INTRODUCTION Hyperglobulinemia is defined as a condition in which a patient has higher than normal concentration of globulins.

Immunoglobulin is produced by plasma cell. Plasma cell comes from proliferation of lymphocyte B cell after contact with antigen. Globulin types are alpha, beta, and gamma globulins, and are differentiated by electrophoretic mobility. Normally, the most result of differentiation is gamma globulin fraction, eventhuogh also found alfa globulin fraction and beta globulin fraction The name of the disorder refers to the position of the excess of proteins after serum protein electrophoresis. Using electrophoretic patterns, they can be classified either as polyclonal (increases in all major immunoglobulin classes) or monoclonal (increases in a single homogeneous immunoglobulin). (1,2,3) There are a variety of immunologic defects in HIV infection that may predispose patients to acquire bacterial infections.(4) Among these immunologic abnormalities are deficits of mucosal immunity, cell-mediated immunity, humoral immunity and the complement system. Humoral immunologic abnormalities are frequent found in HIV patients, but are rarely associated with severe clinical signs. The commonest humoral manifestation of HIV is polyclonal gammopathy, found in 45% of HIV-positive individuals.
(5,6)

Polyclonal gammopathy is usually caused by chronic stimulation or global disregulation of the immune system.(1) It is characteristic of Human Immunodefficiency Virus (HIV), tuberculosis and other chronic infection (4). This case presentation will make us more concern about hyperglobulinemia because it is not always associated with liver abnormality or renal abnormality. Hyperglobulinemia is also attributable to persistent, high level exposure to antigens and occurs in a wide variety of infectious, inflammatory, and immune-mediated diseases..(6)

CASE ILLUSTRATION A 36 years old woman who has been diagnosed as HIV positive since 3 months ago, came to Cipto Mangunkusumo Hospital with chief of complain fever since 4 weeks before admission. The temperature was not too high and fever continued all the time, usually better with antipiretics, but then up again. She also complained cough, with white sputum but without blood. The dyspnea especially came after coughing. Dyspnea relieved if she slept on the right side of her body. 12 days before admitted to first floor of inpatient ward, she was treated in third floor, and then she underwent pleural puncture. The pleural fluid that was taken for diagnostic was about 10 ml. She complained nausea, but no emetic, she could not finish her food even only 75% portion. She complained epigastric pain. On the third floor of ward, she had diarrhea since the 10 days of admission in the third floor. The frequency was 2-3 times per day, the colour of the stool was brown, liquid, no blood, no secret. In 12 hours before coming to first floor, she had already stop diarrhea for 12 hours. In the first floor, she did not suffer diarrhea anymore. Mixion is normal. Based on past history of illness, she denied hypertension, diabetes mellitus, asthma, allergy and cardio pulmonary problem. Based on family history of illness, she denied hypertension, diabetes mellitus, asthma, allergy and cardio pulmonal problem in her family. Based on family history patient was married with a man, she has a daughter. Her husband was an intravena drug user before they married. On examination, her blood pressure was 120/70 mmHg, pulse 100 bpm, respiratory rate 24 breaths per minutes, and temperature was 37,2 C. She had pale conjungtiva, but no icteric sclera. She had oral thrush. Her jugular venous pressure was 5-2 mmHg. She had supraclavicular limphadenopathy. Her chest had minimal smooth wet rhales in the apex-lung fields, but no wheezing. Her right hemithorax vesicular sound was decreased as high as inter costal space IV-V, and fremitus vocal was also decreased started from inter costal space V. Her heart rhythm was regular with no gallops or murmur. Her abdominal examination was flat, supple, right upper quadrant pain was positive, no shifting dullness, spleen was not palpable. Her extremities are normal. Based on laboratory test, haemoglobin level was 9,8 mg/dl, leucocyte 9200/L, neutrophil segment was 83%, platelet count was 274.000/L, ureum was 40 mg/dL, creatinine
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was 0,8 mg/dL, SGOT (ALT) was 20 U/L, SGPT (AST) was 12 U/L, CD4 count was 182, chest radiography showed specific process with minimal pleural effusion, the electrocardiography revealed sinus tachycardia. Abdominal ultrasonography showed thickening of gall bladder wall (suspect cholesistitis). Urine culture result was Clebsiella species + > 100.000/L, sensitive with Meropenem and Imipenem. The conclusion of echocardiography was pleural effusion and ejection fraction was 72%. The problem of this patient were pulmonary tuberculous with right pleural effusion and supraclavicula limphadenopathy on antituberculosis drugs, AIDS with candidosis oral, dyspepsia and poor intake, normositic normocrom anemia, asymptomatic urinary tract infection. Therapy that was given to this patient were Intra Venous Fluid Drug (IVFD) ringer lactate 500 ml/12 hours, high calorie and high protein diet 2100 kcal, Rifampycin 1 x 300 mg, Ethambutol 1 x 750 mg, INH 1 x 300 mg, Ofloxacin 2 x 200 mg, vitamin B6 3 x 1 tablet, Streptomycin was delayed until consultation to Department of Ear, Nose and Throat, Omeprazole 1 x 40 mg, Ondansentron 3 x 4 mg, transfusion of albumin 25% 100 ml once, Cotrimoksazole 2 x 960 mg, Fluconazole 1 x 150 mg, Mycostatin 4 x 1ml. The diagnosis of pulmonary tuberculosis with minimal right pleural effusion was based on fever, productive cough since 4 weeks before admission, no blood, fever, dyspnea. Based on physical examination, there was supraclavicula limphadenopathy, respiratory rate is 24 x/minute, rhales was present. Her chest had minimal smooth wet rhales in the apex-lung fields, but no wheezing. Her right hemithorax vesicular sound was decreased as high as inter costal space IVV, and fremitus vocal was also decreased started from inter costal space V. Based on laboratorium, leucocyte 9200, segment neutrofil is 83%. Chest radiography showed specific process with minimal pleural effusion. Planning of therapy were Rifampycin 1 x 300 mg, Ethambutol 1 x 750 mg, INH 1 x 300 mg, Pyrazinamid 1 x750 mg, Ofloxacin 2 x 200 mg, Vitamin B6 3 x 1 tablet. AIDS is diagnosed based on diagnostic of HIV positive since 3 months before admission. This patient was admitted in the third floor of inpatient ward for ten days before. In the third floor of ward, she had history of diarrhea and oral thrush. Her CD4 count is 182. She was diagnosed as AIDS with oral candidosis, but without history of (anti retroviral therapy) ART. The therapy is Cotrimokaszole 2 x 960 mg, Fluconazole 1 x 150 mg, and Mycostatin 4 x 1 ml.

We plan to start ART after anti tuberculosis drugs was administered about one until two weeks, and by considering of side effect of antituberculosis drugs. Dyspepsia is diagnosed based on nausea and emetic, she could not finish her food even only 75% of the portion and she felt right upper quadrant pain. Based on physical examination, we did not find hepatomegaly, SGOT (ALT) was 20 U/L, SGPT (AST) was 12 U/L. The abdominal ultrasonohgraphy showed thickening of gall bladder wall. We thought dyspepsia in this patient could be caused by cholesistitis. Planning of diagnostic were total direct and indirect bilirubine, cholinesterase and alkali phosphatase. Planning of therapy is Omeparazole 1 x 40 mg intravena, lesicol 3 x 1 tablet and Ondansentron 3 x 8 mg. Normosytic normocrom anemia is diagnosed based on fatigue, pale conjunctiva, haemoglobine level was 9,8 mg%, haematocrite was 27,5, MCV was 84,4 and MCHC was 35,6. We considered normocytic normocrom anemia because of anemia on chronic disease. The differential diagnosed was anemia of Fe deficiency. Planning of diagnostic is recheck complete blood count, morphology, SI, ferritin, TIBC and reticulocyte. Planning of therapy is only observation. Asimptomatic urinary tract infection is diagnosed based on laboratory urine culture is Clebsiella species ( > 100.000/ mL). This patient did not have any symptoms from urinary tract, and also had no pain of suprapubic pressure. This patient got tazocin 4 x 4,5 mg for 7 days before, and then tazocin was stopped. Planning of diagnostic were reanalyzing urine and culture of urine. On the second day of admission, there is citology result of pleural effusion, which showed no malignant cell. Planning of diagnostic was pleural effusion analysis and chest x-ray pro evaluation. Therapy was continued. At the same day, we consulted to pulmonology division. Pulmonology division suggested ultrasonography of supraclavicula limphadenopathy (to evaluate echostructure of limphadenopathy) and Fine Needle Aspiration Biopsy (FNAB) of supraclavicula limphadenopathy. In this day, dyspepsia got better, so we switched injection omeprazole to oral omeprazole 1 x 20 mg tablet, but ondansentron was still continued. The Fe serum was 29 g/dL, total iron binding capacity (TIBC) was 143 d/dL, transferrin saturation was 20,28%. We thought this microcytic hipocrom anemia was caused by Fe deficiency. Planning of diagnostic were serial complete blood count, the therapy was sulfas ferrosus 3 x 1 tablet. The result of albumin was
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2,50, globulin is 6,6, cholinesterase is 5523, anti HCV was negative, HBsAg was negative. Planning of therapy was correction of albumin. On the second day, we asses new problem, hypoalbuminemia and hyperglobulinemia. First, we thought hypoalbuminemia and hyperglobulinemia is caused by reverse ratio which is commonly found in chronic liver disease. But seromarker result of this patient was negative. Plan of diagnostic was serum protein electrophoresa (SPEP). Plan of therapy was observation. On the third day, we got some result of laboratory examination of pleural effusion polymerase chain reaction of tuberculosis (PCR TB) was also negative, but adenosin deaminase (ADA) is positive (56,3 with cut off value of 40) On the fifth day, this patient was clinically better, because her dyspepsia got better and she could eat all her food and the oral trush was also getting better. Total bilirubine was 1,55, direct bilirubine was 1,37 and indirect bilirubine was 0,18. The result of urine analysis was better than before. So we concluded asymptomatic urinary tract infection was relieved. In this day, patient was still in fever, blood sedimentation rate increased (108) , leucocyte 4100 /mm3 and neutrofil (78%) was also increased. We still continue ofloxacin, because there was possibility of possibility of secondary infection in the lung. At the same day, the result of SPEP was total protein of 9,5, albumin was 30,80%, A1 globulin was 4,3%, A2 globulin was 10,1%, beta globulin was 12,9%, gamma globulin was 41,9%. The conclusion of SPEP was polyclonal gammopathy. We were considering about hyperglobulinemia in AIDS patient. On the sixth day, based on chest meeting, we plan to add anti tuberculosis drugs with streptomycine 1 x 750 mg, and administer anti retro viral (ARV) after streptomycin administered for one week, but we plan to consult to Ear, Nose and Throat Division first. In this day we planned to correct hipoalbuminemia by albumin infusion 20% 100 cc in 3 days. On the seventh day, after consultation to pulmonology division, streptomycine was delayed. And if the patient did not suffer fever anymore and supraclavicula limpohadenopathy becomes smaller, she might be discharged, and she could consult to Teratai outpatient clinic. On the eight day, the patient did not suffer fever anymore, nor nausea and emesis, the intake was also good. And then, she was discharged after suggested to visit outpatient clinic routinely.

DISCUSSION The chief complaint of this patient was fever since 4 weeks before admission. We suspect this fever because of tuberculosis with secondary infection. Tuberculosis in this patient was caused by immunocompromised status in HIV patient. The World Health Organization (WHO) estimates that TB is the cause of death for 11% of all AIDS patient. But, nowadays the
6

percentage and absolute number of patients with TB disease who are HIV-1 infected is declining in the United States because of improved infection-control practices and better diagnosis and treatment of both HIV-1 infection and TB(7). Mc Lay said in HIV-infected patients with TB, extrapulmonary disease occurred in 40% of the patients, particularly in those with advanced immune suppression. Among patients with tuberculosis, pleural involvement appears to be more common. In one case-control study of approximately 3000 patients with tuberculosis, pleural involvement was present among 11% of persons with AIDS versus 6 % of those without AIDS (8). Dezube et al said for patients with more advanced immunosuppression (CD4+ T lymphocyte count <200 cells/L) are more likely to have extrapulmonary or disseminated disease. But other opinion said in areas where TB is endemic, certain patients have higher CD4+ T lymphocyte counts at the time HIV-1related TB disease develops, in countries with low rates of TB disease (e.g., United States and countries in Western Europe), more patients have advanced HIV-1 disease at the time TB develops(7). Benson said patients with TB and HIV infection sometimes differ from HIVseronegative patients in their clinical and radiographic presentations. In particular, patients with advanced immunosuppression are more likely to have atypical radiographic findings, smearnegative pulmonary infection, disseminated tuberculosis, and subclinical tuberculosis(9). Spanish investigators reports starting treatment for both HIV and tuberculosis at the same time lowers the risk of death by around 65%, in comparison with deferring HIV treatment for at least three months(10). But other researcher said arguments for delayed treatment of HIV include the risk of immune reconstitution inflammatory syndrome, interactions between anti-HIV and anti-TB drugs and the large number of pills people need to take when they are taking both treatments together(10). This patient also suffered from cholesystitis. Cholecystitis in HIV patient presents with manifestation similar to those seen in immunocompetent hosts but is more likely to be acalculous. Typically the syndrome presents with severe nausea, vomiting and right upper quadrant pain. Icteric was found in 20% cases, commonly not severe (bilirubine < 4,0 gr/dl). If bilirubine level was high, we need to think stone as the cause. Liver function test generally show alkaline phosphatase elevations. (11)
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This patient had hypoalbuminemia and hyperglobulinemia. First, we thought hypoalbuminemia and hyperglobulinemia is caused by reverse ratio which is commonly found in chronic liver disease. But seromarker and liver function test were normal and from the abdominal ultrasonography, we did not find hepatic cirrhosis. Beside that, there was no abnormality of renal function as assessed by normal ureum and creatinine. We checked serum protein electrophoresis, and the result was polyclonal gammopathy. Polyclonal gammopathy is a gammopathy in which there is a heterogeneous increase in immunoglobulins involving more than one cell line, may be caused by any of a variety of inflammatory, infectious, or neoplastic disorders.(1) Polyclonal gammopathy occurs when there is B lymphocyte hyperactivity combined with impaired T lymphocyte function, expressed as polyclonal increase in the gamma globulin fraction.(3) It probably reflects an increased antibody production, which is an attempt on the part of the immune system to compensate for cellular immunodeficiency. In this patient polyclonal gammopathy was caused by HIV and tuberculosis infection. Polyclonal gammopathy is the commonest humoral manifestation of HIV found in 45% of HIVpositive individuals. infectious disease. (12) The hyperviscosity syndrome is rarely described in association with polyclonal hypergammaglobulinemia but most commonly seen in association with monoclonal gammopathies. (13) Hiperviscosity syndrome mostly was found in rheumatoid artrhritis. A patient with rheumatoid arthritis developed retinal venous stasis as part of a hyperviscosity syndrome secondary to a polyclonal gammopathy. It improved following systemic corticosteroid therapy.
(14) (5,6)

Polyclonal gammopathy actually was also found in liver disease,

connective tissue diseases (CTD), hematologic disorders, nonhematologic malignancy and

Polyclonal gammopathy is usually diagnosed by routine serum protein electrophoresis examination. Electrophoresis is the most common way of fractionating serum proteins. In this process, protein solutions are placed on a medium such as paper or starch blocks and exposed to an electrical current. Differences in their electrical charge cause the protein components to migrate at different rates toward the anode or cathode. (15)

No specific therapy is indicated for polyclonal gammopathy. Treatment is directed at the underlying disease. There have been reports of hyperviscosity syndrome associated with polyclonal gammopathy in RA, SLE, Sjgren syndrome, AIDS, chronic active hepatitis, pseudolymphoma, and Castleman disease. Symptomatic hyperviscosity secondary to polyclonal gammopathy has been effectively treated with plasmapheresis or corticosteroids. and anti retroviral therapy.
(16, 17)

In this

patient, we plan to treat the underlying disease by continuing therapy of anti tuberculosis drugs

CONCLUSION HIV is associated with abnormalities of both cellular and humoral immunity, many of which are directly linked to the pathogenesis of the disease. Our knowledge of how certain components of the immune system function in healthy individuals (e.g. NK cells) is limited, which in turn makes it difficult to interpret their importance in the progression or treatment of HIV, because of that may be we need to continue research in these areas. It is important to recognize those features of immune dysregulation commonly associated with HIV, so that the results of diagnostic tests may be interpreted correctly.

LABORATORY RECAPITULATION COMPLETE BLOOD COUNT

03/06 Hb (g/dL) Ht (%) Leu (/L) Basofil (%) Eosinofil (%) Neutrofil (%) Limfosit (%) Monosit (%) Tromb (/L) 225000 274000 11,4 36,0 9200 12/06 9,8 27,5 9200 15/06 9,7 28,9 8300 0,3 0,1 86 5,2 8,7 384000 19/06 9,4 28,7 4100 0.2 0.0 78 10,8 11,0 345000

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LED (mm) MCV (fl) MCH (pg) MCHC (g/dL) Reticulocyte (%) 83,5 26,5 31,7

110 84,4 30,1 33,6

80

105 87,2 28,6 32,8

2,3

ELECTROLYTE DAN RENAL FUNCTION

12/06 Na/K/Cl (mEq/L) Ur/Cr (mg/dL) Blood Glucose (mg/dL) 40/0,8 15/06 132/3,91/105,0 17/0,7 19/06 130/4,18/111 20/0,9 83

COMPLETE BLOOD COUNT 15/06

Erithrocyte Leucocyte Thrombocyte Microcytic Hipocrom, anisopoicilocytosis, target cell, poliychromation Normal amount of leucocyte, lymphopenia Normal morphology and amount of thrombocyte

19/06
Normocytic Normochrom Decreased number, normal morphology Normal number and morphology

LIVER FUNCTION AND OTHERS

03/06 SGOT/SGPT U/L CHE (U/L) Alkali Phosphatase 45/17 08/06 12/06 20/12 15/06 38/18 5523 602 17/06 19/06 37/17 Normal

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Albumin/Globulin (g/dL) Bilirubine T/D/I HBsAg Anti HCV T Helper (CD4+) Abs (sel/L) T Helper (CD4+) (%) Protein Electrophoresis Total Protein (g/dL) Albumin (g/dL) Globulin (g/dL) A1 Globulin A2 Globulin Beta Globulin Gamma Globullin 182 18

2,50/6,60 1,55/1,37/0,18 Negative Negative 186 16

2,30/6,50

9,1 2,50 6,60

9,5 30,80%

6,6 - 8,7 45,0 67,0 %

4,3% 10,1% 12,9% 41,9%

2,0 6,0 % 7 - 13,5% 5-12% 13,5-28%

Bleeding Time (minutes) Clotting Time (minutes) Fe (SI) (g/dL) TIBC (g/dL) Transferrin Saturation (%)

3,30 13,00 29 143 20,28

BTA of Pleural Effusion Pleural Effusion Culture Pleural Effusion Analysis Pleural Effusion Direct Culture

Negative Negative Exudate

Yeast Cell: Negative No yeast

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Colouring of Giemsa Overnight Blood Culture

PCP: Negative Sterile

URINALYSIS
Complete Urine Colour Clarity Sediment Ephytelial cell Leucocyte (/LPB) Erithrocyte (/LPB) Cillinder (/LPK) Hyaline cillinder Cristal Bactery + 10-13 3-5 + 3-5 + 0-1 0-1 0-1 12/06 yellow muddy 19/06 yellow No muddy

pH Proteint Glucose Keton Blood/Hb Billirubine Urobilinogen (mol/L) Nitrit Leucocyte Esterase

6,5 1+ 16,0 + trace

6,5 16,0 -

HEMOSTASES
19/06

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PT (seconds) Control PT (seconds) APTT (seconds) Control APTT (seconds) Fibrinogen (mg/dL) Cuantitative D Dimer (ng/mL)

11,6 12,1 41,1 30,9 203 300,00

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