterol, 14.8% had raised triglycerides, 64.9% had raised LDL-C and 20.8% had low HDL-C. Male subjects generally showed higher mean values and abnormality frequency in TC, TG, LDL-C, TC:HDL-C and LDL:HDL-C as compared to female subjects. Although significant ethnic differences were not detected for certain lipid parameters (e.g. TC, TG and HDL-C), the Indians appeared to have higher mean lipid values (except HDL-C), and higher percentage abnormality for all the lipid parameters as compared to the Chinese and the Malays. In correlation studies, the following lipid parameters:- TC versus TG, LDL-C, TC:HDL-C; TG versus TC:HDL-C and LDL:HDL-C; LDL-C versus TC:HDL-C and LDL:HDL-C; were positively correlated. On the other hand, TC versus HDL-C, TG versus HDL-C, LDL-C and HDL-C, and HDL-C versus TC:HDL-C and LDL:HDL-C were negatively correlated. The coronary risk factors which generally showed positive correlations with lipid parameters were BMI and blood pressure. Positive correlations were also recorded between fasting blood glucose and TG; uric acid with TG, TC:HDL-C and LDL:HDL-C. In contrast, risk factors of negative correlations were observed between HDL-C and the coronary risk factors of BMI, diastolic blood pressure and uric acid. Smoking showed raised per cent lipid abnormality for TG, HDL-C, TC:HDL-C and LDL:HDL-C. Alcohol consumption also increased the mean level and abnormality frequency for TG. The implication of this investigation is discussed.