Topic Update

Chronic lymphocytic leukaemia – the role of conventional and molecular cytogenetics

Volume 7, Issue 1, January 2012

Dr W. S. Wong

Associate Consultant, Department of Pathology, Queen Elizabeth Hospital

Dr. K.F. Wong Chief of Service, Department of Pathology, Queen Elizabeth Hospital

Introduction

Chronic lymphocytic leukaemia (CLL) is the commonest chronic lymphoproliferative disorder of mature B-cells and affects mainly elderly. It is characterized by the presence of≥5x109/L monoclonal and often CD5+CD23+B-lymphocytes in peripheral blood. Haematogists usually have no problem in reaching the diagnosisas the majority of the cases have classical morphological and immunophenotypic features; however, it is an extremely heterogeneous disease clinically with highly variable clinical course.

Some patients are asymptomatic and do not require treatment while others progress early and require aggressive treatment. A number of clinical and biological parameters as well as molecular biomarkers have been demonstrated to predict the clinical outcome of the disease [1]. Molecular diagnostics has greatly improved the understanding of pathogenesis of CLL by pointing to candidate genes, for example 17p13 deletion, a common genetic aberration seen in CLL, corresponds to a tumour suppressor gene TP53. Moreover, different genetic subgroups have been shown to be associated with different prognosis: poor survival in 17p or 11q deletions and better survival in trisomy 12, normal karyotype or 13q deletion with the best survival found in isolated 13q deletion [2]. Cytogenetic studies may also help in the diagnosis of problem cases with atypical morphology or immunophenotypic profiles.

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Laboratory Role in Toxicology: From Diagnostic to Theranostic

Volume 6, Issue 1, July 2011

Dr W. T. Poon

Associate Consultant, Department of Pathology, Princess Margaret Hospital

Introduction

Toxicology analysis involves detection, identification and measurement of foreign compounds and their metabolites in biological and other specimens. It plays a useful role in them a nagement of poisoned patients when the diagnosis is in doubt, the administration of antidotes or protective agents is contemplated, or the use of active elimination therapy is being considered. As the scope and complexity of clinical toxicology continues to increase, continuing effort is required for the laboratory to expand its diagnostic capability and coverage. Apart from patient care, identification of a lethal or emerging toxin also serves to provide useful information for toxico-vigilance of potential public health threats and helps to prevent further poisonings. Some common and important herbal poisonings that have occurred in Hong Kong would be discussed as examples.

Apart from poisoning diagnosis, laboratory test can be used to predict the risk of adverse event to drugs in individual patients. It is now feasible to identify the genetic basis for certain toxic side effects and drugs will then be prescribed only to those who are not genetically at risk. Theranostic is the term used to describe the process of diagnostic therapy for individual patients - to test them for possible reaction to taking a new medication and to tailor a treatment for them based on the test results. In Hong Kong, genotyping for human lymphocyte HLA-B*1502 is recommended prior to administering carbamazepine for patients in order to avoid the development of Stevens-Johnson syndrome. An increasing number of pharmacogenetic tests are now available for clinical application. The criteria required of a pharmacogenetic test to make it useful for local application would be discussed.

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Discovery of novel microbes: more and more coronaviruses after the SARS epidemic

Volume 5, Issue 2, December 2010

WOO, Patrick CY

Professor, Department of Microbiology, The University of Hong Kong

Coronavirus study group, International Committee for Taxonomy of Viruses

Introduction

The Coronaviridae family is classified into two subfamilies, Coronavirinae and Torovirinae. Members of the Coronavirinae subfamily are in general referred to as coronaviruses. Phenotypically, coronaviruses are enveloped viruses of 120-160 nm in diameter. Under electronmicroscopy, coronaviruses have a crown-like appearance and the name “coronavirus” is derived from the Greek word κορώνα, which means crown. Genotypically, coronaviruses are positive-sense, single-stranded RNA viruses with genome sizes of about 30 kb, the largest genome size among all RNA viruses. Traditionally, coronaviruses were classified into three groups based on their antigenic relationships. Groups 1 and 2 are madeup of mammalian coronaviruses and group 3 aviancoronaviruses. Recently, the Coronavirus Study Group of the International Committee for Taxonomy of Viruses (ICTV) has proposed three genera, Alphacoronavirus, Betacoronavirus and Gammacoronavirus, to replace these threetraditional groups of coronaviruses. Before 2003, there were less than 10 coronaviruses with complete genomes available, with only two human coronaviruses, namely human coronavirus 229E (HCoV-229E) and human coronavirus OC43 (HCoV-OC43), which were discovered in the 1960s. The SARS epidemic in 2003 has boosted interest in coronavirus research globally; and most notably, in the discovery of novel coronaviruses and their genomics. In the past six years, our group has discovered 13 novel coronaviruses, including one novel human coronavirus [human coronavirus HKU1 (HCoV-HKU1)], SARS-related Rhinolophus batcoronavirus (SARSr-Rh-BatCoV), eight other bat coronaviruses and three avian coronaviruses, and has sequenced the genomes of nine of them(1-5). Others have also discovered additional coronaviruses, the most notable being human coronavirus NL63 (HCoV-NL63), discovered by a group in the Netherlands (6).

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Molecular Autopsy of Unexplained Sudden Death

Volume 5, Issue 1, June 2010

POON, WM

Senior Medical & Health Officer, Forensic Pathology Service, Department of Health

Introduction

Investigation of sudden death is the commonest challenge encountered by Forensic Pathologists. Most cases of sudden death are due to cardiovascular abnormalities evident at macroscopic and/or microscopic examination, such as coronary heart disease, myocarditis, cardiomyopathies, aortic dissection, etc. Unfortunately, a significant number of sudden death, estimated to be 1-5% (1), remains unexplained despite a thorough autopsy including toxicology, histology and other laboratory tests. This article attempts to look into some recent advances in the understanding of these “negative autopsies”. Issues related to “negative autopsies in infancy, which in itself merits another separate article, will not be covered in this article.”

Most of these cases of “negative autopsies” are believed to be caused by cardiac arrhythmias in “morphologically normal hearts” (2). Many of these “morphologically normal hearts”, however, are genetically abnormal with gene defects in ionchannels (i.e. channelopathies) in the myocytes leading to rhythm disturbances, ECG abnormalities and increased risk of sudden death. There is a growing list of inherited and congenital arrhythmia disorders caused by mutations in genes encoding defective ionic channels proteins governing the cell membrane transit of sodium, potassium and calcium ions including long QT syndrome (LQTS), short QT syndrome (SQTS), Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). 

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Hereditary Breast and Ovarian Cancer – the BRCA1 and BRCA2 genes

Volume 4, Issue 3, December 2009

KHOO, Ui Soon

Clinical Associate Professor, Department of Pathology, The University of Hong Kong, Queen Mary Hospital

Background

Breast cancer is the leading female cancer in Hong Kong. Now at 52.1 per 100,000 (Hong Kong Cancer Registry, 2008) its incidence has been steadily rising over the last few decades, and is the highest reported in Asian regions. There are two major breast and ovarian susceptibility genes, BRCA1 and BRCA2. About 30-70% of patients with hereditary breast/ovarian cancer and about 5-10% of all breast and/or ovarian cancer cases harbor a germline mutation in these genes 1. The defective gene is inherited in autosomal dominance pattern. Individuals carrying a mutation in the BRCA1 or BRCA2 genes have a 85% lifetime risk of breast cancer, and a lifetime risk for ovarian, fallopian tube or primary peritoneal cancer that ranges from 35-60% for BRCA1 and 10-27% for BRCA2 2. 

BRCA mutation carriers tend to develop breast cancer at a young age, may have bilateral breast cancer or have a personal history of both breast and ovarian cancer. There is also an increased risk for prostate and pancreatic cancer as well as male breast cancer in BRCA2 mutation carriers. Other features of increased likelihood of hereditary susceptibility include the presence of two or more individuals in the family with breast cancer, the presence of both breast and ovarian cancer in the family, breast cancer in one or more male family members, and one of more members with two primary cancers. To estimate the probability of heritable genetic mutation in a family, one has to take into account the age of onset of breast cancer, the number of affected relatives, biological relationships of affected relatives, the ratio of affected to unaffected relatives as well as the presence/absence of associated malignancies and ethnic background.

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Genetic Diagnosis of Globin Gene Disorders

Volume 4, Issue 2, August 2009

Dr Jason C. C. So

Associate Professor, Division of Haematology, Department of Pathology, The University of Hong Kong, Queen Mary Hospital

Introduction

Globin gene disorders as a whole are the commonest group of monogenic disease in the world. In Southern China and Southeast Asia, alpha and beta thalassaemias, as well as specific types of haemoglobin (Hb) variants such as Hb E, are prevalent. Most people who have inherited these mutated globin genes are asymptomatic carriers. The number of severely affected patients is relatively small in developed regions where comprehensive antenatal screening and prenatal diagnosis programmes are in place. This is not the situation in less developed countries where the clinical, economical and social load of globin gene disorders is still heavily felt.

Phenotypic Diagnosis of Globin Gene Disorders 

The clinical and haematological manifestations of different forms of thalassaemias are well known. The approach to phenotypic diagnosis is largely standardised among haematology laboratories. Complete blood counting reveals the degree of anaemia. A low mean corpuscular volume (MCV) of red cells serves as an important screening parameter for further testing. Quantitation of HbA2 and F is performed for diagnosis of beta thalassaemia, delta-beta thalassaemia and hereditary persistence of foetal haemoglobin (HPFH). Demonstration of excess beta globin chains (Hb H) indicates alpha thalassaemia. When a Hb variant is suspected, its electrophoretic  mobility is assessed and compared with knownvariants. The advent of technological advances, including sophisticated blood cell analysers, automated high performance liquid chromatography (HPLC), capillary electrophoresis and antibody-based assays has made the analysis of Hb quicker, more accurate and precise. In most cases, the diagnosis of thalassaemias and common Hb variants is straight forward.

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Global Standardization of HbA1c

Volume 4, Issue 1, April 2009

TAI, Morris

Associate Consultant, Department of Pathology and Clinical Biochemistry, Queen Mary Hospital

Introduction

The prevalence of diabetes mellitus (DM) has been increasing in recent years and DM is now a global epidemic. Haemoglobin A1c (HbA1c) plays an important role in the management of DM as the vast majority of outcome  studies on diabetic complications are based on it. The most famous of such studies, which demonstrated the relationship of HbA1c to diabetic complications, are the Diabetes Control and Complications Trial (DCCT) & the United Kingdom Prospective Diabetes Study (UKPDS). HbA1c is formed via a posttranslational nonenzymatic attachment of glucose to haemoglobin in an irreversible fashion. In strict chemical terms, the molecular structure of HbA1c is β-N-(1-deoxy)-fructosyl-haemoglobin and it serves as an indicator of glycaemic control over the preceding 2- to 3- month period.

There are a great number of analytical methods used in the measurement of HbA1c. More than 20 methods were in clinical use as reported in the year 2004. The heterogeneity of methodology eventually generated concerns about comparability and usability of HbA1c, especially when patients’ data were to be compared with study results. The call for test standardization was therefore critical. Various standardization programmes have been carried out since the 1990s. The National Glycohaemoglobin Standardization Program (NGSP) and the International Federation of Clinical Chemistry (IFCC) are the two mostimportant international standardization programmes while local ones such as Japan Diabetes Society/Japanese Society for Clinical Chemistry (JDS/JSCC) and Mono-S have been adopted in Japan and Sweden respectively.

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Antimicrobial Resistance – The Challenge Ahead

Volume 3, Issue 3, December 2008

IP, Margaret

Professor, Department of Microbiology, The Chinese University of Hong Kong

Introduction - Global Concerns and Challenges

Throughout the world, healthcare professionals are concerned at the growing problem of antimicrobial resistance and the global emergence of multi-drug-resistant organisms (MDROs) in the health care setting and in the community. The use of penicillin in early 1940s on a wider scale, and the subsequent newly-introduced antimicrobials, was soon followed by the emergence of resistantmicrobes. Some of the seresistant organisms in relation to the introduction of antimicrobial agents are listed in Table 1. The prevalence of MDROs has increased dramatically worldwide during the last decades [1]. Most alarmingly are in infections caused by MDROs whereby resistance has developed for virtually all currently available drugs and no effective therapies are available. This is compromised by the lack of new discovery of potent classes of antimicrobials in recent time, with shortfalls in funding for the development of new drugs which often relies on interests andsupport from pharmaceutical industries.

In a wider context, this threat to treatment and control of infectious diseases ranges beyond that of common bacterial pathogens. Drug resistance to infectious agents causing tuberculosis, malaria, pandemics of HIV, and in fluenza including H5N1, is also increasingly recognized, affecting treatment and hampering their containment. Antimicrobial resistance makes infections more difficult to treat; prolongs duration and increases severity of illness. This lengthens the period of infectivity, enhances spread and poses the added challenge to infection control. In effect, this translates to increases in direct and indirect health care costs and a higher morbidity and mortality.

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Immunogenetics: MHC and non-MHC

Volume 3, Issue 2, August 2008

KWOK, SY Janette

Associate Consultant, Division of Transplantation and Immunogenetics, Department of Pathology and Clinical Biochemistry, Queen Mary Hospital, Hong Kong

Introduction

Immunogenetics is the study of the immune response in relation to genetic makeup. The immune system protects the vertebrates from all potential harmful infectious agents such as bacteria, virus, fungi and parasites. The growing understanding of the immune system has influenced diversified biomedical disciplines, and is playing a significant role in the study and treatment of many diseases such as cancer and autoimmune conditions.

The launch of immunogenetics could be traced back to the demonstration of Mendelian inheritance of the human ABO blood grouping in 1910. Major developments leading to the emergence of immunogenetics were accounted by the rediscovery of allograft reactions during the Second World War and the formulation of the immunological theory of a llograft reaction and the clonal selection hypothesis by Burnett in 1959.

The field of immunogenetics has exploded during the last 25 years, thus expanding the range of concepts with the potential to improve the field of medicine with regard to transplantation, immunotherapy and the study of immune polymorphisms. Immunogenetics has poised on the brink of a new era, driven by the development of new technologies and shaped by fundamental discoveries about the mech anisms that regulate interactions between the adaptive and innate immune systems. Technologies are developed to revolutionize genetic analysis and providing new strategies for elucidating the genetic mechanisms that influence immune responsiveness and autoimmunity.

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The Autopsy Interview

Volume 3, Issue 1, April 2008

BEH, SL Philip 

Associate Professor (Forensic Pathology), Department of Pathology, Li Ka Shing Faculty of Medicine The University of Hong Kong

The autopsyinterview is an anomaly which arose in Hong Kong at a time when the Coroner did not speak the local language and the police officer investigating the death had very little medical knowledge. The hospital anatomical pathologists and forensic pathologists were therefore delegated the task of obtaining medical information from the Cantonese speaking next-of-kin which may be related to the death and providing a written English summary for the Coroner. The legal authority on the decision to autopsy or to waive an autopsy had always rested with the Coroner. However, the practical decisions were effectively made by the pathologists based on the available me dical information or the lack of information. 

In the context of this background, the autopsy interview developed in Hong Kong. It was a relatively easy exercise for the pathologist. The next-of-kin of the deceased attended interviews with the pathologist in the presence of a police officer. The pathologist asked for medical history and details of the circumstances of the death. The next-of-kin in the 70’s and 80’s were told an autopsy was to be performed as it was a legal requirement. In the rare circum stances where a request was made to waive the autopsy, the pathologist had to be convinced of the existence of a probable cause of death. Where none was evident, the application for waiver was denied and the opportunity to make the written waiver application denied too. The autopsy was again duly ordered by the Coroner on the basis that if the pathologist was unable to provide a cause of death, the cause of death was unknown and had to be established.

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