Can Dengue Virus Infection  Provoke The Occurrence of Fulminant AutoimmuneHepatitis and Systemic Lupus Erimatosus?

T.MUDWAL

Abstract

Acute Liver Failure in patient with an overlap syndrome involving Fulminant Autoimmune Hepatitis and Systemic Lupus Eryyhematosus

Cindy, Andri Thewidya, Emon Winardi, Maisie M.E Johan

Introduction

Autoimmune hepatitis (AIH) is a chronic hepatitis that affects women four times more often than men. Its prevalence is 1.9 per 100.000.1 In 25% of AIH, acute onset of AIH observed, and rare cases of fulminant AIH have been reported.2

Acute liver failure (ALF) occurs 2000 cases per year, the most prominent causes are drug induced liver ijury, viral hepatitis, autoimmune liver disease and hypoperfusion.3,4

The AIH-SLE overlap syndrome is rare. Only 3% patients with AIH satisfy the kriteria for SLE (Systemic Lupus Erythematosus) and 1.7% of patients with SLE had AIH or liver cirrhosis. Patients with liver dysfunction and SLE should be investigated for AIH as these 2 entities can occur together.5,6,7

Case Presentation

A 25-year old female has 3 days of fever, fatigue and nausea, without any history of liver disease. She has leucopenia, thrombocytopenia with negatif Dengue serologic tests, normal bilirubin level and increased level of ALT and AST (110 U/L and 144 U/L).

In the second week, she became icteric with discoid rash and fever. The ALT and AST level were rapidly increased to 748 U/L and 587 U/L, with increased level of GGT (82 U/L), total bilirubin level (15,7 mg/dl), ALP 131 U/L. The serology of viral hepatitis (A,B,C) was negative.

As the total bilirubin level increased to 27,9 mg/dl (conjugated bilirubin 18,3 mg/dl) she became more icteric in the third week, in comatose state. ANA test was positive, anti-ds DNA 29 IU/ml. Gamma globulin increased. C3 & C$ level decreased. She has severe mucosal bleeding with prolongation of a PTT and PT, INR, 3, D-dimer 1200 ng/ml, Anti thrombin III 0%.

We diagnosad this patient with ALF due to Fulminant AIH-SLE overlap syndrome, induced by acute viral infection. She was treated by high-dose corticosteroid, Atithrombin III, Fresh Frozen Plasma, Vitamin K, and other supportive measures. The patient passed away due to severe hemorrhage.

Conclusion

ALF due to AIH has a poor prognosis, therefore an immediate diagnosis and treatment has to be done.5 Antiribosomal P antibody could differentiate SLE-associated hepatitis with AIH.5,6 Test of AMA, anti-SMA, anti-LKM should be done as the means of subclassification of AIH.1,2

Keywords : Acute Liver Failure, Autoimmune Hepatitis, Systemic Lupus Erythematosus.

References :

  1. Heathcote E.J. Autoimmune Hepatitis. In :Tadataka Yamada, et al. Textbook of Gastroenterology fifth edition. UK : Blackwell publishing 2009. p2184-92

  2. Manns M.P., Strassburg C.P. Autoimmune Hepatitis : Clinical Challenges. Gastroenerology. 2001; 120:1502-1517.

  3. Posison J, Lee W.M. AASLD Position Paper : The Management of Acute Liver Failure. Hepatology volume 41. May 2005;5:1779-1196.

  4. Dienstag J.L. Chronic Hepatitis. In :Fauci Kasper, Brauwald, Hauser, Longo, Jameson, et al. Harison’s Principle of Internal Medicine Volume II. 17thed. New York: McGraw-Hill; 2009. p. 1955-69.

  5. Usta Y, Gurakan F, Akcoren Z, Ozen S. Case report : An overlap syndrome involving autoimmune hepatitis and systemic lupus erythematosus in childhood. World J Gastroenterol 2007 May 21; 13(19): 2764-2767.

  6. Iwai M, et al. Autoimmune hepatitis in a patient with systemic lupus erythomatosus. CiinRheumatol. 2003 Sep;22(3):234-6.

  7. Nassar F, Valsbein E, Assy N. Article : Autoimmune hepatitis – Sle overlap syndrome. Gastrohep.com 30 January 2009.

Taken from Naskah Lengkap Pertemuan Ilmiah Tahunan Ilmu Penyakit Dalam 2011.
Editor: Ryan Ranitya, Gurmeet Singh, Dicky.
Pages: 364-365.

 

DISCUSSION

I have not managed to get the complete text of the above patients. Yet I think that the abstract is clear enough to be the subject of discussion and it is very important to be discussed. To answer whether Dengue virus infection can provoke autoimmune hepatitis and SLE, we have to prove first that, the patient, at the moment of admission was suffering from dengue.

WHO says the world’s 2.5 billion people or two fifth soft he world or > 100 countries worldwide has potential for dengue virus infection (World Potential Dengue Infected / WDPI). Of that amount, 70% of the amount living in countries of Southeast Asia (Indonesia, Thailand, Malaysia, Singapore, Vietnam, Philippines, Myanmar, Cambodia, Timor Leste, Laos and Brunei). Therefore it is appropriate, if there are patients with ≤ 7 days fever, must be regarded as Dengue infection untilproven otherwise. Dengue infection suspicion increase in size if the patient has thrombocytopenia. For fact must be recognized that in these countries the most common cause of thrombocytopenia is Dengue infection. Even in patients without fever but having thrombocytopenia, in my humble opinion is only we must still consider it due to Dengue infection until proven otherwise. The presence or absence of fever principally is due on how much arachidonic acid is released by hipotalamaus and stimulation of the hypothalamus to release arachidonic acid depending on how much damage in the circulation. Platelets which falls a little like 125.000/mm3 cannot generate fever if the other damage in circulating has not occurred as a broad plasma leakage, DIC, consumptive coagulopathy, etc. And often, especially in the elderly who are infected by Dengue, platelet 125.000/mm3 quickly rise on their own without any treatment.

Back in the abstract patient written above, this patient comes in the WHO 2009 criteria has been able to put it into Dengue infection with warning sign because of the fever, thrombocytopenia, nausea and weakness, however the dengue serologic tests negative. In the primary infection of Dengue virus, IgM is positive on day 5 of the illness and IgG positive on day 14. While the positive IgG is positive on day 2 in a secondary infection.With this in mind diagnosing this patient with dengue infection with a warning sign orbelieving there is a presence of Dengue infection cannot be blamed. And the possibility of patients experiencing a primary infection ofDengue virus. The truth of the diagnosis will increase as well when there is bleeding in such patients, although only minimally, testsobtained by a positive torniquet orby a positive RumpleLeed test (RL).In the abstractit does not look RL is examine. But even thoughRl test is negative, Dengue infection cannot beruled out based on the description above. And it must be remembered also that the RLtest could be positive when repeated several hours later (because at that time just happened to be a fragility of capillary walls in that area).We should also try the other arm for the RL test because it might be just on the other arm the RL test is positive. In fact often the case that initially a negative test RL is seen again positive after a few minutes later. Positive RL test for patients with fever must alwaysbecaused by dengue infection until proven otherwise. In patients with diabetes mellitus, malnutrition, vitamin C deficiency, test RLcanalso be positive, although not infected by Dengue virus. In addition to the above, when found in the laboratory lymphocyte count < 20%, monocyte count <3%, Ht/Hb > 3x, and lymphocyte blue plasma >1% suspicion of dengue infection is increasingly large. I have discussed it at length in my site www.dhf-revolutionafankelijkheid.net.

How to diagnose the presence of  dengue infection based on WHO 2009 criteria far better than the how to diagnose dengue infection based on 1997 WHO criteria, especially in hyper endemic areas of dengue. Because the criteria in 2009 there is no need for waiting of fever until 2 days or wait until the platelet count falls < 100.000/mm3 to diagnose the presence of Dengue infection. And we do not have to separate between the Dengue fever and Dengue hemorrhagic fever. Waiting for 2 days to determining the fever is something very dangerous matter. Every worst possibility can happen in these 2 days period. That’s the same as waiting for platelet count to reduce to 100.000 is the dangerous act too. Because the platelet count of 140.000 in the beginning can also be rapidly reduced to 5.000 in just a short period of time. To separate Dengue infection into Dengue fever and Dengue hemorrhagic fever is one dangerous act too. In short time, Dengue fever will become Dengue Hemorrhagic fever and then Dengue shock Syndrome which can cause death. The Hematocryte is also must be increased. But to determine the amount of hematocrit to be increased > 20% according to age and gender as criteria for 1997 is a very difficult thing to do. Since we have not agreed how much the hematocrit standard for the nation Indonesia according to age and gender. So is waiting for lower hematocrit until 20% after receiving the liquid will slow the diagnosis of dengue infection.

With the above reasons the number of deaths due to dengue infection if doctors diagnose dengue infection based on 1997 criteria should be high. But we see that the reports on dengue deaths are only around 1-2% and even less than 1%. This happens because of the death of the count was only in patients with DSS / DHF and most of those that died in the hospital. Patients with the diagnosis of Dengue fever are not treated or discharged, and if later the patient is turn into DHF / DSS in his home and then the patient dies it is not statistically recorded as a dengue death. That is why when we use the 1997 criteria to diagnose dengue then we will only see the tip of the  short iceberg and  the body of the iceberg that is invisible. When we use the criteria of 2009 we will see the whole iceberg and the peak is high. So we’ll be more careful and try not to increase the  top of the iceberg in length (Figure 1 & 2). But in my opinion is still not the whole iceberg is visible.Because the WHO criteria of 2009 still requires the presence of fever  to say Dengue infection. Where as my basis on descriptions earlier said that the diagnosis of dengue infection can be established without the presence of fever. Thus the whole image a new iceberg will be seen. Examples of application of the theory T.MUDWAL on various kinds of cases can be read on my site www.dhf-revolutionafankelijkheid.net With the above descriptions of Dengue infection in patients upon hospital admission isdifficult to disprove. Or there may be some colleagues that say that the fever in these patients is caused by acute hepatitis and thrombocytopenia that occurs caused by disruption in length by  acute hepatitis caused by of trombopoitin_ The basis to say that because the functions of  mentioned in the literature is to stimulate of bone marrow of trombopoitin to trombopoisis, ranging stimulate the bone marrow to make platelets so that the formation of platelets. And trombopotin produced by hepatocytes cells.

In this patient the increased are  GOT and the GPT , while the total bilirubin was not increased. GOT / the GPT is produced by many body tissues. Without the increase in means total bilirubin and the GPT GOT is the number organs that-of inflamed produce GOT and the GPT (liver, heart, muscle, lung, kidney, brain). In this patient liver cell damage that very severe newly seen after 2nd week in which the GOT / the GPT increase up to hundreds and extremely high total bilirubin (15.7). Based on the laboratory results the diagnosis is established that it is due to an autoimmune reaction in which the hepatocyte cells turns into antigen and then destroyed. Based on that fever  that occurs in patients upon hospital admission was not caused by by hepatitis. What about of trombopoitin? Most studies show that there is no significant relationship between the number severity trombopoitin with the thrombocytopenia. But turns into extremely significant relationship between the size of the spleen with the severity thrombocytopenia. In this patient upon admission is not the case of severe liver cell damage meaning the number trombopoitin probably still normal. Thus thrombocytopenia is not due to interference trombopoitin. Even in a state of severe liver cell damage thrombocytopenia occurred in these patients at week 3 not also caused by trombopoitin. (according to the literature that I read as written above).

If we have believed that in this patient clearly there Dengue infection then can we indeed enter into the main discussion as it is written on the title : “Could the Dengue virus infection provoke fulminant autoimmune hepatitis and systemic lupus erimatosus?”

In the normal immune system, it should able to react with a a variety of microbes without reacting to the cells or tissues (self antigen). Reacting to the self antigens or failure to distinguish between self and non-self antigens is the basis of the occurrence of autoimmune reactions. Every individual has the autoreactive lymphocytes that ready to react with the self antigen. But this reaction does not occur due to the mechanism of immunological homeostasis system (self tolerance). Failure to maintain self-tolerance can be triggered by things that are antigenic including Dengue virus. The problem is whether the Dengue virus is indeed a potential to causing it or not?I neglect the power of the Dengue virus. Error lies in the excessive response of ourselves against Dengue virus (hypersensitive). Hypersensitivity reactions which facilitate the occurrence of autoimmune reactions and even the occurrence of SLE. So discuss whether the Dengue virus provokes an autoimmune reaction as written on the title of our discussion is actually talking about the possibility of type III hypersensitivity reaction as the basis for pathogenesis and patofisiology Dengue infection. And if it is recognized, then administration high-dose steroid (immunosuppressive doses) should be given as soon as possible after the the diagnosis Dengue infection is established.

The given of corticosteroid in immunosuppressive dose hoped to prevent autoimmune reaction (the ship shouldn’t crash iceberg that already in front of our eye). Because of that we will discuss pathogenesis and pathophysiology of Dengue and then it’s up to us to determine which argument is stronger.

For DHF, principally there are three theories that explain why a person has DHF:

1. Malignancy virus theory

Dengue viruses who collaborate with a poor ecosystems, will lead to the gaining strength of Dengue virus, multiply, and spread to all parts of the country and then beat one’s immune system. Poverty population, low education, will add up quickly to region or country to be branded as a country or region of hiperendemis Dengue. The severity of clinical symptoms in a person depends on the type of malignancy of the virus and a person’s immune system. For Indonesia Dengue 3 virus is considered the most malignant.

2. Malignancy virus theory combined with wrong response to the immune system during the entrance of Dengue virus in the body (Halstead theory).

The body can manage to overcome any dengue infection even the malignant ones, as long as there isn’t any non-neutralizing antibodies. Non-neutralizing antibodies, are newly-formed when the body is infected with viruses of different serotypes (Secondary Heterologous Infection Theory). So indirectly in this theory, there is no term of malignant virus or non malignant virus. All the dengue virus is considered malignant if it succeed in entering the target cells, replicate and increase strength in the target cells and after then itreleased again into the blood. Non-neutralizing antibodies, spur the entry of the virus into target cells.

So based on this theory, what if someone is infected with one kind of virus alone, either one time or continuously, the person would never be ill of DHF (occurring lifelong immunity against that virus / forming a lifelong neutralizing antibodies against that dengue virus). However, immunity against a virus also triggers the formation of both a non-neutralizing antibodies when the body is infected byanother type of dengue virus. So to reduce morbidity and mortality of DHF, the fastest way is to provide immediate vaccination of all four dengue virus serotypes (because there are four serotypes of dengue virus) in hopes to directly increase the neutralizing antibodies against all four dengue virus serotypes. Or to prevent the occurrence of non-neutralizing antibodies in case of infection bydengue virus, one by one. This theory is now widely used around the world.

So based on this theory, if someone is infected with only one type of Dengue virus of any type, either one time or continuously, the person would never be infected by DBD (occurrance of  lifelong immunity against the virus that’s it / formed by neutralizing antibodies against that virus for life alone). However, immunity to a virus at the same time also triggers the formation of non-neutralizing antibodies when the body possessed by Dengue virus of another type. This theory is now widely used around the world.

3. Individual Immune errors responses as the main basis of infection dengue (type III Hypersensitivity theory T. Mudwal / www.dhf-revolutionafankelijkheid.net)

Based on T. Mudwal this theory states:

a. Not all people or race will be exposed to dengue.

DHF mainly on Southeast Asia and Western Pacific (however today, dengue fever has struck nearly 100 countries around the world and a variety of races). Observations over 15 years of DHF patients, showed ethnic of Arabs, Chinese, caucasian origin, are very rarely affected by dengue, even when there was an endemic. Experiences at school in the RSCM, working in the Pacific Caltec Riau and working at this moment, is the basis for this claim besides that there facts are on this earth in the form of written journals.

b. Bad immunity, but  low symptoms.

If we used a benchmark that severe dengue is someone with a history of fever ≤ 7 days, presence of shock, shortness of breath, hepatosplenomegaly, severe bleeding /DIC and platelets ≤ 20.000/mm3, then roughly calculation there are more common in people with good nutrition, have a good immune system rather than a person with malnutrition or those with age> 60 years, which is roughly with a bad immune system. It is difficult for a HIV patient who clearly have a poor immunity to be infected by dengue. Dengue fever can only infect  HIV patient when CD4 count is above 200 cel/mm3. Or the immune system are still pretty good.

c. Error response of our immune system.

Just like Halstead, the antibodies are not capable of neutralizing antibodies (non neutralizing antibody is formed). But T. Mudwal does not say it is non-neutralizing antibodies. T. Mudwal says it is an imperfect Ig G/IgM (because immunologically, our immunoglobulins are IgA, IgE, IgD, IgM, IgG). The formation of imperfect Ig G/IgM is because of the sensitivity of the body against dengue antigens, so that plasma cells which are not old enough to make antibodies, will also  make antibodies. This is evidenced by the discovery of blue lymphocyte plasma cells (LPB) in patients with DHF. Only DHF can cause the LPB cells to be seen in acute phase (<7 days of illness). There are even studies that say, LPB was present in 98% of DHF patients. In healthy people LPB is not visible at all (0%). Ig G/IgM as a result of not fully formed, the virus managed to escape from the bonds of Ig G/IgM and enter the target cells. So at the imperfect Ig G/IgM does not happen to spur the virus to enter the target cells, as proposed Halstead. Association of antigen and antibody persists, but its binding are weak.

Because the target cells from dengue virus is our own soldiers cells (monocytes, macrophages and Kupffer cells), the immune complexes formed, both between perfect Ig G/IgM with antigen and imperfect fraction Ig G/IgM with antigen failed to be destroyed by our troops so that the cells spread throughout the body ( capillary wall, platelets, bone marrow, liver, spleen, brain, heart, eye, and so on). The return of normal function of our soldier cells or the arrival of troops from its headquarters in the normal bone marrow will lead to the destruction of these immune complexes. The degree of severity of DHF depends on the location and number of immune complexes that are destroyed. For that reason T. Mudwal said the basis of pathogenesis and pathophysiology of DHF is Hypersensitivity reaction of the immune complex (Type III Hypersensitivity reactions).

The presence of immune complexes can trigger a lot of chaos in the regulation of our immune system. So it can occurred that the body’s cells should not be destroyed, to be part demolished (autoimmune reaction). At the the highest level, reaction this autoimmune can occurred on a many organ or occurred SLE. If the mechanisms of self tolerance to control the autoimmune reaction is completed or person becomes normal. But when not, then the reaction autoimmune can occurred for life such as ITP, SLE, chronic hepatitis autoimmune, rheumatoid arthritis, etc.. Knowledge of this theory would say that the cause of Evan’s syndrome, or HELLP syndrome is a possibility of Dengue virus infection as well. Another thing to remember is that the healing of damaged organs post Dengue infections may also occurred imperfectly. Aplastic anemia, stroke, impaired vision due to retinal damage and so may have happened. In immunologist, body reaction to immune complex is greater than viral it self or antigen without antibody because body reaction towards antigen without antibody is not going through complement C1, C2, C4 (lectin route/ alternate route).

Other things that proving if Hipersensitivity is the cause of DHF disease is the triumphness in giving the drugs in order to suppress the hypersensitivity reaction (immunosuppressive cortico steroid) by Waly et al (Indonesian University Medical Faculty, 1997), Hendarsih et al (Padjadjaran University Medical Faculty, 2004) and Futrakul et al (Thailand,1987).

Based on the information,a new great DBD reaction will occur if the incoming antigen are polynomial, which formed many imperfect antibody, macrophages infected with dengue is invalid due to its huge quantity, the location and number of immune complexes that are destroyed. Virus infection in a small amount of one kind of virus alone usually may not pose a Type III Hypersensitivity reactions. Or it could give a reaction but usually mild (fever, headache, muscle pains, vision problems, etc.). But it could also deliver a severe reaction as described above, the quantity of antigens are abundant, or tend to be super antigen. Or individual is too sensitive hence the imperefect IgM antibodies which are formed are in large amount or genetic mutations occur either from the virus or the individuals. Difference in the theory T. Mudwal and Haslstead, when Halstead said that one kind of viral infection the first time will result in lifelong immunity then T. Mudwal said no. There is no lifelong immunity in hypersensitive people. The reaction depends on what has been described above. This was the true basis of T. Mudwal to say why the primary infection may give clinical symptoms. One thing that is difficult to answer Halstead. Hence came theantibody dependent enhancement theory to explain why the primary infection can cause clinical symptoms. Where based on this theory, the primary infection reaction is because of the non-neutralizing antibodies from the mother. So if there is infection by dengue virus it is because there was an infection of a different type on his mother. Meanwhile, according to T. Mudwal children from 0-4 months are going to get antibodies from their mothers in accordance with the dengue virus that have been infected by his mother. But after that, it is because of genetics it self. Hence formed sensitive IgM-. After six months of forming the sensitive IgG. So, antibody towards Dengue virus which come from the children’s mother, only last for 6-9 months. After that DHF disease which happened then is because the sensitivity of IgM and IgG those children it self. Sensitivity is genetic. Just like Halstead, dengue virus infection from a second time in small quantities and the same virus, may not happen but the reaction that occur does not give life long immunity. But if there is a viral infection of a second time from a different virus type, although in small quantities is more dangerous than the same virus infection in large numbers. This is because different viruses will provide a stronger stimulus for the occurrence of errors immune response than the same virus. But when a virus infected again by the third or fourth (by other dengue virus) then the reaction will occur much lighter because of some of the properties of the virus has been recognized by our immune system (because all of them is dengue virus).

Thus the discussion of our abstract. Obviously in these patients suffering from DHF or dengue infection. If the diagnosis can be established as soon as possible (we can see the iceberg that was clearly very high ) then I think giving immunosuppressive doses of corticosteroids as soon as possible. Hopefully stroke, autoimmune reaction to such as autoimmune hepatitis, SLE, ITP, rhemtoid arthritis, etc. will not occur. So is the death due to infection or squelle due to Dengue like visual impairment, myocardial, infarction, aplastic anemia, etc. can be avoided (the ship can be diverted to avoid the iceberg that was clearly towering in front of the eye).

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