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THE STUDY ON LIVER FUNCTION

DERANGEMENTS IN ASSOCIATION WITH SEVERITY AND BLEEDING OUTCOME IN

DENGUE FEVER

by

DR FARIZ SAFHAN MOHAMAD NOR

Dissertation Submitted In Partial Fulfillment Of The Requirements For The Degree Of

Master of Medicine (Internal Medicine)

UNIVERSITI SAINS MALAYSIA

2008

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ACKNOWLEDGEMENTS

I would like to take this oppm1unity to express my sincere appreciation to the following individuals who have lent their hands in the preparation and completion of this dissertation. I would like to express my deepest gratitude to my supervisors Dr Abu Dzarr Abdullah (Lecturer and Haematologist, HUSM), Dr Lee Yeong Yeh (Lecturer and Specialist in Gastroenterology) and Dr Tee Hoi Poh (Specialist in Gastroenterology, HT AA Kuantan) who endlessly poured their supp011 and guidance on completion of this dissertation. Special thank you to Dr Tengku Norbanee binti Tengku Hamzah (Lecturer and Statistician) and Dr Kamarul Imran (Lecturer and Statistician) for their valuable time in guiding me with the statistical advice. I would also to express my appreciation to Dato Dr Sapawi Satwi (Head of Medical Department HTAA), my colleagues and staffs at medical wards in HT AA, as well as staffs at the Record Office for their assistance during the study. Finally, I would like to express my deepest love for both my parents Mohamad Nor Rahmat and Rohimi Hashim for their endless supp011, patience, tolerance and love during preparation of this dissertation.

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CONTENTS

Page

Acknowledgements 11

Contents lll

List of table and figures Vlll

List of abbreviations IX

Abstrak X

Abstract XII

I Introduction 2

1.1 Background 2

1.2 Definition of dengue fever and dengue haemon·hagic fever 3

1.2.1 Dengue fever 3

1.2.2 Dengue haemotThagic fever 4

1.2.3 Dengue shock syndrome 4

1.3 Liver function tests 5

1.3.1 Alanine aminotransferases (AL T) 5

1.3.2 Aspartate aminotransferases (AST) 5

1.3.3 Coagulation profile 6

1.3.4 Serum albumin 7

1.3.5 Alkaline Phosphatase (ALP) 7

1.3.6 Serum bilirubin

lll

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1.4

1.5 1.6

1.7 1.8

2

2.1

2.2

3

Pathogenesis of dengue haemorrhagic fever

1.4.1 Role of antibody-dependent enhancement (ADE) 1.4.2 Role of cytokines

1.4.3 Role of complement activation 1.4.4 Vimlence of viruses

1.4.5 Liver involvement in the pathogenesis of dengue haemorrhagic fever

Histological changes in the liver and detection of dengue virus Experimental observations

Immunopathogenic mechanism

Clinical studies of liver involvement in dengue infection

Objectives

General objective Specific objective

Methodology 3.1 Definition

3 .1.1 Definition of dengue infection

8 8 9 10

10 11

11 14 17 19

22

23 23

24

25

IV

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3.1.2 Modified serological diagnosis 25

3.l.2.i Primary infection 25

3.1.2.ii Secondary infection 25

3.1.3 Definition of disease severity 26

3.1.4 Liver function tests 28

3.2 Study design 28

3.3 Study period 28

3.4 Study location and patients 29

3.5 Inclusion criteria 29

3.6 Exclusion criteria 29

3.7 Sampling method 30

3.7.1 Recording demographic data and clinical data 30

3.7.2 Blood taking for full blood count 31

3.7.3 Blood taking for coagulation profiles 31

3.7.34 Blood taking for liver function tests 31

3.8 Approval for study 32

3.9 Data analysis 32

3.9.1 Sample size 32

3.9.2 Statistical analysis 33

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4 Results 35

4.1 Introduction 36

4.2 Demographics 37

4.3 Clinical features of dengue infection 40

4.4 Laboratory data 43

4.4.1 Serological tests 43

4.4.2 Full blood count and coagulation profiles in DF and DHF 45

4.4.3 Liver function test in DF and DHF 50

4.4.4 Liver function test and bleeding outcome 53

4.4.4 Multivariate analysis 57

5 Discussion 59

5.1 Introduction 60

5.2 Demographic 60

5.3 Clinical features 62

5.4 FBC and coagulation profiles 63

5.5 Liver function tests 66

5.5.1 Hepatocellular functions 66

5.5.2 Synthetic function 69

5.5.3 Secretory functions 70

5.6 Clinical implications 71

VI

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6 7 8

Conclusions Limitations

Recommendations List of references

APPENDICES

Clerk Sheet for Dengue Cases Admitted to Medical Ward, HT AA Data Entry Form

Ethical Committee Approval for Study

75 77 79 81

2 3

Vll

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LIST OFT ABLE AND FIGURES

No of figure and table Figure 4.1

Table 4.1 Figure 4.2 Table 4.2 Table 4.3 Table 4.4

Table 4.5

Table 4.6 Table 4.7 Table 4.8 Table 4.9

Table 4.10

Age distribution among patients with dengue infection Demographic comparison between OF and DHF patients Bleeding outcomes in patients admitted with dengue infection Clinical features in OF and DHF patients

Serological diagnosis of dengue infection

The association between FBC and coagulation profiles in DF/DHF

The association between platelet and haematocrit with plasma leakage

The association between platelet level and bleeding outcome The association between liver function test and DF I DHF

The association between liver function test and bleeding outcome Liver function test and bleeding outcome: analysis of significant pairs

Associated factors for higher risk of DHF on multiple logistic regression

Page 38

39 41 42 44

46

47 49 52 55

56

58

Vlll

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LIST OF ABBREVIATIONS

DF DHF DSS WHO AST ALT ALP IgG IgM PCR ELISA IL TNF

CD IFN NSI DEN HS ICAM GRP78 RANTES

Dengue fever

Dengue haemonhagic fever Dengue shock syndrome World Health Organisation Aspartate Transaminases Alanine Transaminases Alkaline Phospatase Immunoglobulin G Immunoglobulin M Polymerase chain reaction

Enzyme linked immunosorbent assay Interleukin

Tumour Necrosis Factor

Cluster of differentiation antigen Interferon

Non structural protein Dengue Serotype Heparin Sulphate

Intercellular Adhesion Molecule Glucose regulated protein 78

Regulated upon activation, normal T cell expressed and secreted

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ABSTRAK

Latar Belakang

Demam denggi mempakan sejenis penyakit berjangkit yang semakin meningkat semula di Malaysia. Kerosakan pada sel hati telah dikaitkan dengan demam denggi, tetapi hubungannya dalam kejadian pendarahan belum dibuktikan secm·a konsisten dalam kajian-kajian yang lalu.

Objektif

Objektif kajian ini ialah untuk menyiasat gangguan pada fungsi hati dan hubungannya dengan demam denggi serius dan pendarahan .

. Metod

Ini adalah kajian keratan rentas melibatkan 144 pesakit di Hospital Tengku Ampuan Afzan Kuantan yang dijangkiti demam denggi (mengikut criteria WHO) dati bulan Oktober 2005 sehingga Mac 2006. Pesakit dikelaskan kepada demam denggi biasa dan demam denggi berdarah. Pesakit juga dibahagikan kepada 4 kumpulan berdasarkan tahap keseriusan pendarahan. Kajian analisa univariat di antara gangguan fungsi hati dan demam denggi berdat·ah dilakukan menggunakan "independent t test" manakala kajian multivariat menggunakan "multiple logistic regression". Kajian diantara gangguan fungsi hati dengan tahap pendarahan dianalisa menggunakan ujian "K.ruskal Wallis" dan "Mann Whitney".

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Keputusan

Purata umur pesakit ialah 31

±

12 tahun. Terdapat 85 (59.7%) pesakit mengidap demam denggi berdarah. Seramai 31 (21.5%) pesakit tiada mengalami pendarahan, 39 (27.1 %) mendapat "petechiae•·, 53(36.8%) mendapat pendarahan minor dan 21 (14.6%) mengalami pendarahan major. Purata nilai AST dalam demam denggi berdarah ialah 253.5

±

205.5 IU/L (p<0.001). Purata nilai ALT dalam demam denggi berdarah ialah 171.1

±

185.2 IU/L (p<O.OO 1 ). Purata nilai albumin dalam demam denggi berdarah ialah 32.0

±

5.7 IU/L (p < 0.001). Purata nilai ALP dalam denggi berdarah ialah 97.6

±

48.9 Jlmol/L (p = 0.027). Purata nilai bilimbin konjugasi dalam denggi berdarah ialah 6.2

±

5.4 (p<O.OOl). Analisa multivariat menunjukkan AST (OR 1.025, p < 0.001, 95% C.l.

1.014 - 1.036) dan ketirisan plasma dikaitkan dengan demam denggi berdarah.

Keseriusan pendarahan juga dikaitkan dengan nilai AST, ALT, albumin (p<O.OOI) dan juga bilimbin konjugasi (p = 0.038) tetapi bukannya nilai ALP (p=0.585) dan INR

(p=0.593).

Rumusan

Kajian ini mununjukkan dengan jelas kaitan di antara gangguan fungsi hati temtamanya AST dengan demam denggi berdarah dan keseriusan pendarahan. AST boleh dijadikan sebagai petanda awal dalam mengenalpasti penyakit denggi yang serius.

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ABSTRACT

Background

Dengue fever is an endemic infective disease which has seen a significant re-emergence in Malaysia. Liver function derangements have been desctibed in dengue infection but its association with bleeding occurrence has not been consistently shown in previous studies.

Objectives

The main objective was to study the association between liver function derangements and the severity of dengue virus infection and bleeding outcomes.

Methodology

This is a cross-sectional study involving 144 patients with dengue virus infection (World Health Organisation criteria) recruited from October 2005 until March 2006 in Hospital Tengku Ampuan Afzan, Kuantan. Severity of dengue infection was classified into uncomplicated dengue fever (DF) and dengue haemmThagic fever (DHF) with or without Dengue Shock Syndrome (DSS). The bleeding outcomes were grouped into "no bleeding", "petechiae", "minor bleeding" and "major bleeding". The association between liver derangement and DHF was analysed using independent t-test and multiple logistic regression analysis. The association between liver derangement and bleeding outcome was analysed using Kruskal-Wallis and Mann-Whitney tests.

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Results

The mean patient's age was 31

±

12 years old. There were 85 (59.7%) patients with DHF. There were 31 (21.5%) patients who had no bleeding, 39 (27.1 %) patients had petechiae, 53 (36.8%) patients had minor bleeding and 21 (14.6%) patients had major bleeding. The mean AST level in DHF was 253.5

±

205.5 IU/L (p<O.OOI), mean ALT level in DHF was 171.1

±

185.2 IU/L (p < 0.001), mean albumin level in DHF was 32.0

±

5.7 IU/L (p < 0.001), mean ALP level in DHF was 97.6

±

48.9 J.tmol/L (p = 0.027) and mean direct bilimbin level in DHF was 6.2 + 5.4 (p < 0.00 I). Multiple logistic regression analysis showed that AST (OR 1.025, p < 0.001, 95% C.l. 1.014- 1.036), as well as abdominal pain and plasma leakage were significantly associated with DHF. Bleeding outcome was associated with the derangement of AST, AL T, albumin (p<O.OO I) and direct bilimbin (p = 0.038) but not with ALP (p=0.585) and INR (p=0.593).

Conclusion

The study showed that a significant association existed between liver function derangements, predominantly AST with DHF and bleeding outcome. AST can be a useful surrogate marker to predict disease severity and bleeding outcome in dengue infection.

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CHAPTER ONE INTRODUCTION

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1. INTRODUCTION

1.1 Background

Dengue is the most prevalent mosquito-home viral disease in people, especially in South East Asia. Dengue virus consisted of four serotypes DEN-I, DEN-2, DEN-3, and DEN-4, ofthe genus Ffavivims, and family Flaviviridae which contains approximately 70 viruses.

Dengue virus is transmitted to the humans by the vector Aedes aegypti mosquitoes. The flaviviruses are relatively small ( 40-50 mm) and spherical with a lipid envelope. All flaviviruses have common group epitopes on the envelope protein that result in extensive cross-reactions in serologic tests (Gubler, 1998). These render unequivocal serologic diagnosis of flaviviruses difficult. This is particularly true among the four dengue viruses serotypes. Infection with one dengue serotype confers lifelong immunity to that virus, but there is no cross-protective immunity to other serotypes. Therefore, a person can be infected with probably four dengue serotypes during their lifetime.

Dengue virus infection had a significant re emergence m many parts of the tropics.

Dengue infection resulted in serious morbidity and mortality in most tropical and subtropical areas of the world; mainly Southeast and South Asia, Central and South America and the Caribbean (Gubler, 1998). There are approximately 2.5 billion people at risk in the world for infection with dengue viruses. Over 500 000 cases of dengue haemorrhagic fever were reported to the World Health Organisation (WHO) annually, with a mortality rate of 1-5% among patients with shock (Kurane, 2007).

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Southeast Asia had seen large epidemics of dengue fever in recent years with mmtality from dengue haemorrhagic fever and dengue shock syndrome (Ong, 2007). In Malaysia, the total dengue cases from 2004 until 2005 (until 24th September 2005) were reported to be 49, 355 cases with 138 deaths (Ministry of Health Malaysia, 2005). Meanwhile, in the state of Pahang, there was a tise from 412 cases in 2004 to 1,159 cases in 2005 (until 24111 September 2005) (Ministry of Health Malaysia, 2005).

1.2 Definition of Dengue Fever (DF) and Dengue Haemorrhagic Fever (DHF) 1.2.1 Dengue Fever (WHO, 2002)

Diagnosis of dengue fever needs to include laboratory tests. A confirmed dengue infection is defined as an acute febrile illness with two or more of the following manifestations;

headache, retro-orbital pain, myalgia, ruthralgia, rash, haemorrhagic manifestations or leucopenia plus supportive serology or occurrence of the same location and time as other confmned cases of dengue fever. Laboratory criteria for confirmation of dengue fever include the following; isolation of the dengue virus from serum or autopsy samples, demonstration of a fourfold or greater change in reciprocal lgG or lgM antibody titres to one or more dengue virus antigens in paired serum samples, demonstration of dengue virus antigen in autopsy tissue, serum or cerebrospinal fluid samples by immunohistochemistry, immunoflourescence or ELISA, or detection of dengue virus genomic sequences in autopsy tissue, serum or cerebrospinal fluid samples by polymerase chain reaction (PCR).

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1.2.2 Dengue Haemorrbagic Fever (DHF) (WHO, 2002)

Dengue haemon·hagic fever is defined once all of the following are present; history of acute fever lasting 2-7 days, haemon·hagic tendencies (either a positive tomiquet test, petechiae, ecchymoses, purpura or bleeding from any location), thrombocytopenia (I 00 xi03/num or less) and evidence of plasma leakage due to increased vascular permeability.

Plasma leakage includes haemoconcentration (haematocrit > 47% for male, > 40% for female, a drop in haematocrit following volume replacement equal or greater than 20% of haematocrit at presentation and signs of plasma leakage evidenced by pleural effusion, ascites and hypoalbuminaemia (albumin< 35 giL)

The severity of DHF was classified as:

Grade I: In the presence of haemoconcentration, fever and non-specific constitutional symptoms, a positive tomiquet test is the only haemorrhagic manifestation

Grade II: Spontaneous bleeding in addition to the manifestation from Grade I

Grade III: Circulatory failure, pulse pressure less than 20 mmHg but systolic pressure is still within normal.

Grade IV: Profound shock, hypotension or unrecordable blood pressure.

1.2.3 Dengue Shock Syndrome (DSS) (WHO, 2002) Grade III and Grade IV ofDHF constitutes DSS.

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1.3 Liver Funtion Tests

Liver function tests represented a broad range of tests for nonnal functions performed by the liver. The cellular function is mainly reflected by the level of alaninine aminotransferases (AL T) and aspartate aminotransferase (AST). The excretory function is reflected by the level of direct bilirubin and alkaline phosphatase (ALP). Meanwhile the biosynthetic function is mainly reflected by the level of albumin, globulin and coagulation profile (prothrombin time or INR level) (Edmundowicz, 2002).

1.3.1 Alanine Aminotransferase (AL T)

This enzyme is the most sensitive marker for hepatocellular damage. It is produced within the cells of the liver. As the cells are damaged, the ALT leaks into the bloodstream leading to a rise in the serum levels. Therefore, it is currently considered that serum AL T correlates with the degree of histological inflammation and necrosis of the liver cell.

Furthermore, the higher the ALT level, the more rapid the development of cirrhosis and hepatocellular carcinoma.

1.3.2 Aspartate Aminotransferase (AST)

Elevation of AST also reflects damage to hepatic cells, but it is less specific for liver diseases. It maybe elevated in other conditions such as myocardial infarction and muscular damage. However, if the elevations are more than four times of the normal upper limit, it

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is a significant indicator for infiltrative liver disease especially in the presence of elevated gamma-glutamyltransferase levels. Although AST is not as specific for liver diseases as the AL T, the ratio between AL T and AST is beneficial to physicians in assessing the etiology of liver enzyme abnonnalities.

1.3.3 Coagulation Profile

The blood clotting factors are synthesized exclusively in the hepatocytes, except for factor VIII. Serum prothrombin time collectively measures factors II, V, VII and X. which are associated with the incorporation of vitamin K metabolites into a protein and allows normal coagulation (clotting of blood). Therefore, prothrombin time is useful to measure hepatic bio-synthetic function and is helpful in both the diagnosis and assessing the prognosis of liver disease. However, a prolonged PT is not a specific test for liver disease, therefore confirmation of other abnmmal liver tests is essential. Diseases such as malnutrition, in which a decreased vitamin K ingestion is present, may result in a prolonged PT time. An indirect test of hepatic synthetic function includes the administration of vitamin K (1Om g) subcutaneously over three days. Several days later, the prothrombin time can be measured. If the prothrombin time normalized, then hepatic synthetic function is considered intact. This test does not indicate that there is no liver disease, but is suggestive that malnutrition may coexist with (or without) liver disease.

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1.3.4 Serum Albumin

Albumin is the major protein present within the blood. Serum albumin is synthesised exclusively by hepatocytes and therefore is a marker for the ability of the liver to synthesize proteins. It has a long half-life, approximately 15 to 20 days with 4%

degradation per day. Therefore it can be used as the chronicity markers of liver disease. In hepatitis, if the albumin levels fall below 3 gldL, it should raise the possibility of chronic liver disease. Since it is easy to measure, it represents a reliable and inexpensive laboratory test for physicians to assess the degree of liver damage present in any particular patient. Malnutrition and to a lesser extent severe infection can also cause low albumin (hypoalbuminemia) with no associated liver disease.

1.3.5 Serum Alkaline Phospatase (ALP)

ALP is an enzyme associated with the biliary tract. However, it is not specific to the biliary tract as it is also found in the bone and the placenta. Renal and intestinal damage may also result in elevated levels of ALP. If the ALP is elevated, biliary tract damage and inflammation should be considered. Isoenzyme determination or characterization can be utilized to determine the causes for raised ALP. Another method to assess the etiology of the elevated ALP is to determine whether the GGT is elevated as well, or whether other tests are abnormal (such as bilirubin).

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1.3.6 Serum Bilirubin

Bilirubin is a major breakdown product of hemoglobin The elevation of bilirubin can be due to elevation in indirect or direct bilirubin. The direct bilirubin fraction is that portion of bilirubin that has undergone metabolism by the liver. When this fraction is elevated, the cause of elevated bilirubin (hyperbilirubinemia) is usually outside the liver, predominantly obstruction to biliary tract. If the direct bilirubin is low, while the total bilirubin is high, this reflected liver cell damage or bile duct damage within the liver itself.

1.4 Pathogenesis of dengue haemorrhagic fever

In its most severe form, DHF was associated with haemorrhagic complications, plasma leakage, shock and disseminated intravascular coagulopathy. Often considered more common in children, DHF was increasingly diagnosed in adults as a consequence of shifting patterns of infection and immunity.

1.4.1 Role of antibody-dependent enhancement (ADE)

The role of host immune responses had been suggested by epidemiologic data. In dengue epidemic of dengue serotype 2 in Cuba in 1981, most DHF cases were those who had acquired dengue antibodies in the previous epidemics by dengue serotype 1 in 1997 and 1978 (Guzman, 1990). Meanwhile, studies in Thailand demonstrated that nearly 90% of DHF cases were those with secondary infection with a serotype of dengue virus different

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from that which caused the primary infection (Halstead, l977a, Gubler, 1998). It was suggested that the pre existing non-neutralizing antibodies may fonn complexes with the virus and enhanced its uptake and replication in the macrophages (Halstead, 1977b, Halstead, 1977a)

1.4.2 Role of Cytokines

A series of studies had suggested that plasma leakage in DHF was caused by malfunction of vascular endothelial cells induced by cytokines or chemical mediators rather than by destruction of the small vessels (Green, 2006). Plasma levels of various cytokines including tumour necrosis factor-alpha (TNF-a), interleukin-2 (IL-2), IL-6, IL-8, IL-l 0 and IL-12 were significantly elevated in DHF than in DF. Both dengue virus infected monocytes or mast cell I basophile line and activated specific T lymphocytes were believed to be responsible for this increased level of cytokines (Kurane, 2007). It was also suggested that on secondary exposure to a different viral serotype, most serotype-cross- reactive CD4+ and CD8+ T cells were able to augment infection by producing various cytokines (Kurane, 2007).

A recent study in Taiwan comparing immune mediators among patients with DHF and DF had demonstrated that patients with DHF had a higher rate of secondary dengue infection as well as higher IL-10, higher soluble vascular cell adhesion molecule level 1 (svCAM) levels than DF patients (Chen, 2007). However, they had a lower interferon-gamma (IFN-

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Y.) level. Thus it had been suggested that predominant Th2 responses (IL-2, IL-l 0) occur in DHF while Thl (IFN-y,) responses seem to protect against infections.

1.4.3 Role of Complement Activation

It was reported that the levels of complement 3a (C3a) and complement 5a (C5a) were COITelated with the severity of DHF, and the levels reached the peak at the time of defetvescence when the plasma leakage became more obvious. It had been assumed that complement was activated by various mechanism in DHF including immune complexes and high levels of secreted non-structural protein 1 (NSI) and pre-existing cross-reactive antibody (A viruthan, 2006).

1.4.4 Virulence of viruses

There were multiple genotypes in each of the four dengue viruses serotypes. There were some cases in which primary dengue infection resulted in DHF, and this suggested that virulent dengue virus strains cause DHF. The introduction of Southeast Asian genotype coincided with the appearance of DHF in different countries in the America continent, while the original American genotype was only correlated with DF, not DHF (Rico-Hesse, 1997b, Rico-Hesse, 1997a). The molecular determinants of dengue virus virulence were still not exactly determined, and attempts had been made by many groups to determine it.

One group researched that the determinants for virulence resided at the amino acid 390 of

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the E protein, in the 5' non-translated region and in the upstream 200 nucleotides of the 3' non-translated region (Leitmeyer, 1999). Further studies were required to define further the molecular bases underlying different dengue virulence.

1.4.5 Liver involvement in the pathogenesis of dengue demorrhagic fever

Dengue virus can infect many cell types and resulted in diverse clinical and pathological effects. Its main effects were on the vascular and hematological systems. However, both clinical and experimental observations suggested that there was liver involvement during dengue infection, especially a more severe and complicated form of dengue infection.

Although the liver was not a major target organ, the involvement of the liver in the pathogenesis of dengue virus infection, in particular concerning the development of DHF was demonstrated by the abnormal liver function tests, tissue injury, presence of viral antigens, and RNA in human liver tissue.

1.5 Histological changes in the liver and detection of dengue virus

Most reports of histological changes in the liver of dengue were based on small numbers of samples obtained from fatal cases. The changes include hepatocellular necrosis, microvesicular steatosis, Kuppfer cell hyperplasia and destruction, Councilman bodies and cellular infiltrates at the portal tract (Seneviratne, 2006). Hepatocellular necrosis in dengue generally occurred in the midzonal area and sometimes the centrilobular area. It was believed that the hepatocytes in this area were more prone to hypoxia or the products of an

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